Kidney study notes Intro to Kidney Disease - in health, your total body fluid tonicity is regulated by ADH and thirst - in health, your body fluid volume is regulated by atrial natriuretic peptide, which is produced when the right atrium feels that extra stretch, and which mediates a host of effects - in health, your total body potassium is reglated primarily by diffusion of potassium out of the near portion of the distal convoluted tubule in response to intracellular pH shifts - in health, your total body base is regulated by the carbonic anhydrase in the proximal tubule - the more CO2 on board, the more intracellular bicarbonate is produced, the more bicarbonate is resorbed, and the more protons get sent away in the urine - every year, 35,000 people in the US will get end-stage kidney disease and about as many will die of it - kidney failure due to acute tubular necrosis is a common, deadly complication in the intensive care unit; renal insufficiency due to underperfusion or due to obstruction are extremely common - at least 10% of women will get acute pyelonephritis during their reproductive years, often during pregnancy - at least 1% of people will pass a kidney stone Normal Anatomy and Physiology - each adult kidney weighs about 150 grams and is composed of over 1 million nephrons which drain into 14 calyces - a pt with any sort of impaired kidney function will have increased creatine and urea nitrogen in the blood, or azotemia - hypertension, edema, and/or hyperkalemia may develop in renal disease; renal edema is first visible around the pts eyes - metabolic acidosis is characteristic of severe renal failure - the kidney also makes renin and erythropoietin, and activates vitamin D - the three filtration barriers are endothelial cells, glomerular basement membrane, and visceral epithelial cell - endothelial cells have fenestrae which give plasma free access to the GBM - the GBM is a largely special collagen (type IV) which is the major permeability barrier; it also contains polyanions and other substances that are additional barriers - visceral epithelial cells (podocytes) display interdigitating cell processes which grasp capillaries - the whole filter is very permeable to water and small solutes - loss of polyanions will let albumin through; if the filtration barrier is severely damaged, larger proteins will leak out; a leaky GBM results in the nephrotic syndrome - glomerular capillary pericytes are called mesangial cells; mesangial cells are contractile and probably phagocytize most things that shouldn't have gotten through the filtration membrane - the glomerular filtration rate should be about 120 ml/min for an adult - the juxtaglomerular apparatus is a group of special cells at pole of nephron formed from both afferent arteriole and distal tubule - they produce renin and adjust the GFR as necessary to maintain adequate systemic blood pressure - renin generates angiotensin II, which in turn raises systemic bloop pressure by constricting arterioles, causing thirst, and causing production of aldosterone - insensitivity of vessels to angiotensin II is called Bartter's syndrome; these people have huge JGA's, greatly increased serum renin, angiotensin II, and aldosterone, hypokalemia, but normal blood pressure - the proximal convoluted tubule resorbs substances from the glomerular filtrate, including ions, glucose, phosphate, bicarbonate, amino acids, vitamins, and the smallest proteins in isotonic solution; it also makes para-aminohippuric acid, uric acid, and probably erythropoeitin - a patient with imparied function of the proximal tubule will l;ose substances in the urine - the distal tubule retains or excretes water, ions, and protons, as required for homeostasis - a patient with imparied distal tubule cannot concentrate urine - the loop of Henle is responsible for maintaining a hypertonic interstitium in the medulla - the distal convoluted tubule is the site of sodium resorption, and of potassium and proton excretion - a high GFR produces rapid flow through the distal convoluted tubule resulting in little sodium resorption - the distal convoluted tubule is also influenced by aldosterone, which promotes sodium retention and potassium and proton loss - the collecting duct is the site of anti-diuretic hormone (hADH) action - inability of the collecting duct to resond to hADH produces nephrogenic diabetes insipidus - renal interstitium - in the cortex it is scanty, but in the medulla it is responsible for maintaining the ability of the urine to be concentrated; damage to this will cause inability to concentrate urine - vessels - all the blood that supplies one nephron flows through the glomerulus first; if the glomerulus dies, the whole nephron dies - narrowing of the arteries and/or arterioles supplying some or all of the kidney tissue will produce systemic high blood pressure - if blood pressure in the glomerulus is low, then that results in too much water and sodium being resorbed in the distal convoluted tubule - the JGA produces too much renin; most high blood pressure resulting from kidney diseaseis high renin hypertension Syndromes of Kidney Disease - nephritic syndrome (nephritis) - indicates acute inflammation of the glomeruli - hematuria (including red cell casts) - mild to moderate proteinuria, oliguria, hypertension and mild edema - if the process continues, the gloerulus may be destroyed - nephrotic syndrome - indicates excessive permeability of the filtration membrane to plasma proteins - heavy proteinuria, hypoalbuminemia - sever generalized edema - hyperlipidemia - longstanding heavy proteinuria is itself harmful to the kidney and will lead to renal failure after several years - the lack of plasma protein results in a loss of effective circulating volume; this in turn causes salt and water retention and accumulation of yet more fluid in tissue spaces; secondary hypoeraldosteronism also plays a part in causing the edema - hyperlipidemia is due in part to the liver making more lipoproteins to compensate for the loss of albumin - renal vein thrombosis often occurs in nephrotic syndrome; explanations include loss of protein S in the urine and increased levels of certain big proteins - also very prone to infections - the nephrotic kidney is extra-prone to sudden shutdown - rapidly progressive glomerulonephritis (RPGN) - indicates rapid destruction of most of the glomeruli - nephrotic syndrome will probably also be present - the common denomenator is the GBM is ruptured, and fibrin is present in Bowman's capsule - asymptomatic hematuria - most glomerular diseases commonly do enough damage to produce at least microscopic hematuria - red cell casts are proof that hematuria originates in the nephron - stones, sickle cell nephropathy, bleeding disorders, and cancers are other important diseases that produce bleeding at the level of the kidney; they seldom produce red cell casts - hemolytic-uremic syndrome - endothelial damage and platelet microthrombus formation in the renal vascular bed, resulting in evidence of red cell fragmentation and renal failure - many different causes, including an infectious disease of young children related to vicious E. coli, malignant high BP, vasculitis, etc. - pyelonephritis - bacterial infection of the kidney generally produces fever, flank pain, proteinuria, pyuria, and white cell casts - proximal tubule dysfunction - a group of conditions in which the proximal tubule fails to conserve one or more substances, which are lost in the urine - in mild impairment, small molecular weight proteins are lost in the urine - in serious impariment, there is wasting of bicarbonate, calcium, phosphate, potassium, amino acids, other small molecules, etc. Kidney Failure: loss of renal function - acute renal failure usually presents as oliguria plus azotemia; hyperkalemia is the main threat to life during the oliguric phase - chronic renal failure is the end result of irreversible kidney damage from any cause - signs ans symptoms are those of uremia - anuria is rare in acute renal failure - the major exception is diffuse cortical necrosis - high blood pressure - renal hypertension results from decreased GFR and/or increased renin - kidney stones - flank pain and hematuria (but no red cell casts); secondary infection is common - progressive loss of remaining renal function - once the kidney is damaged to a certain degree, it continues to deteriorate even if the underlying disease is cured - contributing factors include hypertension, hyperlipidemia, high dietary phosphate Uremia - by contrast, azotemia means increased urea in blood; when kidney function falls below about 10% of normal, uremia becomes apparent - fluid, electrolyte, and acid-base disturbances - volume overload - metabolic acidosis - hyperkalemia - fluid shifts - calcium-phosphorus problems - inability to activate vitamin D to the active 1,25-dihydroxy form - phosphate retention, hyperphosphatemia, and hypocalcemia - metastatic calcification of vessels and/or pulmonary alveoli, with respiratory failure - eventually, resistence to the effects of vitamin D - bone problems - secondary hyperparathyroidism, with loss of calcium and eventually collagen from bones - osteomalacia, mostly refractory to vitamin D treatment - cardiopulmonary - high blood pressure with all its associated problems - fibrinous pericarditis - accelerated atherosclerosis - hematopoietic - anemia - poor platelet function - immunosuppression - GI - nausea, vomiting, bleeding, pancreatitis - skin - pruritis - one cause is calcium sulfate and calcium phosphate precipitating in the sweat ; others include excesses of vitamin A metabolites and histamine - uremic frost - neuromuscular - peripheral neuropathy - encephalopathy - impotence in men - amyloidosis (amyloid H tends to accumulate in joints causing arthritis, and in flexor retinalculum causing carpal tunnel syndrome) - pica (low serum zinc causeing alterations in sense of taste) - poor appetite and altered sense of smell - emotional problems - infections - staph infections often kill patients who have survived years on dialysis - other - glucose intolerance due to insulin resistance - a 5-fold increase in the incidence of renal cell and uterine carcinomas - short stature Kidney Malformations - birth defects - hypoplasia - a kidney with less than five lobules and calyces - pelvic kidney - horseshoe kidney - 1in 500; fusion of upper and lower poles - apart from cystic renal dysplasi, these diseases feature tubules whose cells proliferate to form cysts, which are involved with remodeling of the interstitium - cystic renal dysplasia - persistence of primitive mesenchyme, which may produce cartilage, undifferentiated mesenchyme, and immature collecting ducts - autosomal dominant kidney disease - common (500,000 in US) with complete penetrance - hundreds of cysts, measuring up to 4 cm in diameter, develop from all levels of nephron including Bowman's capsule; as they form, the surrounding normal kidney cells undergo apoptosis - by age 40, the kidneys are the size of footballs; half of these patients are on dialysis - pts get high BP usually before kidney failure develops - many die of ruptured berry aneurysms - autosomal recessive polycystic kidney disease - rare autosomal recessive disease with huge, white, smooth-surfaced kidneys - cysts may develop at collecting ducts, the kidneys are huge - normally fatal in infancy or early childhood; typically, the enormous kidneys restrict the ability of the lungs and gut to function - many children also have congenital portal fibrosis of the liver - medullary sponge kidney - very common (1 in 200) idiopathic process - dialted distal portions of collecting ducts superficially resemble cysts - sometimes stones form in the cysts, and low back pain results Acquired Dialysis Cystic Disease (trans-stygian kidney) - misleading name for the kidneys in people who have been kept alive for a long time on dialysis -kidneys are useless - in addition to scar tissue and a few chronic inflammation cells, the pathologisy may find squamous metaplasia of glomerular epithelium, oxalate crystals in the tubules, fibromuscular masses in the blood vessles, and cortical adenomas and renal cell carcinomas - these kidneys can develop stones, painful bleeding, aggressive carcinomes - can happen in patients not on dialysis; common thinking is it is casued by ischemia Simple Cysts - a few cysts in the kidney is common; these often develop after small kidney infarcts; no danger to health - hyaline casts in the urine are normal; other casts in the urine indicate disease in the nephron Intro to Glomerular Disease - classified according to: - clinical manifestations - histology and ultrastructural appearance of injury - mechanisms of glomerular injury - diffuse (all glomeruli) vs focal (only some glomeruli) - global (entire glomerulus) vs segmental (a part of a glomerulus) - sclerosis - enough increase in basement membrane - mesangial matrix material to compromise the lumens of capillaries (stains positive with silver) - fibrosis - type I collagen (organized scar) Histologic Alterations in Glomerular Disease - cellular proliferation - endothelial and mesangial cells may proliferate - this tends to narrow and occlude the capillaries - visceral and parietal epithelial cells and fibroblasts may also proliferate - this is always caused by fibrin leaking out of glomerular capillaries - if the leak is small, a fibrous adhesion between a few capillaries and Bowman's capsule may result - if the leak is big, a cellular crescent soon fills Bowman's space- and will become a fibrous scar - leukocyte infiltration - PMNs in the glomerulus indicate complement is being fixed there; enzymes from polys will damage the glomerulus - polys almost never cross the GBM - visceral epithelial cell swelling and detachment - highly characteristic of several common causes of the nephrotic syndrome; injured epithelial cells swell and obliterates the discete foot processes - GBM thickening - may be thicker as in diabetic glomerulosclerosis - may appear thicker because of immune-complex deposits - necrosis - seen in the most severe glomerular disease; karyorrhexis of glomerular cells is the surest sign - glomerular hyalinization - evidence of chronic, irreversible damage - hyalinization of the tuft itself may be: - basement membrane-meangial matrix material - amyloid - collagen that has accumulated in layers on the inner surface of Bowman's capsule - an organized crescent, as after any severe injury Mechanisms of Glomerular Injury - most involve antibody-antigen complexes - in situ immune-complex formation - anti-GBM Abs- discrete granular deposits are not seen , but linear deposition is seen on immunoflourescence, and eluates from diseased kidney deposit in linear fashion on normal kidney - Abs against other fixed antigen - evenly-spaced, fine granular deposits are seen on immunoflourescence - circulating immune-complex deposition - coarse granular deposits are usually seen on IF - immune-complex related injury is mediated by complement activation, polys, perhaps also macrophages, coagulation system, etc., etc. - some glomerular damage is apparently not immune-mediated Diffuse Proliferative Glomerulonephritis - acute post-streptococcal glomerulonephritis is the commonest cause of this reaction pattern - this produces the nephritic syndrome in kids two weeks or so following a respiratory or skin infection with a "nephrititic strain" of group A, beta-hemolytic streptococci - the cause is deposition of circulating immune complexes which fix complement and attract PMNs - the glomerulocapillaries are damaged - you can find polys in the tufts, but none cross into the urine - IF shows coarse granular deposits containing immunoglobulin and complement - these granules are located sub-epithelially - other causes include infections (staph, infected AV shynts, sepsis, viral infections) and severe systemic lupus Rapidly Progressive Glomerulonephritits - this syndrome invovles rapid loss of renal function, usually with the nephritic syndrome - the morphologic correlate is severe glomerular injury; there are several familiar causes, and you should know the contemporary classification: - RPGN I - anti-GBM disease - RPGN II - RPGN superimposed on any immune complex disease - RPGN III - RPGN without significant immune deposits; usually with vasculitis - RPGN I : anti-GBM disease (Goodpasteur's, Masugi) - 20% of RPGN - the patient makes Abs against an antigen uniformly distributed along the GBM - Goodpasteur's syndrome is anti-GBM disease with RPGN and lung hemorrhages - the auto-Ab cross-reacts with pulmonary basement membrane - pts commonly asphyxiate on their own blood after a few months, unless they die of renal failure first - one known cause is the drug penicillamine - thought to expose the antigen by breaking sulfhydryl linkages - Masugi nephritis is an experimental anti-GBM disease; it is produced in rats by injections of anti-rabbit kidney Abs prepared by immunizing rabbits with rat kidney tissue - in anti-GBM disease, IF shows a diffuse linear pattern of antibody deposition almong the GBM - RPGN II - severe immune complex disease - virtually any of these diseases can produce RPGN if it is severe enough - post-infectious RPGN isthe severe form of post-stretococcal glomerulonephritis - RPGN III - the vasculitis syndromes - within the last few years, RPGN III has been strongly associated with systemic vasculitis syndromes, including Wegner's granulomatosis and polyarteritis nodosa - all these vasculitis syndromes tend to produce a segmental necrotizing glomerulonephritis with crescents - these is now a trend to treat all RPGN III/segmental necrotizing GN cases with cyclophosphamide and prednisone; evidence : 1) it works 2) polyarteritis nodosa confined to the kidney is now a recognized entity 3) idiopathic RPGN III / SNGN pts have the same anti-neutrophil cytoplasmic ABs that characterize small-vessel polyarteritis nodosa and Wegner's granulomatosis Mesengial Proliferative Glomerulonephritis - this is an anatomist's diagnosis which covers a variety of relatively minor illnesses, including mild systemic lupus, resolving post-streptococcal glomerlunephritis, etc. - light microscopy shows only mesangial cell proliferation and increased mesangial matrix - IF and electron microscopy show immune deposits in the mesangium in a majority of these cases - prognosis is good for most patients - pts with IgA deposition have IgA nephropathy and have microhematuria and mild proteinuria; pts with C3-only "C3-nephropathy" and have the same clinical picture - pts with IgM deposition have "IgM nephropathy" and usually have more proteinuria and good response to treatment Membranous Glomerulopathy - this reaction pattern is the commonest cause of nephrotic syndrome in adults - some pts have only mild proteinuria, and many recovery completely; around half of adults go on to chronic renal failure after 10-15 years of heavy, nonselective proteinuria - EM shows uniform, evenly spaced subepithelial immune-complex depositis; IF shows a finely granular pattern of IgG, C3, sometimes more - these deposits soon become incorporated into the GBM, making it look thicker on light microscopy - most cases of membranous glomerulopathy are still idiopathic - known causes are SLE and infections (HBV) - treating membranous glomerulopathy usually begins with steroids, and may then receive cyclophosphamine; lots stay stable and go away by itself Minimal Change Glomerulopathy - the commonest cause of the nephrotic syndrome in children; EM microscopy reveals diffuse loss of foot processes of epithelial cells - there is no obvious evidence of immunologic disturbance, and the glomeruli appear normal by light microscopy - many adults will also have Hodgkin's disease; the kidney problem is treated when the malignancy is successfully treated - proteinuria is heavy but selective, and renal function remains good - the long-term prognosis is excellent, often with dramatic response to corticosteroid therapy - there is unexplained loss of polyanions from the GBM, making it more permeable to albumin Focal-Segmental Glomerulosclerosis - another pattern of glomerular injury which sometimes causes nephrotic syndrome in children and adults; it is considered a nonspecific response to non-immunologic injury of the glomerular microvasculature - it is the major cause of nephrotic syndrome in black adults - pts usually have non-selective proteinuria, oliguria, hypertension, and progress to chronic renal failure despite steroid treatment after several years; it is notorious for recurring in transplants - microscopic study shows diffuse loss of foot processes plus focal-segmental sclerosis and granular IgM and C3 in the sclerotic areas - most FSGS is idiopathic, but there are several recognized causes - AIDS nephropathy and most cases of heroin nephropathy show this pattern - regardless of cause, the prognosis is not good; glucocorticosteroids are of limited use for common FSGS, but work for AIDS nephropathy IgA Nephropathy - Berger's disease is now used to describe any idiopathic IgA nephropathy - idiopathic IgA nephropathy is the commonest serious glomerular disease - variable prognosis, no effective treatment - pts have gross or microscopic hematuria, often with high blood pressure; perhaps a third eventually develop renal failure - mesangial and focal-segmental proliferation and sclerosis may be seen by light microscopy; in bad cases, crescents develop - IF shows IgA deposited in the mesangium - serum IgA is often elevated, and IgA-containing immune complexes are often demonstrable, whether or not there is some primary disease to explain their presence - Henoch-Schonlein purpura - a fairly common syndrome most often occurring in children featuring: - purpuric dermal lesions - abdominal pain, GI bleeding - nonmigratory arthralgias - renal abnormalities - all signs and symptoms are attributed to immune-complex deposition in the vessels, joint spaces, etc. Chronic Glomerulonephritis - a major cause of chronic renal failure in adults; an end-stage pool of glomerular diseases - light microscopy shows hyaline obliteration of glomeruli, transforming them into acellular hyaline masses made of mesangial matrix, basement-membrane material, dense collagen, and trapped plasma protein - tubules are lost, vessel walls are thickened, and ultimately the kidney is totally destroyed - these pts suffer from uremia, get dialyzed, get transplanted, and eventually die Systemic Lupus Erythematosus - there is clinical evidence of glomerular involvement in the majority of SLE pts and renal failure is the cause of death in 30-40% of these people - the pathologist looks for tubular arrays, hematoxylin bodies, hyaline thrombi, and organized fingerprint immune complex deposits - hematoxylin bodies are specific for lupus - useful subclassifications - lupus with no renal lesion - mesangial lupus nephritis - immune complex deposits in the mesangial areas with or without mesangial cell proliferation - diffuse proliferative lupus nephritis - massive mesangial, subepithelial, and/or subendothelial immune complex deposits with diffuse proliferation and sometimes even necrosis of glomeruli - these pts typically have the acute nephritic syndrome Glomerulonephritis of Bacterial Endocarditis - there is often an immune complex nephritis caused by deposition of circulating bacterial antigen-Ab complexes - the glomerular lesion ranges from focal GN or MCGN I to crescentic GN - pts have varying degrees of hematuria, proteinuria, even RPGN Diabetic Glomerulosclerosis - the single most common cause of end-stage renal disease - all diabetics get hyperfiltration, thickened glomerular basement membranes, and increased mesangial matrix - both hyperfiltration and GBM thickening appear to be secondary to hyperglycemia - the current principle suspect is advanced glycation products turning on the gene to make basement membrane collagen - deterioration of glomerular function in diabetics can be slowed by ACE inhibitors - genetic makeup determines whether a diabetic will have slow or fast deterioration of renal function, one key gene is the ACE itself - in many cases there is also nodular glomerulosclerosis ("Kimmelstiel-Wilson lesion), with round masses of GBM-mesangial matrix materila in the glomerular tufts - many diabetics have albuminuria, which progresses over years to renal failure - diabetic neuropathy - atherosclerosis, arteriolar sclerosis, pyleonephritis, staph and candida infections, and papillary necrosis seen in this disease Renal Amyloidosis - amyloidosis A almost always invovles the glomeruli, and amyloidosis B often does also - generally deposited first in the mesangium - these pts get the nephrotic syndrome Thin GBM Disease - a poorly-understood, mild, fairly common family of illnesses, usually presenting as asymptomatic henaturia in childhood - renal biopsy shows patchy thinning of the GBM, without immune deposits; mild hearing problems are common Cryoglobulinemia - refers to the presence in the blood of marginally-soluble proteins that gel either in the cold or in the local hemoconcentration of the glomerulus - hallmark is pseudo-thrombus, a cryoglobulin plug in the capillary loop - also tends to produce subendothelial deposits in glomeruli, and pts may get a glomerulonephritis with proteinuria, hematuria, or even renal failure Hereditary Glomerulonephritis - Guthrie's disease - most familiar is the Alport's family, autosomal dominant or X-linked dominant nerve deafness plus progressive nephritis - common X-linked Alport's is a defect in a collagen chain - prevents proper winding of basement membrane collagen - the most common cause of protein in the urine is orthostatic proteinuria, from renal venules that ooze protein when hydrostatic pressure is high - focal-segmental glomerular lesions are seen in focal segmental glomerulosclerosis, mesangial proliferative glomerulonephritis, IgA nephropathy, vasculitis, and Goodpastuer's - Fabry's is the only important storage disease with significant renal involvement Disorders of the Proximal Tubule - congenital - inborn errors of transport - renal transport aminoacidurias (blood levels normal, but proximal tubules cannot resorb one or more amino acids from the glomerular filtrate) - cystinuria - cysteine and ornithine are lost - congenital Faconi syndrome - bicarbonate, phosphate, glucose, amino acids, calcium, and potassium are all lost - acquired Faconi syndrome - poisoning - lead, cadmium, bismuth, oxalate, outdated tetracycline Acute Tubular Necrosis - acute tubular necrosis is the designation for all forms of acute renal failure associated with damage to tubular epitelial cells - ischemic ATN - nephrotoxic ATN - caused by a wide variety of renal poisons, including heavy metals, organic solvents, and antimicrobial drugs - pigment nephropathy - massive hemolysis, massive rhabdomyolysis, etc. - the pathophysiology of ATN is complex - the ischemia and nephrotoxins directly damage tubules - systemic hypotension and severe poisoning also cause intrarenal vasoconstriction, which compounds ischemic damage and lowers GFR - damaged tubules become obstructed by casts and crud, lowers GFR - direct glomerular damage may occur - tubular backleak contributes to loiguria - in ATN, the renal output is normal or low; the urine is iso-osmotic with sodium concentration close to that in the glomerular filtrate - the histology reflects the pathophysiology - ischemic ATN - you may see a few necrotic cells or denuded basement membrane, but they are rare; look for dialted tubules and interstitial edema; proximal tubualr cells show evidence of regeneration at all stages - nephrotoxic ATN - frank necrosis is seen, usually limited to the proximal tubules, without rupture of basement membranes - clinical picture of ATN - onset during a medical catastrophe - oliguric stage, with urine production 50-400 ml/24 hr, and isotonic - diuretic stage, with rapid loss of fluid and potassium - other casues of acute renal shutdown, other than ATN include: - atheroembolization - drug hypersensitivity - hepatorenal syndrome - severe rapidly-progressive glomerulonephritis - vasculopathies - severe pyelonephritis - DIC-diffuse renal cortical necrosis - acute urate nephropathy - also rule out prerenal causes Hepatorenal Syndrome - kidney failure that develops in pts with liver failure, without anatomic changes in the kidney - usually this follows enthusiastic administration of high-powered diuretics to a cirrhotic "to help with the ascites" - the pathophysiology remains to be discovered - liver failure from any cause produces hypotension, and hepatorenal syndrome may also have a component of shock kidney; but unlike ATN, urine sodium is low, while urine osmolality tends to be around 100 mOsm higher than serum Pyelonephritis and other Upper Urinary Tract Infections - an extremely common, serious problem in clinical medicine - causes - ascending infection, hematogenous infection - acute pyelonephritis - predisposing conditions - bacterial virulence, sex and age (up to 40, females predominate, over 40 males predominate), urinary obstruction/stasis, vesicoureteral reflux, mechanical factors, asymptomatic bacteriuria, pre-existing renal diseases, diabetes mellitus, and not being circumscribed - PMNs infiltrate the interstitium and tubules; even if 1 or 2 polys in the tubules - pts have fever, pain at costovertbral angle, PMNs and white cells in the urine - papillary necrosis is a dreaded complication of pyelonephritis that occurs mostly in diabetics - chronic pyelonephritis - any chronic renal infection - always produces some renal scarring around the calyces and pelvis and among the tubules - pathologist looks for broad, U-shaped scars associated with distorted calyces - microscopically, this is a patchy process with periglomerular fibrosis and interstitial scarring - insidous onset of renal insufficiency and hypertension - xanthogranulomatous pyelonephritis is a special type of chronic pyelonephritis, usually in older women who have had several episodes of acute pyelonephritis, caused by Proteus infection and some problem with cGMP, and probably beginning as a penetrating ulcer of a calyx - other causes of acute interstitial nephritis include lupus and other "autoimmune" problems which generate anti-TBM antibody Chronic Interstitial Nephritis - is scarring of the kidney associated with some process that is primarily interstitial - Lupus and Sjogrens often include an acute or chronic interstitial nephritis - grnaulomatous CIN is due to drugs or sarcoid - anti-tubular basement membrane antibody is a research tool, but its importance in human disease is not clear Tubulointerstitial Nephritis casued by Drugs and Poisons - acute drug-induced nephritis - within a month after drug exposure, the victim develops fever, skin rash eosinophilia, hematuria, proteinuria, sterile pyuria, and eosinophiliuria - methicillin is the best known offender - sulfa drugs, rifampin, and cyclosporine are also causes - edema is always present, and interstitial mononuclear cell infiltration, eosinophils, and neutrophils may be found too - analgesic nephritis - chronic renal failure caused by excessive intake of phenacetin-containing combinations - chronic interstitial inflammation in characteristic, and many pts develop papillary necrosis - NSAID agents - most common cause of renal shutdown; prognosis is good when drug is stopped - when the circulating plasma volume becomes low, some people's renal microcirculation is kept open only by the local prostaglandins; when these people take an NSAID, they get vasomotor nephropathy, and recover in a few days - another typical syndrome is a combination of minimal-change glomerulopathy histology with nephrotic and/or nephrotic syndrome, plus marked chronic interstitial nephritis Hypercalcemic Nephropathy - extensive metastatic clacification of the kidney tubules can cause chronic inlflammation or obstruction - because the ascending loop of Henle is damaged first, one early problem is inability to concentrate urine - even in hte abscence of tubular calcification, hypercalcemia produces a prerenal azotemia by causing constriction of the small renal arteries - when the serum potassium is low, the kidney cannot concentrate the urine Plasma Cell Myeloma Kidney - the problem is precipitation of Bence-Jones protein within the tubules causing renal shutdown; pts experience acute or insiuous onset of renal failure - remember that plasma cell myeloma pts often get amyloidosis B Oxalate Nephropathy - antifreeze drinkers, inborn errors, and extreme ascorbic acid abusers - 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 Nephrogenic Diabetes Insipidus - a family of diseases in which the collecting duct is unable to respond to ADH; this includes inborn errors of metabolism, gross and widespread damage to the medulla, and the late effects of lithium therapy for mania Gout - gout is the disease resulting from precipitation of monosodium urate crystals in the body; the acute attack lasts several days and ends as mysteriously as it began, perhaps returning on another occasion when the pt has indulged - all pts with too-high serum uric acid levels from any cause are said to have hyperuricemia - only hyperuricemic pts can get gout, but most never do - little correlation between serum uric acid levels and severity of gout - gout pts are classified according to hteir current symptoms and signs - the typical pt with gout has repeated, transient, severe inflammation of one or a few joints - 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 fiobrosis - the whole thing is called a trophus - trophi are common in the helices of ears, in the joints and their bursae, and in the kidney - sometimes it presents with a stone or some other manifestation of renal gout - 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, and a few rare, well-characterized genetic syndromes - secondary gout is hyperuricemia and resulting gout because of some other disease - the tissue changes are the same in primary and secondary gout - etiologies - primary hyperuricemia and gout (90+%); the majority of these men both overproduce and underexcrete uric acid; attacks peak during the 40's, though the hyperuricemia begins at puberty - secondary hyperuricemia and gout (5-10%) - heavy ingestion of purines can raise serum uric acid and trigger an acute attack of gout; remember lymphoma, leukemia, and other malignancies - chemotherapy and/or radiation often excrete tremendous amounts of uric acid - in diseases of the proximal tubule, secretion of uric acid is poor and gout can result - secretion is also inhibited by thiazide diuretics, ethanol, and acetoacetic acid - gentetic disease causes of secondary gout: - type I glycogen storage disease - Lesh-Nyhan syndrome - acute gouty attack - attacks begin and end suddenly; it is preceeded by a precipitation of insoluble monosodium urate crystal in relatively avascular tissue; the acute attack begins when some crystals effectively activate the plasma proteases; monosodium urate crystals themselves can active factor XII and C5; 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 cause damage; more phagocytes arrive and the same thing happens; as the inflammation causes the pH in the joint to go down, more and more urate crystalizes; probably self-limited because the heat of inflammation redissolves the crystals - the chronic disease - the enduring lesion of gout is the tophus; when you suspect gout, feel around the helix and anti-helix for crystals; the most commonly involved area is the big toe, but other cold places are often involved; tophi in the medulla and the pyramids cause acute and chronic kidney problems - clinical diagnosis - 1) the pt with gout is seldom the first family member affected; 2) serum uric acid is routine on most automated chem profiles; 3) compensated polarization of synovial fluid, tophus, or kidney stone can identify the uric acid crystals; 4) uric acid crystals and amorphus reported on urinalysis are of essentially no significance, and are common in normals - treatment - colchicine stops an acute attack; NSAIDS are useful for joint disease; allopurinol prevents the formation of uric acid (this is the mainstay treatment) High Blood Pressure - a longstanding increase in systolic and/or diastolic blood pressure above desirable levels (160/90); affects maybe 15% people - 90% are idiopathic - 10% are secondary - endocrine diseases - Cushing's, 11-B-hydroxylase deficiency, hyperaldosteronism, pheochromocytome, eclampsia, reninoma, and hypercalcemia - renal hypertension - diabetics - sleep apnea - low birth weight - longstanding high blood pressure - increased incidence of cerebrovascular accidents, esp. hemorrhage - some acceleration of atherosclerosis, and hypertensive heart disease - high blood pressure from any cause eventually damages the kidney - iatrogenic disease secondary to the noxious side effects of antihypertensive agents is widespread and serious Benign Essential Hypertension - affects about 15% of the population, prevalence increases with age - females more than males, blacks more than whites - the basic trouble is most patients does seem to be generalized arteriolar vasoconstriction and/or inability to dump a salt load - the kidneys of most hypertensives seem to have difficulty disposing of a sodium load - the newly-characterized peptide endothelin is often elevated in hypertension - obese pts, anb black pts who are developing hypertensive renal insufficiency, are likely to have much increased plasma volume - arteriolar nephroscelosis - seen in pts with high blood pressure from any cause; thus associated with benign essential hypertension - smallish, symmetric kidneys with finely granular surfaces - small 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 - walls of the smallest arteries hyalinize with PAS-positive material "because the intima is permeable", and this narrows the lumen - uncomplicated arteriolar nephrosclerosis causes renal failure in less than 5% of its victims - as high as 25% of idiopathic high blood pressure pts have white jacket syndrome - a transient rise in BP caused by the emotional consequences ofa BP check - hypertension from any cause can accelerate or enter a malignant phase - scleroderma and adult hemolytic-urmeic syndrome often terminate in malignant hypertension - glomeruli show scattered necrosis and hemorrhage; bleeding into the glomerular spaces appear as petechia on the cortical surfaces - intimal proliferation of small arteries is characteristic; this badly narrows lumens, renin levels increase, and renal infarcts occur - the media fills with fibrinoid because of endothelial damage Renal Vascular Hypertension - renal artery stenosis - usually caused by atherosclerosis of an ostium - adult polycystic kidney plays havoc with the microvasculature, and high-renin hypertensionoccurs - Dr. Goldblatt noticed that many pts at autopsy who had high blood pressure in life possessed one normal-sized kidney and one small kidney - the kidney supplied by the narrowed artery is often small and fibrotic and may contain infarcts from atheroembolic episodes Hemolytic-Uremic Syndrome - 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 - the fundamental problem is selective damage to the endothelium of the renal microvasculature - the most important cause of renal shutdown in kids - usually follows viral illness or bacterial bloody diarrhea - adult hemolytic-uremic syndrome - this follows complications of pregnancy and administation of endothelial poisons - it typically ends in chronic renal fialure and sometimes malignant hypertension - biopsy shows intimal onion-skinning in small renal arterioles, fibrin thrombi and/or red cell fragments in the glomeruli Diffuse Cortical Necrosis - this results from severe DIC plus shock, usually post-partum; the kidney vessels are normal - the pt has acute renal failure that doesn't get better; at autopsy, fibrin thrombi plug the glomerular capillaries Atheroembolization - a common cause of acute renal failure in older pts, especially those with abdominal aortic aneurysms - the diagnosis is difficult to make during life; look for livido reticularis on the lower extremities, increased eosinophils in the blood and the urine - at autopsy, the pathologist finds platelike crystals of cholesterol in the renal arteries, with an associated foreign-body reaction - survivors of this end up with a kidney with one or more V-shaped scars Sickle Cell Disease Nephropathy - cells tend to sickle in the hypertonic milieu of the renal medulla; this results in hematuria and/or decreased ability to concentrate urine, loss of vaso rect, renal tubular sclerosis, etc. - sicklers (HbSS, HbSC) often get papillary necrosis Obstructive Disease of the Kidney - causes include malformations, blood clots, calculi, tumors, prostatic hyperplasia, 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, eventually with fibrosis and tubular atrophy of the kidney Kidney Stones - kidney stones form in the renal pelvis - they are painful, especially during passage, and dangerous as a cause of chronic infection - calcium stones are the commonest, and the majority of these pts have hypercalciuria - hypercalcemia in a pt who first presents with kidney stones is probably due to a parathyroid adenoma - some calcium oxalate stone formers have increased absorption of oxalic acid from the gut; others are vitamin C abusers - most calcium stone formers seem to have calcium in the urine for no clear reason - magnesium ammonium phosphate stones often result from urinary tract infection by urea splitters like proteus - only half of uric acid stones are associated with hyperuricemia Kidney Tumors - benign tumors - hemangiomas can bleed on and off - cortical adenomas - angiomyolipomas can occur in anyone, but are very common in tuberous sclerosis - renal cell carcinoma - a common, capricious cancer infamous for the many ways in which it can present clinically - the classic triad is fever, hematuria, and back pain - may present as hypercalcemia, amyloidosis, polycythemia, high BP, estrogens, Cushing's eosinophilia, leukemoid reaction, or as metastases - only a few make erythropoeitin and cause polycythemia - renal cell carcinomas are usually bulky, yellow cancers that occur in middle-aged or elderly pts - tobacco is a known rick factor - we know that trans-stygian kidneys often give rise to renal cell carcinomas - the cell of origin is almost always the proximal tubular cell, but otherwise the pathology is quite variable - in both familial and sporadic cases, the anti-oncogene at the Von Hippel Lindau locus is apparently always deleted - benign adenomas lack the 3p deletion - Wilm's tumor - one of the commonest pediatric solid tumors - a tumor of variable histopathology, often a carcinosarcoma, often with embryonic renal blastoma, mesenchyme, muscle, sometimes cartilage, plus attempts to form tubules and glomeruli - pts often have andridia, hemihypertrophy, and/or rests of undifferentiated blastema - urothelial carcinoma - tumor of olderadults; much less common than renal cell carcinoma; usually arises multifocally along the cancers in urinary bladder - similar to bladder cancer; papillary growth is usual, prognosis is not good