New Biomarkers to Predict Risk for Nephropathy in Diabetes

Editor's Note: The following is an edited transcript of a conversation taped at the 2014 annual meeting of the European Association for the Study of Diabetes. Alfred Penfornis, MD, PhD, a diabetologist in Besançon, France, and Pierre-Jean Saulnier, MD, PhD, of the Clinical Investigation Center of Poitiers, France, discussed the increased rate of nephropathy in diabetic patients over the past 50 years, as well as new investigational biomarkers that could help better identify patients at risk for progression toward renal failure.

Dr Penfornis: The life expectancy of patients with type 1 and type 2 diabetes has increased dramatically over the past 50 years. It is still not on par with that of the general population, but it comes close. This is mainly due to the decrease in cardiovascular (CV) complications and mortality.

The downside is that we have seen the emergence of end-stage renal disease (ESRD). Before, diabetic patients were dying of CV complications before reaching this stage. Then, increasingly, they were dying on dialysis.

We now see patients on dialysis living longer, and we see the emergence of foot ulcers. Besides that, we continue to see a reduction in CV mortality and microvascular complications, and fewer and fewer patients reach the point of blindness, but also fewer reach the point of amputation. After a very unfavorable rise in the rates of ESRD, there has been stagnation, and now a slight decrease of this complication. We can, hopefully, expect more improvement in this area in the coming years.

Dr Saulnier: Yes, we now have studies on several biomarkers that will allow us to identify patients most at risk of developing renal complications, some with conditions severe enough to start dialysis. These biomarkers come from different pathways.

In the inflammatory pathways, we looked at the tumor necrosis factor (TNF) receptor as a particular biomarker. We also investigated the pathways of natriuresis and that of an antidiuretic hormone with a marker called copeptin, and we also studied the pathways of endothelial function with adrenomedullin.^[1]

In one study, we followed 1500 type 2 diabetic subjects for more than 10 years in Poitiers, France (the SURDIAGENE cohort). We were able to show that the TNF receptor was involved in predicting kidney disease: The more inflammation, the more TNF, the more TNF receptors, the higher the likelihood of kidney complications and going on dialysis. That was the first step.

We tried to assess whether this marker assay in routine practice would provide clinicians with an additional tool to complement the tools we have now (clinical and biological markers). We have in fact observed that the assay for this TNF receptor improves the accuracy of predicting dialysis risk at 5 years in patients with type 2 diabetes.

We are not yet in a position to offer this marker in clinical practice; however, that is the goal of ongoing research.

Other markers also are being studied to predict kidney lesions, tubular lesions, and glomerular lesions, along with older markers such as uric acid, which was also associated with the risk for kidney complications and the risk of being placed on dialysis.^[2] The decline of renal function through the annual slope of glomerular filtration rate serves as an interim marker.

An upcoming clinical trial will take the next step in this research process. Researchers have proposed to use allopurinol to reduce uric acid in patients with type 1 diabetes, to evaluate the therapeutic benefit of targeting this pathway in terms of renal protection. That is the next step, to evaluate causality, and we imagine that after the study ends—in 2 or 3 years—we will have a new tool to limit the deterioration of renal function in patients with type 1 diabetes.^[3]

Dr Penfornis: If the results are positive, indeed. For the TNF receptor, it is too early to consider a therapeutic pathway; we must first confirm that it is actually a marker.

Then it should be studied in a randomized trial, as it will be done with allopurinol, with the aim of studying causality and making this marker a risk factor on which we could intervene.

These are promising pathways to further reduce complications, and it is true that kidney failure remains a very serious complication in our patients.

Dr Saulnier: Dialysis is certainly feared, which is why we are interested in studying earlier degradation or complications that arise before dialysis.

Regarding insulin therapy, type 1 diabetes, and nephropathy, there is an interesting trial being conducted by the Danish team of the Steno Diabetes Center. They are looking at whether continuous subcutaneous insulin infusion was more effective in protecting renal function (ie, deterioration of glomerular filtration rate and onset of microalbuminuria) compared with multiple daily injections.^[4] It is not a randomized clinical trial but a study conducted using retrospective data from their center.

It actually appears that the continuous infusion is more favorable in preventing renal function decline and microalbuminuria. The study involved 500 patients over 4 years of follow-up. This information is valuable, but there was no available information on the glycemic variability, which was not recorded. I believe they will continue to work in that direction to couple the continuous glucose monitoring with continuous infusion in order to prevent renal complications.

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