9.10 Cystic Kidney Disease, Obstructive Uropathy, Tubulointerstitial Disease & Hematuria

1. Hematuria: The First Fork in the Road

Microscopic hematuria is defined as three or more red blood cells per high-power field on a properly collected specimen. A positive dipstick without red cells on microscopy indicates myoglobin or hemoglobin, not hematuria, and points toward rhabdomyolysis or intravascular hemolysis.

The single determination that organizes everything is glomerular versus non-glomerular.

Clots are never glomerular. Blood arising within the nephron is exposed to urokinase and does not clot; visible clots localize bleeding to the collecting system, ureter or bladder.

Common causes:

• Glomerular: IgA nephropathy (the most common glomerular cause worldwide), thin basement membrane nephropathy, Alport syndrome, postinfectious glomerulonephritis, lupus nephritis, vasculitis.
• Non-glomerular: urologic malignancy, nephrolithiasis, urinary tract infection, benign prostatic hyperplasia, trauma, exercise, and papillary necrosis.

Risk-stratified evaluation of non-glomerular hematuria weights age, sex, smoking history, degree of hematuria and irritative symptoms. Anticoagulation does not explain hematuria and does not excuse a patient from evaluation — hematuria on an anticoagulant frequently unmasks an underlying lesion.

Papillary necrosis — sloughed papillae causing hematuria, flank pain and occasionally obstruction — occurs in sickle cell disease or trait, analgesic nephropathy, diabetes, pyelonephritis and urinary obstruction.

2. Tubulointerstitial Disease

A separately named blueprint subsection covering disease of the tubules and interstitium rather than of glomeruli or vessels.

Acute interstitial nephritis is most often drug-induced. Culprits include proton pump inhibitors (an increasingly common and easily missed cause), NSAIDs, beta-lactams, sulfonamides, fluoroquinolones, rifampin, allopurinol and checkpoint inhibitors. The classic triad of fever, rash and eosinophilia is present in only a minority, so its absence does not exclude the diagnosis. Urinalysis shows white cells, white cell casts and sterile pyuria; urine eosinophils are neither sensitive nor specific. Withdrawal of the offending drug is the primary treatment, with corticosteroids considered if creatinine does not improve.

Chronic tubulointerstitial disease presents insidiously with a bland urine sediment, modest proteinuria, and tubular dysfunction disproportionate to the reduction in filtration — concentrating defects with polyuria and nocturia, renal tubular acidosis, and salt wasting. Causes include chronic obstruction, reflux nephropathy, analgesic nephropathy, lithium, calcineurin inhibitors, heavy metals (lead, cadmium), sarcoidosis, Sjogren syndrome, myeloma cast nephropathy and hyperuricemia or hypercalcemia.

Lithium deserves particular mention: it causes nephrogenic diabetes insipidus and chronic tubulointerstitial disease, and amiloride is the agent used to counteract the concentrating defect.

3. Cystic Kidney Disease

Autosomal dominant polycystic kidney disease

The most common inherited kidney disease, from PKD1 (earlier failure) or PKD2 mutation.

Renal features: progressive bilateral cyst growth with kidney enlargement, flank pain, hematuria from cyst hemorrhage, cyst infection, nephrolithiasis (uric acid and calcium oxalate), hypertension (early and nearly universal), and progression to kidney failure typically in middle age.

Extrarenal manifestations are what exam items target:

Management: rigorous blood pressure control with renin-angiotensin blockade, high fluid intake, avoidance of nephrotoxins, and tolvaptan for rapidly progressive disease, which slows the decline in glomerular filtration rate at the cost of aquaresis and hepatotoxicity risk requiring liver enzyme monitoring.

Other cystic diseases: medullary sponge kidney (benign, associated with stones and hematuria), autosomal dominant tubulointerstitial kidney disease (formerly medullary cystic disease, with bland sediment and slow progression), and acquired cystic disease of dialysis, which carries an increased risk of renal cell carcinoma.

4. Obstructive Uropathy

An enumerated blueprint topic and one of the few fully reversible causes of kidney failure — but only if identified early, because prolonged obstruction produces permanent injury.

When to suspect it:

• Anuria, or fluctuating urine output alternating between anuria and polyuria — highly suggestive of intermittent complete obstruction
• Acute kidney injury with no other explanation
• Known malignancy, retroperitoneal disease, prior pelvic radiation, or stone disease
• Bilateral hydronephrosis on imaging

Remember that bilateral obstruction, or obstruction of a solitary kidney, is required to raise the creatinine. A unilateral obstructed kidney with a normal contralateral kidney produces a normal creatinine, which is why unilateral obstruction can be silent until the kidney is lost.

Causes:

Ultrasonography is the initial test, though hydronephrosis may be absent very early or when the ureters are encased by tumor or fibrosis. CT identifies the level and cause.

Treatment is decompression — bladder catheter for outlet obstruction, ureteral stent or percutaneous nephrostomy for ureteral obstruction. Two post-relief phenomena to anticipate:

• Post-obstructive diuresis — a large solute and water diuresis after relief of prolonged bilateral obstruction. Monitor volume status and electrolytes and replace judiciously; over-replacement perpetuates the diuresis.
• Hematuria and hypotension after rapid bladder decompression, which is why gradual drainage of a very distended bladder is often advised.

Retroperitoneal fibrosis presents with medial ureteral deviation and obstruction, and may be idiopathic, IgG4-related, drug-associated (methysergide, ergot derivatives) or secondary to malignancy or aortic disease.

5. Diabetic Nephropathy

Enumerated under other kidney disorders and the leading cause of end-stage kidney disease in the United States.

Natural history: glomerular hyperfiltration, then moderately increased albuminuria (formerly microalbuminuria), then severely increased albuminuria with declining filtration rate, then kidney failure. Screening is by urine albumin-to-creatinine ratio annually, confirmed on repeat because exercise, fever, infection, heart failure and marked hyperglycemia transiently raise albumin excretion.

Diabetic retinopathy usually accompanies diabetic nephropathy in type 1 diabetes. Its absence, or the presence of an active urinary sediment, rapidly declining function, or nephrotic syndrome of abrupt onset, should prompt consideration of a non-diabetic cause and possible biopsy.

Treatment combines glycemic control, blood pressure control, renin-angiotensin blockade for albuminuria, SGLT2 inhibition, and a non-steroidal mineralocorticoid receptor antagonist such as finerenone for residual albuminuria — a combination that now defines cardiorenal protection in type 2 diabetes.

6. Renal Vein Thrombosis

An enumerated topic presenting with flank pain, gross hematuria, a sudden increase in proteinuria and worsening kidney function. It is strongly associated with membranous nephropathy and other nephrotic states, in which urinary loss of antithrombin and other regulatory proteins produces a hypercoagulable state. Other causes include malignancy (particularly renal cell carcinoma with tumor thrombus), trauma and hypercoagulable disorders. Diagnosis is by CT or MR venography, and treatment is anticoagulation.