Cyberfriends: The help you're looking for is probably here.

Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at www.afraidtoask.com.

If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

With one of four large boxes of "Pathguy" replies.

I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.

This page was last updated February 9, 2008.

During the thirteen years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!

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Describe what the kidneys do in health. Describe the different parts of the nephron, what each does, and what things are likely to happen when each malfunctions.

Recognize the causes of acute renal shutdown and of irreversible renal failure. Describe the many clinical and anatomic consequences of uremia.

Recall the clinical, gross, and microscopic pictures, when applicable, for each of the following:

Horseshoe kidney
Adult polycystic kidney disease
Autosomal recessive polycystic kidney disease
Acquired dialysis cystic disease ("trans-stygian kidneys")
Medullary sponge kidney
Simple cysts
Multicystic dysplastic kidney ("cystic dysplasia")

Describe what is happening in each of the following syndromes. Tell what you might see clinically, grossly (when applicable) and microscopically (when applicable), and mention its common causes.

Nephritic syndrome
Nephrotic syndrome
Rapidly progressive glomerulonephritis
Asymptomatic hematuria of glomerular origin
Hemolytic-uremic syndrome
Acute tubular necrosis
Tubular proteinuria
Fanconi syndromes
Acute pyelonephritis
Chronic interstitial nephritis (including "chronic pyelonephritis")
Urate, oxalate, hypokalemic, myeloma, and radiation nephropathies
Benign "essential" high blood pressure
Malignant hypertension
Renal high blood pressure
Other secondary high blood pressure syndromes
Atheroembolization
Hydronephrosis
Nephrolithiasis
Renal cell carcinoma
Wilms tumor
Transitional cell (urothelial) carcinoma of the renal pelvis

Explain how casts form. Mention the various casts that may appear in the urine in health and disease, and what they mean.

NOTE: For changes in blood chemistry (blood urea nitrogen, creatinine, creatinine clearance, etc.), see my unit on renal function testing I also have a unit on urinalysis.

QUIZBANK... Metabolic #'s 82-92; Kidney (all)

"Patterns": Kidney #'s 1-40
"Glomeruli": Kidney #'s 78-172
"Tubulointerstitial": Metabolic #'s 82-92; Kidney #'s 41-53, 63-77, 173-179, 192-204, 220-240
"Hypertension / Tumors / Stones": Kidney #'s 54-62, 180-191, 205-219

"What's the difference between beer and urine?"
"About twenty minutes!"

"What's the difference between a nephrologist and a neurologist?"
"The 'p'!"

One thing that makes kidney pathology so hard is that many of the words sound alike. Here are the most troublesome words:

Collagenized glomeruli: These glomeruli have been obliterated by dense type I collagen. Most often, the collagen has been laid down concentrically on the inner surface of Bowman's capsule, as in longstanding arterial/arteriolar disease. Collagenized glomeruli are more often called hyalinized or obsolescent, despite the fact that these terms are less specific.

Diffuse: As applied to glomerular disease, all the glomeruli are involved.

Fibrosis: Dense, type I collagen deposited in the glomeruli and/or interstitium and/or vessels.

Focal: As applied to glomerular disease, some glomeruli are involved and some are not.

Global: As applied to glomerular disease, if a glomerulus is involved, all portions of it are involved.

Glomerulonephritis: As usually used, this implies that the glomeruli are sufficiently inflamed to cause at least a few of them to lose blood into the tubules.

("Glomerulonephritis" without nephritic syndrome -- i.e., "membranous glomerulonephritis", "minimal-change glomerulonephritis", etc. -- is a less-common usage. Better to call these "glomerulopathy".)

Glomerulopathy: Any primary problem with the glomeruli.

Glomerulosclerosis, diffuse: Thickening of the basement membrane as a result of diabetes mellitus.

Glomerulosclerosis, focal/segmental: A pattern of injury with foot process fusion and hyalinization of some lobules in some glomeruli. It has nothing to do with diabetes mellitus.

Glomerulosclerosis, nodular: Diabetes mellitus with Kimmelstiel-Wilson disease. Always superimposed on diffuse glomerulosclerosis.

* Hyalinosis: A distinctive, homogeneous pink blob seen in certain sick glomeruli, notably those damaged by FSGS, diabetes, or other causes of hyperfiltration.

Hyalinized glomeruli: A term that can mean collagenized or sclerotic glomeruli.

Hypernephroma: Obsolete term for renal cell carcinoma.

Nephritis: Used by itself, this means "glomerulonephritis".

Nephritis, interstitial: Inflammation of the kidney that spares the glomeruli. Includes cases formerly diagnosed as "chronic pyelonephritis". Causes U-shaped cortical scars.

Nephroblastoma: The common childhood cancer of the kidney -- Wilms tumor.

Nephrocalcinosis: Calcification of the basement membranes of the tubules in the medullae. It has nothing to do with calcium stones. A little calcification here is common, especially in older people. Extensive calcification suggests hypercalcemia ("metastatic calcification").

Nephrolithiasis: Stones (calculi) in the pelvis of a kidney

Nephropathy: Anything wrong with the kidney -- glomeruli, tubules, or vessels.

Nephrotic syndrome: The sequelae of heavy protein leakage at the glomerular capillaries.

Nephrosclerosis: Disease of the renal arteries and/or arterioles.

Nephrosclerosis, arterial: Multiple small infarcts destroying scattered groups of glomeruli. Causes V-shaped cortical scars. Usually caused by atheroembolization.

Nephrosclerosis, arteriolar: Vascular disease that destroys scattered individual nephrons. Causes sandpaper-surface kidney. "Benign nephrosclerosis". Caused by high blood pressure and/or diabetes.

Nephrosclerosis, benign: Arteriolar nephrosclerosis due to "benign essential hypertension".

Obsolescent glomeruli: Another term that can mean collagenized or sclerotic glomeruli.

Pyelonephritis: Inflammation of the interstitium of the kidney. Current usage mostly limits this to bacterial infection.

Sclerosis: As applied to kidney, this means increased basement membrane/mesangial matrix material obliterating loops of a glomerulus.

Sclerotic glomeruli: These glomeruli are fully replaced by basement membrane/mesangial matrix material, as in advanced diffuse, nodular, or focal-segmental glomerulosclerosis. They are also called hyalinized or obsolescent.

Segmental: As applied to glomerular disease, some portions of some glomeruli are involved and some other portions of the same glomeruli are spared.

Here is a list of the more important entities that are likely to be caused by a particular pattern:

Subepithelial, large, irregularly-spaced ("coarse granules") Diffuse proliferative GN (especially post-streptococcal) Membranoproliferative GN type I Lupus, class IV

Subepithelial, uniform, evenly-spaced ("fine granules evenly spaced") Membranous glomerulopathy (any cause) Lupus, class V

Anti-GBM diseases ("smooth linear" -- don't expect to see these on EM) Goodpasture's, others

Subendothelial (various descriptions, you will only need to recognize on EM) Membranoproliferative GN type I Lupus, especially class IV ("wire loops") Cryoglobulinemia Hemolytic-uremic syndrome ("fluff") Also look here for amyloid deposits.

Intramembranous (various descriptions, depends on the disease) Dense deposit disease (membranoproliferative GN type II) Late membranous glomerulopathy Late stages of any other progressive immune complex disease

Mesangial ("mesangial pattern") IgA nephropathy IgM mesangial-proliferative glomerulopathy Membranoproliferative GN type I Lupus, any class Also look here for amyloid deposits.

{11850} kidney, model
{11851} kidney, model, close-up

INTRODUCTION TO KIDNEY DISEASE

To review:

In health, your body fluid tonicity is regulated by ADH and thirst. These mechanisms work extremely well.

In health, your body fluid volume is regulated primarily by atrial natriuretic peptide, which is produced when the right atrium feels that extra stretch, and which mediates a host of effects. Since body fluid tonicity is so well-regulated, body fluid volume is essentially a measure of total body sodium. This mechanism works pretty well.

In health, your total body potassium is regulated primarily by diffusion of potassium out of the near portion of the distal convoluted tubule in response to intracellular pH shifts, which in turn reflect your potassium load. This mechanism doesn't work very well.

In health, your total body base ("the metabolic component of your pH adjustment", etc., etc.) is regulated by the carbonic anhydrase mechanism in the proximal tubule, i.e., the more CO₂ on board, the more intracellular bicarbonate is produced, the more bicarbonate is resorbed, and the more protons get sent away in the urine. This mechanism works kind-of, and it takes days.

Kidney disease is prevalent and usually serious.

In 2004 in the USA, 100,000 people began dialysis, and 335,000 were receiving ongoing dialysis. The numbers keep increasing mostly because the population is living longer, Uncle Sam is happy to dialyze people at any age, and today's end-stage kidney has usually been taking damage for decades from hypertension, diabetes, chronic infection, and/or cystic disease. The picture is similar around the world: Lancet 365: 331, 2005.

In the mid-1990's, the US government paid $11 billion annually to maintain its chronic hemodialysis program. (I can't find the current expenses -- anybody know?) Everyone has a "right" to hemodialysis under this program, which is curious. By contrast, most other industrialized democracies ration dialysis but provide basic health care to everyone (JAMA 273: 1118 & 1123, 1996).

The typical end-stage kidney patient spends a few years on dialysis (not as bad as it once was, but still not fully healthy -- Am. J. Kid. Dis. 27: 557, 1997, annual cost to "somebody" at the time was $47,000 for peritoneal dialysis and $76,000 for hemodialysis) and perhaps gets transplanted a few times (a better way to live, and cheaper; costs are around $52,000 per transplant procedure Surg. Clin. N.A. 78: 149, 1999).

Right now, we have 70,000 people in the US actually awaiting kidney transplantation (Am J. Kid. Dis. 49: 180, 2007). If you start on hemodialysis and you do not get a transplant, you chance of being alive in five years is 35% (NEJM 357: 1316, 2007), and you will experience a great deal of malaise and fatigue.

All about dialysis: Lancet 353: 737, 1999. Today, a very sick patient may be placed on "continuous renal replacement therapy" instead of being dialyzed every few days; it's more expensive and it's not clear that outcomes are much better (Crit. Care Med. 31: 449, 2003; probably no better JAMA 299: 739, 2008).

*  Ethics: Am. J. Kid. Dis. 15: 218, 1990 (classic article). What to do when somebody wants to discontinue and die: Am. J. Kid. Dis. 28: 147, 1996. The elderly seldom live long on dialysis: JAMA 271: 29 & 34, 1994. A search shows that there has been no "controversy" for the past decade about allowing folks to discontinue dialysis -- autonomy as a principle of medical ethics is once again triumphant.

Whether you get kidney disease is mostly dumb luck. But whether it progresses to end-stage kidney failure does depend largely on what gets done about it.

Once kidney disease gets underway, it is self-perpetuating, causing sclerosis of the glomeruli. ACE inhibitors and dietary protein restriction greatly slow the process. See Lancet 338: 419 & 423, 1991 (protein restriction is now challenged: Nat. Clin. Pr. Nephro. 3: 383, 2007). Update on slowing the progression of renal disease (in-the-works are such things as endothelin blockers, anti-oxidants, antifibrotics, cytokines, statins-for-all, etc.): Am. J. Med. 118: 1323, 2005.

The JAMA proclaimed in 2007 that the prevalence of chronic kidney disease (i.e., microalbuminemia and elevated serum creatinine) in the US is increasing (1988-1994 vs. 1999-2004). However, most of this is due to more hypertension and diabetes, and no one questions that the likelihood of progresion to dialysis dependence is less today.

* Before you accept this uncritically, note that the authors themselves admit that they assumed everyone with a high-normal creatinine had "decreased GFR", i.e., every man who strength-trains, and every "big" man, is suddenly a kidney case. Your lecturer (a carnivorous, physically-fit middle-aged man who runs his BUN 25-35 mg/dL and his creatinine of 1.3 - 1.4 mg/dL) would be considered to have partial kidney failure. The authors also admit that their database "oversampled" minorities and the elderly, and it's not clear that the two eras were comparable demographically.

* Historically, African-Americans are more at risk for end-stage kidney disease, for reasons that include the greater severity and frequency of hypertensive kidney disease in this population. Whether their problems are neglected by doctors, or treated less skillfully, or whether the real explanation lies elsewhere, seems to me to remain unanswered. The discrepancies are disappearing (or have perhaps completely disappeared when one controls for poverty: Med. Clin. N.A> 89: 419, 2005).

The Zuni people of our southwest have a terrible problem with both diabetic kidney disease and glomerulonephritis (Arch. Path. Lab. Med. 113: 148, 1989; ongoing Am. J. Kid. Dis. 39: 358, 2002; Am. J. Kid. Dis. 41: 1195, 2003; J. Am. Soc. Neph. 14(7S2): S-139, 2003). I would not be surprised if the cause is virus (betting on an undiscovered hantavirus), but this is not proved. By contrast, the pathologists at the New Mexico medical school think it is IgA nephropathy secondary to alcoholic liver disease (J. Histochem. Cytochem. 38: 699, 1990). Since the Zuni are highly inbred and genetics obviously plays a role in the IgA nephropathy (Kid. Int. 57: 1818, 2000) as well, very likely we are looking at an unfortunate series of events.

Hantavirus in the kidney Korean hemorrhagic fever Yutaka Tsutsumi MD

Adenovirus of the kidney Advanced students Yutaka Tsutsumi MD

In just one town, at least 66 people who wrecked their own kidneys by shooting heroin ("heroin nephropathy") were being maintained in the 1980's at a yearly cost of over $1.3 million to the public (JAMA 250: 2935, 1983). I doubt that things are much different today. The true prevalence and cost of heroin nephropathy are probably many times higher.

In the United State, society now balks at expensive, life-saving care for children who are in the country illegally. Dialysis, along with chemotherapy and transplantation, features prominently in these discussions (Pediatrics 114: 1316, 2004).

Foregoing dialysis for the severely mentally handicapped seems to be much more acceptable nowadays than in the past (Am. J. Med. Sci. 320: 374, 2000 -- "paternalism" is of course still wicked but "autonomy is out of the question").

Kidney failure due to acute tubular necrosis is a common, potentially lethal complication in the intensive-care unit. Renal insufficiency due to underperfusion (dehydration, shock or a failing heart) or due to obstruction are extremely common.

High blood pressure commonly results from kidney problems, and in turn always damages the kidneys to some extent.

At least 10% of women will get acute pyelonephritis during their reproductive years, often during pregnancy.

At least 1% of people will pass a kidney stone, producing some of the most severe pains in disease. Because of dehydration (hot temperatures, poor-quality drinking water), one out of every eight of our soldiers in Vietnam passed a kidney stone while there.

Kidney transplantation allows a near-normal, healthy life -- as long as the graft lasts. The histopathology is reviewed in Am. J. Surg. Path. 8: 243, 1984 (still good); NEJM 349: 2326, 2003 (how the changes progress with today's therapy). See below.

CHRONIC ALLOGRAFT NEPHROPATHY is the usual cause of a graft failing. It is a combination of:

• intimal thickening in the arteries


• hyalinization and narrowing of the arterioles


• inflammation and fibrosis/sclerosis of the glomeruli


• atrophy of the tubules


• fibrosis of the interstitium


• splitting of basement membranes in arteries, arterioles, and glomeruli ("tram tracks" -- we'll see them again)


• T-cells where they don't belong, especially attacking vessels and tubules



Pathologists grade it by the 1995 Banff system. Since the worst problem is really vascular narrowing (arteries plus arterioles plus glomeruli), its severity can be estimated without biopsy by measuring blood flow resistance using Doppler (NEJM 349: 115, 2003), sparing your patient a biopsy.

The classic idea that the heart must still be beating if the kidney taken for transplant is to work well is now challenged by new data (Br. J. Surg. 92: 113, 2005). I hope this works out.

One big surprise in recent years is that with today's immunosuppressive regimens, a kidney from your husband or wife lasts almost as well as "somebody who is a wonderful HLA match" (NEJM 333: 333 & 379, 1995). This discovery has transformed the whole business of transplantation, and has been a major boost to the practice, now common in some nations, of the living selling their organs to those in need. See below.

The glomerular diseases that tend to recur in transplanted kidneys are FSGS, membranous GN, membranoproliferative GN, and IgA nephropathy. Still, fewer than 10% of people with glomerulonephritis lose the graft to a recurrence (NEJM 347: 103, 2002.)

Worth knowing in the transplant era: Lymphocytes under the endothelium? "Endothelialitis" -- vascular transplant rejection!

Acute transplant rejection Vessel changes KU Collection

Kidney transplant WebPath Photo

REVIEW OF NORMAL ANATOMY AND PHYSIOLOGY

Normal kidney Uncut WebPath Photo

Normal kidney Cut section WebPath Photo

Baby kidneys WebPath Photo

Baby kidneys WebPath Photo

Glomeruli forming
in newborn
ERF/KCUMB

* According to most contemporary biologists, kidney design makes the most sense in light of its former functions in prehistoric life and present-day ocean creatures. Otherwise, the kidney is hard to understand.

Each adult kidney weighs around 150 grams and is composed of about 1 million nephrons that drain into about 14 calyces.

By forming urine, the kidney performs three important functions.

1. The kidney excretes the waste products of metabolism

A patient with any sort of impaired kidney function will have increased creatinine and urea nitrogen in the blood, or azotemia. If the kidney is adequately perfused, itself normal, and its outflow not obstructed, blood urea nitrogen levels will remain within normal limits.

2. The kidney regulates the body's content of water, sodium, and potassium.

Hypertension, edema, and/or hyperkalemia may develop in renal disease. Renal edema is first visible around the patient's eyes.

3. The kidney maintains the appropriate acid-base balance of plasma

Metabolic acidosis is characteristic of severe renal failure, because you cannot get rid of the sulfate and phosphate ions that you generate from burning your food.

The kidney also makes renin (REE-nin, please) and erythropoietin, and activates vitamin D.

High blood pressure, anemia, and bone demineralization are common in serious kidney disease.



Endothelial cells have fenestrae (70-100 nm in diameter) that give plasma free access to the glomerular basement membrane.

Glomerular basement membrane ("GBM") is largely special collagen (type IV) that is the major permeability barrier. It also contains polyanions (heparan sulfate, etc.) and other substances that are additional barriers.

* The alleged division of the GBM into lamina rara interna, lamina densa, and lamina rara externa is an artifact of no consequence.

Visceral epithelial cells ("podocytes") display interdigitating cell processes (foot processes) that grasp the capillaries. The foot processes are separated by "filtration slits" that are bridged by diaphragms with little rectangular pores (4 x 14 nm).