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.

Nephrology
Internal Medicine
Forms

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:

Anything in between is a partial response, which may be due to insufficient ADH but may also be due to other issues like limited solutes. Personally, I don't compare urine osmolality to serum osmolality. You can have inappropriate ADH if the sodium is low (so excess free water) and urine is not maximally dilute. For example, a patient with a sodium of 110 could have an ADH with urine Osm 250 and serum Osm 300 - the urine should be much more dilute than 250 even though it is still below serum osmolality.

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:

Renal retention or loss may have many causes

Potassium can be lost through the GI tract in several ways:

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:

Causes of Hyperkalemia

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.

Expanded Differential for a NON-Gap Acidosis

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.

Differential for Metabolic Alkalosis

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:

Cardiology Guidelines (includes CAD, CHF, HTN, A-Fib, and more)

COPD

Asthma

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.

  1. MDI is "Metered Dose Inhaler". This is the J-shaped 3-inch or so hand-held inhalers Picture
  2. HFA is Hydrofluoroalkane. This is the intert gas that a drug is mixed with in MDI inhalers.
  3. Spacer is a chamber that an MDI fits into and makes it easier to inhale the med Picture
  4. 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.
  5. Diskus is a circular shaped Picture

Stroke

NIHSS Stroke Scale:

Guidelines for the Early Management of Adults With Ischemic Stroke

Multiple Myeloma

Pulmonary Emboli and DVT

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
  • Unfractionated Heparin unless HIT
  • LMWH (Enoxaparin) unless renal
  • Bivalirudin (anti-Thrombin)
  • Fondaparinux (Factor Xa blocker)
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
  • Unfractionated Heparin unless HIT
  • LMWH (Enoxaparin) unless renal
  • Bivalirudin (anti-Thrombin)
  • Fondaparinux (Factor Xa blocker)
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.

Critical Care

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

GI Topics

Scales


ECOG:
Grade 0Fully active; no restrictions
Grade 1Cannot perform strenuous activity. Can perform light work and also can care for self
Grade 2Can fully care for self, but cannot work. Up and out of chair and bed more than 50% of the day
Grade 3Cannot fully care for self. Up and out of chair and bed less than 50% of the day
Grade 4Cannot care for self, disabled. Confined to chair or bed
Grade 5Dead

METS:

4walking 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:

1Dressing, Bathing
2Walk around your house
3Walk a block
4Climb a flight of stairs
5Run a short distance
6Wash dishes
7Vacuum or carry in groceries
8Scrub floor or move heavy furniture
9Rake leaves
10Sex
11Golf or bowling
12Swimming 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

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.

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.

Pituitary Nodules

Get Prolactin, TSH, IGF-1 levels, and a 24-hour cortisol collection.






Hypertension

Target blood pressures

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).

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



Common CVVH Settings





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.

There are several possibly ways to reconcile the AKIKI and ELAIN trials:

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.

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:

Note that a patient with inflamed peritoneum (as in acute peritonitis) will temporarily become a rapid transporter because the inflammation makes capillaries leaky. To see if a non-inflamed patient is a rapid transporter, do a PET test one month after initiating PD. A PET test is a 4 hour dwell of 4.25% dialysate. If they UF less than 400 mL then they are a rapid transporter. You wait a month because everybody has some inflammation for the first month after starting PD.

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) * 7
Peritonitis
PD Dialysis Troubleshooting

Dialysis Filter Clearance and KT/v

Predicted Kt/V

K * t / V where:

FilterBFR 200BFR 300BFR 400BFR 500
Fresenius Optiflux-160NR194266308
Fresenius Optiflux-180NR196274323
Fresenius Optiflux-200NR197277330
Baxter Exceltra-170196260310341
Baxter Exceltra-190197273323354
Baxter Exceltra-210199287350384
Baxter Revaclear196271321353
Baxter Revaclear-MAX198282339376




Other CKD - NSAID, PKD, AIN

NSAIDs
NSAIDs will injury the kidney with several mechanisms:



Polycystic Kidney Disease

Genetics

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:


Criteria if no Family History:

Complications:

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

Rhabdo
Treat:

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, fever

Common 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

Utility of Urine Eosinophils in the Diagnosis of Acute Interstitial Nephritis Angela K. Muriithi*, Samih H. Nasr†, Nelson Leung* CJASN September 2013 CJN.0133021 http://cjasn.asnjournals.org/content/early/2013/09/18/CJN.01330213.abstract

Some other causes of AIN and CIN

Chronic Interstitial Nephritis
Pathology
Gross findings: dilated calyces, paranchymal thinning

Light 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
AV Fistula Physical Exam
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

Features INconsistent with pre-eclampsia

Risk factors

Treat: There is no BP target for pregnancy.

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?)

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

Injury Types Seen on Pathology



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


Classes III, IV and V are each further subdivided into "active" and "chronic" III and IV are also subdivided into Segmental and Global, depending on whether they affect the entire glomerulus or less than half of each glomerulus.
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

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/

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.

After initial therapy is complete, start maintenance therapy. There are several possible regimens.

If a patient has complete remission, then treat with maintenence for at least one year. One review course had a well known expert say he would use maintenance therapy for up to 3 years. If there is a partial response, then treat longer, but there is no evidence to suggest how long. Average durations in many trials was 3.5 years. Check urine Prot/Cr ratios, complements, dsDNA, and Creatinine.

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.

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
The Glom appears normal under light microscopy - capillaries are open, BM is not thick, no mesangial hypercellularity. This can affect patients of any age, not just kids.
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)

May have relapses, and/or become steroid dependant. If you use Cyclosporine or Tacrolimus, then taper it to the minimum dose that can maintain remission.

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.

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

There are several subtypes identified in light microscopy.

Endothelial tubular-endoreticular inclusions are associated with high IFN level so due to HIV (mainly) and SLE (less common).

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)

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
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:

At all stages, there is podocyte foot process effacement, which seems to cause the nephrotic proteinuria. It seems that the subepithelial deposits are somehow toxic to the podocytes.
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

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.

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:

Newer taxonomy divide the disease by the type of deposit

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 I

The 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
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
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

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

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:

One third of ANCA patients also have anti-GBM, so always check for that - it will affect therapy.

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.

There are also lerger vessel arteritis diseases, which may affect the renal, interlobar, arcuate or interlobular arteries, but typically not capillaries. Polyarteritis Nodosa is similar to Microscopic Polyangiitis, but Polyarteritis Nodosa affects these larger vessels while Microscopic Polyangiitis affects capillaries in the glomerulus.
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

About 90% of all patients will be ANCA positive, but then 10% are ANCA negative. The ANCA antibodies seem to be pathogenic, not just a marker of disease. Removing the antibodies (plasmex, B-cell targeted therapies) is important.

There are several subtypes, each seems to be triggered by a different auto-antigen.

Systemic Symptoms and Signs
This is a systemic inflammation, and so may be part of a systemic disease This is a relapsing/remitting disease. Most predictive marker for relapse is PR3 ANCA. It can affect small to medium sized arteries.
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 Interestingly, IV Cyclophosphamide at 3-4 week intervals is equally effective and has fewer side effects than daily PO Cyclophosphamide. Treat 3 to 6 months. If there are NO extra-renal symptoms and the patient is dialysis dependant, then stop Cyclophosphamide after 3 months.

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.

Remission is defined as no symptoms or signs of vasculitis, no hematuria and stable or improving Cr and proteinuria.

Maintenance Therapy

Treat for at least 18 months.

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 There is no maintenance Therapy. Oddly, once people are treated there is little recurrence. Treat for 8-16 wks and then can stop IS. People rarely relapse if pure anti-GBM. Now, if there is a combination AntiGBM/ANCA, then they need long term treatment for the ANCA.

There is no recurrence after transplant - maybe because because the transplanted kidney does not expose the hidden antigens?




Alport

Systemic Symptoms

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

  1. MAHA (microangiopathic hemolytic anemia - anemia, schistocytes, high LDH, Low Hapto)
  2. Thrombocytopenia
  3. Organ dysfunction - renal/neuro/GI
  4. Exclude DIC - Normal PT/PTT

TMA Causes

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

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.
Disorganized Deposits of Immunoglobulin Chains

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 2
Subtypes

This is the Renal Pathology Society classification

There are also stages based on symptoms and overal renal functional status

Diagnosing Diabetic Nephropathy
Some common features:

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:





Renal Pathology Notes

The arteries are fairly simple

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:





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

Elevated FGF-23 is bad

Low Klotho is bad.

High PTH is bad, but it usually has to be very high before treating.

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.





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. Each person has 6 HLA genes, with 2 alleles per gene (one from mother and one from father) so a total of 12 alleles. Each allele may have many different gene values (for example, there are many different types of HLA A gene). In transplant, we seem to mainly look at HLA A, HLA B, HLA DR. Why not all 6? Maybe there is less variation in the others, or their antigens are more buried in the HLA protein complex so they are less immunogenic.

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).
Banff Grading
Give a score of 0 (none), 1 (mild), 2 (moderate), 3 (severe) for each of 4 areas: infiltrate, tubulitis, arteritis, glomerulitis
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

Induction Immunosuppression

Use a depleting induction for

Immunosuppression and Rejection Studies

Chronic Immunosuppression Take one from group 1 and one from group 2.

Studies

Tacrolimus levels. These are not standardized - every center will have different guidelines.

Manage CNI side effects

Calcineurin is also used in Insulin signalling, which may be part of why Cancineurin inhibitors lead to decreased Insulin secretion and Insulin Resistance.

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

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

Eosinophillia is not useful.

Utility of Urine Eosinophils in the Diagnosis of Acute Interstitial Nephritis Angela K. Muriithi*, Samih H. Nasr†, Nelson Leung* CJASN September 2013 CJN.0133021 http://cjasn.asnjournals.org/content/early/2013/09/18/CJN.01330213.abstract

Cell Shapes

Crystals

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

Possible Causes

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

Stone Risks

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

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 velocity
It 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:
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:

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

Pathophysiology

Diagnostic Criteria

Treat 












 

AKI vs ATN Thoughts




Lets start with a few definitions - 





There are several causes of ATN





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:




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 HAP


Criteria for HAP (as opposed to CAP)




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)




Duration - 7-day course of antimicrobial therapy 



Ventillator Associated Pneumonia

This is taken from IDSA Guidelines for HAP


Cover MRSA, Pseudomonas aeruginosa, and other gram-negative bacilli in all empiric regimens.




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




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 CAUTI
 

Cystitis Empiric Treatment:


    

Acute Pyelonephritis Empiric Treatment


    

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:


Blood cultures do not provide additional clinically relevant information. 
Diffuse peritonitis should undergo an emergency surgery. If suspected appendicitis, then surgery as soon as possible and start empiric antibiotics. 
If no immediate surgery, then keep inpatient for at least 2 days and antibiotics at least 3 days.
Generally, if immediate surgical repair of anything, then stop antibiotics within 24hrs. 
If severe necrotizing pancreatitis, no empiric antibiotics.
If no improvement after 4-7 days of antibiotics, then repeat CT or ultrasound. 



Empiric Antibiotics:







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.


Treat for 4-7 days







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


Empiric coverage should also cover MRSA if the patient was colonized or is at particularly high risk, so may include Vanc.
Treat for 4-7 days







Cholecystitis and Cholangitis


Empiric antibiotics


Treat for 4-7 days. Empiric enterococci coverage is not required. 
Stop antibiotics 24hrs after cholecystectomy unless there is infection outside the gall bladder.









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









 

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