CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease

Abstract

The increasing global prevalence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has prompted research efforts to tackle the growing epidemic of diabetic kidney disease (DKD; also known as diabetic nephropathy). The limited success of much of this research might in part be due to the fact that not all patients diagnosed with DKD have renal dysfunction as a consequence of their diabetes mellitus. Patients who present with CKD and diabetes mellitus (type 1 or type 2) can have true DKD (wherein CKD is a direct consequence of their diabetes status), nondiabetic kidney disease (NDKD) coincident with diabetes mellitus, or a combination of both DKD and NDKD. Preclinical studies using models that more accurately mimic these three entities might improve the ability of animal models to predict clinical trial outcomes. Moreover, improved insights into the pathomechanisms that are shared by these entities - including sodium-glucose cotransporter 2 (SGLT2) and renin-angiotensin system-driven glomerular hyperfiltration and tubular hyper-reabsorption - as well as those that are unique to individual entities might lead to the identification of new treatment targets. Acknowledging that the clinical entity of CKD plus diabetes mellitus encompasses NDKD as well as DKD could help solve some of the urgent unmet medical needs of patients affected by these conditions.

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

“…However, the incidence of amputations was not increased with use of canagliflozin in the CREDENCE trial, with use of empagliflozin in the EMPA‐REG OUTCOME trial or with use of dapagliflozin in the DECLARE–TIMI 58 trial . In a meta‐analysis of the CVOTs, significant heterogeneity (I = 79.1%) for amputations was found across the three CVOTs, with an increased risk of amputation observed only in the CANVAS study …”

“…Canagliflozin significantly reduced the risk of the primary composite efficacy outcome for the composite of ESRD, doubling of serum creatinine or death from renal or CV causes by 30% ( P = .00001) . In the DECLARE–TIMI 58 trial, dapagliflozin was associated with a 24% reduction in the risk of the composite of at least a 40% decrease in eGFR to less than 60 mL/min/1.73 m, ESRD or death from renal or CV causes, with a 47% reduction in the risk of the composite of at least a 40% decrease in eGFR to less than 60 mL/min/1.73 m, ESRD or death from renal causes, with a 46% reduction in the risk of a sustained decrease in eGFR of at least 40% to less than 60 mL/min/1.73 m, and with a 59% reduction in the risk of ESRD or death from renal causes compared with placebo . The renoprotective benefits of dapagliflozin were observed among patients with a relatively high level of renal function at baseline (mean eGFR, 85 mL/min/1.73 m), indicating a potential role for dapagliflozin in the early prevention of CKD in patients with T2D .…”

“…The DELIGHT study reported the renoprotective effects of dapagliflozin in patients with T2D and moderate‐to‐severe CKD who were undergoing antihypertensive treatments . Treatment with dapagliflozin for 24 weeks resulted in significant reductions in albuminuria, with a mean change from baseline in urine albumin‐to‐creatinine ratio of −21.0% (95% confidence interval [CI], −34.1 to −5.2; P = .011) and in eGFR, with a mean change from baseline of –2.4 mL/min per 1.73 m (95% CI, −4.2 to −0.5; P = .011) as compared to placebo . Taken together, these findings indicate that SGLT‐2is may provide renal protection, in addition to CV benefits, in patients with T2D.…”

“…The underlying mechanisms of diabetic kidney disease include changes in haemodynamic, metabolic and inflammatory pathways that result in impaired renal function (Figure ) . Chronic hyperglycaemia in patients with T2D may also contribute to the development of diabetic kidney disease by inducing thickening of the glomerular basement membrane and podocyte injury . Glomerular hyperfiltration may be caused by efferent arteriolar vasoconstriction as the result of increased levels of angiotensin II, because of activation of the renin–angiotensin–aldosterone system, and of endothelin 1 .…”

“…Patients with type 2 diabetes (T2D) are at increased risk of developing macrovascular and microvascular complications, which are associated with high morbidity and mortality . In cardiovascular outcomes trials (CVOTs) of patients with T2D and established CV disease (CVD) or varying levels of CV risk, significant improvements in composite CV and renal end points have been observed with some sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is) (dapagliflozin, empagliflozin and canagliflozin) compared with placebo .…”