Residency · Residency · Nephrology

Nephrolithiasis

Introduction

Nephrolithiasis affects 10 to 15 percent of men and 5 to 7 percent of women over a lifetime, with prevalence increasing globally in parallel with the obesity epidemic. Without preventive therapy, the recurrence rate is approximately 50 percent within 5 to 10 years. The most common stone compositions are calcium oxalate at 70 to 80 percent, calcium phosphate at 10 to 15 percent, uric acid at 5 to 10 percent, struvite at 5 to 10 percent, and cystine at 1 to 2 percent. Nephrolithiasis is not merely a urologic condition; it is associated with increased cardiovascular disease risk, chronic kidney disease, and bone disease, underscoring the systemic implications of recurrent stone formation.

Stone Composition and Pathogenesis

Calcium Oxalate Stones (Most Common)

Calcium oxalate stones exist in two crystalline forms: monohydrate (whewellite), which is smooth and dark with a greater tendency to adhere to the renal papilla through Randall's plaque, and dihydrate (weddellite), which has a characteristic bipyramidal "envelope" shape and is more likely to form from supersaturation. The Randall's plaque hypothesis proposes that interstitial calcium phosphate (apatite) deposits form in the renal papilla, erode through the papillary surface, and serve as a nidus for calcium oxalate crystallization. Risk factors for calcium oxalate stone formation include hypercalciuria, hyperoxaluria, hypocitraturia, low urine volume, and hyperuricosuria.

Calcium Phosphate Stones

Calcium phosphate stones include brushite (calcium hydrogen phosphate) and apatite (hydroxyapatite) forms. These stones preferentially form in alkaline urine with a pH above 6.5. They are associated with distal renal tubular acidosis (type 1), primary hyperparathyroidism, and medullary sponge kidney. Calcium phosphate frequently coexists with calcium oxalate in mixed stone compositions.

Uric Acid Stones

Uric acid stones form in acidic urine with a pH below 5.5, as uric acid is insoluble at low pH values. Risk factors include metabolic syndrome and insulin resistance, which decrease renal ammoniagenesis leading to chronically low urine pH, gout, myeloproliferative disorders, chronic diarrhea causing bicarbonate loss and acidic urine, and high purine dietary intake. Uric acid stones are radiolucent on plain X-ray but visible on CT. A critically important clinical feature is that uric acid stones can be dissolved medically through urine alkalinization with potassium citrate, targeting a urine pH of 6.0 to 6.5, making surgery rarely necessary for this stone type.

Struvite (Magnesium Ammonium Phosphate) Stones

Struvite stones are infection stones that form in alkaline urine produced by urease-producing organisms. The responsible organisms include Proteus (the most common), Klebsiella, Pseudomonas, Staphylococcus saprophyticus, Ureaplasma, and Corynebacterium. Urease cleaves urea into ammonia and carbon dioxide, raising the urine pH above 7.5 and creating conditions for supersaturation with magnesium ammonium phosphate. Struvite stones can grow rapidly into staghorn calculi, large branching stones that fill the renal pelvis and calyces. Treatment requires complete surgical removal, typically by percutaneous nephrolithotomy, combined with eradication of the underlying infection. Acetohydroxamic acid, a urease inhibitor, can be used for recurrent or residual disease.

Cystine Stones

Cystinuria is an autosomal recessive disorder resulting from mutations in SLC3A1 (type A) or SLC7A9 (type B), which impair proximal tubular reabsorption of the dibasic amino acids cystine, ornithine, lysine, and arginine (remembered by the mnemonic COLA). Cystine is poorly soluble and crystallizes when urine cystine concentrations exceed 250 mg/L. Hexagonal crystals on urinalysis are pathognomonic. The disease typically presents in childhood or adolescence with recurrent bilateral stones. Treatment requires massive hydration exceeding 3 liters per day, urine alkalinization with potassium citrate targeting a pH above 7.0, and thiol-binding agents such as tiopronin (preferred) or D-penicillamine, which reduce cystine to more soluble disulfide compounds.

<image>Visual guide to stone composition showing five panels, each with the stone's gross appearance, crystal morphology under microscopy, and radiographic characteristics. Panel 1: Calcium oxalate - dark brown/black spiculated stone; envelope-shaped (dihydrate) or dumbbell-shaped (monohydrate) crystals; radiopaque on X-ray. Panel 2: Calcium phosphate - smooth white/gray stone; amorphous or rosette crystals; radiopaque. Panel 3: Uric acid - smooth yellow-orange stone; rhomboid or rosette crystals; radiolucent on X-ray (visible on CT). Panel 4: Struvite - large brown/yellow staghorn calculus filling renal pelvis; "coffin lid" rectangular crystals; moderately radiopaque. Panel 5: Cystine - waxy yellow-green stone; hexagonal crystals (pathognomonic); faintly radiopaque. Include urine pH range favoring each stone type.</image>

Clinical Presentation and Diagnosis

Acute Renal Colic

Acute renal colic presents with sudden onset of severe flank pain radiating to the groin and lower abdomen, following the course of the ureter. The pain results from ureteral obstruction causing capsular distension rather than from the movement of the stone itself. Associated symptoms include nausea, vomiting, hematuria in 85 to 90 percent of cases, and urinary frequency and urgency with distal ureteral stones. The differential diagnosis includes pyelonephritis, appendicitis, ectopic pregnancy, ovarian torsion, abdominal aortic aneurysm, and musculoskeletal pain.

Imaging

Non-contrast CT of the abdomen and pelvis is the gold standard for kidney stone evaluation, with a sensitivity of 95 to 97 percent and specificity of 96 to 98 percent. It identifies all stone types and assesses for obstruction. Renal ultrasound is the first-line imaging modality in pregnancy and children, detecting hydronephrosis with a sensitivity of 45 to 60 percent for direct stone visualization. KUB X-ray has limited sensitivity but is useful for monitoring radiopaque stone burden and treatment response. Dual-energy CT represents an emerging technology that can differentiate uric acid from calcium stones in vivo, determining chemical composition without the need for stone retrieval.

Laboratory Evaluation

During an acute episode, evaluation should include a basic metabolic panel for creatinine, potassium, and calcium; a complete blood count; urinalysis with microscopy; and urine culture. Stone analysis by infrared spectroscopy or X-ray diffraction is essential for every first-time stone former, as it directs the subsequent metabolic evaluation and prevention strategy. A comprehensive metabolic evaluation with 24-hour urine collection is recommended for recurrent stone formers and first-time formers with high-risk features including bilateral stones, family history, non-calcium stones, CKD, solitary kidney, or pediatric presentation. The 24-hour urine should measure volume, calcium, oxalate, citrate, uric acid, sodium, potassium, creatinine, pH, and cystine when suspected. Serum testing should include calcium, phosphorus, PTH if hypercalcemia is present, uric acid, and bicarbonate. The evaluation should be performed on the patient's habitual diet, at least 6 weeks after the acute episode.

Metabolic Risk Factors and Treatment

Hypercalciuria (Most Common Metabolic Abnormality)

Hypercalciuria is defined as urinary calcium excretion exceeding 250 mg/day in women, 300 mg/day in men, or 4 mg/kg/day. Absorptive hypercalciuria, resulting from increased intestinal calcium absorption, is the most common form and is usually idiopathic, though vitamin D excess can contribute. Renal hypercalciuria from a primary renal calcium leak is less common. Resorptive hypercalciuria from primary hyperparathyroidism should be suspected in any hypercalcemic stone former, prompting PTH measurement. Treatment includes thiazide diuretics, with hydrochlorothiazide 25 to 50 mg/day, chlorthalidone 25 mg/day, or indapamide 2.5 mg/day, which increase distal tubular calcium reabsorption and have been shown in randomized controlled trials to reduce recurrent calcium stones by 50 percent. Dietary sodium restriction to less than 2 grams per day is important because urinary calcium excretion parallels urinary sodium. A counterintuitive but essential principle is that adequate dietary calcium intake of 1000 to 1200 mg per day from dietary sources, not supplements, should be maintained, as low calcium diets paradoxically increase oxalate absorption and stone risk.

Hyperoxaluria

Primary hyperoxaluria is a group of rare autosomal recessive disorders including type 1 from AGT deficiency, type 2 from GR/HPR deficiency, and type 3 from HOGA1 mutations. Primary hyperoxaluria type 1 is now treated with lumasiran, an siRNA targeting glycolate oxidase that reduces hepatic oxalate production and has received FDA approval, as well as nedosiran, an siRNA targeting LDH also FDA-approved for PH1. Enteric hyperoxaluria occurs in fat malabsorption states such as Crohn disease, following bariatric surgery, or in chronic pancreatitis, where free fatty acids bind calcium in the gut, leaving increased free oxalate available for absorption in the colon. Treatment includes calcium supplementation with meals to bind oxalate in the gut, cholestyramine, and a low-fat, low-oxalate diet. Dietary hyperoxaluria results from excessive intake of high-oxalate foods including spinach, rhubarb, nuts, chocolate, tea, and beets. Ethylene glycol poisoning causes acute oxalate nephropathy.

Hypocitraturia

Citrate is a critical inhibitor of calcium stone formation, functioning by chelating calcium and inhibiting crystal growth. Hypocitraturia is defined as urinary citrate below 320 mg/day. Causes include chronic metabolic acidosis from renal tubular acidosis or chronic diarrhea, hypokalemia, high animal protein diet, and ACE inhibitor/ARB use which causes a mild reduction. Treatment consists of potassium citrate at 20 to 30 mEq twice or three times daily, which raises both urine citrate and urine pH. Lemonade therapy with approximately 120 mL of lemon juice per day diluted in water is an adjunctive measure but is less effective than potassium citrate supplementation.

Low Urine Volume

Increasing urine volume is the single most important and simplest intervention for stone prevention. The target is urine output exceeding 2.5 liters per day with a urine specific gravity below 1.010. Increased fluid intake reduces supersaturation of all stone-forming salts regardless of composition. Water is the preferred fluid; citrus beverages provide additional benefit, while sugar-sweetened beverages should be minimized.

Hyperuricosuria

Hyperuricosuria, defined as exceeding 800 mg/day in men or 750 mg/day in women, promotes calcium oxalate stone formation through heterogeneous nucleation, in which uric acid crystals serve as a nidus for calcium oxalate crystallization. Treatment with allopurinol at 300 mg/day has been shown in the Ettinger trial to reduce calcium oxalate stone recurrence specifically in hyperuricosuric calcium stone formers.

<image>Comprehensive metabolic evaluation and treatment algorithm for recurrent calcium nephrolithiasis. Start with 24-hour urine collection results. Show parallel evaluation pathways for each metabolic abnormality: (1) Low volume (<2 L/day) → increase fluid intake to >2.5 L/day. (2) Hypercalciuria (>300 mg/day men, >250 women) → dietary sodium restriction (<2 g/day), adequate dietary calcium (1000-1200 mg/day), thiazide diuretic if persistent. (3) Hyperoxaluria (>40 mg/day) → dietary oxalate restriction, calcium with meals (enteric), evaluation for primary hyperoxaluria if severe (>80 mg/day). (4) Hypocitraturia (<320 mg/day) → potassium citrate 20-30 mEq BID-TID, reduce animal protein. (5) Hyperuricosuria (>800 mg/day men) → dietary purine restriction, allopurinol. (6) Low urine pH (<5.5) → potassium citrate to raise pH. Include monitoring: repeat 24-hour urine in 3-6 months to assess response. Show target values for each parameter.</image>

Surgical Management

Conservative Management

Ureteral stones smaller than 5 mm have a spontaneous passage rate of 68 to 98 percent. Stones measuring 5 to 10 mm pass spontaneously in approximately 47 percent of cases, and medical expulsive therapy may be beneficial. Medical expulsive therapy with tamsulosin 0.4 mg daily or nifedipine 30 mg daily provides the most benefit for distal ureteral stones measuring 5 to 10 mm, with a number needed to treat of approximately 4 to 5. Pain management should employ NSAIDs, particularly ketorolac, as first-line therapy because they reduce ureteral spasm and inflammation, with opioids reserved for breakthrough pain. Urgent intervention is required for concurrent urinary tract infection with obstruction due to urosepsis risk, AKI, a solitary kidney, bilateral obstruction, or intractable pain and vomiting.

Interventional Options

Shock wave lithotripsy is a non-invasive option for stones smaller than 2 cm located in the renal pelvis or upper ureter. It is contraindicated in pregnancy, with anticoagulation, and in the presence of aortic or renal artery aneurysms, and is less effective for cystine and calcium oxalate monohydrate stones due to their hardness. Ureteroscopy with flexible ureteroscope and laser lithotripsy using holmium or thulium lasers is preferred for distal and mid-ureteral stones and is excellent for stones up to 1.5 to 2 cm. Percutaneous nephrolithotomy is the preferred approach for large stones exceeding 2 cm and staghorn calculi, requiring nephrostomy tract access with a higher complication rate including bleeding and renal injury. Combination therapy with PCNL followed by SWL or URS may be necessary for complex staghorn calculi.

Key Clinical Pearls

• Stone analysis is essential for every stone episode; it directs metabolic evaluation and prevention strategy
• Dietary calcium RESTRICTION increases calcium oxalate stone risk by increasing free oxalate absorption; recommend adequate dietary calcium (1000-1200 mg/day) consumed WITH meals
• Potassium citrate is the single most versatile medical therapy: it raises urine citrate (inhibitor), raises urine pH (dissolves uric acid stones, treats RTA), and provides potassium (corrects hypokalemia-induced hypocitraturia)
• Uric acid stones can be dissolved medically with urine alkalinization alone (target pH 6.0-6.5); surgery is rarely needed
• A stone former presenting with recurrent UTIs and alkaline urine (pH >7.5) should raise suspicion for struvite stones and urease-producing organisms

References

1. Zisman AL, Evan AP, Coe FL, Worcester EM. Do Kidney Stone Formers Have a Kidney Disease? Kidney Int. 2015;88(6):1240-1249.
2. Pearle MS, Goldfarb DS, Assimos DG, et al. Medical Management of Kidney Stones: AUA Guideline. J Urol. 2014;192(2):316-324.
3. Borghi L, Schianchi T, Meschi T, et al. Comparison of Two Diets for the Prevention of Recurrent Stones in Idiopathic Hypercalciuria. N Engl J Med. 2002;346(2):77-84.
4. Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med. 2021;384(13):1216-1226.
5. Coe FL, Evan A, Worcester E. Kidney Stone Disease. J Clin Invest. 2005;115(10):2598-2608.

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