C4d Identified as Independent Predictor of Disease Progression in IgA Nephropathy in new research

IgAN is also known as Berger's disease. It is a leading cause of renal failure with no consolidative cure and remains a permanent member of many registries in developing countries. Due to the lack of any evidence for the relevance of therapies for this disease, complement system involvement has been an area of growing interest in relation to IgAN. The lectin pathway of the complement system was associated with the pathogenesis of the disease, and this study advances towards identifying C4d as the prognostic marker that would predict the outcome of the disease.

This case-control prospective study tried to evaluate the prognostic value of C4d in primary IgAN, particularly the incidence rate of C4d deposition and its relationship with the progression of disease. It was a monocentric cohort study on patients selected from the kidney biopsy register at Dubrava University Hospital, Croatia, within the time span between January 2007 and December 2017. The inclusion criteria were IgAN or IgA vasculitis, more than or equal to 8 glomeruli available for microscopy, and no known secondary cause of IgAN.

Kidney failure was the primary outcome, which was assessed as eGFR less than 15 mL/min/1.73 m² or the start of kidney replacement therapy. The patients were further stratified into C4d-positive or C4d-negative categories based on the staining of the kidney tissue by immunohistochemistry. Further studies were conducted at outpatient sites to monitor the disease progression among the patients.

• Among the 95 subjects included in the final analysis, 45.3% of the participants were C4d-positive.

• The median age at diagnosis was 44.6 years, and the cohort had 71.6% males.

• Clinical indicators at diagnosis were poorer for the C4d-positive patients compared with the C4d-negative patients as evidenced by higher levels of systolic blood pressure (135 vs 130 mmHg; P = 0.039), diastolic blood pressure (90 vs 80 mmHg; P = 0.006), proteinuria (2.7 vs 1.5 g/day; P = 0.018), and lower levels of kidney function (53 vs 79 mL/min/1.73 m²; P < 0.001).

• A median follow-up of 102.2 months elapsed before progression to kidney failure in 17.9% of patients.

• The high proportion and the statistically significant difference between C4d-positive and C4d-negative patients further emphasize the relevance of this finding: 15 of the 17 kidney failure patients were C4d-positive (P < 0.001), compared with only 2 C4d negative.

• Among those without kidney failure, last follow-up showed a worse result in the patients positive for C4d (higher degree of proteinuria: 1 vs. 0.35 g/d, P < 0.001; and lower eGFR: 52 vs. 81 mL/min/1.73 m²; P < 0.001).

This study highlights the importance of focusing on the complement system, most specifically the lectin pathway, in IgAN. Deposition of C4d as a marker for activation of the complement system within the kidney underscores mechanisms involved in progression of the disease and thus may be targeted as drug targets. Current studies of complement-interfering agents are promising, but studies are needed to make clearer the precise role of the complement system and C4d in IgAN pathogenesis.

C4d is a highly significant marker in the determination of the disease outcome of the patients with IgA nephropathy. In summary, the findings suggest that positivity for C4d is associated with worse renal survival and an increased likelihood to progress into end-stage renal failure. The characterization of C4d as an independent predictor of the disease outcome establishes its further potential role in guiding clinical decisions and subsequently designing therapeutic strategies in IgAN.

Reference:

Zagorec N, Horvatić I, Kasumović D, et al. C4d Is an Independent Predictor of the Kidney Failure in Primary IgA Nephropathy. J. Clin. Med. https://doi.org/10.3390/jcm13175338