Cystic Disease, Stones & Renal Cancer

Polycystic kidney disease

ADPKD. The most common inherited kidney disease. About 85% of cases are PKD1 (chromosome 16, polycystin-1), which is the more severe form; the rest are PKD2 (chromosome 4, polycystin-2). Cysts progressively replace functioning parenchyma, so both kidneys become massively enlarged. Presentation is in adulthood: hypertension (cyst compression activates renin), hematuria, flank pain (bleeding into a cyst, infection, stones), and gradual progression to ESRD. Extrarenal associations:

• Berry (saccular) aneurysms of the circle of Willis, whose rupture causes subarachnoid hemorrhage ("worst headache of my life").
• Hepatic cysts, the most common extrarenal finding.
• Mitral valve prolapse and colonic diverticulosis.

Treatment. Control blood pressure with ACE inhibitors or ARBs. Vasopressin-driven cAMP promotes cyst growth, so tolvaptan (a V2-receptor antagonist) slows enlargement.

ARPKD. Caused by PKHD1 mutations (fibrocystin) and presents in neonates or infants with bilateral, symmetrically enlarged kidneys. It travels with congenital hepatic fibrosis, which causes portal hypertension in children who survive. Severe disease in utero reduces fetal urine output, and the resulting oligohydramnios produces Potter sequence: pulmonary hypoplasia (the usual cause of death), flattened facies, and limb deformities.

Nephrolithiasis

Presentation. Colicky flank pain radiating to the groin, with hematuria. Stones lodge at the three physiologic narrowings of the ureter: the ureteropelvic junction, the pelvic brim (where the ureter crosses the iliac vessels), and the ureterovesical junction. Low urine volume is the universal risk factor, so high fluid intake prevents every stone type. Non-contrast CT is the most sensitive imaging study.

Calcium stones. About 80% of stones; calcium oxalate is more common than calcium phosphate, and both are radiopaque. Oxalate crystals are envelope- or dumbbell-shaped. Risk factors are hypercalciuria, hyperoxaluria, and hypocitraturia (citrate normally chelates urinary calcium). In Crohn disease and other fat malabsorption, unabsorbed fatty acids bind gut calcium and leave oxalate free to be absorbed (enteric hyperoxaluria); ethylene glycol and excess vitamin C are metabolized to oxalate. Calcium phosphate stones form in alkaline urine, whereas calcium oxalate formation is largely pH-independent. Thiazides (which increase distal calcium reabsorption and lower urine calcium) and citrate reduce recurrence; dietary calcium should not be restricted, because low calcium intake increases oxalate absorption.

Struvite. Magnesium ammonium phosphate stones form in alkaline urine (pH >7) produced by urease-positive organisms (Proteus, Klebsiella, Staphylococcus saprophyticus) that split urea into ammonia. They are radiopaque, show coffin-lid crystals, and grow into staghorn calculi that fill the renal pelvis. Treat the infection and remove the stone, since retained fragments harbor bacteria.

Uric acid. Radiolucent (invisible on plain X-ray, seen on CT) and formed in acidic urine (pH <5.5). Risks are hyperuricemia (gout), high cell turnover (leukemia, tumor lysis), and hot, arid climates that concentrate the urine. Crystals are rhomboid or rosette-shaped. Treat by alkalinizing the urine with potassium citrate, which dissolves them, plus allopurinol.

Cystine. Cystinuria is an autosomal recessive defect in proximal tubule reabsorption of the COLA amino acids (Cystine, Ornithine, Lysine, Arginine); only cystine is insoluble enough to form stones. Look for hexagonal crystals, a positive urinary cyanide-nitroprusside test, childhood onset, and possible staghorns. Stones are faintly radiopaque because of their sulfur. Treat with hydration, urinary alkalinization, and chelators (penicillamine, tiopronin).

Radiopacity sorts stones first: calcium (most common) and struvite (staghorn, infection) are radiopaque, uric acid is radiolucent and needs CT, and cystine is faintly radiopaque. Crystal shape and urine pH then lock the diagnosis.

Renal cell carcinoma and VHL

Origin and genetics. RCC arises from proximal tubule epithelium. Clear-cell carcinoma, the most common subtype, has cells packed with lipid and glycogen and is driven by loss of chromosome 3p, the site of the VHL gene. It is most common in men aged 50–70; the main risk factors are smoking and obesity, and acquired cystic kidney disease from long-term dialysis adds risk.

Presentation and spread. The classic triad of hematuria, flank pain, and a palpable mass is often absent, and many tumors are found incidentally. RCC invades the renal vein and can extend up the IVC. Because the left gonadal vein drains into the left renal vein, left-sided invasion causes a left varicocele that does not reduce when supine. Hematogenous spread goes to lung (cannonball nodules) and bone (lytic lesions). Localized disease is resected; RCC resists conventional chemotherapy and radiation, so metastatic disease is treated with immunotherapy and VEGF-targeting tyrosine kinase inhibitors.

Paraneoplastic products. RCC is a classic hormone secretor:

• Erythropoietin → polycythemia
• PTHrP → hypercalcemia
• Renin → hypertension
• ACTH → Cushing syndrome

Von Hippel-Lindau disease. Autosomal dominant loss of the VHL tumor suppressor (3p25). The VHL protein normally tags hypoxia-inducible factor (HIF) for ubiquitin-mediated degradation; without it, HIF is stabilized and drives VEGF (angiogenesis) and EPO. The result is bilateral, multifocal clear-cell RCC at a young age, CNS (especially cerebellar) and retinal hemangioblastomas, pheochromocytoma, and angiomatosis.

Wilms tumor and urothelial carcinoma

Wilms tumor (nephroblastoma). The most common renal malignancy of childhood, peaking at ages 2–4, caused by loss of the WT1 tumor suppressor (chromosome 11p13). It presents as a large, palpable, unilateral flank mass that usually does not cross the midline, often with hematuria and hypertension. Histology is triphasic: primitive blastema, stroma, and epithelium forming immature tubules and glomeruli. Associated syndromes:

• WAGR: Wilms tumor, Aniridia, Genitourinary anomalies, and intellectual disability (the "R" of Retardation); an 11p13 deletion that removes WT1 and the neighboring PAX6.
• Denys-Drash: WT1 mutation with early-onset nephrotic syndrome and gonadal dysgenesis.
• Beckwith-Wiedemann: 11p15 defect with organomegaly, macroglossia, and hemihyperplasia.

Urothelial (transitional cell) carcinoma. The most common tumor of the collecting system (calyces, renal pelvis, ureter, bladder), classically an older adult with painless hematuria. Risk factors follow "Pee SAC": Phenacetin, Smoking (the most important), Aniline dyes (aromatic amines), and Cyclophosphamide. Carcinogens bathe the entire urothelium, producing field cancerization: tumors are multifocal and recur after resection.

Schistosoma haematobium causes squamous cell carcinoma of the bladder, not urothelial carcinoma (Middle East and Africa); chronic irritation from long-term catheters or stones also drives squamous metaplasia.