The New Biology of Diabetic Kidney Disease-Mechanisms and Therapeutic Implications

Abstract

Diabetic kidney disease remains the most common cause of end-stage kidney disease in the world. Despite reductions in incidence rates of myocardial infarction and stroke in people with diabetes over the past 3 decades, the risk of diabetic kidney disease has remained unchanged, and may even be increasing in younger individuals afflicted with this disease. Accordingly, changes in public health policy have to be implemented to address the root causes of diabetic kidney disease, including the rise of obesity and diabetes, in addition to the use of safe and effective pharmacological agents to prevent cardiorenal complications in people with diabetes. The aim of this article is to review the mechanisms of pathogenesis and therapies that are either in clinical practice or that are emerging in clinical development programs for potential use to treat diabetic kidney disease.

Graphical Abstract

Figure 1.

Proposed anti-inflammatory mechanisms in the kidney mediated by SGLT2 inhibition in diabetes. SGLT2, sodium glucose co-transporter 2.

Figure 2.

Summary of renal composite outcomes with SGLT2 inhibition in EMPA-REG OUTCOME, CANVAS, DECLARE, and CREDENCE Trials. The renal composite outcome shown for EMPA-REG, CANVAS, and CREDENCE is incident or worsening nephropathy, defined as progression to macroalbuminuria; a doubling of the serum creatinine level; the initiation of renal-replacement therapy; or death from renal disease. For DECLARE, the renal composite outcome shown is sustained decline of at least 40% in estimated glomerular filtration rate to <60 mL/min/1.73 m², end-stage renal disease, or death from renal causes. CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy; DECLARE, Dapagliflozin Effect on Cardiovascular Events; EMPA-REG, Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; HR, hazard ratio.

Figure 3.

Forest plot of hazard ratios for the primary and secondary outcomes of the SONAR Trial. Composite renal outcome: composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min/1.73 m² sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure. Cardiorenal composite endpoint: doubling serum creatinine, end-stage kidney disease, cardiovascular death, nonfatal myocardial infarction, or non-fatal stroke. Primary outcome in all patients (responders and nonresponders combined). Cardiovascular composite endpoint: cardiovascular death, nonfatal myocardial infarction, or non-fatal stroke. Abbreviations: CI, confidence interval; eGFR, glomerular filtration rate; SONAR, Study of Diabetic Nephropathy with Atrasentan.