Complement Activation in Patients With Diabetic Nephropathy

Abstract

IntroductionComplement activation plays a role in various organs in patients with diabetes. However, in diabetic nephropathy (DN), the role of complement activation is poorly understood. We examined the prevalence and clinical significance of complement deposits in the renal tissue of cases with type 1 and type 2 diabetes with and without DN.MethodsWe measured the prevalence of glomerular C4d, C1q, mannose-binding lectin (MBL), and C5b-9 deposits in 101 autopsied diabetic cases with DN, 59 autopsied diabetic cases without DN, and 41 autopsied cases without diabetes or kidney disease. The presence of complement deposits was scored by researchers who were blinded with respect to the clinical and histological data.ResultsC4d deposits were more prevalent in cases with DN than in cases without DN in both the glomeruli (46% vs. 26%) and the arterioles (28% vs. 12%). C1q deposits were also increased in the glomerular hili (77% vs. 55%) and arterioles (33% vs.14%), and were correlated with DN (P < 0.01). MBL deposits were only rarely observed. C5b-9 deposits were more prevalent in the cases with diabetes mellitus (DM) than in the cases without DM (69% vs. 32%; P < 0.001). Finally, glomerular C4d and C5b-9 deposits were correlated with the severity of DN (ρ = 0.341 and 0.259, respectively; P < 0.001).ConclusionComplement activation is correlated with both the presence and severity of DN, suggesting that the complement system is involved in the development of renal pathology in patients with diabetes and is a promising target for inhibiting and/or preventing DN in these patients.

Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis

“…27 In contrast, complement-mediated endothelial injury could also lead to podocyte injury. We previously reported that C4d is often present in the kidneys of patients with extensive endothelial injury, [28][29][30][31] and others have shown that complement activation is involved in endothelial injury in a variety of kidney diseases. [32][33][34][35] Experimental models have shown that podocyte damage can follow primary endothelial cell injury, 36 and subsequent podocyte depletion has been suggested as the final common pathway resulting in proteinuria and reduced estimated glomerular filtration rate.…”

Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin

“…DN has always been recognized as ESRD all over the world, which may be attributed to severe hyperglycemia [30]. Researches already evaluated the various treatments and therapeutic targets, which ameliorating renal fibrosis, including drugs, endocrine hormones, complement systems and miRNAs [8,[31][32][33]. However, these methods have different disadvantages, which hinder the efficacy of the clinical application.…”

Association of Glomerular Complement C4c Deposition With the Progression of Diabetic Kidney Disease in Patients With Type 2 Diabetes

“…Moreover, patients and animals with DKD exhibited kidney increase in C1q and C3 ( 28 , 29 ). Glomerular depositions of C1q, C4d, and C5b-9 in patients with DKD were more common than those without DKD, and glomerular depositions of C4d and C5b-9 were associated with the DKD severity ( 11 ). In our study, not only proteinuria but also the rate of DKD progression were significantly higher in biopsy-proven DKD patients with the glomerular immune complex of combined C4c with one or two of C3/C1q deposition than those with negative C4c deposits by the Kaplan-Meier survival analysis.…”

“…Several clinical studies have reported the association between complement component C4 and diabetes. Plasma C4 levels were associated with microvascular disease in diabetic patients ( 11 ). In addition, the serum C4 was significantly associated with the progression of Type 2 DKD ( 12 ).…”