Chronic kidney disease (CKD) affects 11% of the US population, costs tens of billions of dollars annually, and can lead to progressive kidney failure, cardiovascular disease (CVD), and early mortality. Although we understand much about the epidemiology of CKD and its associations with CVD, the underlying mechanisms of CKD pathogenesis, progression, and complications remain less well understood. In this proposal, we seek to test the hypothesis that oxalate-a toxic terminal metabolite that accumulates in all forms of CKD-contributes to the progression and complications of CKD. Kidney failure from oxalate nephropathy is a devastating complication of genetic and acquired diseases in which excessive oxalate is generated (primary hyperoxaluria) or absorbed (enteric hyperoxaluria). Oxalate has been shown to cause endothelial dysfunction, mitochondrial damage, oxidative stress, and inflammation in vitro and in animal models of oxalate nephropathy. As kidney function declines in all forms of CKD, oxalate levels increase in the plasma and glomerular ultrafiltrate, leading to increased systemic and intra-renal exposure to oxalate and consequent tissue injury. To test this hypothesis, we propose an ancillary study to the Chronic Renal Insufficiency Cohort (CRIC), an NIH-sponsored longitudinal study of 3,939 individuals with CKD that has stored biospecimens and adjudicated kidney and cardiovascular outcomes over an average of 6 years of follow-up. We will measure oxalate levels in baseline plasma and 24h urine samples to determine their associations with subsequent adverse CKD outcomes. Confirmation of our hypothesis may lead to a paradigm shift in CKD evaluation and risk stratification, and identify oxalate as a novel therapeutic target for interventional trials aimed t reducing oxalate absorption or generation.
Chronic kidney disease (CKD) can be a progressive disease that leads to kidney failure, cardiovascular complications, and early mortality. In this proposal we will test whether higher levels of plasma and urine oxalate-a toxic terminal metabolite that accumulates in patients with CKD-are associated with a higher risk of kidney failure and cardiovascular disease events. Identification of oxalate as a risk factor and potential mediator of tissue injury in CKD may lead to the incorporation of oxalate measurements into the routine evaluation of CKD patients and focus efforts to test therapies to limit oxalate absorption or generation.
|Leaf, David E; Waikar, Sushrut S (2017) End Points for Clinical Trials in Acute Kidney Injury. Am J Kidney Dis 69:108-116|
|Leaf, David E; Body, Simon C; Muehlschlegel, Jochen D et al. (2016) Length Polymorphisms in Heme Oxygenase-1 and AKI after Cardiac Surgery. J Am Soc Nephrol 27:3291-3297|
|Leaf, David E; Srivastava, Anand; Zeng, Xiaoxi et al. (2016) Excessive diagnostic testing in acute kidney injury. BMC Nephrol 17:9|