Medical Department III, Endocrinology, Nephrology and Rheumatology, Division of Nephrology, University of Leipzig Medical Center, Leipzig, Germany.
Nephrol Ther. 2021 Apr;17S:S88-S94. doi: 10.1016/j.nephro.2020.02.003.
Kidney stone disease comprising nephrolithiasis and nephrocalcinosis is a clinical syndrome of increasing prevalence with remarkable heterogeneity. Stone composition, age of manifestation, rate of recurrence, and impairment of kidney function varies with underlying etiologies. While calcium-based kidney stones account for the vast majority their etiology is still poorly understood. Recent studies underline the notion that genetic susceptibility together with dietary habits constitutes the major driver of kidney stone formation. In addition to single gene (Mendelian) disorders, which are most likely underestimated in the adult population, common risk alleles explain part of the observed heritability. Interestingly, identified GWAS loci often match those of Mendelian disease genes and vice versa (CASR, SLC34A1, CYP24A1). These findings provide mechanistic links related to renal calcium homeostasis, vitamin D metabolism, and CaSR-signaling regulated by the CaSR-CLDN14-CLDN16/19 axis (paracellular Ca reabsorption) and TRPV5 (transcellular Ca reabsorption). Recent identification of new single gene disorders of calcium-oxalate-nephrolithiasis (SLC26A1, CLDN2) and distal renal tubular acidosis with nephrocalcinosis (FOXI1, WDR72, ATP6V1C2) enabled additional insights into the kidney-gut axis and molecular prerequisites of proper urinary acidification. Implementation of centralized patient registries on hereditary kidney stone diseases are necessary to build up well characterized cohorts for urgently needed clinical studies.
肾结石病包括肾结石和肾钙质沉着症，是一种患病率不断增加的临床综合征，具有显著的异质性。结石成分、发病年龄、复发率和肾功能损害因潜在病因而异。虽然钙基肾结石占绝大多数，但它们的病因仍知之甚少。最近的研究强调了遗传易感性与饮食习惯共同构成肾结石形成的主要驱动因素的观点。除了在成年人群中很可能被低估的单基因（孟德尔）疾病外，常见的风险等位基因解释了部分观察到的遗传性。有趣的是，已确定的 GWAS 位点通常与孟德尔疾病基因匹配，反之亦然（CASR、SLC34A1、CYP24A1）。这些发现提供了与肾钙稳态、维生素 D 代谢以及 CaSR 信号转导相关的机制联系，CaSR-CLDN14-CLDN16/19 轴（细胞旁 Ca 重吸收）和 TRPV5（细胞内 Ca 重吸收）受其调节。最近对新的单基因疾病（SLC26A1、CLDN2）和伴有肾钙质沉着症的远端肾小管酸中毒（FOXI1、WDR72、ATP6V1C2）的钙草酸肾结石的鉴定，使我们对肾脏-肠道轴和适当尿液酸化的分子前提条件有了更多的了解。实施遗传性肾结石病的集中患者登记是必要的，以建立特征明确的队列，进行急需的临床研究。
