Progress in Understanding the Genetics of Calcium-Containing Nephrolithiasis

Abstract

Renal stone disease is a frequent condition, causing a huge burden on health care systems globally. Calcium-based calculi account for around 75% of renal stone disease and the incidence of these calculi is increasing, suggesting environmental and dietary factors are acting upon a preexisting genetic background. The familial nature and significant heritability of stone disease is known, and recent genetic studies have successfully identified genes that may be involved in renal stone formation. The detection of monogenic causes of renal stone disease has been made more feasible by the use of high-throughput sequencing technologies and has also facilitated the discovery of novel monogenic causes of stone disease. However, the majority of calcium stone formers remain of undetermined genotype. Genome-wide association studies and candidate gene studies implicate a series of genes involved in renal tubular handling of lithogenic substrates, such as calcium, oxalate, and phosphate, and of inhibitors of crystallization, such as citrate and magnesium. Additionally, expression profiling of renal tissues from stone formers provides a novel way to explore disease pathways. New animal models to explore these recently-identified mechanisms and therapeutic interventions are being tested, which hopefully will provide translational insights to stop the growing incidence of nephrolithiasis.

Keywords: Vitamin D; genetic renal disease; kidney stones; molecular genetics; polymorphisms.

Figure 1.

Oxalate metabolism and a model of intestinal and renal tubular oxalate transport. (A) Dietary oxalate is between 80 and 130 mg/d, of which 5%–15% is absorbed via intestinal anion exchangers (B). Oxalate within the gut binds to calcium and is eliminated via the stool. Low calcium diets increase gut oxalate absorption. Oxalate-degrading bacteria, such as Oxalobacter formigenes, play a role in protecting against oxalate hyperabsorption. Malabsorption syndromes may lead to a lack of such bacteria and promote hyperabsorption of oxalate. Endogenous production of oxalate occurs within the liver (15–45 mg/d). Autosomal recessive inherited PH secondary to mutations in AGXT, GRHPR, or HOGA1 leads to systemic oxalosis (with endogenous production of >100 mg/d) and hyperoxaluria. Figure modified from Hoppe et al. (B) A proposed model of small intestine epithelial cell transporters highlights the molecular players in oxalate transport/exchange. Apical oxalate transporters include anion exchangers SLC26A6 (PAT1) and SLC26A3 (DRA) that mediate oxalate secretion and uptake, respectively. A sulfate anion transporter (SAT1, SLC26A1) is localized at the basolateral membrane and allows sulfate resorption in exchange for anions (including Cl⁻, HCO3⁻, oxalate, and SO₄²⁻). A murine knockout model of Slc26a6 (Pat1) leads to reduced oxalate secretion and an overall net increase in reabsorption, increasing the filtered oxalate load and predisposing to calcium oxalate precipitation. Slc26a3 (DRA) knockout mice exhibit reduced oxalate absorption and reduced urinary oxalate levels (whereas human SLC26A3 mutations cause congenital chloride diarrhea). Murine knockouts of Slc26a1 (Sat1) cause a reduction in intestinal secretion of oxalate, leading to hyperoxalemia and hyperoxaluria. Human SLC26A1 mutations lead to nephrolithiasis by presumed similar mechanisms. (C) Oxalate is freely filtered by the glomerulus. SLC26A6 is localized on the apical membrane of the proximal tubule and forms a complex with NaDC-1, the sodium-dependent dicarboxylate cotransporter (encoded by SLC13A2). SLC26A6 inhibits NADC-1 so that when it is actively transporting oxalate into the filtrate citrate absorption is reduced. In addition, the apical SLC26A6 exchanges chloride for other anions (including Cl⁻, HCO3⁻, and SO₄²⁻) and therefore allows oxalate and sulfate recycling. SLC26A1 (SAT1) is localized to the basolateral membrane. Slc26a1 knockout mice are hyperoxaluric (even in the absence of dietary oxalate) suggesting a role for Slc26a1 in reducing urinary oxalate secretion.