Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology

Abstract

Advances in biomedical research allow for the capture of an unprecedented level of genetic, molecular, and clinical information from large patient cohorts, where the quest for precision medicine can be pursued. An overarching goal of precision medicine is to integrate the large-scale genetic and molecular data with deep phenotypic information to identify a new mechanistic disease classification. This classification can ideally be used to meet the clinical goal of the right medication for the right patient at the right time. Glomerular disease presents a formidable challenge for precision medicine. Patients present with similar signs and symptoms, which cross the current disease categories. The diseases are grouped by shared histopathologic features, but individual patients have dramatic variability in presentation, progression, and response to therapy, reflecting the underlying biologic heterogeneity within each glomerular disease category. Despite the clinical challenge, glomerular disease has several unique advantages to building multilayered datasets connecting genetic, molecular, and structural information needed to address the goals of precision medicine in this population. Kidney biopsy tissue, obtained during routine clinical care, provides a direct window into the molecular mechanisms active in the affected organ. In addition, urine is a biofluid ideally suited for repeated measurement from the diseased organ as a liquid biopsy with potential to reflect the dynamic state of renal tissue. In our review, current approaches for large-scale data generation and integration along the genotype-phenotype continuum in glomerular disease will be summarized. Several successful examples of this integrative biology approach within glomerular disease will be highlighted along with an outlook on how achieving a mechanistic disease classification could help to shape glomerular disease research and care in the future.

Focal Segmental Glomerulosclerosis

“…RCT, randomized, controlled trial; ACE, angiotensin-converting enzyme. (122,123). Medication-associated FSGS can generally be managed by stopping the offending medication, and virus-associated FSGS can be best addressed by initiating antiviral therapy with additional adjunctive therapies as indicated.…”

Pooled Analysis of Multiple Crossover Trials To Optimize Individual Therapy Response to Renin-Angiotensin-Aldosterone System Intervention

“…Further studies are needed that focus on the patient's specific genetic or molecular profile to unravel the underlying mechanisms of therapy response. In contrast to oncology, where deep-phenotyping has contributed significantly to discovering determinants of therapy response, precision medicine in the field of nephrology has yet to be implemented (26). However, improvement in experimental techniques and technologies offers the potential to better understand molecular mechanisms of therapy response.…”

Digital pathology in nephrology clinical trials, research, and pathology practice

“…In the setting of large consortia for clinical research, data sharing, and analytic platforms that facilitate mining of different large-scale datasets are necessary [13 ▪▪ ]. Two glomerular diseases consortia, NEPTUNE and CureGN, adopted tranSMART, an open source software (transmartfoundation.org) originally developed by Johnson & Johnson (New Brunswick, New Jersey, USA) [14], as a platform for data mining and sharing.…”