Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today

Abstract

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.

Keywords: clinical trials; disease pathway; patient communication.

Figure 1 ∣. Nosology of nephrotic syndrome based on an integrative view of disease pathways.

Disease initiation by interaction of gene and environmental causal factors (filled circles) combined with disease progression factors (open circles) lead to chronic kidney disease (CKD) via progressive loss of kidney function. The current descriptive diagnostic categories, like focal segmental glomerular sclerosis (FSGS) and minimal change disease (MCD), show significant overlap in underlying mechanism of disease initiation and progression. Current and future therapies can target disease-initiating or progression pathways in glomerular diseases.

Figure 2 ∣. Three-step approach to developing the Nephrotic Syndrome Study Network (NEPTUNE) framework to test precision medicine in nephrotic syndrome.

Step 1: establishment of a knowledge network for comprehensive and prospective disease phenotypes. Step 2: definition of mechanistic disease subtypes using diverse data for patient segmentation via genetic-molecular-clinical-histology data layers. Step 3: mapping pathways targeted in ongoing and future trials to patients’ molecular activation profiles to match patients to trials. FSGS, focal segmental glomerular sclerosis; MCD, minimal change disease; MGN, membranous glomerulonephritis; SSNS, steroid-sensitive nephrotic syndrome.

Figure 3 ∣. Flow diagram of Nephrotic Syndrome Study Network (NEPTUNE) Match.

The NEPTUNE knowledge network is used to establish a tissue-level target activation signature. Noninvasive biomarkers of the target activation signature are developed and tested in the available NEPTUNE sample repository. NEPTUNE study participants joining Match provide biosamples for biomarker profiling and adjudication of their signature in a trial-specific context. Target activation signatures are adjudicated by the Match Molecular Nephrology Board. Activation signatures for the participating trials are communicated to patients to aid in their selection of nephrotic syndrome trials. Outcomes are reported back by the independently executed trials to test for association with the Match activation signature.

Figure 4 ∣. Example of distribution of activation profiles in Match.

Number of targetable mechanisms for a sample of Nephrotic Syndrome Study Network (NEPTUNE) participants (n = 85) with either minimal change disease or focal segmental glomerular sclerosis based on a combination of transcriptional “response” profiles and urine markers.