Clinical and Pathological Significance of Autoantibodies to Erythropoietin Receptor in Type 2 Diabetic Patients With CKD

Abstract

IntroductionWe examined the impact of autoantibodies on the erythropoietin receptor (EPOR) in type 2 diabetic patients with chronic kidney disease (CKD).MethodsA total of 112 Japanese patients with type 2 diabetes who had CKD were enrolled in this study and followed for a mean of 45 months. Sera from these patients were screened for anti-EPOR antibodies using enzyme-linked immunosorbent assays.ResultsAnti-EPOR antibodies were detected in 26 patients (23%). Anti-EPOR antibodies were associated with low hemoglobin concentrations and decreased renal function. In patients with biopsy-proven diabetic nephropathy, anti-EPOR antibodies were associated with increased levels of interstitial inflammation. A decrease in renal function was observed more frequently in patients with antibodies than in those without antibodies, and the presence of the antibodies together with well-known clinical parameters, including proteinuria and low glomerular filtration rate, was a significant risk factor for end-stage renal disease. In human tubular epithelial HK-2 cells, IgG fractions containing anti-EPOR antibodies upregulated the expression of monocyte chemoattractant protein-1 mRNA under a high concentration of glucose.ConclusionAnti-EPOR antibodies might be involved in the progression of renal lesions and in the impaired erythropoiesis in type 2 diabetic patients with CKD. Furthermore, the presence of anti-EPOR antibodies may be an additional predictor for end-stage renal disease in type 2 diabetes.

Comparison of Circulating Biomarkers in Predicting Diabetic Kidney Disease Progression With Autoantibodies to Erythropoietin Receptor

“…We have previously reported using a homogenous Japanese cohort with DKD (mean eGFR was 42 ml/min/1.73 m 2 and mean urinary protein was 2.7 g/day) that elevated anti-EPOR antibodies levels carried the highest risk of ESKD compared to those with undetectable or low anti-EPOR antibodies levels (hazard ratio 2.78 [95% CI 1.20, 6.43]). 10 We validated these findings in the current study using a more diverse cohort of the ADVANCE trial cohort that consists of individuals with earlier stages of DKD (mean eGFR J o u r n a l P r e -p r o o f was 74 ml/min/1.73 m 2 and median UACR was 15 mg/g). Our findings further suggest that anti-EPOR antibodies can be a useful circulating biomarker for predicting the risk of kidney disease progression even in earlier stages of DKD.…”

“…This may explain the clinical observation that individuals with diabetes mellitus are more likely to be anaemic than individuals without. 5,6 We also found that anti-EPOR antibodies upregulated the expression of monocyte chemoattractant protein-1 (MCP-1) mRNA on human tubular epithelial cells under high glucose conditions, 10 suggesting a mechanistic link of anti-EPOR antibodies with the inflammatory cascade.…”

“…However, we previously reported that the association between anti-EPOR antibodies and kidney outcome remained significant even after adjusted for hemoglobin. 10 Finally, at the Table 2. Adjusted odds ratios (and 95% confidence intervals) for the composite kidney outcome after adjustment for other circulating biomarkers.…”

“…Plasma levels of anti-EPOR antibodies were measured by enzyme-linked immunosorbent assay (ELISA), as previously described. 10 In brief, 96-well microplates…”

Diabetic Nephropathy: A Comparison of the Clinical and Pathological Features between the CKD Risk Classification and the Classification of Diabetic Nephropathy 2014 in Japan

“…Recently, anti-erythropoietin receptor (EPOR) antibodies have been reported to be pathologically associated with renal interstitial inflammation in type 2 diabetic patients. Furthermore, autoantibodies to EPOR may be involved in disease progression and are a useful serologic marker for the progression of kidney dysfunction in type 2 diabetic patients with CKD (22,23). These biomarkers may be clinically useful and valuable.…”