ABSTRACT
OBJECTIVE: Social determinants of health (SDoH) likely contribute to outcome disparities in lupus nephritis (LN). Understanding the overall burden and contribution of each domain could guide future health equity-focused interventions to improve outcomes and reduce disparities in LN. Objectives of this meta-analysis were to 1) determine the association of overall SDoH and specific SDoH domains on LN outcomes and 2) develop a framework for the multidimensional impact of SDoH on LN outcomes. METHODS: We performed a comprehensive search of studies measuring associations between SDoH and LN outcomes. We examined pooled odds of poor LN outcomes including death, end-stage kidney disease, or cardiovascular disease in patients with and without adverse SDoH. Additionally, we calculated the pooled odds ratios of outcomes by four SDoH domains: individual (eg, insurance), health care (eg, fragmented care), community (eg, neighborhood socioeconomic status), and health behaviors (eg, smoking). RESULTS: Among 531 screened studies, 31 meeting inclusion criteria and 13 with raw data were included in meta-analysis. Pooled odds of poor outcomes were 1.47-fold higher in patients with any adverse SDoH. Patients with adverse SDoH in individual and health care domains had 1.64-fold and 1.77-fold higher odds of poor outcomes. We found a multiplicative impact of having two or more adverse SDoH on LN outcomes. Black patients with public insurance and fragmented care had 12-fold higher odds of poor LN outcomes. CONCLUSION: Adverse SDoH is associated with poor LN outcomes. Having two or more adverse SDoH, specifically in different SDoH domains, had a multiplicative impact leading to worse LN outcomes, widening disparities.
ABSTRACT
BACKGROUND: Intrarenal complement activation has been implicated in the pathogenesis of tubulointerstitial fibrosis in lupus nephritis (LN) based on prior animal studies. The assembly of the membrane attack complex (MAC) by complement C5b to C9 on the cell membrane leads to cytotoxic pores and cell lysis, while CD59 inhibits MAC formation by preventing C9 from joining the complex. We hypothesize that complement activation and imbalance between complement activation and inhibition, as defined by increased production of individual complement components and uncontrolled MAC activation relative to CD59 inhibition, are associated with interstitial fibrosis and tubular atrophy (IFTA) in LN and correlate with the key mediators of kidney fibrosis- transforming growth factor receptors beta (TGFRß), platelet-derived growth factor beta (PDGFß) and platelet-derived growth factor receptor beta (PDGFRß). METHODS: We included urine samples from 46 adults and pediatric biopsy-proven lupus nephritis patients who underwent clinically indicated kidney biopsies between 2010 and 2019. We compared individual urinary complement components and the urinary C9-to-CD59 ratio between LN patients with moderate/severe IFTA and none/mild IFTA. IFTA was defined as none/mild (<25% of interstitium affected) versus moderate/severe (≥ 25% of interstitium affected). Proteomics analysis was performed using mass spectrometry (Orbitrap Fusion Lumos, Thermo Scientific) and processed by the Proteome Discoverer. Urinary complement proteins enriched in LN patients with moderate/severe IFTA were correlated with serum creatinine, TGFßR1, TGFßR2, PDGFß, and PDGFRß. RESULTS: Of the 46 LN patients included in the study, 41 (89.1%) were women, 20 (43.5%) self-identified as Hispanic or Latino, and 26 (56.5%) self-identified as Black or African American. Ten of the 46 (21.7%) LN patients had moderate/severe IFTA on kidney biopsy. LN patients with moderate/severe IFTA had an increased urinary C9-to-CD59 ratio [median 0.91 (0.83-1.05) vs 0.81 (0.76-0.91), p=0.01]. Urinary C3 and CFI levels in LN patients with moderate/severe IFTA were higher compared to those with none/mild IFTA [C3 median (IQR) 24.4(23.5-25.5) vs. 20.2 (18.5-22.2), p= 0.02], [CFI medium (IQR) 28.8 (21.8-30.6) vs. 20.4 (18.5-22.9), p=0.01]. Complement C9, CD59, C3 and CFI correlated with TGFßR1, PDGFß, and PDGFRß, while C9, CD59 and C3 correlated with TGFßR2. CONCLUSION: This study is one of the first to compare the urinary complement profile in LN patients with moderate/severe IFTA and none/mild IFTA in human tissues. This study identified C3, CFI, and C9-to-CD59 ratio as potential markers of tubulointerstitial fibrosis in LN.
