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.

A related problem (PHOSPHATE NEPHROPATHY) is acute renal shutdown in patients who may seem to have normal kidneys but who get kidney failure from calcium phosphate desposited in their kidneys after sodium phosphate bowel-preps (Arch. Path. Lab. Med. 130: 101, 2006; also NEJM 349: 1006, 2003 and J. Am. Soc. Nephr. 16: 3389, 2005).

This is the reason for the current teaching that one should not give "Fleets" to patients with kidney disease or on diuretics or ACE inhibitors. I can't quite follow the physiology -- "be cautious" makes more sense. One patient in the Archives study had bad Crohn's and hence over-absorbed phosphate.

HYPOKALEMIC NEPHROPATHY

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

* At autopsy, the pathologist finds coarse vacuolization of tubular cells, and dilatation of intercellular spaces (i.e., the tubular cells look white and broken).

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 distal tubules causing renal shutdown. Patients experience the acute or insidious onset of renal failure.

The pathologist will see amorphous pink cast-plugs, often surrounded by a foreign-body reaction with multinucleated giant cells. There's a considerable range of pathology, and the proximal tubular cells may contain curious findings as well: Arch. Path. Lab. Med. 131: 1368, 2007.

* If you induce 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 give the same tubular casts.

Remember that plasma cell myeloma patients often get amyloidosis AL.

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. Long suspected, it's now proved that it is indeed the crystals that do the damage in ethylene glycol poisoning (Clin. Tox. 47: 859, 2009).

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 (update Am. J. Neph. 26: 1, 2006; Kid. Int. 69: 644, 2006)

A rapidly-progressive interstitial nephritis that occurs in about ten, very sharply-defined areas of Rumania, Yugoslavia, and Bulgaria. Epidemiologically, the disease typically occurs in farm workers (and their pigs: Vet. Rec. 142: 190, 1998), and shows a strong familial tendency ("Danubian endemic familial nephropathy"). Obviously some toxin in the environment is interacting with genes.

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. There are three competing ideas about the cause.

1. The fungal poison OCHRATOXIN A was abundant in moldy grain stored in the upper stories of houses. The particular school of communism in the Balkans opposed barns for ideological reasons. 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.

2. An illness very similar to Balkan nephropathy was produced when ARISTOLOCHIA, a poisonous plant, ended up in a "holistic Chinese herbal remedy" for obesity, prompting an epidemic of kidney failure and urothelial cancer: NEJM 342: 1686, 2000. 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 (European birthwort) growing in the wheatfields (Croat. Med. J. 46: 116, 2005).

3. Since the disease did not disappear with the improved living conditions after the fall of communism, perhaps the cause is toxins from the low-rank coals leaching into the well water on the involved farms. I'm betting it is the Aristolochia.

* 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

Uric acid deposit Kidney KCUMB Team

Uric acid deposit Kidney -- polarized KCUMB Team

Gout Photomicrograph of tophus KU Collection

Gouty Arthritis Australian Pathology Museum High-tech gross photos

Tophus in kidney Surprise at autopsy KCUMB Team

Gout Uric acid crystals WebPath Tutorial

Gout WebPath Tutorial

Gout X-ray WebPath Tutorial

Gout Tophus 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.) Occasionally a tophus can weaken a bone sufficiently to cause a pathologic fracture (kneecap Clin. Orth. 445: 250, 2006). Laryngeal tophi can compromise the airway (J. Laryngol. Otol. 116: 140, 2002). 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 2008, somebody noticed that fructose (from corn syrup in soft drinks) raises uric acid and correlates with gout (BMJ 336: 285, 2008). 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. It is now getting some competition from febuxostat, a new nonpurine xanthine oxidase inhibitor (NEJM 353: 2450, 2005). 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.

* 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, Paget's of bone, beriberi, aortic valve insufficiency, patent ductus arteriosus).

Recently (early 2000's), "increased pulse pressure due to stiffening of the arterial walls" has come to be considered a risk factor for atherosclerosis. This is part of "normal aging" (like stiffening of your tendons), and is exacerbated by hypertension (no one knows why) and diabetes (cross-linking of glycation products). New Rx (ALT-711 / Alagebrium / Alteon) "to break cross-links": Circulation 104: 1464, 2001; Am. J. Hypert. 17: 23-S, 2004) has been shown to reduce pulse pressures in humans.

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.

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 physician's long personal history of high blood pressure and its treatment over decades: 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 as a factor in hypertension (Am. J. Med. Sci. 303: 271, 1994).

* The idea that hypertensives' arteries won't dilate when they should 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) and may prove to be a cardiac risk factor (Heart 92: 1583, 2006).

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).

This is a very well-known lesion in the kidneys (where I suspect it may not regress); * surprisingly it was omitted from "Big Robbins".

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. "Salt abuse: the path to hypertension": Nat. Med. 14: 16, 2008 -- focuses on lasting changes in vascular myosin phosphorylation caused by longstanding salt-overloading (Nat. Med. 14: 64, 2008). The pop notion that everyone should avoid salt has been called both unscientific and probably false (Lancet 351: 781, 1998) -- however, if the new work is accurate, we may want to reconsider. Interestingly, no one looks at how much water folks drink... which we'd expect to remove salt from the system. Stay tuned; this will get more confusing. Salt intake reduction as a public health education initiative: NEJM 362: 650, 2010.

One idea, still popular, 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).

* Didja know that sodium nitroprusside works by producing nitric oxide?

* 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 eventually lose the ability to dilate appropriately. This is probably due at least partly to the hyaline (etc.) arteriolar sclerosis that develops from the hypertension.

Endothelin is often elevated in hypertension, regardless of etiology. At the very least, this seems to 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. In 1994, I predicted endothelin would prove a major player; it is now (with insulin) the "primary suspect" in the hypertension that tneds to run with the metabolic syndrome (J. Clin. Endo. Metab. 92: 379, 2007).-

* 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.

Much work in common high blood pressure still 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 is still good, as others have been elusive), 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).

Update on the especially aggressive nature of hypertension in blacks: Arch. Int. Med. 168: 832, 2008.

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").

You already remember the problems caused by hypertension on the microvasculature. Stiffening of the arteries and arterioles has long been measurable, and now researchers are actually measuring the numbers of circulating endothelial cells (i.e., cells that were forced off the inner walls by hypertensive damage -- larger numbers indicate worse outcomes (Chest 132: 1540, 2007).

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. If you do a PAS stain, you'll see the remnant of the tuft collapsed near the pole and encased by collagen.

The molecular basis of "hypoxia-related glomerulopathy" and tubulopathy is now being worked out -- don't expect this to have any clinical impact any time soon (Am. J. Path. 176: 594, 2010).

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 and arterioles hyalinize with PAS-positive material; a very important phenomenon that remains mysterious. Of course, 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

Hyaline arteriolar sclerosis, kidney Great labels Romanian Pathology Atlas

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 turmoil 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 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 (clinically) or necrosis of the vessels themselves (autopsy)

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. Rediscovered: Arch. Path. Lab. Med. 131: 1817, 2007.

{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, in older folks.

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. The beaded appearance of the renal artery on angiography is typical. Treating it with an endovascular prosthesis: NEJM 336: 459, 1997.

* The vast majority of people who have the fibromuscular dysplasia beads have no problems;in fact, the variant affects at least 2% of humankind and is not a reason not to use the kidney for transplantation (Lancet 369: 187, 2007).

* Takayasu's arteritis, * von Recklinghausen's neurofibromatosis, 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.)

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

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"; "Shiga-like toxin", Stx), 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.

* 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.

"Atypical hemolytic-uremic syndrome", with a poor prognosis and not always a clear cause, occurs about half the time in folks with various mutations in complement modulating proteins; an additional 5% have mutant thrombomodulin (THBD; NEJM 361: 468, 2009). Update on "atypical HUS": NEJM 1676: 361, 2009.

One to watch: Hemolytic-uremic syndrome histology is now a recognized complication of treatment with bevacizumab, the anti-VEGF cancer treatment (why might this be?). See NEJM 358: 1129, 2008; Am. J. Med. 122: 322, 2009.

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 only superficial similarities to HUS. The thrombi are widespread (not just confined to the kidneys as in HUS), mostly composed of platelets, neurologic defects are more prominent, and the patient is either cured or dies.

THROMBOTIC MICROANGIOPATHY is now an umbrella term for a host of renal lesions that have in common damage to the endothelium.

THE CAUSES OF THROMBOTIC MICROANGIOPATHY
• hemolytic-uremic syndrome as above (look for trapped RBC's in the gloms)
• thrombotic thrombocytopenic purpura as above
• malignant hypertension as above
• scleroderma kidney
• anti-phospholipid antibody / anticardiolipin antibody syndrome(s)
• Balkan nephropathy
• some drug allergies
• calcineurin inhibitors (cyclosporine, tacrolimus) as above
• eclampsia
• bevacizumab

THE FINDINGS IN THROMBOTIC MICROANGIOPATHY

• endothelial swelling in the glomeruli (early; most pronounced if the cause is eclampsia)
• finely granular debris between endothelium and basement membrane
• "split" (double-coutoured) GBM / mesangial cell interposition (late; like in MPGN I)
• * mesangiolysis
• red cell fragments trapped in the glomerular capillaries or arteriolar intima
• myxoid change (early) and/or onionskinning (late) in the arterioles
• large arteries are spared
• the worse the disease in the small arteries, the worse the prognosis

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. (They appear here first, of course, because protein is concentrated here.)

ATHEROEMBOLIZATION

{16900} atheroembolus; scar has formed around it

Shrivelled kidney Attributed to atherosclerosis WebPath Photo

Kidney infarct WebPath Photo

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 -- one group after reviewing the difficulty of making the call found that statins help some, even after the event: Circulation 116: 298, 2007). 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"). You will see V-shaped scars (i.e., narrow and deep) whenever the distribution of entire interlobular arteries is destroyed (and replaced by contracted scar).

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.

* The glomeruli are affected in about 50% of sickle cell disease patients as well. There's a roughly equal division among focal-segmental glomerulosclerosis, membranoproliverative type I, FSGS, and simply clogged capillaries (Medicine 89: 18, 2010).

Renal medullary carcinoma is a rare cancer seen almost exclusively in people with sickle cell disease or trait. You won't be asked to recognize it, but it's a good thing to know on rotations. It always contains abundant neutrophils.

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"; Am. Fam. Phys. 63: 1329, 2001; BMJ 334: 468, 2007)

{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?)

* Worth watching is NHERF1, the gene for protein controlling phosphate resorption; mutations here predispose to kidney stones and osteomalacia (NEJM 359: 1128 & 1171, 2008). A severe autosomal recessive disease ("hereditary hypophatemic rickets with hypercalciuria) is at the NPT2c locus.

* In 2007-2008, unscrupulous food producers in China added melamine to animal food and powdered infant milk to boost the assayed protein content. Melanine is lost in the urine, and it's been sugggested that this is the cause of the sand-like kidney stones seen in some of these children; because of selection bias and the composition of the stones being uncertain, the real risk remains unclear (NEJM 360: 1067 & 1139, 2009; Lancet 373: 353, 2009).

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. She was the founder of an anti-medical sect; the fact that she found so many followers simply reminds us that, in her era, mainstream medicine (without antibiotics, without safe surgery, without high-therapeutic-index medications, etc.) had much less to offer than it does nowadays.

* 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: 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 and its variant sporadic lymphangioleiomyomatosis. 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, and some less-well-known melanoma markers also show (Arch. Path. Lab. Med. 125: 751, 2001; Arch. Path. Lab. Med. 126: 49, 2002).

Sirolimus, the mTOR signal inhibitor, for angiomyolipomas: NEJM 358: 140, 2008.

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

Renal angiomyolipoma
H&E
Wikimedia Commons

* 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") turn up commonly as incidental findings on scans, and are often multiple. Their behavior is almost always benign unless there's obvious cellular atypia (* I'd rather call these oncocytic RCC's). They have a characteristic pattern of chromosome breaks, always have a central stellate scar, etc. See Am. J. Surg. Path. 21: 871, 1997. This was the first neoplasm to be linked to an abnormality of mitochondrial (rather than nuclear) DNA: Am. J. Path. 134: 967, 1989. The cell of origin is distal tubule (* future pathologists: stain with Galectin-3: Arch. Path. Lab. Med. 134: 90, 2010).

CLEAR-CELL RENAL CELL CARCINOMA ("hypernephroma," "adenocarcinoma", "Grawitz tumor", "RCC"; Lancet 373: 1119, 2009; all renal cancers Arch. Path. Lab. Med. 133: 1026, 2009)