Pathophysiology and Treatment of Enteric Hyperoxaluria.

Enteric hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric hyperoxaluria was completed as part of a Kidney Health Initiative-sponsored project to describe enteric hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.

End Points for Clinical Trials in Primary Hyperoxaluria.

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.