What are the urinary keystones that predispose to nephrolithiasis and what is the recommended evaluation and management?

Urinary Risk Factors (Keystones) for Nephrolithiasis

The critical urinary keystones predisposing to nephrolithiasis are low urine volume, hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria, and abnormal urine pH—each requiring targeted evaluation through 24-hour urine collection and specific dietary or pharmacologic interventions based on stone composition. 1

Primary Urinary Risk Factors

Low Urine Volume

• Inadequate fluid intake resulting in urine output below 2 liters daily is the single most critical modifiable risk factor across all stone types. 1
• Concentrated urine increases supersaturation of all stone-forming salts, promoting crystallization regardless of stone composition. 1

Hypercalciuria

• Elevated urinary calcium excretion is the most common metabolic abnormality in recurrent stone formers, present in approximately 40-50% of calcium stone patients. 1
• Hypercalciuria increases calcium oxalate and calcium phosphate supersaturation, directly promoting stone nucleation and growth. 1

Hypocitraturia

• Low urinary citrate (typically <320 mg/day) removes a critical inhibitor of calcium stone formation. 1
• Citrate normally binds urinary calcium and inhibits crystal aggregation; its deficiency substantially increases stone risk. 1

Hyperoxaluria

• Elevated urinary oxalate (>40-45 mg/day) dramatically increases calcium oxalate supersaturation. 1
• Even modest increases in urinary oxalate have disproportionate effects on stone risk due to the low solubility of calcium oxalate. 1

Hyperuricosuria

• Elevated uric acid excretion (>800 mg/day in men, >750 mg/day in women) promotes calcium oxalate stone formation even without forming uric acid stones. 1
• Uric acid crystals can serve as a nidus for calcium oxalate crystallization through heterogeneous nucleation. 1

Abnormal Urine pH

• Persistently acidic urine (pH <5.5) is the primary driver of uric acid stone formation, more important than hyperuricosuria itself. 2, 3
• Alkaline urine (pH >6.5) promotes calcium phosphate stone formation and is characteristic of renal tubular acidosis type 1. 1

Recommended Evaluation

Initial Assessment

• Obtain stone analysis for all first-time stone formers to guide targeted therapy; stone composition dictates metabolic evaluation and treatment strategy. 2
• Perform 24-hour urine collection measuring volume, pH, calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine. 2
• Collect the 24-hour urine at least 6 weeks after an acute stone episode to avoid acute-phase alterations in urinary composition. 1

Serum Testing

• Measure serum calcium, phosphorus, parathyroid hormone, and creatinine to identify primary hyperparathyroidism and renal tubular acidosis. 1
• Check serum uric acid in patients with suspected gout or uric acid stones. 1

Follow-up Monitoring

• Repeat 24-hour urine collection within 6 months of treatment initiation to assess metabolic response to dietary or pharmacologic interventions. 2
• Continue annual 24-hour urine collections to monitor adherence and long-term metabolic control. 2

Management Strategy by Stone Type

Calcium Oxalate/Phosphate Stones (80% of all stones)

First-Line: Dietary Modification

• Increase fluid intake to achieve at least 2 liters of urine output daily—this intervention alone reduces stone recurrence by 55% (RR 0.45). 4
• Maintain normal dietary calcium intake of 1,000-1,200 mg/day; calcium restriction paradoxically increases stone risk by enhancing intestinal oxalate absorption. 2, 1
• Limit sodium intake to <2,300 mg/day, as high sodium increases urinary calcium excretion by reducing renal tubular calcium reabsorption. 1
• Reduce animal protein to <0.8-1.0 g/kg/day, as excessive protein generates sulfuric acid that increases urinary calcium and reduces citrate. 1
• Avoid sugar-sweetened beverages, particularly colas acidified with phosphoric acid (not citric acid). 1, 5

Second-Line: Pharmacologic Monotherapy

• For hypercalciuria: Thiazide diuretics (hydrochlorothiazide 50 mg daily or chlorthalidone 25-50 mg daily) reduce stone recurrence by 48% (RR 0.52). 4
• For hypocitraturia: Potassium citrate 30-60 mEq daily in divided doses reduces stone recurrence by 75% (RR 0.25). 4
• For hyperuricosuria: Allopurinol 300 mg daily reduces stone recurrence by 41% (RR 0.59), particularly effective in patients with baseline hyperuricemia or hyperuricosuria. 4
• Monotherapy is as effective as combination therapy and minimizes adverse effects; combination regimens offer no additional benefit. 4, 5

Uric Acid Stones (10% of stones)

Primary Treatment

• Urinary alkalinization with potassium citrate to achieve urine pH 6.0-6.5 is first-line therapy; most patients have low urinary pH rather than hyperuricosuria as the predominant risk factor. 2, 3
• Increase fluid intake to achieve 2 liters of urine output daily. 2
• Oral chemolysis with alkalinization (citrate or sodium bicarbonate to pH 7.0-7.2) can dissolve existing uric acid stones. 2

Adjunctive Measures

• Reduce purine intake by limiting red meat, organ meats, and seafood. 1
• Consider allopurinol 300 mg daily only if hyperuricosuria persists despite dietary modification and alkalinization. 2

Struvite (Infection) Stones

Definitive Management

• Complete surgical stone removal is mandatory, as residual fragments harbor bacteria and serve as a nidus for recurrent infection and stone growth. 4
• Struvite stones form from urinary tract infection with urease-producing organisms (Proteus, Klebsiella, Pseudomonas) that create alkaline urine and high ammonia concentrations. 4
• Bacteria reside within the stone matrix itself, making medical therapy alone ineffective. 4

Surgical Options

• Percutaneous nephrolithotomy (PNL) is first-line for staghorn calculi, offering superior stone-free rates compared to shock wave lithotripsy. 4
• Combination PNL and shock wave lithotripsy may be used for complex stones. 4
• Open surgery (anatrophic nephrolithotomy) is reserved for cases where minimally invasive approaches fail. 4

Cystine Stones (1-2% of stones)

Stepwise Approach

• Increase fluid intake to achieve 3-4 liters of urine output daily (higher than other stone types due to cystine's poor solubility). 2
• Restrict sodium to <2,000 mg/day and protein to <0.8 g/kg/day. 2
• Alkalinize urine with potassium citrate to achieve pH 7.0-7.5 (higher than for other stone types). 2
• If conservative measures fail, add thiol-binding agents (tiopronin or D-penicillamine), though these have significant adverse effects. 6

Monitoring for Adverse Effects

Thiazide Diuretics

• Monitor serum potassium for hypokalemia (most common adverse effect). 2
• Check fasting glucose periodically for glucose intolerance. 2
• Assess serum uric acid, as thiazides can precipitate gout. 2

Potassium Citrate

• Monitor serum potassium for hyperkalemia, particularly in patients with chronic kidney disease or those taking ACE inhibitors/ARBs. 2
• Gastrointestinal upset is common; use wax-matrix formulations to improve tolerance. 2

Allopurinol

• Check liver enzymes at baseline and periodically, as hepatotoxicity can occur. 2
• Screen for allopurinol hypersensitivity syndrome (rare but potentially fatal), especially in patients with HLA-B*5801 allele. 2

Common Pitfalls to Avoid

• Do not restrict dietary calcium—this increases intestinal oxalate absorption and worsens stone risk while promoting osteoporosis. 2, 1
• Do not assume stone passage after dietary changes indicates treatment failure; distinguish pre-existing stone passage from new stone formation. 1
• Do not rely on Hounsfield units alone to guide medical management without metabolic evaluation via 24-hour urine collection. 2
• Do not use combination pharmacologic therapy as initial treatment; monotherapy is equally effective with fewer adverse effects. 4, 5
• Do not obtain 24-hour urine collection during or immediately after an acute stone episode; wait at least 6 weeks for accurate baseline assessment. 1