Tubular Nephropathies From Chile In Spanish

TUBULOINTERSTITIAL NEPHRITIS CAUSED BY DRUGS AND POISONS: "All drugs are poisons, and all poisons are (potential) drugs." There are several important patterns. All about drug-induced renal toxicity: Med. Clin. N.A. 74: 909, 1990.

Acute drug-induced ("hypersensitivity") nephritis

Within a month after drug exposure, the victim develops fever, skin rash eosinophilia, hematuria, proteinuria, sterile pyuria and eosinophiliuria. Withdrawal of drugs makes things better.

Methicillin is the best-known offending drug.

Sulfa drugs, rifampin (Am. J. Kid. Dis. 32: 533, 1998), cyclosporine, * penicillin, * furosemide ("Lasix"), * thiazides, and * another "Chinese herbal remedy" (Lancet 341: 387, 1993; also a carcinogen, it has ruined many, many kidneys NEJM 342: 1686, 2000) are other important causes.

If biopsied, edema is always present, and interstitial mononuclear cell infiltration, eosinophils and neutrophils may be found too.

The mechanisms are obscure. Obviously, some of the problem is immunity.

NOTE: The other important cause of eosinophiliuria is atheroembolization. See next handout.

Analgesic nephritis ("analgesic abuse nephropathy")

Chronic renal failure used to be common in people who took phenacetin-containing combinations for pain. Phenacetin gives some people a buzz and there was a tendency to abuse it.

Chronic interstitial inflammation is characteristic, and many patients develop papillary necrosis.

* Urothelial carcinoma of pelvis may also result from patients who overdid phenacetin. Around 10% of abusers develop it here or in the bladder.

Classic non-steroidal anti-inflammatory agents (NEJM 332: 1514, 1515, 1995; Am. J. Kid. Dis. 32: 351, 1998)

This very useful class of drugs (arthritis, menstrual cramps, etc.) is also today's most common cause of renal shutdown in outpatients. The prognosis is generally excellent when the drug is withdrawn. See Ann. Int. Med. 150: 268, 1990.

When the circulating plasma volume becomes low for any reason, some people's renal microcirculation is kept open only by the local prostaglandins (PGE2 and PGI2) (NEJM 332: 647, 1995). When these people take a classic NSAID, they get vasomotor nephropathy, and recover in a few days. (ACE inhibitors, which prevent formation of angiotensin II, do the same thing.) * Sulindac is supposed to be the easiest on the kidneys, though there is no unanimity about this. Many (if not most) very-old folks given classic NSAIDs get azotemic (JAMA 264: 471, 1990; Br. Med. J. 311: 392, 1995); as a matter of fact, don't give NSAID's to folks who depend on their kidneys to excrete drugs with low therapeutic indices low therapeutic index (notably lithium).

Another typical syndrome is a combination of minimal-change glomerulopathy ("foot process disease") histology with nephritic and/or nephrotic syndrome, plus marked chronic interstitial nephritis. * Fenprofen's the worst drug for causing this, but they all do it.

The prevalence of NSAID-induced membranous nephropathy, which thankfully reverses on removal of the offending drug, is just now being recognized (JAMA 276: 466, 1996).

The new selective cyclooxygenase-2 (COX-2) inhibitors are much safer (Am. J. Med. Sci. 321: 181, 2001).

Lithium nephropathy: mostly nephrogenic diabetes insipidus, supposedly due to fibrosis around the collecting duct.

* There may also be FSGS.

Cyclosporine nephropathy presents lesions that, in combination, are fairly distinctive. The interstitial fibrosis that it produces seems to result from direct toxicity to the tubular epithelial cells (Am. J. Path. 167: 395, 2005.

Pathologists look for:
• hydropic change in the proximal tubular cells


• tubular microcalcifications


• giant mitochondria in the tubular cells


• necrosis of the smooth muscle cells of blood vessels (?!)


• myxoid change in the intima of small vessels
• eventually tubular atrophy and interstitial fibrosis

Other poisons: lead, cadmium (Arch. Env. Health. 45: 35, 1990 for the Japanese pollution nightmare) and bismuth (interstitial nephritis, acid-fast "Cowdry A" inclusions in the proximal tubules, Fanconi syndrome), carbon tetrachloride (fatty change), etc.

HYPERCALCEMIC NEPHROPATHY (Am. J. Kid. Dis. 19: 604, 1992)

Extensive metastatic calcification of the kidney tubules (nephrocalcinosis) can cause chronic inflammation or obstruction. Because the ascending limb of Henle's loop is damaged first, one early problem is inability to concentrate urine.

Even in the absence of tubular calcification, hypercalcemia produces a prerenal azotemia by causing constriction of the small renal arteries.

HYPOKALEMIC NEPHROPATHY

When serum potassium is low, the kidney cannot concentrate urine.

* At autopsy, the pathologist finds coarse vacuolization of tubular cells, dilatation of intercellular spaces.

PLASMA CELL MYELOMA KIDNEY (Arch. Path. Lab. Med. 128: 875, 2004)

{17274} plasma cell myeloma, cast; PAS stain shows magenta tubules

The problem is precipitation of Bence-Jones protein within the tubules causing renal shutdown. Patients experience the acute or insidious onset of renal failure.

Amorphous pink casts, often surrounded by a foreign-body reaction with multinucleated giant cells.

* If you include dehydration or osmotic diuresis in a plasma cell myeloma kidney patient (as, by ordering an intravenous pyelogram), you will destroy their kidneys.

* Light-chain nephropathy can also include tubular casts.

Remember that plasma cell myeloma patients often get amyloidosis B.

OXALATE NEPHROPATHY

Antifreeze drinkers (ethylene glycol), inborn errors (Am. J. Kid. Dis. 19: 546, 1992), extreme ascorbic acid abusers (Arch. Int. Med. 950, 1985), and * those infected with "Aspergillus niger", which produces oxalate as its waste product (Arch. Path. Lab. Med. 119: 558, 1995).

* The anesthetic gas methoxyflurane was banned for causing oxalate nephropathy.

Sharp oxalic acid crystals ruin the kidney.

RADIATION NEPHRITIS

Following therapeutic radiation involving the kidney, the interlobular arteries narrow. This eventually causes high blood pressure and sometimes renal failure.

* Not surprisingly, children give total-body radiation to cure their leukemia sometimes end up with renal failure (Arch. Dis. Child. 72: 382, 1995).

* BALKAN NEPHROPATHY

A rapidly-progressive interstitial nephritis that, under the Soviet-backed tyrannies, was the major public health problem in well-defined areas of Rumania, Yugoslavia, and Bulgaria.

Epidemiologically, the disease occurred almost exclusively in farm workers, and struck whole families at the same time. The cause was probably ochratoxin A from moldy grain stored in the upper stories of houses. Their particular school of communism opposed barns for ideological reasons.

The pathology is that of tubular loss, interstitial fibrosis, and myxoid thickening of the intima of small arteries. The subcapsular cortex is most severely involved. Renal failure develops in a few months or years.

Supporting the link to a fungal toxin: These patients, and their neighbors, also often develop urothelial cancer, and ochratoxin is a urothelial carcinogen. Of course there may have been other factors operating, but the geography of the fungus and the disease matched closely. There's a nearly-identical fungal nephropathy in Tunisia: Arch. Tox. 69: 553, 1995; Tox. Lett. 83: 869, 1995.

A similar illness was produced when aristolochia ended up in a "holistic Chinese herbal remedy" for obesity, prompting an epidemic of kidney failure and urothelial cancer: NEJM 342: 1686, 2000. If this had been a US drug company, think of the consequences.

The similarity of the Balkan nephropathy lesion to the aristolochia fiasco prompted an study and, sure enough, people in the endemic regions remembered Aristolochia clematitis (birthwort) growing in the wheatfields (Croat. Med. J. 46: 116, 2005).

* RENAL HYPERTROPHY

The cells of the proximal and distal convoluted tubules (and, to a lesser extent, the other cells of the nephron) have a limited ability to increase in size.

This occurs in a solitary kidney (congenital, after unilateral nephrectomy), and sometimes in chronic metabolic derangements.

NEPHROGENIC DIABETES INSIPIDUS

A family of diseases in which the collecting duct is unable to respond to ADH. This includes inborn errors of metabolism (Nature 359: 233, 1992; lack of ADH receptor or other proteins in its let-the-water-back-out cascade), gross and widespread damage to the medulla, and the late effects of lithium therapy for mania.

GOUT An Important Kidney Disease

{25521} gout, tophi
{25522} gout, tophi
{24641} gout, bone
{11559} gout, histology of tophi; uric acid crystals are pale and surrounded by granuloma
{24642} gout, uric acid crystals under polarized light
{24643} gout, uric acid crystals unpolarized; they are brown

Gout Photomicrograph of tophus KU Collection

Gouty Arthritis Australian Pathology Museum High-tech gross photos

Gout Love the polarizers Rockford Case of the Month

Gout WebPath Tutorial

Gout X-ray WebPath Tutorial

Gout Tophus WebPath Tutorial

Gout Uric acid crystals WebPath Tutorial

Uric Acid Metabolism: Uric acid is the catabolic end-product of purines from food and from broken-down cells. It is excreted in the urine. (The way in which the kidney handles it is interesting.) The complexities of normal uric acid metabolism have been worked out by biochemists. Gout, however, remains somewhat mysterious.

Introduction and Classification: Gout is the disease resulting from precipitation of monosodium urate crystals in the body. Everyone knows the classic story. Gout strikes the middle-aged, overweight man, who after an evening of good food and fine wine, is awakened at 2 AM by an agonizing pain and swelling in the first joint of one of his big toes. The acute attack lasts several days and ends as mysteriously as it began, perhaps returning on another occasion when the patient has "indulged".

All patients with too-high serum uric acid (i.e., urate) levels from any cause are said to have hyperuricemia. (Hyperuricemia is an abnormal lab test, gout is a disease.) Only hyperuricemic patients can get gout, but most never do. Up to 15% of adult men have serum uric acid levels in excess of uric acid's theoretical solubility (7 mg/dL), but perhaps one adult man in 200 has an attack of gout per year. There is surprisingly little correlation between serum uric acid elevation and the presence and severity of the gout.

Gout patients are classified according to their current symptoms and signs. The typical patient with gout has repeated, transient, severe inflammation of one or a few joints (most commonly the coldest ones, i.e., the big toe). This is "acute gouty arthritis". Longstanding gout results in deposition of crystals of monosodium urate surrounded by a chronic inflammatory reaction with a foreign body reaction and fibrosis. The whole thing is called a "tophus" (plural "tophi", and yes, they do count as granulomas.) Tophi are common in the helices of the ears, in the joints and their bursae ("chronic tophaceous arthritis"), and in the kidneys. (Feel the finger pads for tophi before gouty arthritis manifests: Arch. Int. Med. 148: 1830, 1988.) Sometimes gout presents not with joint problems, but as a uric acid kidney stone or some other manifestation of "renal gout".

Gout patients are also subdivided by etiology. Primary gout is any form of gout caused by a known or assumed inborn error of uric acid metabolism, without other systemic manifestations. It includes primary idiopathic gout (the great majority of gout sufferers), and a few rare, well-characterized genetic syndromes. Secondary gout is hyperuricemia and resulting gout because of some other disease. These are outlined below. But the tissue changes are the same in primary and secondary gout.

Etiologies of gout: Primary Hyperuricemia and Gout (90+%) ("idiopathic gout", "common gout") In most cases, the reason for the hyperuricemia is unknown (and assumed to be "genetic and multifactorial"). While the condition runs in families, the molecular biology has eluded scientists, various mechanisms are at work in various patients, and there is no simple pattern of inheritance. The majority of these men both overproduce and underexcrete uric acid. Some cases are less idiopathic than others. Several "partial enzyme defects" (* including an overactive phosphoribosyl pyrophosphate synthetase) have been identified. Primary idiopathic gout is a disease of adult males (95%). Attacks peak during the 40's, though the hyperuricemia begins at puberty.

Secondary Hyperuricemia and Gout (5-10%): Hyperuricemia is common in certain conditions, but actual gout is uncommon. Heavy ingestion of purines (i.e., organ meats) can raise serum uric acid and trigger an acute attack of gout. Diseases with increased cell turnover or widespread cell destruction increase uric acid production. Remember lymphoma, leukemia, other malignant tumors, * sometimes even psoriasis. Cancer patients receiving chemotherapy and/or radiation that works often excrete tremendous amounts of uric acid. People with functional obesity have increased production and diminished secretion of uric acid. The reasons are unknown. In diseases of the proximal tubule (most notably lead poisoning), secretion of uric acid is poor and gout can result. Secretion is also inhibited by thiazide diuretics, ethanol, and acetoacetic acid. (Only about 5% of patients with chronic kidney failure get clinical gout.) Uric acid reabsorption is increased in low-volume states with slow flow through the proximal tubules, and in heavy alcohol use.

Some causes of "secondary gout" are known genetic diseases:

Type I Glycogen Storage Disease (von Gierke): Gout in this disease result from over-production of uric acid plus and decreased urate secretion. These are due to the presence of abnormal carbohydrate metabolites.

Lesch-Nyhan Syndrome: An X-linked recessive trait with complete deficiency of "salvage enzyme" (hypoxanthine-guanine phosphoribosyl transferase, HGPRT). Therefore, hypoxanthine cannot be salvaged, more hypoxanthine becomes uric acid, and more purines must be made from scratch (only to become more uric acid). Severe gout is one feature of this terrible disease. * A less complete deficiency is one known cause of "primary gout".

The Acute Gouty Attack: The attacks begin and end so suddenly, and are so severe, that a vicious cycle obviously underlies them. It is preceded by precipitation of insoluble monosodium urate crystal in relatively avascular tissue (cartilage, epiphyseal bone, periarticular bone, extraskeletal). This has probably been going on during the years of hyperuricemia, but sequestered somehow without producing symptoms. The acute attack begins when some crystals effectively activate the plasma proteases. Monosodium urate crystals themselves can activate factor XII and C5. Monosodium urate crystals can also adsorb whatever opsonins may be around, rendering them tasty to phagocytes. Polys and monos soon arrive and start trying to eat the crystals. The crystals then rupture the lysosomes and lyse the phagocytes. Enzymes from the dead phagocytes enter the synovial fluid and damage tissue, activate complement, etc. More phagocytes arrive and the same thing happens again. Whatever urate crystals may be present in tophi or microtophi within the joint will probably be released as the process continues. Plus, as the inflammation causes the pH in the joint to go down, more and more urate crystallizes. Acute attacks probably are self-limited because the heat of inflammation redissolves the crystals.

The Chronic Disease: Although the acute attack is the most dramatic aspect of gout, the enduring lesion of gout is the tophus. Future pathologists -- the crystals are water soluble, so unless you process the tissue specially, they will dissolve away. (Use absolute alcohol). Future clinicians -- when you suspect gout, feel for tophi in the helix and antihelix of the pinna. Joints: Repeated acute attacks, or uric acid buildup, wrecks the cartilage and underlying bones, which may become fused, lipped, etc. The most commonly involved site is the big toe, but other cold places, such as the elbows, wrists and fingers, are often involved. Perhaps one fourth of gout patients develop uric acid kidney stones. Future radiologists -- remember that, unlike most kidney stones, uric acid stones are radiolucent. A sudden rush of uric acid at low pH within the renal tubules can shut them down ("acute urate nephropathy"). Tophi in medulla and pyramids ("chronic urate nephropathy") cause acute and chronic kidney problems. Finally, patients with hyperuricemia tend to develop high blood pressure. Why this happens remains unknown.

Clinical Diagnosis: Some reminders. (1) The patient with gout is seldom the first family member affected. (2) Serum uric acid is routine on most automated chemical profiles. (3) Compensated polarization of synovial fluid, tophus, or kidney stone can identify the uric acid crystals. (4) "Uric acid crystals" and "amorphous urates" reported on urinalysis are of essentially no significance, and are common in normals with acid urine.

Treatment: Colchicine, the mitotic spindle poison from the crocus flower, blocks leukocyte function and stops the acute attack. Non-steroidal anti-inflammatory agents are also useful for the joint disease. Allopurinol, a purine analogue, inhibits xanthine oxidase and prevents the formation of uric acid. The precursors are excreted instead. Allopurinol, though expensive, is the mainstay of chronic treatment of gout. Probenecid makes renal clearance of uric acid more effective (helps the hyperuricemia and joint disease, but clearly not a way to prevent kidney stones from forming in over-producers). If the urine is kept alkaline, uric acid is much less likely to precipitate in the kidney.

The Johns Hopkins prospective Gout Study: JAMA 266: 3004, 1991.

Renovascular I From Chile In Spanish

Renovascular II From Chile In Spanish

HIGH BLOOD PRESSURE ("hypertension")

A long-standing increase in systolic and/or diastolic blood pressure above desirable levels, i.e., 160/90 or thereabouts). This affects maybe 15% of people in the U.S., largely (but not exclusively) among older people.

* Please review: The current flap over "who needs to be treated". If you believe the WHO recommendation that normal is "systolic 130 or under", you'll believe anything (Lancet 355: 175, 2000).

Classification

90% idiopathic (essential hypertension)

This includes the common "benign essential hypertension" and the commonest form of the rare "malignant hypertension." (Clinically, you'll call hypertension "malignant" if it causes papilledema.)

10% secondary hypertension (review Hosp. Pract. 29(4): 137, 1994 April 15, 1994)

Endocrine diseases: Cushing's, 11-beta-hydroxylase deficiency and its kin (J. Clin. End. Metab. 77: 687, 1993), hyperaldosteronism, pheochromocytoma, eclampsia (a tremendous killer of women, especially in the poor nations: Br. J. Ob. Gyn. 99: 547, 1992), reninoma, hypercalcemia, licorice abuse (really, * it inhibits cortisol oxidase and 11-beta-hydroxylase: NEJM 325: 1223, 1991), Liddle's syndrome, others.

Renal hypertension: coarctation of aorta, known renal or renal arterial disease

Nobody understands where diabetes fits into the picture. Hypertensive diabetics tend to hang onto sodium for some reason. * The old hyperinsulinemia- hypertension hypothesis deflated: J. Clin. End. Metab. 76: 544, 1993; Diabetes 39: 1430, 1990.

Nobody really knows where sleep apnea fits into all this, but the relationship (at least) is impressive independent of obesity (Chest 104: 775, 1993; Am. J. Med. 91: 190, 1991; questioned Chest 102: 367, 1992; more Am. J. Med. 98: 118, 1995, Br. Med. J. 320: 479, 2000).

Nobody understands, either, why low birth weight predicts adult hypertension, but the effect seems powerful. The effect increases depending how low the birth weight was, and how old the patient now is (Br. Med. J. 306: 24, 1993). Sounds like a positive-feedback things that starts in the womb.

* Two molecules to watch are chromogranin A, which is overabundant in essential hypertension, and its catecholamine-release-inhibiting fragment catestatin (J. Clin. Inv. 115: 1942, 2005).

Not included in this classification are the causes of increased pulse pressure, due to loss of arterial compliance (atherosclerosis, really extensive Monckeberg's) or greatly increased cardiac output (exercise, emotion, fever, hyperthyroidism, AV fistulas, beriberi, aortic valve insufficiency, patent ductus arteriosus).

Regardless of cause, longstanding high blood pressure is bad. Patients get:

• increased incidence of cerebrovascular accidents, especially hemorrhage ("hypertensive hemorrhage" -- though the relationship is questionable)
• some acceleration of atherosclerosis (with resultant coronary artery disease), and hypertensive heart disease
• high blood pressure from any cause eventually damages the kidney. (NOTE: Regardless of the original disease, most advanced renal disease patients seem to benefit from angiotensin converting enzyme inhibition).
• damage to the white matter of the brain ("Binswanger's", "white matter hyperintensities"), which is an under-recognized cause of dementia in older folks (Neurology 56: 921, 2001). Even non-impaired older folks with high blood pressure have these (Neurology 63: 1892, 2004). The vascular changes in the brain parallel the familiar hypertensive changes in the retina (Neurology 59: 1536, 2002). The brain damage seems synergistic with Alzheimer's if the two are both present (Neurology 64: 263, 2005).
• iatrogenic disease secondary to the noxious side effects of antihypertensive agents is widespread and serious. Diuretics cause hypokalemia that can be disabling or fatal. Many other drugs cause fatigue, depression, impotence ( Ann. Int. Med. 144: 613, 1991).

BENIGN ESSENTIAL HYPERTENSION (common "high blood pressure", "the silent killer", etc.);

Affects about 15% of the population, prevalence increases with age. Five percent of people in 30's, 30% of people in 50's. All ages females more than males, blacks more than whites. A personal history of high blood pressure and its treatment: Br. Med. J. 298: 445, 1989.

Usually slow, progressive, asymptomatic increase in blood pressure.

What causes "benign" essential hypertension? This continues to elude us:

The basic trouble in most patients does seem to be generalized arteriolar vasoconstriction and/or inability to dump a salt load.

Vasoconstriction by catecholamines ("released in response to emotional stress") figured prominently in older explanations, especially those by psychiatrists. The sympathetic nervous system has been rediscovered as a factor in hypertension (Am. J. Med. Sci. 303: 271, 1994.

* Some other suggestions focus on other mediators, such as prostaglandins, lack of atrial peptides, etc., etc,. A mouse with deficient atrial natriuretic peptide has sodium-sensitive hypertension (Science 267: 679, 1995), just as you would expect.

* Hypertensives seem to have increased activity of Na+-H+ exchangers on a variety of cell membranes. There is talk of increased calcium channels, etc., etc.

It's well-known that hypertensives' small arterioles lose the ability to dilate appropriately. This is probably due to the hyaline (etc.) arteriolar sclerosis that develops from the hypertension.

* There has been talk of selective loss of the ability to dilate, depending on the mediator; this was questioned in the 1990's (NEJM 330: 1036, 1994) but has found new support from measurements of the retinal vessels in two big prospective studies. The artioles narrow BEFORE high blood pressure appears (Br. Med. J. 329: 79, 2004; Ann. Int. Med. 140: 138, 2004).

Media-to-lumen ratio (i.e., just how much too thick is that wall?) seems to be the foremost predictor of disaster in hypertension, regardless of cause (Circulation 108: 2230, 2003).

The larger arteries also take a beating. Fibroelastic thickening of the intima smooth muscle hypertrophy in the media both occur in the larger and medium-sized arteries; this regresses when the hypertension is treated (Circulation 101: 2601, 2000).

Watch for sporadic rat-borne hantavirus infection as an explanation for why some people just turn bad-hypertensive. Only 0.25% of adults have antibodies against any hantavirus, but 6.5% of people with end-stage renal disease due to hypertension (but not other uremics) have such antibodies. J. Inf. Dis. 167: 614, 1993. There's a new Yugoslavian hantavirus that devastates the renal vasculature (J. Inf. Dis. 166: 113, 1992), and the Korean one is old news (Ann. Int. Med. 113: 385, 1990). Currently, hantavirus is a "usual suspect" in the US for "mysterious" ATN, "mysterious" IgA nephropathy, and "mysterious" segmental necrotizing glomerulonephritis (Am. J. Kid. Dis. 33: 734, 1999).

The molecular biology is only starting to be understood. Whatever is really happening, the kidneys of most hypertensives seem to have difficulty disposing of a sodium load. (And, of course, we in the US eat too much salt....). However, salt-loading will not cause high blood pressure in most people.

The American salt craving: Am. Sci. 75: 27, 1987. The pop notion that everyone should avoid salt is both unscientific and probably false (Lancet 351: 781, 1998).

One interesting new lead involves diminished production of nitric oxide ("endothelially-derived relaxation factor", "EDRF"; NEJM 323: 22, 1990; cause or result?). Now we know that the production of this stuff falls off as we get old (J. Geront. 49: B-157, 1994). Nitric oxide update in salt sensitive hypertension: Am. J. Kid. Dis. 28: 775, 1996.

* Didja know that sodium nitroprusside works by producing this stuff?

* Endothelin is often elevated in hypertension, regardless of etiology. This is probably not the cause, but an effect that may help perpetuate the problems. Endothelin supposedly constricts the renal vasculature, makes the mesangial cells contract, prevents resorption of sodium and water, and causes hyaline to accumulate in vessels and gloms. Since the kidney must clear it, enhanced levels of endothelin and renal failure probably promote each other. Update Mayo Clin. Proc. 80:

* Mouse model in which superoxide radicals destroy EDRF and cause hypertension: Proc. Nat. Acad. Sci. 88: 10045, 1991. All about endothelin: NEJM 333: 356, 1995.

More evidence for a paracrine vicious cycle, with vascular hypertrophy-hyperplasia leading to long- lasting hypertension, in a rat model in which vascular smooth muscle responds too well to growth factors: Am. J. Med. 92(4B): 35S, 1992. This very likely happens in people, too (Am. Heart. J. 122: 198, 1994).

The most interesting work right now in common high blood pressure involves angiotensin II.

The gene for the spontaneously hypertensive rat was been mapped to the angiotensin converting enzyme gene (Nature 354: 521, 1991), and soon afterwards we discovered that "the spontaneously hypertensive human" (i.e., the hypertensive without some recognized syndrome) very often has a mutation here too (NEJM 330: 1565, 1992.)

* The good allele is "I", the bad one "D". Angiotensin II is an important growth factor, and it's now considered the main cause of fibrointimal hyperplasia and cardiac myocyte hypertrophy (Circulation 101: 148, 2000).

Hereditary factors (the hypertension genes: Science 272: 676 1996), personality variables, environmental stress (for example, job strain: JAMA 263: 1929, 1990; West. J. Med. 153: 180, 1990; and of course the classic "repressing your anger", which has found new support JNMD 177: 15, 1989), and obesity (Ann. Int. Med. 128: 81, 1998) all seem important in hypertension.

Obese patients, and black patients who are developing hypertensive renal insufficiency, are likely to have much increased plasma volume (i.e., total-body sodium).

Among blacks, both genetics (there must have been some selection for a tendency to retain salt under the deplorable conditions of slavery) and environment (salt in the diet, socioeconomic stress) appear to be important (JAMA 265: 599, 1991; Am. J. Med. Sci. 307(S1): S-38, 1994; Am. J. Med. Sci. 304: 306, 1992); barriers to care also exist (Am. J. Kid. Dis. 19: 397, 1992).

Black hypertensives seem to produce much more TGF-β1, which releases endothelin and renin and probably causes hyalinization of small blood vessels (Proc. Nat. Acad. Sci. 97: 3479, 2000).

Young adults with newly-discovered high blood pressure are likely to have inappropriately high cardiac output with normal peripheral resistance (i.e., they do not have generalized vasoconstriction), usually are not sodium-overloaded, etc.

The benefits of exercise (aerobic, strength training) in the treatment of hypertension seem less impressive than the common wisdom suggests: JAMA 266: 2098, 1991. A realist writes on diet in the pathogenesis and treatment of hypertension (Med. Clin. N.A. 77: 831, 1993; "we don't know much about causes, we can't promise much benefit, we can't expect compliance").

Arteriolar nephrosclerosis ("benign nephrosclerosis")

Seen in patients with high blood pressure from any cause; thus, the kidney lesion of "benign essential hypertension", the commonest cause.

Smallish, symmetric kidneys with finely granular (sandpaper) surfaces. (Each pit is the site where a nephron has been lost and the scar has contracted.)

Some glomeruli are replaced by collagen, with corresponding tubular atrophy and interstitial fibrosis.

The small renal arteries and afferent arterioles of hypertensives show a variety of changes:

• first hypertrophy and hyperplasia, then loss, of medial muscle, and its replacement by fibrous scar
• some proliferation of endothelial cells and reduplication internal elastic membrane, and some intimal fibrosis ("intimal fibroplasia"); review Arch. Path. Lab. Med. 120: 261, 1996.
• walls of the smallest arteries hyalinize with PAS-positive material "because the intima is permeable" (* insudation or * plasmatic vasclosis"), and this narrows the lumen.

{21010} arteriolar nephrosclerosis with plenty of little cysts (gross)
{10575} arteriolar nephrosclerosis, sandpaper kidney
{11777} arteriolar nephrosclerosis, hyalinized artery
{40267} arteriolar nephrosclerosis, gross
{25760} hypertension, bad fibrous intimal proliferation
{08871} hypertension, intimal fibroplasia
{25764} hypertension, intimal fibroplasia

Arteriolar Nephrosclerosis Dino Laporte's PathosWeb

Sandpaper kidney Benign nephrosclerosis WebPath Photo

All these changes are even more pronounced in diabetics, though diabetes also hyalinizes the efferent arterioles. Treating hypertension in diabetics, especially young ones, is a must: Ped. Clin. N.A. 40: 81, 1993.

{25763} hypertension
{25764} hypertension
{25765} hypertension; trichrome
{25766} hypertension; reticulin

Some such arteriolar changes are seen in any elderly person, or anyone with high blood pressure affecting the kidney, from any cause. It starts in young people: Arch. Path. Lab. Med. 116: 50, 1992.

When arteriolar narrowing develops, it may contribute to the hypertension, but is not the primary cause.

Uncomplicated arteriolar nephrosclerosis causes renal failure in less than 5% of its victims (mostly blacks).

However, you want to prevent arteriolar nephrosclerosis. This is one of the reasons you want to treat hypertension early (Arch. Int. Med. 150: 2073, 1990).

"Bright's riddle": Dr. Bright noticed that patients at autopsy who had left ventricular hypertrophy often had small kidneys with finely-granular surfaces, and vice versa.

WARNINGS:
• Perhaps as high as 25% of U.S. patients with "idiopathic high blood pressure" are not sick at all, but have "white jacket syndrome", a transient rise in blood pressure caused by the emotional consequences of a blood pressure check. Give them a cuff and have them check it themselves at home.

Perhaps not surprisingly, one study found about 50% of "hypertensive" children merely have white jacket hypertension (J. Fam. Pract. 33(6): 617, Dec. 1991).

• An unknown percentage of "hypertensives" are fat or super-muscular people whose blood pressure was measured using a thin person's cuff.... (Lancet 336: 410, 1990).
• We spend $20 billion per year in the U.S. treating high blood pressure. The drugs still drive people to chronic ill health and suicide. Use common sense.

MALIGNANT HYPERTENSION: High blood pressure causing papilledema.

Hypertension from any cause can accelerate or enter a malignant phase.

Malignant hypertension may develop in previously healthy patients, but usually is superimposed with pre-existing benign hypertension (develops in 1% of cases).

It is more common in males than females; more common in blacks than Caucasians.

Scleroderma and adult hemolytic-uremic syndrome often terminate in malignant hypertension. (All three display onion-skinning of the intima of the small renal arteries.) Scleroderma kidney Kid. Int. 41: 462, 1992.

Cocaine abuse precipitating malignant hypertension: Am. J. Med. Sci. 312: 295, 1996.

{25757} malignant hypertension, bleeding into the kidney
{25759} malignant hypertension, most of kidney is infarcted
{25761} malignant hypertension, intimal proliferation (trust me this was malignant hypertension)
{25762} malignant hypertension, fibrinoid necrosis
{25762} malignant hypertension

Malignant hypertension Necrotic kidney arteries KU Collection

Malignant hypertension Necrotic kidney arteries KU Collection

Fibrinoid in malignant hypertension WebPath photo

Malignant hypertension WebPath Photo

Malignant hypertension Fibrinoid WebPath Photo

Malignant hypertension Onion skinning WebPath Photo

Patients have rapidly rising blood pressure, generally reaching levels greater than 200/110. This has many bad effects.

Hypertensive encephalopathy (papilledema, behavioral changes, nausea and vomiting, headache, visual disturbances, seizures)

Congestive heart failure (ask a cardiac pathophysiologist; increased volume or resistance must be rough on the heart) or intracerebral hemorrhage

Malignant nephrosclerosis: the renal lesion of malignant hypertension

The essential feature is damaged, non-inflamed arterioles.

Glomeruli show scattered necrosis and hemorrhage. Bleeding into the glomerular spaces appear as petechiae on the cortical surfaces ("flea-bitten kidneys", seen also in the nephritic syndrome).

Intimal proliferation ("onion-skinning") of small arteries is characteristic; this badly narrows the lumens, renin levels increase, and renal infarcts occur.

The media fills with "fibrinoid" because of endothelial damage. (There may also be some necrosis of the media.)

Of course, the kidneys will also show "arteriolar nephrosclerosis" if there was pre-existing "benign" hypertension.

Malignant nephrosclerosis destroys the kidney in a few months (except in a minority of patients who die of stroke).

RENAL VASCULAR HYPERTENSION:

Renal artery stenosis

You already know how stenosis of one renal artery causes high blood pressure by making the kidney produce excess renin.

It is usually caused by atherosclerosis of an ostium.

The damage is largely done (to the other kidney and the body's microvasculature) by the time the patient gets diagnosed. The results of the popular balloon procedure to re-open the artery are discouraging: NEJM 342: 1007, 2000.

Adult polycystic kidney plays havoc with the microvasculature, and high-renin hypertension occurs early (NEJM 323: 1091, 1990).

Fibromuscular dysplasia (actually a congenital malformation, and not anaplastic or pre-malignant) is a rare cause of this in young people. Treating it with an endovascular prosthesis: NEJM 336: 459, 1997.

* Takayasu's arteritis, * von Recklinghausen's disease, and * adhesions from previous surgery are the other causes.

"Goldblatt's riddle": Dr. Goldblatt noticed that many patients at autopsy who had high blood pressure in life possessed one normal-sized kidney and one small kidney with a narrowed renal artery (the "Goldblatt kidney").

Dr. Goldblatt answered his own riddle by producing high blood pressure in animals, using a clamp to produce subtotal occlusion of one renal artery.

"Goldblatt hypertension" exhibits (at least at first) high serum renin levels. (* Stay tuned for the introduction of renin inhibitors into clinical practice: Nature 357: 446, 1992).

The kidney supplied by the narrowed artery is often small and fibrotic and may contain infarcts from atheroembolic episodes.

Eventually, however, the resultant hypertension will cause the other kidney to show changes of nephrosclerosis. The kidney with the renal artery stenosis will show less arteriolar change than the other kidney, due to the protective effect of the stenosis. (So the "Goldblatt kidney" is sometimes the larger one.)

Another tipoff is that these patients tend to have good responses to angiotensin converting enzyme (ACE) inhibitors (why?) But remember that these ideally are surgical or angioplasty diseases.

* "Low blood pressure", a fad diagnosis in France and Germany, is probably a myth (Br. Med. J. 301: 362, 1990).

HEMOLYTIC-UREMIC SYNDROME ("HUS"; review of the thrombopathy NEJM 346: 23, 2002):

A pattern of renal injury with several causes, all with platelet clumping in small renal blood vessels, resulting in microangiopathic hemolysis, thrombocytopenia, and acute renal failure. (* Don't confuse HUS with DIC, as the clotting factors are not consumed with the platelets; fibrinogen levels, PT, and PTT all stay normal; there are overlap syndromes which resemble both HUS and TTP).

The pathogenesis is just now being worked out. The fundamental problem is selective damage to the endothelium of the renal microvasculature.

* Pathologists recognize a characteristic anatomic pattern of injury.

Childhood hemolytic-uremic syndrome (NEJM 323: 1050 & 1161, 1990) is an important epidemic disease, presently becoming more frequent, and is now the most important cause of acute renal shutdown in kids.

It usually follows viral illness or bacterial bloody diarrhea (* "D+ HUS"). The child usually recovers completely (* "D- HUS" is more mysterious and more ominous).

There were epidemics in California in the early 1980's. The current epidemic in Minnesota: NEJM 323: 1050 & 1167, 1990. Remember the "Jack-in-the-Box" hamburger fiasco (JAMA 272: 1349, 1994)? Most kids recover but around 10% have residual kidney damage: Br. Med. J. 303: 489, 1991

The best-established cause (* of "D+") is verocytotoxin ("shiga toxin"), a poison from certain strains of E. coli (notably 0157:H7, currently spreading among cattle; beware raw burgers or raw milk for kids -- Postgrad. Med. 88: 135, Oct. 1990; Br. Med. J. 303: 800, 1991; Lancet 337: 138, 1991; NEJM 333: 364, 1995). The related "Shiga toxin" from Shigella dysenteriae does the same thing. This damages endothelial cells, and causes them to release factor VIII aggregates, which clump platelets (Nephron 51: 207, 1989).

Once the process gets going, neutrophil products probably contribute to the general mayhem.

* Paradoxically, there is are excessive amounts of tissue plasminogen activator and d-dimer in the plasma; is something inhibiting small-vessel fibrinolysis?

* Future blood bankers! Verocytotoxin, which binds to specific receptors on the renal endothelial surfaces, also binds to P1 red cell antigen, which buffers it. Kids lacking this antigen are at much greater risk for HUS.

Adult hemolytic-uremic syndrome:

This follows complications of pregnancy (* rarely exposure to exogenous estrogens), administration of endothelial poisons, notably * mitomycin C (an anti-cancer drug) * cyclosporine, * "collagen- vascular diseases", and * crack cocaine (Am. J. Med. Sci. 299: 366, 1990). It typically ends in chronic renal failure and sometimes malignant hypertension.

Biopsy shows intimal onion-skinning in small renal arterioles (* the more of this, the worse the prognosis), fibrin thrombi and/or red cell fragments in the glomeruli, and "fuzz" (a mix of fibrin and amorphous junk) in the subendothelial spaces.

* Thrombotic thrombocytopenic purpura has similarities to HUS. The thrombi are mostly composed of platelets, neurologic defects are more prominent, and the patient is either cured or dies.

DIFFUSE CORTICAL NECROSIS

{10570} diffuse cortical necrosis
{10574} diffuse cortical necrosis
{21026} diffuse cortical necrosis

This results from severe DIC plus shock, usually post-partum. (* Snake bite: Kid. Int. 35: 891, 1989). Unlike in HUS, the kidney vessels are normal.

The patient, of course, has acute renal failure that doesn't get better. At autopsy, fibrin thrombi plug the glomerular capillaries.

ATHEROEMBOLIZATION

{16900} atheroembolus; scar has formed around it

Shrivelled kidney Attributed to atherosclerosis WebPath Photo

Kidney infarct WebPath Photo

Kidney infarct WebPath Photo

Kidney Infarct Photo and mini-review Brown U.

A common cause of acute renal failure in older patients, especially those with abdominal aortic aneurysms.

The new thrombolytic therapies for myocardial infarctions tend to remove surface thrombi from ulcerated atherosclerotic plaques, releasing their contents. You'll see a few kidneys destroyed in this way.

The diagnosis is difficult to make during life. (* It doesn't really matter, because atheroembolization isn't treatable.) Look for livido reticularis on the lower extremities, increased eosinophils in the blood and urine.

At autopsy, the pathologist finds platelike ("needle-shaped") crystals of cholesterol in the renal arteries, with an associated foreign-body reaction.

Survivors of this (or any other sort of renal embolization) end up with a kidney with one or more V-shaped scars ("arterial nephrosclerosis").

SICKLE CELL DISEASE NEPHROPATHY

Cells tend to sickle in the hypertonic milieu of the renal medulla, even in heterozygotes. This result in hematuria and/or decreased ability to concentrate urine, loss of vasa recta, renal tubular acidosis (type 4), etc.

Sicklers (HbSS, HbSC) often get papillary necrosis (even carriers' cells sickle in the hypertonic milieu), many other problems.

* We have already mentioned the glomerulopathy, which is poorly understood (J. Ped. 136: 749, 2000); the thankfully rare medullary carcinoma of the kidney usually occurs in those with the disease or trait.

OBSTRUCTIVE DISEASE OF THE KIDNEY

Causes include malformations, blood clots, calculi, tumors, prostatic hyperplasia, * retroperitoneal fibrosis, and neurologic bladder problems.

Clinical pictures:

Unilateral obstruction may be clinically silent.

Bilateral partial obstruction will first manifest as loss of concentrating ability due to tubular atrophy.

Bilateral complete obstruction results in anuria.

Obstruction produces dilatation of the calyceal system (hydronephrosis), eventually with fibrosis and tubular atrophy of the kidney (relative sparing of glomeruli. Of course, there are many other causes of hydronephrosis).

Obstruction predisposes to acute and chronic pyelonephritis and (less often) renal papillary necrosis.

{10573} hydronephrosis
{10577} hydronephrosis

Hydronephrosis WebPath Photo

KIDNEY STONES (renal calculi, "urolithiasis"; NEJM 327: 1141, 1992; Am. Fam. Phys. 63: 1329, 2001)

{40264} kidney stone
{09786} staghorn kidney stone
{09789} kidney stone
{18787} staghorn stone
{49322} kidney stone

Hydronephrosis and stones From Chile In Spanish

Kidney stone Animation WebPath Photo	Kidney stone WebPath Photo
Kidney Stones Dino Laporte's PathosWeb	Staghorn kidney stone WebPath Photo

Kidney stones form in the renal pelvis. They are painful, especially during passage, and dangerous as a cause of chronic infection.

Calcium stones (oxalate, phosphate, others) are the commonest, and the majority of these patients have hypercalciuria (with or without hypercalcemia).

Hypercalcemia in a patient who first presents with kidney stones is probably due to a parathyroid adenoma.

Causes of hypercalciuria with normal serum calcium include milk-alkali syndrome (old ulcer cure; Am. J. Med. 99: 102, 1995), vitamin D abuse, mild sarcoidosis, dolomite pills (*  polished rocks sold in health-food stores and promoted to athletic coaches "to prevent cramps due to hypocalcemia"), ketogenic anti-epileptic diets that include water restriction (J. Urol. 164: 464, 2000), and mild renal calcium or phosphate leaks. The recommended calcium supplementation for osteoporosis prophylaxis isn't enough to cause kidney stones in normal people.

Some calcium oxalate stone formers have increased absorption of oxalic acid from the gut (i.e., terminal ileitis, intestinal bypass, spinach gourmets); others are vitamin C abusers; still others have a minor inborn error of metabolism (* usually glycolic aciduria).

However, most calcium stone formers seem to have more calcium in the urine for no clear reason, i.e., probably they just absorb calcium from their gut too well. (This runs in families.) You'll be treating these people with diuretics (if nothing else, it makes them drink more water!) and magnesium citrate (know how this works?)

Magnesium ammonium phosphate stones ("* struvite stones", "triple stones", "infection stones") often result from urinary tract infection by urea splitters like proteus.

Most staghorn calculi, which fill the renal pelvis, are magnesium ammonium phosphate.

Only half of uric acid stones are associated with hyperuricemia. (* Ask them if they are taking any medications, especially non-steroidal anti-inflammatory agents.)

Cystine stones indicate cystinuria, which requires pharmacologic treatment.

Triamterene stones (from patients on "Dyazide"): An intriguing subject. The stones are generally mixed. Also Aciclovir stones and Indinavir stones.

Future radiologists: calcium oxalate, calcium phosphate, and cystine stones are radio-opaque. Magnesium ammonium phosphate stones are slightly radio-opaque, and uric acid stones are radiolucent.

Future clinical pathologists: The lab does chemical analysis of calculi using many interesting procedures.

* Although "pain isn't real", you might enjoy reading about Mary Baker Eddy's experience with "the illusion of kidney stones", for which she took morphine.

* This is a good place to mention the uncommon and mysterious "loin pain hematuria syndrome". Patients have gross or at least microscopic hematuria, intractable loin pain, and seem to benefit from having the kidney moved surgically (autotransplantation -- could this work simply by severing the pain fibers to the kidney?) See J. Urol. 160: 1232, 1998.

KIDNEY TUMORS: Pathology-for-beginners Ur. Clin. N.A. 20: 193, 1993; Heidelberg classification J. Path. 183: 131, 1997.

Kidney Tumors From Chile In Spanish

Kidney Nice case photos Charam M. Ramnani MD

The benign tumors

Papillary adenomas resemble small (less than 5 mm) papillary RCC's histologically and cytogenetically.

* Future pathologists: Any clear-cell area makes it cancer.

Hemangiomas (really hamartomas, not tumors) can bleed on-and-off.

* Laser cure: South. Med. J. 88: 759, 1995.

* Renal medullary fibromas are common incidentalomas at autopsy.

Angiomyolipomas can occur in anyone, but are very common in tuberous sclerosis. Review Arch. Path. Lab. Med. 118: 735, 1994; J. Urol. 152: 35, 1994.

* The HMB-45 stain, which usually only lights up melanomas, also stains these tumors. Nobody knows why, a some less-well-known melanoma markers also show (Arch. Path. Lab. Med. 125: 751, 2001; Arch. Path. Lab. Med. 126: 49, 2002).

{25360} angiomyolipoma, gross; aorta is small because this is from a child
{25361} angiomyolipoma

* Hemangiopericytomas (JGA-oma, renin-oma) are rare, make renin (rhomboid granules), cause high blood pressure (J. Urol. 146: 1607, 1994; reviews J. Urol. 153: 1781, 1995; Am. J. Clin. Path. 116: 854, 2001).

Hürthle cell adenomas ("oncocytomas") are suddenly quite common and are often multiple. Their behavior is almost always benign unless there's obvious cellular atypia (* I'd rather call these oncocytic RCC's, which they act like). They have a characteristic pattern of chromosome breaks, always have a central stellate scar, etc. See Am. J. Surg. Path. 21: 871, 1997. This is the first "cancer" to be linked to an abnormality of mitochondrial (rather than nuclear) DNA: Am. J. Path. 134: 967, 1989.

Clear-cell renal cell carcinoma ("hypernephroma," "adenocarcinoma", "Grawitz tumor", "RCC")

{21021} renal cell carcinoma, gross
{21022} renal cell carcinoma invading the vein
{09754} renal cell carcinoma, gross
{09788} renal cell carcinoma, gross
{09823} renal cell carcinoma, gross
{17204} renal cell carcinoma, microscopic; the nuclei look deceptively benign
{17207} renal cell carcinoma, microscopic
{35582} renal cell carcinoma, microscopic
{00080} renal cell carcinoma, clear cells

Renal Cell Carcinoma
Ed Uthman's Pathology Gallery

Renal Cell Carcinoma Photo and mini-review Brown U.

Renal cell carcinoma Renin granules Pittsburgh Pathology Cases

Renal cell carcinoma WebPath Photo

Renal cell carcinoma WebPath Photo

Renal cell carcinoma This one turned mostly to mush WebPath Photo

Renal cell carcinoma Invading the renal vein WebPath Photo

Renal cell carcinoma Clear cells WebPath Photo

Mesoblastic nephroma Virtual Hospital

Clear-cell RCC is a common, capricious cancer infamous for the many ways in which it can present clinically.

The classic triad is fever, hematuria, flank pain.

Or the tumor may present as hypercalcemia (J. Urol. 145: 248, 1991), amyloidosis, polycythemia, high blood pressure, estrogens, Cushing's, eosinophilia, leukemoid reaction, or as metastases (especially as single masses in the head and neck). Only a few make erythropoietin and cause polycythemia.

Clear-cell renal cell carcinomas are usually bulky, yellow cancers that occur in middle-aged or elderly patients.

Tobacco is a known risk factor (* at least in men who smoke non-filter cigarets). Obesity is a minor risk factor in both genders (NEJM 343: 1305, 2000).

* Aspirin, touted as a risk factor, didn't pan out; others seem even softer Cancer 75: 2552, 1995.

We now know that trans-stygian kidneys often give rise to renal cell carcinomas.

* Perhaps they are marginally vascularized, and the tubular epithelium often dies off and regenerates.

* The 1997 TNM staging system (Cancer 91: 354, 2001) defined tumors up to 7 cm -- which would be huge if they occurred elsewhere -- as at the lowest stage with a good prognosis if there are not positive lymph nodes or metastases (about 90% chance at a cure). If it's 4 cm or less, they do even better (J. Urol. 165: 1103, 2001). The newest TNM system validated: J. Urol. 173: 1889, 2005.

Since with new scanning procedures we're finding little kidney tumors all the time, learning to manage these is big topic right now. Most of them won't grow, but you can't know which ones (J. Urol. 164: 1143, 2000). Alternative to radical surgery include laparoscopic surgery, cryotherapy (what the pathologist sees after: J. Urol. 173: 720, 2005), and radiofrequency ablation. (All three of these high-tech procedures are really cool technology. Have a radiologist or surgeon show you the equipment!)

The cell of origin is the proximal tubular cell, and there are always clear cells. variable.

The clear cells are, rich in both fat and glycogen, with no vacuoles; they may look wildly anaplastic or deceptively benign.

* Leave it to the pathologists to worry about subtypes, including the ones that mimic sarcomas (Arch. Path. Lab. Med. 129: 1057, 2005).

Sarcomatoid RCC
Leave the diagnosis to us
Loyola Med


There is considerable interest right now in cytogenetics of RCC, especially in 3p deletions and translocations that are characteristic of these tumors (Urol Clin. N.A. 20: 207, 1993, many others).

In both familial and sporadic cases, the anti-oncogene (VHL) at the Von Hippel Lindau locus is apparently always deleted (Am. J. Hum. Genet. Dec. 1994; JAMA 273: 564, 1995).

* If there is any persistent VHL expression in the tumor, it is a very good prognostic sign: Am. J. Path. 163: 1013, 2003.

The Fuhrman grading of system for RCC's is based entirely on nuclear morphology (Am. J. Surg. Path. 6: 655, 1982 for the classic article; J. Clin. Path. 47: 324, 1994). This is likely to be supplemented by ploidy and proliferation markers (Cancer 77: 164 & 514 & 1154, 1996; J. Urol. 155: 459, 1996); molecular markers prognosticate in metastatic disease (J. Urol. 173: 1496, 2005).

Grade I: Nuclei about 10 microns, look very tame
Grade II: Nuclei about 15 microns, irregular borders, small nucleoli
Grade III: Nuclei about 20 microns, even more irregular borders, large nucleoli
Grade IV: Nuclei very bizarre

Since about 10% of RCC patients will get a second one, you can probably safely treat the little (3 cm) ones with partial nephrectomy (J. Urol. 153: 620, 1995).

The tumor typically metastasizes by the bloodstream (unusual for a carcinoma; the other three carcinomas that tend to do this are hepatocellular carcinoma, adrenal cortical carcinoma, and follicular carcinoma of thyroid).

About 50% of clear-cell RCC's invade and grow up renal vein, and can pass right through the tricuspid valve, causing right-sided heart failure. (Such tumors are often successfully cured by removal: Am. J. Surg. 168: 205, 1994; a majority seem to be cured surgically J. Urol. 155: 448, 1996.) This shouldn't surprise you if you remember basic cancer biology. If the tumor has grown this big without the patient dying of metastases, the tumor hasn't yet acquired the ability to metastasize.

* Massive embolization of tumor itself to the pulmonary arteries is also infamous (Ann. Thoracic Surg. 61: 708, 1996).

Five year survival may be about 70% for surgically-excised localized tumors, but survival is poor if tumor invades perinephric far or metastasizes.

Taking them out via laparoscope: J. Urol. 155: 1180, 1996. Nephron sparing for small tumors, leaving some of the involved kidney behind: J. Urol. 155: 1191 & 1868, 1996, many others.

Cancer chemotherapy has not been a striking success for clear-cell RCC (J. Urol. 163: 408, 2000). Progesterone may be tried, but there are no good studies supporting its use. Interleukin 2 gives good temporary tumor regression occasionally, but makes the patient sick (NEJM 338: 1272, 1998). Interferon gamma-1b was a flop (NEJM 338: 1265, 1998). Combining cytokines gets slightly better results but is very unpleasant: NEJM 338: 1272, 1998. Treating RCC's: CA 46: 284, 1996.

Unlike most cancers, renal cell carcinoma will occasionally remit spontaneously (J. Urol. 152: 156, 1994), and nobody has a clue how. Or the metastases may remit after the primary is removed (J. Urol. 153: 751, 1995).