Multidimensional Data Integration Identifies Tumor Necrosis Factor Activation in Nephrotic Syndrome: A Model for Precision Nephrology
Authors: Mariani Laura H. , Eddy Sean , AlAkwaa Fadhl M. , McCown Phillip J. , Harder Jennifer L. , Martini Sebastian , Ademola Adebowale D. , Boima Vincent , Reich Heather N. , Eichinger Felix , Saghir Jamal El , Godfrey Bradley , Ju Wenjun , Nair Viji , Tanner Emily , Vega-Warner Virginia , Wys Noel L. , Adler Sharon G. , Appel Gerald B. , Athavale Ambarish , Atkinson Meredith A. , Bagnasco Serena M. , Barisoni Laura , Brown Elizabeth , Cattran Daniel C. , Dell Katherine M. , Derebail Vimal K. , Fervenza Fernando C. , Fornoni Alessia , Gadegbeku Crystal A. , Gibson Keisha L. , Greenbaum Larry A. , Hingorani Sangeeta R. , Hladunewich Michelle A. , Hodgin Jeffrey B. , Hogan Jonathan J. , Hogan Marie , Holzman Lawrence B. , Jefferson J. Ashley , Kaskel Frederick J. , Kopp Jeffrey B. , Lafayette Richard A. , Lemley Kevin V. , Lieske John C. , Lin Jen-Jar , Menon Rajarasee , Meyers Kevin E. , Nachman Patrick H. , Nast Cynthia C. , Neu Alicia M. , O’Shaughnessy Michelle M. , Otto Edgar A. , Reidy Kimberly J. , Sambandam Kamalanathan K. , Sedor John R. , Sethna Christine B. , Singer Pamela , Srivastava Tarak , Tran Cheryl L. , Tuttle Katherine R. , Vento Suzanne , Wang Chia-shi , Ojo Akinlolu O. , Adu Dwomoa , Gipson Debbie S. , Trachtman Howard , Kretzler Matthias 
Published: September 2021

Background

Classification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.

Methods

Systems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.

Results

Transcriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p <0.001 for predicted vs observed score). Kidney organoids confirmed TNF-dependent increase in transcript and protein levels of these markers in kidney cells, as did snRNAseq from NEPTUNE biopsy samples.

Conclusions

Molecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.

Significance Statement

Mechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.