Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common cause of end-stage renal disease (ESRD) in the United States. The course of the disease is characterized initially by a stable GFR despite enormous expansion of kidney volume due to growth of cysts. The finding of a stable GFR despite significant structural distortion in the renal parenchyma presents a significant challenge to designing clinical trials in patients with ADPKD. Therefore, a process to identify early markers of disease progression in order to recognize patients with a worse prognosis is desperately needed if we are going to alter the natural history of ADPKD.
In a recent report in AJKD, Perrone et al provide a detailed description of the first ever Clinical Data Interchange Standards Consortium (CDISC) data standard for ADPKD by the Polycystic Kidney Disease Outcomes Consortium (PKDOC). The PKDOC was created as a collaboration between the Polycystic Kidney Disease Foundation, the CDISC, and several other prominent organizations to provide a structure for consistent understanding and exchange of data. These data will also be used to support the regulatory qualification of Total Kidney Volume (TKV) as an acceptable endpoint to assess the progression of ADPKD in clinical studies looking at new therapeutics.
TKV was identified as a potential biomarker early in the disease process that is capable of predicting subsequent clinical outcome in patients with ADPKD. Studies have shown that TKV, adjusted for a height of 600 cc/m, predicts the risk for development of chronic kidney disease stage 3 within 8 years. Prior to this publication, the FDA did not recognize TKV as a valid end point for therapeutic clinical trials in ADPKD.
There are significant challenges to collecting prospective data from a sufficient number of patients to validate TKV as an endpoint for PKD clinical trials. Data from long-term registries and long-term clinical trials lacked uniformity. The FDA recommended standardization of this data for the purpose of integration into a disease mode. This resulted in compilation of Common Data Elements (CDEs) from case report forms, long-term registries from several universities, the HALT-PKD STUDY, and the Consortium for Radiologic Imaging Studies for PKD registry.
Over 1200 data elements were identified in various categories based on separate aspects of the disease. The process of selection of these CDEs is shown in figure 1 of the article. Finally 338 CDEs were identified out of the 1200 for inclusion in the Study Data Tabulation Model (SDTM). This has resulted in the creation of a standard user guide, which is publicly available through CDIC Therapeutic Area Standards. This standard establishes an agreed upon nomenclature and guideline for organization, basic structure, and format for ADPKD data that can be used for future clinical trials, health records, and observational studies. The application of this standard will help bring efficiency and rigor to clinical studies in ADPKD. While several CDEs have been established, researchers will be able define and choose those CDEs that are relevant to their particular study. On August 31, at the culmination of this tremendous effort, C-Path announced that the U.S. Food and Drug Administration (FDA) had issued a qualification decision supporting the use of TKV as a prognostic biomarker to select patients for clinical trials of new therapies for ADPKD.
How should the nephrology community react to this report? First, we should salute the magnificent effort put forth by these collaborators for the development of the first ever-clinical data set in kidney disease. Second, we should strive to put these sets of data into use by performing clinical trials that will help lead to the development of new therapeutics for ADPKD. Please share your thoughts with us.
– Post written by Dr. Sandeep Dayanand and Dr. Abdo Asmar, AJKD Blog Advisory Board member