Grant: Project Grant

Kidney stones are common costly and painful. Moreover, there are limited effective therapies to help persons with recurrent kidney stone episodes and the efficacy of a common therapy, thiazide diuretics has recently been called into question by a paper in the New England Journal of Medicine. The greatest risk factor for kidney stones is peeing too much calcium, which is called hypercalciuria. This can occur due to a failure of the kidney to hold onto calcium. Previous work from the Alexander laboratory has revealed how the kidney holds onto calcium by a part of the functional unit known as the proximal tubule. This proposal aims to understand how genetic mutations in genes which encode proteins contributing molecular machinery responsible for the proximal tubule to hold onto calcium cause hypercalciuria and an increased risk of kidney stones. We will also test whether persons with these mutations can be effectively treated with the common kidney stone drug, hydrochlorothiazide. We will use cellular and animal models to determine if these mutations alter how calcium is held onto by the kidney. We will also test the ability for hydrochlorothiazide, a kidney stone therapy drug, to lower urinary calcium content in mice lacking the proteins responsible for proximal tubule calcium handling and people with these genetic mutations. These studies will identify new genes that when mutated result in increased urinary calcium content and thus an increased risk for kidney stone formation. Moreover, our work will identify a sub population of kidney stone formers who will not benefit from thiazides i.e. will need another therapy, and thus inform a precision health approach to kidney stone treatment.