12.2 Genitourinary Pathology: Glomerular, Tubulointerstitial, Vascular & Cystic Kidney Disease, Renal Tumors, Obstruction & Genital Disorders

Why this area matters

The TOS lists:

• glomerular, tubular and interstitial, vascular and cystic diseases of the kidney;
• tumors of the kidney;
• obstructive uropathies;
• male and female genital disorders.

Chronic kidney disease is a growing cause of death and dialysis in the Philippines, driven by diabetes, hypertension and chronic glomerulonephritis.

Renal Pathology

Nephrotic Syndrome ($> 3.5\text{ g/day}$ Proteinuria, Hypoalbuminemia, Edema, Hyperlipidemia, Lipiduria)

• Minimal Change Disease (MCD): Most common cause of nephrotic syndrome in children. Light microscopy (LM) is normal; Immunofluorescence (IF) is negative; Electron microscopy (EM) shows diffuse effacement (flattening) of podocyte visceral epithelial foot processes. Highly responsive to oral corticosteroids.
• Focal Segmental Glomerulosclerosis (FSGS): Most common cause in adults, African Americans, HIV infection, and heroin abuse. LM shows sclerosis affecting only some glomeruli (focal) and part of the capillary tuft (segmental); EM shows foot process effacement; poor response to steroids with frequent progression to end-stage renal disease.
• Membranous Nephropathy: Most common primary cause in Caucasian adults; 85% primary due to autoantibodies against phospholipase A2 receptor (anti-PLA2R); secondary causes include hepatitis B, NSAIDs, SLE, and solid tumors. LM shows diffuse, uniform thickening of capillary loops; silver stain reveals pathognomonic "spike-and-dome" pattern; IF shows granular capillary wall IgG/C3; EM demonstrates subepithelial immune complex deposits.

Nephritic Syndrome (Hematuria, RBC Casts, Azotemia, Oliguria, Hypertension)

• Post-Streptococcal Glomerulonephritis (PSGN): Develops 1 to 3 weeks after Group A streptococcal pharyngitis or 2 to 6 weeks after impetigo. LM shows diffuse endocapillary hypercellularity; IF shows granular "starry-sky" or "lumpy-bumpy" deposits of IgG and C3; EM demonstrates pathognomonic large subepithelial electron-dense "humps". Associated with depressed serum C3.
• IgA Nephropathy (Berger Disease): Most common primary glomerulonephritis worldwide. Characterized by episodic gross hematuria occurring within 1 to 2 days of a mucosal respiratory or GI infection (synpharyngitic hematuria, lacking the long latent period of PSGN). LM shows mesangial proliferation; IF shows prominent mesangial granular IgA deposition.
• Rapidly Progressive Glomerulonephritis (RPGN): Rapid decline in GFR over days to weeks. Histopathologic hallmark is glomerular crescents in Bowman's space composed of proliferating parietal epithelial cells, macrophages, and fibrin:
  • Type I (Anti-GBM disease): Smooth linear IgG staining along glomerular basement membrane; when accompanied by pulmonary hemorrhage, termed Goodpasture syndrome (autoantibodies against alpha-3 chain of Type IV collagen).
  • Type II (Immune Complex): Granular IF; seen in Lupus nephritis (Class IV) or PSGN.
  • Type III (Pauci-Immune): Negative / pauci-immune IF; associated with ANCA-positive vasculitides (c-ANCA / PR3 in Granulomatosis with Polyangiitis; p-ANCA / MPO in Microscopic Polyangiitis).
• Acute Tubular Necrosis (ATN): Most common cause of hospital-acquired acute kidney injury. Ischemic (patchy, straight $S_3$ proximal tubule and thick ascending limb) or Nephrotoxic (diffuse, proximal convoluted tubule; aminoglycosides, radiocontrast, myoglobinuria). Histology shows loss of brush borders, tubular epithelial necrosis, and diagnostic muddy brown granular casts.

More glomerular disease

• Diabetic nephropathy: the leading cause of end-stage renal disease. It shows glomerular basement membrane thickening, diffuse mesangial sclerosis, Kimmelstiel-Wilson nodules (nodular glomerulosclerosis) and hyaline arteriolosclerosis of both afferent and efferent arterioles. Microalbuminuria comes first.
• Lupus nephritis: immune-complex disease. Class IV (diffuse proliferative) is the most common and severe form, with "wire-loop" capillaries and subendothelial deposits.
• Membranoproliferative glomerulonephritis: "tram-track" basement membranes, associated with hepatitis C and B.
• Alport syndrome: a type IV collagen defect causing hematuria, sensorineural deafness and eye defects.

Tubulointerstitial disease

• Acute pyelonephritis: ascending infection by gram-negative enteric bacteria (E. coli), helped by vesicoureteral reflux, obstruction, pregnancy, catheterization and diabetes. It causes fever, flank pain and costovertebral tenderness. Patchy interstitial neutrophils, tubular abscesses and WBC casts are seen. Complications are papillary necrosis (diabetes, sickle cell disease, analgesic abuse) and perinephric abscess.
• Chronic pyelonephritis: coarse, asymmetric corticomedullary scars over dilated, blunted calyces. "Thyroidization" of tubules (eosinophilic casts) is seen.
• Drug-induced acute interstitial nephritis: caused by NSAIDs, penicillins, rifampicin, diuretics and proton pump inhibitors. It causes fever, rash, eosinophilia and eosinophiluria.
• Acute tubular necrosis: described above. Muddy brown granular casts appear, and patients recover through oliguric, diuretic and recovery phases.

Vascular disease of the kidney

• Benign nephrosclerosis: found in long-standing hypertension and aging. Hyaline arteriolosclerosis produces small, finely granular kidneys.
• Malignant nephrosclerosis: found in severe hypertension (diastolic over about 120 to 130 mmHg). Arterioles show hyperplastic "onion-skin" arteriolosclerosis, fibrinoid necrosis (necrotizing arteriolitis) and petechial "flea-bitten" kidneys. Patients have papilledema and acute kidney injury.
• Renal artery stenosis: atherosclerosis in older men, fibromuscular dysplasia ("string of beads") in young women. Renin-driven hypertension develops.
• Thrombotic microangiopathies (hemolytic uremic syndrome, TTP) cause microthrombi, microangiopathic hemolysis and renal failure. Diarrhea-associated HUS in children follows Shiga toxin-producing E. coli.

Cystic kidney disease

Renal tumors

• Renal cell carcinoma (clear cell type is most common) arises from proximal tubules. It is associated with smoking, obesity, hypertension and von Hippel-Lindau syndrome (VHL loss on chromosome 3p).
  • Classic triad: hematuria, flank pain and a palpable mass.
  • It invades the renal vein and inferior vena cava and spreads through the blood to the lungs and bone.
  • Paraneoplastic effects include erythrocytosis (erythropoietin), hypercalcemia (PTHrP) and fever.
• Wilms tumor (nephroblastoma) is the most common renal cancer of children (2 to 5 years). It presents as a large flank mass with blastemal, stromal and epithelial elements, and is associated with WT1 syndromes (WAGR, Denys-Drash).
• Urothelial (transitional cell) carcinoma of the bladder and renal pelvis is linked to smoking, aniline dyes and cyclophosphamide. Painless hematuria is the usual sign. Schistosoma haematobium causes squamous cell carcinoma of the bladder.
• Oncocytoma and angiomyolipoma are benign; angiomyolipoma is associated with tuberous sclerosis.

Obstructive uropathy and stones

Obstruction causes hydronephrosis, with progressive atrophy of the parenchyma, infection and stone formation.

• Causes: stones, benign prostatic hyperplasia, tumors, strictures, pregnancy and congenital anomalies such as posterior urethral valves in boys and ureteropelvic junction obstruction.
• Calcium oxalate stones: the most common type; related to hypercalciuria and hyperoxaluria.
• Struvite stones (magnesium ammonium phosphate): form staghorn calculi with urease-producing organisms (Proteus).
• Uric acid stones: radiolucent; seen in gout and high cell turnover.
• Cystine stones: hexagonal crystals in cystinuria.
• Stones cause renal colic and hematuria. Obstruction above an infection is a urologic emergency.

Male genital disorders

• Cryptorchidism: raises the risks of infertility and germ cell tumor; orchiopexy is done before about 1 year of age.
• Benign prostatic hyperplasia: nodular hyperplasia of glands and stroma in the transition zone, driven by DHT. It causes urinary obstruction (frequency, nocturia, retention) but is not premalignant.
• Prostate adenocarcinoma: arises in the peripheral zone and is felt as a hard nodule on rectal examination. It is graded by Gleason score (grade groups), raises PSA, and gives osteoblastic bone metastases.
• Testicular tumors: about 95% are germ cell tumors.
  • Seminoma: uniform cells with clear cytoplasm and lymphocytic stroma. It is radiosensitive, has a good prognosis, and may mildly raise hCG.
  • Non-seminomatous tumors: embryonal carcinoma; yolk sac tumor (raised AFP, Schiller-Duval bodies); choriocarcinoma (raised hCG); teratoma.
• Testicular torsion and orchitis: mumps orchitis in adults can cause infertility.

Female genital disorders (pathology overview)

• Cervix: HPV-driven squamous intraepithelial lesions arising in the transformation zone progress to squamous cell carcinoma. Screening by Pap smear, visual inspection with acetic acid (VIA) and HPV testing is discussed in OB-GYN.
• Endometrium:
  • Hyperplasia results from unopposed estrogen (obesity, PCOS, anovulation).
  • Endometrioid carcinoma (type I) follows hyperplasia. Serous carcinoma (type II, p53) arises in atrophic endometrium in older women.
• Myometrium: leiomyomas (fibroids) are the most common tumors of women.
• Ovary:
  • Functional cysts.
  • Epithelial tumors: serous and mucinous, benign to malignant; CA-125 raised in serous carcinoma.
  • Germ cell tumors: the mature cystic teratoma (dermoid) is the most common ovarian neoplasm in young women.
  • Sex-cord stromal tumors: granulosa cell tumor (estrogen), Sertoli-Leydig tumor (androgens).
• Gestational trophoblastic disease:
  • Complete mole: 46,XX of paternal origin, no fetus, very high hCG, choriocarcinoma risk.
  • Partial mole: triploid, with fetal parts.