Nephrolithiasis, Calcium Oxalate

A number sign (#) is used with this entry because of evidence that calcium oxalate nephrolithiasis (CAON) is caused by compound heterozygous mutation in the SLC26A1 gene (610130) on chromosome 4p16. One such patient has been reported.

Description

Kleta (2006) reviewed aspects of renal stone disease. Nephrolithiasis and urolithiasis remain major public health problems of largely unknown cause. While disorders such as cystinuria (220100) and primary hyperoxaluria (see 259900) that have nephrolithiasis as a major feature have advanced understanding of the metabolic and physiologic processes of stone formation in general, they have not addressed the etiology of calcium oxalate stone formation, responsible for approximately 75% of urolithiasis cases in humans. Men are affected twice as often as women, but children show no such gender bias. The recurrence rate is also high. In populations of European ancestry, 5 to 10% of adults experience the painful precipitation of calcium oxalate in their urinary tracts.

Thorleifsson et al. (2009) noted that between 35 and 65% of hypercalciuric stone formers and up to 70% of subjects with hypercalciuria have relatives with nephrolithiasis, and twin studies have estimated the heritability of kidney stones to be 56%.

Clinical Features

Oxalate is a major component of two-thirds of all kidney stones. Small changes in the urinary concentration of oxalate have a critical influence on calcium oxalate stone formation. Abnormally high urinary excretion and intestinal absorption of oxalate has been found in cases of 'idiopathic' calcium oxalate nephrolithiasis (Hodgkinson, 1978; Robertson and Peacock, 1980; Marangella et al., 1982). The family history is usually positive in cases of calcium oxalate urolithiasis (McGeown, 1960; Ljunghall, 1979).

Gram (1932) described an extensive pedigree of oxalate urolithiasis in 5 generations. Urinary oxalate concentrations were not reported. Several presumed carrier females did not have calculi. Fifteen males (and no females) in 10 sibships were affected.

The systematic genetic study of calcium oxalate renal calculi done by Resnick et al. (1968) led to the conclusion that monogenic inheritance could be excluded; the findings were considered compatible with the hypothesis that the tendency to form calcium oxalate renal stones is regulated by a polygenic system, with less risk for females than males.

Baggio et al. (1984, 1986) found that transmembrane oxalate flux in red cells of patients with idiopathic calcium oxalate nephrolithiasis is faster than in subjects without stones; that the anomaly of oxalate transport is inherited as an autosomal dominant trait with complete penetrance; and that the 'defect' can be corrected by diuretic agents (e.g., hydrochlorothiazide or amiloride). Use of hydrochlorothiazide to prevent recurrence of renal stones was first suggested by Yendt and Cohanim (1978) because of its hypocalciuric action. Cousin and Motais (1976) showed that oxalate exchange is drastically reduced by furosemide, and to a lesser extent by hydrochlorothiazide. Hyperoxaluria occurs with various forms of intestinal disease as an abnormality in absorption of dietary oxalate (Smith and Hofmann, 1974).

Patients With Confirmed SLC26A1 Variants

Gee et al. (2016) reported a boy of Macedonian descent with onset of acute renal failure due to calcium oxalate nephrolithiasis at 5 years of age. He also had ureteropelvic junction obstruction necessitating surgery. Urinary analysis showed hyperoxaluria. An unrelated boy, born of consanguineous European-American parents, developed nephrolithiasis; urinary oxalate and renal function were normal. The paternal grandfather of this patient also had nephrolithiasis.

Pathogenesis

Oxalobacter formigenes is a gram-negative, anaerobic bacterium that metabolizes oxalate in the intestinal tract and is present in most adults. Kaufman et al. (2008) hypothesized that the absence of O. formigenes could lead to increased colonic absorption of oxalate and that the subsequent increase in urinary oxalate could favor development of stones. They performed a case-control study of 247 patients with recurrent oxalate stones and 259 matched controls and found that the prevalence of O. formigenes, cultured from stool, was 17% in patients and 38% among controls. The inverse association was found independently of age, gender, race/ethnicity, region, and antibiotic use. Median urinary oxalate excretion did not differ with the presence or absence of O. formigenes colonization. Kaufman et al. (2008) concluded that colonization with O. formigenes is associated with a 70% reduction in risk of being a recurrent calcium oxalate stone former and that O. formigenes is a potential probiotic.

Molecular Genetics

In a boy with calcium oxalate nephrolithiasis, Gee et al. (2016) identified compound heterozygous missense variants in the SLC26A1 gene (T185M, 610130.0001 and S358L, 610130.0002). Another boy with calcium oxalate nephrolithiasis was homozygous for a missense variant in the SLC26A1 gene (A56T; 610130.0003); however, the pathogenicity of this variant was questioned by Wu et al. (2016). The patients in the study of Gee et al. (2016) were ascertained from a cohort of 348 unrelated patients with kidney stones who were screened for mutations in 18 candidate genes. In vitro functional expression assays using mouse orthologs suggested that the variant proteins caused a decrease in transporter function.

Associations Pending Confirmation

Suzuki et al. (2008) found that an ancestral TRPV6 haplotype, consisting of 3 nonsynonymous SNPs, C157R (rs4987657), M378V (rs4987667), M681T (rs4987682), and defined by arg157, val378, and thr681 (RVT), was present at a significantly higher frequency among 274 Swiss renal calcium stone formers compared to a control group of 341 Swiss nonstone formers (7.6% vs 5.4%; p = 0.039). Functional expression studies in Xenopus oocytes showed that the RVT ancestral haplotype resulted in higher calcium uptake activity compared to the derived CMM haplotype (p less than 0.01) and that the val378 allele of the extracellular M378V SNP, which is located between transmembrane domains 1 and 2, significantly increased calcium transport activity, suggesting that the M378V SNP mainly contributes to the increase in calcium transport activity associated with the RVT haplotype. There was no difference in phenotype between stone-forming patients who were heterozygous for the RVT haplotype and stone-forming patients homozygous for the CMM haplotype. One stone-forming patient was RVT haplotype homozygous and had absorptive hypercalciuria and more than 5 episodes of stones; however, he had no family history of stones. Suzuki et al. (2008) suggested that the ancestral RVT haplotype represents a gain-of-function haplotype in TRPV6 and may play a role in increased risk of calcium stone formation.

Animal Model

Jiang et al. (2006) showed that Slc26a6 (610068)-null mice develop a high incidence of calcium oxalate urolithiasis. Slc26a6-null mice have significant hyperoxaluria and elevation of plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. Jiang et al. (2006) concluded that the anion exchanger, SLC26A6, has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis. Kleta (2006) commented that the findings of Jiang et al. (2006) suggest a genetic explanation for a common form of renal stone disease in humans.

Dawson et al. (2010) found that Slc26a1-null mice showed increased serum oxalate and increased oxalate excretion, decreased serum sulfate and increased sulfate excretion, calcium oxalate urolithiasis, and nephrocalcinosis. Mutant mice also showed increased acetaminophen-induced liver toxicity compared to wildtype, and Dawson et al. (2010) noted that sulfate is required for the detoxification of xenobiotics, and suggested that Slc26a1 deficiency may result in hepatotoxicity.