Patients with newly diagnosed nephrotic syndrome due to minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN) display an impressive amount of variability in disease severity, symptom burden, response to initial therapy, and risk of relapse. Although this heterogeneity is a clinical challenge—frustrating patients and clinicians alike—it is also an opportunity for researchers to partner with patients under routine clinical care to collect the data and bio-samples needed to better define mechanistically relevant subgroups. The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium that was established to develop such a translational research infrastructure with the goal to better understand underlying disease pathogenesis and guide further investigation for targeted therapies (1) (Figure 1).
Now in its third grant-funding phase, the prospective cohort studies have consented over 1100 patients from 34 centers since 2010. Children and adults are enrolled at the time of the first clinically indicated biopsy, with proteinuria >500 mg/day in phase 1 and >1500 mg/day in phases 2 and 3. Participants who had other kidney disease diagnoses beyond MCD, FSGS, and MN were retained as a relevant comparison group. An additional pediatric cohort of patients not undergoing biopsy but presenting within 30 days of treatment initiation was added in phases 2 and 3 and now includes over 170 children. Patients with secondary glomerular disease (e.g., lupus and myeloma) and solid organ transplant were excluded.
The overarching goal of NEPTUNE has been to aggregate comprehensive, longitudinal clinical and molecular data into a resource for use by the entire scientific community to better unravel the heterogeneity of nephrotic syndrome. NEPTUNE participants are followed prospectively with up to three visits in the first year and two visits per subsequent year, up to 3 years. Multiple unique data elements and biosamples are available, which span the genotype-phenotype continuum. These include demographics, comorbidities, medications, laboratory values, physical exam, patient-reported outcomes, SMS texting, and census tract, as well as whole genome sequencing, targeted proteomics, and urine and blood biosamples. At the time of biopsy, an extra core of tissue is obtained for RNA sequencing (i.e., transcriptomics) after the tissue is manually micro-dissected to separate the glomerular from tubulointerstitial compartments. The kidney tissue slides, stained per usual clinical practice, are scanned into whole slide images and stored in the NEPTUNE Digital Pathology Repository. In the current study phase, NEPTUNE has launched a program to test the matching of disease mechanism biosignatures to enrolling clinical trial drug mechanisms on a patient level. This program allows patient participants to join in the review of research results.
As one example of combining high-dimensional datasets, a recent NEPTUNE study of 221 MCD and FSGS participants leveraged the unique digital pathology data and combined them with clinical outcome and molecular data (2). The NEPTUNE Digital Pathology Scoring system was developed to comprehensively and agnostically quantify structural changes in the biopsy (3). Pathologists enumerate glomeruli across levels and stains before scoring each glomerulus for the presence or absence of various features, called descriptors. In this study, the percentage of glomeruli with each descriptor was calculated for each patient biopsy. A clustering analysis of these data revealed three subgroups, each of which included both MCD and FSGS patients. One of the clusters had lower probability of remission of proteinuria and greater loss of estimated glomerular filtration rate over time. Importantly, the gene expression profile of this poor-outcome group revealed a unique signature, including potentially targetable pathways of inflammation and immune response.
With studies such as this one and many others leveraging the additional high-dimensional datasets and biosamples, NEPTUNE aims to support a variety of experimental approaches that can move nephrotic syndrome treatment closer to precision medicine. Investigators, internal and external to the consortium, are encouraged to propose ancillary studies (see NEPTUNE-Study.org) to bring this vision to fruition.
Funding Acknowledgments: The Nephrotic Syndrome Rare Disease Clinical Research Network III (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Office of Rare Diseases Research (ORDR). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. All RDCRN consortia are supported by the network's Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS).
Hodgin JB, et al. Quantification of glomerular structural lesions: Associations with clinical outcomes and transcriptomic profiles in nephrotic syndrome. Am J Kidney Dis [published online ahead of print December 2, 2021]. doi: 10.1053/j.ajkd.2021.10.004; https://www.ajkd.org/article/S0272-6386(21)01004-0/fulltext