New Strategies To Improve Clinical Outcomes For Diabetic Kidney Disease

Abstract Background: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. 

Main body: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remains to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. Conclusion: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize the treatment of DKD in patients with type 2 diabetes. 

Keywords: Type 2 diabetes, Diabetic kidney disease, Kidney protective agents

Background 

According to the International Diabetes Federation, 537 million adults (20–79 years of age) were living with diabetes mellitus worldwide in 2021, and this number is expected to increase to more than 780 million by the year 2045 [1]. Of these, an estimated 90–95% have type 2 diabetes (T2D) [2, 3]. Among people with T2D, nearly half will develop diabetic kidney disease (DKD), previously termed “diabetic nephropathy” [4, 5]. DKD is the most common cause of kidney failure and end-stage kidney disease (ESKD) leading to the need for kidney replacement therapy (dialysis or transplant) in the world [6, 7]. Moreover, DKD is a leading cause of cardiovascular disease and overall mortality in people with diabetes [8, 9]. Given the ever-increasing prevalence of T2D, early detection and proper management of DKD is of great clinical importance. This review provides an update on DKD pathophysiology, clinical manifestations, and recent breakthroughs in DKD therapies.

Pathophysiology 

Multiple diabetes-driven pathways including hyperglycemia and associated metabolic disturbances, glomerular hemodynamic changes, and proinflammatory and profibrotic factors contribute to kidney damage in DKD [10–13]. These pathways often lead to glomerular hyperfiltration accompanied by glomerular hypertrophy, and evidence suggests that this may further lead to sclerosis, particularly with comorbid hypertension [11]. Obesity and systemic hypertension, common among people with T2D, also exacerbate glomerular hyperfiltration [14]. Arteriolar hyalinosis along with tubulointerstitial infammation and fibrosis are also dominant features of DKD (Figs. 1 and 2) [11]. Increasing permeability to albumin, marked by high levels of albuminuria, results from progressive glomerular injury [15]. Albuminuria typically develops prior to loss of filtration, but eGFR decline may also occur without the occurrence of albuminuria in DKD [16–18]. In people who experience a decline in eGFR without albuminuria, the kidney tissue typically shows prominent vascular lesions and interstitial fibrosis [18]. Table 1 provides a description of typical findings of glomerular lesion biopsies common in DKD.

Clinical manifestations

DKD often progresses to kidney failure or leads to cardiovascular events that cause death in about half of those affected [11, 20]. Therefore, early awareness, detection, and intervention are essential to improve clinical outcomes.

Diagnostic tools and laboratory practices for DKD

A persistent elevation in urinary albumin to creatinine ratio (UACR, ≥30mg/g [≥3 mg/mmol]), and/or a persistent reduction in eGFR (<60 mL/min/1.73m2 ) in a person with diabetes indicates DKD [21]. To qualify as DKD, however, these lesions must be due only to diabetes-related factors [21]. Te American Diabetes Association (ADA) Standards of Medical Care recommends that people with T2D be screened for DKD at their initial diagnosis and annually thereafter [21]. As shown in Fig. 3, there are three categories of albuminuria [22]:

• Stage A1, normal to mildly increased albuminuria: <30 mg/g (<3 mg/mmol) UACR in urine sample

• Stage A2, moderately increased albuminuria, microalbuminuria: 30–300 mg/g (3–30 mg/mmol) UACR; occurring ≥2 times, 3–6 months apart [21]. Tis low-grade albuminuria is a less efective predictor of disease progression than macroalbuminuria [23]

• Stage A3, severely increased albuminuria, macroalgae minutia: >300 mg/g (>30 mg/mmol) UACR; occurring ≥2 times, 3–6 months apart [21]

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is the most commonly used formula to estimate GFR from serum creatinine. Recently, the American Society of Nephrology and the National Kidney Foundation have made recommendations to use race-agnostic methods excluding race in the equation to diagnose and classify chronic kidney disease as a path toward equitable healthcare [24, 25]. A major development is a new CKD-EPI 2021 eGFR equation. This new equation does not include a term for race, with the intent to increase awareness of chronic kidney disease as well as to encourage more timely detection and therapeutic interventions, for all groups of people. The addition of the serum cystatin-C to the CKD-EPI 2021 eGFR equation improves accuracy and precision [25]. Although the serum cystatin-C test is available in some regions of the world, it is not widely used yet due to costs and lack of assay standardization [26–29]. Albuminuria and decreased eGFR, in both general and high-risk populations, are also associated with increased risks for cardiovascular events and mortality, as well as all-cause mortality [30, 31]. Therefore, as a holistic approach to assessing kidney and cardiovascular risks, these tests should be checked at least twice a year in people with diabetes and UACR >30 mg/g (>3 mg/mmol) and/or eGFR <60 mL/min/1.73 m2 [21].

In addition to monitoring for kidney damage and function, people with T2D should have their glycated hemoglobin (HbA1c) tested every 3–6 months to monitor their blood glucose control [32]. The ADA recommends that people with T2D work with their physician to set an individualized goal for glycemic control avoiding hypoglycemia but with a general target of HbA1c <7% (53 mmol/mol) [32].

Table 1 Overview of classes and biopsy findings saw in glomerular lesions associated with diabetic kidney disease (DKD)

1. Manage glycemic control—goal HbA1C ≤7% (53 mmol/mol) [32] 

2. Control blood pressure—the ADA recommends blood pressure below 140/90 mmHg for people with diabetes, with a lower target (e.g., 130/80 mmHg) potentially beneficial for those with macroalbuminuria [21]. KDIGO recommends treating to a target systolic blood pressure of <120 mmHg, as tolerated, in people with chronic kidney disease with or without diabetes, but not those having had a kidney transplant or on dialysis [34]. Measures to control blood pressure should include the use of either: i. Angiotensin-converting enzyme inhibitors (ACEi) or ii. Angiotensin II receptor blockers (ARB) [22] 

3. Manage cholesterol levels—ideally, low-density lipoprotein (LDL) of <100 mg/dL (2.59 mmol/L), total cholesterol of <150 mg/dL (3.88 mmol/L) i. Statins—used to treat high cholesterol [35, 36] 

4. Lifestyle changes—weight reduction, increased physical activity, and smoking cessation [8, 27]

In addition to the beneficial effects that blood pressure-lowering medications have on the progression of DKD [37], other types of medications are also used to manage DKD in people with T2D. Table 2 lists the classes, examples, and modes of action of these medications. Optimal management of blood glucose is the first step in preventing the onset of DKD. Both sodium-glucose transport protein 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) have shown beneficial effects on DKD, such as a reduction in albuminuria or lower risk of new-onset albuminuria, largely beyond glycemic control [44, 51]. Tables 3, 4, and 5 provide summaries of recent clinical trials of agents (SGLT-2i, GLP-1 RA, and non-steroidal mineralocorticoid receptor antagonists, MRAs) showing promise in managing DKD.

Fig. 4 Clinical strategies to prevent the development/progression of chronic kidney disease in people with diabetes. This figure was developed by Kidney Disease Improving Global Outcomes (KDIGO) [27] and reproduced with permission from KDIGO. Abbreviations: SGLT2, sodium-glucose transport protein 2; RAS, renin-angiotensin system; CKD, chronic kidney disease.

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