Increased parathyroid hormone (PTH) secretion is usually from benign adenoma of one or more parathyroid glands or hyperplasia of two or more glands. All of the manifestations of primary hyperparathyroidism can be accounted for by exaggeration of the physiological effects of parathyroid hormone on kidney and bone. These effects result in intestinal calcium hyperabsorption, increased bone turnover, low bone mass, hypercalcemia, hypercalciuria, hypophosphatemia and calcium oxalate or calcium phosphate stone formation. The diagnosis rests on demonstration of hypercalcemia and an elevation of PTH by radioimmunoassay. Current assays measure intact PTH and will differentiate primary hyperparathyroidism from other causes of hypercalcemia in 95% of cases (Table 4). Five percent of patients have PTH that is not frankly elevated but is inappropriately high for the prevailing elevated serum calcium. Urine calcium is high in most patients.

Primary hyperparathyroidism is the second most common cause of calcium kidney stones, and contributes from three to 13 percent of all stone formers (9). Metabolic disturbances that predispose to stone formation include hypercalciuria, hyperphosphaturia, and alkaline urine. Excess PTH inhibits tubule bicarbonate reabsorption with resultant urine pH above 6.5. This alkaline urine and the excess urine phosphate increase urine supersaturation for both calcium oxalate and calcium phosphate and therefore favor kidney stone formation. The most common stone is that of calcium phosphate (brushite), but calcium oxalate stones and stones that contain both calcium oxalate and calcium phosphate are common as well.

Calcium nephrolithiasis is an indication for curative parathyroidectomy. Surgical cure of the hyperparathyroidism normalizes serum calcium and returns calcium filtered load to normal, reduces urine phosphate, and lowers urine pH. As a result, urinary supersaturation with respect to calcium phosphate and calcium oxalate decreases, and stone-free status is achieved in over 95% of patients.

Greater than 50% of patients with calcium oxalate nephrolithiasis have idiopathic hypercalciuria (IH). IH is characterized by normocalcemia, urine calcium excretion of greater than 300 mg per 24 hr for men, 250 mg 24 hr for women, greater than 140 mg calcium per gram urine creatinine, or greater than 4.0 mg calcium per Kg body weight for either sex in the absence of known causes of normocalcemic hypercalciuria (10). The diagnosis is one of exclusion of known causes of normocalcemic hypercalciuria (Table 5). Hypercalciuria increases the risk for calcium oxalate nephrolithiasis by about 10-fold, and about 10% of those with hypercalciuria will form at least one calcium oxalate kidney stone (4, 11). IH is common in the general population, affecting about 7% of the population. Children and adults have the same rate of IH, strongly suggesting that hypercalciuria begins early in infancy or childhood and persists throughout life.

The familial pattern of IH is consistent with an autosomal dominant pattern of inheritance. Males and females are equally affected, hypercalciuria occurs in successive generations, and one-half of first degree relatives of a given proband are hypercalciuric (12, 13). Additional support for a genetic basis for IH is the appearance of spontaneous hypercalciuria and calcium nephrolithiasis in male and female offspring of genetic hypercalciuric stone-forming (GHS) rats (14). Potential genes responsible for IH have used either linkage analysis or association studies. Scott et al (15) using a sib-pair linkage analysis reported a potential linkage of the VDR locus to idiopathic calcium stone formation and relevant quantitative traits. Linkage analysis was also used by Reed et al (16, 17) to map a gene defect possibly responsible for absorptive hypercalciuria to chromosome 1q23.3-q24. A gene product identified in this region shares homology with the rat soluble adenylate cyclase, but the potential function of the cyclase remains to be determined. Weber et al (18) reported a potential link between a heterozygous PCLN-1 mutation and hypercalciuria in calcium stone-formers. The role of a number of potential candidate genes have been assessed in association studies, including the Ca-sensing receptor (CaR, 19), VDR (20, 21), TRPV5, TRPV6, calbindins, and CLCN5. None of the studies have yielded conclusive evidence implicating any of these genes as primary causes of IH.

Patients with IH have high urine calcium and normal oxalate concentrations. The excess urine calcium creates a supersaturation of the urine with respect to calcium oxalate and favors spontaneous calcium oxalate crystal formation. Delete the following:The aggregation of crystals and subsequent attachment of the crystal mass on the surface of Randall’s plaques in the renal papillae are early events in what can become a clinical stone. The evidence supporting a role of hypercalciuria in the pathogenesis of calcium oxalate stones include: 1) the high frequency of hypercalciuria among calcium oxalate stone formers; 2) urine supersaturation with calcium oxalate in stone formers; 3) and the reduction in new stone formation upon reversal of the hypercalciuria as by thiazide diuretic therapy.

The source of the excess urine calcium is due to both over-absorption of dietary calcium and increased bone resorption (12). Intestinal calcium hyperabsorption is found in the vast majority of IH patients at all levels of dietary calcium intake (22). Pathologic renal over-production of 1,25-dihydroxyvitamin D [1,25(OH)2D] and high serum levels is found in about 50% of patients (23). For them, the high 1,25(OH)2D levels can explain the high calcium absorption rates. In the other patients with normal serum 1,25(OH)2D levels, intestinal calcium absorption rates are elevated but the cause is not known. Elevated intestinal vitamin D receptor (VDR) levels have been found in genetic hypercalciuric (GHS) rats, which may be a model for human IH (24), and peripheral blood monocyte VDR levels have been reported to be twice that of non-stone-formers (25). It is proposed that high vitamin D target tissue VDR increases the number of 1,25(OH)2D/VDR complexes and the biologic actions of 1,25(OH)2D. Animal experimental data demonstrate a direct relationship between tissue VDR and 1,25(OH)2D actions.

IH patients also have an abnormality in the renal handling of calcium (27). The filtered load of calcium is not different between IH patients and normal subjects, as both have normal total and ionized blood calcium. However, tubular calcium reabsorption of the filtered load is reduced in IH. The mechanism for the decreased tubular calcium reabsorption is not known, but may involve partial suppression of parathyroid hormone, or excessive calcium-sensing receptor in the distal nephron, or both.

Under conditions of adequate calcium intake, most of the excess urine calcium is dietary in origin (12). During dietary calcium restriction, urine calcium declines. However, in about 50% of patients, urine calcium does not decrease sufficiently, and negative calcium balance ensues (22,27). That is, they have more calcium in the urine than is in the diet. Prolonged low calcium intake and negative calcium balance eventually lead to bone loss, low bone mass and increased risk for fracture (28). Indeed, low bone density has been well documented in IH (22) and may be more common than calcium oxalate stone formation.

IH may be a heterogeneous disorder, as all of the observed changes in calcium metabolism cannot be understood by any one pathophysiologic model. Elevated serum 1,25(OH)2D levels can account for the increased intestinal calcium absorption, high bone resorption, and low bone mass. The increased 1,25(OH)2D production and high serum 1,25(OH)2D may be due to hypophosphatemia in about one-third and elevated parathyroid hormone levels in about 5%.

Patients with normal serum 1,25(OH)2D levels may have elevated tissue VDR levels that would amplify vitamin D biologic responses to the normal serum 1,25(OH)2D levels. In these patients, increased intestinal calcium absorption, bone resorption, and decreased tubule calcium reabsorption would occur simultaneously and continuously. Increased peripheral blood monocytes have been shown to over-produce cytokines that are active in stimulating bone resorption. Increased IL-1, TNF-, and IL-6 may account for increased bone resorption and low bone mass in some patients (29,30) but do not explain the increased intestinal calcium absorption and reduced renal tubule calcium reabsorption (delete 22 here).

Because the state of supersaturation is an accurate estimate of the risk that a solution such as urine will create and enlarge a solid phase, rational therapy to prevent the risk of stone recurrence seeks to reduce urine supersaturation with respect to the major constituents of the stone formed. In IH, calcium oxalate monohydrate and dihydrate crystals form in urine that is supersaturated with respect to the calcium and oxalate ion product. Effective therapy lowers either or both calcium and oxalate sufficient to reduce supersaturation (31,32, 33). Estimates of supersaturation are also useful in following the efficacy of therapy, as failure of reduction of supersaturation predicts a high risk of stone recurrence (33).

Because of the high stone rate of recurrence in IH, treatment following the initial stone is advised. A rational approach to the treatment of IH is reduction of calcium oxalate supersaturation. The thiazide class of diuretic agents reduces urine calcium excretion through a direct action on the distal tubular nephron to increase calcium reabsorption (34). The multiple actions of thiazide agents include increased sodium excretion, volume contraction, and a resulting decrease in glomerular filtration rate (GFR). Decreased GFR enhances distal tubule calcium reabsorption, lowers urine calcium, and improves calcium balance. Although dietary calcium restriction reduces urine calcium excretion, calcium oxalate supersaturation is not decreased presumably because reduced dietary calcium permits an increase in the intestinal availability of oxalate for absorption (35). As a result, calcium oxalate stone formation is not decreased (36). As diet calcium restriction promotes negative calcium balance and bone loss (22), a reasonable target calcium intake should be 800 to 1,000 mg per day (36). Food sources of calcium are preferable, as the rapid dissolution and absorption of calcium from calcium supplements may increase urine calcium supersaturation and promote calcium oxalate crystal formation even for brief periods of time.

The efficacy of thiazide therapy has been evaluated in six prospective trials (22). Two studies that demonstrated efficacy in reducing new stone formation were of three years duration, and did not show efficacy at one year. These results are consistent with the failure of studies of 1-2 year duration to reduce new stone appearance (22,37,38). Trials less than three years showed variable efficacy. The thiazide agents shown to be effective in prospective trials are shown in Table 6. As chronic thiazide use is associated with hypokalemia, potassium supplements are often required. The preferable form of potassium replacement is potassium citrate, as increased citrate intake increases urine citrate, which in turn lowers calcium oxalate supersaturation.

A five-year, randomized study conducted in male recurrent calcium oxalate kidney stone-formers showed that recurrent stone formation was reduced by about 50% among those who ingested a diet with normal calcium (1,200 mg calcium), and low in animal protein (52 g per day) and salt (2,900 mg sodium chloride) compared to men who ate a low calcium (400 mg calcium) diet (39). Urine calcium levels were lower with both diets, but the decline in urine calcium oxalate supersaturation was greater in the men ingesting the normal calcium, low protein, low salt diet. The decline in relative supersaturation of calcium oxalate was due to a decline in urine oxalate in those eating a normal calcium diet and rose in those who ingested a low calcium diet.

Adequate fluid intake (at least two liters daily) is part of all management plans for the prevention of calcium oxalate stones, however fluid intake alone has not been sufficient to prevent new stone formation in hypercalciuric patients (40).

Systemic hyperchloremic acidosis, alkaline urine, medullary nephrocalcinosis, calcium phosphate nephrolithiasis, and low bone mass characterize type 1 renal tubular acidosis (RTA, reference 41). Alkaline urine increases the proportion of urinary phosphate in the divalent and trivalent states and raises calcium phosphate supersaturation. The state of calcium phosphate supersaturation and the lack of effect of urine pH on calcium oxalate supersaturation predict the formation of calcium phosphate or brushite stone formation. Two other major factors that contribute to stone formation are low urine citrate and hypercalciuria. Hypocitraturia is due to enhanced proximal tubule citrate reabsorption and occurs in any cause of acidosis. The hypercalciuria is due to calcium release from bone during bone buffering of the acidosis and to suppressed tubule calcium reabsorption.

Alkali therapy reverses the acidosis and reduces urine calcium excretion. Therapy for stones that occur in type 1 RTA includes modification of risk factors and alkali therapy in the form of potassium citrate.

Urine citrate forms soluble calcium citrate complexes and thereby reduces calcium oxalate and calcium phosphate supersaturation. As a result, calcium oxalate and calcium phosphate stone formation decreases (22). Low urine citrate removes an important inhibitory action on nucleation, growth, and aggregation of calcium oxalate and is a common cause of calcium oxalate stone formation in women. Several causes of low urine citrate are known (Table 7), however the majority of men and women with low urine citrate are idiopathic. Women with calcium oxalate nephrolithiasis are more likely to have hypocitraturia than are men.

Non-stone forming women have higher urine citrate than men (600 mg/L vs 400 mg/L), which may account for the lower rate of stone formation in women (42). Normal and stone-forming men have comparable urine citrate levels, and these levels are similar to urine citrate levels found in stone-forming women.

Potassium citrate is effective in reducing new calcium oxalate stone formation in men and women with hypocitraturia through improvement in urine citrate levels and reduction in calcium oxalate supersaturation (43,44).

Non-stone formers excrete 20 to 40 mg of oxalate in the urine daily. Normal urine oxalate excretion is found in idiopathic hypercalciuria, however, a variety of genetic and acquired disorders raise urine oxalate above 45 mg per 24 hour, increase urine calcium oxalate supersaturation, and raise the risk of calcium oxalate stone formation. The causes of hyperoxalurias can be classified as either oxalate over-synthesis, or intestinal oxalate hyperabsorption (Table 8).

Intestinal oxalate hyperabsorption, or enteric hyperoxaluria, is the most common acquired form of hyperoxaluria (45,46). Each of these causes (Table 8) may increase the risk of calcium oxalate stone formation 25- to 100- fold. Increased colon oxalate absorption is thought to be due to malabsorption of fatty acids and bile salts with subsequent increased distal delivery into the colon and increased colonic oxalate permeability. Also, fatty acids bind luminal calcium and form insoluble calcium soaps. As a result, in the presence of lower luminal calcium, more oxalate is available for absorption. Hyperoxaluria from small bowel malabsorption often surpasses 100 mg/24 hour, which is sufficient to raise the rate of stone formation.

Management of enteric hyperoxaluria is directed at decreasing intestinal oxalate absorption by limiting dietary oxalate and fat, and increasing calcium in the form of calcium carbonate. At doses of calcium in the range of 250 mg to 1,000 mg four times daily, calcium oxalate precipitation in the intestinal lumen reduces oxalate absorption. The ion exchange resin cholestyramine, 4 to 16 g per day in four divided doses, binds intestinal luminal oxalate, fatty acids, and bile salts and thereby diminishes oxalate absorption. For those patients with malabsorption, hypocitraturia may also be present and require correction as well.

Excess urinary oxalate may be due to high intake of foods rich in oxalate. Dietary excesses of oxalate-rich foods such as nuts, cocoa, chocolate, tea, spinach, rhubarb, parsley, and pepper can raise urinary oxalate to 50 to 60 mg per day. However, dietary sources alone do not increase urine oxalate to the levels that occur in enteric hyperoxaluria. Dietary calcium and fiber sources can bind oxalate in the intestinal lumen of the small intestine and colon and limit absorption. Treatment of dietary-induced hyperoxaluria is dietary modification to limit ingestion of oxalate-rich foods.

Oxalate overproduction occurs as a result of two rare inherited disorders of oxalate metabolism (47). Type 1 primary hyperoxaluria is an autosomal recessive disorder caused by decreased activity of the hepatic peroxisomal alanine glycoxylate amono-transferase. The accumulated glycoxylate is converted to oxalic acid. Type 2 primary hyperoxaluria is due to a deficiency of D-glyceric dehydrogenase. Both hereditary forms result in high urine oxalate excretion, usually in excess of 130 mg/24 hr. The natural history of untreated inherited hyperoxaluric disorders includes nephrolithiasis beginning in early childhood followed by nephrocalcinosis, renal insufficiency, and systemic oxalosis. Increased urine volume to 3 liters daily plus potassium citrate can lower urine oxalate concentration and thereby reduce urine supersaturation. Combined liver and kidney transplantation has been performed to restore the missing enzyme. As patients with extensive oxalosis have done poorly following transplantation, transplantation should be performed prior to the development of systemic oxalosis.

Pyridoxine is a cofactor in the conversion of glycoxylate to glycine, and therapy for genetic hyperoxaluria types 1 and 2 includes the early use of pyridoxine 400 mg daily. Therapy must be initiated before renal insufficiency appears.

Hyperuricosuria is defined as urine uric acid of greater than 800 mg per 24 hr in men and greater than 750 mg per 24 hr in women. Excess urine uric acid excretion is a well-recognized risk factor for calcium oxalate nephrolithiasis (41,44). Urine may become supersaturated with sodium hydrogen urate when the urine has a pH of greater than 5.5 in the presence of hyperuricosuria. Crystals of monosodium urate may facilitate crystallization of calcium oxalate and the aggregation of these crystals into a stone by heterogeneous nucleation.

Increased urine uric acid has many causes (Table 9). Over-ingestion of purine-rich foods including meat, fish, and poultry accounts for the majority of patients with hyperuricosuria who form calcium oxalate stones. A minority over-produce uric acid, and hyperuricosuria persists despite ingestion of a low purine diet. Urine supersaturation with respect to uric acid may also occur through an increase in uric acid concentration during dehydration. In addition, urine pH below 6.0 reduces the solubility of uric acid, and uric acid stone formers have as a group, lower urine pH compared with patients who form calcium oxalate stones (pH 5.5 vs 6.0) (6).

Recurrence of hyperuricosuric calcium oxalate stone formation due to uric acid overproduction can be lessened by the administration of allopurinol at a dose that is sufficient to inhibit uric acid synthesis. As a result of the treatment, urine uric acid supersaturation is diminished and new stone formation can be reduced by 50% compared to hyperuricosuric stone formers not taking allopurinol (50).