From Screening to Treatment: The New Diabetic Nephropathy Landscape | BMC Medicine

The prevalence of diabetes worldwide in 2021 was 537 million people. This number is expected to increase to 580 and 700 million cases by 2030 and 2045, respectively. [1,2,3]. Additionally, the number of Americans with diabetes (37 million) was estimated at 10.5% of the population in 2018, and is also expected to increase to 14% by 2030. [4]. According to the Centers for Disease Control and Prevention (CDC), 1 in 7 Americans suffered from chronic kidney disease (CKD) in 2021, with diabetes being the leading cause in more than half of the cases. [5]. The growing number of CKD patients in the United States can be attributed in large part to the emerging epidemic of diabetes. In fact, it is estimated that there will be more than one million end-stage kidney disease patients in the United States by 2030, an increase of almost 40% since 2015. [6]. Worldwide, in 2010, there were nearly 500 million adults with CKD, more than 75% of whom resided in low- and middle-income countries (LMICs). [7]. Due to these trends, society as a whole, but health systems and families in particular, will face an increasing financial burden.

From screening to therapeutic advances

Between 2011 and 2014, only about 21% of people with CKD stages 3 and 4 with diabetes were aware of their diagnosis [5]. This problem has led the National Kidney Foundation to call CKD an “underrecognized public health crisis” in the United States. [8]. However, one of the challenges in 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 cost of screening, among others. The authors found that screening for CKD in people with diabetes is generally infrequent in LMICs, which is due to the lack of a fully funded healthcare program for people with CKD. not on dialysis, resulting in high direct costs. To reduce the burden and progression of diabetes, the Kinney Disease Improving Global Outcomes (KDIGO) guidelines recommend that all patients with diabetes undergo annual estimated glomerular filtration rate (eGFR) based on serum creatinine and urine testing to assess albuminuria [12]. However, in PRITIs, the urine protein dipstick test remains the most frequently used due to its cost-effectiveness and accessibility. As the authors point out, the inclusion of serum cystatin C in eGFR estimating equations was found to be more accurate than creatinine-based estimates. However, whether this is true in different populations around the world remains to be determined. Finally, predictive models to estimate the risk of undiagnosed CKD and the risk of CKD progression in diabetics are increasingly used in the United States. Although they identify those most likely to benefit from more aggressive interventions, they are population specific. Notably, albuminuria or altered eGFR alone are associated with a 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].

Glucose monitoring and intensive glycemic control still play an important role in preventing diabetic nephropathy (DRN) in the early stages, although overall CKD progression and cardiovascular mortality are not significantly reduced after onset. of the MRC [15]. KDIGO guidelines recommend a target hemoglobin A1c (HbA1c) of

Despite alarming statistics on predicted rates of increase in diabetes and room for improvement in screening for DKD, among US adults with diabetes, all-cause mortality has decreased by 20% [5]. This has been attributed to intensified and targeted therapies and a decrease in 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 clearance rates (eGDR), a surrogate for insulin resistance, predict all-cause mortality in type 2 diabetes, independent of DKD. Therefore, in this collection, Penno and colleagues observed that the higher the insulin resistance, the higher the risk of CVD. This relationship was independent of traditional CVD risk factors. Additionally, eGDRs significantly affected mortality in people with non-DKD and normoalbuminuric DKD, but not in those with albuminuric DKD. The authors suggest that mortality may be mediated by albuminuria in people with albuminuric DKD and not by insulin resistance [17].

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

As Hanouneh and colleagues have pointed out in this collection, treatment can be targeted to the stage of DKD. Therefore, in the early stages, intensive glycemic control is essential, with metformin and sodium-glucose cotransporter 2 (SGLT2is) inhibitors being excellent candidates when eGFR is greater than 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. In addition, optimal blood pressure control should be achieved with a blood pressure goal of less than 130/80 mmHg, ideally with a renin-angiotensin-aldosterone system (RAAS) blocking agent. [12, 20]. Additionally, KDIGO guidelines suggest that people with DKD follow a low sodium diet (

Table 1 Recent randomized clinical trials in chronic kidney disease of SGLT2is and the selective nonsteroidal mineralocorticoid receptor antagonist

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

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