Pathology 20 p935-955
Tubular and Interstitial Diseases
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Acute Kidney Injury (AKI; Acute Tubular Necrosis, ATN)= acute diminution of renal function and
morphologic evidence of tubular injury; most common cause of acute renal function
o Causes:
 Ischemia (decreased or interrupted BF) -> microscopic polyangiits, malignant
hypertension, microangiopathies, thrombosis (TTP, DIC)
 Direct toxic injury to tubules
 Acute tubulointerstitial nephritis (drug hypersensitivity)
 Urinary obstruction
o Reversible renal lesion
o Ischemic AKI -> inadequate BF, hypotension and shock
o Nephrotic AKI -> from drugs (gentamicin and antibiotics), radiocontrast, poison (heavy
metals), organic solvents
o Ischemia + Nephrotic AKI -> mismatched blood transfusion and hemolytic crises
(hemoglobinuria, myoglobinuria)
 Intratubular hemoglobin or myoglobin casts
o Pathogenesis:
 Tubule cell injury -> structural changes (swelling, loss of brush border and
polarity, blebbing, cell detachment) and lethal injury (necrosis and apoptosis)
 ↓ ATP, ↑ Ca, proteases (calpain), phospholipases, ROS
 Loss of cell polarity -> ↑ Na delivery to distal tubules (vasoconstriction)
 Cell detachment -> luminal obstruction
 Disturbances in BF -> intrarenal vasoconstriction (↓ GFR and O2) via
tubuloglomerular feedback and injury releasing endothelin, NO, PGI2
 Patchy and BM maintained -> allow repair
 Mediated by autocrine or paracrine stimulation
o Morphology:
 Ischemic AKI: necrosis with large skip areas, rupture of BM (tubulorrhexis)
 Straight proximal tubule and ascending thick limb vulnerable
 Distal tubule eosinophilic hyaline and pigmented granular casts (TammHorsfall protein)
 loss of brush border, cell swelling, sloughing of cells, dilated vasa recta
 Toxic AKI -> injury in proximal convoluted tubule, necrosis sometimes specific to
toxin
 Mercury chloride has acidophilic inclusions
 CCl4 has neutral lipid accumulation
 ethylene glycol has ballooning, PCT degeneration w/ Ca oxalate crystals
o Clinical:
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Initiation phase = inciting medical, surgical or obstetric event in ischemic form
(decline in urine output and rise in BUN)
 Maintenance phase = sustained decreased urine output (oliguria), Na andH2O
overload, rise BUNE, hyperkalemia, acidosis
 Recovery phase = increase in urine volume, hypokalemia, vulnerable to
infection, BUN and creatinine decline
 95% recovery in nephrotic AKI if toxin hasn’t injured other organs, 50% recovery
if shock from sepsis, burns, or multi-organ failure
 Up to 50% do not have oliguria = nonoliguric AKI (nephrotoxins)
Tubulointerstitial nephritis = may occur with disease of glomerulus; secondary TN also in
polycystic kidney disease and diabetes
o Acute TN -> rapid onset, interstitial edema, eosinophil/neutrophils, focal tubule necrosis
o Chronic TN -> mononuclear leukocytes, interstitial fibrosis, diffuse tubular atrophy
o Defects in tubular function (impaired concentrating ability, polyuria and nocturia,
metabolic acidosis
o Pyelonephritis and Urinary Tract Infection = tubules, interstitium and renal pelvis
affected
 Acute pyelonephritis -> bacterial infection (associated with UTI)
 Chronic pyelonephritis -> bacterial infection, vesicoureteral reflux, obstruction
 Pyelonephritis is a complication of UTI -> may be asymptomatic bacteriuria and
remain localized to bladder (cystitis)
 Pathogenesis:
 Most common from gram-negative bacilli (normal in intestinal tract) ->
Escherichia coli, Proteus, Klebsiella, and Enterobacter
 Streptococcus faecalis, staphylococci and other bacteria/fungi too
 In immunocompromised, Polyomavirus, CMV, and adenovirus
 In most patients, infecting organisms derived from pts own fecal flora
o Through blood (hematogenous infection)
o From lower urinary tract (ascending infection)
 Colonization of distal urethra and inroitus (specific
adhesins ([pap] gene) associated with infection
 From urethra to the bladder (catheterization, more
common in females)
 Urinary tract obstruction and stasis of urine
 Vesicocureteral reflux (incompetence of the
vesicoureteral valve) -> may be from SC injury
 use voiding systourethrogram
 Intrarenal reflux (upper and lower poles of kidney)
o Acute Pyelonephritis = acute suppurative inflammation from bacteria
 Morphology:
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Patchy interstitial suppurative inflammation, intratubular aggregates
of neutrophils and tubular necrosis
Neutrophils along involved nephron (glomeruli resistant to infection)
o Candida (fungal pyelonephritis) affects glomeruli
Complications: 1) papillary necrosis (diabetics and obstruction;
coagulative), 2) pyonephrosis (obstruction), 3) perinephric abscess
Pyelonephritic scar associated withinflammation, fibrosis, and
deformation of calyx and pelvis
Clinical:
 Predisposing conditions -> urinary tract obstruction, instrumentation,
vesicoureteral reflux, pregnancy, gender and age, preexisting renal
lesions, DM, immunosuppression and immunodeficiency
 Pain at CVA, fever, malaise, dysuria, frequency, urgency, pyuria
(leukocytes in urine), leukocyte casts (renal involvement)
 Polyomavirus causes pyelonephritis in kidney allografts -> polyomavirus
nephropathy
o Nuclear inclusions of crystalline-like lattices
o Chronic pyelonephritis and reflux nephropathy = chronic tubulointerstitial
inflammation and renal scarring (pelvocalyceal damage)
 Important cause of ESRD
 Reflux nephropathy = more common form, in childhood, vesicoureteral and
intrarenal reflux, uni or bilateral
 Chronic obstructive pyelonephritis = uni or bilateral
 Morphology:
 Scarring of kidneys (asymmetric) -> coarse discrete, corticomedullary
scars overlying dilated, blunted, deformed calyces and flat papillae
 Dilated tubules with colloid casts (thyroidization)
 Vascular sclerosis (with hypertension -> hyaline arteriosclerosis)
 Fibrosis around calyceal epithelium
 Xanthogranulomatous pyelonephritis -> accumulation of foamy
macrophages (Proteus infections and obstruction)
 Clinical:
 Back pain, fever, pyuria, bacteriuria
 Reflux nephropathy in hypertensive children
 Polyuria and nocturia from loss of tubular function
 Secondary focal segmental glomerulosclerosis with proteinuria
Tubulointerstitial Nephritis induced by drugs and toxins = trigger interstitial immunological
reactions (hypersensitivity), acute renal failure, cumulative injury to tubules (analgesic abuse;
chronic renal insufficiency)
o Acute Drug-Induced Interstitial Nephritis = use of sulfonamides, synthetic penicillins
(methicillin, ampicillin), antibiotics (rifampin), diuretecs (thiazides), NSAIDs, cimetidine
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Fever, eosinophilia, rash, and renal abnormalities (hematuria, mild proteinuria,
leukocyturia); rising serum creatinine or acute renal failure with oliguria
 Pathogenesis:
 Immune response, serum IgE levels increased (late-phase reaction of an
IgE-mediated (type 1) hypersensitivity)
 Drugs act as haptens (become immunogenic)
 Morphology:
 Interstitial abnormalities (edema, mononuclear infiltrate)
 With methicillin and thiazides -> non-necrotizing granulomas with giant
cells
 “Tubulitis”
 Glomeruli normal (except w/ NSAIDS)
 Clinical:
 Withdrawal of drug followed by recovery
Analgesic Nephropathy = chronic renal disease from excessive intake of analgesic
mixtures with chronic tubulointerstitial nephritis and reanl papillary necrosis
 Mixtures with phenacetin, aspirin, caffeine, acetaminophen, and codeine
 Pathogenesis:
 Papillary necrosis first, cortical tubulointerstitial nephritis follows from
impeded urine outflow
 Acetaminophen (depletes glutathione) generates oxidative metabolites
 Aspirin inhibits vasodilating effect
 Morphology:
 Depressed areas (cortical atrophy)
 Varying papillary necrosis, calcification, fragmentation and sloughing
o Early stage: patchy necrosis. Late stage: “ghosts” of tubules and
calcification
 Cortical columns of Bertin spared from atrophy
 Clinical:
 Women > men
 High with recurrent headaches, muscle pain, psychoneurotic patients
and factory workers
 Hyposthenuria (can’t concentrate urine), renal stones, headache,
anemia, GI symptoms and hypertension, UTI in 50%
 With drug withdrawal, renal function stabilizes or improves
 Transitional papillary carcinoma of the renal pelvis
Nephropathy Associated with NSAIDS = inhibit prostaglandin synthesis
 Induce acute renal failure, acute hypersensitivity interstitial nephritis, acute
interstitial nephritis and minimal-change disease, membranous nephropathy
Aristolochic Nephropathy = from artistolochic acid (in herbal remedies), increased
incidence of carcinoma, cause of Balkan nephropathy
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Other Tubulointerstitial Diseases
o Urate Nephropathy =
 Acute uric acid nephropathy -> uric acid crystals in collecting ducts obstruct
(leukemias and lymphomas w/ chemotherapy)
 Chronic urate nephropathy -> aka gouty nephropathy; deposition of
monosodium urate crystals in DT and collecting ducts (increased lead
exposure…from “moonshine” whiskey)
 form birefringent needle-like crystals in tubular lumens or interstitium
 induce a tophus
 Nephrolithiasis -> uric acid stones
o Hypercalcemia and nephrocalcinosis = associated with hyperparathyroidism, multiple
myeloma, VitD intoxication, metastatic cancer, or excess-Ca intake
 Damage to tubular epithelial cells (mito distortion), Ca deposits in mito, DM,
cytoplasm -> obstruction
 Inability to concentrate urine, tubular acidosis, salt-losing nephritis
o Acute Phosphate Nephropathy = calcium phosphate crystal accumulation (from oral
phosphate solutions for colonoscopy prep), partial recovery
o Light-chain Cast Nephropathy (“myeloma kidney”) = malignant tumor (multiple
myeloma ) kidney involvement, tubulointerstitial from tumor complication or therapy
 Bence Jones (light chain) proteinuria and cast nephropathy -> renal failure,
direct toxicity to epithelial cells, combine with Tamm-Horsfall protein forming
casts
 Amyloidosis -> AL type, forms λ type light chains
 Light-chain deposition disease -> κ type light chains in GBM and mesangium
 Hypercalcemia and hyperuricemia
 Morphology:
 Bence Jones cases are pink-blue amorphous masses
 Casts surrounded by multinucleate giant cells
 Granulomatous inflammatory reaction
 Clinical:
 Chronic renal failure develops (common form) or acute renal failure
with oliguria
 Precipitating factors -> dehydration, hypercalcemia, acute infection,
nephrotoxic antibiotics
 Bence Jones proteinuria in 70% of multiple myeloma
 Non-light-chain proteinuria (albuminuria) -> AL amyloidosis of LC
deposition disease
Vascular Diseases
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Most kidney disease involves renal blood vessels secondarily
Benign nephrosclerosis = sclerosis of renal arterioles and small arteries (focal ischemia of
parenchyma) with glomerulosclerosis and chronic tubulointerstitial injury
o Associations: increased age, blacks > whites, hypertension and DM
o Pathogenesis:
 Medial and intimal thickening
 Hyaline deposition in arterioles
o Morphology:
 Cortical surface resembles grain leather
 Moderate reduction in size
 Hyaline arteriolosclerosis
 Interlobular and arcuate arteries show medial hypertrophy, reduplication of
elastic lamina, increased myofibroblastic tissue in intima = fibroelastic
hyperplasia
 Collapse of glomerular basement membrane
o Clinical:
 Reduced renal BF (but normal GFR)
 Mild proteinuria
 African descent, high BP, and underlying disease (i.e. DM) all with hypertension
increase risk of renal failure
Malignant hypertension and accelerated nephrosclerosis = form of renal disease associated
with malignant or accelerated phase of hypertension
o Often superimposed on other forms of hypertension or renal disease
(glomerulonephritis or reflux nephropathy)
o Frequent cause of death from uremia in scleroderma
o Younger individuals, men, blacks
o Pathogenesis:
 Initial insult = vascular damage to kidneys -> increased permeability of small
vessels to fibrinogen and protein, endothelial injury, death of wall cells, platelet
deposit (fibrinoid necrosis)
 Markedly elevated levels of plasma renin, high aldosterone (salt retention)
 Malignant arteriosclerosis in entire body and nephrosclerosis in kidney
o Morphology:
 Petechial hemorrhages -> “flea bitten” appearance
 Fibrinoid necrosis of arterioles (eosinophilic)
 Intimal thickening of interlobular arteries -> onion-skinning (concentric)
o Clinical:
 Systolic pressure >200 mmHg and diastolic >120 mmHg
 Papilledema, retinal hemorrhage (scotomas), encephalopathy, cardio
abnormality, renal failure
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 Hypertensive crises sometimes (loss of consciousness)
 Proteinuria, hematuria
 Medical emergency -> antihypertensive treatment
Renal artery stenosis = unilateral (2-5% of hypertensive cases)
o Pathogenesis:
 Goldblatt -> constriction of 1 artery = hypertension proportional to amount of
constriction (stimulates renin secretion of JGA)
 Elevated plasma or renal vein renin levels (improve with block of
angiotensin II activity)
 Sodium retention contributes to maintenance
o Morphology:
 Most common cause -> atheromatous plaque at origin of renal artery
(concentrically placed)
 In men, elderly and DM
 Fibromuscular dysplasia also causes
 Subclasses: intimal, medial (most common), and adventitial hyperplasia
 In women and younger age
 Diffuse ischemic atrophy (crowded glomeruli, interstitial fibrosis, inflamm
infiltrates)
 Arterioles of ischemic kidney protected but contralateral kidney have
arteriolosclerosis
o Clinical:
 Bruit on auscultation, high renin, response to ACE inhibitor, renal scan and IV
pyelography aid with diagnosis (usually arteriography required)
Thrombotic microangiopathies = hemolytic anemia, thrombocytopenia, renal failure, thrombotic
lesion in capillaries/arterioles
o Schistocytes in blood smears (normal coag unlike DIC)
o Two forms: hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic
purpura (TTP)
 Typical HUS (epidemic, classic, diarrhea-positive) = bacteria-contaminated food
(Shiga-like toxins)
 Atypical HUS (non-epidemic, diarrhea-negative) = inherited mutation of
complement-regulatory proteins, antiphospholipid antibodies, complications of
pregnancy/oral contraceptives, scleroderma and hypertension, chemo and
immunosuppressive drugs (endothelial injury)
 TTP = deficiency of ADAMTS13 (regulates vWF)
o Pathogenesis:
 Endothelial injury
 In typical HUS, Shiga-like toxin triggers
 In atypical HUS, excess activation of complement
 ↓ endothelial PGI2 and NO and adhesion molecules -> thrombosis
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Platelet activation/aggregation
 In TTP, platelet aggregation (induced by vWF multimers)
 Deficiency of ADAMTS13 from autoantibodies
 Tissue dysfunction from microthrombi, vascular obstruction, tissue ischemia
o Typical HUS = most follow E. coli (O157:H7) infection with Shiga-like toxin from ground
meat, water, raw milk, and contact transmission or sporadic; children preferentially
 Sudden onset of bleeding manifestations (hematemesis and melena), severe
oliguria, hematuria (micoangipathic hemolytic anemia, thrombocytopenia,
neurologic changes), hypertension (50%)
 Toxin induces adhesion molecules -> platelet activation and vasoconstriction
 Manage with dialysis for full recovery in weeks
o Atypical HUS = adults; inherited deficiency of complement-regulatory protein (factor H),
or mutation in complement factor I and CD46; normal ADAMTS13
 Associated conditions:
 Antiphospholipid syndrome (primary or secondary to SLE)
 Postpartum renal failure
 Vascular diseases affecting kidney (sclerosis, malig hypertension)
 Chemo and immunosuppressive drugs
 Kidney irradiation
o TTP = fever, neurologic symptoms, microangiopathic hemolytic anemia,
thrombocytopenia, and renal failure; deficit of ADAMTS13
 Most common cause -> inhibitory antibodies (younger women)
 CNS involvement dominant, renal involvement 50%
 Relapsing-remitting course with transfusion and immunosuppression
o Morphology:
 Acute active disease -> cortical necrosis and subcapsular petichiae; glomerular
capillaries with thick walls occluded by thrombi; mesangiolyis; interlobular
arteries and arterioles fibrinoid necrosis
 Chronic (atypical HUS and TTP) -> double contours or tram tracks of BM, “onionskinning”
Atherosclerotic Ischemic Renal Disease = bilateral renal artery disease (arteriography
diagnosis), chronic ischemia, surgical revascularization reverses
Atheroembolic Renal Disease = embolization of plaque, elderly with severe atherosclerosis (esp
after ab surery), arcuate and interlobular arteries with cholesterol crystals (rhomboid clefts)
Sickle-Cell Disease Nephropathy = disease (homozygous) or trait (heterozygous), hematuria,
diminished concentrating ability (hyposthenuria), patchy papillary necrosis, proteinuria
Diffuse cortical necrosis = after obstetric emergency (abruption placentae), septic shock,
extensive surgery -> glomerular and arteriolar microthrombi
o Fatal if bilateral and symmetric without therapy
o Morphology:
 Ischemic necrosis limited to cortex (acute ischemic infarction)
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 Patchy with coagulative necrosis
 Hemorrhage in glomeruli with fibrin plugs in capillaries
 Sudden anuria -> uremic death
Renal infarcts = “end-organ” nature of blood supply and limited collateral circulation; most due
to embolism (mural thrombosis in left atrium and ventricle from MI)
o Morphology:
 “white” anemic infarct
 Solitary or multiple and bilateral lesions ringed by zone of intense hyperemia
 Wedge-shaped infarct -> scarring with V-shape
 Ischemic coagulative necrosis
o Many clinically silent, CVA pain/tenderness