Calcium excretion > 250 mg/d in women and >300 mg/d in men is defined as hypercalciuria, as shown in Table 1
. It is important to note that the reference values listed in Table 1
are continuous rather than fixed variables, and stone risk can be increased even with values in the “normal” range. Urinary calcium amplifies the ionic activity of crystallizing calcium salts and binds stone inhibitors such as urinary citrate. Hypercalciuria can occur secondary to an underlying systemic disorder such as primary hyperparathyroidism, sarcoidosis, malignant neoplasm, Cushing syndrome, distal RTA, or vitamin D excess. Hence, when approaching a patient with calcium stones, a treatable underlying disease must be excluded. When plasma calcium level is elevated, it is imperative to measure parathyroid hormone and 25-hydroxyvitamin D as part of the stone evaluation. Rare monogenetic disorders such as Dent disease or mutations of the calcium-sensing receptor similarly present with hypercalciuria.
Table 1Reference Values for Lithogenic and Protective Substances in a 24-Hour Urine Sample
In the vast majority of patients, no specific cause for hypercalciuria can be identified, and it is referred to as idiopathic hypercalciuria. Idiopathic hypercalciuria comprises a variety of physiologic defects that lead to the same “symptom,” namely hypercalciuria. It is frequently observed among young and middle-aged men and is associated with higher risk for hypertension, obesity, and osteopenia. Whereas no single cause for this phenomenon has been identified, several features mimicking tissue vitamin D activation have been described, such as increased intestinal calcium absorption and bone mineral mobilization.
There are 2 main sources of urinary oxalate in humans: endogenous oxalate production and exogenous oxalate absorption. The kidney is responsible for oxalate excretion. Oxalate enters the proximal tubule through filtration and secretion. Hyperoxaluria is present in 10% to 50% of calcium stone formers and defined as urinary oxalate excretion > 40 mg/d. Elevated urinary oxalate excretion increases supersaturation, risk for crystal formation, and tubular damage.
Primary hyperoxalurias are autosomal recessive disorders that lead to oxalate overproduction in the liver secondary to defects in glyoxylate metabolism. Currently, primary hyperoxaluria types I, II, and III have been described, with type I being the most common. Primary hyperoxaluria is associated with recurrent kidney stones, progressive nephrocalcinosis, and end-stage renal disease. As kidney disease ensues and oxalate is not sufficiently excreted by the kidney (glomerular filtration rate < 30-40 mL/min/1.73 m2), plasma oxalate levels increase and patients are at risk for systemic oxalosis, characterized by oxalate deposition in heart, bone, retina, and skin.
In addition to endogenous oxalate production, dietary oxalate is absorbed by passive and paracellular transport across the tight junctions of the intestine, mainly in the colon. Foods high in oxalate include spinach, rhubarb, beetroot, cocoa, and iced tea. Similarly, vitamin C is metabolized to oxalate, and increased supplementation has been shown to increase hyperoxaluria and stone risk.
Fat malabsorption observed in patients with chronic inflammatory bowel disease, cystic fibrosis, chronic pancreatic insufficiency, and biliary cirrhosis and with certain medications (eg, the lipase inhibitor orlistat) increases free fatty acids that bind calcium in the intestinal lumen and impair calcium from binding oxalate. This in turn increases the amount of soluble oxalate available for intestinal absorption. Fatty acids and unabsorbed bile salts have also been shown to increase the colonic mucosal permeability of oxalate. Furthermore, colonization of the intestinal tract with Oxalobacter formigenes, a bacterial species using oxalate as an energy source, reduces intestinal oxalate absorption and hyperoxaluria. Following bariatric surgery or frequent antibiotic treatment, colonization with O. formigenes is reduced, increasing the amount of oxalate available for absorption. Therefore, the conditions described foster calcium oxalate stone formation.
Citric acid is a tricarboxylic acid that mostly stems from endogenous oxidative metabolism. It is freely filtered through the glomerulus and, in contrast to oxalic acid, actively reabsorbed in the proximal tubule. Hypocitraturia is associated with calcium nephrolithiasis in 20% to 60% of all cases. It is defined by citrate concentration < 325 mg/d. Citrate inhibits stone formation by complexing with calcium in urine, reducing spontaneous nucleation, and preventing agglomeration of crystals. Acid-base balance is the key determinant of tubular citrate reabsorption; acidosis and hypokalemia increase the demand of citrate as a bicarbonate source and as a consequence, reduce urinary citrate concentration. Hence, systemic acid-base status, serum potassium level, and urine pH have profound effects on risk for stone formation. Several clinical settings that are associated with metabolic acidosis can therefore cause hypocitraturia: chronic diarrhea, high protein intake, and RTA. Hypocitraturia can be treated with alkali (bicarbonate or citrate); because sodium load is a risk factor for kidney stones itself, potassium-containing alkali products are preferred.
Hyperuricosuria is detected in 10% of all calcium stone formers and defined as uric acid excretion > 750 mg/d in women or >800 mg/d in men. Hyperuricosuria decreases the solubility of calcium oxalate and may promote calcium oxalate crystallization. However, Curhan et al could not demonstrate a correlation between higher urine uric acid excretion and risk for calcium oxalate stone formation in a cross-sectional study of more than 3,000 participants.