Obviously, these are just my personal notes, and you should never use my writings
to decide whether to see a doctor, how to treat a patient, or study for a test.
Salt And Free Water Thoughts
Hypernatremia and Hyponatremia seem to be confusing to a lot of people. Here is how I think of this.First, you have to rephrase the problem. High or low sodium is not a problem with sodium, it is a problem with too much or too little free water. This is different than other electrolyte issues - hypokalemia is (usually) a deficiency of potassium, and you treat it by replacing potassium. Hypomagnasemia is (usually) a deficiency of magnesium, and you treat it by replacing magnesium. BUT, hyponatremia is an excess of free water; you have diluted the sodium. Similarly, hypernatremia is a deficit of free water; you have concentrated the blood.
To solve a sodium problem, I convert the sodium imbalance to a free water imbalance. Hypernatremia is a deficit of free water and hyponatremia is an excess of free water. Don't think about sodium after this - it's all about free water.
OK, so at this point, we have translated the problem from one about salt, to one about free water. What's next? Much of the body regulation of free water happens in the kidney, so now we have to decide whether the kidney is behaving appropriately. The kidney regulates free water by responding to Vasopressin/ADH, which controls Aquaporins in the collecting duct and controls how much free water is lost to urine. We don't measure Vasopressin directly, so instead we measure its effect by measuring urine osmolality. Urine Osm is essentially "a biomarker for Vasopressin". Vasopressin is regulated by osmolality sensors in the Hypothalamus and pressure sensors. It is released when Osmolality rises, and when BP drops. ADH release starts at around 280 mOsm in euvolemic patients, and around 270 in hypovolemic patients.
The next step is to see if the kidneys are responding appropriately. They should be retaining or wasting free water depending on whether the serum sodium is high or low respectively. I generally think of Osm as follows:
- Below 100 mOsm/L is maximally dilute. The kidney is trying to remove free water
- Over 800 mOsm/L is maximally concentrated. The kidney is trying to retain free water. Actually, I say that any ADH over 300 is inappropriate in a hyponatremic patient, and you could stretch this to 200.
Notice that the hormones monitor pressure or osmolality in serum, which is intravascular. Don't get too obsessed with things like edema, as that is fluid outside the vasculature. We really care about the intra-vascular volume status, not the total body fluid.
Now, check if the kidneys are part of the solution or part of the problem. If the kidneys are responding appropriately, then the problem is somewhere else. For example, if a patient has low sodium but kidneys are trying desperately to remove as much free water by making very dilute urine, then the patient is too much free water intake. This may be psychogenic polydipsia or beer potomania or an athlete like a marathon runner who drinks lots of water or low sodium sports drinks. In a hospital patient it can also be free water through IV drips. If a patient has high sodium and the kidneys are trying to retain free water by making very concentrated urine, then the problem is somewhere else, likely free water loss through osmotic diarrhea or through the skin in a burn patient.
So, how do we measure the kidney's response? Measure how much the kidney is clearing free water. Originally, people tried to measure it with urine osomolality,
but, that is affected by urea and all urine osmols, and those are not limited to vascular space. Now we just look at electrolytes:
Urine Volume = ElectrolyteClearance + ElectrolyteFreeWaterClearance
or: ElectrolyteFreeWaterClearance = Urine Volume - ElectrolyteClearance
We define the electrolyte clearance just with the most important ions for osmolality:
ElectrolyteClelarance = (( UruneSodium + UrinePotassium ) / SerumSodium) * Urive Volume
Combining the previous 2 equations:
ElectrolyteFreeWaterClearance = Urine Volume - ((( UruneSodium + UrinePotassium ) / SerumSodium) * Urive Volume)
or: ElectrolyteFreeWaterClearance = Urine Volume x (1 - ( ( UruneSodium + UrinePotassium ) / SerumSodium ))
If FreeWaterClearance > 0 then pt is losing free water and Na will rise
If FreeWaterClearance < 0 then pt is retaining free water and Na will drop
Notice, that giving IV saline will not help an SIADH patient. The kidneys are retaining free water and making very concentrated urine. If you give fluids that are less concentrated than the urine, then the kidneys will hold onto even *more* free water to make the very concentrated urine. So, for example, 0.9 percent Normal saline contains 154 mEq/L sodium. If you give 1 liter of NS, then you give 1 liter of water with 154 mEq of sodium. If the kidneys are in a high ADH state, then they may be making urine that is 300 mEq/liter sodium. This means they will remove the 154 mEq of sodium you gave them with only 500 mL of water (154 mEq / 0.5 L = 300 mEq/L). Where does the extra water go? Nowhere, it stays in the patient. Now, 1/3 is extracellular and of that only 1/4 is in the vasculature, so this means 1/12 or around 80 mL goes to the blood. But, the point is you have LOWERED serum sodium because you gave fluids that are more dilute than the urine. For comparison, 3 percent saline contains 513 mEq/L sodium and that may be more concentrated than urine, but do not give this unless the patient has symptoms (lethargy, seizures) and then only give small amounts to stop the seizures or you will overcorrect and cause central pontine demyelenation.
Hypernatremis is a deficiency of free water.
Causes of hypernatremia (free water loss) include Osmotic diarrea (lose free water), osmotic diuresis (TPN), excess loss (burns), insufficient water intake (geriatrics, newborns, CNS lesion), Post ATN diuresis, Diabetes Insipidis (Lithium, Cisplatin).
Check to see if the kidneys are responding. If urine Osm is below 800, then this is inappropriately low, and loss of free water is due to renal wasting (DI or Osmotic diuresis).
If urine Osm is below 800, then this is appropriate, so loss of free water is extra-renal (diarrhea or water deprivation).
Free water deficit and total sodium deficit
This is used when there is a deficiency of free water, so the serum Na is elevated.
Free water deficit = TotalBodyWater * ((CurrentNa / TargetNa) - 1)
where TotalBodyWater is 0.6 * WeightInKg for men, 0.5 * WeightInKg for women and geriatrics
Typical American diet is 1200 osmols / day
Cirrhosis triggers ADH release because of the low blood pressure caused by lack of vascular tone. MDMA (Ecstasy) causes massive ADH release
Low total body sodium is associated with Osteopenia, because the bone is a large resevoir of sodium. So chronically low Na leads to low bone density.
In acute hyponatremia, a Head CT will show cerebral edema. In chronic hyponatremia, the brain is euvolemic because neurons have compensated by shifting ions out of the cell to balance osmolatity with ECF.
Potassium Thoughts
Decide whether the kidneys are responding appropriately. If Urine chloride is below 25 in an alkalotic patient then the kidneys are retaining volume, and so have a high Aldo state Why do we look at Urine chloride? If a patient is alkalotic, then the kidneys will waste bicarb, as HCO3-, but this is an anion so to keep urine electrically neutral it wastes a cation, sodium, or NaHCO3" So, Na will be high in an alkalotic patient, so to assess volume status look at urine Cl. If the kidneys hold onto Na for retaining volume in response to high Aldo, then they also retain an anion Cl-. So urine Cl- tells us how much Na is being wasted for volume management independant of how much Na is being wasted for acid/base management.The differential includes GI loss (diarrhea) or renal loss. The differential for renal loss includes high Aldo state or renal wasting (like diuretics) The differential for high Aldo state includes hyper-aldo or high renin due to renal artery stenosis. Note that RAS could be due to many causes (atherosclerosis, fibromuscular dysplasia, inflammation like PAN or Scleroderma renal crisis) Note also that there may be pseudo-hyperaldo (channelopathies like Liddle or losss of protection from Cortisol due to very high Cortisol states in Cushings, or inactivation of 11 beta hydroxysteroid, or Drosperinone which is an oral contraceptive).
K is also affected by cell shift:
- Cell uptake of K - beta agonists, alpha blockers, alkalosis, high insulin.
- Cell release of K - alpha agonists, beta blockers, acidosis, low insulin like DKA Hyperkalemia in DKA is mainly caused by lack of insulin and hypertonicity of blood. Much less effect from acidosis.
- T3 from HyperThyroid can cause K shift into cells, but revving up Na/K-ATPase.
Renal retention or loss may have many causes
- K secretion in the collecting duct is partially through the Maxi-K channel, and depnds on tubule flow rates
- K secretion in the distal tubule depends on Na load to the distal tubule. If there is a high Na load (like due to a Thiazide) then there will be Na reabsorption and K loss. Note the Na reabsorption is not enough to get all Na, so thiazides still lose some Na.
Potassium can be lost through the GI tract in several ways:
- Diarrhea
- Oglivie Syndrome - intestinal pseudoobstruction. Slower gut motility causes more K loss to stool
- K secretion in the collecting duct is partially through the Maxi-K channel, and depnds on tubule flow rates
- K secretion in the distal tubule depends on Na load to the distal tubule. If there is a high Na load (like due to a Thiazide) then there will be Na reabsorption and K loss. Note the Na reabsorption is not enough to get all Na, so thiazides still lose some Na.
An important cause of hyperkalemia is RTA Type IV, which is associated with Diabetic nephropathy. This is a low-renin and Llow-aldo state. There are several possible causes:
- Diabetes injures the Juxtaglomerular apparatus, which will decrease renin release. This is similar to the mechanism of NSAIDs, which inhibit the Arachodonic pathway and so reduce renin release.
- There is a high insulin state, which drives the WNK system, and lead to blocking WNK4, so this disinhibits NCC. Upregulating NCC will reduce the Na load delivered to the CD, and so decrease K secretion. This is similar to Gordon's syndrome, which is a defect in WNK4 also leading to disinhibition and upregulation of NCC. Treat Gordon's with a Thiazide, and that will block NCC. ??? Can we also treat diabetic nephropathy with a thiazide? ??? I am not sure this is the mechanism of diabetic nephropathy, since that may not be a low renin state???
Causes of Hyperkalemia
- ESRD and high-K diet (usually fruits)
- Seizures
- Salt-substitute (this is often Potassium Chloride)
- Digoxin - inhibits Na/K-ATPase so leaves K outside the cell
- Tumor Lysis
Note, Gordon's syndrome is similar to Aldosterone escape. Normally, high Aldo will cause volume rentention and low K (there is increased Na reabsorption through ENaC and K loss though RoMK). In Aldo escape, there is a sudden diuresis several days after the start of high Aldo with. This is partially explained by a response to the hypervolemia from high Aldo, but it is also due to downregulation of NCC. So, in a hyper-Aldo state, the kidney starts wasting Na and retaining K. Why?
Low K and high NaCl from the Aldo will increase NCC in the DCT. This reabsorbs more Na in the DCT so less Na is delivered to the collecting duct. Low Na in the collecting duct means less K wasting, so K rises. Why does low K cause this effect on NCC? High NaCl and Low K will increase levels of NCC on membrane and phosphorylated NCC because low K is more powerful control of NCC than NaCl. Low serum K leads to low Cl levels inside the cell, and it seems to inhibit WNK4, which in turn disinhibits NCC. This is like Gordon's Syndrome (Terker, et al, “Potassium Modulates Electrolyte Balance").
Acid-Base Thoughts
Expanded Differential for an Anion Gap Acidosis
The anion gap reflects the levels of measured anions, including albumin, lactate, sulfate, phosphate and more. We can start with the old pneumonic MUDPILES, but also add some more.
- M - Methyl Alcohol. Look for Osm gap and Anion gap, also concern for putamen hemorrhage
Multiple Myeloma - Ig are Positively charged, so they bind Cl. We are increasing free Cl, so the AG (Na - Cl - HCO3) will decrease.
- U - Uremia
- D - Diabetic Ketoacidosis, but also consider Starvation Ketoacidosis.
In starvation, insulin drops and glucagon rises, and there is high betahydroxybutyrate but negative acetoacetate. The anion gap won't show up right away, initially the patient can amke enough urine to clear ketoacids, but once they start to become volume depleted then ketoacids build up and then the gap appears.
This also inclused EtOH Ketoacidosis. Metabolizing EtOH will increase NADH/NAD which diverts Glc toward anaerobic because Krebs cycle needs NAD. This increases Lactic acid, but also depletes products of the Krebs cycle, especially oxaloacetate. That is needed for gluconeogenesis. This also increases fatty acid mtabolism and ketogenesis.
- P - Some clinically significant ones (forget Paraldehyde, a rarely used anti-convulsant)
- Propylene Glycol which is used in Lorazepam drips
- Pyroglutamic Acid (also called Oxoproline) which is in chronic acetaminophen use usually in an under-nourished patient because it is aggravated by a lack of Glutathione.
- Propofol - causes lactic acidosis. Also causes Pancreatitis, Rhabdo, Cardiac Arrhythmias, Hypotension
- Paraproteinemias - Ig will bind Cl- and raise the anion gap. See Myeloma above.
- I - Iron and Isoniazid
- L - Lactic Acid
- L-Lactate, made by human cells
- Type A - Ischemia
- Type B - Medications - Metformin, Linezolid, Propofol, nRTI (Tenofovir), Isoniazid. Metformin causes decreased Oxidative-reduction in the mitochondria, so shifts glucose metabolism away from the Krebs cycle.
- Linezolid causes a lactic acidosis
- D-Lactate, made by bacteria, often short gut so Undigested Carbs reach bacteria in colon and they grow and release lactate (maybe SIBO as well?). This will not show up on a normal serum lactate assay.
- E - Ethylene Glycol. This also causes an elevated lactate and low Ca. See Ca-Oxalate dihydrate stones in urine (needle shaped, but the envelopes which are Ca-Ox Dihydrate). The Osmolar gap will appear only after the Ethylene Glycol starts to get metabolized and will disappear once it has all been metabolized. The anion gap lasts after it has been all metabolized.
- M - Salicylate (fevers, tachypnea, tachycardia, AG acidosis, resp alkalosis).
The AG acidosis is due to lactate and ketoacids. Salicylate uncouples oxidative respiration (electron transfer chain) so increases anaerobic.
- Rhabdo
- Iatrogenic Sodium, like NaPhos, which adds Na so will increase gap
Expanded Differential for a NON-Gap Acidosis
- Diarrhea
- RTA (RTA IV has high K, RTA 2 is usually Fanconi, RTA 1 has low K)
- Dilutional (lots of IV normal saline)
- CKD - loss of acid clearance which is sort of like a combination of RTA 1 and 2 but with high K.
- Urinary diversion - the gut reabsorbs
- Compensation to a chronic respiratory alkalosis
- Topiramate
- Non-Gap acidosis in DKA Early in DKA, body loses bicarb and Na-salts. While it is euvolemic, it is losing in urine both Na-bicarb and Na-KA (where KA is a ketoacid). This leads to a non-gap acidosis. Bicarb drops but Na drops as well so no change in gap. Later in DKA, pt becomes volume contracted. Now, kidney retains Na, so you retain Na-KA but still lose Na-bicarb but also bicarb with other cations so gap increases, you lose bicarb but retain more Na. After volume repletion, you go back to non-gap acidosis. Once again, you can lose Na-KA and Na-bicarb in the urine.
The RTA's
They are ordered by when they were discovered, not by where they are in the tubule.
In general, Urine pH is not helpful. H secretion depends on Na load and volume status.
- RTA 1 - Inability to secrete acid in the distal. It has low K because Na/K exchange is overactive to compensate for loss of Na/H exchange.
Several things that can injure the CD cell can cause an RTA-1.
- Ampho - cell backleak of H+
- Autoimmune - Sjogren, Lupus
- RTA 2 - inability to reabsorb bicarb in the proximal. It is usually Fanconi so kidneys also waste Phos, K, Glucose, amino acids.
It is usually self-limiting, so serum bicarb usually wont drop below 16 or so. If you bolus a bicarb, then it will saturate the
ability to reabsorb and the urine will immediately turn alkaline.
Fanconi is any injury to the PCT, and can have several causes.
- Multiple Myeloma - reabsorbed light chains are resistant to proteases and plug the PCT cells
- Aminoglycosides - Mitochondrial injury
- Tenofivir, Cidofovir
- Ifosfamide
- RTA IV has high K
Anything that slows Aldosterone can cause this.
- ACE/ARB or Spironolactone
- NSAID
- Diabetes
- Cancineurin Inhibitors
- Heparins, includine Enoxaparin
Differential for Metabolic Alkalosis
- Post-hypercapnic metabolic alkalosis. Look for this in a patient that was recently intubated.");
- Any high Aldosterone state, including volume depletion but also hyper-Aldo or pseudo-hyperaldo, glucocorticoid-remedial hyperaldo, also Cushings
- Milk-Alkalai. Give high doses of bicarbonate
- Hypokalemia - low K prevents NKCC2 in TAL from working, so it is like a loop diuretic. This increases Na load to CD and increases Na/H exchange.
- Hypercalcemia - High Ca activates CaSR which blocks RoMK and prevents NKCC2 in TAL from working, so it is like a loop diuretic. This increases Na load to CD and increases Na/H exchange.
Cholesterol
2013 Cholesterol Guidelines
These guidelines are written by carefully looking at what the trials report, and sticking close to the exact results of the trials, not what we assume the implications are. As a result, these guidelines are closely modeled after the experimental protocol of the trials, not on what we think a clinician should do. For example, in clinic we frequently titrate meds to meet a goal, such as blood pressure or glucose. However, the actual trials all would test patients with and without a statin, or with a low dose or high dose statin. They would not look at patients with different LDL values. As a result, these guidelines do NOT target specific LDL values. Instead, they broadly group patients according to risk factors, and then give a low, medium or high dose statin. By the way, these risk factors are also closely modelled after the inclusion criteria of the trials.
It seems that patients may benefit from a statin, but not from a specific LDL level. So, some patients may have high LDL but low overall cardiac risk. They may not necessarily need a statin. Other patients, may have high cardiac risk due to several factors, and they would benefit from a statin. This latter group is one of the places where people complain about these new guidelines. They say that if you have an obese smoker with low LDL, then it's true they have high cardiac risk, but you should tell them to stop smoking and lose weight, not put them on a statin. However, these guidelines say that in general people with high risk *do* benefit from statins. So, either this group of people with high risk but low LDL are very rare, or else LDL can never be too low, so even if LDL is "normal" further lowering it can still help.
Moreover, it seems that the relative reduction of LDL is more important than the absolute value. So, a patient lowering LDL from 200 to 100 gets the same benefit as a patient lowering from 140 to 70. As a result, statins are grouped according by the percent they lower LDL in a typical patient.
- High Intensity Statins - Lower LDL by 50% or more. Atorva 40 or 80, Rosuva 20
- Medium Intensity Statins - Lower LDL by 30-50%. Atorva 10-20, Rosuva 10, Simva 20-40, Prava 40-80, Lova 40, Fluva 40
- Low Intensity Statins - Lower LDL by 30% or less. Simva 10, Prava 10-20, Lova 20
The guidelines:
- Under 75yo with CAD (MI, stable or unstable angina, CVA, TIA, PVD, CABG) High intensity statin. If they cannot tolerate high intensity, try medium intensity.
- Over 75yo with CAD Moderate intensity statin. High intensity does not do better.
- 21-75yo with LDL over 190 High intensity statin Also, rule out secondary causes of high LDL like EtOH, DM, diet, drugs (diuretics, glucocorticoids, amiodarone), biliary obstruction, hypothyroid, obesity
- 40-75yo Diabetics Moderate intensity statin This is the big change. So, EVERY diabetic should be on a statin.
- 40-75yo with normal LDL (which is below 190)
Compute 10-year risk of MI.
- If 7.5% risk then moderate or high intensity statin
- Pts with 5 to 7.5% risk would benefit, but the chances of adverse effects are greater than benefits.
- There is no good evidence for 10-year risk values in pts under 40, and no good evidence for pts over 75.
- Pts with NYHA heart failure class II through IV and patients on dialysis No guidelines for or against
Some other considerations:
- If 2 consecutive LDL values are <40, then may decrease dose of statin
- Statins are CONTRAINDICATED in pregnancy.
- You may start a second med if LDL does not lower by target. A common second med is Ezemitide, which blocks cholesterol absorption. Really, however, if the patient ate a perfectly healthy diet, then Ezemitide would be unnecessary. But, we all eat western diets.
Vancomycin Dosing
In general, Doses of 15–20 mg/kg (of actual body weight, not ideal body weight) given every 8–12 hr. Here are some useful guidelines:
- Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists This is a 2009 guideline that discusses Vancomycin independant of the disease. The recommendations are summarized on page 3 of the report, which is labelled page 84 of the journal it appeared in.
- Management of MRSA Infections in Adult Patients 2011 Clinical Practice Guidelines by the Infectious Diseases Society of America This is a newer guideline (2011), but it is in the form of a lecture given by one of the IDSA panel members rather than a position paper.
- Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children These have the same recommendations. It is a 2011 guideline, but it discusses Vanc in the context of MRSA.
Cardiology Guidelines (includes CAD, CHF, HTN, A-Fib, and more)
- JNC-7 Guidelines for Hypertension
- ACC/AHA 2007 Guidelines for UA/NSTEMI
and the changes for 2011
- ACC/AHA 2004 Guidelines for STEMI
and the changes for 2007
- ACC/AHA 2005 Guidelines for Heart Failure
and the changes for 2009
- Framingham Tables (for pts withOUT CAD)
- Risk Factors for patients with CAD
- Framingham Heart Study
Circulation. 2008; 117: 743-753 doi: 10.1161/CIRCULATIONAHA.107.699579
The latest formula (2008) for Framingham CVD Risk scores. This is used for various things, including prescribing statins. - RALES Study
Spironolactone (Aldo blocker) reduces morbidity in CHF patients. Aldosterone leads to cardiac and vascular fibrosis, vascuular damage, and more. The mortality reduction is partly due to lowering Na retention and lowering BP, but part of the mortality benefit is also due to blocking these other deleterious effects of Aldo. In this study, there was not a significant drop in BP, but there was a significant reduction in mortality. Moreover, Spironolactone reduces mortality in patients who are already on ACE-inhibitors. So, this seems to provide additional suppression. This makes sense since other papers show that alternate (non-ACE) pathways can still make Aldo. - Isosorbide Dinitrate and Hydralazine for heart failure
The most common paper seems to be Taylor et al, but it has several points that are often overlooked:
This combination is very effective, but it is for managing heart failure, not hypertension. Systolic BP dropped an average of only 1.9, but there was a 43% reduction in mortality. I have heard people say these drugs are not useful because they are not good for managing hypertension, but that is not what they are intended for. This study was done on patients with NYHA class III and IV heart failure.
The main benefit seems to be prevention of cardiac remodelling.
The study was only on African-American patients, because previous studies had shown that these patients get more benefit from nitric oxide donors. (I'm still following up on these studies). However, this does not say that the drugs should be avoided in other patients. Question: Can we do a study showing the benefits in all races, especially post-MI? - EKG Notes
- Infarct (anterior or septal)
- ST-elevation in 2 adjacent leads that is 80ms after the J-point, and lose R waves in v1, v2, v3 (lose R-wave progression)
- Q-waves must be > 0.03sec long or taller than 1/3 the size of the R wave, or ≥ 0.04sec wide
- A Q in III is free
- Infarct (RV or posterior)
- ST-elevation in lead 1.
- No ST-elevation in any other leads
- ST-depression in v1, v2
- LVH
- Cornell: R-aVL + S-V3 > 28 (men) or 20 (women)
- R-aVL > 11
- S-V1 + R v5or6 > 35
- RVH
- R > S in V1 or R > 7mm in V1 -or- S > 7mm in V5 or V6
- Right Bundle Branch Block
- There is delayed contraction in RV, so slower contraction travels left to right (opposite normal)
- RSR' in V1, V2
- Slurred-S in I, aVL, V5, V6. S is wider than R and/or S is ≥ 40ms. Overall QRS is > 120ms. ??Is this because the left relaxation is not balanced by the RV contraction?
- Left Bundle Branch Block
- There is delayed contraction of the LV, and activation travels right to left (normal direction)
- Broad notches R in I, aVL, V5, V6. May look like RSR'
- A-Flutter
- This often has negative p-waves
- CVA or Cranial Hemorrhage
- Deep T-inversion in some but not all leads. The EKG changes may be caused by Epinephrine release
- Strain
- Down-sloping ST-segment with TWI
- Placing EKG leads (normal)
- v1, v2 are parasternal on left and right side respectively.
- V4 is mid-clavicular
- V6 is mid-axillary
- Lead reversal: Normally, you should see inverted P waves in I.
- Infarct (anterior or septal)
COPD
- GOLD - Global Strategy for the Diagnosis, Management and Prevention of COPD
This is the 2011 Guidelines
- Pathology is chronic inflammation that changes normal inflammatory process. Imbalance between proteases (degrade elastin) and antiproteases, and increase in CD8 T-cells. The physiology of COPD is very different than asthma.
- Inflammation lowers FEV1, parenchyma destruction lowers gas exchange. Other effects include air trapping, hyperinflation, reduced muscle contractility (maybe a Starling curve for inspiratory muscles?), reduced ventilatory drive (chronic hypercapnea), mucous hypersecretion in Chronic bronchitis (goblet cell proliferation), pulmonary hypertension (due to hypoxic vasoconstriction).
- Exacerbations are triggered by infection, pollutants or idiopathic.
- This defines "Patient Groups" (A through D) which use a combination of
Spirometry and symptoms like these:
- MRC breathlessness scale - a subjective score 1 to 5 of how breathless the patient feels.
- CAT Score - a sum of 8 questions asking about breathing symptoms, each question is subjectively reported on a scale of 0 to 5.
2011 Guidelines FEV1/FVC FEV1 Exacerbations mMRC CAT Score Meds Group A <70% GOLD I or II, >50% predicted <2 per year < 2 < 10 SABA or Short-acting anticholinergic Group B <70% GOLD I or II, >50% predicted <2 per year > 2 ≥ 10 LABA or long-acting anticholinergic Group C <70% GOLD III or IV, <50% predicted ≥2 per year < 2 < 10 ICS plus
(LABA or Long-acting anticholinergic)Group D <70% GOLD III or IV, <50% predicted ≥2 per year > 2 ≥ 10 ICS plus
(LABA or Long-acting anticholinergic)Where
SABA is Short Acting Beta Agonist (Albuterol, Tertbutaline)
LABA is Long Acting Beta Agonist (Salmeterol, Formoterol)
Short-acting Anticholinergics (Ipratropium)
Long-acting Anticholinergics (Tiotropium)
ICS is Inhaled corticosteroids include Beclamethasone, Budesonide, Fluticasone, Triamcinalone.Notice, that this recommends LABA (long-acting beta agonists) alone for COPD class B even though there are FDA warnings for LABAs in asthma treatment. Yes, well, that confuses me as well.
- In 2011 Guidelines, the exacerbations have separate recommendations, and should use a list of treatments
- Supplemental Oxygen and regular monitoring (ABG)
- Inhaled bronchodilators - increase dose and frequency from home meds
- Systemic Glucocorticosteroids (oral or IV)
- Antibiotics (pneumonia prevention?)
- Non-invasive Positive-Pressure Ventilation
Asthma
- NIH 2007 Guidelines for the Diagnosis and Management of Asthma
Here is a simplified table for adults and kids over 12yo. Note that there is a separate table for kinds younger than 12, but I am not trying to memorize that.
Symptoms
(# PRN SABA uses)FEV1 Meds Intermittent ≤ 2x per week >80% predicted PRN SABA Mild Persistent not daily >80% predicted Low dose ICS
plus PRN SABAModerate Persistent daily 60%-80% predicted Medium dose ICS
or Low dose ICS plus LABA
plus PRN SABASevere Persistent throughout the day <80% predicted Medium dose ICS + LABA
plus PRN SABA
or High dose ICS + LABA
plus PRN SABAWhere
SABA is Short Acting Beta Agonist (Albuterol 90mcg/puff, Tertbutaline, etc.)
LABA is Long Acting Beta Agonist (Salmeterol DPI 50 mcg q12h, Formoterol DPI 12 mcg q12h)
ICS is Inhaled Corticosteroid (Budesonide, Beclomethasone, Fluticasone, and more).For asthma exacerbations, you may also need oral systemic corticosteroids (Methylprednisone, Prednisolone, Prednisone). The Guidelines also discuss Leukotrirene Modifiers (Monteleukast and Zafilleukast). I also see that the guidelines include Theophyline as an alternative for Mild and Moderate Persistent Asthma, but I have been told that that drug is old, has a narrow therapeutic range, and lots of side effects, so I won't use it until somebody teaches me how.
- Mild Asthma (Bel, Elisabeth; N Engl J Med 2013; 369)
This paper describes mild-persistent asthma, not intermittent asthma.
Asthma is airway hyperresponsiveness, but there seems to be several different mechanisms, and this may or may not involve eosinophils.
Smoking reduces airway responsiveness to asthma meds in all patients, and can increase severity of asthma in kids.
Treatment starts with a SABA, like Albuterol or Tertbutaline. Daily use of a low dose inhaled staroid is modestly better than intermittent use. Any inhaled steroid seems to be better than a Leukotrirene modifier like Monteleukast.
COPD compared/contrasted with Asthma
I like to think of asthma as a purely immune-driven airway response. Remember, young kids get asthma; a 12-year-old doesn't have 50 pack years of smoking and his airway restriction comes from an immune-drive overreaction that affects bronchial musculature. COPD, on the other hand, starts with parenchymal destruction. Now, COPD may eventually lead to immune-driven overactivity (which is why steroids are useful in a COPD exacerbation), but it starts with destruction of connective tissue, leading to things like mid-acinar collapse of alveoli. Of course, that destructive process may be partially macrophage-driven, and so may have some immune activity, but it is tissue destruction, possibly involving macrophages, whereas asthma is muscle constriction driven by immune response.
Notice that beta blockers are the basis for COPD treatment. In other words, it is about dilating airways that are destroyed by oxidative destruction from tobacco. It is less about stopping inflammation as is the case in asthma. I like to think of it as COPD treatment is like putting poles to raise a sagging tent, while asthma treatment is like trying to pry loose somebody's fist gripping a soft tube. Or whatever. Anyway, beta blockers are frequently contraindicated in asthma, but what about COPD, where they are more important? This paper suggests that the benefits of beta blockers for COPD'ers with heart disease will outweigh their detrements to COPD treatment.
There are several ways to deliver an inhaled medication, and this always confuses me.
- MDI is "Metered Dose Inhaler". This is the J-shaped 3-inch or so hand-held inhalers Picture
- HFA is Hydrofluoroalkane. This is the intert gas that a drug is mixed with in MDI inhalers.
- Spacer is a chamber that an MDI fits into and makes it easier to inhale the med Picture
- DPI is Dry Powder Inhaler. This is often a Diskus, but there are also other designs. It holds several doses (like 60), and it allows you to inhale 1 dose at a time.
- Diskus is a circular shaped Picture
Stroke
NIHSS Stroke Scale:
- Level of conciousness: 0 - 3
- Ask month and age: 0 - 2
- Blink eyes and squeeze hands: 0 - 2
- Horizontal Extraocular movements: 0 - 2
- Visual Fields: 0 - 3
- Facial Palsy: 0 - 3
- Left arm motor drift: 0 - 4
- Right arm motor drift: 0 - 4
- Left leg motor drift: 0 - 4
- Right leg motor drift: 0 - 4
- Limb ataxia (FNF and Heel/shin) 0 - 2
- Sensation: 0 - 2
- Language/aphasia: 0 - 3
- Dysarthria: 0 - 2
- Inattention: 0 - 2
Guidelines for the Early Management of Adults With Ischemic Stroke
- Always start with a CT (but contrast and radiologist read are not necessary) The goal of the CT is only to look for hemorrhage vrs ischemia; other signs on CT affect prognosis but not treatment. The goal is 25 min to do a CT, 20 min to read it, and so can start tPA within 45 min of presentation.
- tPA within 3hrs of symptoms (within 90min is better) if ischemic (see all requirements below).
- Anticoagulation (*therapeutic* Heparin or LMWH) is NOT recommended. It might lower recurrent stroke but definately increases intracranial hemorrhage, so so it is not overall beneficial. But, you can give prophylactic Heparin (5000 u q8) for DVT prophylaxis (p. 1689).
- Do give Asa within 24-48 hours of stroke.
- Other antiplatelets (clopidigrel and others) are not yet fully evaluated. Trials are underway, but don't use them until proven safe.
- During initial workup, do a cardiac physical exam, but most patients do not need CXR or LP.
- Fever is bad (use acetaminophen), but lowering body temp below normal is not proven beneficial.
- If Cheynes-Stokes breathing (fast, deep, periodic apnea) give additional O2 with goal O2 sat > 92% (same as COPD)
- Monotor EKG on telemetry for first 24hrs since arrhythmias often occur
- Lowering blood pressure can help by reducing brain edema and reducing hemorrhagic conversion, but hurt by lowering perfusion. Only give anti-hypertensives if SBP is above 220 or DBP is above 110. Note, BP above 185/110 is a contraindication to rtPA. BP drops by itself an average 28% during first day after CVA with or without medications. If you do give anti-hypertensives, a reasonable goal is to lower BP by 15-25% per day. Dropping SBP by > 20mm Hg per day causes bad outcomes. You may normally restart a patient's at-home anti-hypertensives after ~1 day.
- These guidelines say to treat hyperglycemia if Glc>140mg/dL, but this is controversial.
Multiple Myeloma
- Diagnosis - This is based on International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma, Rajkumar et al, Lancet Oncol. 2014 Nov;15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5
- Evidence of end organ damage due to the Myeloma with any one of:
- Calcium over 11mg/dL
- Creatinine over 2 mg/dL
- Bone lesions (lytic lesion on skeletal radiography, CT, or PET/CT)
- A chemistry marker with any one of:
- Free light chain ratio over 100:1 if FLC level is at least 100 mg/L. However, note this will only define a kappa monoclonal myeloma. I assume that a ratio under 0.01 would also suffice, as that would be what you see for a lambda myeloma.
- At least 60% plasma cells on bone marrow biopsy
- More than one Lytic lesions over 5mm on MRI
- Evidence of end organ damage due to the Myeloma with any one of:
- Staging - This is based on International staging system for multiple myeloma, Greipp et al, J Clin Oncol. 2005 May 20;23(15):3412-20.
This paper surveyed 10,750 patients (60% IgG, 24% IgA, 11% FLC-only, 3% IgD, 2% other) Older staging systems (Durie Salmon) included number of lytic bone lesions, which was observer-dependant, but this paper found beta2-microglobulin was sufficiently predictive. Note, the average lab values were median M-Protein 3.9 g/dL, median Hgb 10.5, median Cr 1.1, median beta2-microglobulin 3.8 ug/mL, median Albumin 3.6. Moreover 43% had 3 or more lytic bone lesions, 25% had pathologic fractures, Mean bone marrow plasma cell count 40%. Really, these are surprisingly normal, so don't expect a severe AKI or anemia to tip you off.
- Stage 1: beta2-microglobulin < 3.5 mg/L, albumin > 3.5 g/dL
- Stage 2: Not stage I or III
- Stage 3: beta2-microglobulin > 5 mg/L
- Treatment - This is based on International Myeloma Working Group recommendations for global myeloma care, Ludwig et al, Leukemia. 2014 May;28(5):981-92.
- Monitor Vit D, Ca, Phos
- Check serum Albumin and beta2-microglobulin for staging
- Check Lactic Acid Dehydrogenase for bone lesion marker
- During treatment, watch serum light chains to monitor response, as well as urine UPCR
- Skeletal survey to look for spinal cord compression
- IV fluids - alkalinization
- Bisphosphonates - Pamidronate 30mg every 4 weeks for 2 years
- Prophylactic vaccination - Pneumococcal, Haemophilus Influenza, Influenza
- Consider Acyclovir if on Bortezimib
- Consider daily Bactrim
- Aspirin 81mg unless 2+ risk factors (CKD or DM, obesity, past VTE, Pacemaker) then consider Coumadin
- Avoid loop diuretics
- Fluids, target urine output over 3L per day
Renal Pathology Findings
Light Microscopy: Large casts in the tubules, may be surrounded by multinucleated giant cells (these giant cells with casts are diagnostic of MM and are formed from Monocytes). The casts themselves may have many different colors, including brightly eosinophilic, PAS negative. Casts may also be lamellated. Tubule epithelial cells may be necrotic or sloughed off. The tubule basement membrane may be ruptured. The interstitium has edema, and infiltrate of inflammatory cells.
The casts are PAS (periodic acid-Schiff) negative - they contain all light chain and Uromodulin while PAS will stain positive for glycoproteins or polysaccharides.
Renal Pathology Findings of Light Chain Deposition Disease and Heavy-Chain Deposition Disease
This is a non-immune deposit of light chains and may appear in several places: Basement membranes, both in the glomerulus and tubules Mesangium (LCDD and AL-Amyloid make nodules in the mesangium) These are pieces of Immunoglobulins, but when they accumulate they do not cause an active inflammation like, for example, lupus immune complexes. Instead they act more like amyloid.Light Microscopy: This may look similar to diabetic nephropathy with widening of the mesangium (so more space between capillary loops) and sometimes crescents. The tubule basement membranes are also thickened. These are non-specific findings, so you need the immunofluorescence staining to confirm the diagnosis.
Immunofluorescence: There is staining for the appropriate Immunoglobulin fragment in all basement membranes, glomerular, tubular and also peritubular capillaries.
Pulmonary Emboli and DVT
- American Heart Assoc Guidelines for Pulmonary Embolism, Iliofemoral
Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension
A massive PE is a PE with > 15 minutes of hypotension with SBP < 90mm, while a submassive PE is without hypotension but RV dysfunction (dilation, or BNP increase) or myocardial damage. A low risk PE has none of these clinical markers. There are a number of tests to measure prognosis in a PE patient (CT, Troponins, BNP, Echo, and more), but these seem to measure Right heart strain, and are not good at diagnosing PE. For ECG, look for Tachycardia, RBBB or ST elevation or depression, or T-wave-inversion.Treatment is anticoagulation. Use Subcutaneous LMWH, or Subcutaneous or IV Heparin with monitoring, or Fondaparinux. If the patient has history of HIT, then use Argatroban, Bivalirudin or Lepirudin. Heparin (or similar) alone does not improve pulmonary blood flow in the first 24 hours; so it takes a while to have effect.
If there is a massive PE, then consider thrombolysis, but if submassive, then don't. Streptokinase or Alteplase both activate the enzyme Plasmin which degrades Fibrin. This improves pulmonary blood flow faster than heparin alone, but there is no difference by 7 days. So, it only accellerates recovery, not change final outcomes, which is only important if the patient is in acute trouble, like circulatory failure (hypotension and shock due to new heart strain) or pulmonary failure (hypoxia). Fibrinolysis also raises risks of bleeding, but many reports define bleeding widely and include things like bruising or oozing from IV sites. However, for massive PE only, one study showed a "significant eduction in recurrent PE or death from 19.0% with Heparin alone to 9.4% with fibrinolysis." Note, most of these studies gave heparin along with the fibrinolysis, so it augments heparin not replaces it.
Submassive PE usually has more risk from bleeding than reward so generally don't use thrombolysis. However, they state that "Fibrinolysis may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis .... and low risk of bleeding complications". Thrombolysis is recommended for DVTs that are limb-thereatening, or rapidly growing despite anticoagulation, but are not advised for chronic DVT.
Finally, the same contraindications apply. If a patient with PE or DVT has contraindications to anticoagulation, then an IVC Filter should be used. Now, ahem, IVC filters are confusing. On the plus side, one study showed that they reduce the incidence of recurrent PE at 12 days (1.1% vrs 4.8%) and at 8 years (6.2% vrs 15.1%). However, the same study showed they also increase the risk of DVT at 2 years (20.8% vrs 11.6%) and there was no difference in overall death. As a result, the guideline says "IVC filter placement, whether with permanent or retrievable filters, should be accompanied by subsequent anticoagulation once the patient can safely be given anticoagulant drugs". It seems that they are a good temporary solution in a patient who cannot be otherwise anticoagulated, but eventually they either need to be removed or the patient should later start antuicoagulation when possible. They are also used if a patient has a PE despite already being anticoagulated. If a patient has contraindications to thrombolysis but suffered a massive PE, then you can consider surgical thrombectomy.
Paradoxical emboli (clot passing through a patent foramen ovale to cause a CVA) are more than boards trivia. A PFO in a massive PE will increase the risk of death by relative risk 2.4, and risk of CVA by relative risk of 5.9. So, always do a Echo with Bubble study. If a PFO is found, then this may indicate surgical thrombectomy.
The guidelines don't discuss long-term anticoagulation (ie Warfarin) for PE, but they do discuss it with DVT. Note that DVT starts with the initial Heparin or comparable short term anticoag, but then longer term Warfarin.
- First DVT with known and reversible risk factor - 3 months
- Recurrent or unprovoked DVT - 6 months to life
Pneumovax
- 13-valent Pneumovax then 8 weeks later 23-valent Pneumovax
- Five years later - 23-valent Pneumovax
Anti-Coagulation
NSTEMI | Ischemic CVA (proven with CT) | PE and DVT | |
Aspirin (inhibit COX so reduces Thromboxane, so indirectly anti-platelet) |
162-325mg | 325mg within 24hrs | Not used. |
Anti-Platelet (block the ADP receptor) |
Clopidigrel | NOT currently recommended, but currently in trials so possibly in the future | Not used. |
GP IIIb/IIa Blocker (also anti-platelet - blocks the GP IIIb/IIa receptor) |
Abciximab iff PCI or angiography | Not recommended | Not used. |
Anti-Coagulation | Use whichever is tolerated
|
Do NOT give Heparin or LMWH or similar agent for acute treatment. They increase the risk of intracranial bleed and may not lessen risk of recurrent stroked. This is true even when rtPA is NOT given. However, prophylactic Heparin for DVT prophylaxis is OK. Moreover, you will eventually have to give Heparin as a bridge to Warfarin, but they don't specify the timing. | Use whichever is tolerated
|
Thrombolysis | Cath within 90 min of presentation | rtPA if within 3hrs of onset, but within 90 min is better.
Streptokinase is unsafe, a trial was halted because excess hemorrhage. |
For massive PE, or DVTs that are limb-thereatening, or rapidly growing despite anticoagulation. Note there is no time-limit, only severity criteria. |
- Requirements for thrombolytics in CVA
- Ischemic, not hemorrhagic.
- Symptoms started <3 hrs ago.
- No head trauma, CVA, MI within past 3 months
- No GI or UG bleed within past 3 weeks
- No surgery within past 2 weeks
- Never previous intracranial hemorrhage
- BP under 185/110
- Not taking PO anticoag, OR INR < 1.7
- Platelets > 100,000
- Blood Glc above 50
- No seizure with permanent impairment (Hx of transient seizure OK?)
- Requirements for thrombolytics in STEMI and PE
- No prior intracranial hemorrhage
- No cerebrovascular disease (like AV-malformation)
- No malignant intracranial neoplasm
- No Ischemic stroke in past 3 months
- No suspected aortic dissection
- No "recent" surgery on spine or brain
- No "recent" closed head trauma
- Relative Requirements for thrombolytics in STEMI and PE
- Age < 75yrs
- Not pregnant
- No current use of thrombolysis
- No recent internal bleed in past 2-4 weeks
- No non-compressible venous punctures
- No CPR longer than 10 minutes
- No HTN with SBP>180 or DBP>110
Diabetes
- ACCORD Study
Maintaining HbA1c between 7 and 7.9% corresponds to lower risk of hypoglycemic events than trying to hold A1c below 7%. It does not directly address other outcomes, simply lower risk of hypoglycemia. "The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group"A follow-up paper by Bonds et al found a correlation between hypoglycemia and mortality. OK, so low HbA1c targets leads to more hypoglycemia, which then is linked with increased mortality. Simple, right? Well, Bonds et al found more increased mortality in the aggressive treatment group than can be explained by hypoglycemia alone. I am not sure if I buy their statistical argument, but statistics can be terribly counter-intuitive. However, even if other factors are also involved, they claim "the risk of death was found to be higher in participants who had experienced at least one episode of symptomatic, severe hypoglycemia".
- ADA Position on Diabetes Diagnosis (Jan 2010) - including A1C criteria
The American Diabetes Association criteria for Diabetes is- Fasting glucose > 125 (think of morning labs before breakfast)
- Post-Glc-Challenge glucose > 200
- A1C > 6.5
Pre-diabetes is a category to find people at risk but not diabetic yet, and is used to start lifestyle changes before true DM starts. The criteria is fasting Glc 100-125 (Impaired Fasting Glucose) or 2hrs post-Glc-challenge Glc 140-199 (Impaired Glucose Tolerance). There is no official A1c guideline for pre-diabetes, but they suggest that an A1c between 5.7 and 6.4 is a "reasonable" tool, since it is specific (88%) but not very sensitive (66%).
There are also a few things that bear repeating. DM Type 1 may have a slow onset and not present until any age, even 8th or 9th decade. It is a cell-mediated innune response (T-Cells?) but also has some Ig markers including anti-islet-cell, anti-insulin, anti-GAD, anti-Tyrosine phosphatases IA-2 and IA-2beta. So, this is more than a similarity between a foreign antigen and a host protein (like the case of Group A Strep's M-Protein). Instead, there seems to be a broader decision that the whole islet cell and its related proteins are foreign, which in my opinion somewhat resembles the immune process behind the ANCA-related diseases.
Critical Care
- ICU Drips
- Nitroglycerine. (5-100 mcg/min)
- Norepinephrine. (8-12mcg/min)
- Esmolol. (50-200 mcg/kg/min)
- Dopamine (1-20 mcg/kg/min. Often 5 mcg/kg/min starting dose)
- Octreotide (Bolus 25-100 mcg, then 25-50 mcg/hr)
- Pantoprazole (Bolus 80mg IV then 8 mg/hr)
- Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012
- Labs
- Lactate (and ABG Q4h)
- Blood cultures, procalcitonin, beta glucan, mannan
- Antibiotics
Total Abx for 7-10 days. May deescalate after 3d.- Vanc, Zosyn Azithro/Doxy
- Echinocandin (Micafungin) or Fluconazole
- Fluid Resuscitation
Goals: MAP ≥ 65, CVP 8-12 (12-15 if on vent), Urine > 0.5ml/kg/hr, ScvO2 ≥ 70%, or mixed venous O2 > 65%
Start with 30 mL/Kg initial bolus of crystalloid. - Pressors
- Norepi first
- Vasopressin (0.04 Units/min)
- Epi
- Dobutamine
If adequately resuscitate and ScvO2 < 70 or Mixed Venous O2 < 65, then there is insufficient cardiac output. So, start Dobutamine. - Steroids
- - Hydrocortisone 50mg Q6h
Only do this if there is inadequate response to fluids - Transfusion - Keep Hgb > 7
- Insulin - Start insulin drip if Glc > 180
- Stress Ulcers - PPI or Ranitidine 150mg BID
- Ventillation for ARDS
Vt = 6mL/Kg, and use PEEP. Do not use empiric beta agonists (ie Albuterol). May use only if Asthma.
- Labs
- Ventillator Notes
- Control Modes
All assist modes will assist with *every* breath. The patient may initiate when breaths happen, but once a patitne starts a breath then the vent will assist. The vent will detect when a patient starts a breath in several ways.- When the pressure in the airway drops below a threshold
- When a minimal amount of air is moved.
In both cases, the patient takes a small breath and the vent will then help move more air to create a larger breath. In a sense, the vent is a multiplier of the patients own respiratory function.
These modes "control" one variable, either pressure or volume. If you control the volume, then the vent applies whatever pressure is needed to deliver that exact volume. If you control the pressure, then the vent dynamically changes the volume to maintain that fixed pressure.
Now, *really* there is a third variable, the flow rate. For example, I could say that you must move a specific amount of air at a fixed pressure. If I say to move a lot of air at a low pressure, that may be possible, but a single breath may take far too long.
- Volume Control
The vent applies whatever pressure is needed to deliver a preset volume. The operator will set these parameters:- Tidal volume
- Triggers that indicate a breath is starting
- PEEP
- Flow rate
- Min rate of breaths per minute
You can change the I:E ratio (inspiratory time to expiratory time) by changing the flow rate. The flow rate is the rate at which the air is delivered. Higher flow rates correspond to higher pressures. By selecting a higher flow rate, the air is moved faster, and at a higher pressure, and so the inspiration is faster and shorter. This leaves more time for expiration, and so changes the I:E ratio. Selecting a lower flow rate does the opposite; it makes for a slower flow rate, at lower pressure, and causes inspiration to take more time.
- Pressure Control
The vent dynamically changes the volume to maintain that fixed pressure. This means some breaths may be very shallow if the lungs are fibrotic and stiff and the fixed pressure is set at a low level. But, it also means you will never exceed a known pressure and cause barotrauma.The operator will set these parameters:
- Pressure
- Triggers that indicate a breath is starting
- PEEP
- Inspiratory time
- Min rate of breaths per minute
This lets you directly control the I:E ratio by specifying the inspiratory time.
- PRVC
This is like Volume Control, except instead of the operator specifying a flow rate, now the vent will compute a flow rate. First the vent will *observe* th epatient taking several natural breaths. From this, it can measure the pressure and the amount of air actually moved. This allows it to compute the lungs' own natural elasticity. Then, the vent uses this observed elasticity, to compute what pressure would be required to deliver the fixed volume. - BiLevel
The vent will maintain a constant pressure that regularly cycles between a low pressure and a high pressure. In practice, the machine is mostly at the high pressure with short breaks at low pressure. This is a more effective PEEP, since the long stretches of high pressure will open up the lungs, (like PEEP) and the short breaks at low pressure allows air to escale from the now open lungs.The patient may initiate a breath at *any time*, either at low or high pressure. In practice, patients seem to start breaths at the high pressure and will exhale when the vent is on low pressure, because that is easier, but they are not strictly synchronized to the vent.
This mode is used to recruit alveoli, and is often used to maintain a constant high pressure for ARDS. If we had a high PEEP with volume control, then we would risk barotrauma by delivering an even higher pressure to deliver the controlled volume. If we put him on pressure control, then we would have to paralyze, and th eparalytics have adverse neuro effects. So, as a third option, we use bi-level with a continuous high pressure and high differential between high and low pressures.
- Spontaneous Breathing
The patient starts all breaths, and this has several modesPressure Control. This is BiPAP; there is a PEEP and a different higher pressure when the patient is breathing. (? How is this different than Pressure Control with PEEP?)
- SIMV
This allows a patient to take spontaneous breaths that are *not* assisted, while the vent will assist other breaths. So, the vent will assist N breaths per minute (for some N that is set by the operator) and if the patient takes N + K breaths, then the other K breaths are not assisted.The operator will set these parameters:
- Rate of breaths per minute
- Triggers that indicate a breath is starting
You can use SIMV with any Assist Control mode, including Pressure control and Volume control. As a result, the operator will also set additional parameters for the specific assist control mode (like Tidal volume for volume control, or pressure for pressure control).
This is often used by surgeons in PACU, and it is good for weaning a patient off a vent. In effect, it allows the patient to try to breathe as much as they can, but the vent is there to make sure that a minimal amount of breathing is done. That makes sense for a patient recovering from anaesthesis, whose lungs work fine but they are still waking up so they may not have normal inspiratory drive. In these patients, if they do take a breath on their own, then their lungs work well enough to take a decent breath. But, what about the patient with COPD, or ARDS, or terrible pneumonia? These patients may have a normal inspiratory drive, but their lungs are malfunctioning, so each breath does not move much air or the air does not transfer to blood well. In these other patients, it doesn't matter how often they breathe. More important, no matter how much they breathe, every breath needs assistance from the vent to pass through the sick lungs.
- Auto Peep
This is not a vent mode, but rather some may be effects that happen to a patient who is on a vent. This happens when a patient does not have enough time to fully exhaly. So, inhaled air accumulates in the lung. This ubild-up of air will lead to a buildup of pressure.
- Control Modes
Liver
Most of these notes are from The American Association for the Study of Liver Diseases published guidelines.
AASLD - The Management of Acute Liver Failure: Update 2011
AASLD - Alcoholic Liver Disease
AASLD - Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis
AASLD - Management of Adult Patients with Ascites Due to Cirrhosis
AASLD - The diagnosis and management of non-alcoholic fatty liver disease
AASLD - Chronic Hepatitis B: Update 2009
- History and Physical
- Shifting dullness is areas of dullness to percussion on the flanks when supine and new location when standing or decubitus.
- Encephalopathy
- Grade I (mild confusion, slurred speech, disordered sleep) - Admit to Ward bed
- Grade II (lethargy, moderate confusion) - Admit to ICU. Get Head CT to r/o other causes.
- Grade III (stuporous, incoherent, sleeping but arousable) - Admit to ICU. Intubate. Get Head CT to r/o other causes.
- Grade IV - Coma - Admit to ICU. Intubate. Get Head CT to r/o other causes.
- Ask about mushrooms (if present then antidote is Pen G), and Herbal or OTC meds
- Labs and Scores
- Labs
- CBC, CMP, INR, ABG, Lactate (look for shock liver), maybe urine lytes
- NH3, GGT
- Acetaminophen level, Ceruoplasm
- Hep A/B/C: (HAV IgM, HBsAg, Anti-HBc IgM, anti-HEV, anti-HCV, HCV RNA)
- HSV IgM, VZV
- Scores
- MELD
3.8[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.6[Ln serum creatinine (mg/dL)] + 6.4
This esitmates severity and mortality in chronic liver disease.
The 3 month mortality for MELD scores is (≥40) 71.3%, (30–39) 52.6%, (20–29) 19.6%, (10–19) 6.0%, (<9) 1.9% - Child-Pugh
This grades severity of cirrhosis, and things like variceal risk are correlated to this score. (5-6) Grade A and is compensated, (7-9) Grade B and is decompensated, (10-15) is Grade C and is decompensated. - Maddrey Discriminant Function (MDF)
ONLY for Alcoholic Hepatitis. Index = 4.6 * (ProthrombinTime - ControlProthrombinTime) + Bilirubin
If >32, then higher mortality and will benefit from steroids.
- MELD
- Labs
- Variceal Bleeds
Varices are caused by portal hypertension. Best measure is the Wedged Hepatic Venous Pressure (WHVP) and normal is 3-5mm Hg and >12mm Hg is linked with variceal bleeding. Gastric varices are different (sometimes less serious) than esophogeal varices. Esophogeal varices are small, or large (>5mm)- Transfusion. Keep Hgb > 8 (not 7-9 as in the latest sepsis guidelines)
- Antibiotics
These prevent sepsis from open bleeds in the gut.- Norfloxacin 400mg PO BID for 7 days
- Ceftriaxone 1g IV daily for 7 days
- Splanchnic Vasoconstrictors to stop bleeding
- Octreotide (a synthetic Somatostatin analog). 50 mcg bolus then 50 mcg/hr
- Vasopressin (0.2-0.4 units/min) combined with Nitroglycerine drip (40 mcg/min). This is the most powerful, but has many side effects.
- Non-selective Beta Blockers
NEVER give these with an active bleed. Only give these to prevent bleeds and/or when bleeding has stopped. Also, only give these if varices are seen. They prevent existing varices from bleeding, but do NOT prevent varices from developing in the first place. They reduce Cardiac Output and cause splanchnic vasoconstriction.- Propranolol (20mg BID), and Nadolol (40mg daily). Give as high a dose as can be tolerated.
- If a patient is already on a selective BB (Metoprolol, Atenolol) then switch them to Propranolol
- Transfusion. Keep Hgb > 8 (not 7-9 as in the latest sepsis guidelines)
- Alcoholic Hepatitis
There are 3 stages of EtOH damage: fatty liver/steatosis, Alcoholic Hepatitis, and Cirrhosis (which is chronic hepatitis with hepatic fibrosis). EtOH Hepatitis may be an acute exacerbation on top of chronic cirrhosis.- Diagnosis
No definitive lab test, but there are markers that make it likely. AST > 2x ALT, really > 3x is even more likely. Also AST < 500, ALT < 200 - Steroids
Steroids help patients with Maddry score ≥ 32, but they do not seem to help with lower scores. For patients with lower scores, just treat with nutrition and supportive care- Prednisolone 40mg/day x4 weeks, then tapered over 2-4 weeks. This is better than prednisone
- If steroids are contraindicated (asthma, severe DM), then use Pentoxifylline 400mg PO TID x4 weeks. This is a PDE-blocker, and also a TNF-blocker.
- Treating Nutrition
Thiamine, Folate, Multivitamin. Check B12 and folate levels - Abstinence is the best therapy. Once you have 1 episode of EtOH Hepatitis, then must have complete abstinence. 2/3 pts have some recovery in 3 months, but only 25% of abstinents have complete liver recovery
and 20% STILL progress to cirrhosis. Disulfuram does not improve abstinence. Naltrexone does help abstinence but is also liver toxic. Acamprosate is a GABA miminc and helps with withdrawal.
- Baclofen may reduce EtOH craving (5mg PO TID x3 days, then 10mg PO TID daily)
- Diagnosis
- Acute Liver Failure (ALF)
Diagnose: INR ≥ 1.5 and some encephalopathy- Manage Hemodynamics. Target MAP ≥ 75 (note, this is higher than sepsis guidelines), and use fluids first and then Norepi followed by Vasopressin if no response
- Manage Bleeding
- H2 Blocker - Ranitidine 150mg BID
- Vit K (5-10mg subcu)
- Manage Encephalopathy - Lactulose
- Empirically treat Acetaminophen toxicity
Typically, ALT > 3500
Activated Charcoal (1gm/kg PO) if within 4 hrs of ingestion
NAC: 150mg/kg loading, then 50mg/kg over 4hrs, then 100 mg/kg over 16hrs - Check for Wilson Disease
This is a hemolytic anemia (Coombs negative). Look for high Bili, low ceruloplasm.
TBili / ALP ratio over 2.0 indicates possible Wilson.
- Manage Hemodynamics. Target MAP ≥ 75 (note, this is higher than sepsis guidelines), and use fluids first and then Norepi followed by Vasopressin if no response
- Ascites
The three main complications of cirrhosis are ascites, varices and encephalopathy. The causes of ascites include Cirrhosis, Cancer, Nephrotic Syndrome, Heart Failure (R-sided)- Paracentesis
- Insert needle in LLQ or RLQ, 2 fingers medial and superior to anterior superior iliac spine. The abdominal wall is thinnest here.
- Labs: Cell count, Bacterial culture, Albumin, Total protein, LDH, Glucose. Note, most all patients with cirrhosis will have an elevated CA-125; this does not mean cancer if there is cirrhosis.
- Portal Hypertension if:
- SAAG (serum-ascites Albumin Gradient) > 1.1
- SBP if there is ≥ 250 WBC/mL in peritoneal fluid.
- Secondary SBP is caused by an intra-abdominal abscess, or bowel leak. Usually is polymicrobial, and must have 2 of the following: (i) Glc < 50, (ii) LDH > serum level, (iii) total Protein > 1g/dL
- Gut perforation if LDH > 240 u/L
- Treatment
- EtOH abstinence
- Reduce salt (<2g Na per day). Goal is (Urine-sodium / Urine-potassium) > 1.0 This means you lose more Na than K and are net diuresing. Do NOT fluid-restrict, unless serum Na is < 125.
- Diuretics. Spironolactone 100mg and Furosemide 40mg, (or doses in 100:40 ratio up to 400:160). Combining both diuretics will balance potassium loss/retention. But, do NOT give diuretics if there is GI bleeding or hepatic encephalopathy or renal dysfunction (avoid hepatorenal). The goal is net negative 0.5L per day on intake and output. You may also substitute Amiloride (10-40mg daily) for Spironolactone if there is painful gynecomastia (a bigger issue in a cirrhotic with elevated estrogens).
- Albumin 25g weekly
- Be careful about low BP. Avoid ACEi, ARBs, or anti-hypertensives. Target a MAP > 82, since that is linked with better survival. It seems that there is portal hypertension, which causes a reflex vasodilation that affects the rest of the body and can lead to systemic hypOtension. Oddly, even Propranolol can lead to increased mortality except when it is needed to avoid varices. The guideline doesn't say how to balance this in a patient with BOTH cirrhosis AND varices. I would probably tend to go with giving propranolol to avoid bleeds and then stop all other antihypertensives.
- Midodrine (7.5mg PO TID) for refractory ascites. This is an alpha-agonist, so it is a pro-sympathetic, like Phenylephrine. This goes along with the idea that vasoconstriction is actually good in ascites. You can give Midodrine along with diuretics.
- Serial paracentesis. This is second line; first line therapy is always Na restriction and diuretics. If you do a large paracentesis, then replete 6 to 8g of Albumin for every Liter of fluid removed.
- TIPS (Trans-Intrahepatic Portosystemic Shunt). This is a shunt from portal to vena cava that is placed by IR. It is used when a patient is reftactory to diuretics.
- Vaptans (Vasopressin blockers). These may cause too-rapid serum Na drop, and can cause central pontine demyelenation. I am avoiding these for now.
- Avoid PEG tubes with active ascites
- Spontaneous Bacterial Peritonitis
- Paracentesis EVERY cirrhotic patient with ascites (be aggressive) (this advise is not from the papers).
- It is very common, and approx 20% of cirrhotics have SBP.
- It is often asymptomatic, but if untreated will progress and become symptomatic with very high mortality
- Fluid rarely grows positive cultures, because there is so much fluid you may not get bacteria in a random sample.
- Look for other markers besides positive cultures, like low protein (< 1.5 g/dL) or high cell count (> 250 cells).
- Low protein fluid means low immunoglobulins, so this is highly succeptible to infection.
- High cell count means there is a response to an active infection, even if you can't culture bacteria
- Treat with empiric antibiotics (be aggressive).
- When there is ≥ 250 WBC/mL in peritoneal fluid, EVEN IF cultures are negative.
- Treat even if there is < 250 WBL/mL so long as there are signs of possible SBP: Abdominal pain, fever, encephalopathy
- Treat with 3rd generation cephalosporin, preferably Cefotaxime 2g IV Q8h. One study showed Ceftriaxone (1g IV BID x5d) is also effective.
- If SBP does not respond to antibiotics, and there is concern for gut rupture, then emergently call surgery.
- Prophylaxis
- Ceftriaxone 1g IV daily x7days (best)
- Norfloxacin 400mg PO BID x7days
- Give to patients with fluid protein < 1.5g/dL AND AKI or CKD (Cr>1.2, BUN>25) OR Liver failure
- The most common bugs are E coli, Klebsiella, Strep pneumo. However, frequent use of quinolones for SBP prophylaxis
has led to increase in ESBL Enterobacter and other bugs.
- Secondary SBP is caused by an intra-abdominal abscess, or bowel leak. Usually is polymicrobial, and must have 2 of the following: (i) Glc < 50, (ii) LDH > serum level, (iii) total Protein > 1g/dL.
- Paracentesis EVERY cirrhotic patient with ascites (be aggressive) (this advise is not from the papers).
- Hepatorenal Syndrome
- Diagnosis
- Cirrhosis with ascites + Creatinine > 1.5 + NO improvement in Cr after 2 days with IV fluids and albumin (1g/kg) and NO diuretics
- Type I: rapid, double Cr in less than 2 weeks
- Type I: slower, but worse prognosis
- Renal biopsy shows glomerular-tubule reflux
- Prevention
- Albumin IV
- Pentoxyfilene
- Treatment
- Albumin 10-20g IV daily x20 days
- Octreotide 200 mcg subcu TID
- Midodrine titrated up to max 12.5mg PO TID. Goal is to raise SBP by 15mmHg
- Diagnosis
- Hepatic Hydrothorax
- Ascitic fluid entering chest through a diaphragm defect (usually right sided)
- Abdominal and thoracic fluid have different protein composition, and SBP may only affect one compartment
- Chest tube is CONTRAINDICATED
- Treatment
- Sodium restriction
- Diuretics
- TIPS if diuretics and diet fail
- Rifaximin PLUS Lactulose
A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy- Lactulose + Rifaximin together have lower hepatic encephalopathy and improved mortality.
- The two meds have different mechanisms of action, so they complement each other.
- Rifaximin is a synthetic form of Rifamycin, which is an antibiotic against GPC and GNR. Rifaximin is minimally absorbed and kills enteric bacteria. (??? Does it also work against NH3-producing bacteria???).
- Lactulose lowers colonic pH, so NH3 forms non-absorbably NH4+.
- Paracentesis
- Hepatitis C
There are 6 genotypes (1 through 6, and types 1a and 1b are most common in US). 15-45% of patients spontaneously clear the infection, but this is more common with pediatrics. 5%-25% will advance to cirrhosis over 25-30 years.- Testing
- Test patients with HIV, dialysis, past IV drug use, transfusion or transplant before 1992. Do not test if tatoos/piercings.
- First test anti-HCV Ig. These appear 6-8 weeks after infection
- Then if Ig is present, test for viral load and genotype.
- If genotype 1, then get liver biopsy (this recommendation is now under debate)
- Repeat tests in 6 months after treatment to assess response.
- Sustained Virologic Response - no RNA in 6 mos after treatment.
- Rapid Virologic Response - no RNA in 4 weeks after treatment.
- No Response - RNA has not declined 99% after 12 weeks
- In the US, 8.4% of dialysis patients and 1.7% of staff are Hep C positive. CKD be caused by Hep C Cryoglobulinemia. If proteinurua and cryoglobulins, then screen for HCV.
- Testing
- Non-Alcoholic Fatty Liver (NASH)
- This is a diagnosis of exclusion. You must rule out other causes like EtOH and infection.
- Liver biopsy is the gold standard. You should see steatosis without ANY signs like cell ballooning.
- Pioglitazone does improve mortality in NASH and can be used to specifically treat steatohepatitis in NASH, not just DM-2. It was specifically tested on NASH patients who were NOT diabetic.
- Metformin has not been shown to have any benefit for NASH specifically
- Vitamin E (800 IU/day) improves liver function, but do not give if the patient is diabetic.
- Statins are generally safe in patients with chronic liver disease.
Diagnosis
Weight Loss
Treat by managing metabolic syndrome, dyslipidemia, and any diabetes.
Weight loss must be at least 5% of body weight to help the liver. Bariatric surgery is not recommended specifically for NASH, but it is recommended for morbid obesity.Medications
Alcohol. Avoid heavy EtOH use, but there are no recommendations about light occasional use. I personally think abstinence is best, but the evidence does not show any conclusive harm from very light EtOH use.
- Hemochromatosis
Look for elevated Ferritin and Transferrin
GI Topics
- Celiac Disease - Fasano and Catassi; N Engl J Med 2012; 367:2419-2426
- More common in women and people with other autoimmune disorders (DM-1, Hashimoto, Rheumatoid, etc)
- There is a series of different gluten reactions
- Celiac. Autoantibodies always present.
- Gluten Sensitivity. No autoantibodies
- Wheat Allergy. No autoantibodies
- All types of reactions may include both GI symptoms (diarrhea, wt loss, malabsorption) and systemic symptoms (neuro, ??migraines?)
- Diagnosis
Measure markers these when the patient is eating gluten, not after they are on a gluten-free diet.- IgA anti-Trans-Tissue Glutaminase. Sensitivity 95%, Specificity 95%. This is first line screening. Use IgA, since IgG is not as good.
- IgA anti-Endomysial. Sensitivity 90%, Specificity 98%. Use this if antiTTG is uncertain. Use IgA, since IgG is not as good.
- Deaminated gliadin peptide antibodies. In the future, this may be better than anti-trans-tissue-gliaden.
Biopsy is usually required for confirmation, but may be seldom done in practice. - Treatment
- Avoid gluten. (Not clear whether oats are ok, different people may vary in their response).
- Nutrient repletion for malabsorption (Ca, Fe, Folate)
- Even when avoiding gluten and there are no detectable antibodies in serum, intestinal damage may persist.
Scales
ECOG:
Grade 0 | Fully active; no restrictions |
Grade 1 | Cannot perform strenuous activity. Can perform light work and also can care for self |
Grade 2 | Can fully care for self, but cannot work. Up and out of chair and bed more than 50% of the day |
Grade 3 | Cannot fully care for self. Up and out of chair and bed less than 50% of the day |
Grade 4 | Cannot care for self, disabled. Confined to chair or bed |
Grade 5 | Dead |
METS:
4 | walking up 2 flights of stairs, making a bed |
One MET is the resting basal oxygen consumption of a normal 40-year-old 70-kg male.
Functional status is Excellent(over 10 Mets) Good(7-10 Mets) Moderate(4-6 Mets) Poor(below 4 Mets).
Duke Activity Scale:
1 | Dressing, Bathing |
2 | Walk around your house |
3 | Walk a block |
4 | Climb a flight of stairs |
5 | Run a short distance |
6 | Wash dishes |
7 | Vacuum or carry in groceries |
8 | Scrub floor or move heavy furniture |
9 | Rake leaves |
10 | Sex |
11 | Golf or bowling |
12 | Swimming or singles tennis |
Incidental Radiology Findings
Lung Nodules
These guidelines seem to be mostly focused on solitary pulmonary nodules. If you get a CT with multiple unepexcted nodules, then you will have to use these only as loose guidelines. These are the Fleischner Society Recommendations, and are taken from Gould et al, "Evaluation of Patients With Pulmonary Nodules: When Is It Lung Cancer? ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)", Chest. 2007;132
- Less than 4mm If low risk for cancer then do nothing. But, if high risk for cancer, then repeat non-contrast CT in 12 months. If the nodules are unchanged by that time, then no further followup.
- 4-6mm If high risk for cancer, then repeat non-contrast CT in 6-12 months, and again 18-24 months after the second non-contrast CT.
- 6-8mm If high risk for cancer, then repeat non-contrast CT in 3-6 months, and again 9-12 months after the second CT.
- Over 8mm If high or low risk for cancer, consider immediate Contrast CT, or PET or biopsy. Also, follow repeat non-contrast CT in 3 months, 6 months and 9 months.
These recomendations are for high risk patients. In all of these, if the patient is a low risk (such as never smoker with no family history and no industrial exposures) then treat a nodule with the recommendations of a high risk patient with 1-size smaller nodule.
If a nodule is unchanged after two years, then you can stop following it.
Thyroid Nodules
Check TSH, Free T4. If it is non-functioning, get an Ultrasound. If it is functioning, get Iodine uptake scan.
- Over 1cm and solid FNA
- Over 2cm and cystic FNA
- Over 4cm Surgery
Adrenal Nodules
A non-trivial fraction (10 to 20 percent) of Adrenal "incidentalomas" are biologically active. "Although most adrenocortical masses are nonhypersecretory adenomas, 5–47% secrete cortisol and 1.6–3.3% mineralocorticoids" from Mansmann et al, "The Clinically Inapparent Adrenal Mass: Update in Diagnosis and Management", Endocrine Reviews 25(2):309–340. I don't know what to make of "4-47" percent, that is such a wide range I question the number. But even if you agree with the low end, like 5-10%, then that could mean 1 of every 10 patients with an incidental finding really has a hyper-functional adenoma. These are common findings on CT, if 10% of CT's have them. That deserves at least a lab workup.
Get Aldosterone and Renin levels, 24hr urine free cortisol, plasma free metanephrines and normetanephrines, 24-hour urine metanephrines and normetanephrines. Also consider an overnight Dexamethasone suppression test. By the way, most Pheos are diagnosed now from incidentaloma workup than symptoms. Be careful, Labetalol, Buspirone, and others can falsely raise metanephrines and normetanephrines.
- Under 1cm If there are no symptoms, then ignore.
- Over 6cm Surgery whether it is functioning or not.
- Functional tumor (any size) Surgery unless it is Aldosterone-secreting, in which case you treat medically with Aldosterone blockers.
Pituitary Nodules
Get Prolactin, TSH, IGF-1 levels, and a 24-hour cortisol collection.
- Under 1cm Serial MRI if there are no symptoms
- Over 1cm Surgery
- Functional tumor (any size)c Surgery unless it is Prolactin-secreting, in which case you treat medially with Dopamine agonists.
Hypertension
Target blood pressures
- SPRINT - systolic 120, but this has no diabetic or symptomatic CHF patients (though about 10 percent had some CHF history) or past stroke, or proteinuria over 0.6g/d. http://hyper.ahajournals.org/content/68/2/318
- JNC 8 - 140/90 if under 60, otherwise 150/90. This decreased stroke risk but did not include patients with Cr over 1.7. https://jamanetwork.com/journals/jama/fullarticle/1791497
- European Societies of Hypertension and Cardiology 2013 - 24-hour average of 130/80 mmHg or below, with 135/85 during the day and 120/70 at night. https://www.ncbi.nlm.nih.gov/pubmed?term=23817082
- USPSTF - Systolic below 140 for patients under 60yo. https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/high-blood-pressure-in-adults-screening
- American Society of Hypertension 2013 - below 140/90 for patients under 60yo. http://www.ash-us.org/documents/ASH_ISH-Guidelines_2013.pdf
- NICE (United Kingdom) 2013 - below 140/90 for patients under 80yo, and below 150/90 for patients over 80yo. https://www.nice.org.uk/guidance/qs28/resources/hypertension-in-adults-2098552495813
Check for Hyper-Aldo
The differential for high Aldo state includes hyper-aldo or high renin due to renal artery stenosis.
Note that RAS could be due to many causes (atherosclerosis, fibromuscular dysplasia, inflammation like PAN or Scleroderma renal crisis)
Note also that there may be pseudo-hyperaldo (channelopathies like Liddle or losss of protection from Cortisol due to very high Cortisol states in Cushings, or inactivation of 11 beta hydroxysteroid).
Diagnosing Hyper-Aldo
Renal Artery Stenosis
ASTRAL and CORAL were both negative trials, showing no difference between intervention and medical management. But, they did not enroll all patients with worst vascular disease.
Moreover, you would still intervene if you cannot medically manage a patient, or if the patient has symptomatic heart failure. You also intervene for Fibromuscular dysplasia (stenosis in middle of artery, typical patient is a young woman).
- Screening - random Aldo, renin. Look for Aldo over 10 and renin below 1.0. The time of day does not matter. It cna be false negative if patient is on Spironolactone or Triamterene or Amiloride. Try to replace these with another agent like Doxazosin or Hydralazine 6 weeks before. ACE/ARB does not seem to matter as much but it can still lead to higher Renin.
- Diagnostic - 24-hour urine on 200 mmol/day salt load. Look for Aldo over 10 mcg/dal.
Pheochromocytoma
Commonly associated with VHL, MEN2a/b, Neurofibromatosis
Check urine metanephrines. SNRI, Cocaine, TCA can all cause false positive of serum and urine metanephrines.
Norepi comes from adrenals, and CNS and peripheral sympathetics. But Epi only comes from adrenals.
Common Renal Drips and Meds
- Heparin/Protamine
- Heparin between 300 to 500 units per hour. If there is a history of HIT then you can use Argatroban 0.5 - 1 mg/hr but that has a complex dosing.
- Protamine 1.5 mg/hr for every 100u/hr Heparin
- Bicarbonate
You can always titrate up but this is a modest starting place both from an acid-base and a volume perspectiveOne liter with 150 mEq bicarb (3 amps) is 0.15 mEq/mL. So, 70 mL/hr is a good starting place, which will give 10.5 mEq/hr. You can always titrate up but this is a modest starting place both from an acid-base and a volume perspective.
- Calcium
The big issue here is whether there is Calcium in the Prescription fluid. If there is not, then you MUST replace calcium and will replace it at a higher rate. If there is Calcium in the prescription, then you may or may not need to replace Calcium.
There is no perfect recipe. I have been told to start at 1-2 mEq/hr if there is Calcium in the prescription fluid, and 6 mEq/hr if there is no Calcium in the prescription fluid. I also saw an online presentation from UAB about CRRT, which gives this recipe: "Add 10 amps of calcium gluconate to 1L of 0.9% saline. Final calcium concentration 93mEq/L", and they start rate at 60 ml/hr and then titrate to the ionized Calcium.
Always titrate to ionized Calcium, and target 4.5-5.5 mg/dL, which is 1.1-1.35 mmol/L
- Nicardipine
5mg/hr is a good starting point. I often have to send patients to a stepdown ICU where they will only run fixed rate drips, but that actually works out well. The nurse will start or stop the drip depending on blood pressure, but they won't change the rate. This still gives you a simple tool for controlling HTN Urgency without having to go to MICU. If you do titrate, you can go up or down in 2.5mg/hr increments.
- CAPD Heparin for Fibrin clots
500-1000 u/L in peritoneal dialysate
- Fomeprazole (4-Methylpyrazole) for Ethylene Glycol
- Loading dose: 15 mg/kg IV over 30 min
- Maintenance: 10mg/kg Q12hrs x4 doses, then 15mg/kg Q12hrs until serum EthyleneGlycol level is below 20mg/dL
Common CVVH Settings
- Choosing Flow Rates
- Blood Flow Rate of 300 mL/min is max for a typical catheter
- Prescription Rate is usually 20 – 30 mL/kg/hr
- Filtration Fraction
Intuitively, the ratio is: Amount removed per minute / Amount that flows through per minute
Or: Amount removed per hour / Amount that flows through per hour
In a pre-dilution system (replacement fluid added to circuit before the filter) this is:
((PrescriptionRate mL/hr) + UF mL/hr + Citrate) / (PRE-FILTER-PrescriptionRate mL/hr) + (BFR mL/min * 60 * (1 - Hct)) + Citrate
Note we multiply by 60 to convert from mL/min to mL/hr.
In a post-dilution system (replacement fluid added to circuit before the filter) this is:
((PrescriptionRate mL/hr) + UF mL/hr + Citrate) / (BFR * 60 * (1 - Hct)) + CitrateExample
Replacement Fluid is added pre-filter, BFR is 300, PrescriptionRate is 3000 and Hct is 0.3 and we are running even (so UF=0).
Filtration Fraction = 3000 mL/hr / (3000 mL/hr + (300mL/min * 60min/hr * (1 - 0.3)))
Filtration Fraction = 3000 / (3000 + 12600)
Filtration Fraction = 3000 / 15600
Filtration Fraction approx= 0.2Goal is to keep Filtration Fraction below 0.2 or you risk clotting. If your filtration fraction is over 0.2 - Try lowering Prescription Rate Increasing the blood flow rate reduces the filtration fraction (which is good) because BFR is in the denominator. However, if you are adding Citrate, then you also should increase the Citrate if you increase the blood rate. Increasing the POST-filtration fluid rate will increase the filtration fraction (which is bad) because it is in the numerator. Changing from post-filter to pre-filter reduces the filtration fraction (which is good) because prescription rate was previously only in the numerator but now is in both the numerator and the denominator.
- Nutrition
Tube feeds should include protein of 1.5 - 2.5 g/kg/day, and 25-35 Kcals/kg/day.
- What does it mean to run even? Opinions vary…
If you transfuse blood, does the volume get removed with UF? Some nurses will do this automatically, but many will not. If a surgeon orders IV fluids (drip, bolus) does the nurse continue to UF this off? (This happens!) Fluids go in through the IV and then immediately back out through UF on the filter. You may not want to fix this at 3am, but in the morning you may diplomatically ask the primary team to stop fluidsYou may specify what you want in your note: Nurse will UF to remove any volume given for medications
Usually does not count any IV fluids given for hypotension in the Intake and Output. You may bolus and not count that fluid volume in the intake/output balance Use Normal Saline as needed to replace losses from drain outputs (like chest tubes and more)
- What do you do when the acidosis is not correcting or correcting very slowly?
- First, try to increase the replacement fluid rate. This is sort of an expensive bicarb drip, but it is easy to do in the middle of the night. Try 30, 35 up to 50 mL/hg for a very acidotic patient.
- Start a bicarb drip
- Troubleshooting a dialysis catheter
- Reposition the patient and/or the lines (nurses usually do this before calling you)
- Try flushing the line (nurses usually do this before calling you)
- Try reversing the lines
- Try retracting the catheter 1cm (retract is ok, advance is not sterile)
- Change the catheter over the wire
- Place a different line in another location
- How is Calcium measured?
Different units are used at different hospitals- mmol/L – Normal range for ionized Ca is 1.1-1.35
- mg/dL – Normal range for ionized Ca is 4.4-5.4
Convert from mg/dL mmol/L DIVIDE by 4 (or multiply 0.2495)
Convert from mmol/L mg/dL MULTIPLY by 4 (or divide by 0.2496)Total vs ionized Calcium
- Total includes Calcium bound to Albumin. Normal Range: 8.9-10.1 mg/dL
- Ionized Calcium is just free calcium. Normal Range: 4.4-5.4 mg/dL (1.1-1.35 mmol/L)
A very approximate rule (when it’s 3am and you wonder what “0.9” means…)
mmol/L --> mg/dL Multiply by 4
Ionized --> total Multiply by 2
So, multiply by 8 to convert ionized mmol/L to total mg/dL
Example: ionized Ca of 1.1 mmol/L = 1.1 x 4 x 2 is approximately 8.8 mg/dL total Ca (lower limit of normal)
Early vs Late Initiation of Dialysis
So, should you start dialysis when a patient has life-threatening electrolyte or volume disturbances, or before it gets to that point. Dialysis has some risks (infection, line placement, anti-coagulation, volume and electrolyte shifts), so this has to be managed against the potential benefits. This has been a long debate in the dialysis community. There have been many trials and meta analyses, a few are discussed below.
- Karvellas et al, A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Crit Care. 2011;15(1):R72. doi: 10.1186/cc10061
Early dialysis had a survival advantage, but this was a meta analysis and different studies used different criteria for "early" vs "late" initiation.
The paper is a meta study, and it says of the studies it included, "The overall methodological quality was low". Nonetheless,
it showed that early dialysis improved 28-day mortality but did not affect "overall summary estimate for mortality".
Early also had better renal recovery decreased ICU stay.
- AKIKI Trial (NOT STATISTICALLY POSITIVE) - Gaudry et al, "Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit", N Engl J Med 2016; 375:122-133July 14
620 patients, and all had to be KDIGO Stage 3 AKI, and either on a vent or pressors, so these are all sick patients. Early dialysis was started within 6 hours of meeting KDIGO 3 AKI, and late was waiting until life-threatening electrolyte or volume disturbances. This showed no statistically significant difference in mortality at 60 days, so it was a negative study. However, Early patients had 48.5% overall mortality, late initiation patients had 61.8% overall mortality, and patients randomized to the late initiation who recovered or died before starting dialysis had 37% mortality. - ELAIN Trial (POSITIVE) - Zarbock et al, Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016 May 24-31;315(20):2190-9. doi: 10.1001/jama.2016.5828.
250 patients, and all had to be KDIGO Stage 2 AKI, and either sepsis, pressors, or severe volume overload, so these are less sick patients. Early dialysis was started within 8 hours of reaching KDIGO 2, and late dialysis was started within 12 hours of reaching KDIGO 3. This showed a 15% reduction in mortality at 90 days, so this was a POSITIVE trial. - STARRT-AKI Trial - Wald et al, Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury, Kidney Int. 2015 Oct;88(4):897-904. doi: 10.1038/ki.2015.184
This is still underway. All patients have AKI with KDIGO Stage 2. Early is within 12 hours of randomization, while late is K over 6.0, bicarb below 10 or ARDS (PaO2/FiO2 below 200). - IDEAL-ICU Trial
This is still underway. All patients have AKI with KDIGO Stage 3. Early is within 12 hours of randomization, while late is K over 6.5, pH below 7.15 or bicarb below 18, pulmonary edema. A bicarb of 17 is not too uncommon in an ICU, so this is still fairly aggressive.
There are several possibly ways to reconcile the AKIKI and ELAIN trials:
- AKIKI had mostly medical ICU patients, while ELAIN had mostly surgical ICU patients. Why would this matter? Surgical patients may be mostly post-operative ischemia and volume overload, while medical may be more sepsis and possibly intrinsic renal. I think volume overload is a big issue, and perhaps rapid correction is really important, while solume and electrolyte clearance is less useful in a sepsis patient, but this is only my personal guess.
- The LATE arm in ELAIN was the EARLY arm in AKIKI. So, maybe if you wait the extra 6 hours before "early" start then you have lost any benefit.
- AKIKI was half IDH and half CRRT while ELAIN was all CRRT, but other studies have shown no difference between modality.
One argument is that people randomized to the early group may have recovered without dialysis at all.
I'm not sure I understand this - in a random trial some patients in the therapy arm may have done well
even without the therapy. Now, these studies only compare early vs late dialysis, but don't include patients
who never got dialysis at all. But if somebody didn't need dialysis (because they would have gotten better on their own)
then it should not matter whether they are in the early or late group (either group would give no benefit and still have the same risks of dialysis).
Peritoneal Dialysis - Rapid Transporters, Peritonitis and PD Troubleshooting
Rapid Transporters
PD clearance uses both diffusion and convection.- Diffusion is molecules moving across a membrane, down a concentration gradient
- Convection is water and electrolytes moving down an osmolar gradient. The water carries some molecules along with it, called "solute drag", so you are removing both water and solute, nut just pure water.
Some patients are "rapid transporters" while othere are not - it all depends on their peritoneal microvasculature. A rapid transporter has "leaky" capillaries in their peritoneal membrane, so they allow solute to diffuse more freely. This is great for moving solute out of the blood, but you quickly lose the osmolar gradient so it is bad for ultrafiltration. In general, rapid transporters have:
- Rapid loss of concentration gradient
- More clearance by diffusion
- Less Ultrafiltration
- Less clearance by convection
Over time, the peritoneal capillaries in most patients will become more permeable, so most patients become rapid transporters over time. This is why you repeat a PET test regularly.
Sodium Sieving and Icodextran
PD will remove water through aquaporing in the peritoneal capillaries, and water and solute through small channels in the peritoneal capillaries. A Sodium gradient will cause the aquaporins to open, and this happens rapidly, after dwelling. The small channels in the peritoneal capillaries take longer to open, so the first part of any dwell inly removes free water, not water and solute. This is called sodium sieving, because it will remove only free water and leave sodium behind. Eventually, the small channels in the peritoneal capillaries open and you will remove sodium as well. Icodextran does not open the Aquaporins, so there is no sodium sieving.Adequacy
Target a weekly Kt/V of 1.7. This should include any residual renal function. (Dialysate Cr / Serum Cr) * (Daily dwell volume + UF) * 7Peritonitis
- Diagnosis
On admission, draw a sample fromt he peritoneal dialysate (may need a dialysis nurse for this). Send the sample for culture, gram stain, cell count and cytology.
Peritonitis can be diagnosed with peritonitis if there are over 100 WBC per unit volume in peritoneal fluid and over 50% neutrophils
- Empiric Antibiotics
- Vancomycin 30 mL/kg in first bag of PD dialysate every 5 days. Treat for 3 doses if there is Gram positive.
- Cefepime 1g intraperitoneal daily, usually first bag of the day. Treat for 2 weeks if there is Gram negative.
Initially (before cultures return) give both antibiotics. The two antibiotics must be in separate bags - they don't mix, so try for the first and second bag each day. Each bag of antibiotics should dwell of 5 hours.
If the patient has a Vanc allergy, then you may have to give IV Linezolid or Gentamycin. However, be careful with Gent as the patient may have residual renal function.
You generally do not have to change the PD catheter if the patient responds to initial antibiotics. However, if there are still sick after 2 to 3 days, then remove the catheter. You may have to switch to Hemodialysis for a PD vacation before putting in a new catheter. However, you must remove the catheter if this is a fungal peritonitis or a bacterial infection that does not respond to antibiotics.
- Outpatient Management
Generally, this can be treated as an outpatient unless the patient sounds really sick. If they are sick, then go to the ER immediately for hospital admission. Otherwise, they can try the following:- Do not do any more exchanges until patient goes to home dialysis unit. So, limit potassium and fluid intake.
- Bring in a bag of drained fluid to home dialysis clinic so they can send off cultures.
- Home PD clinic will then provide the patient with some PD bags that contain antibiotics, along with directions for when and how to use each bag.
If this is over a weekend, then the patient can take PO Cipro (750 mg PO once daily) until the next Monday when they can go to the home dialysis unit.
PD Dialysis Troubleshooting
- Leaky Bag. If there is a leak, then you must assume the patient has contaminated fluid.
- Do not do any more exchanges until patient goes to home dialysis unit. So, limit potassium and fluid intake.
- Take PO Ciprofloxacin 750 mg PO daily
- Bring in a bag of drained fluid to home dialysis clinic so they can send off cultures.
- Slow to drain
- Reposition patient
- Bowel regimen - Lactulose 30g PRN, Miralax scheduled
- CAPD Heparin for Fibrin clots, 500-1000 u/L in peritoneal dialysate
- Interventional Radiology to reposition the catheter
Dialysis Filter Clearance and KT/v
Predicted Kt/V
K * t / V where:
- T is duration in minutes
- V is Distribution Volume of Urea in mL. This is close to Total Body Water in mL, which is approximated by 0.6 * Wt in kg * 1000
- >K is Urea Clearance in mL/min:
Filter | BFR 200 | BFR 300 | BFR 400 | BFR 500 |
Fresenius Optiflux-160NR | 194 | 266 | 308 | |
Fresenius Optiflux-180NR | 196 | 274 | 323 | |
Fresenius Optiflux-200NR | 197 | 277 | 330 | |
Baxter Exceltra-170 | 196 | 260 | 310 | 341 |
Baxter Exceltra-190 | 197 | 273 | 323 | 354 |
Baxter Exceltra-210 | 199 | 287 | 350 | 384 |
Baxter Revaclear | 196 | 271 | 321 | 353 |
Baxter Revaclear-MAX | 198 | 282 | 339 | 376 |
Other CKD - NSAID, PKD, AIN
NSAIDs
NSAIDs will injury the kidney with several mechanisms:
- Inhibit the Arachodonic acid pathway so block Prostaglandin synthesis. This has multiple effects:
- Inhibit Sodium excretion
- Inhibit vasodilator synthesis. This allows a net constriction of the afferent arteriole, so reduce renal blood flow.
- Inhibit prostaglandin synthesis in Macula Densa, so cause a low Renin and low Aldo state. This leads to Na-wasting, K-retention, low BP. The low Aldo will have systemic effects, but low Renin also causes low AngII so efferent dilation and reduced GFR.
- Inhibit vasodilators, so create a systemic hypertension. This does not go through the RAAS pathway, so no loss of H+, Na+ or extra gain in K+
- Prostaglandin also regulates ADH, so reduced prostaglandins rarely causes an SIADH
- Cause podocyte effacement, which can cause a nephrotic proteinuria, similar in presentation to Minimal Change, but it is a different pathology.
- Cause an AIN. Perhaps the NSAIDs inhibit inhibitory prostaglandins? I do not know. In any case, this will cause a sterile pyuria with only Neutrophils.
Polycystic Kidney Disease
Genetics
- Dominant PKD - ADPKD1 and ADPKD2 genes. These both express Polycystin (1 and 2 respectively) and the two polycystin proteins combine to make a single structure. So, if either gene is defective, you have a defective protein structure and the same phenotype, but ADPKD1 seems to have a worse prognosis with faster progression to ESRD (50 year olds vs 70 yr olds in ADPKD2).
- Recessive PKD - ARPKD gene, which expresses Polyductin. This causes many diffuse tiny cysts, presents in early infancy.
Diagnosis
It seems that the genes are hard to clone (not sure why) but the genetic tests have lower (80 to 90 percent?) sensitivity. As a result,
we usually diagnose with imaging. Ultrasound is preferred - MRI will find smaller cysts but the criteria is based on US findings.
Criteria if positive Family History:
- Ages 15-39yo - 3 or more cysts total (in both kidneys)
- Ages 40-59yo - 2 cysts in each kidney, 4 or more cysts total
- Ages 60+yo - 4 cysts in each kidney, 8 or more cysts total
Criteria if no Family History:
- 5 or more cysts total (in both kidneys)
Complications:
- Liver Cysts (most common, 80 percent)
- Cerebral aneurysm (5-10 percent of PKD, but 25 percent of PKD patients with family history of aneurysm)
- Mitral Prolapse (15 percent of PKD)
- Renal Stones (20 percent of PKD)
- Diverticulosis
Prognosis: Poor prognosis signs include proteinuria and hypertension, but these all seem to be markers for renal volume. So, all prognosis is based on total renal volume or renal volume scaled by height.
Renal Volume in mL (both kidneys) | Significance |
650 | Increased risk of CKD Stage III |
1000 | Hypertension |
1500 | Reduced GFR |
Treatment
- Tight BP control with at least an ACE/ARB
- Maybe vaptans (approved in Europe and Japan, but not yet in the US)
Rhabdo
Treat:
- IV fluids, prefer D5 + 150mEq bicarb. Target urine output of 200 mL/hr
- If overloaded, then diuretics
- Mannitol, up to 200 g/day for 4 days
- Manage hyperkalemia
Acute Interstitial Nephritis
This will be a part of several other diseases, including systemic diseases like lupus, transplant rejection, glomerulonephritides. It can alco be drug-induced, reactive, and idiopathic. Often presents with AKI, rash, feverCommon causes are NSAIDs and antibiotics, and there often is nephrotic proteinuria.
Glomeruli and vessels are usually not involved. Instead, there is edema and cells in the interstitium and it may be a mix of Eos as well as macrophages and monocytes and lymphocytes. Look for increased space between the tubules with cells. The inflammation may extend into the tubule walls (tubulitis). The proximal tubules often lose brush border by staining, and there may be complement deposits in the tubule basement membranes.
Eosinophillia is not very useful
- 1 percent eos is 30 percent sensitive and 68 percent specific
- 5 percent eos is less sensitive and slightly more specific
Some other causes of AIN and CIN
- IgG4. IgG4 is a systemic disease, affects many organs (autoimmune pancreatitis, cholangitis and cholecystitis, salivary glands, skin lesions, pericarditis, and prostatitis) but also affects the kidney. When there is renal involvement, it is an AIN with plasma cell infiltrate in the interstitium, but this is a chronic immune disease, not a specific drug reaction.
- Aristocholic Acid. This was Balkan Nephropathy. Symptoms are AIN, Fanconi Syndrome, and proteinuria.
- Analgesic Nephropathy. Causes papillary necrosis and chronic interstitial nephritis
- Sarcoidosis
- Obstructive Uropathy
- Chronic Pyelo
- Sjogren - 25 percent of Sjogren will have some chrinic interstitial nephritis, and many will have an RTA I.
- Lithium
Chronic Interstitial Nephritis
Pathology
Gross findings: dilated calyces, paranchymal thinningLight Microscopy: Tubular atrophy and interstitial fibrosis. Thin dilated tubules, and also maybe some ruptured tubules. Many inflammatory cells throughout the interstitium - monocytes, plasma cells, lymphocytes - all responding to ruptured tubule contents. There also may be neutrophils if there is active infection. Arteries may have intima fibrosis, and muscular hypertrophy. Glomeruli may be hypertrophied. There is a sharp border between regions with scarring and normal regions. Look for a "two-face" appearance on light microscopy.
Tubulointerstitial Nephritis with Uveitis (TINU)
TINU is a tubulointerstitial nephritis with uveitis. Presents with eye pain and redness, and an AIN with Eos and often with granulomas. modified CRP is found in uvea and renal tubular cells, and may be the common antigen.Plasmapharesis
- Remove 1 to 1.5 plasma volumes
- Blood volume is approx 70 mL/kg, and plasma volume is (1 - HCT) x BloodVolume
- For TTP - Replace plasma with FFP
- For GBS (or anything else) - Replace with Abumin
AV Fistula Physical Exam
- Pulsatility - present or not. Pulsatile implies stenosis
- Thrill - present or not
- Augmentation - Does fistula soften with arm raised and engorge with arm lowered
- Murmur - continuous vs discontinuous. Discontinuous implies stenosis, lower flow during diastole
Pre-Eclampsia
Placenta releases sFLT and sEng to counter PIGF, but then there is an upsurge of unopposed sFLT1 which can injure the kidney. The Podocytes expose VEGF, which maintained the Glomerular endothelium. sFLT1 blocks this so causes a direct endothelial injury in the glomerulus. The proteinuria in pre-eclampsia is directly caused by the initial injury - it is not a late side effect of hypertension but rather due to direct endothelial injury.Symptoms
- Hypertension, usually starting *after* 16 weeks gestation
- Heavy proteinuria (often Nephrotic)
- Hematuria
Features INconsistent with pre-eclampsia
- A sFLT1 / PIGF ratio below 38
- Hypertension before 16 weeks gestation
Risk factors
- Single kidney (includes transplant donor)
- Any past AKI, even with seemingly complete recovery
- Lupus
- Diabetic nephropathy
Treat: There is no BP target for pregnancy.
- Safe Medications: Methyldopa, Labetalol
- Maybe safe meds: Nifedipine, Nicardipine, Hydralazine
- Avoid diuretics - patient is usually volume depleted
Pregnancy and Kidneys
Normal changes during pregnancy: increased GFR but also increased proteinuria. A mild increase in proteinuria is just due to the higher GFR, and is not something you need to treat. You also normally expect to see some mild hydronephrosis which also does not need to be treated. Pregnancy is also normally associated with increased blood volume, lower BP, higher HR.
Placenta releases vasopressinase, which degrades ADH. The result can be a transient Diabetes Insipidis.
Mortality and Kidney Disease
In CKD patients, leading cause of death is heart failure and cardiac events. Among other things, they often have metabolic bone disease and hyper phosphatemia, but the EVOLVE trial did not show better mortality from Cinacalcet.
In dialysis patients, leading cause of death is "Sudden Cardiac Death", more than MI or heart failure. This may be due to sudden shifts in electrolytes and volume. Daily short hemodialysis has better mortality.
Troponins are 18-40 percent higher in CKD patients, 7 to 20 percent higher in ESRD patients.
Statins seems to help in CKD, not in ESRD (maybe ESRD patients don't live long enough to see the benefit?)
- 4D Trial - no benefit in statins for ESRD patient. Fewer Cardiac events on statins but oddly more strokes. Wanner et al, "Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis", N Engl J Med. 2005;353(3):238
- AURORA Trial - Statins had no reduction in MI for ESRD patients. Fellström et al, "Rosuvastatin and cardiovascular events in patients undergoing hemodialysis" N Engl J Med. 2009;360(14):1395
- SHARP Trial - Simvastatin plus ezetimibe reduced "atherosclerotic cardiovascular events" in patients with CKD not on dialysis, underpowered for ESRD patients.
In patients over 65yo, dialysis carries a 25 percent annual mortality with a 20 percent 5-year survival.
This is roughly the same as brain or lung cancer (https://seer.cancer.gov/csr/1975_2014/results_merged/topic_survival.pdf).
Glomerulonephritis Thoughts
General Comments
Many of these entities (FSGS, RPGN, MPGN, and more) are "patterns of injury", not diseases. They are a histologic pattern seen on a renal biopsy sample and come from a Pathologist description of the tissue, not the disease. They are not a disease any more than "fever" or "tenderness to palpation" is a disease; each may correspond to many different causal diseases. Other entities, like Lupus, are in fact diseases, and others (IgA) are a specific part of the disease process but may have several different causes.
Complements
- Low C3 and Low C4 - Lupus, MPGN (especially due to Hep C), Endocarditis, Post-Infectious
- Low C3 and Normal C4 - Post-Strep Glomerulonephritis, Dense Deposit Disease, C3 Glomerulonephritis
- Normal C3 and Normal C4 - IgA Nephropathy, ANCA vasculitis (GPA, MPA, EGPA), anti-GBM, HIVAN, HIVICK
Injury Types Seen on Pathology
- Hyper-Cellularity - This is an increase in cells that are already there - podocytes, endothelial, mesangial, epitheilal. It may also be leukocytes in the capillaries or the mesangium. Increases cells in the mesangium is "proliferative" and in the urinary space is "crescentic".
- Increased mesangial protein - often nodular deposits
- Sclerosis - Increased matrix, a fibrosis with oblitertaion of capillaries. Global is the whole glomerulus. Segmental is part of the glomerulus, sometimes obliterating some but not all capillaries.
- Crescents - cells and extracellular material in the urinary space. This is caused by capillary wall breakdown. It is accompanied by podocyte proliferation and monocyte infiltration.
- Double Contours - Mesangial cells and monocytes move into the capillary wall, often in response to endothelial cell damage. They move between the endothelial cell and the basement membrane, and so the endothelial cell lays down another basement membrane.
- Interstitial Tubules separate with both edema and fibrosis. Fibrosis has atrophied tubules and thick basement membranes. There may be also deposits of fibrin or immune complexes
- Endocapillary proliferation - increased number of endothelial cells and endothelial cells appear swollen.
- Subenodthelial deposits - have smooth outer margin, because this is molded by the BM.
Lupus Nephritis
Subtypes
Up to 90% of SLE patients will have some renal deposits, but only 40% may have actual renal disease signs or symptoms. It is useful to classify the renal injury by biopsy, as the biopsy histology will guide treatment.WHO Classes
- Class I - Normal glomeruli by light microscopy, IF and EM will show Ig deposits in the mensangium only.
- Class II - Light microscopy will show mesangial hypercellularity, and also IF and EM will show Ig deposits in the mesangium. There can be podocyte foot process effacement. But, class I and II are pure mesangial injury, no interstitial or tubular injury.
- Class III - Focal proliferative glomerulonephritis (Less than 50 percent).
- Light Microscopy: Endocapillary hypercellularity, mesangial hypercellularity, may have crescents. Segmental capillary proliferation. Some (not all) capillary loops are closed (due to cellularity?) Light microscopy may show thickened BM, with subEndothelial deposits on EM. There can also can be fibrinoid necrosis, which is bright pink amorphous eosinophilic deposits where cells died. The change from Class II to Class III is really a change from mesangial involvement to endocapillary involvement - in class III it starts to looks like more of an active vasculitis and not just systemic immune complexs collecting in the kidney. You change from II to III when there are endocapillary hypercellularity or crescents. The Focal lesions of Class III may be either segmental (part of the glomerulus) or global (the entire glomerulus).
- Immunofluorescence: Full house - IgG, IgM, IgA, C1q, C3 deposits in subendothelium, but also in the mesangium. They are subenodthelial. Be caureful, the deposits seen on IF may be in every glom, but this is Class III if Light microscopy only shows less than 50% of glomeruli are involved. There may also be some scattered subepithelial deposits.
- Electron Microscopy: Tubuloreticular inclusions are deposits in the cytoplasm of epithelial cells, seen in Lupus but also in viral infections like HIV or in patients getting Inerferon.
- Class IV - Diffuse proliferative glomerulonephritis (More than 50%). See all the changes for Class III.
- IV-S - gloms have segmental capillary closure
- IV-G - gloms have global capillary closure
- Class V - Membranous - Thickened glomerular basement membranes, and large subepithelial deposits. This affects more than 50% of glomeruli.
This looks like Membranous glomerulonephritis, except it will stain for IgG, IgA, IgM, C1q and C3, and there are reticular deposits in epithelial cells.
Capillary loops are open, but BM thickening with spikes
"Wire loops" are just thick subendothelial deposits
Endothelial cells may have endoreticular inclusions
May also have endocapillary hypercullarularity if it is associated with class III or IV.
- Light Microscopy: Mesangial hypercellularity, may have thickening of capillary wall with spikes.
- Immunofluorescence: Deposits in capillary wall but in the mesangium. They are subepithelial, which is in contrast to Class III and IV which may have subendothelial deposits.
- Electron Microscopy: Tubuloreticular inclusions are deposits in the cytoplasm of epithelial cells, seen in Lupus but also in viral infections like HIV or in patients getting Inerferon.
- Class VI - Over 90% sclerotic tubules, no active inflammation
Classes III, IV and V are each further subdivided into "active" and "chronic"
- A - Active. Proliferative lesions. Treat this. Look for hypercellularity, cellular crescents, interstitial inflammatory cells
- C - Chronic. Fibrosis and scarring. Do not treat this. Look for fibrous crescents, interstitial fibrosis, tubular atrophy, glomerulosclerosis.
- A/C - Active and Chronic. Treat this.
Pathology
See above the the Glomerular lesions, including the lupus classes.Vascular Lesions:
Lupus usually does not have vasculitis, it's more about immune deposits than inflammation against the endothelial cells.
There may be immune deposits seen in arterioles along the basement membrane, but this is not specific or significant. It should stain for C3 and C1q, but maybe not the Ig.
There also may be necrosis but without specific inflammation, so no inflammatory cells, just eosinophilic hyalinization of the arteriole wall. There may also be thrombi
in the arteriole lumens, due to thrombotic Microangiopathy.
Tubules
There may be subepithelial immune deposits, but this is usually caused by interstitial inflammation spilling over, not
any specific process in the tubule. There may be tubular atrophy and interstitial fibrosis.
Markers
- anti-dsDNA - Disease activity
- anti-ssDNA - non-specific, not useful.
- anti-Ro-SSA - Associated with cutaneous
- anti-La-SSB - Associated with neonatal
- anti-Smith - Very specific to Lupus. Most diagnostic
- anti-URNP - Mixed Connective Tissue Disorder
- anti-Histone - Drug induced lupus, also systemic sclerosis
- Anti-phospholipid - hypercoagulable
Treatment
Class I - You usually do not have to treat the renal condition, though Rheum may treat the other systemic manifestations.
Class II - If there is less than 1 gram/day proteinuria, then usually do not have to treat the renal condition, though Rheum may treat the other systemic manifestations. If, however, there is over 3 grams/day proteinuria, then treat as you would treat MCD or FSGS, which is initially steroids only.
Class III and Class IV (with or without a superimposed Class V). Remember only treat active disease or active/chronic, but never chronic. There have been several older protocols. The old NIH protocol was high dose Cyclophosphamide, but then the Eurolupus trial showed that low dose Cyclophosphamide was just as effective. Finally, the ALMS trial showed a non-Cyclophosphamide protocol with Mycophenolate Mofetil only that was as effective as Cyclophosphamide. Mycophenolate Mofetil has fewer side effects and not the righs of hemorrhagic cyctitis or bladder cancer.
ALMS Trial protocol. See Gerald B. Appel, et al, "Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis" J Am Soc Nephrol. 2009 May; 20(5): 1103–1112. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678035/
- Mycophenolate mofetil - 0.5g PO BID daily for week 1, 1.0g PO BID daily for week 2, 1.5g PO BID daily after for 22 more weeks. May reduce dose to 2g per day (1.0g BID) if there are adverse events. Treat for 24 weeks. Followup at 2 weeks, 4 weeks and then every 4 weeks.
- Steroids, start at 60mg daily then taper over 6-12 months
NIH Cyclophosphamide protocol. In the US we mainly use IV, The Eurolupus trial showed that low dose is equally effective, but was only tested in white patients.
- Cyclophosphamide 0.5 - 1.0 g/m^2 monthly for 6 months
- Steroids, start at 60mg daily then taper over 6-12 months
After initial therapy is complete, start maintenance therapy. There are several possible regimens.
- Mycophenolate Mofetil 1-2 grams/day divided into 2 doses, plus low dose steroids (less than 10mg/day). The ALMS trial extension phase showed Mycophenolate Mofetil is superior to Azathioprine
- Azathioprine 1.5-2.5 mg/kg/day
Only about 60% of patients have any renal response to any treatment at 6-12 months. Some studies show complete remission is only 8% to 30% at 6-12 months. The response to treatment is defined differently for Lupus nephritis than for other GN's.
- Complete response - Serum Cr returns to normal and proteinuria goes below 500 mg/g.
- Partial Response - Cr plateaus, and 50% decrease in urine prot/Cr ratio.
LUNAR trial showed that Rituximab and MMF does not have better clinical outcomes than MMF alone. It did have more responders and lower anti-dsDNA and C3/C4 levels, but did not change overall outcomes. "Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.", Rovin BH1, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G; LUNAR Investigator Group. Arthritis Rheum. 2012 Apr;64(4):1215-26 https://www.ncbi.nlm.nih.gov/pubmed/22231479
Lupus is a replapsing disease, and 40% of responders and 60% of partial responders will relapse within 41 months. A relapse may also progress from class III to IV. Yoy may need a repeat biopsy. In any case, if Cr or proteinuria worsen, then with an alternate treatment. For example, if you started with ALMS then consider trying low dose Cyclophosphamide.
So, what about Rituximab? One trial showed no difference between Rituximab and placebo at 12 months, but Rituximab is recommended as a salvage therapy for a patient that has failed all other therapies.
Class V If there is superimposed Class III or IV, then treat that, as discussed above. If it is purely class V, and less than 1 g/day proteinuria, then KDIGO recommends ACE/ARB and antihypertensives. But, if there is over 1 g/day and especially if there is nephrotic proteinuria, then they say you can treat with steroids and immunosuppression. They do not specify specific regimens (there are not enough good RCT's), so you can use ALMS as you would for class III or IV. There is one small trial that shows Cyclophosphamide or Cyclosporine has greater response than steroids alone, but it does not seem to compare overall mortality.
All patients with lupus should be on Hydroxychloroquine, in addition to any other treatment for their nephritis. Dose is 6 - 6.5 mg/kg of ideal body weight. Hydroxychloroquine seems to slow renal damage in addition to its systemic effects.
Minimal Change Disease
Minimal Change Disease and Focal Segmental Glomerulosclerosis are 2 points on the same spectrum of disease. FSGS will affect more and more glomeruli, starting with just a few and then progressing. This is why getting 10 and ideally 20 gloms per core sample is important.Podocyte Foot processes effacement in MCD can be a temporary cell response to injury or stress that can be reversed in some cases. In other diseases, like Focal Segmental Glomerulosclerosis, foot process effacement is permanent. Minimal Change Disease and Focal Segmental Glomerulosclerosis may be two points on the same spectrum of disease. FSGS will affect more and more glomeruli, starting with just a few and then progressing.
Subtypes
- Primary. Usually affects Kids (usually under 10yo) and adults (usually geriatric).
- Secondary. Usually due to malignancy (Hodgkins, any lymphoma or PTLD) or drug reaction or AIN - NSAIDs, Lithium, Hodgkin's Lymphoma, HIV (the virus directly infects Podocytes)
- Undetected FSGS (may be missed on a biopsy)
Pathology
Light Microscopy: MCD has no changes by light microscopy, until it develops increased matrix with obliteration of capillaries. So, no change until protein deposition destroys the capillary.
Immunofluorescence: There are no immune complexes, and serum complements are normal.
Electron Microscopy: Foot process effacement. There is usually less than 50% podocyte involvement in secondary FSGS, while more in primary FSGS. In HIVAN, there are also deposits ("reticular aggregates") in the endothelial cells.
Treatment
May spontaneously remit, but this can take years. Start with steroids (Prednisone 1mg/kg up to 80mg daily) for 4 to 16 weeks until remission. Then taper slowly over 6 months. If there is a relapse, then go up on steroids and restart the taper.If steroid resistant or frequently relapsing, then consider any of the following (in descending order)
- Cyclophosphamide 2-2.5 mg/kg/day for 8 weeks
- Cyclosporine 3-5 mg/kg/day. There is benefit to adding low dose steroids to Cyclosporine
- Tacrolimus 0.05-0.1 mg/kg/day
- Mycophenolate 500-1000mg BID
Urine levels of CD80 are increased in MCD but not FSGS, and this is a protein on cell membranes that binds to activated T-Cells.
FSGS - Focal Segmental Glomerular Sclerosis
In FSGS and Membranous there is podocyte detachment and podocyte apoptosis. So, the slit diaphragm is broken, causing large non-selective protein leak. The fenestrated endothelium and basement membrane are both still intact, so there are no RBCs in urine.FSGS is a scarring process in the glomerulus. It is analogous to cirrhosis, which is hepatic scarring. Like cirrhosis, which can be caused by different things (NASH, viral hepatitis, EtOH, etc), the scarring of FSGS can also be caused by very different things. Really, the scar is focal, but all Podocytes may be affected. For example, Primary FSGS has over 90% foot process effacement, but still a segmental scar.
There are two types of FSGS, and they are actually quite different.
- Primary FSGS
This is a podocyte process and is possibly an advanced form of Minimal Change Disease. Note, however, that only some MCD will progress to FSGS and only some FSGS (primary) is related to MCD. Like Chronic Hepatitis, some MCD will smolder and stay indolent, while others will progress to a fibrotic scarring state. The host tissue (the glomerulus in this case) may be more or less prone to scarring. - Secondary FSGS
This is less of a podoctye process, and is more glomerular remodelling in response to some other injury. Secondary FSGS may be a result of any other glomerular disease, particularly nephrotic processes such as membranous, membranoproliferative, but also hypertensive nephropathy. The foot processes are urually *preserved*, it's an adaptation of the glom to some other disease process or drug.- Reflux nephropathy, Pre-eclampsia, TTP or any TMA
- Familial (mutations in NPHS1 (nephrin) or NPHS2 (podocin), APOL1, TRPC6, alpha Actinin 4, Inverted Formin 2, or other genes)
- Viral - mainly HIV and Parvovirus
- Medications - Heroin, Pamidronate, Lithium, IFN, anabolic steroids, NSAIDs
- Adaption to reduced kidney mass - Unilateral Renal Agenesis, reflux nephropathy, any advanced CKD with loss of nephrons
- Obesity
- Diabetes
- Hypertension
- Cyanotic Heart Disease
- Sickle Cell
- C1q nephropathy is grouped with MCD and FSGS because there is widespread foot process effacement. However, there are also mesangial deposits of C1q, which is sort of similar to the C3 Glomerulonephropathy associated with MPGN. C1q also seems to be a dysregulation of the complement system, and there is no signs of Lupus involvement.
FSGS is caused by circulating factors in blood and will recur in a transplanted kidney. In one case report, a transplanted pt with FSGS recurred, then the kidney put into a non-fsgs pt and no recurrence. FSGS seems to be temporarily slowed with plasmaphoresis, but will recur when PLEX is stopped. This suggests the primary mechanism is antibody, or at least cytokine, driven.
Additionally, many diseases may end with Segmental Scarring, which is the same injury pattern as FSGS but is a different causal disease. For example, the "S" in IgA MEST-C scoring is segmental scarring, which is/looks-like FSGS. This may be the scar left from some other disease, such as a crescentic IgA Nephropathy of an RPGN like ANCA. So, this is really a scar and may have more collagen.
In all case, the podocytes are effaced, retract foot processes which increases permeability to Albumin. Then, Parietal epithelial cells attach to the denuded basement membrane, which collapses the urinary space and causes the segmental sclerosis.
Pathology
Light Microscopy:
In general you see
- Loss of Bowman space
- Increase pink Hyalinization in the mesangium
- Collapse of capillaries
There are several subtypes identified in light microscopy.
- Collapsing Glomerulopathy.
Closed capillary lumens, but the capillary is not blocked by deposits. The capillaries are collapsing, not the glom. Look for glom capillaries with no lumen.
The tree of capillaries shrivels, not individual capillaries collapsing. So, much of the Glom space is epithelial cells, and the central stalk of
capillaries is shriveled and more confined to one area. But, there may not be a pronounced crescentic fibrosis.
Poor prognosis and often due to HIV, Pamidronate, Parvovirus, CMV, others.
The podocytes die, which cause the capillary to collapse. Podocyte death is often due to HIVAN (HIV infects the podocyte) but many other causes.
- Tip Lesion - next to the takeoff of the PCT. Tip lesions are adhesion of foam cells in the capillary to the PCT pole of the glomerulus. Good prognosis
- Perihilar - next to capillaries, Usually secondary FSGS, often obesity
Immunofluorescence may show deposits of IgG, IgM, and C3, so this is almost full-house Lupus staining, but C1q is the dominant deposit.
NSAID toxicity may present as a variant - with podocyte foot process effacement, but also signs of AIN, with edema, lymphocytes and eos in the interstitium.
Obesity FSGS has foot process effacement, glomerular hypertrophy, thick GBM, and some mesangial "expansion" (? with cells? Protein? What?)
Treatment
Treat only primary FSGS; for secondary FSGS treat the underlying cause. Also only treat Primary FSGS with nephrotic proteinuria; KDIGO seems to say you don't treat non-nephrotic FSGS with steroids or immunosuppression. The treatment is similar to the treatment for Minimal Change, except no recommendations for Cyclophosphamide. Excpect a relapse rate up to 40 percent.Start with steroids (Prednisone 1mg/kg up to 80mg daily) for 4 to 16 weeks until remission. Then taper slowly over 6 months. If there is a relapse, then go to other immunosuppression (KDIGO recommendation 6.3.1).
If relapsed or intolerant to steroids, then consider any of the following (in descending order)
- Cyclosporine 3-5 mg/kg/day for 4 to 6 months, or up to 12 months.
- Mycophenolate 500-1000mg BID with high dose Dexamethasone
In HIV, HAART will help renal function and improve eGFR in addition to controlling the HIV.
The apolipoprotein A1 gene is linked with FSGS in African Americans.
Membranous Nephropathy
This is nephrotic and is also associated with hypercoagulable state due to loss of clotting factors. Watch for Renal Vein Thrombosis (get US with dopplers).Subtypes
- Primary
This is associated with more diffuse foot process effacement and more proteinuria. There are several causes- anti-PLA2R. This has no special association with malignancy, a patient with anti-PLA2R membranous has normal risks of malignancy, so just do normal screening. Serum levels of anti-PLA2R antibody seems to correlate with disease activity, but this is not yet used in practice. If you treat this successfully, then the PLA2R levels will decline first, before proteinuria improves, so it is a good marker to follow for monitoring response to therapy. This also has a high recurrence after transplant, even if serum levels of anti-PLA2R are undetectable after treatment and before transplant.
- anti-Thrombospondin type-1 domain-containing 7A. This is usually associated with malignancy.
This is usually C1q negative, mostly IgG4. - Secondary
- Malignancy - really anything but breast, lung, renal, ovarian carcinomas and non-carcinomas including any Leukemia and all of the Hodgkins and non-Hodgkins lymphomas.
- Any autoimmume - Lupus, Crohn's, Sjogren, RA, Ankylosing Spondylitis
- Medications: NSAIDs, Captopril, Clopidogrel, Lithium
- Infections: Hepatitis B or C, HIV, Syphillis. Most Hep B GN is membranous (not MPGN).
This is usually C1q positive, mostly IgG4.
Pathology
Light Microscopy: Thickening of capillary membranes, usually affecting all glomeruli, and forming spikes that protrude into urinary space. On silver stains there are GBM spikes. Typically, no inflammatory cell infiltrate, and no crescents. Protein leaks into the tubule and gets taken up by epithelial cells, which become "foam cells" because of the droplets of protein in lysosomes.
Immunofluorescence: Uniform immune complex deposits of IgG (with Ideopathic Membranous it's IgG4) form around glomerular basement membranes. Usually no deposits in mesangium, only around BM. This is important, because it means the endothelium is intact, and there is usually no immune cell infiltrate since they are kept out by the intact basement membrane. It also means this is a nephrotic and not nephritic syndrome.
Electron Microscopy: Subepithelial electron dense deposits (so it crosses the BM from capillary, but is stopped by podocytes). Basement membrane forms spikes between the electron dense deposits. At the resolution of EM, the deposits are discrete clumps, while it looks like a continuous ribbon at the coarser resolution of Light and IF. There are 4 stages of changes:
- Stage 1: Subepithelial deposits, decrete clumps on EM
- Stage 2: Basement membrane forms spikes between the clumpy deposits
- Stage 3: Spikes of BM continue to grow and surround the clumps, forming a thickened BM
- Stage 4: Severe thickening of BM and degradation of the clumpy deposits.
Pathophysiology
In Membranous there is subepithelial deposits, podocyte detachment and podocyte apoptosis. So, the slit diaphragm is broken, causing large non-selective protein leak. The fenestrated endothelium and basement membrane are both still intact, so there are no RBCs in urine.Treatment
Treat only patients with proteinuria over 4 g/day, or life-threatening Nephrotic syndroms under 4g/d proteinuria. The key is that approximately 30-35 percent or patients with proteinuria under 4 g/day will have spontaneous remission within 6 months, so often you can delay, give ACE inhibitors and see if there is remission (20 percent complete, 15 percent partial remission). Complete remission is proteinuria below 300 mg/day (so it is microproteinuria) and partial remission is decrease to non-nephrotic proteinuria (below 3.5 g/d). The guidelines (KDIGO) grade the proteinuria as follows: low risk (normal baseline GFR and proteinuria below 4g/d, about 80% chance of worsening CKD) medium risk (normal baseline GFR and proteinuria 4-8 g/d, 60-80% chance of worsening CKD, start immunosuppression if no improvement after 6 mos) and high risk (proteinuria over 8g/d, start immunosuppression immediately). Ponticelli Regimen- Month 1 - Methylpred 1g IV x3 days then PO Prednisone 0.5 mg/kg daily x27 days
- Month 2 - oral Cyclophosphamide (2.0 mg/kg/d) x30 days
- Month 3 - Methylpred 1g IV x3 days then PO Prednisone 0.5 mg/kg daily x27 days
- Month 4 - oral Cyclophosphamide (2.0 mg/kg/d) x30 days
- Month 5 - Methylpred 1g IV x3 days then PO Prednisone 0.5 mg/kg daily x27 days
- Month 6 - oral Cyclophosphamide (2.0 mg/kg/d) x30 days
Trials have shown that steroids alone is inferior, and Mycophenolate Mofetil and some but reduced efficacy. There have been several trials with Cyclophosphamide, and many have small n and some quoted trials have p over 0.05, but the remission rate for Ponticelli seems to vary between 60 and 90 percent. It has comparable efficacy to Chlorambucil with fewer side effects. Alternates to Cyclophosphamide are Cyclosporine, Tacrolimus.
- Cyclosporine 3.5-5.0 mg/kg/day divided into 2 doses daily for 6 to 12 months months plus PO Prednisone 0.15 mg/kg daily for 6 months. 69% remission, and 45% relapse.
- Tacrolimus 0.05-0.075 mg/kg/day divided into 2 doses daily for 6 months. 90% remission, but half will relapse.
- Rituximab is NOT recommended yet due to limited evidence, but early pilot studies are promising.
Contraindications to Ponticelli include CKD with Creatinine over 3.5, urinary retention, untreated infection, active neoplasm. Risks to Ponticelli include opportunistic infection, hemorrhagic cystitis, transitional cell carcinoma or bladder or urethra, other malignancy.
After completing the 6 months, treat with ACE inhibitor and monitor. About 25 percent of patients given Cyclophosphamide will relapse within 5 years and 40-50 percent of patients given Cyclosporine or Tacrolimus will relapse within 5 years. If a relapse happens then repeat the Ponticelli regimen except substitute Cyclophosphamide with Cyclosporine or if you used Cyclosporine then substitute that with Cyclophosphamide. Do not give a total of more than 2 courses of Cyclophosphamide per lifetime (total 100 grams), as the cumulative dose increases risk of bladder cancer.
Give Bactrim SS one tab daily for PJP prophylaxis while on Ponticelli. Also give a PPI and consider a bisphosphonate while on steroids.
MPGN - Mebranoproliferative Glomerulonephritis
Subtypes
Thee old classification was just:- MPGN I - subendothelial deposits, may contain Ig or complement. Often associated with Hep B or C
- MPGN II - Intramembranous deposits of complement, but no Ig. Now called Dense Deposit Disease
Newer taxonomy divide the disease by the type of deposit
- MPGN - this contains Immunoglobulin - usually there will be IgG, IgM, IgA, C3, and C1q. This is called "Full House" and is most often associated with Lupus, BUT this pattern
of injury can be found with any injury involving the classic complement pathway, including many infectious GN's, and is not specific to Lupus.
Hep C will often cause this, as will other chronic infections and also autoimmune disorders.
There is further subdivided:
-
1
- I - Monoclonal Ig deposits - a paraproteinemia usually due to a plasma cell dyscrasia
- II - Polyclonal immune complex deposits - Lupus, Hep C
- III - Polyclonal - Ig deposits due to cheonic inflammation. Usually endocarditis or diabetic wound
- C3 Glomerulonephritis and Dense Deposit Disease - These both have deposits of C3 Complement, and may be associated with atypical HUS. This is often due to either a congenital mutation or an aquired autoantibody against Factor H or C3 convertase.
MPGN (not C3 GN or DDD) uses the classical complement pathway, and involves immune-complex depositions and is usually polyclonal Ig.
Pathology
This is caused by immune complex deposits or monoclonal proteins. This used to be called MPGN-I. The disease formerly called MPGN-II is now dense-deposit disease.Light Microscopy: Glomerular lobules stand out separately, like a Cauliflouer appearance. MPGN used to be called Lobular GN. There are also double contours of GBM and Sub-endothelial deposits. There may also be subepithelial humps, but the real injury is the smaller subendothelial deposits. Thickening of capillary walls, endocapillary proliferation, mesangial expansion. The capillaries may look closed, crowded by cells in the membrane. There also may be cryoglobulin plugs in the capillary.
Immunofluorescence: Stain positive for IgG and IgM and complement. The immune complexes may be due to a chronic disease or a specific antigen. The deposits light up all along the capillary basement membrane, so the quantity of deposit looks like Membranous on IF.
Electron Microscopy: There are endothelial deposits, so on the vascular side of the BM and thus this is more a nephritic than nephrotic disease.
This will progress to a double-countoured tram-track basement membrane, which is really caused by monocytes are attracted tyo chemotaxins, and squeeze between the
endothelial cells and the BM. The endothelial cells then law down a second basement membrane, causing the tram-track.
C3 Glomerulopathy and Dense Deposit diseases
C3 Glomerulopathy and Dense Deposit diseases are C3-only diseases, previously called MPGN-II. This is a disease of the alternate complement pawthway. Normally, C3-convertase is regulated, but these cause from an overactivation of C3 Convertase. Usually this is due to loss of Factor H or IThe deposits in the glomerulus only contain complement, no Ig, so all staining for Ig should be negative.
Labs:
Low C3 levels, with C3 deposits on biopsy. There is no full house staining, because it is not based on immune-complexes.
Pathology
Subendothelial deposits, but mostly Complement and no/little Ig. As opposed to MPGN which is Ig and compement.Light Microscopy: They also have the endocapillary proliferation and mesangial proliferation. There may be Crescents. Capillary and tubular basement membranes are thickened, and stain brown with silver stain. There usually is *not* the monocyte interposition between the endothelial cell and the BM.
Immunofluorescence: Stain positive mainly for C3 complement, though htere may be low levels of other stains.
Electron Microscopy: In DDD, the BM may thicken and darken on microscopy. In C3 Glomerulonephritis, there may be deposits in the mesangium or subepithelial space.
This is interesting, because the C3 deposits cross the BM and accumulate in the subepithelial space, similar to the immune complexes in Membranous.
Post-Infectious Glomerulonephritis
Subtypes
Stpretococcus causes 28-47% of the cases, while Staph causes 12-24% of cases, and Gram negative bacteria cause up to 22% (source: KDIGO 2012). The GN follows 1-2 weeks after a Strep tonsillitis and 4-6 weeks after impetigo.Pathology
In general complements will be low, usually both C3 and C4 but sometimes C4 can be normal.Light Microscopy: There is endocapillary proliferation (increased number of endothelial cells and endothelial cells appear swollen). Inflammatory cells in the capillaries, usually Neutrophils, and may also appear in the mesangium and bowmans space. The glomerulus may appear on light microscopy similar to MPGN. Usually, the tubules and interstitium are normal - though there may be occasional inflammatory cells.
Immunofluorescence: There are deposits of C3 and Ig along capillart walls. The Ig is usually IgG but may be IgA. There is no C1q, which distinguishes this from Lupus.
Electron Microscopy: Subepithelial cone-shaped deposits, called "humps". Podocyte foot processes directly on the humps may be effaced. Oddly, these are on subepithelial side, but this is more nephritic than nephrotic.
Treatment
Generally, just treat the underlying infection - be it HIV, HCV, HBV or bacterial. In HIV, HAART will help renal function and improve eGFR in addition to controlling the HIV. In Bacterial infection, antibiotics will not help the renal function, but of course are needed if there is active infection.IgA Nephritis
Systemic Symptoms and Signs
There are several different presentations- Episodic gross hematuria, often after exercise. Often spontaneously remits.
- Asymptomatic microscopic hematuria and proteinuria. Commonly HTN and AKI as well. Remission is uncommon.
- RPGN
- IgA Vasculitis (HSP) - palpable purpura, gut disease. Similar symptoms as ANCA and Cryo except this has a waxing/waning course. World-wide it is the most common GN, but is much less common than Diabetic nephropathy in the US. It may coexist with Diabetes, MCD, and others. Over 1 gram/day proteinuria is a bad prognostic indicator.
Pathophysiology
This is caused by a defect in the hinge region of IgA, so it lacks Galactose. This exposes normally-hidden antigens, so there can be anti-IgA IgG. These form immune complexes that deposit in skin and the kidney.The levels of Galactose-deficient IgA seems to correlate with disease progression, but this is currently only used in research.
Subtypes
- Primary
- Secondary, which may have several causes
- Cirrhosis - decreased metabolism of IgA immunoglobulins
- Celiac Disease
- HIV
- Hep B and Hep C
- Autoimmune diseases - Ankylosing spondylitis, Crohn's
- Malignancies - Small cell carcinoma, Hodgkin lymphoma, T-cell lymphomas
Pathology
Dominant staining of IgA in the glomeruli, always in the mesangium and may optionally also involve capillary loops. There may be IgG and IgM as well, but IgA is the dominant globulin, and there should be no more than trace C1q (or else consider SLE). There is no difference on pathology between IgA Vasculitis (like HSP) and pure IgA Nephropathy, except the vasculitis may have crescents more frequently.Oxford Classification - MEST
- M - Mesangial Hypercellularity (score 0 or 1). This is defined as over 4 mesangial cells/mesangial area = 04 – 5 = 16 – 7 = 2> 8 = 3
- E - Endocapillary Proliferation (score 0 or 1). This is defined as increased number of cells within glomerular capillary lumend. However, this does NOT seem to be a useful predictor of progression.
- S - Segmental Sclerosis (score 0 or 1). This is defined as tuft involved in the sclerosis. It may resemble scarring FSGS.
- T - Tubular atrophy and fibrosis (score 0, 1 or 2). This seems to be the strongest indicator of progression to ESRD. It is defined as the percent of the tissue that is atrophied or sclerosed. Give a score of 0 for less than 25 percent, a score of T1 for 26-50 percent, and T2 for over 50 percent.
- C - Crescents (score 0, 1, 2).
Light Microscopy: IgA may have ANY form - including normal, but also MPGN, Crescentic GN (up to 33% may have crescents), or even FSGS.
Immunofluorescence: Predominantly IgA deposits, though you may also see C3 and other IgG or IgM.
Electron Microscopy: Electron dense deposits in the mesangium, but they may also appear subepithelial, subendothelial and in the basement membrane. There also may be podocyte foot process effacement.
Treatment
Immunosuppression depends on the biopsy, specifically whether this is Crescentic or Non-Crescentic.Non-crescentic IgA GN Proteinuria over 1g/day has much worse prognosis than proteinuria below 1g/day. However, lower proteinuria is better, so 0.5g/day has better prognosis than 1g/day.
If there is proteinuria over 1g/day, then start a 6-month course of steroids - oral Prednisone starting at 0.5 - 1.0 mg/kg/day, and then after 2 months start to titrate down 0.2 mg/kd/day every month. There have been several trials on steroids
- Possi et al, JASN 2004, positive result, but patients wree not also on ACE/ARB
- J Lv et al, AJKD 2009, positive result, all patients were on ACE/ARB. Jicheng Lv et al, "Combination Therapy of Prednisone and ACE Inhibitor Versus ACE-Inhibitor Therapy Alone in Patients With IgA Nephropathy: A Randomized Controlled Trial", January 2009Volume 53, Issue 1, Pages 26–32, http://www.ajkd.org/article/S0272-6386(08)01230-4/abstract
- Manno et al, NDT 2009, positive result, all patients were on ACE/ARB
- STOP-IgA Trial, negative result, steroids reduced proteinuria but did not slow disease progression.
- Start with ACE-I or ARB. This has superior outcomes to other anti-hypertensives, even when the same BP is achieved. There seems to be something specific about the RAS cascade (maybe diverting more protein away from the Glomerulus) that helps beyond simple BP control.
- Target blood pressure below 130/80
- There is no recommendations for other immunosuppression. There have been some trials that showed slight benefit, but either the trials were small with high p, or else the benefit was not considered worth the adverse effects of immunosuppression. Azathioprime and Mycophenolate Mofetil have been studies.
- In all cases, you may add Fish oil - there are slight benefits and extremely low adverse effects. But, use Omacor brand, as that is the only one with any evidence. Many over the counter fish oils are too low in dose or not the right oils, so have no evidence of efficacy. There are mixed results about Omacor, (some positive and some negative trials) but it has low risk of adverse effects so it is worth trying.
Crescentic IgA GN with over 50% crescents:
6-month course of steroids and cyclophosphamide, similar to the ANCA treatment.
Complete remission is 0.16 g/day proteinuria, and below 0.5 g/day for partial remission.
RPGN - ANCA and anti-GBM
This is a group of diseases, all have small-vessel vasculitis with necrosis in arterioles, capillaries and venules. They all seem to be aggressive and will rapidly progress and lead to crescents on light microscopy. They do not cause immune complex deposition, so there is no immune staining on biopsy.There are several subtypes of RPGN:
- Pauci-Immune - ANCA vasculitis like GPA, EGPA, MPA
- Anti-GBM
Note, crescentic Glomerulonephritis can be seen with several other diseases, but that is likely more the injury pattern - a rapidly progressing crescentic injury - than the disease itself.
- Ig A - especially Henoch-Scholnein
- Any other vasculitis, such as Microscopic Polyangiitis, Takayasu vasculitis, Giant Cell Atertitis and more
- Cryoglobulinemia
- Lupus Nephritis
ANCA
ANCA stands for Anti-neutrophil cytoplasmic antibody, and the ANCA diseases are antibodies against Neutrophils, not the kidney specifically. A normal Neutrophil will follow chemotactic signals, leave the capillary, and then in the interstitium it will become activated to start inflammation. In ANCA, the Neutrophil is pre-activated in the blood by the ANCA antibodies. Neutrophils leave the capillary in the Glom but it is already in an active state so it causes immediate injury, right there at the Glomerulus. They activate complement pathway, release free oxygen radicals, and cause rapid cell damage. T-cells are not involved in the disease, so anti-T-Cell therapy is useless.Some unknown trigger causes formation of anti MPO or PR3 antibodies, which then binds to Neutrophils
There are several antibodies
- anti-PR3 - More upper resp disease. Relapse more frequently.
- anti-MPO - More renal disease.
There are several subtypes, each seems to be triggered by a different auto-antigen.
- GPA - Granulomatosis with Polyangiitis. This is often anti-PR3 but may also be anti-MPO, Granulomas but no Eosinophils) This affects kidneys and upper respiratory.
- EGPA - Eosinophillic Granulomatosis with Polyangiitis (formerly Churg Strauss, Granulomas AND Eosinophils) This affects kidneys and bronchi with asthma)
- MPA - Microscopic Polyangiitis (usually anti-MPO. No granulomas or Eosinophils). This affects lungs and kidneys. This will affect capillaries, like the glomerular capillaries.
- Drug Induced ANCA - Hydralazine, Allopurinol, Levamisol, Procainimide, Penicillimene. High titers of both PR3 and MPO Both anti-PR3 and anti-MPO (usually high levels) - Drugs, like Levamisol
Systemic Symptoms and Signs
This is a systemic inflammation, and so may be part of a systemic disease- Renal - Hematuria (microscopic with dysmorphic RBCs and RBC casts) and proteinuria.
- Upper and lower respiratory tract - nodules or cavities. Hemoptysis. About 10% of patients may have severe pulmonary hemorrhage.
- Skin - purpura
- Neuro - neuropathies
- Upper Resp - Sinusitis
- Myalgias and Arthralgias - migratory polyarthritis
- Heme - 10% of patients have Clotting
Pathology
Light Microscopy: Crescentic and necrotizing glomerulonephritis. The necrosis is often fibrinoid, so look for pink fibrin, but there may also be a cellular infiltrate. There may also sometimes be necrotizing arteritis, which will be a pink fibrinoid layer around the circumference of an arteriole.
Immunofluorescence: Pauci immune is called this because there is little (less than 2+) staining of Ig in the vessels. So, the Ig does not collect in the subendothelial or subepithelial space, instead it stays in the vessel lumen and seems to attach the endothelial cells.
Electron Microscopy:
Treatment for ANCA
Induction- Cyclophosphamide 0.75 gram/meter^2 every 3-4 weeks.
- Pulse methylprednisolone 500mg IV x3 days
- Add plasmaphoresis 60 mL/kg volume replacement if patient has diffuse alveolar hemorrhage or requires dialysis or has rapidly worsening Creatinine or there is anti-GBM.
Rituximab has equal efficacy in the short term, but there are no long term trials complete yet. We may eventually switch to Rituximab as first line but the evidence is still in the works. Note, that Rituximab is anti-CD20, so it only works against B-cells, not plasma cells. Clearing B cells alone does not seem to help improve.
- RAVE trial showed Rituximab was non-inferior to Cyclophosphamide for GPA and MPA. All patients also got steroids and no difference in adverse effects. Stone et al, "Rituximab versus cyclophosphamide for ANCA-associated vasculitis", N Engl J Med. 2010;363(3):221. https://www.ncbi.nlm.nih.gov/pubmed?term=20647199
- RITUXVAS trial showed Rituximab was non-inferior to Cyclophosphamide. All patients also got steroids. Jones et al, "Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial", Ann Rheum Dis. 2015 Jun;74(6):1178-82 https://www.ncbi.nlm.nih.gov/pubmed?term=25739829
Remission is defined as no symptoms or signs of vasculitis, no hematuria and stable or improving Cr and proteinuria.
Maintenance Therapy
- Azathioprine 1-2 mg/kg/day orally. This is slightle superior.
- Mycophenolate Mofetil 1 gram PO BID
Continue low dose steroids (7.5 mg daily) for at least 12 months.
Add bactrim if there is pulmonary involvement.
Anti-Glomerular Basement Membrane Glomerulonephritis
This is usually antibodies against a normally hidden epitope in Collagen type IV, usually alpha 3 chain. One epitope represents almost all cases of the disease. If affects men in their 30's, women in their 70's, and men are more likely to have Pulm and kidney involvement.Systemic Symptoms and Signs
Half of anti-GBM patients will have Diffuse pulmonary hemorrhage. If there are pulmonary hemorrhages, then there is 50 percent mortality, so it is a medical emergency.Pathology
Light Microscopy: Crescentic and necrotizing glomerulonephritis. The capillary walls will be normal, and Glomeruli that are not necrotic with crescents may look grossly normal. There may be Neutrophil infiltration
Immunofluorescence: IgG and C3 all along the GBM. There usually is no IgA. So, this is sort of the opposite of Lupus (Full House) because there really is mainly just IgG.
Electron Microscopy: No immune complex deposits. The IgG directly attacks the GBM. This is not due to collection of immune activity elsewhere in the blood.
Treatment
Treat Agressively if there is pulmonary Involvement- Cyclophosphamide 2 mg/kg/day PO for 3 months
- Pulse methylprednisolone 500 - 1000 mg IV x3 days then Prednisone 1 mg/kg/day
- Plasmaphoresis 4-Liter exchange with 5% albumin and add 150-300 mL FFP after each exchange. 60 mL/kg volume replacement if patient has diffuse alveolar hemorrhage or requires dialysis or has rapidly worsening Creatinine or there is anti-GBM.
There is no recurrence after transplant - maybe because because the transplanted kidney does not expose the hidden antigens?
Alport
Systemic Symptoms
- Hematuria starts early, and patients also develop hearing loss and blindness.
- Proteinuria
- Hearing loss
- Optical defects
It is X-linked. Alports often progresses to ERCP.
Alports causes proteinuria and hematuria and hearing loss, while Thin Basement Membrane disease usually just causes hematuria.
Pathophysiology
X-Linked defect in Type IV collagen (usually the alpha 3, alpha 4 or alpha 5 chain of Collagen IV).Pathology
Light Microscopy: No significant light changes. Toward end of disease there is normal glomerulosclerosis.Immunofluorescence: The key finding is a LACK of staining for normal collagen. No staining for alpha 3, 4, 5 chains of Collagen IV in the glomerular basement membrane, distal tubule basement membrane, or Bowman's capsule. There will not be much Ig staining, maybe some slight IgM.
Skin Immunofluorescence: This is only useful for classic X-linked Alport, not the autosomal recessive forms. The skin will lack alpha-5 chain for Collagen IV.
Electron Microscopy: There is still a basement membrane, but it is thin and irregular shaped. The GBM will thicken normally with age.
In adults, a GBM thinner than 250 nm is considered pathologic. The BM will have multiple lamina, appearing like stripes and called "basket weaving".
Fibrillary Glomerulonephritis
This presents with proteinuria, hematuria, Hypertension and renal injury.Pathology
Light Microscopy: Increased mesangial cellularity and thickened capillary walls. Fibrils in mesangium and capillary walls.
Immunofluorescence: Deposits of Polyclonal (oligoclonal) IgG, C3 and one or both types of light chains. They are Congo-Red-negative (not amyloid)
Electron Microscopy: These proteins form 15-25nm thick fibrils in the mesangium.
Immunotactoid
This presents with proteinuria, hematuria, Hypertension and renal injury.Pathology
Light Microscopy: Increased mesangial cellularity and thickened capillary walls.
Immunofluorescence: Deposits of Monoclonal IgG
Electron Microscopy: These proteins form over 30nm thick microtubules.
Thrombotic Microangiopathy (TMA)
These are mimics of a vasculitis, and have several causes. They all cause microangiopathic hemolytic anemia, thrombocytopenia, and AKI.Criteria - need all 3
- MAHA (microangiopathic hemolytic anemia - anemia, schistocytes, high LDH, Low Hapto)
- Thrombocytopenia
- Organ dysfunction - renal/neuro/GI
- Exclude DIC - Normal PT/PTT
TMA Causes
- Classic HUS - Diarrhea. Caused by Shiga Toxin from O157:H57 E coli, causes endothelial injury and endothelial apoptosis
- TTP - autoantibody to ADAMTS13 with ADAMTS13 < 5%. ADAMTS13 cleaves vWF, so reduces its activity. Without ADAMTS13, vWF multimers grow and trigger clotting cascade
- Familial TTP - Congenital deficiency of ADAMTS13
- aHUS - Disregulated complement, and may be caused by genetic deficiency that disables Factor H or I, so uncontrolled complement immune system. It has waxing/waning course, with relapses, often leads to ESRD. It is often triggered by Pregnancy or Infection or Cancer.
- VEGF Inhibition - due to sFLT1 from Pre-eclampsia or medications like Sunitinib, Soratenib, Bevaclizumab
- Gemcitabine (not via VEGF pathway)
- Cisplatin and other platinums
- Malignancy, usually solid tumors
- Tacrolimus, Cyclosporine (not via VEGF pathway)
- Tyrosine Kinases (Imatinib)
- Sclerodermal renal crisis
- Malignant Hypertension
- Sickle Cell
- Anti-phospholipid
- HIV
The difference between TTP and HUS is TTP is defective ADAMTS13 and HUS is direct endothelial injury. Testing for ADAMTS13 activity generally will distinguish between the two, but some HUS may have reduced activity as well.
Symptoms
- TTP - Fever, Anemia, Thrombocytopenia, Renal Injury, Neuro Symptoms (HA, seizure, encephalopathy)
- HUS - Anemia, Thrombocytopenia, Renal Injury
Basic Workup
To diagnose TMA: Smear/LDH/Hapto, Stool for Shiga toxin, HIV, ADAMTS13, ANA/dsDNA/antiSm
To manage TMA: Get ADAMTS13 and Shiga Toxin. If Shiga positive, then treat that. If ADAMTS13 below 5 percent, then treat TTP. Otherwise it's aHUS.
Pathology
Thick deposits in subendothelium - no Ig it's all Fibrin. Capillary wall thickening, with fibrin deposits
Treatment
TTP: Plasma Exchange (urgent) plus high dose steroids plus Rituximan
Paraproteinemias
May be due to monoclonal Ig from plasma cells but can also be from a leukemia or lymphome.Every different patient may make monoclonal proteins with a unique amino acid sequence, and the amino acid sequence of the monoclonal protein may determine the injury pattern for this protein. Some make casts, some deposit in basement membranes and the structure and appearance of these deposits will vary depending on the amino acid sequence. So, there are several different injury patterns that all are cased by monoclonal proteins. Usually, each single patient will have one injury pattern.
In Multiple Myeloma Cast Nephropathy, the proteinuria is the monoclonal protein. In other injury patterns, however, the proteinuria may be albumin. In these cases, there are monoclonal protein deposits in the basement membranes, but monoclonal protein itself does not get into the urine in significant quantities. Instead it seems to injure the tubule to cause albuminuria.
Be careful - a paraprotein can activate complement and lead to Full House staining (IgG, IgM, C3, C4, C1q)
Organized Deposits
All form Mesangial and tubular basement membrane deposits.- Amyloid. 8-12nm fibrils deposits in mesangium, Congo-Red Positive, Often positive fat pad biopsy.
There are several types of Amyloid - each is a different protein but all stain positive on Congo Red.- AA - caused by the SAA protein which is made in the liver. This is an acute phase reactant
- AL - Light chain, a paraproteinemia that deposits in the capillary and tubular basement membrane
- Beta 2 Mucroglobulin - Often seen in chronic dialysis patients. Presents with bone cysts, deposits in joint synovial tissues (shoulder pad sign). High flux dialyzers seem to clear beta 2 microglobulin better and may reduce the risk.
- Fibrillary. 20nm fibrils. Only 15% of fibrillary are monoclonal gammopathy, the rest seem to be polyclonal. Often MPGN or Mesangial Proliferative.
- Immunotactoid. 30-90nm microtubules, most are monoclonal gammopathy. Low complements. Biopsy looks like diabetes (mesangial deposits and nodules) except the protein is the Ig
- Cryoglobulinemia. Usually MPGN type 2.
Up to 50% of Hep C patients have Cryoglobulinemias, but only a small fraction of these have Cryo GN or other Cryo Vasculitis. Hep C activated B cells, though it does not necessarily infect B cells The activated B cells can cause cryos or lead to Non-HodgkinsTypes
- Type 1 - Monoclonal Ig, cause B cell Lymphoproliferative disease
- Type 2 - Monoclonal Ig against polyclonal Ig, RF+, activate complement, Hep C causes this. Treat the Hep C first. There is now Hep C treatments approved for CKD4 and ESRD. If continued GN with proteinuria, then Rituximab or Cyclophosphamide. Cyclophosphamide is anti-B-Cell, so it is like an older/more toxic Rituximab
- Type 3 - Polyclonal Ig, RF+, Hep C causes this
Disorganized Deposits of Immunoglobulin Chains
- Monoclonal Immunoglobulin Deposition Disease (MIDD). This replaces the names Light Chain Deposition Disease (LCDD), Heavy Chain Deposition Disease (HCDD), and Light Heavy Chain Deposition Disease (LHCDD), 20 to 50 percent of patients have multiple myeloma, and the rest have MGRS. All patients have abnormal free light chains, but SPEP may be negative. This causes deposits in mesangium and all tubule basement membranes, non-congo red, and not fibrils.
- Multiple Myeloma Cast Nephropathy. Casts do not stain with PAS.
- C3 Glomerulonephritis may be triggered by monoclonal proteins.
Renal Biopsies in Multiple Myeloma
Cryo 30%, MIDD 29%, Casts 20%, AL Amyloid 20%, Case series, 2003, AJKD, Fogo.
Also see Chang et al, "A 66-year-old woman with progressive renal insufficiency, nephrotic syndrome, and monoclonal protein", American Journal of Kidney Diseases Volume 41, Issue 2, February 2003, Pages 508-517
Also see Nasr et al, "Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies" Am J Kidney Dis. 2012 Jun;59(6):786-94
Diabetic Nephropathy
Apol1 mutation is not a risk factor for diabetic nephropathy. Tight glucose control, clear benefit in Type 1, but not clear benefit in type 2Subtypes
This is the Renal Pathology Society classification
- Subtype I - GBM thickening only
- Subtype II - Mesangial matrix expansion, but no mesangial Kimmelstiel-Wilson nodules
- Subtype III - Mesangial Kimmelstiel-Wilson nodules
- Subtype IV - Glomerular sclerosis
There are also stages based on symptoms and overal renal functional status
- Stage I - Increased GFR, hyperfiltration, large kidneys on US
- Stage II - Normal GFR, microalbuminuria, <30mg/day
- Stage III - Slightly reduced GFR, 30 - 300mg/day albuminuria
- Stage IV - Reduced GFR, over 300mg/day albuminuria
Diagnosing Diabetic Nephropathy
Some common features:- Proteinuria 10-15 yrs after start of disease
- Retinopathy (90-95% of Type 1 and 60-65% of Type 2)
- Type 1 develop HTN only after they develop CKD (10-15 yrs after diagnosis). They may not have essential HTN, but rather secondary HTN due to renal injury.
- Type 2 develop HTN early, usually before CKD, and this is part of metabolic syndrome and is more Essential primary HTN
Pathology
Light Microscopy: Enlarged glomeruli, thickened GBM. There is mesangial matrix expansion - this is the matrix itself, not cells in the mesangium, so it will be eosinophillic protein between the capillary loops. There may also be nodules, patches of lighter or darker protein in the middle of this expanded mesangial matrix. Nodular or non-nodular does not have clinical significance. This may be caused by mesangial cells reacting to hyperglycemia and secreting more matrix proteins. The proteins may also become glycosylated. The KW nodules may suggest chronicity, but are not very injurious by themselves.
There will also be arteriosclerosis, with hyalinization in the arteriole walls The tubules will have thickened basement membranes. In rare cases (like 5%) there may be crescents.
Immunofluorescence: There is linear staining of the GBM for IgG and isolated light and heavy chains. It is not clear why there is IgG; maybe it is glycosylated IgG from the blood sticking there. The tubule basement membrane also stains for IgG. The Immunofluorescence alone may look like anti-GBM disease, but the overall clinical picture will tell you this is diabetes not anti-GBM.
Electron Microscopy: There are no granular deposits in the GBM, so subendothelial or subepithelial deposits. The matrix expansion will be electron-dense, and there may also be capsular drops in Bowmans space.
SGLT2 Blockers
In the PCT, glucose reabsorption happens through the SGLT2, and this is blocked by meds like empagliflozin. Blocking this will decrease Glc uptake in the PCT.Normally, hypERglycemia will cause SGLT2 to absorb more glucose in the PCT. SGLT2 activity also increases Na+ and water reabsorption in the PCT. The result is less Na+ and Cl- and K+ are left inside the tubule, so less will eventually reach the macula densa. The macula densa sees a lower Na+ and Cl- and K+ concentration, and so interprets this as lower blood flow. It responds with the Tubular Glomerular Feedback, causing afferent arteriole dilation with PGE and efferent arteriole constriction with Renin-Ang II. The result is incleased hydrostatic pressure to the glomerular capillaries and increased GFR. This causes the hyperfiltration in early diabetes.
SGLT2 antagonists blocks this extra Glc reabsorption and so stops the hyperfiltration. It seems to be associated with slowing of progression
of diabetic nephropathy. Unfortunately, SGLT2 is contraindicated for GFR below 30, and should be dose reduced for GFR below 45. It is good for
early diabetes, but not advanced disease. Moreover, SGLT2 is also used in the pancreas, so these meds can cause the pancreas to decrease insulin
secreation and increase glucagon secreation. This can lead to euglycemic ketoacidosis.
References:
- Vallon et al, "SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice" Am J Physiol Renal Physiol. 2014 Jan 15; 306(2): F194–F204. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920018/
- KDIGO Guidelines, 2012
- Fundamentals of Renal Pathology by Agnes Fogo, Jan A. Bruijn, Arthur H. Cohen, Robert B. Colvin, J. Charles Jennette
Renal Pathology Notes
The arteries are fairly simple
- Renal artery and vein - enter and leave the kidney at the hilum
- Interlobar arteries - travel from the hilum, through the medulla to the corticomedullary junction
- Arcuate arteries - travel between the medulla and the cortex, sort of like a septum travels between lobes in the lung
- Interlobular arteries - branch from the arcuates, and travel perpendicular, up through the cortex to the capsule
- Afferent arterioles - branch off the interlobulars
Glomerular structure
The mesangium is an extension of the arteriole wall, and it contains smooth muscle myocytes (as well as other cell types) just like you would expect in an artery wall.
This raises a question, does CAD and atheromatous plaques affect the glomerulus as much as they do other cell walls?
Charge
The endothelial cells have negative charge on their membrane, as are the proteoglycans of the basement membrane, as are the surfaces of the epithelial cells.
So, there is a large anion charge one the whole structure between capillary lumen and the urinary space.
Deposits These are deposits in the glomeruli that are detected by immunofluorescence. Typical stuudies use fluorescent tagged antibodies to IgA, IgM, C1q, C3, Albumin, Fibrin and lambda and kappa light chains. So, any "Deposits" are tagged antibodies to one of these proteins, so the deposit itself is made of one of those select proteins. There are 2 types of deposits:
- Granular - these are electron dense, and are visible in light microscopy and electron microscopy
- Linear - NOT visible in light nor electron microscopy
Calcium and Phos
Cardiovascular death is the leading cause of death in CKD, and Ca and Phos directly contribute to vascular calcification. In CKD, the progression seems to be:Klotho declines ==> FGF23 rises ==> 1,2 Vit D declines ==> PTH rises ==> Phosphorus rises
So, why does phos rise, when FGF23 and PTH both increase Phos wasting by inhibiting Phos reabsorption in the kidney? FGF23 and PTH both remove the NaPi transporters from the membrane of PTH epithelial cells. Phos excretion probably declines as GFR drops, so even though PTH and FGF23 try to waste it, there is nephron loss.
Elevated Phos is bad
- Increased Phos is associated with increased mortality
- High phos causes smooth muscles to calcify and causes vascular calcifications
- Serum Calcium does not correlate with calcification "Serum Calcium is not a fuel guage". Russo et al, Am Journal Nephrol 2007
- Phos binders reduce coronary artery calcification (Russo, KI 2007)
- Non-Calcium binders have less mortality, and Calcium binders increase coronary artery calcifications
Elevated FGF-23 is bad
- High FGF-23 is associated with cardiac hypertrophy (FGF-23 stimulates Fibroblasts, it's name is "Fibroblast Growth Factor 23")
- Increased FGF-23 is associated with increased mortality.
Low Klotho is bad.
- Klotho protects against vascular calcification
High PTH is bad, but it usually has to be very high before treating.
- PTH causes bone resorption, increase in Vit D, renal Phos wasting, renal Ca reabsorption
- Do not use Cinacalcet in a non-dialysis patient
If Calcium and Phos have moved together (either both are high or both are low) then this suggests a Vitamin D issue (either too much or too little). If Calcium and Phos have moved separately (either one is high and the other is normal or low or one is low and the other is normal or high) then consider PTH or FGF23. If there is high PTH and high Ca, then consider primary or tertiary hyperparathyroid.
Bone lesions are often either too much or too little PTH.
- Osteitis Fibrosa Cystica - Caused by Hyper-Parathyroid. Very high PTH, for a long time, leads to osteoclasts forming lesions in bones (visible on X-Ray). Treat with Cinacalcet (to reduce the PTH levels)
- Adynamic Bone - Caused by HypO-parathyroid. Often overtreatment of CKD, leads to bone that is unresponsive to PTH.
- Osteomalacia - Caused by Vit D insufficiency.
Renal Transplant Rejection
HLA and MHC
HLA (human leukocyte antigen) is a set of 6 genes that express the MHC (major histocompatibility complex) proteins. We often use them interchangeably. HLA genes are found on chromosone 6, and there are a total of 6 genes. The HLA structures are actually large, and each is made from several proteins, each from a different HLA gene, so several genes are used to make any HLA.- Class I (make up MHC I) - HLA A, HLA B, HLA C
- Class II (make up MHC II) - HLA DP, HLA DQ, HLA DR
Of course, two people may have identical HLA genes for the 3 we test for, but have differences between their other HLA genes (like HLA-DP). Moreover, maybe two people have identical alleles for all 6 HLA genes, but some other subtle differences - like some cell receptor that can still be sensed by the immune system. All of these smaller differences are not detected. Only identical twins can be the same, and only if neither has a de novo mutatino. But, it means that a "perfect match" in transplant is not truly a perfect match, only a "reasonably close" match.
All nucleated cells express MHC I, which presents antigens from the cell internal cytoplasm (usually virus pieces or viral protein products). This tells the immune system, "Help! I am infected!". All antigen presenting cells express MHC II, which presents antigens from the extracellular environment (usually bacterial pieces). This tells the immune system, "Hey! Look what I found in the blood!".
These genes are: HLA A, HLA B, HLA C, HLA DP, HLA DQ, HLA DR.
Donor-Specific Antibodies (called DSA), are usually anti-HLA antibodies. We check for DSA against HLA-A, HLA-B, and HLA-DR cells. Note that HLA-A and HLA-B are part of MHC I complex, and are present on the surface of all graft cells. This donor HLA will bind with recipient CD8 cells, which directly causes T-cell activation. So, a mismatch here will cause a T-cell mediated response, and *may* lead to a more cellular response. In any case, this has a worse prognosis than a B-Cell activating cross-match. HLA-DR are part of the MHC II complex, and are present on the surface of antigen-presenting cells and also some graft tubule epithelial cells. This donor HLA will bind with recipient CD4 cells, causing B-Cell activation. This could cause either humoral or cell rejection.
Crossmatch
These will test for the presence of pre-formed antibodies in a transplant recipient. It won't tell you if the recipient will later reject, but it does tell you whether the recipient is ready to immediately reject now (hyperacute).- Panel Reactive Antibodies
Add recipient serum to a number of standard antigen samples. This may be 100 or so common HLA antigens that are common in your pool of potential donors. Wash away the serum and see if there were antibodies in the recipient serum that stuck to each HLA sample. Often, this may be done by adding fleurescent-labelled anti-Antobody immunoglobulins and see if they bind to recipient antibodies.Why do this? These are generic HLA antigens, and do not tell you anything about a specific donor organ. But, if you react to a lot of common HLA antigens, then you have pre-formed antibodies, likely due to past pregnancies or blood transfusions or past transplant, then you are highly sensitized. This tells you that it may be difficult finding a donor, and the recipient should be prepared to take a lower quality kidney if it matches.
- Cytotoxic Crossmatch
This tells you about a specific donor. Add recipient serum to donor cells that express MHC I. This could be any cells, but we typically use B and T cells just because they can be easily collected from a simple blood draw. They are a standin for the renal parenchyma cells. Add the donor cells to the recipient serum and also add some complement (C3, C4, C5) and see if the donor cells get lysed. If so then the recipient has pre-formed antibodies to donor cellsPositive cytotoxic crossmatch is an absolute contraindication to transplant.
- Flow Crossmatch
This is a lot like Cytotoxic crossmatch, except it uses a different mechanism to detect antibody attack. It still tells you about a specific donor. Add recipient serum to donor cells that express MHC I. This could be any cells, but we typically use B and T cells just because they can be easily collected from a simple blood draw. Now, wash away the serum and see if there were antibodies in the recipient serum that stuck to the cells. Specifically, add fleurescent-labelled anti-Antobody immunoglobulins and see if they bind to recipient antibodies. We look for the labelled anti-Ig antibodies in a flow cytometry detector.Positive Flow crossmatch is not an absolute contraindication to transplant but it means it is a high risk transplant. There could be either Cell or antibody mediated rejection.
- Virtual Crossmatch
Make beads with known HLA antigens attached to them, and with recipient serum. Add anti-Ig immunoglobulins (anti-Ig Ig) that have a fleurescent tag. We look for the labelled anti-Ig antibodies in a flow cytometry detector.
Banff Grading
Give a score of 0 (none), 1 (mild), 2 (moderate), 3 (severe) for each of 4 areas: infiltrate, tubulitis, arteritis, glomerulitis- Banff type I - Tubulitis
More than 4 lymphocytes in the tubule cross-sections.
- IA - Less than 25 percent of tubules involved
- IB - More than 25 percent of tubules involved
Acute T-cell mediated rejection: tubiulointerstitial
Acute Antibody-mediated rejection: Acute tubular injury
Chronic T-cell mediated rejection: Tubulointerstitial - Banff type II - Arteritis
Acute T-cell mediated rejection: endarteritis, endotheliatis
Acute Antibody-mediated rejection: Capillary inflammation
Chronic T-cell mediated rejection: Transplant arteriopathy - Banff type III
Acute T-cell mediated rejection: Arterial transmural inflammation or fibrillary necrosis
Acute Antibody-mediated rejection: Arterial fibrillary necrosis
Acute Cellular-Mediated Rejection
This is usually a T-cell mediated reaction (both CD4 and CD8), and starts soon (1-8 weeks) after transplantation. It usually does respond to steroids.Antibody mediated rejection - Neutrophils in Capillaries and endotheliatis. C4D staining
Cell mediated rejection - Neutrophils in Tubules and tubulitis
Light Microscopy:
Usually (95%) the glomerulus is spared.
Banff I - Tubulointerstitial infiltrates of lymphocytes, mostly T cells but also some B cells and Foxp3+ cells (T-Reg cells).
Banff II - Lymphocytes on surface of endothelium and outside media of arteries and arterioles. This is endarteritis, and it is *different* than
necrotizing arteritis, which is usually antibody-mediated and has a worse prognosis than endarteritis.
Banff III - Lymphocytes inside the arteriole medium.
Immunofluorescence: Little if any staining. You may see C3 deposits.
Electron Microscopy: Usually not used for this
Treatment often uses pulse steroids and ATG (anti-thymocyte globulin), previously used OKT3 (Muromonab-CD3, an anti-T-Cell antibody)
Acute Antibody-Mediated Rejection - Acute Humoral Rejection
This can happen anytime (soon or late) after transplantation and is usually less responsive to steroids. There is *Positive* Donor-Specific Antibodies (called DSA), usually anti-HLA antibodies. Hyperacute rejection may happen minutes to hours after transplant, and is just Humoral Rejection in a recipient that was pre-sensitized to the donor organ and already had antibodies waiting to attack.Antibody mediated rejection - Neutrophils in Capillaries and endotheliatis. C4D staining
Cell mediated rejection - Neutrophils in Tubules and tubulitis
Light Microscopy:
Banff I - Acute tubular injury with little inflammation.
Banff II - Peritubular and glomerular injury. Neutrophils in peritubular capillaries and glomeruli. Arteriolar thromboses and necrosis.
Banff III - Necrotizing Arteritis. Neutrophiles in arteriole, arteriolar media and around arteriolar.
There also is arteriolar necrosis, with fibrinoid (which is brightly eosinophilic stuff) in the wall.
Immunofluorescence: Peritubular capillaries will stain positive for C4d (After binding to a target, Complement C4 is cleaved to C4a and C4b, and then C4b deactivates into C4d). So, C4d is a lasting marker that indicates recent complement activity. But, it is only significant if C4d is in Glomerular or peritubular capillaries - it may be normally found in Mesangium.
Electron Microscopy: Usually not used
Treatment often uses Plasmapharesis, IVIG, Rituximab
Chronic Antibody-Mediated Rejection - Chronic Humoral Rejection
The rate of Chronic Allograft Nephropathy (CAN) has not changed over recent years, despite a large drop in acute rejection. Deceased donor grafts have a half-life of 8.8 years, living donor grafts have a half-life of 11.4 years and HLA-identical sibling grafts have a half-live of 20 years. But, if chronic Humoral rehection is diagnosed, then the graft halflife is 18 months. Like acute humoral rejection, chronic humoral rejection will also have Donor-Specific antibodies.Light Microscopy: Commonly has Transplant Glomerulopathy, which is mesangial hypercellularity and duplication of the Glomerular Basement Membrane. Commonly Crescents. Glomerular capillaries have monocytes. Arterioles have thickening of media and intima, calcifications, and T-cells and macrophages around the external elastica.
Immunofluorescence: Half the time there are C4d deposits in peritubular capillaries.
Electron Microscopy: Foot process effacement, and increased mesangial cellularity. Endothelial cells will lose fenestrations. Additionally, peritubular capillaries will split and duplicate their basement membranes, similar to glomerular capillaries. This may look like an onion-skin outer layer of the capillary.
Immunosuppression Regimens
For this, remember the sequence of T-cell activation- Antigen-Presenting Cell cell binds MHCI with CD8 or MHCII with CD44
- Antigen-Presenting Cell binds CD 80/86 with CD28 <== Belatacept blocks this
- T-Cell is activated and starts the Calcineurin Pathway <== Tacro/Cyclo blocks this
- Cancineurin activates NF-AT and emits IL-2
- IL-2 binds the CD25 receptor on other T-Cells <== Basiliximab blocks this
- IL-2 Receptor activates the mTor pathway <== Sirolimus blocks this
Induction Immunosuppression
- Thymoglobulin - Polyclonal Ig against B and T cells. Rabbit is superior to Equine, equine is off the market now. Rabbit tends to induce more TH17
- Alemtuzimab - Bind CD52 and cause BCell and TCell apoptosis. It's off market currently. Depleting and long lasting.
- Basiliximab - antagonist to the IL2 receptor (CD-25). The only NON-depleting induction.
Use a depleting induction for
- Cold ischemia time over 24hrs
- Increased HLA mismatches
- Young or African recipient
- High PRA
- ABO Incompatible
Immunosuppression and Rejection Studies
- Steroids - late withdrawal associated with rejection, but those studies used old IS meds
- Acute cellular rejection associated with worse survival
- Better IS associated with less acute rejection, but no change in long term survival
- Basiliximab "equivilent" to ATG for low risk, but ATG has less acute rejection
- Alemtuzimab is better than Basiliximab in low risk patients, but Alemtuzimab has more drug reactions
- Alemtuzimab similar to ATG in high risk patients.
Chronic Immunosuppression Take one from group 1 and one from group 2.
- Group 1 (T-Cell activation) - Tacrolimus, Cyclosporine, Sirolimus
- Group 2 (B-Cell and T-Cell proliferation) - Mycophenolate (block Purine synthesis), Azathioprine (block Purine synthesis), Sirolimus
Studies
- Belatacept is CONTRAINDICATED in EBV-negative patients, can cause PTLD.
- Tacrolimus is better than Cyclosporine for decreasing acute cellular rejection
- Tacrolimus has more Diabetes, Cyclosporine has more dislipidemia.
- Both Tacrolimus and Cyclosporine have AKI, HTN (CNI's cause more endothelin synthesis)
- mTor inhibitors have better cancer suppression than Calcineurin inhibitors.
- mTor inhibitors are contraindicated for eGFR below 40)
- MMF seems to have the least side effects (GI symptoms, myelosuppression) but it is Teratogenic.
- CNI withdrawal leads to worse outcomes
Tacrolimus levels. These are not standardized - every center will have different guidelines.
- First 6 months: 8 - 10
- Second 6 Months: 6 - 8
- Year 2: 4 - 6
- After Year 2: 4
Manage CNI side effects
- CNI-induced diabetes with Metformin (assuming eGFR is ok) and DDP4 blockers like Sitagliptan.
- CNI dislipidemia use Fluvastatin or Pravastatin or Rosuvastatin. Simvastatin is contraindicated becasue of P450 interactions.
- CNI Hypertension, use CCB or ACE/ARB.
Delayed graft Function
Need dialysis in the first week after transplant. May be a regular AKI or an acute rejection.
Get a renal US with dopplers to rule out renal vein thrombosis.
Start maintenance IS on post-op day 1. Don't delay or slow Induction but also start maintenance immediately.
BK - Polyoma Virus Toxicity
BK virus attacks the urothelium, and is only dangerous in immunosuppressed patients. However, it is rare among other patients on immunosuppression, such as liver, heart and lung transplants, or in patients on immunosuppression for autoimmune or other diseases. This affects renal transplants maybe because the virus is in urothelial cells, and in a transplant those are donor cells that have mismatching MHC proteins, so cannot present viral antigens ot the host immune system.Treatment
- Stop MMF
- Reduce immunosuppression - replace Tacrolimus with Cyclosporine
- Cidofovir (an antiviral).
Biopsy
Light Microscopy: Interstitial nephritis. Monocytes are in the interstitium, and tubules.
Tubular epithelial cells will enlarge, and have viral nuclear inclusions
Immunofluorescence: There is BK antigen in urine and on epithelial cells that can show in immunofluorescence.
Electron Microscopy: Intranuclear viral particles.
Posttransplant Lymphoproliferative Disease (PTLD)
T-Cells seem to regulate growth of B-Cells. If you suppress T-Cells enough, then you remove this regulatory mechanism and you can have uncontrolled growth of B-Cells. A B-Cell lymphoma is an inherent defect in the B-Cell itself, so it ignores regulatory signals and grows out of control. Posttransplant Lymphoproliferative Disease (PTLD) is a loss of regulatory signals, so the B-Cell would stop replication if it were told to, but there are not enough T-cells to send this signal so the B cells grow uncontrollably.Belatacept is CONTRAINDICATED in EBV-negative patients, can cause PTLD.
Calcineurin Inhibitor Toxicity
This will appear similar to acute rejection, except there is no endarteritis. Calcineurin toxicity also has vacuoles in proximal tubule epithelial cells. Immunofluorescence is negative and EM just shows these vacuoles.There is also an arteriolopathy, which is necrosis of myocytes around the arterioles, and vacuoles in some of the remaining myocytes. Note, however, that this affects the myocytes, not the endarteritis which may be more the endothelium. This is the best distinction between Calcineurin toxicity and acute rejection - only acute rejection will affect the endarteritis.
There is also a thrombotic microangiopathy,
CMV
Presents with Leukopenia, transaminitis, fevers.To diagnose: serum viral load
Treat: IV Gancyclovir or PO Valgancyclovir. If Gancyclovir-resistant bug, then Cidofovir
Urine Microscopy and Urinalysis
Microscopy
First, spin at 3000 RPM for 5 minutes. Do not spin at too high a speed and do not let the sample sit for too long, as you will lose casts.
If the urine is red, but after centrifugation the supernatant is yellow, then this is Rhabdo.
Casts
- Hyaline vs Waxy casts
- Hyaline casts are translucent and are associated with volume depletion.
- Waxy casts are opaque, often have notches inthe sides, and are non-specific but associated with late CKD.
- WBC casts
These are associated with GN's, AIN but also Pyelonephritis. - Fatty Casts.
These are really cells engorbed with endosomes full of lipid. They may resemble RBC casts except they look different under polarized light.
Eosinophillia is not useful.
- 1 percent eos is 30 percent sensitive and 68 percent specific
- 5 percent eos is less sensitive and slightly more specific
Cell Shapes
- Renal Tubule Epithelial Cells - Round, single nucleus usually to side of cell, may sometimes have granuoles
- Acanthrocytes (blebs, micky-mouse ears). Over 5 percent acanthrocytes is very specific for a GN.
Crystals
- Ca-Oxalate - rods and envelopes. The rods are Ca-Oxalate monohydrate and are associated with Ethylene Glycol. The envelopes are Ca-Oxalate dihydrate and are associated with high Oxalate. These can happen at low or high urine pH
- Ca-Phos - Needles (like shards of glass) and Star-shaped. These can happen at high urine pH (usually 6.5 - 7.5). This is why you don't alkalinize urine for Tumor Lysis Syndrome - you may prevent Urate stones, but you cause Ca-Phos stones. A Von Kossa stain will detect Ca-Phos but not Ca-Ox crystals. These may also be caused by phos-containing enemas.
- Uric Acid - parallelogram (flattened football). These can happen at low urine pH, and is a risk during Tumor Lysis.
- Cysteine - hexagon. These can happen at low urine pH.
- Ammonium-Phos, Coffin-lid shaped (or I like to think Emerald cut). They are caused by bacteria that release Urease-splitting enzymes. Typical bacteria are Proteus or Klebsiella. Urease will break down Urea (Urea --> 2NH3 + CO2) and then the CO2 forms bicarb (CO2 + H2O --> HCO3- + H+) and the H+ combines with NH3 (NH3 + H+ --> NH4+). So it releases *both* NH4+ and bicarb.
- Sulfa crystals - fan-shaped, like a sea shell, or also called a bouquet of wheat
- Bactrim crystals - star-shaped
- Methotraxate - Brown cuboidal
- Acyclovir - needle
Hematuria
If the patient is over 45yo, then work up malignancy. Cystoscopy is the first test. Also on the differential is "nutcracker" which is compression of renal vein because it lays between SMA and aorta. Check the dopplers.
If however, there is a glomerular source, then IgA is the most common cause.
Renal Stones
Stones smaller than 8mm usually pass spontaneously.
Types of Stones
- Calcium Oxalate. Forms in all pH (low and high).
- Calcium Phosphate. These can happen at high urine pH (usually 6.5 - 7.5) which is why you don't alkalinize urine for Tumor Lysis Syndrome.
- Uric Acid. Not radio-opaque on XRay, you need a CT. They form in acidic urine pH.
- Cystine. Not radio-opaque on XRay, you need a CT. They form in acidic urine pH. Treat with Penicillamine to make Cystine more soluble.
- Struvite. Ammonium-Phos, Coffin-lid shaped (or I like to think Emerald cut). They are caused by bacteria that release Urease-splitting enzymes. Typical bacteria are Proteus or Klebsiella. Urease will break down Urea (Urea --> 2NH3 + CO2) and then the CO2 forms bicarb (CO2 + H2O --> HCO3- + H+) and the H+ combines with NH3 (NH3 + H+ --> NH4+). So it releases *both* NH4+ and bicarb.
Possible Causes
- Gastric Bypass - this causes has fat malabsorption, which leads to Ca chelation in the GI tract, leaving free Oxalate to remain unbound and reabsorbed, where it is eventually filtered by the kidneys and binds with Ca in the urine instead of the stool.
Treatment
If infected stone (fever, white count, etc), this is a medical emergency and needs admission for nephrostomy tube placement. Toradol for pain control.
However, hydronephrosis in the abscence of infection is not a medical emergency accoding to one review I read, but I would be worried and still consider Urology consult with possible neph tube placement.
Stone Prevention
- Drink until at least 2L of urine daily
- Low Na diet - reduces Ca in urine because NCC is down-regulated.
- K-Citrate. This chelates Calcium in the urine
- For Calcium stones - Thiazide to increase Ca reabsorption and lower Ca levels in urine. This is not useful for Urate or Cysteine stones.
- Increase PO calcium, to bind Phos in the GI
Stone Risks
- Urine Volume less than 2L/day
- Urine Citrate less than 450 mg/day
- Urine Calcium more than 200 mg/day in wonem or 250 mg/day in men
- Urine Oxalate more than 40 mg/day
- Urine Uric Acid more than 750 mg/day in women and 800 mg/day in men
- Urine Sodium - any high value increases risk of stones.
Urine Cr is usually 20-25 mg/kg of body weight in men, 15-20 mg/kg of body weight in women. Ideally, use lean body weight (because Cr comes from muscle, not fat).
DKA in ESRD Patients
- - Insulin drip. If the K does not quickly correct then dialyze. The patient may still have an anion gap, due to uremia, but we need to first stop hepatic production of ketoacids.
- - Do not give IV saline or LR or isotonic fluids - he is anuric and is euvolemic.
- - OK to give D10W or D5W, as these are not confined to the vascular space and you will need some glucose source for the insulin drip if his serum glucose normalizes before ketoacidosis stops.
- - Continue drip until glucose is normalized and acidosis reduces. The gap may not fully close due to uremia but wait until it significantly improves, then switch to subcu insulin. If we finish dialysis, then the uremia should be resolved so you can expect the anion gap to close.
- - Dialysis nurse to draw blood cultures from TDC to work up cause.
Parathyroidectomy
There is risk of hungry bone syndrome leading to hypocalcemia. - Check ionized Calcium Q4h - Check PTH Q24h - Ca-Carbonate 750mg PO TID - Calcitriol 1mcg daily - PRN IV Calcium Gluconate Ok to discharge home tomorrow if no IV calcium needed in 24hrs
Renal Ultrasound
Resistive Index
Resistive index = (Peak systolic velocity - diastolic velocity) / Peak systolic velocityIt is the percent change of blood velocity between diastole and systole. Normal values are 0.6 - 0.7. Renal Artery Stenosis will have a low resistive index, because the stenosis will prevent high systolic flow, so the numerator is lower.
Sizes
Normal kidneys are 10 - 12 cm. Some causes of large kidneys include:- Diabetic nephropathy
- Cell infiltrate - Multiple Myeloma
- Amyloid
- HIV
Shadowing
This is when a bright hyperechoic area leaves a dark shadow below it. Essentially, all of the US signal bounces off the bright hyperechoic mass and nothing reaches the area below it. This is a common feature of renal stones.CardioRenal Syndrome
There are 4 subtypes:- Acute CHF causes AKI
- Chronic CHF causes CKD
- AKI causes cardiac injury
- CKD causes chronic heart failure
Decreased cardiac output causes venous congestion, including in the kidneys.
Treatment centers on dialysis. CARESS-HF Trial showed no benefit of UF over dialysis.
Treating RAS may improve heart failure. See Kane et al, "Renal artery revascularization improves heart failure control in patients with atherosclerotic renal artery stenosis" Nephrol Dial Transplant. 2010 Mar;25(3):813-20 https://www.ncbi.nlm.nih.gov/pubmed/19666661
HepatoRenal Syndrome
Some say up to 25 percent of patients with decompensated cirrhosis have HRS eventually.Subtypes
- Type 1 - acute, caused by AKI
- Type 2 - chronic
Pathophysiology
- Cirrhosis leads to portal hypertension - with ascites. The ascites is important because it means there is portal hypertension and at least suggests splanchnic hypotension. Cirrhosis also may lead to loss of vasodilator clearance (specifically NO) so there is unopposed dilation at least in the splanchnic vasculature but cirrhotics often have systemic hypotension. There may also be loss of vasoconstrictor synethesis, but this is not clear.
- This leads to splanchnic vasodilation, with pooling of blood. This may worsen the ascites.
- This leads to low intravascular volume
- This leads to systemic hypOtension and renal hypOtension.
- The kidney responds with severe vasoconstriction, and ascutally is dependant on the RAAS system to preserve renal blood flow. This is why ACE/ARB is so bad in HRS. There have been imaging studies with arteriograms before and after death that showed intense intrarenal vasoconstriction immediately before death that resolves right after death, so this is a reversible vasoconstriction not an irreversible scarring or fibrosis.
- The ascites also leads to abdominal compartment syndrome
Diagnostic Criteria
- Cirrhosis with ascites. The ascites is important because it means there is portal hypertension and at least suggests splanchnic hypotension.
- AKI with AKIN 1. This is the mildest criteria for AKI, and Cr rises 50 percent or by 0.3 within 48hrs
- No shock
- No nephrotoxic drugs (NSAIDs, no chemotherapy, etc)
- No ACE/ARB
- No benefit from volume expansion - Hold diuretics and Albumin 1 g/kg daily for 2 days. Note, this means that even thought he patient has ascites, you hold the diuretics.
- No other obvious cause of renal injury
- Not large Hematuria - Urinalysis has fewer than 50 RBC's per field
- Not large Proteinuria - Less than 500 mg/g Protein/Albumin ratio.
- Normal Renal US (no Hydro or mass)
Treat
- Albumin 1g/kg/day once then 50g daily for 2 more days
- Midodrine and Octreotide
- Paracentesis to relieve abdominal compartment syndrome
- TIPS
AKI vs ATN Thoughts
Lets start with a few definitions -
- Acute Kidney Injury (AKI) means simply the kidney is not filtering blood well, and is usually evidenced by a rise in serum Creatinine but there are other indicators. Creatinine should be filtered out, and if it is high then the kidney is not doing its job. I tell patients it is like walking into a hotel room and finding dirty towels all over the gound, you know the maid has not been there. Creatinine is not a toxin, so high Creatinine alone is not dangerous, but it is a marker for poor filtration and high Creatinine suggests high levels of real toxins which we do not measure (or even have isolated).
- Pre-renal AKI means the kidney is not filtering blood well because not enough blood is reaching the kidney. The kidney may be working normally, but it is not seeing enough blood. There are many reasons for this, including blood loss, heart failure (a weak heart does not pump blood fast enough to get sufficient blood delivered to the kidney) and volume depletion (loss of water and salt).
- Acute Tubular Necrosis (ATN) is kidney parenchymal injury. Now, it does not matter whether enough blood reaches the kidney - the kidney is damaged and so it cannot properly filter any blood that does arrive.
There are several causes of ATN
- Ischemic - patchy cell injury, often ischemia but may sometimes be non-lethal cell injury
- Toxic - Usually the proximal tubule. Tenofovir, Gentamycin, Lead
The denitive test for ATN is urine microscopy - if you see clumps of dead renal cells, then you know the kidney is injured. Typically these are muddy casts, but they can also appear as shed tubule epithelial cells. But, not seeing those cells does not mean there is not an injury. For example, if I am wearing a turtle neck sweater, do you know if I have a rash on my back?
ATN will injury the kidney with several mechanisms:
- Injury to Macula Densa cells, causing a loss of the juxtaglomerular feedback. This causes the efferent arteriole to dilate, so blood bypasses the kidney.
- Casts obstruct the tubule
- Cell injury causes decreased Cr (and other toxin) secretion
Arguably, prerenal AKI is not really a renal pathology at all. It reflects systemic volume depletion and is the kidneys appropriate response. The kidney cannot completely separate urination from filtration, so once intravascular volume decreases it will reduce urine output which necessitates reducing filtration. If this is only needed for a short time, then there is no injury. Howwever, filtered blood also provides the source of renal parenchymal perfusion (the efferent arteriole of one glomerulus will branch and provide peritubular capillaries to sustain other gloms). As a result, if filtration drops too much for an extended period of time, then this causes ATN, which is renal ischemic injury. It is a bit like a type 2 NSTEMI becoming severe and leading to ischemic myocardial injury. However, this may not be irrecoverable - ATN can havee a partial recovery over a period of time.
FENa is really a marker of tubule Na reabsorption, which is associated with tubule function. In a healthy kidney, FENa > 2% means reduced Na reabsorption, so there is tubule injury and thus ATN. In a CKD kidney, the tubule is injured at baseline. FENa may be > 1% even if there is pre-renal state, because the tubule is injured at baseline so Na reabsorption is always impaired, even when volume depleted.
We can measure Fractional Excretion of Urea (FEUrea) to get an idea of whether the kidney is working well, or whether not enough blood is reaching the kidney. If the FEUrea is low, then that means the kidney is reabsorbing urea, and so is evidence that it is working well. If it can reabsorb Urea, then it typically does everything else correctly as well. Typically, if FEUrea is below 35% then the kidney is probably doing a good job. So, if Creatinine is high, the kidney is not filtering blood, but if FEUrea is also low in this situation, then we *assume* that the kidney is doing a good job on whatever blood it receives, so the problem must be that it is just not getting enough blood to filter. This is the idea behind pre-renal AKI.
Now, if a kidney has pre-renal AKI long enough, then it not only does not filter blood for the body, but the kidney does not get enough blood for its own oxygen requirements. This injures the kidney and causes ATN. So pre-renal AKI, if it lasts long enough, can lead to ATN. However, other things, like toxins, can also cause ATN, and those are not pre-renal AKI. For example, if somebody gets shot in the kidney or drinks antifreeze - these are not pre-renal but they do injure the kidney.
Alternately, if the FEUrea is high, then the kidney is not filtering blood well. Maybe it gets enough blood to filter or maybe it does not - in either case whatever blood it does get is not filtered well. Urea is not being reabsorbed, which the kidney should do if it is working correctly. So, if Urea is being spilled into Urine, then the kidney is not working well.
So, how high is too high for FEUrea? We say if it is below 35%, then the kidney is filtering well. Does over 35 mean it is not working well? No. In fact, there is no strong boundary, only a rough guideline. It is more important to look at the whole context.
Did a treatment (like IV fluids or diuretics) fix an increase in Creatinine? If not, then I suggest ATN would be the leading diagnosis. In other words, you tried to fix the renal perfusion - did this fix the Serum Creatinine? If so then this was a pre-renal AKI due to reduced cardiac output. If not, then whether this started as pre-renal or not this is becoming an ATN.
Pathology of Ischemic ATN
Light Microscopy: Both proximal and distal tubules are affected, and both tubules dilate and epithelial cells flatten. Proximal tubules lose their brush border, and Distal tubules may form Uromodulin (Tamm-Horsfall) protein casts. There are also brown casts - brown color comes from heme pigment. Oddly, you will usually NOT see necrosis of tubular cells. But, you will often see gaps in the tubule epithelium caused by loss of cells. You may also see cell regeneration, with mitotic figures, in epithelial cells. The S3 section of the proximal tubule (the straight portion) is often injured. Additionally, some work (Rosen, Brezis et al) have shown that ischemia affects the thick ascending limb, which can affect Tubulo-glomerular feedback and Uromodulin secretion. Interestingly, the Glomerular capillaries are usually not affected.
Pathology of Toxic ATN
Frank necrosis of cells in the proximal convoluted tubule. After a week or so, the PCT has new flattened cells with mitotic figure and at 2 weeks the replacement cells are cuboid. The PCT basement membrane is often not damaged. Gentamycin toxicity often causes myeloid bodies (lysosomes with phospholipid), Tenofovir causes crystals inside PCT cells, and lead causes intranuclear inclusions.Antibiotics
Hospital Acquired Pneumonia
This is taken from IDSA Guidelines for HAPCriteria for HAP (as opposed to CAP)
- hospitalization for more than 48 hours in the last 90 days
- residence in a nursing home or extended care facility
- home infusion therapy
- chronic dialysis within one month
- home wound care
- a family member with a multi-drug resistant organism
Use endotracheal aspiration with semiquantitative cultures to diagnose VAP, rather than bronchoscopy. Also, use clinical criteria alone, rather than Procalcitonin or CRP or Modified Clinical Pulmonary Infection Score, to decide whether to start antibiotics.
Antibiotics for Empiric Treatment of Clinically Suspected HAP (Non-VAP)
- Low Risk of Mortality or MRSA: Piperacillin-tazobactam 4.5 g IV q6h, Cefepime 2 g IV q8h, Levofloxacin 750 mg IV daily, Imipenem 500 mg IV q6h, Meropenem 1 g IV q8h
- Low Risk of Mortality but Risk of MRSA:
- Vancomycin 15 mg/kg IV q8–12h with goal to target 15–20 mg/mL trough level (consider a loading dose of 25–30 mg/kg), or Linezolid 600 mg IV q12h
PLUS - Piperacillin-tazobactam 4.5 g IV q6h, Cefepime or ceftazidime 2 g IV q8h, Levofloxacin 750 mg IV daily, Ciprofloxacin 400 mg IV q8h, Imipenem 500 mg IV q6h, Meropenem 1 g IV q8h, Aztreoname 2 g IV q8h
- Vancomycin 15 mg/kg IV q8–12h with goal to target 15–20 mg/mL trough level (consider a loading dose of 25–30 mg/kg), or Linezolid 600 mg IV q12h
- Pseudomonas in critically ill patient: combination therapy using 2 antibiotics to which the isolate is susceptible rather than monotherapy
- Acinetobacter
- Either a carbapenem or ampicillin/sulbactam
- OR - IV polymyxin (colistin or polymyxin B)
- Carbapenem-Resistant Pathogens: IV polymyxins (colistin or polymyxin B)
- ESBL-producing gram-negative rods: ?Ertapenem
Duration - 7-day course of antimicrobial therapy
Ventillator Associated Pneumonia
This is taken from IDSA Guidelines for HAPCover MRSA, Pseudomonas aeruginosa, and other gram-negative bacilli in all empiric regimens.
- Gram-Positive coverage With MRSA - Vancomycin 15 mg/kg IV q8–12h (consider loading dose of 25–30 mg/kg) or Linezolid 600 mg IV q12h
- Gram-Negative coverage With Antipseudomonal - Piperacillin-tazobactam 4.5 g IV q6hb, Cefepime 2 g IV q8h, Ceftazidime 2 g IV q8h, Imipenem 500 mg IV q6hd, Meropenem 1 g IV q8h, Aztreonam 2 g IV q8h
- Gram-Negative coverage (NON-Beta-Lactams) - Ciprofloxacin 400 mg IV q8h, Levofloxacin 750 mg IV q24h, Amikacin 15–20 mg/kg IV q24h, Gentamicin 5–7 mg/kg IV q24h, Tobramycin 5–7 mg/kg IV q24h, Polymyxin B 2.5–3.0 mg/kg/d divided in 2 daily IV doses
Empiric treatment for MSSA (and NOT MRSA), piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem. Oxacillin, nafcillin, or cefazolin are preferred agents for treatment of proven MSSA.
Use two antipseudomonal from different classes for patients with a risk factor for antimicrobial resistance or in an ICU with over 10 percent of bugs are resistant to monotherapy
Community Acquired Pneumonia
This is taken from IDSA Guidelines for CAP- No risk factors for drug-resistant S. pneumoniae (DRSP):
A macrolide (azithromycin, clarithromycin, or erythromycin)
- Comorbidities (CHF, CKD, DM, Cancer, etc or antimicrobials in past 3 months):
- A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
OR - β-lactam plus a macrolide (High-dose amoxicillin [e.g., 1 g 3 times daily] or amoxicillin-clavulanate [2 g 2 times daily] is preferred; alternatives include ceftriaxone, cefpodoxime, and cefuroxime [500 mg 2 times daily]; doxycycline [level II evidence] is an alternative to the macrolide.)
- A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
- Inpatient, non-ICU treatment
- Respiratory fluoroquinolone
- OR β-lactam plus a macrolide (Preferred β-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline as an alternative to the macrolide. If PCN-allergic, respiratory fluoroquinolone)
- OR β-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin or a fluoroquinolone (if PCN-allergic, respiratory fluoroquinolone and aztreonam)
- Pseudomonas infection
Use an antipneumococcal, antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg dose) or the above β-lactam plus an aminoglycoside and azithromycin or the above β-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, substitute aztreonam for the above β-lactam).
- Community-acquired MRSA
Vancomycin or linezolid
Early treatment (within 48 h of the onset of symptoms) with oseltamivir or zanamivir is recommended for influenza A. BUT oseltamivir and zanamivir are not recommended for patients with uncomplicated influenza with symptoms for over 48 h except if hospitalized. These drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia.
Duration of antibiotic therapy - minimum of 5 days, should be afebrile for 48–72 h, and should have no more than 1 CAP-associated sign of clinical instability before discontinuation of therapy
If severe hypoxemia (PaO2/FiO2 ratio, below 150) and require intubation, start with low-tidal-volume ventilation (6 cm3/kg of ideal body weight)
All patients over 50yo should get Flu vaccine, and patients over 65yo should get Pneumococcal vaccine
UTI
This is taken from IDSA Guidelines for Cystitis and Pyelonephritis and also IDSA Guidelines for CAUTICystitis Empiric Treatment:
- Trimethoprim-sulfamethoxazole (160/800 mg [1 doublestrength tablet] twice-daily for 3 days)
- Fluoroquinolones (ofloxacin, ciprofloxacin, and levofloxacin), are highly efficacious in 3-day regimens (A-I) but have a propensity for collateral damage
- Nitrofurantoin monohydrate/macrocrystals (100 mg twice daily for 5 days)
- Beta-Lactam agents (amoxicillin-clavulanate, cefdinir, cefaclor, and cefpodoxime-proxetil) 3–7-days, but these have less efficacy. Amoxicillin or ampicillin should not be used for empirical treatment
Acute Pyelonephritis Empiric Treatment
- Oral ciprofloxacin (500 mg twice daily) for 7 days, with or without an initial 400-mg dose of intravenous ciprofloxacin, or levofloxacin (750 mg for 5 days). If fluoroquinolone resistance is over 10 percent, an initial IV dose of a long-acting antimicrobial, such as 1 g of ceftriaxone
UTI in patients with indwelling urethral, indwelling suprapubic, or intermittent catheterization, a UTI is defined by the symptoms compatible with UTI and with about 10^3 CFU. UTI is also defined as 10^5 cfu/mL of about 1 bacterial species in asymptomatic man with a condom catheter. In a patient with a Foley, pyuria is NOT diagnostic of UTI.
Seven days is the recommended duration of antimicrobial treatment for patients with CA-UTI who have prompt resolution of symptoms, but 10–14 days if delayed response. A 5-day regimen of levofloxacin may be considered in patients with CA-UTI who are not severely ill.
Abdominal Infection
Women obviously get a pregnancy test. Then, start with imaging:
- Suspected Appendicitis, if not pregnant, Helical CT of the abdomen and pelvis with intravenous (not oral or rectal) contrast.If pregnant, get an ultrasound or MRI.
- Suspected Cholecystitis and Cholangitis the initial imaging is Ultrasound
- Other intra-abdominal infection: CT is preferred imaging.
Empiric Antibiotics:
- Acute Appendicitis or Mild-to-Moderate Community-Acquired Infection (perforated or abscessed appendicitis and others)
Target enteric gram-negative aerobic and facultative bacilli and enteric gram-positive streptococci. If there is obstruction or paralytic ileus, then also cover obligate anaerobic bacilli. You do not need to cover Enterococcus or Candida. Also, Ampicillin-sulbactam, Cefotetan and clindamycin are not recommended for use because of increasing resistance
- Single Agent: ticarcillin-clavulanate, cefoxitin, ertapenem, moxifloxacin, or tigecycline
- Combinations: combinations of metronidazole with cefazolin, cefuroxime, ceftriaxone, cefotaxime, levofloxacin, or ciprofloxacin
High-Risk Community-Acquired Infection (APACHE II scores 115 or medically unstable or elderly or immunocompromised)
Empiric antimicrobials should target gram-negative organisms and enterococci. It is not necessary to cover MRSA or yeast unless there is evidence of infection with them. Quinolone-resistant E. coli have become common in some communities, so you may need to avoid those.
- Single Agent: Imipenem-cilastatin, meropenem, doripenem, or piperacillin-tazobactam
- Combinations: Metronidazole PLUS any of: Cefepime, ceftazidime, ciprofloxacin, or levofloxacin
Health Care–Associated Infection (including post-operative)
Empiric treatment should cover gram-negative aerobic and facultative bacilli. Add antifungals (Fluconazole or caspofungin, micafungin, or anidulafungin) if Candida is grown from intra-abdominal cultures Empiric should also include Anti-enterococcal coverage (particularly Enterococcus faecalis). These antibiotics include
- Pip/Tazo
- Ampicillin
- Vancomycin. Don't automatically cover VRE unless high risk patient, including liver transplant or previous VRE infection.
Cholecystitis and Cholangitis
Empiric antibiotics
- Mild-to-moderate community-acquired acute cholecystitis: Cefazolin, cefuroxime, or ceftriaxone
- Severe community-acquired acute cholecystitis OR Health care–associated biliary infection OR bilio-enteric anastamosis: metronidazolea PLUS (Ciprofloxacin, levofloxacin, Cefepime, Pip/Tazo, Imipenem-cilastatin, meropenem, doripenem)
Skin and Soft Tissue Infections
Impetigo - Gram stain and culture the pus to distinguish between Staph and Strep - Topical antibiotics: Mupirocin or retapamulin x5 days - Alternatively use oral abx for 7days, Cephalexin or dicloxacillin (for MSSA). If suspect MRSA then Doxy, Clinda, or Bactrim
Purulent Soft Tissue Infection - Gram stain and culture the pus to distinguish between Staph and Strep - I&D - If MSSA - Cefazolin 1g Q8h, Clinda 600mg IV Q8h or 500mg PO QID, Cephalexin 500mg PO Q6h, Bactrim 1-2 DS PO BID - If MRSA - Vanc 30 mg/kg Q12h, Linezolid 600mg PO Q12h, Clinda 600mg IV Q8h or 300-450mg PO QID, Ceftaroline 600mg IV BID, Doxy 100mg PO BID - If Strep - Clinda 600-900mg IV Q8h, Cefazolin 1g Q8h, Cephalexin 500mg PO Q6h Treat for 7 days If recurrent abscess, treat for 5-10 days If recurrent cellulitis (3-4 episodes per year), consider PO Erythromycin for 4-52 weeks Consider 5 days decolonization with intranasal mupirocen If immunocompromised
Erysipelas - Blood Cultures if immune suppressed Treat for 5 days - If MSSA - Cefazolin 1g Q8h, Clinda 600mg IV Q8h or 500mg PO QID, Cephalexin 500mg PO Q6h, Bactrim 1-2 DS PO BID - If MRSA - Vanc 30 mg/kg Q12h, Linezolid 600mg PO Q12h, Clinda 600mg IV Q8h or 300-450mg PO QID, Ceftaroline 600mg IV BID, Doxy 100mg PO BID - If Strep - Clinda 600-900mg IV Q8h, Cefazolin 1g Q8h, Cephalexin 500mg PO Q6h
Surgical Site Infections - If MSSA - Cephalosporin or anti-staph PCN - If MRSA Vanc or Linezolid or Ceftaroline Add empiric coverage for GNR is abdominal or GU surgery. (Cephalospiron or Quinolone) PLUS flagyl
Necrotizing Fasciitis including Fournier Gangrene Clostridial Gas Gangrene - Surgical eval - Vanc PLUS (Zosyn or Carbepenem)
Pyomyositis - Vanc - MRI
Animal Bite - If non-infected. Give PPX for 3-5 days if immunocompromised If infected (or ppx) cover aerobe and non-aerobes Augmentin 875/125 PO BID Unasyn 875/125 IV BID Doxy 100mg PO BID Flagyl 250-500 mg TID Clinda 300mg PO TID Cipro 500-750mg PO BID Levofloxacin 750mg PO daily Doxy 100mg PO BID - Tdap if pt is without tetanus vaccine in 10yrs - Do not close wound
Zoster - Acyclovir
Infective Endocarditis
Infective Endocarditis - CTA Head - CXR
SCM Hints
To add text labels, first go to the Preferences menu at the top, then select Toolbar Change the Text Options to "Show Text Labels" as shown above Make a patient list for each of our Division of Hospital Medicine teams. Select New Visit List Select the Location as "UK Chandler Medical Center" and add it to the box on the right Select the team under the Service tab The Chandler teams are labeled as "Medicine / Internal Medicine Team 1" (or 2, 3, 4, etc.) The Good Samaritan teams are labeled as "Medicine / Internal Medicine GS Team 1" (or teams 0 through 5) Save your list, and repeat for each of the remaining Medicine team Make a private patient list This will help you keep track of your patients as level of care is changed or they are discharged Select all the patients you wish to save to a personal list (you can use the "Select All Patients" button from a team list) Click the "Save Selected Patients" button Manually created lists have an asterisk before the name Customize Lists Go to the list you wish to modify Click on "Select Visit List Column" Make sure that you have the Flag New and New Results columns added The list above contains some good basic columns, but some other columns to consider are: Acetaminophen 24-hr (or 96-hr Dosing) - Shows cumulative Tylenol use Foley Days - Counts number of days since a Foley was inserted Isolation Protocol - Shows the type of isolation/contact precautions It is also recommended to add New Orders and To Sign Go to the Preferences menu and select "Document Entry" From the "Inpt. Provider Notes" menus, choose the following note titles from the left, and then click "Add" to move them to the box on the right Attending History and Physical Note and Attending Consult Note (from the "H&P and Consultation Notes" submenu) Attending Progress Note and Attending Consult Follow Up Note (from the "Progress Notes" submenu) Discharge Summary. (from the "Discharge Summary" submenu) Note that "Discharge Summary." and Discharge Summary" are not the same, and only the note titled "Discharge Summary." (with the period at the end) will show up when you try to write your note Create templates: Press F6 to access the UK SmartPaste window Select "9. Note templates" Select "1. My templates" Click "Modify Templates" button Open the "Template" menu and select "Search Other Providers Templates" Items within brackets (such as [<>] or [< >] below) will automatically insert text or data from other parts of the chart You now have an opportunity to modify the template before saving it You can add data fields from the list on the right, which will pull text or data into your note The fields that start with "UK_Snapshot" pull the text from the respective box on the Snapshot tab into your note - It is only recommended to use these if you plan on using the Snapshot tab to prepare your notes (see 2. Basics - Writing a note - Using the Snapshot tab) Use the Template menu to "Save" or "Save as" your file (or use the disc icon) Finding a user Click the "Find Visit" button - which will search only currently admitted patients Click the "Find Patient" button - which will search from all patients with records at UK (you can view a list of past visits for any selected patient) Select all the patients you wish to save to a personal list, and then click "Save Selected Patients" You need to make sure that the Flag New box is checked for each patient To review the patients orders, select the Orders tab Use Filters (in the left sided panel) to select orders, like view only Active orders, or labs pending collection To view the vital signs, use the Flowsheets tab Using the sidebar on the left, you can look back in time (change the dates) To review vital signs from the ED, select the ED flowsheet To view lab data Select the Results tab and then the relevant category and date (Hematology, Chemistry, etc.) Choosing Report by Order will give a chronologic timeline of all results (from the dates selected) Imaging reports (and reports from endoscopy, echo, etc.) can be found in their own sections Press F6 to open the SmartPaste window, then select 3. Lab test results (or 4. Radiology and other results for images) To view images Select the Images tab, then either PACS (for radiology results), or ECG Or select Results tab and select the relevant result To see the MAR Select the icon labeled Task Viewer To Read Notes: Click the Documents tab To see notes from prior admissions, select All available charts and expand the Date Range Search for older notes with F6 SmartPaste menus (select "7. Snapshot and Notes", then select "1. Select text from all notes") For outpatient records, run the program called "AEHR UKHC Prod" or use the new UKonnect tab Writing Orders Click the Enter Order icon (a clipboard and pen) in the upper left corner Most imaging studies can be found by starting to type the imaging modality, such as "XR", "CT" or "MR" Search within the orders by using the % symbol, like "%duplex" Some orders will open up an order set window, including: COM – Admit (the standard core admission order set) COM – Neb (which includes most of our MDI or nebulizer options) EM - Common Radiology Orders (a quick way to find imaging orders) MD - Adult - Admission (for common admitting orders) MD - Adult - Rounding orders (for common daily orders) MD - Adult - Chest pain MD - Adult - Complaint meds MD - Adult - COPD/asthma MD - Adult - Cystic fibrosis exacerbation (includes the CF-specific nebulizer orders, and may be helpful for initial antibiotic dosing) MD - Adult - GI bleed MD - Adult - Hospice standing orders (may help with hospice/comfort care symptom control orders) MD - Adult - Hospice subcutaneous orders MD - Hypo/hyperglycemia MD - Hyponatremia workup MD - Paracentesis (for ordering peritoneal fluid studies) MD - Pneumonia MD - Syncope COM - Adult – SubQ Insulin Orders COM - Adult - ACS/MI heparin protocol COM - Adult - Full dose heparin protocol COM - Adult - Low dose heparin protocol COM - Adult - Alcohol and sedative withdrawal - Non-intubated COM - Adult - Anti-emetics for non-pregnant patients COM - Adult - Colonoscopy prep COM - Adult - Foley orders COM - Adult - Hyperkalemia treatment COM - Adult - IV contrast allergy premedication protocol COM - Adult - TB diagnostics COM - Alteplase for CVAD occlusion COM - AM labs COM - Comfort care orders COM - Cortisol Stim Test COM - CSF notification (for CSF studies) COM - DKA - Adult COM - Rivaroxaban (includes the loading dose orders) EM - Common Radiology Orders PUL - Thoracentesis Admit a patient Enter the COM - Admit order, which includes several key components: Facility (Chandler or Good Samaritan) Service and Team Attending Level of care (do not select ED Observation for observation patients) Patient type (this is where you can choose Inpatient or Place in observation) Patient type (select Medicine) Telemetry Diagnosis Estimated length of stay VTE risk (with an automatic order for prophylaxis if appropriate) Core measures alert (if the patient has one of the listed diagnoses) Permission for the nurses to enter nicotine replacement orders If patient is going to Good Sam Admit the patient to Chandler Enter Capacity Ctr Consult order Enter the order Bed Request - Transfer to Good Sam Click on Order Reconciliation Choose Admission Enter a reconciliation for each item Save as Incomplete; The pharmacist will complete this document later Enter the remainder of your orders for the patient MD - Adult - Admission order set is a quick way to enter many common orders Diet Adult order Complete your admission note by clicking on the Enter Document icon Making myself the provider Not necessary if I admit a patient myself Enter a single ADT order Click on the "Enter Order" icon Enter the ADT (Change ADT Demographics) order Or - Go to the Snapshot tab, and then select Hand-Off Management Select the patients you wish to change (or use the "Select All" button) Then, find your name at the bottom and click "Assign ADT" You can use this method to assign your pager to several patients at once Go to the Snapshot tab, and then select Hand-Off Management Select the patients you wish to change (or use the "Select All" button) Then, enter your pager number (and any other information) in the relevant line, and click "Set Pager" Writing a Note Select the Enter Document icon Select your document type (such as admission note, progress note, or discharge) When you open the new document, you must select the appropriate "Service / Team" You can use F6 to access your note templates Print a Patient List You can use F6 to access your note templates Make sure that you have "Patient List" selected. Physician Rounding Report (1 patient per page) Prints a page for each patient, including the vital sign range, recent lab results, and a medication list The Signature manager is the best way to make sure that you have not missed any orders or notes that require your co-signatur Select the tab on the far right of the tab list When signing documents, remember to enter the document first if you need to add an addendum For non-urgent issues, these may be signed out through Snapshot. Remember that this only applies to Chandler teams MT4, 5, 6, 7, 8, 9, 10, and 13. MT11 and MT12 are covered at night by the resident moonlighter. Please also remember to take your patients off the cross coverage list in the morning (unless there is an ongoing issue to communicate to the night teams). Enter your signout instructions in the "Coverage To-Do List" box on Snapshot. You must add the patient to the signout list, which has been entered under team M18. Select Team Management Select "Consulting", team "M18 - Medicine / Internal Medicine Team 18", and then "Add Consulting Team. This is the same screen you should return to when you remove your patients from the cross coverage list M18 will now appear under Consulting Teams. This will make the patient show up on the M18 patient list To confirm that the patient is showing up correctly, you should create a M18 / Cross coverage team list Discharging a Patient - Use the Workflow Management Select the Workflow Management icon Choose the Discharge Workflow option Click on the Discharge Reconciliation line to open the Order Reconciliation Manager Choose the Discharge option Each item must be either 1) Continued (without a prescription), 2) Prescribed, or 3) Discontinued You can also use the icons at the top to 1) Continue all home medications 2) Discontinue everything that has not been acted on yet, 3) Enter Home Medications 4) Enter prescriptions that are not included in the list below Save as Complete at the bottom, Print or e-prescribe the medications When e-prescribing, be sure to double check which pharmacy is selected If using the Meds-to-beds service, select either "UK – Chandler retail pharmacy" or "UK – Good Samaritan retail pharmacy"; Remember that you must also place the "Meds-to-Beds" order in SCM if it is not already entered Click on the Discharge Instructions from the Workflow Management tool The actual note is fairly self-explanatory Complete the relevant and required fields, then save the note Click on the Discharge Summary from the Workflow Management tool Be sure that the Date of Service and Discharge Date at the top are correct (or you will get a letter from Medical Records) Note that the Instructions portion at the bottom of the discharge summary (from Diet, and down) will only update the actual Discharge Instructions if there is NO other Discharge Instructions document in progress Click the discharge order from either the Workflow Management tool You will have to complete the required fields within the discharge order, which includes identifying a discharge diagnosis
Statistics
Receiver Operator Curve: This estimates the accurracy of a diagnostic test. It is the probability that a randomly selected patient with Disease will have a higher test result than a randomly selected patient withOUT the disease, where a positive test should indicate that the patient has the disease.. See Hanley and McNeil, "The meaning and use of the area under a receiver operating characteristic (ROC) curve", Radiology, 143, 1982
Observational studies only show association, not causality