Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Racial-ethnic differences in health-related quality of life among adults and children with glomerular disease.

INTRODUCTION: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships between race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease. METHODS: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: 1. Missed school or work due to kidney disease; 2. Responses to Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression. RESULTS: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than White or Asian participants. Black adults missed work or school most frequently due to kidney disease (30% versus 16-23% in the other three groups, p=0.04), and had the worst self-reported global physical health (median score 44.1 versus 48.0-48.2, p<0.001) and fatigue (53.8 versus 48.5-51.1, p=0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status were associated with HRQOL. CONCLUSIONS: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by Black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children.

Glomerular permeability activity: prevalence and prognostic value in pediatric patients with idiopathic nephrotic syndrome.

BACKGROUND: A circulating factor that increases in vitro glomerular permeability to albumin (P alb ) has been isolated from patients with recurrence of focal segmental glomerulosclerosis in their renal allografts. The prevalence and prognostic significance of permeability activity has not been examined in children with idiopathic nephrotic syndrome (INS). METHODS: P alb activity level was determined in sera from 26 children with new-onset INS before the initiation of therapy by using an in vitro assay. Permeability factor was considered present if P alb was greater than 0.5. The following clinical and laboratory data for patients were tabulated: demographic information, serum albumin and cholesterol concentrations, calculated glomerular filtration rate, age at disease onset, response to corticosteroid treatment, and long-term outcome. RESULTS: Patients ranged in age from 2 to 18 years, and 19 patients (73%) were male. Mean P alb was 0.45 +/- 0.04 (SEM). P alb in patients with a steroid-responsive course (n = 17) did not differ from that of patients with steroid-resistant disease (n = 9). Percentages with P alb greater than 0.5 did not differ between patients with steroid-responsive and steroid-resistant disease (47% and 33%, respectively). P alb was determined after 41 +/- 5 months in 6 patients with steroid-responsive INS. These patients had normal serum creatinine concentrations, and 4 of 6 patients were in prolonged remission. P alb at the onset of INS before therapy was 0.51 +/- 0.09 (P alb > 0.5 in 2 patients) and was not changed at follow-up (P alb = 0.40 +/- 0.12; P alb > 0.5 in 2 patients). CONCLUSION: Permeability activity, defined as P alb greater than 0.5, is present in pretreatment serum samples from nearly half the children with INS. The presence of permeability activity does not predict clinical response to steroid treatment, renal histopathologic characteristics, or clinical outcome at up to 5 years of follow-up.