The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

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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.

Absent a remission of proteinuria, primary membranous nephropathy (MN) can lead to ESRD over many years. Therefore, use of an earlier end point could facilitate the conduct of clinical trials. This manuscript evaluates complete remission (CR) and partial remission (PR) of proteinuria as surrogate end points for a treatment effect on ESRD in patients with primary MN with heavy proteinuria. CR is associated with a low relapse rate and excellent long-term renal survival, and it plausibly reflects remission of the disease process that leads to ESRD. Patients who achieve PR have better renal outcomes than those who do not but may have elevated relapse rates. How long PR must be maintained to yield a benefit on renal outcomes is also unknown. Hence, available data suggest that CR could be used as a surrogate end point in primary MN, whereas PR seems reasonably likely to predict clinical benefit. In the United States, surrogate end points that are reasonably likely to predict clinical benefit can be used as a basis for accelerated approval; treatments approved under this program must verify the clinical benefit in postmarketing trials. Additional analyses of the relationship between treatment effects on CR and PR and subsequent renal outcomes would inform the design of future clinical trials in primary MN. J Am Soc Nephrol 26: 2930-2937, 2015. doi: 10.1681 Primary membranous nephropathy (MN) is an important cause of nephrotic syndrome in adults, and it is associated with significant morbidity, including the progressive loss of renal function, leading to ESRD.Primary MN affects patients of all ages and races, but it affects men more commonly than women and adults more commonly than children, with a peak incidence occurring during the fourth and fifth decades of life; 70%-80% of patients with MN present with nephrotic syndrome (proteinuria $3.5 g/24 h per 1.73 m 2 , hypoalbuminemia, hyperlipidemia, and edema). 1,2 The remaining 20%-30% of patients present with subnephrotic levels of proteinuria (,3.5 g/24 h) and are usually asymptomatic. 3,4 Primary MN has a variable course ranging from spontaneous remission to progressive loss of GFR over several years. Studies of the natural course (without immunotherapy) of idiopathic MN reveal that spontaneous remissions occur in approximately one third of patients, most commonly within the first 2 years of diagnosis. [5][6][7][8][9] Although patients who attain a spontaneous remission typically have a good long-term prognosis, patients with heavy and persistent proteinuria are at high risk of progressive loss of renal function, leading to ESRD. In the absence of remission of proteinuria to at least subnephrotic levels, ESRD occurs in about 25% of patients by 8 years and 50% of patients by 10-15 years. 9 Given the extended time frame for progression to ESRD, there has been great interest in identifying an earlier end point that could be used in clinical trials to establish the efficacy of therapies for patients with primary MN who are at high risk of developing ESRD. In April...

Novel biomarkers of kidney toxicity are powerful tools not only with respect to their clinical applications but also because of their impact on drug development. These biomarkers can influence the assessment of efficacy of new drugs for kidney diseases as well as the risk management for new drugs. The science behind these novel biomarkers reflects the evolution over the past decade of genomic and proteomic platforms that have transformed the discovery and development of new biomarkers for preclinical and clinical applications in drug development. Several of these biomarkers are in use as transcriptomic biomarkers in animal models as well as translational proteomic biomarkers in animal models and in humans. Their ability to detect kidney damage earlier than is possible with currently accessible biomarkers is being given qualification through regulatory biomarker-qualification programs, which will help establish consensus for their widespread use.