Is There any Clinical Value in determining GDF-15 during the Progression of Diabetic Nephropathy?

Diabetic nephropathy is a progressive kidney disease and affects 20–40% of Type 1 (T1D) and 2 (T2D) diabetic patients. Type 1 diabetic patients who have progressed to the final stages of nephropathy, eventually develop kidney failure - 50% of them within 10 years from the onset of overt nephropathy and >75% by the 20 year mark. Currently, this condition is diagnosed through the detection of increased urinary albumin excretion, but a growing body of evidence suggests that the risk for developing diabetic nephropathy starts when urinary albumin excretion levels are still within the normal range. If the onset of nephropathy could be detected before urinary albumin rises, patients could potentially be placed on treatment to prevent this development. We also know that the development of proteinuria and focal glomerulosclerosis is directly associated with myocardial damage. An increase in circulating troponins is observed commonly in patients with chronic kidney diseases (CKD) and is associated with the kidney disease progression and death. The association of circulating troponin and kidney damage is related rather to the cardiac injury than the diminished clearance. 

Growth Differentiation Factor 15 (GDF15), also termed Macrophage-Inhibiting Cytokine 1 (MIC-1), is a member of the transforming Growth Factor- superfamily. GDF15 is a cytokine released from various cells (including macrophages, cardiomyocytes and adipocytes) under stressful conditions. Circulating GDF-15 is present in the blood of all individuals at levels ranging from 200 to 1200 pg/mL in the apparently healthy; the level rises dramatically when disease develops. The overall and serum GDF-15 expression levels increase with age, body mass index (BMI), development of insulin resistance, T1D and development of T2D. Higher GDF-15 levels are associated with the development of various CVDs, including heart failure, atrial fibrillation and acute coronary syndrome. 

Higher plasma GDF-15 was associated with incidence of CKD and indicates rapid decline in renal function. The higher levels were also predictive of deterioration of kidney function. Studies on renal injury in animal models suggest two possible reasons for the increase in GDF-15 levels during renal diseases. Either the GDF-15 clearance from the circulation is decreased, or during the development of renal diseases its synthesis is increased, or both. In diabetic renal injury the increase in urinary GDF-15 levels has been proved to be associated with proximal tubule injury, thus suggesting that the hypothesis of diminished clearance of GDF-15 through the kidneys is not correct. Renal GDF-15 expression also appears to be up-regulated in response to metabolic acidosis and kidney injury. Besides other well-known cardiovascular risk factors, like NT-proBNP and GFR, higher levels of GDF-15 are a predictive marker of cardiovascular mortality in patients with diabetic nephropathy. Higher plasma GDF-15 levels were also associated with the Mogensen stage in Type 2 diabetic nephropathy and thus, it is an independent risk factor for increased microalbuminuria. Being significantly correlated with microalbuminuria and eGFR, GDF-15 could be useful in early diagnosis, evaluation, and prediction of the outcome of Type 1 and 2 diabetic nephropathy. 

Overall the progressive increase of plasma levels of GDF-15 in patients with either T1D or T2D is associated with renal function decline, thus suggesting that GDF-15 might serve as a biomarker of an early renal structural injury of glomerular or tubular origin. Since, nowadays, an automated method for the measurement of GDF-15 levels is available, it must undergo rigorous validation in multiple cohorts prior to its implementation in the clinical assessment.