KIDNEY DISEASE
Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com

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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.

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Pathology's modern founder, Rudolf Virchow M.D., left a legacy of realism and social conscience for the discipline. I am a mainstream Christian, a man of science, and a proponent of common sense and common kindness. I am an outspoken enemy of all the make-believe and bunk that interfere with peoples' health, reasonable freedom, and happiness. I talk and write straight, and without apology.

Throughout these notes, I am speaking only for myself, and not for any employer, organization, or associate.

Special thanks to my friend and colleague, Charles Wheeler M.D., pathologist and former Kansas City mayor. Thanks also to the real Patch Adams M.D., who wrote me encouragement when we were both beginning our unusual medical careers.

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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.

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.

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More of Ed's Notes: Ed's Medical Terminology Page

Perspectives on Disease
Cell Injury and Death
Accumulations and Deposits
Inflammation
Fluids
Genes
What is Cancer?
Cancer: Causes and Effects
Immune Injury
Autoimmunity
Other Immune
HIV infections
The Anti-Immunization Activists
Infancy and Childhood
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Environmental Lung Disease
Violence, Accidents, Poisoning
Heart
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Porphyria
Urinalysis
Spinal Fluid
Lab Problem
Quackery
Alternative Medicine (current)
Alternative Medicine (1983)
Preventing "F"'s: For Teachers!
Medical Dictionary

Courtesy of CancerWEB

Atlas of Renal Pathology
Vanderbilt / National Kidney Foundation
Agnes Fogo MD -- thank you!

Kidney Images
University of Washington
Pictures and comments

Urinary Tract
Iowa Virtual Microscopy
Have fun

Nephrology
Utah cases for path students
Juliana Szakacs MD

Urinary System
First Section
Chaing Mi, Thailand

Pathology of GU infections
Great site
Yutaka Tsutsumi MD

Urinary System
Second Section
Chaing Mi, Thailand

Urinary System
Third Section
Chaing Mi, Thailand

Urinary System
Fourth Section
Chaing Mi, Thailand

Urinary System
Fifth Section
Chaing Mi, Thailand

Renal Cases and Tutorial
J. Charles Jennette MD
University of North Carolina

Kidney Exhibit
Virtual Pathology Museum
University of Connecticut

Kidney Transplant Pictures
Great site
Transplant Pathology Internet Services

Kidney Transplant
From Chile
In Spanish

Tulane Pathology Course
Great for this unit
Exact links are always changing

Kidney I
Great pathology images
Indiana Med School

Renal Pathology
Virginia Commonwealth U.
Great pictures

Gross Kidneys
Tulane
Big selection

The Kidney in Systemic Disease I
From Chile
In Spanish

The Kidney in Systemic Disease II
From Chile
In Spanish

Primary Nephropathies I
From Chile
In Spanish

Primary Nephropathies II
From Chile
In Spanish

Primary Nephropathies III
From Chile
In Spanish

Primary Nephropathies IV
From Chile
In Spanish

Renal
Photos, explanations, and quiz
Indiana U.

Renal Disease
Mark W. Braun, M.D.
Photomicrographs

Kidney I
Introductory Pathology Course
University of Texas, Houston

Kidney II
Introductory Pathology Course
University of Texas, Houston

Kidney and Male Pathology
Photomicrograph collection
In Portuguese

Kidney Gross
Introductory Pathology Course
University of Texas, Houston

Kidney Histology
Ed's Histology Notes

Kidney
"Pathology Outlines"
Nat Pernick MD

Atlas of Diseases of the Kidney
Robert W. Schrier
Classic photo series

Learning Objectives

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:

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.

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)

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

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

VOCABULARY

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.

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.

IMMUNE DEPOSITS

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:

Kidney disease is prevalent and usually serious.

Hantavirus in the kidney
Korean hemorrhagic fever
Yutaka Tsutsumi MD

Adenovirus of the kidney
Advanced students
Yutaka Tsutsumi MD

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

{46463} scanning electron micrograph of podocytes

      The whole filter (essentially the GBM) is very permeable to water and small solutes, but it excludes most albumin and larger proteins from the filtrate.

        The permeability barrier is size-dependent (3.5 nm), and is also charge-dependent (the polyanions exclude albumin and other anionic macromolecules.)

        Loss of polyanions will let albumin through (selective proteinuria). If the filtration barrier is severely damaged, larger proteins will leak out (nonselective proteinuria). A leaky GBM results in the nephrotic syndrome.

        If some of the capillaries rupture, there will be hematuria. If the capillaries are badly enough damaged to release much fibrin, the glomerulus will probably get replaced by scar tissue, and the tubule will atrophy and probably disappear.

    Glomerular structure and function:

      The glomerulus is essentially a tuft of around 50 capillaries, each of which is a unit of the filter. They are surrounded by Bowman's capsule, which encloses the urinary space.

        The capillaries in a glomerulus arise from one afferent arteriole and drain into one efferent arteriole.

        They tend to group loosely into lobules of about ten capillaries each. Don't expect to be able to distinguish the lobules of a healthy glomerulus.

      Glomerular capillary pericytes are called mesangial cells.

        These produce mesangial matrix, which is the supporting framework for the GBM and is chemically the same.

        Mesangial cells are contractile, helping regulate flow and filtration rate in the glomerular tuft; Am. J. Kid. Dis. 16: S-2, 1990) and probably phagocytize most things that shouldn't have gotten through the filtration membrane.

        * Tip: In looking at an electron micrograph of glomerulus, orient yourself by finding something you are sure is a red cell, or are sure is the GBM.

      The parietal epithelial cells that surround the tuft, together with their basement membrane, make up Bowman's capsule.

        As noted, the capsule encloses the "urinary space" and is continuous with the proximal convoluted tubule.

      Glomerular filtration rate ("GFR", i.e., the volume of plasma filtered into the urinary space per minute) should be about 120 mL/min for an adult. (GFR is estimated clinically by measuring creatinine clearance.)

        Naturally, this varies directly with blood pressure, which in turn reflects the volume of fluid that is effectively circulating.

        A working definition of adult chronic kidney disease is GFR<=60 for three months, or albuminuria >=30 mg/gm of creatinine.

    The juxtaglomerular apparatus is a group of special cells at pole of nephron formed from both afferent arteriole and distal tubule.

      They are sensitive to volume, pressure, and sodium concentration in both.

      They produce renin and adjust the GFR (by constricting the afferent arteriole, etc.) as necessary to maintain adequate systemic blood pressure.

      Renin generates angiotensin II, which in turn raises systemic blood pressure by constricting arterioles, causing thirst, and causing production of aldosterone.

      Renin isn't produced when microvascular disease has damaged the JGA. This is probably an important mechanism of "renal tubular acidosis type 4", a popular diagnosis, in which there is underproduction and/or under-response to aldosterone (hence, often hyperkalemia).

    Tubular function:

      The PROXIMAL CONVOLUTED TUBULE reabsorbs substances from the glomerular filtrate, including ions, glucose, phosphate, bicarbonate, amino acids, vitamins, and the smallest proteins (albumin, beta2-microglobulin), in isotonic solution. Of course, most of the sodium, potassium, chloride, and water in the glomerular filtrate are absorbed here, too.

        The proximal convoluted tubule also secretes para-aminohippuric acid, uric acid, etc., and probably makes erythropoietin.

        A patient with impaired function of the proximal convoluted tubule will lose substances in the urine (glycosuria, amino-aciduria, microglobulinuria, potassium, "renal tubular acidosis type 2").

      The DISTAL NEPHRON retains or excretes water, ions, and protons, as required for homeostasis.

        A patient with impaired function of the distal nephron cannot concentrate urine (hyposthenuria / nephrogenic diabetes insipidus).

          The patient will first notice this when he or she starts having to get up at night to urinate (nocturia).

          In severe disease, the specific gravity becomes fixed at 1.010 (iso-osmotic urine; "isosthenuria" -- healthy folks can usually dilute to 1.003 and concentrate to 1.030).

        A patient with impaired function of the distal nephron often cannot dispose of protons (renal tubular acidosis type 1; these patients also tend to become hypokalemic -- why?)

          Some genetic forms involving ion exchangers are known, but most result from renal or systemic disease.

          * Untreated, the most severe cases can result in "Tiny Tim's disease" (Arch. J. Dis. Child. 146: 1403, 1992), with growth retardation, crippling and malforming osteomalacia, and episodes of weakness.

          "Renal tubular acidosis type 3" is just a combination of types 1 and 2.

      The individual units of the distal nephron are:

      The LOOP OF HENLE is responsible for maintaining a hypertonic interstitium in the medulla. This is the famous "countercurrent multiplier" mechanism.

      The DISTAL CONVOLUTED TUBULE is the site of sodium (and hence water) resorption, and of potassium and proton ("fixed acid") excretion.

        A high GFR produces rapid flow of filtrate through the distal convoluted tubule, resulting in little sodium resorption. A low GFR will have the opposite effect. This of course is important in regulating intravascular fluid volume and blood pressure.

        The distal convoluted tubule is also influenced by aldosterone, which promotes sodium retention and potassium and proton loss. Aldosterone comes from adrenal gland under stimulus of renin-angiotensin and of salt-and-water depletion.

      The COLLECTING DUCT is site of anti-diuretic hormone (hADH) action.

        This neuropeptide is produced when osmoreceptors in the hypothalamus determine the need for the body to retain water. It opens little pores in the walls of the collecting ducts, allowing water to flow back into the hypertonic renal interstitium.

        Inability of the collecting duct to respond to hADH produces nephrogenic diabetes insipidus.

        "Atrial natriuretic factor" (hANF, atriopeptins, etc.), the most important of several natriuretic peptides (NEJM 399: 321, 1998). It comes from the atria, cause loss of water and sodium by several mechanisms. It's released when the right atrium is stretched. This is probably the overriding way in which we regulate our volume in health.

          ANF...

          • relaxes the mesangial cells, letting more salt water filter out of the glomerular capillaries;
          • blocks the effects of most vasoconstrictors on most blood vessels;
          • blocks production of hADH by the neurohypophysis;
          • blocks production of renin in the juxtaglomerular apparatus.
          • probably does something to the distal nephron as well, since you get rid of sodium very effectively.

      Tubular diseases that prevent reabsorption of water (or a non-resorbable substance in the filtrate) will produce polyuria (urine volume more than 1500 mL/day). Plugged or leaky tubules (or low GFR) will cause oliguria (urine volume less than 500 mL/day.)

      Casts in the urinary sediment are cylinders of congealed Tamm-Horsfall protein produced by the tubular cells. They may contain other formed elements that aid in the diagnosis of kidney disease.

        Hyaline casts do not contain formed elements, and are a normal finding.

        Epithelial casts contain renal tubular cells and suggest interstitial disease or acute tubular damage. Fatty casts are epithelial casts in which the cells contain abundant lipid (i.e., the patient has the nephrotic syndrome.)

        Red cell casts ("active sediment") indicate bleeding into the nephron (i.e., glomerular disease). Hemoglobin casts usually mean the red cells have hemolyzed, often in the bloodstream.

{17244} red cell cast

        White cell casts contain polys and indicate acute inflammation in the renal interstitium.

        Granular casts are cellular casts in which the cells have undergone necrosis and fragmentation.

        Casts that contain a lot of lipid mean nephrotic syndrome (which you should already be aware is present.)

          * Fun to know: Under polarized light, the cholesterol-rich cells and casts in the urinary sediment of a nephrotic syndrome patient look like hot cross buns. For some reason, they are instead called "Maltese crosses" (a quadruple fishtail cross).

        Broad and waxy casts are very large casts that indicate a low rate of flow through the tubules and hence serious disease.

    Renal interstitium:

      The interstitium in the cortex is scanty, but in the medulla it is responsible for maintaining the ability of the urine to be concentrated.

        Damage to the interstitium will result in inability to concentrate the urine.

    Vessels:

      Blood to the kidney goes successively through the renal artery, its primary divisions, the interlobar arteries, the arcuate arteries, the interlobular arteries, the afferent arterioles, the glomerular capillaries, the efferent arterioles, the intertubular capillaries (including vasa recta), and finally into the veins.

      All the blood that supplies one nephron flows through the glomerulus first. If the glomerulus dies, the whole nephron dies.

      Narrowing of the arteries and/or arterioles supplying some or all of the kidney tissue will produce systemic high blood pressure.

        Blood pressure in the glomerulus is lower than it should be, resulting in too little filtrate being produced, and too much sodium and water being resorbed in distal convoluted tubule.

        Plus, the juxtaglomerular apparatus produces too much renin. Most high blood pressure resulting from kidney disease is "high renin" hypertension.

SYNDROMES OF KIDNEY DISEASE: Am. J. Kid. Dis. 10: 181, 1987 (still good)

    NEPHRITIC SYNDROME ("nephritis")

      Indicates acute inflammation of glomeruli

      • hematuria (including red cell casts)
      • mild to moderate proteinuria
      • oliguria, hypertension and mild edema

      If the process continues, the glomerulus may be destroyed (i.e., rapidly progressive glomerulonephritis or chronic glomerulonephritis will result.)

      You will want to remember that each of these is likely to cause the nephritic syndrome:

      • all diffuse-proliferative glomerulonephritis syndromes

        • post-streptococcal glomerulonephritis

        • bacterial endocarditis

        • after other infections (uncommon; review of post-strep and other post-infectious GN today in Medicine 87: 21, 2008

        • lupus IV

        • cryoglobulinemia

      • mild / early RPGN syndromes

        • anti-GBM (Goodpasture's, other)

        • Wegener's

        • polyarteritis (small-vessel)

        • * polyarteritis nodosa?

      • bad IgA-family (Berger's, Henoch-Schonlein, Zuni, etc.)

      • bacterial endocarditis (worth mentioning again)

      • lupus II (if severe), III, or IV

      • membranoproliferative glomerulonephritis ("nephritic nephrotics")

      • Note that all of these except anti-GBM disease, Wegener's, and polyarteritis are immune-complex diseases.

    NEPHROTIC SYNDROME ("nephrosis", an archaic term): NEJM 338: 1202, 1998 (great photos); kids Lancet 362: 629, 2003

      Indicates excessive permeability of the filtration membrane to plasma proteins.

      • heavy proteinuria (adult more than 3.5 gm/day -- ask about frothy urine, first related to "dropsy" by Dr. Hippocrates)
      • hypoalbuminemia (less than 3.0 gm/dL)

          In mild cases, only the small plasma proteins (albumin, etc.) will be lost, and the patient has selective proteinuria. Severe cases show nonselective proteinuria.

      • severe generalized edema (the etiology is complex)
      • hyperlipidemia (usually with fat inside renal tubular cells in the urine; these are called "oval fat bodies. * Look also for foam cells in the glomerular mesangium.)

      Some cases of the nephrotic syndrome may resolve with or without treatment. Longstanding heavy proteinuria is itself harmful to the kidney and will lead to renal failure after several years.

      Although the patient is edematous and has increased total body water, the lack of plasma protein results in a loss of effective circulating volume. This in turn causes salt and water retention and accumulation of yet more fluid in tissue spaces. Secondary hyperaldosteronism also plays a part in causing the edema.

      NEPHRIN ("heparan binder") is a protein normally located along the surfaces of podocytes, forming the basic structure of the "slit diaphragm". Several different molecules involved in immune injury can cause it to be lost from the cell surfaces, either by allowing the polyanions to escape, or from the slit diaphragms being lost. In each case, the nephrotic syndrome results (Am. J. Path. 158: 1723, 2001), and this is probably the common denominator for most (maybe all) causes of nephrotic syndrome.

      Hyperlipidemia is due, at least in part, to increased production of lipoproteins by the liver to compensate for the loss of albumin. This is a modest coronary risk, and you may treat it with statins (Am. J. Card. 76: 97A, 1995.)

      Patients with nephrotic syndrome are at increased risk for thrombosis throughout the body. Various explanations have been proposed; easiest to believe is loss of antithrombin 3 in the urine.

        Especially, thrombosis often occurs in nephrotic syndrome from any cause, since this is where the blood proteins are most concentrated. It is not itself the cause of nephrotic syndrome, but can make a nephrotic's renal function deteriorate impressively (Am. J. Med. 308: 119, 1994).

      Renal vein thrombus

      WebPath Photo

        And patients with nephrotic syndrome are generally at increased risk for thrombosis. There are numerous explanations given; perhaps the easiest to understand is heavy urinary loss of antithrombin 3.

      Nephrotic syndrome patients are also very prone to infection, notably with gram-positive cocci ("cellulitis", "primary pneumococcal peritonitis", etc., etc.) Loss of complement factors B and D is cited as a cause, and of course there is also iatrogenic immunosuppression.

      Finally, the nephrotic kidney is extra-prone to sudden shutdown (probably a combination of prerenal azotemia and acute tubular necrosis; see Am. J. Kid. Dis. 19: 201, 1992).

      Causes of the nephrotic syndrome:

      • amyloidosis

      • diabetic glomerular disease

      • foot process disease

        • minimal change glomerulopathy

        • focal-segmental glomerulosclerosis

      • membranous glomerulopathy

      • membranoproliferative glomerulonephritis ("nephritic nephrotics")

      • * birth defects

        • ...Finnish (gene NPHS1 for nephrin as above; Am. J. Path. 155: 1681, 1999)
          ...others

{16764} nephrotic syndrome
{16857} kidney, yellow cortex of nephrotic syndrome
{16800} lipid in tubule, nephrotic syndrome, oil red O (lipid is red)

Nephrotic Syndrome
Text and pictures
From "Big Robbins"

    RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS ("RPGN")

      Indicates sudden, severe injury to most of the glomeruli.

      The nephritic syndrome will probably also be present.

      The common denominator is that the glomerular basement membrane is ruptured, and fibrin (and hence "crescents" -- unwholesome things made of fibrin and mixed cells) is present in Bowman's space.

      You'll want to remember these as causes...

      • RPGN I: anti-GBM disease ("linear fluorescence")

      • RPGN II: nasty cases of any immune complex disease ("lumpy bumpy fluorescence") (don't forget endocarditis)

      • RPGN III: vasculitis syndromes (Wegener's, small-vessel polyarteritis, and so forth -- no fluorescence)

      The three categories (I, II, and III) are about equally common. Note that this list overlaps with nephritic syndrome, which is how most RPGN starts out.

    ASYMPTOMATIC HEMATURIA (gross or microscopic):

      Mild nephritic-type diseases may produce only microscopic hematuria. Of course, there is always proteinuria when there is hematuria.

      Red cell casts are proof that hematuria originates in the nephron (i.e., the patient probably has glomerular disease).

        Kidney stones, sickle cell nephropathy, bleeding disorders, and cancers are the other important diseases that produce bleeding at the level of the kidney. These seldom produce red cell casts.

      The cause of asymptomatic glomerular hematuria that you'll see most often is thin GBM disease, the mild variant of Alport's with mutated collagen IV (Clin. Ped. 40: 607, 2001).

      IgA nephropathy is also likely to fall into this category.

    HEMOLYTIC-UREMIC SYNDROME

      Endothelial damage and platelet microthrombus formation in the renal vascular bed, resulting in evidence of red cell fragmentation (schistocytes) and renal failure.

      There are many different causes, including an infectious disease, mostly affecting young children caused by vicious E. coli, shigellosis, estrogen effects (oral contraceptive, pregnancy), malignant high blood pressure, vasculitis, etc., etc.

    PYELONEPHRITIS

      Bacterial infection of the kidney generally produces fever, flank pain, proteinuria, pyuria (PMN's in the urine), and white cell casts.

    PROXIMAL TUBULE DYSFUNCTION

      A group of conditions (mostly not-so-serious) in which the proximal tubule fails to conserve one or more substances, which are lost in the urine.

      In mild impairment, small-molecular weight proteins (beta2- microglobulin, light chains, * lysozyme, * retinol-binding protein, vitamin-D binding protein) are lost in the urine (tubular proteinuria).

        * Megalin (or LDL-receptor-related protein 2) is a protein on renal tubules that is responsible for reabsorbing these little molecules (Am. J. Path. 155: 1361, 1999).

      When the proximal tubule is seriously impaired (the various renal Fanconi syndromes), there is wasting of bicarbonate ("renal tubular acidosis type 2"), glucose ("renal glycosuria"), calcium (kidney stones, rickets, osteomalacia), phosphate, potassium, amino acids, other small molecules, etc. etc.

    Kidney failure: loss of renal function.

      ACUTE RENAL FAILURE usually presents as oliguria (less than 500 mL urine/day) plus azotemia.

        Hyperkalemia is the main threat to life during the oliguric phase.

      CHRONIC RENAL FAILURE is the end result of irreversible kidney damage from any cause.

        Sometimes the cause of the "end-stage contracted kidney" cannot be determined even at autopsy. Once a sufficient number of nephrons are destroyed, it causes the remainder of them to die off inexorably.

        Signs and symptoms are those of uremia.

        Anuria, the complete cessation of urine production, is rare in acute renal failure -- the major exception is diffuse cortical necrosis. It may occur late in chronic renal failure. Much more often, anuria is due to obstruction of ureters or urethra or (most often) Foley catheter. (Some people will define "anuria" to be "less than 100 mL/day").

        * Spontaneous recovery of renal function is rare but does occur (around 1%, more in patients with lupus; see Am. J. Kid. Dis. 15: 61, 1990.)

    HIGH BLOOD PRESSURE ("hypertension"): In kidney failure from any cause, blood pressure will rise for various reasons (Am. J. Kid. Dis. 32: 705, 1998).

      "Renal" hypertension results from decreased GFR and/or increased renin (usually stenosis of arteries).

      In time, the high blood pressure will surely cause further damage to the kidney arteries, producing a vicious cycle (Am. J. Kid. Dis. 19: 484, 1992 is stil good).

    KIDNEY STONES: Flank pain and hematuria (but no red cell casts). Secondary infection is common.

    PROGRESSIVE LOST OF REMAINING RENAL FUNCTION: Once the kidney is damaged to a certain degree, it continues to deteriorate (i.e., undergo more scarring, notably glomerular sclerosis) even if the underlying disease is cured.

      How this happens is still somewhat mysterious. In health, mesangial matrix is normally synthesized and degraded over time. In progressive renal failure, something slows the degradation.

      Contributing factors include hypertension, hyperlipidemia, high dietary protein, and high dietary phosphate.

      Many molecules are involved; in particular, excess plasminogen activator inhibitor-1 seems to prevent the normal breakdown/recycling of matrix by t-PA (review J. Clin. Inv. 112: 379, 2003), and this is a possible target for therapy (J. Clin. Inv. 112: 326, 2003).

      * Apolipoprotein E genotype influences the rate of progression, with episilon4, which is bad elsewhere, being good here (JAMA 293: 2005.)

      This part of the process can be slowed with anti-hypertensive therapy (especially angiotensin converting enzyme inhibitors; see Am. J. Kid. Dis. 31: 161, 1998 and NEJM 334: 939, 1996 were the great historic articles) and dietary protein restriction.

      And it turns out that angiotensin II actually mediates a lot of the fibrosis in longstanding renal disease. When its receptors are stimulated, there's local production of a variety of substances (notably TGF-beta1, TNF-alpha, PDGF A-chain) that are implicated in the deadly scarring-up of glomeruli and vessels (Am. J. Kid. Dis. 31: 171, 1998.)

      Another "usual suspect" is indoxyl sulfate, a breakdown product from the diet (J. Lab. Clin. Med. 124: 96, 1994; Am. J. Kid. Dis. 37 (1S2): S7-12), 2001).

        * There are now medications ("Kremezin") that block absorption of its precursors (Am. J. Kid. Dis. 47: 565, 2006, several others). These may become mainstream in the US.

      And nowadays we are using statins to slow this process when the underlying cause is nephrotic syndrome (Am. J. Kid. Dis. 15: 16, 1990, Clin. Pharm. Ther. 67: 427, 2000, lots of others).

UREMIA: The clinical signs and symptoms of renal failure; especially, the clinical problems associated with chronic renal failure. Today, the definition excludes electrolyte, calcium, blood pressure, and vitamin D problems. Update NEJM 357: 1316, 2007.

    AZOTEMIA means increased urea and/or creatinine in blood from any cause.

    When kidney function falls below about 10% of normal, uremia becomes apparent.)

    Fluid, electrolyte, and acid-base disturbances:

    • volume overload (high blood pressure, systemic and pulmonary edema, congestive heart failure) -- two types of CHF are described (hypertensive-hypertrophic and dilated-mysterious).
    • metabolic acidosis (unable to excrete sulfate and phosphate)
    • hyperkalemia (banana suicides, etc.)
    • fluid shifts (muscle cramps, miserable -- and a prominent part of today's "dialysis disequilibrium syndrome"

    Calcium - phosphorus problems

    • inability to activate vitamin D to the active 1,25-dihydroxy form
    • phosphate retention, hyperphosphatemia, and thus hypocalcemia
    • metastatic calcification (from high phosphate) of vessels (producing gangrene; the dread calciphylaxis Am. J. Kid. Dis. 32: 514, 1998; Am. J. Clin. Path. 113: 280, 2000; picture NEJM 357: 1326, 2007) and/or the pulmonary alveoli, with respiratory failure, and/or the dermis itself.
    • eventually, resistance to the effects of vitamin D; the mechanism is complex but the end-result is irreversible loss of the vitamin D receptors (Kid. Int. 85-S: S6, 2003).

    Bone problems: the miserable "renal osteodystrophy" that includes:

    • secondary hyperparathyroidism, with loss of calcium and eventually collagen from bones, and...
    • osteomalacia (increase in unmineralized osteoid), mostly refractory to vitamin D treatment.
      • No one really knows why the parathyroid glands undergo hyperplasia and become overactive in renal failure. The obvious explanation (lack of vitamin D along with too much blood phosphate) is supported by the finding that simply giving oral vitamin D helps (update J. Clin. Endo. Metab. 91: 2480, 2006).

          * Nowell's law in operation: As the parathyroid cells proliferate, there are often monoclonal overgrowths bearing trademark genetic mutations (the hard-to-treat "nodular parathyroid hyperplasia": J. Clin. Endo. Metab. 91: 563, 2006).

        Uremic toxins causing altered gene expression may be part of the picture as well (J. Clin. Endo. Metab. 91: 563, 2006).

        Exactly what causes the osteomalacia isn't fully understood, either.

        In the 1990's, it became clear that aluminum retention was a major part of the problem (Mayo Clin. Proc. 68: 510, 1993); its levels are now assayed (along with iPTH) when it is necessary to sort out the nature of a kidney patient's bone disease. Another current suspect is beta-2 microglobulin. Update on uremic bone disease: Am. J. Med. Sci. 320: 85, 2000.

    Cardiopulmonary:

    • high blood pressure with all its associated problems
    • fibrinous pericarditis (mild to miserable; why it occurs is unknown).
    • accelerated atherosclerosis (kills dialysis patients after a while -- even moderate chronic renal failure is a risk factor for atherosclerosis commensurate with poorly-controlled diabetes: South. Med. J. 100: 20, 2007).
      • * The most likely explanation is that something toxic (very likely, advanced glycosylation end-products) that are ordinarily filtered by the kidney are not being removed by dialysis (Lancet 343: 1519, 1994).

    • A large minority of chronic renal failure patients get fibrosis of the cardiac interstitium throughout large areas. This stiffens the heart ("diastolic dysfunction") and greatly enlarges it, but surprisingly is clinically mild (Kid. Int. 69: 1839, 2006).

    Hematopoietic:

    • anemia (low erythropoietin, slow GI bleeding, * ?hyperparathyroidism, etc.)
      • Recombinant human erythropoietin (* "Epogen") has been a big help.

          * It costs perhaps $6000/patient per year, yet was originally spawned by the orphan drug act of 1983.

    • poor platelet function (still poorly understood)
    • additional problems with hemostasis (still poorly understood)

    Burr Cells, supposedly seen in uremia
    Text and photomicrographs. Nice.
    Human Pathology Digital Image Gallery

    GI:

    • nausea and vomiting (miserable)
    • GI bleeding -- "uremic gastritis" features pinpoint bleeds in the stomach mucosa; counterintuitively, these patients actually seem to have less chance of being infected with the urea-loving helicobacter than do their peers (Hepato-Gastroent. 50: 2255, 2003)
    • pancreatitis (mysterious; see Medicine 73: 8, 1994)

    Skin:

    • pruritus (miserable)
      • One cause of pruritus is calcium sulfate and calcium phosphate precipitating in the sweat. Others include excesses of vitamin A metabolites and histamine. Erythropoietin therapy can help: NEJM 326: 969, 1992.

        * "Calcinosis cutis" affects about 1% of dialysis patients; it's a calcification syndrome caused by elevated serum calcium (Arch. Derm. 142: 900, 2006) that expresses itself only if, for some reason, osteopontin is locally produced. Picture NEJM 357: 2615, 2007.

    • uremic frost (urea crystals)

{24577} uremic frost

    • turn yellow, smell like a men's washroom that needs cleaning.
    • * newly-recognized entity that has probably been long-overlooked: nephrogenic systemic fibrosis, in which increased collagenization occurs in various organs, especially the skin of the trunk and legs, mimicking peau d'orange (orangepeel; Arch. Path. Lab. Med. 131: 145, 2007, also Am. J. Kid. Dis. 46: 763, 2005). Presently, the gadolinium used as a contrast agent in MRI is suspected as contributing (Radiology 243: 148, 2007; J. Am. Acad. Derm. 56: 21, 2007; it's probably right, based on epidemiology AJR 188: 586, 2007), and the lawyers are involved.

    Neuromuscular:

    • peripheral neuropathy (miserable)
    • encephalopathy (miserable). We are just now rediscovering that cognitive impairment is extremely common among dialysis patients compared to their healthier peers (Neurology 67: 216, 2006). No one knows whether this is due to uremic toxins, some effect of dialysis itself, and/or the underlying diseases.

        The old "dialysis dementia" was due to aluminum accumulation and is still studied. Aluminum seems to tangle tau protein in neurons, forming the same paired helical filaments seen in Alzheimer's: Lancet 343: 993, 1994.

        It's claimed that mentation slows when GFR drops below 50% of normal (J.Am. Soc. Neph. 18: 2205, 2007).

    • impotence in men
    • amyloidosis ("amyloid H", made from beta2-microglobulin, tends to accumulate in joints causing arthritis, in the bones causing "cysts" (hollowed-out areas), and in flexor retinaculum causing carpal tunnel syndrome. * Kidney stones made of amyloid H are reported in dialysis patients.
    • pica (low serum zinc causes alterations in sense of taste)
    • bad breath ("fishy", trimethylamine)
    • poor appetite and altered sense of smell ("everything smells bad").
    • emotional problems. In the 1980's, at least 15% of these patients eventually committed suicide (JAMA 250: 49, 1983). Today, patients and families have little trouble getting doctors to discontinue dialysis when the quality of life is no longer satisfactory: JAMA 289: 2113, 2003 ("to have that option is a blessing").
      • * Only during the 1990's (perhaps coinciding with the advent of managed care), did people being writing about what to do to make the death of a person refusing dialysis more pleasant (Lancet 346: 3 & 506, 1995). The death can be "good" if the "war on drugs" doesn't prevent the patient from receiving pain medicine (Arch. Int. Med. 155: 42, 1995), etc., etc.

    Infections:

    • Uremic patients are prone to infections. Staphylococcal infections often kill patients who have survived years on dialysis.
      • * One factor is loss of Fc receptors on macrophages: NEJM 332: 717, 1990.

    Other:

    • Glucose intolerance due to insulin resistance.

    • A 5-fold increase in the incidence of renal cell and uterine carcinomas.

    • Short stature (in kids): Arch. Dis. Child. 73: 30, 36, 1995 (* Includes "horrid ethical problems" involved in a study of the effects of growth hormone for these kids)

    All about the "uremic poisons" that accumulate in the body and cause symptoms: Kid. Int. 33(S24): S-4, 1988 (whole volume on uremia).

    * Supplementing dialysis patients with carnitine, a small molecule involved in lipid metabolism and lost during dialysis, is now mainstream (Am. J. Kid. Dis. 32: 32, 265, 1998; Clin. Pharm. 68: 238, 2000).

{05904} peritoneal dialysis guy
{05905} peritoneal dialysis, how-to
{05913} hemodialysis, fistula
{05914} hemodialysis machine

    * King Herod's death in 4 BC, re-examined as chronic renal disease with severe pruritus, then GI ulcers, encephalopathy and Fournier's gangrene (Arch. Int. Med. 164: 833, 2004). You lecturer believes that Herod Jr. ("smote down, and was then eaten by worms") had atheroembolization with cerebral infarction and lower-extremity gangrene.

KIDNEY BIOPSY (standards J. Clin. Path. 49: 233, 1996; J. Clin. Path. 53: 433, 2000)

    For a better understanding of what is going on in your patient's kidneys, you (or, better, the nephrology consultant) can obtain a piece of one for the pathologist using a special hollow "needle" that is passed in through the skin.

      You will learn the indications for this procedure on rotations. Nowadays, kidney biopsies can be obtained by your radiologist via the transjugular approach (Radiology 215: 689, 2000).

KIDNEY MALFORMATIONS

    Birth defects:

      You remember that if enough urine is not produced before birth, the unborn child will be deformed by pressure from the uterus ("Potter's"; oligohydramnios sequence), with flattening of the nose and ears, and often clubfoot.

      Agenesis

      Agenesis of the kidneys
      WebPath Photo

      Hypoplasia: a kidney with fewer than five lobules and calyces

      Pelvic kidney (kinked ureter can result in poor drainage, stones, and infection); some of these are midline "cake kidneys" that never separated.

      Horseshoe kidney: present in 1/500 or so autopsies, fusion of upper or lower poles of the kidneys. Seldom a problem as long as the ureters are not compressed badly.

{16972} horseshoe kidney

Kidney Malformations
From Chile
In Spanish

Horseshoe kidney

WebPath Photo

Double ureters
Common, and seldom a problem
WebPath Photo

    RENAL TUBULAR DYSGENESIS is a rare, lethal syndrome with kidneys that look normal grossly but have extreme hypoplasia of the proximal tubules.

      Unborn children have oligohydramnios and pulmonary hypoplasia. The recessive genetic loci are those of the renin-angiotensin system (i.e., renin, angiotensinogen, ACE, or the angiotensin II receptor): Nat. Genet. 37: 964, 2005.

      Non-genetic causes of the same kidney picture are ACE-inhibitor use by the mother, and twin-twin transfusion syndrome (Path. Res. Pract. 196: 861, 2000).

Renal tubular dysgenesis
Potter's baby
Pittsburgh Pathology Cases

Renal Tubular Dysgenesis
Human Pathology
Several great photos

    Abnormal differentiation / hyperplasia of tubular elements leads to the cystic diseases of the kidney (Kid. Int. 33: 8, 1988 -- * by my late teacher, Dr. Frank Carone, a leader in this field.)

      Apart from "cystic renal dysplasia", these diseases feature tubules whose cells proliferate to form cysts, which are involved with remodelling of the interstitium.

    CYSTIC RENAL "DYSPLASIA" (today, "multicystic dysplastic kidney", or "obstructive renal dysplasia" if hydronephrosis is present): persistence of primitive mesenchyme, which may produce cartilage, undifferentiated mesenchyme, and immature collecting ductules

      Most are "idiopathic"; a few genes are known that produce a multicystic dysplastic phenotype without obvious obstruction (Hum. Mol. Genet. 15: 2363, 2006; Am. J. Kid. Dis. 47: 1004, 2006).

      Regardless of phenotype, most cases probably result from failure of glomeruli to drain into the ureter during embryonic life (Virch. Arch. 439: 560, 2001; Ped. Int. 45: 605, 2003). There may be subtle failure of the ureteric bud to meet the blastema, or the lower urinary system may be malformed. Review Am. J. Kid. Dis. 32: 535, 1998. Update Kid. Int. 69: 190, 2006.

{10563} renal multicystic dysplasia (this is NOT polycystic kidney)
{10241} renal multicystic dysplasia
{39684} renal multicystic dysplasia; find the cartilage
{08453} renal multicystic dysplasia
{21006} renal multicystic dysplasia (this is NOT polycystic kidney or tumor)

Multicystic dysplastic kidney

WebPath Photo

Multicystic dysplastic kidney

WebPath Photo

Multicystic dysplastic kidney

WebPath Photo

    AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE ("adult polycystic kidney disease", "ADPKD", * "Potter III" in the old classification): NEJM 329: 332, 1993; Am. J. Kid. Dis. 28: 788, 1996; nice picture NEJM 333: 31, 1995).

      Common (500,000 cases in the U.S.) autosomal dominant disease with complete penetrance (1 in 800 people or so).

      Usually, the disease is on chromosome 16p1.3 (PCKD 1 locus) where it codes for "polycystin 1", a tubular organizer (Proc. Nat. Acad. Sci. 93: 1524, 1996); polycystin 2 has been identified as an integral membrane protein (PCKD2 locus, Science 272: 629, 1996, milder but not benign Lancet 353: 103, 1999). Prognosticating adult polycystic kidney disease: NEJM 323: 1085, 1990 (still good; if your ultrasound is normal as a young adult, you probably don't have it).

      Hundreds of cysts, measuring up to 4 cm in diameter, develop from all levels of nephron including Bowman's capsule. As they form, the surrounding normal kidney cells undergo apoptosis (NEJM 333: 18 & 56, 1995).

      By the time the patient is forty years old, the kidneys are often the size of footballs. Surprisingly, they may still be working. Half of these patients are on dialysis or transplanted by age 70 or so.

      Patients typically get high blood pressure as adults, years before renal failure develops. Many die of ruptured berry aneurysms (management of the prospective berry aneurysm patient with PCKD: NEJM 327: 916, 1992).

      Cyst infections are hard to treat.

      About a third of these patients have harmless hepatic cysts too, and a few have them in the pancreas. You'll spot these on CT scan.

      The big news is that, in the mouse model, a vasopressin receptor antagonist prevents the formation of cysts (Nat. Med. 10: 363, 2004).

{00056} adult, autosomal-dominant polycystic kidney (26 lb!)
{00059} adult, autosomal-dominant polycystic kidney (same case as 56)
{10553} adult, autosomal-dominant polycystic kidney
{05965} adult, autosomal-dominant polycystic kidney, histology

Adult polycystic kidneys

WebPath Photo

Adult polycystic kidneys
With transplant
WebPath Photo

Polycystic kidneys
Nice case
Pittsburgh Pathology Cases

Adult polycystic kidney

WebPath Photo

Polycystic Kidneys
Australian Pathology Museum
Hey, how about a ruler?

    AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE ("childhood" or "infantile" polycystic kidney disease", "ARPKD"; update Pediatrics 111: 1072, 2003; spectrum and forme frustes Medicine 85: 1, 2006)

      Rare autosomal recessive disease with huge, white, smooth-surfaced kidneys. Cysts 1-2 mm in diameter develop from the collecting ducts; they are arranged in a radial, "sun-ray" pattern perpendicular to the capsule (because the collecting ducts are dilated). These kidneys are huge at birth.

      This is normally fatal in infancy or early childhood; typically, the enormous kidneys restrict the ability of the lungs and gut to function. Many children also have congenital portal fibrosis of the liver.

      * Keeping these babies may require cutting out one kidney to preserve room for the rest of the abdominal organs (there's a bit of renal function remaining, at least at birth): J. Ped. 127: 311, 1995.

{16978} infantile, autosomal-recessive polycystic kidney disease
{17223} infantile, autosomal-recessive polycystic kidney disease
{15817} infantile, autosomal-recessive polycystic kidney disease (huge kidneys)
{15818} infantile, autosomal-recessive polycystic kidney disease
{17224} infantile, autosomal-recessive polycystic kidney disease, histology

Infantile polycystic kidneys

WebPath Photo

Infantile polycystic kidneys

WebPath Photo

Infantile polycystic kidney

WebPath Photo

Hepatic fibrosis
Seen with infantile polycystic kidney
WebPath Photo

Autosomal recessive PCKD
WebPath Photo

    MEDULLARY SPONGE KIDNEY

      Very common (1 in 200 people) idiopathic process. Dilated distal portions of collecting ducts superficially resemble cysts.

      Usually it is just a radiologist's curiosity. Sometimes stones form in the "cysts", and this entity is in the "differential" of chronic back pain.

{25322} medullary sponge kidney, sketch

    UREMIC MEDULLARY CYSTIC DISEASE / "nephronophthisis"

      A group of diseases (including an "autoimmune familial syndrome", with cysts at the corticomedullary junction and severe damage to the cortex.

      The hereditary forms include three diseases coded by NPHP1 ("nephrocystin"), NPHP2, and NPHP3, which are the most common causes of endstage renal disease in children and young adults (genes Proc. Nat. Acad. Sci. 98: 9836, 2001; update Nat. Genet. 34: 455, 2003.).

      Milder, autosomal dominant forms are carried at the MCKD1 and MCKD2 loci (Kid. Int. 64: 788, 2003; Kid. Int. 68: 1472, 2005).

      As with most diseases that begin in the medulla, the initial manifestations are inability to retain sodium and water.

{16985} medullary cystic disease, the bad kind, gross; it has been in formalin for a long time and lost its color
{25323} medullary cystic disease, the bad kind, sketch
{25324} medullary cystic disease, the bad kind, gross

* OTHER CYSTIC DISEASES

    At least several syndromes not yet fully characterized genetically feature cystic kidneys. Often there is co-existing risk for berry aneurysms, muscle cramps, and/or hematuria. Update NEJM 357: 2687, 2007.

"ACQUIRED DIALYSIS CYSTIC DISEASE" ("trans-stygian kidney")

    This is a misleading name for the kidneys in people who have been kept alive for a long time on dialysis.

      The kidneys are useless nubbins with a few remaining tubules stretched wide open ("cysts").

      In addition to scar tissue and a few chronic inflammatory cells, the pathologist may find squamous metaplasia of glomerular epithelium, oxalate crystals in the tubules, fibromuscular masses in the blood vessels, and cortical adenomas and renal cell carcinomas (J. Urol. 151: 129, 1994; radiologists enjoy Radiology 195: 667, 1995).

    These kidneys can develop stones, painful bleeding, and/or aggressive carcinomas (not rare; Am. J. Kid. Dis. 16: 452, 1990).

    We do not really know why this happens to the kidney, but it occurs in patients who have not been dialyzed. Most plausible seems to be the idea that the underlying problem is the extreme vascular narrowing, with cells dying off when perfusion drops slightly and then proliferating again when minimally-adequate circulation is restored. The vessels in badly-damaged kidneys become extremely narrowed, and trans-stygian kidneys can develop behind a single stenotic renal artery.

    * "Trans-stygian" refers to the river Styx that the dead crossed in Greek mythology.

{38869} acquired dialysis cystic disease" (trans-stygian kidney)

Trans-stygian kidneys

WebPath Photo

Renal cell carcinoma
Trans-stygian kidney
WebPath Case of the Week

SIMPLE CYSTS

Pathology of Kidney Cysts
WebPath Tutorial

Simple kidney cyst

WebPath Photo

Simple renal cysts

WebPath Photo

    A few cysts in a kidney (especially in an old person) is one of the commonest incidental finding at autopsy. These often develop after small kidney infarcts ("arterial nephrosclerosis"). No danger to health.

    These keep turning up on scans and causing consternation, but the distinction from the more serious cystic diseases is obvious (Am. J. Roent. 176: 843, 2001).

    * Tuberous sclerosis patients often have several simple cysts; this is perhaps the least of their many problems. Animal model Am. J. Path. 162: 457, 2003.

    * Leave the diagnosis of "multilocular cyst" ("cystic nephroma", a curious hamartoma) to us. It looks like localized renal dysplasia but supposedly has no solid areas.

Remember: Hyaline casts in the urine are normal. Other casts in the urine indicate disease in the nephron.

INTRODUCTION TO GLOMERULAR DISEASE (update for clinicians Arch. Int. Med. 161: 25, 2001; pathologists Med. Clin. N.A. 81: 653, 1997)

        Dr. Richard Bright of Guy's
        Had several patients large in size.
        Their legs were swollen as could be;
        Their eyes so puffed they could not see.
        To this edema Bright objected,
        And so he had them venesected.
        He took a teaspoon by the handle,
        Held it over a tallow candle,
        And boiled some urine over the flame,
        (As you or I might do the same.)
        To his surprise, we find it stated,
        The urine was coagulated.
        Alas, his dropsied patients died.
        Our thoughtful doctor looked inside:
        He found their kidneys large and white,
        Their capsules were adherent quite.
        So that is why the name of Bright is
        Associated with nephritis.

            -- Anonymous!

    This is the most difficult lecture in Medical Pathology.

    Glomerular diseases are classified according to

    • Clinical manifestations (by clinicians; nephritic syndrome, nephrotic syndrome, RPGN, hemolytic-uremic syndrome, asymptomatic hematuria, etc.)
    • Histologic and ultrastructural appearance of injury (by light and electron microscopists; diffuse, segmental, proliferative, necrotizing, sclerosing, etc.)
    • Mechanisms of glomerular injury (by immunologists; anti-GBM disease, mesangial IgA disease, etc.)
    • Named diseases (by service pathologists):
      • Diseases that primarily involve the glomerulus (acute post-streptococcal glomerulonephritis, Balkan nephropathy, etc.)
      • Systemic disease in which there are glomerular changes (systemic lupus, amyloidosis, diabetes, Goodpasture's syndrome, etc.)

      To make matters worse, the mechanisms of glomerular injury are often obscure. It is difficult or impossible to correlate abnormal structure and abnormal function for most glomerular diseases.

    Some definitions:

      DIFFUSE (all glomeruli) vs. FOCAL (only some glomeruli, maybe under 80%)

      GLOBAL (entire glomerulus) vs. SEGMENTAL (a part of a glomerulus)

        Global diseases are usually diffuse, and segmental diseases are usually focal. The one major exception is glomerular damage from high blood pressure, which is focal-global fibrosis. (Why? Hint: Each glom has exactly one afferent arteriole.) Unless otherwise specified, the diseases we will describe in this lecture are global-diffuse.

          * Should you run into the uncommon "focal-global glomerulosclerosis", think of something that might clog the afferent arteriole -- sickle cell, Fabry's, etc. Lately it's been noticed in thin GBM disease gone bad (Kid. Int. 51: 1596, 1997; Arch. Path. Lab. Med. 130: 1533, 2006).

      * HYALINOSIS ("fibrinoid"): deposits of plasma proteins. (This stuff doesn't stain blue with "trichrome" or black with "silver", distinguishing it from fibrosis and sclerosis respectively.)

      SCLEROSIS: enough increase in basement membrane - mesangial matrix material to compromise the lumens of capillaries. (The distinguishing feature is that this stains positive with silver).

      FIBROSIS: type I collagen, i.e., an organized scar. (Blue on "trichrome". Unlike hyalinosis and sclerosis, this is essentially PAS-negative.)

HISTOLOGIC ALTERATIONS IN GLOMERULAR DISEASE

  • Cellular proliferation
    • Endothelial and mesangial cells may proliferate (intracapillary proliferation).

        This tends to narrow and occlude the capillaries.

        Why these cells proliferate in some disease states is generally unknown.

        Mesangial cell proliferation, so common in glomerular disease, seems to have as a major cause platelet-derived growth factor, and the mesangial cells themselves seem to produce a protein that turns this potent stimulus off as recovery begins. Am. J. Path. 148: 1153, 1996. In the meantime, several drugs are under investigation to inhibit this proliferation (Kid. Int. 68: 474, 2005, others).

      Macrophages are typically numerous. Visceral and parietal epithelial cells and fibroblasts may also proliferate (extracapillary proliferation).

        This is always caused by fibrin leaking out of glomerular capillaries. (Why the capillaries are leaking is not always obvious. You may see a break in the GBM.)

        If the leak is small, a fibrous adhesion between a few capillaries and Bowman's capsule may result.

        If the leak is big, a cellular "crescent" soon fills Bowman's space, which ultimately becomes a crescent-shaped fibrous scar.

          Crescents indicate the glomerular basement membrane itself has been seriously damaged. To make things worse, the crescent will crunch the glomerular capillaries and obstruct the outlet to the proximal tubule.

  • Leukocyte infiltration
    • Polymorphonuclear leukocytes in the glomerulus indicate complement is being fixed there. Enzymes from polys (as well as complement itself) will damage the glomerulus.

        Polys almost never cross the GBM. Regardless of how severe the acute inflammation is in the glomerulus, the polys will not appear in the urine.

        * Monocytes can also be involved in some cases of glomerulonephritis.

  • Visceral epithelial cell swelling and detachment ("foot process fusion", etc.)
    • This is highly characteristic of several common causes of the nephrotic syndrome (and is the characteristic finding in minimal change glomerulopathy and * focal-segmental glomerulosclerosis). Injured epithelial cells swell, and this obliterates the discrete foot processes.

      This is almost always accompanied by focal detachment of the cells from the GBM. Of course, the underlying problem is disruption of the cytoskeleton as all this happens: Am. J. Path. 148: 1283, 1996. The molecular biology is now being worked out (* "dynamin" is a molecule responsible for maintaining podocyte actin structure, and it is cleaved by a cathepsin in these diseases: J. Clin. Inv. 117: 2095, 2007.

  • "Glomerular basement membrane thickening"
    • The GBM may actually be thicker (as in diabetic glomerulosclerosis and membranoproliferative glomerulonephritis.)

      The GBM may appear thicker because of immune-complex deposits ("electron-dense deposits", etc.) These are just barely visible by light microscopy.

        They may be subendothelial, intramembranous, subepithelial or mesangial in location. (Why immune complexes localize where they do is still mysterious.)

  • * Hyalinosis
    • Hyaline material is deposited subendothelially in certain capillary loops. The stuff stains dark pink and is lipid-rich. It includes the old "fibrin caps" of diabetes, and the changes seen in solitary kidneys (congenital, following massive infarcts or subtotal nephrectomy, etc) and other over-perfused kidneys -- even live kidney donors eventually get hyalinosis, proteinuria, and occasionally impaired renal function (J. Urol. 152: 312, 1994).

      The common denominator seems to be hyperfiltration.

  • * Mesangiolysis -- loss of pericytes, with aneurysmal dilatation of capillaries and edema of the matrix. Am. J. Kid. Dis. 31: 559, 1998
    • This is seen in diabetes (nodular glomerulosclerosis or Kimmelstiel-Wilson disease) and light-chain disease, and occasionally in malignant hypertension, glomerulonephritis, DIC, HUS, radiation injury, graft-vs.-host, transplant rejection, sicklers (Am. J. Kid. Dis. 15: 361, 1990), and cobra envenomation.

  • Necrosis
    • This is seen in the most severe glomerular disease. Karyorrhexis of glomerular cells (not just PMN's) is the surest sign of necrosis. (Look for "fibrinoid", too, of course. Later, there is obvious red infarction.)

      More insidious processes show no necrosis on renal biopsy, but destroy the kidney just as effectively.

  • Glomerular changes resulting from ischemia:
    • Early ischemic changes in the glomerulus include corrugation and irregular thickening of the GBM and Bowman's basement membrane. It's as if it crumples as it deflates.

      Later, the whole glomerulus is replaced with collagen ("obsolescent"). The tuft can usually be identified as a PAS-positive nubbin at the vascular pole.

      * JGA hyperplasia is seen in chronic ischemia of the glomerulus, but there are better ways to detect renal vascular disease....

  • Glomerular hyalinization ("obsolescence")
    • This is evidence of chronic, irreversible damage.

      Hyalinization of the tuft itself may be:

      • basement membrane-mesangial matrix material ("sclerosis"), as in diabetes, hypertension, or several primary glomerular diseases), or
      • amyloid (as in amyloidosis or plasma cell myeloma).

      Hyalinization around the tuft (i.e., in Bowman's space) is usually type I collagen. It may be:

      • collagen that has accumulated in layers on the inner surface of Bowman's capsule (a process typical of chronic ischemia), or
      • an organized crescent, as after any severe injury.

      * Do not confuse either of these with "hyalinosis" lesion, which looks like lipstick smudges in serious glomerular disease.

Great fibrin cap (hyalinosis in diabetes)
Slide from Andrea McCollum MD
Cuyahoga County Coroner's Office

Normal glomerulus

WebPath Photo

Normal glomerulus
PAS stain
WebPath Photo

Normal glomerulus
EM -- Sketch
WebPath Photo

Normal glomerulus
EM
WebPath Photo

MECHANISMS OF GLOMERULAR INJURY

    Most of the known mechanisms involve antibody-antigen complexes. These include:

      In situ antibody deposition / immune complex formation

        Anti-GBM antibodies (i.e., experimental Masugi nephritis, clinical Goodpasture's syndrome and its variants): discrete granular deposits are not seen, but linear deposition is seen on immunofluorescence, and eluates from diseased kidneys deposit in linear fashion on normal kidney.

        Antibodies against other fixed antigens (i.e., experimental Heymann nephritis caused by anti-FX1A, an antibody against proximal tubule brush border Am. J. Path. 146: 1481, 1995; evenly-spaced, fine granular deposits are seen on immunofluorescence.