From screening to treatment: the new landscape of diabetic kidney disease

Between 2011 and 2014, only about 21% of people with CKD stages 3 and 4 with diabetes were aware of their diagnosis [5]. This issue led the National Kidney Foundation to label CKD as “the under-recognized public health crisis” in the USA [8]. However, one of the challenges of diagnosing CKD is that patients often remain asymptomatic until the disease has reached an advanced stage [9, 10]. In this collection, George C. and colleagues highlight the disproportionately high burden of CKD and diabetes in LMICs [11]. Some factors that play a role include lack of disease awareness, late referrals, and the cost of screening, among others. The authors found that screening for CKD in people with diabetes is generally infrequent in LMICs, which is contributed by the lack of a fully subsidized healthcare program for people with non-dialysis CKD, resulting in high out-of-pocket costs. In order to reduce the burden and progression of diabetes, Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend that all patients with diabetes undergo annual serum creatinine-based estimated glomerular filtration rate (eGFR) and urine tests to evaluate for albuminuria [12]. However, in LMICs, the dipstick test for urinary protein remains the most frequently used due to its cost-effectiveness and accessibility. As the authors point out, the inclusion of serum cystatin C in the eGFR estimation equations has proven to be more accurate than creatinine-based estimations. However, it remains to be explored whether this is true across different populations in the globe. Finally, prediction models to estimate the risk of undiagnosed CKD and the risk of progression of CKD in diabetics are being increasingly used in the USA. Even though they allow identifying those most likely to benefit from more aggressive interventions, they are population specific. Notably, albuminuria or impaired eGFR alone are associated with 10-year mortality of 18% and 24%, respectively, in people with diabetes. However, mortality is more than additive when both abnormalities are present, reaching nearly 50% [13, 14].

Glycemic monitoring and intensive glycemic control still play an important role in preventing diabetic kidney disease (DKD) in the early stages, although overall CKD progression and cardiovascular mortality may not be significantly reduced after the onset of DKD [15]. KDIGO guidelines recommend a target hemoglobin A1c (HbA1c) ranging from < 6.5 to < 8.0% unless the patient is at increased risk of hypoglycemia [12]. However, as Hassanein and Shafi pointed out in this collection, HbA1c is a less reliable marker for diabetes control due to the concomitant presence of anemia in people with DKD, particularly in those with advanced CKD [16]. Nevertheless, to date, it remains the gold standard method to monitor blood glucose control in this high-risk population. The authors present data showing that continuous glucose monitoring correlates with hemoglobin A1c and other indirect markers such as fructosamine, glycated albumin, and 1,5-anhydroglucitol in people with diabetes. But they also carry their own caveats. Proteinuria and hypoalbuminemia, common findings in CKD patients, can affect fructosamine and glycated albumin levels. Regarding 1,5-anhydroglucitol, it is highly dependent on tubular glucose reabsorption, which could be variable in patients with CKD. As one can realize, none of these markers are reliable in a population with DKD. Therefore, we suggest continuous glucose monitoring as an emerging tool to achieve glycemic control, but certainly, more studies are required to validate its efficacy in this population [16].

Despite the alarming statistics about the projected rates of increase in diabetes and the room for improvement in screening for DKD, among US adults with diabetes, all-cause mortality has declined by 20% [5]. This has been attributed to intensified, targeted therapies and lower cardiovascular disease (CVD). However, people with diabetes still have higher mortality than the rest of the population, suggesting the role of other risk factors. Previous literature has shown that estimated glucose disposal rates (eGDRs), a surrogate of insulin resistance, predict all-cause mortality in type 2 diabetes, independent of DKD. Therefore, in this collection, Penno and colleagues observed that the more insulin resistance, the higher the CVD risk. This relationship was independent of traditional CVD risk factors. Furthermore, eGDRs significantly affected mortality in people with non-DKD and normoalbuminuric DKD but not in those with albuminuric DKD. The authors suggest that mortality could be mediated by albuminuria in people with albuminuric DKD and not by insulin resistance [17].

Overall, patients with CKD are over 5 times more likely to die from cardiovascular causes than to progress to ESKD [9]. Cardiovascular morbidity also plays an essential role in people with diabetes. A major public health concern is the impact of coronary artery disease and stroke on disability and healthcare costs. In this collection, Kaze and colleagues looked at factors that increase the risk of stroke in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The authors reported that the higher the albuminuria (above 30 mg/g) and the lower the eGFR (below 60 mL/min/1.73 m²), the higher was the risk of stroke. Further, compared to no CKD, worsening CKD stages defined by the KDIGO criteria were associated with an increased risk of stroke [18].

As outlined by Hanouneh and colleagues in this collection, treatment can be targeted to the stage of DKD. Therefore, in the early stages, intensive glycemic control is critical, with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) being excellent candidates when the eGFR is above 30 ml/min per 1.73 m² [19]. Glucagon-like peptide-1 receptor agonists are an additional tool to manage hyperglycemia in this high-risk population. Further, optimal blood pressure control should be achieved with a blood pressure goal below 130/80 mmHg, ideally with a renin–angiotensin–aldosterone system (RAAS) blockade agent [12, 20]. In addition, KDIGO guidelines suggest that individuals with DKD follow a diet low in sodium (< 2 g/day), maintain a protein intake of 0.8 g/kg/day for those not on dialysis, and exercise for at least 150 min per week as tolerated [12]. Fortunately, new treatment strategies have emerged to help curve the epidemic of DKD. SGLT2is were found to have significant cardiovascular benefits and to be renoprotective, independent of the blood-glucose-lowering effect [21‐23]. Additionally, finerenone, a highly selective nonsteroidal mineralocorticoid receptor antagonist (MRA), produces potent anti-inflammatory and antifibrotic effects beyond RAAS blockade agents and significantly reduces proteinuria and DKD progression [24]. These therapeutic advances are summarized in Table 1.

Importantly, a recent study highlighted in this series on DKD identified predictors of cardio-kidney complications and treatment failure in this high-risk population treated with SGLT2 inhibitors. Using a retrospective study design and analyzing data from a large administrative health claims database of a national insurer, Kovesdy and colleagues identified the following risk factors, such high baseline CVD risk profile, atrial fibrillation, peripheral arterial disease, and heart failure [25].