, Volume 47, Issue 1, pp 43–56 | Cite as

Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules

  • Nicolas Faller
  • Nasser A. Dhayat
  • Daniel G. FusterEmail author
Invited Review


Twin and genealogy studies suggest a strong genetic component of nephrolithiasis. Likewise, urinary traits associated with renal stone formation were found to be highly heritable, even after adjustment for demographic, anthropometric and dietary covariates. Recent high-throughput sequencing projects of phenotypically well-defined cohorts of stone formers and large genome-wide association studies led to the discovery of many new genes associated with kidney stones. The spectrum ranges from infrequent but highly penetrant variants (mutations) causing mendelian forms of nephrolithiasis (monogenic traits) to common but phenotypically mild variants associated with nephrolithiasis (polygenic traits). About two-thirds of the genes currently known to be associated with nephrolithiasis code for membrane proteins or enzymes involved in renal tubular transport. The thick ascending limb of Henle and connecting tubules are of paramount importance for renal water and electrolyte handling, urinary concentration and maintenance of acid–base homeostasis. In most instances, pathogenic variants in genes involved in thick ascending limb of Henle and connecting tubule function result in phenotypically severe disease, frequently accompanied by nephrocalcinosis with progressive CKD and to a variable degree by nephrolithiasis. The aim of this article is to review the current knowledge on kidney stone disease associated with inherited defects in the thick ascending loop of Henle and the connecting tubules. We also highlight recent advances in the field of kidney stone genetics that have implications beyond rare disease, offering new insights into the most common type of kidney stone disease, i.e., idiopathic calcium stone disease.


Kidney stone Nephrocalcinosis dRTA Bartter FHHNC Thick ascending limb of Henle Connecting tubule 



DF was supported by the Swiss National Centre of Competence in Research NCCR TransCure and the Swiss National Science Foundation (Grants # 31003A_135503, 31003A_152829 and 33IC30_166785/1).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest. DF has served as a consultant for Otsuka Pharmaceuticals. DF has received unrestricted research funding from Novartis, Abbvie and Otsuka Pharmaceuticals.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Nephrology and Hypertension, InselspitalBern University Hospital, University of BernBernSwitzerland
  2. 2.Swiss National Centre of Competence in Research NCCR TransCureUniversity of BernBernSwitzerland
  3. 3.Swiss National Centre of Competence in Research Kidney.CHUniversity of ZürichZurichSwitzerland

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