Nephrolithiasis
Seth Goldberg
General Principles
Kidney stones are crystalline structures in the urinary tract that have achieved sufficient size to cause symptoms or be visible by radiographic imaging techniques.
Most kidney stones in Western countries are composed of calcium salts and occur in the upper urinary tract. Conversely, in developing countries, most stones are composed of uric acid and occur in the urinary bladder. Dietary factors likely account for this difference, with Western diets high in protein and sodium.
The immense economic impact of kidney stones includes loss of productivity and emergency department visits, in addition to surgical extraction or fragmentation of stones and the need for preventive treatment.
Stone formation is associated with increased risk of chronic kidney disease.1
Classification
As specific therapeutic maneuvers depend upon the chemical composition of a patient’s kidney stone, extracted or passed stones should be collected and submitted for analysis.
Calcium salts: In Western societies, about 80% of all kidney stones are composed of calcium salts. While a majority of these are of mixed composition (calcium oxalate and calcium phosphate), stones of pure calcium oxalate or calcium phosphate are observed and should prompt a search for an underlying metabolic risk factor.
Uric acid stones: These account for approximately 10% of all stones in the urinary tract, and are notable for their radiolucency and insolubility in acidic urine.
Struvite stones: These are also described as triple phosphate or magnesium-ammonium-phosphate and frequently form a staghorn configuration. They account for approximately 10% of all kidney stones and are associated with an alkaline urine in the setting of urea-splitting bacteria and urinary tract infections (UTIs).
Cystine stones: The hereditary disorder cystinuria (not to be confused with cystinosis) accounts for less than 1% of all stones. Cystinuria is characterized by an amino acid transport defect in the proximal tubule, resulting in a urinary loss of dibasic amino acids.
Other: Rarely, stones can be formed by poorly soluble drugs (e.g., triamterene, indinavir, sulfonamide), xanthine, hypoxanthine, or ammonium urate.
Epidemiology
Nephrolithiasis is one of the most common diseases in Western countries, with an incidence that is increasing.
The peak age of onset is the third decade, with increasing prevalence until the age of 70 years. In women, there is a second peak at the age of 55 years.
Lifetime risk of developing a kidney stone is 12% for men and 6% for women. Historically, men have had a two to three times greater risk than women.2
More recently, an increasing rate of nephrolithiasis has been attributed to larger body mass index. This effect appears to be magnified in women.3
Pathophysiology
One can infer from the variety of stones observed that several pathophysiologic mechanisms are responsible for stone formation. Nevertheless, a common pathway leading to stone formation is urinary supersaturation. Crystals form when the amount of solute in the urine exceeds its solubility limits.
Stone Formation
Three steps are necessary to form a stone:
Formation of a small initial crystal, or nidus.
Retention of a nidus in the urinary tract. If washed away by urine flow, crystal formation would remain a mere physiologic curiosity.
Growth of a nidus to a size at which it either becomes symptomatic or visible by imaging.
Solubility
Solubility product: This describes the level of a solution’s saturation with solute at which solid-phase material exists in equilibrium with liquid-phase material. The concentration of lithogenic solutes, stone inhibitors, and urine pH may all contribute to the solubility product.
Urine pH: Urinary pH has a variable effect depending on the solutes involved.
Low urine pH significantly decreases the solubility of uric acid and cystine stones, contributing substantially to the risk of formation. In the case of uric acid stones, a urinary pH below 5.3 is more relevant as a risk factor than the actual amount of uric acid excretion.
High urine pH significantly decreases the solubility of calcium phosphate and struvite stones, with an increased risk of formation above a urine pH of 6.7 to 7.0. Struvite stones are more commonly associated with the presence of a UTI caused by urea-splitting bacteria.
Inhibitors of crystallization: Several compounds are protective against stone formation.
Citrate, the primary inhibitor of crystallization of calcium salts, complexes with calcium to form a soluble calcium citrate compound. By doing so, it makes less calcium available to precipitate out as calcium oxalate or calcium phosphate. Hypocitraturia is a common finding among calcium stone formers, particularly when associated with a distal renal tubular acidosis (RTA).
Magnesium also inhibits crystallization of calcium salts, although its effect is not as significant as that of citrate.
Risk Factors
Risk Factors for Calcium Oxalate Nephrolithiasis
Low urinary volume: As with all stone types, a low urine flow rate increases the risk of stone retention and growth. The commonly accepted threshold is 2 L/day although large randomized controlled trials have not definitively defined the optimum daily urine output.
Hypercalciuria: To understand how hypercalciuria may occur, it is important to consider the normal handling of calcium.
Over 99% of the body’s calcium is stored in the bone, with the serum concentration tightly regulated by parathyroid hormone (PTH). Dietary fluctuations and gastrointestinal (GI) absorption of calcium will result in the appropriate changes to the PTH level to ensure a steady serum concentration. Thus, calcium ingestion alone is rarely a cause of hypercalcemia or hypercalciuria. Instead, hypercalciuria (>200 to 250 mg/day) is frequently idiopathic and not associated with concomitant elevations in serum calcium. Recent genetic studies have suggested
a role for claudins, which regulate the paracellular reabsorption of calcium within the nephron.4
TABLE 16-1 DIFFERENTIAL DIAGNOSIS OF HYPERCALCIURIA
Normal serum calcium
Idiopathic hypercalciuria
PTH-dependent elevated serum calcium
Primary hyperparathyroidism: adenoma or hyperplasia
PTH-independent elevated serum calcium
Malignancy: squamous cell carcinoma, breast cancer, bladder cancer, multiple myeloma, lymphoma
Granulomatous disease: sarcoidosis, tuberculosis, berylliosis
Hypervitaminosis D
Hyperthyroidism
PTH, parathyroid hormone.
Nonetheless, conditions of increased bone turnover (i.e., hyperparathyroidism, metabolic acidosis) can shunt calcium from the skeleton to the urinary tract and should be sought in the evaluation of a patient with calcium-based stones. A number of disease processes can result in hypercalciuria (Table 16-1).
Calcium excretion is influenced by dietary sodium intake. Excessive sodium intake leads to extracellular volume expansion and diminished sodium resorption along the nephron. Volume expansion results not only in natriuresis but also in calciuresis. Hence, dietary salt restriction can be an effective method of ameliorating hypercalciuria.
Thiazide diuretics reduce hypercalciuria by increasing calcium resorption at the distal tubule, indirectly through the calcium-selective apical transient receptor potential cation channel subfamily V member 5 (TRPV5) channel. Thiazides, through their diuretic action, also cause a reduction in the extracellular fluid volume, leading to enhanced proximal reabsorption of calcium.
Hyperoxaluria is divided into dietary, enteric, or primary forms (Table 16-2).
Dietary hyperoxaluria: Normal daily urinary excretion of oxalate is <40 mg/day. Excessive dietary intake of oxalate-rich foods can result in a mild form of dietary hyperoxaluria (urinary oxalate excretion of 50 to 60 mg/day). Oxalate-rich foods include nuts, sunflower seeds, spinach, rhubarb, chocolate, Swiss chard, lime peel, star fruit, peppers, and tea. Intake of vitamin C exceeding 100 mg/day can cause hyperoxaluria due to its conversion to oxalate.
Enteric hyperoxaluria: Fat malabsorption and saponification of calcium in the gut by free fatty acids result in increased free oxalate and its absorption in the colon. The resultant hyperoxaluria is more severe than the dietary form (often exceeding 100 mg/day). Thus, small bowel resection, jejunal bypass surgery, and inflammatory bowel disorders can lead to calcium oxalate nephrolithiasis, and even chronic renal failure due to nephrocalcinosis. In addition to hyperoxaluria, malabsorption has several other consequences that predispose to stone formation, including low urine volumes due to diarrheal loss of water, hypomagnesemia due to magnesium malabsorption, and hypocitraturia due to chronic metabolic acidosis and hypokalemia.
Primary hyperoxaluria: Primary forms of hyperoxaluria result from well-described metabolic defects.5 These are characterized by excessive endogenous production of oxalate, resulting in profound hyperoxaluria (135 to 270 mg/day). Stone
formation often begins in childhood. Deposition of calcium oxalate in the tubulointerstitial compartment of the kidneys (renal oxalosis) often leads to progressive loss of renal function. Deposition of calcium oxalate also occurs in the heart, bone, joints, eyes, and other tissues. Two major defects are worth mentioning:
TABLE 16-2 CAUSES OF HYPEROXALURIA
Dietary Hyperoxaluria
Enteric Hyperoxaluria
Primary Hyperoxaluria
Cause: excessive dietary oxalate intake
Foods rich in oxalate: cocoa, chocolate, black tea, green beans, beets, celery, green onions, spinach, rhubarb, Swiss chard, mustard greens, berries, dried figs, orange and lemon peel, summer squash, nuts, peanut butter
Mild elevation in urinary oxalate excretion, with increased risk of calcium oxalate nephrolithiasis
Causes: small bowel malabsorption, Crohn disease, jejunoileal bypass, celiac sprue, short bowel syndrome, chronic pancreatitis, biliary obstruction
Moderate-to-severe elevation of urinary oxalate excretion; may result in nephrocalcinosis and renal failure
Type I: deficiency of alanine glyoxylate aminotransferase
Type II: D-glycerate dehydrogenase or glyoxylate reductase deficiency
Severe hyperoxaluria, resulting in nephrocalcinosis and renal failure
Type I primary hyperoxaluria is an autosomal-recessive disorder that results from reduced activity of hepatic peroxisomal alanine glyoxylate aminotransferase. This increases the availability of glyoxylate, which is irreversibly converted to oxalic acid. Liver transplantation may ultimately be required to replace the missing enzyme.
Type II primary hyperoxaluria is a much rarer form of the disease, caused by D-glycerate dehydrogenase or glyoxylate reductase deficiency.
Hypocitraturia: This is defined as a urinary citrate excretion <250 to 500 mg/day. It is observed in over 40% of patients with nephrolithiasis.
The presence of hypocitraturia should arouse suspicion of a disorder associated with chronic metabolic acidosis, such as distal RTA or a GI disorder.
Hypocitraturia can also be seen in the setting of hypokalemia or with the use of carbonic anhydrase inhibitors such as topiramate.
Hyperuricosuria: This is seen in up to a quarter of calcium stone formers defined as a urinary uric acid excretion >750 mg/day. Although the stone is not primarily composed of uric acid, this chemical can form the nidus upon which the calcium oxalate builds.
The amount of uric acid in the urine is determined by daily production of uric acid and is not necessarily associated with hyperuricemia or gout. High intake of animal proteins or other purine-rich foods or beverages (alcohol) can also lead to hyperuricosuria.Related posts:
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