The level of urinary C4d is associated with disease progression in IgA nephropathy with glomerular crescentic lesions: a cohort study

Abstract

Background Positive glomerular C4d staining, representative of lectin pathway activation, has been proven to be associated with unfavorable outcomes in IgA nephropathy (IgAN). Our previous study suggested that urinary C4d correlated positively with an increase in crescents. While the relationship between urinary C4d and disease severity and progression remains unelucidated. Methods In this study, we enrolled 168 patients diagnosed of IgAN with varying proportions of crescents formation at the time of biopsy. An independent cohort of 107 IgAN patients were enrolled for validation. Kidney biopsy specimens were stained using immunohistochemistry. Urinay C4d levels at renal biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was end-stage kidney disease (ESKD). Results Higher urinary C4d/Ucr levels were associated with a lower estimated glomerular filtration rate (eGFR); massive proteinuria; hypertension; and severe Oxford-M, Oxford-E, Oxford-T and Oxford-C scores. After a median follow-up of 19 months (interquartile range, 9–27 months), 53 (31.5%) participants reached end-stage of kidney disease (ESKD). High urinary C4d/creatinine ratio levels were independently and significantly associated with a risk of developing ESKD (hazard ratio [HR], per standard deviation increment of log transformed C4d/creatinine of 7.623; 95% confidence interval [CI]: 4.117–14.113). Conclusions Urinary C4d/creatinine ratio was a potential useful biomarker that was associated with disease severity and progression in patients with IgAN and crescents.

Systematic Review of the Link Between Oxford MEST-C Classification and Complement Activation in IgA Nephropathy

“…, 30 2022 C4d Spain Adult 34 IHC 34 46 85 (72–101) 2.9 (0.9–3.7) Wang et al. , 11 2022 C4d China Adult 34 urine, ELISA 34 56 33.4 (16.2–61.7) 3.5 (1.7–5.1) Itami et al. , 31 2020 C3, C4, C4d, C1q, C5b9, MBL, MASP1/3, MASP2, properdin, factor B Japan Adult 132 IF 52 55 61.1 (9.7–162) 1.3 (0.04–7.8) Yang et al.…”

“…, 30 2022 Lectin pathway Higher levels in patients with M1, E1, T1-2, C1-2 classes c Wang et al. , 11 2022 No relationship with MEST-C classes a Itami et al. , 31 2020 Associated with T1-2 class a Yang et al.…”

“… 4 , 10 However, the relationship between the MEST-C classification and complement activation in IgAN is not fully understood, and the available evidence is limited and conflicting. Some studies have suggested that complement activation is associated with more severe MEST-C scores, 11 , 12 , 13 , 14 , 15 whereas others have reported no significant correlation between the 2. 16 , 17 , 18 , 19 …”

Clinicopathological characteristics and predictors of renal outcomes in diffuse crescentic glomerulonephritis : a retrospective single-center study from Western China study

“…Plasma exchange therapy has been proven bene cial for patients with ANCA-associated vasculitis or crescentic glomerulonephritis caused by anti-GBM antibodies [19,20]. However, Wang et al suggested that plasma exchange therapy does not improve the prognosis of patients with crescentic IgA nephropathy on top of conventional immunosuppressive therapy [21]. Within our follow-up cohort, a total of 16 patients underwent combination therapy involving plasma exchange, glucocorticoids, and cyclophosphamide.…”

Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy

“…32 In patients with IgA nephropathy, urinary C3a and C5a levels, as well as several inflammatory factors, were increased and related to impaired kidney function and/or disease progression. 33,34 Inflammatory cells residing in the local glomerular were frequently observed in IgA nephropathy, 35 indicating active inflammation in the glomeruli. 36,37 Taking these clues together, we speculated that in addition to the MAC, the inflammation induced by complement activation might also take part in kidney injury and progression of IgA nephropathy.…”