Diabetic Nephropathy: from bench to bedside

Diabetes mellitus together with arterial hypertension are the most common causes of chronic kidney disease (CKD). Notably, diabetic kidney disease (DKD) remains a major and independent risk for premature mortality. Therefore, continuous and accurate control of risk factors for the development of diabetic nephropathy is mandatory. Measurement of serum creatinine levels and calculation of estimated glomerular filtration rate (eGFR) according to CKD-EPI equation must be performed annually, Also, measurement of urine albumin and calculation of the urine albumin to creatine ratio rate (uACR) is recommended to be performed annually, too, as  uACR > 30 mg/g creatinine is considered to be a continuous risk factor for cardiovascular disease. Equally important is good glycemic control, as determined by glycated hemoglobin levels of < 7%, as well as control of hypertension, often with more than three anti-hypertensive drugs needed to achieve this goal. Inhibition of the renin-angiotensin-aldosterone system (RAAS) is not only effective in managing hypertension, but seems to reduce albuminuria levels among patients with diabetic nephropathy. However, combination of  angiotensin converting enzyme inhibitors  (ACE’s) with angiotensin receptor antagonists (AT2) or with direct renin inhibitors is not recommended due to the increased risk of hyperkalemia, hypotension and acute kidney injury.  Other antihypertensive drugs which decrease albuminuria levels are the newer dihydropyridines calcium blockers manidipine and the latest b-blockers (carvedilol). Dyslipidemia parameters should be improved, too, especially the serum LDL-cholesterol levels <100 mg/dl. Vitamin D analogues have been shown to decrease albuminuria if eGFR < 60 ml/min/1.73 cm2 on account of a) inhibition of RAAS b) immunomodulatory and anti-inflammatory effects and c) inhibition of interstitial fibrosis in conjunction with FGF-23 (Fibroblast Growth Factor-23). Besides, sodium glucose co-transporter 2 inhibitors, which produce glucosuria seem to possess nephroprotective properties among type 2 diabetic patients. In particular, the EMPAREG study has documented that empagliflozin reduces the relative risk of serum creatinine doubling by 44%, while the relative risk of introducing hemoperfusion has been decreased by 55% within four years. It seems likely that atrasentan, a selective antagonist of the receptor of endothelin A also reduces albuminuria by approximately 35%. Moreover, the significance of substances with anti-inflammatory properties, such as oxidase inhibitors, pentoxyfilline, and N-acetyl-cysteine remains to be elucidated. It is noteworthy that weight loss together with dietary consultation, not only are implicated in better glycemic control and dyslipidemia management, but also  in improving diabetic nephropathy per se.