Progression of diabetic kidney disease: Who is at risk?

Inhibition of rennin angiotensin system is the cornerstone of the management of diabetic kidney disease (DKD) for decades[1] with latest addition of SGLT2 inhibition.[2] Despite these measures, after the onset of overt nephropathy in type 2 diabetes, kidney disease is progressive and is a major cause of End Stage Renal Disease (ESRD) worldwide. Identifying and addressing the new modifiable risk factors can potentially add to the optimum management of DKD. Current definition and classification of chronic kidney disease (CKD)[3] doesn't give an insight into the risk of progression of the disease. This is especially so in patients with no significant albuminuria and mildly reduced glomerular filtration rate (GFR) who in fact are largely contributing to the rising incidence of CKD. Although most of these individuals will never progress to more severe or dialysis requiring renal failure; it is important to distinguish “progressors” from “nonprogrerssors” in earlier stages of CKD so as to effectively focus the therapies to the patients who deserve them the most.

In this issue of JPGM,[4] Huanget al. evaluated a cohort of 320 patients with type 2 diabetes and CKD stage 3 for the identification of the risk of disease progression over an observation period of 7 years. They have reported that female sex, change in eGFR in first 2 years, fluctuations in diabetes and blood pressure control were independent risk factors for disease progression. Male sex is associated with significantly higher risk of progression of kidney disease in the reported literature.[5] On the contrary, Huang et al[4] have noted that female sex was an independent risk factor for progression in their patients, a finding that deserve further exploration looking at genetic, hormonal as well as factors like socioeconomic status, and gender bias in access to the health care which is not uncommon in east Asian countries. Change in eGFR in the first 2 years was identified as another risk factor for progression, for which there may be two possible explanations. First, initial GFR decline identifies patients at the risk of progression due to genetic or traditional risk factors and so are destined to progress faster than those whose kidney function was stable in the first few years after diagnosis. Second, renal function decline in the first 2 years may be due to episodes of Acute Kidney Injury (AKI) which are not only more common in patients with underlying CKD but are known to recover by maladaptive repair mechanisms[6] leading to residual damage and accounting for apparently faster progression of CKD.

Observational studies are limited by their design and definitive conclusions about causality of the observed associations merit further research. Two other risk factors that were found to be associated with CKD progression in this study4need careful interpretation: namely fluctuations in the blood pressure and blood sugar. Increasingly, it is realized that clinically measured blood pressure [BP] is not a reliable metric of BP control[7] and conclusions based on such readings can be misleading. It is well known that BP regulation is one of the important functions of the kidney; and that controlling the patient's BP becomes increasingly difficult with progression of the stage of CKD. Similarly, it is well known that blood glucose control can get adversely affected with renal function decline. Insulin resistance is increased in earlier CKD stages[8] and risk of hypoglycemia increases in advanced renal failure due to impaired degradation of insulin.[9] These factors may explain the observed variations in the blood glucose levels in the present study.4

The present study[4] also poses an important question about definition and classification of CKD in population over age of 60 years. CKD has long been defined and staged by serum creatinine based eGFR which can greatly overestimate the incidence of CKD (especially CKD stage 3) in elderly population.[10] This not only is the cause of panic and anxiety, but also diverts the focus of preventive and therapeutic interventions. Age calibration of CKD classification[11] is one of the suggestions to account for physiological aging-related decrease in GFR and identify those who are likely to develop clinical consequences of reduced GFR. Also, more objective measurements of renal function such as mGFR (measured GFR) should be considered in future research studies analyzing risk factors for CKD progression.