Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes

Abstract

Diabetic nephropathy is the leading cause of end stage renal disease. The urinary albumin to creatinine ratio is used as a predictor for the development of nephropathy but it is neither sensitive nor specific. Here we used liquid chromatography/mass spectrometry on urine of eight normoalbuminuric patients with type 2 diabetes from the VA Diabetes Trial to identify candidate markers for loss of renal function. Initial verification of 7 markers (agrin, haptoglobin, mannan-binding lectin serine protease 2, LAMP-2, angiotensinogen, NGAL and uromodulin) in the urine of an additional 30 patients showed that haptoglobin was the best predictor of early renal functional decline. We then measured this in the urine of 204 patients with type 2 diabetes who did not yet have significant kidney disease (eGFR stage 2 or better and an albumin to creatinine ratio less than 300 mg/g). In comparing the highest to lowest tertile, the odds ratio for having early renal function decline was 2.70 (CI 1.15, 6.32) using the haptoglobin to creatinine ratio compared to 2.50 (CI 1.14, 5.48) using the albumin to creatinine ratio after adjusting for treatment group and use of ACE inhibitors. Addition of the haptoglobin to creatinine ratio to a model using the albumin to creatinine ratio to predict early renal function decline resulted in improved predictive performance. Thus, the haptoglobin to creatinine ratio may be useful to predict patients with type 2 diabetes at risk of nephropathy prior to the development of macroalbuminuria or reduced GFR.

Prediction of development and maintenance of high albuminuria during chronic renin–angiotensin suppression by plasma proteomics

“…The accumulation of reactive oxygen species produced by activated neutrophils and macrophages [18], the endoplasmic reticulum stress and cytoskeletal changes, cause local lipid peroxidation producing alterations in glomerular permeability, leading to development of protein leakage into the Bowman's space [19]. The urinary levels of haptoglobin are correlated with the loss of GFR prior to the development of very high albuminuria, owing to the increased glomerular permeability that allows haptoglobin in the serum to leak into the urinary space [20]. We have seen elevated plasma levels of HP in very high albuminuric patients, which might not be counteracted by an increased urinary excretion.…”

The role of novel biomarkers in predicting diabetic nephropathy: a review

“…By including the haptoglobin/ creatinine ratio to a model using the albumin/creatinine ratio to predict early decline in renal function, some investigators reported an improvement in its predictive performance. 54 Thus, it was concluded that the haptoglobin/creatinine ratio may be useful to predict patients with T2DM at risk of nephropathy prior to the onset of macroalbuminuria or reduced GFR.…”

Urinary biomarkers of diabetic nephropathy

“…Of the seven candidate markers that were initially found, only haptoglobin was verified to be the best to predict early renal functional decline. 94 However, when compared with albuminuria, urinary haptoglobin was equivalent in predicting early decline, although the combination of both albuminuria and urinary haptoglobin improved the ability to predict decline than either biomarker alone.…”