Plasma Galactose-Deficient IgA1 and C3 and CKD Progression in IgA Nephropathy

Abstract

Background and objectives: Increased circulating galactose-deficient IgA1 and subsequently complement activation both play important roles in the pathophysiology of IgA nephropathy. However, their relationship to disease severity and progression remains unclear.

Design, setting, participants, & measurements: We assessed 1210 participants in a cohort study of biopsy-proven IgA nephropathy at Peking University First Hospital. Plasma concentrations of galactose-deficient IgA1 and complement component C3 were measured at the time of biopsy. We tested associations of galactose-deficient IgA1 and galactose-deficient IgA1/C3 ratio with CKD progression event, defined as ESKD or 50% decline in eGFR, using Cox proportional hazards models and restricted cubic splines.

Results: After a median follow-up of 43 months (interquartile range, 24-76 months), 172 (14%) participants reached the CKD progression event. The association of galactose-deficient IgA1 levels and CKD progression event showed a nonlinear relationship. The risk of CKD progression events was greater with higher plasma galactose-deficient IgA1 levels but reached a plateau when galactose-deficient IgA1>325 U/ml, whereas the risk of CKD progression events monotonically increased with higher galactose-deficient IgA1/C3 ratio. After adjustment for traditional risk factors (demographics, eGFR, proteinuria, hypertension, Oxford pathologic score, and corticosteroids/immunosuppressive therapy), higher levels of galactose-deficient IgA1/C3 ratio were independently associated with CKD progression event (per natural log-transformed [galactose-deficient IgA1/C3], hazard ratio, 2.03; 95% confidence interval [95% CI], 1.25 to 3.29; P=0.004). In reference to the first quartile of the galactose-deficient IgA1/C3 ratio, hazard ratios were 1.71 (95% CI, 1.01 to 2.89) for the second quartile, 1.55 (95% CI, 0.91 to 2.63) for the third quartile, and 2.17 (95% CI, 1.33 to 3.56) for the fourth quartile.

Conclusions: In IgA nephropathy, plasma galactose-deficient IgA1/C3 ratio was associated with CKD progression event independent of clinical and biopsy characteristics.

Keywords: IGA glomerulonephritis; IgA nephropathy; adrenal cortex hormones; biopsy; chronic kidney failure; chronic renal insufficiency; complement activation; complement c3; demography; follow-up studies; galactose; glycation; hypertension; immunoglobulin A; kidney development; proportional hazards models; proteinuria; risk factors; universities.

Graphical abstract

Figure 1.

Associations of plasma galactose-deficient IgA1 concentration and plasma galactose-deficient IgA1/C3 ratio with CKD progression. Models were performed using restricted cubic splines with knots at the 25th, 50th, and 75th percentiles. The reference value was set at the medians. The solid line represents the estimated hazard ratio, the shaded area represents the 95% confidence bands, and the histogram represents the distribution of galactose-deficient IgA1/C3 ratio in participants with IgA nephropathy. Models were adjusted for age; sex; eGFR; proteinuria; hypertension; Oxford M (mesangial hypercellularity score), E (the presence of endocapillary proliferation), S (segmental glomerulosclerosis/adhesion), T (severity of tubular atrophy/interstitial fibrosis), and C (presence of crescent) scores; and corticosteroids/immunosuppressive therapy. Gd-IgA1, galactose-deficient IgA1; ln, natural log transformation.

Figure 2.

Kaplan–Meier kidney survival curves of participants with IgA nephropathy according to plasma galactose-deficient IgA1/C3 ratio. The time zero was kidney biopsy. The division between the four groups of participants was on the basis of quartiles of galactose-deficient IgA1/C3.