Renal pathology

Question 1

Hartnup disease

Answer 1

Autosomal recessive deficiency of neutral amino acid (e.g. tryptophan) transporters in proximal renal tubular cells and enterocytes, which leads to neutral aminoaciduria and decreased absorption from the gut

Pellagra-like symptoms

Tx: high-protein diet and nicotinic acid

Question 2

Fanconi syndrome

Answer 2

Reabsorptive defect in the PCT, leading to increased excretion of amino acids, glucose, phosphate, and bicarb (type II RTA).

Causes: Wilson disease, ischemia, nephrotoxins/drugs

Order of renal tubular defects: Fanconi, Bartter, Gitelman, Liddle (“the kidneys put out FABulous Gliterring Liquid”)

Question 3

Bartter syndrome

Answer 3

Autosomal recessive reabsorptive defect in thick ascending loop of Henle. Affects Na/K/2Cl cotransporter (effects similar to loop diuretics)

Results in hypokalemia and metabolic alkalosis with hypercalciuria

Question 4

Gitelman syndrome

Answer 4

Autosomal recessive reabsorptive defect of NaCl in DCT. Affects similar to thiazide diuretics.

Hypokalemia and metabolic alkalosis without hypercalciuria.

Less severe than Bartter syndrome

Question 5

Liddle syndrome

Answer 5

Autosomal dominant, increased activity of epithelial Na⁺ channels in distal and collecting tubules.

HTN, hypokalemia, metabolic alkalosis, decreased aldosterone.

Tx: amiloride

Question 6

Polycystic kidney disease (PKD)

Answer 6

Inherited defect leading to bilateral enlarged kidneys with cysts in the renal cortex and medulla

Autosomal recessive form - presents in infants; cysts in kidney and liver; portal HTN (due to hepatic fibrosis)

Autosomal dominant form - presents in young adults; mutation in APKD1/2; cysts in kidney, liver, and brain (berry aneurysms); mitral valve prolapse

Question 7

Acute tubular necrosis

Answer 7

Most common cause of intrarenal azotemia; presents with brown granular casts and hyperkalemia

Etiology may be ischemic or nephrotoxic

• Proximal tubule and medullary segment of thick ascending limb are most susceptible to ischemic damage
• Proximal tubule is most susceptible to nephrotoxins

Question 8

Nephrotoxins

Answer 8

Nephrotoxins cause acute tubular necrosis.

• Aminoglycosides (e.g. gentamicin)
• Heavy metals (e.g. lead)
• Myoglobinuria
• Ethylene glycol (oxalate crystals in urine)
• Radiocontrast dye
• Urate (tumor lysis syndrome; PPx with hydration and allopurinol)

Question 9

Acute interstitial nephritis

Answer 9

Drug-induced hypersensitivity involving interstitium and tubules; characterized by oliguria, fever, and eosinophils in urine

Causes: NSAIDs, penicillin, diuretics

May progress to renal papillary necrosis

Question 10

Renal papillary necrosis

Answer 10

Presents with gross hematuria and flank pain

Causes:

• Chronic analgesic abuse (penacetin/aspirin use)
• Diabetes
• Sickle cell
• Severe acute pyelonephritis

Question 11

Nephrotic syndrome

Answer 11

Glomerular disorders characterized by proteinuria (> 3.5 g/day) resulting in:

• Hypoalbuminemia (pitting edema)
• Hypogammaglobulinemia (increased risk of infection)
• Hypercoagulable state (loss of antithrombin III)
• HLD and hypercholesterolemia (fatty casts in urine)

Question 12

Minimal change disease

Answer 12

Nephrotic syndrome; most common in children.

May be associated with Hodgkin lyphoma (cytokine release disrupts podocytes)

Effacement of foot processes results in loss of albumin but not immunoglobulin

Excellent response to steroids (unique among nephrotic syndromes)

Question 13

Focal segmental glomerulosclerosis (FSGS)

Answer 13

Nephrotic syndrome

Hispanics and African Americans

HIV, heroin use, sickle cell disease

Like MCD, FSGS involves effacement of the foot process

Unlike MCD, FSGS does NOT respond well to steroids. Progresses to chronic renal failure

Question 14

Membranous nephropathy

Answer 14

Nephrotic syndrome

Caucasian adults

Hepatitis B or C, solid tumors, SLE, drugs (e.g. NSAIDs, penicillamine)

Immune complexes deposit below the podocytes (subepithelial deposits) to produce granular IF and “spike and dome” appearance on EM

Progresses to chronic renal failure

Question 15

Membranoproliferative glomerulonephritis (MPGN)

Answer 15

Mixed nephrotic/nephritic syndrome

“Tram-track” appearance on H&E and granular IF

• Type I MPGN - subendothial immune complex deposits; associated with HBV and HCV
• Type II MPGN - intramembranous immune complex deposits; associated with C3 nephritic factor (leads to overactivation of complement and inflammation)

Progresses to chronic renal failure

Question 16

Effect of diabetes on the kidneys

Answer 16

1. Nonenzymatic glycosylation of vascular basement membrane
2. Hyaline arteriosclerosis (especially glomerular efferent arteriole)
3. Hyperfiltration injury leads to nephrotic syndrome (sclerosis of mesangium with Kimmelstiel-Wilson nodules)

PPx: ACE inhibitors

Question 17

Effect of systemic amyloidosis on the kidneys

Answer 17

Amyloid deposits in mesangium, resulting in nephrotic syndrome

Question 18

Post-streptococcal glomerulonephritis (PSGN)

Answer 18

Nephritic syndrome

Presents 2-3 weeks after infection with nephritogenic strain of GAS (M protein virulence factor)

Immune complex deposition (granular IF) due to IgG, IgM, and C3 deposition; subepithelial “humps” on EM

Increased anti-DNase B. Decreased complement.

Usually resolves, but 25% of adults progress to rapidly progressive glomerulonephritis

Question 19

Rapidly progressive glomerulonephritis (RPGN)

Answer 19

Nephritic syndrome

Progresses to renal failure in weeks to months

Crescents in Bowmn space (comprised of fibrin, C3b, and macrophages)

Etiology of RPGN determined by IF pattern:

• Linear (anti-basement membrane antibody) - Goodpasture syndrome
• Granular (immune complex deposition) - PSGN or diffuse proliferative glomerulonephritis
• Negative IF (pauci-immune) - Wegener granulomatosis (c-ANCA), microscopic polyangitis (p-ANCA); Churg-Strauss (p-ANCA and granulomas/asthma/eosinophilia)

Question 20

IgA nephropathy

Answer 20

Nephritic syndrome

Usually follows mucosal infection (e.g. gastroenteritis)

IgA deposits in mesangium

Question 21

Alport syndrome

Answer 21

Nephritic syndrome

X-linked defect of type IV collagen

Isolated hematuria, sensory hearing loss, ocular disturbances

Question 22

Calcium oxalate/calcium phosphate nephrolithiasis

Answer 22

Most common type of nephrolithiasis.

Envelope/dumbbell shaped crystals

Idiopathic hypercalciuria, hypercalcemia.

Ethylene glycol (antifreeze), vitamin C abuse, and Crohn disease promote formation of oxalate crystals.

Calcium phosphate crystals precipitate at alkalinic pH. Calcium oxalate crystals precipitate at acidic pH

Tx: HCTZ (Ca-sparing diuretic), citrate

Question 23

Ammonium magnesum phosphate (struvite) nephrolithiasis

Answer 23

Coffin lid-shaped crystals

Infection with urease-positive organisms (e.g. Proteus, Staph or Klebsiella) that hydrolyze urea to ammonia

Staghorn calculi (nidus for UTIs) precipitate at alkalinic pH

Tx: Surgical removal of staghorn calculi, eradication of pathogen

Question 24

Uric acid nephrolithiasis

Answer 24

Radiolucent (unique among stones); rhomboid-shaped crystals

Hyperuricemia (leukema, myeloproliferative disorders, gout)

Risk factors include low urine volumes and acidic pH

Tx: hydration, alkalinization of the urine (potassium bicarbonate), allopurinol

Question 25

Cystine nephrolithiasis

Answer 25

Hexagonal shaped crystals Children; associated with decreased reabsorption of cysteine Staghorn calculi (like ammonium magnesium phosphate stones) Tx: hydration and alkalnization of urine

Question 26

Chronic renal failure

Answer 26

* Uremia (nausea, anorexia, pericarditis, platelet dysfunction, encephalopathy with asterixis, deposition of urea crystals in skin) * HTN * Hyperkalemia with metabolic acidosis * Anemia (decreased EPO production by renal peritubular interstitial cells) * Hypocalcemia and hyperphosphatemia (decreased 1-alpha-hydroxylation by proximal renal tubule cells) * Renal osteodystrophy due to secondary hyperparathyroidism, osteomalacia (decreased mineralization), and osteoporosis (metabolic acidosis) * Dyslipidemia (hypertriglyceridemia) * Waxy casts Increases risk for RCC

Question 27

Renal cell carcinoma

Answer 27

Hematuria, palpable mass, flank pain Paraneoplastic syndromes: EPO, renin, PTHrP, ACTH Left-sided varcocele due to involvement of left renal vein Loss of VHL (3p) tumor suppressor gene Sporadic tumors - single tumor in upper pole of kidney; adult male smokers Hereditary tumors - bilateral tumors, young adults.

Question 28

Von Hippel-Lindau disease

Answer 28

Autosomal dominant disorder associated with inactivation of VHL gene Hemangioblastoma of the cerbellum and bilateral renal cell carcinomas

Question 29

WAGR syndrome

Answer 29

**WAGR: W**ilms tumor, **A**niridia, **G**enital abnormalities, mental and motor **R**etardation Deletion of WT1 tumor suppressor gene (11p13)

Question 30

Denys-Drash syndrome

Answer 30

Wilms tumor, progressive glomerular disease, male pseudohermaphroditism Mutation of WT1 tumor suppressor gene (11p13)

Question 31

Beckwith-Wiedemann syndrome

Answer 31

Wilms tumor, neonatal hypoglycemia, muscular hemihypertrophy, organomegaly (including tongue) Mutations in WT2 gene cluster

Question 32

Urothelial (transitional cell carcinoma)

Answer 32

Arises from urothelial lining of renal pelvis, ureter, bladder, or urethra Risk factors: cigarette smoke, naphtylamine, azo dyes, long-term cyclophosphamide or phenacetin use Painless hematuria Two pathways: flat (high-grade, early p53 mutation), papillary (low-grade, late p53 mutation) Tumors are often multifocal and recur ("field defect")

Question 33

Squamous cells carcinoma of the bladder

Answer 33

Risk factors: * Chronic cystitis (older woman) * Schistosoma hematobium infection (young Egyptian male) * Long-standing nephrolithiasis

Question 34

Adenocarcinoma of the bladder

Answer 34

Etiologies: * Urachal remnant (tumor develops at dome of bladder) * Cystitis glandularis (chronic inflammation of bladder) * Exstrophy (congenital failure to form caudal portion of anterior abdominal and bladder walls)

Question 35

Diffuse proliferative glomerulonephritis

Answer 35

Nephritic syndrome. Etiology of rapidly progressive glomerulonephritis Sub-endothelial deposits of IgG and C3 "Wire-looping" of capillaries Most common caused of death in SLE

Question 36

Metabolic alkalosis with low urine Cl^-

Answer 36

Often associated with volume depletion (increased reabsorption of bicarb in the proximal tubule) Responds to saline infusion (repletes Cl^- and volume) Etiologies: vomiting, contraction alkalosis, previous thiazide use, cystic fibrosis

Question 37

Metabolic alkalosis with high urine Cl^-

Answer 37

Often associated with volume expansion and hypokalemia Resistant to saline infusion therapy Etiologies: hyperaldosteronism, severe hypokalemia, current diuretic therapy, Bartter's syndrome or Gittelman syndrome, aminoglycoside toxicity