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 [10,11,12,13]. 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 inflammation 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 [16,17,18]. 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.

Fig. 1
figure 1

Histology images showing structural changes related to diabetic glomerulopathy. A Normal glomerulus. B Diffuse mesangial expansion with mesangial cell proliferation. C Prominent mesangial expansion with early nodularity and mesangiolysis. D Accumulation of mesangial matrix forming Kimmelstiel-Wilson nodules. E Dilation of capillaries forming microaneurysms, with subintimal hyaline (plasmatic insudation). F Obsolescent glomerulus. A–D and F were stained with period acid-Schiff stain. E was stained with Jones stain. Original magnification ×400. Reprinted with permission from American Society of Nephrology (Alicic et al., Diabetic Kidney Disease: Challenges, Progress, and Possibilities; CJASN 2017; 12; (2032-45) [11]

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Fig. 2
figure 2

Histology images showing tubulointerstitial changes seen in diabetic kidney disease. A Normal kidney cortex. B Thickened tubular basement membrane and interstitial widening. C Arteriole with an intimal accumulation of hyaline material with significant luminal compromise. D Renal tubules and interstitium in advancing diabetic kidney disease, with thickening and wrinkled tubular basement membranes (solid arrows), atrophic tubules (dashed arrow), some containing casts, and interstitial widening with fibrosis and inflammatory cells (dotted arrow). All sections stained with period acid-Schiff stain, original magnification ×200. Reprinted with permission from American Society of Nephrology (Alicic et al. [11])

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

The 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]. This low-grade albuminuria is a less effective predictor of disease progression than macroalbuminuria [23]

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

Fig. 3
figure 3

Prognosis of chronic kidney disease by GFR and albuminuria category. This figure was developed by Kidney Disease Improving Global Outcomes (KDIGO) [22] and reproduced with permission from KDIGO

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The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is the most commonly used formula to estimate GFR from the 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. 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 [26,27,28,29]. 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 assess 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].

Treatments and medications

Several strategies exist that can help prevent DKD development and slow its progression [8, 33]. While healthy lifestyle changes are foundational, achieving optimal glycemic, blood pressure, and cholesterol levels generally require use of medications. A summary of the Kidney Disease Improving Global Outcomes (KDIGO) guideline for people with chronic kidney disease and diabetes is shown in Fig. 4.

Fig. 4
figure 4

Clinical strategies to prevent 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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Current goals/targets for people with T2D are:

  1. 1.

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

  2. 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 use of either:

    1. i.

      Angiotensin-converting enzyme inhibitors (ACEi) or

    2. ii.

      Angiotensin II receptor blockers (ARB) [22]

  3. 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)

    1. i.

      Statins—used to treat high cholesterol [35, 36]

  4. 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 progression of DKD [37], other types of medications are also used to manage DKD in people with T2D. Table 2 lists 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].

Table 2 Medications used in type 2 diabetes and their role in managing diabetic kidney disease
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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.

Table 3 Recent clinical trials of SGLT-2i agents with kidney outcomes
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Table 4 Recent clinical trials of GLP-1 RA agents with kidney outcomes
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Table 5 Recent clinical trials of MRA agents with kidney outcomes
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SGLT-2i agents (Table 3)

Two double-blind, randomized, placebo-control trials, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) [41] and Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) [43], included kidney disease endpoints as the primary outcome. In CREDENCE, participants assigned to canagliflozin had a 30% reduced risk (hazard ratio (HR)=0.70 [95% confidence interval (CI): 0.59–0.82]) of the primary kidney composite outcome (ESKD, doubling of serum creatinine from baseline sustained for at least 30 days, or death from kidney or cardiovascular disease causes) as compared with participants assigned to placebo [41]. A similar effect was seen in DAPA-CKD, with participants assigned to dapagliflozin having a 39% reduced risk (HR=0.61 [95% CI: 0.51–0.72]) of the primary kidney composite outcome (>50% decline in eGFR from baseline or kidney- or CV-related death) as compared to those in the placebo arm [43]. The majority of participants in both trials were already receiving ACEi or ARBs in maximum tolerated doses where possible. Approximately one third (n=1398) of the participants in DAPA-CKD did not have T2D [43].

Other clinical trials with SGLT-2i investigated kidney disease outcomes as a secondary outcome. Four trials, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) [44], Canagliflozin Cardiovascular Assessment Study (CANVAS, CANVAS-R) [46], Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) [47], and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure, Reduced Ejection Fraction (EMPEROR REDUCED) [49], reported lower rates of kidney disease composite outcomes in those assigned to the active drug than to placebo (EMPA-REG OUTCOME HR=0.61 [95% CI: 0.53–0.70]; CANVAS, CANVAS-R HR=0.73 [95% CI: 0.67–0.79]; DECLARE-TIMI 58 HR=0.76 [95% CI: 0.67–0.87]; EMPEROR REDUCED HR=0.50 [95% CI: 0.32–0.77]) [44, 46, 47, 49]. Composite kidney disease outcomes were somewhat similar between studies (e.g., composite of sustained decrease in eGFR of 40% or more, to less than 60 mL/min/1.73 m2, incident ESKD, death from kidney or cardiovascular disease causes in DECLARE-TIMI 58 and incident chronic dialysis or kidney transplantation, profound and sustained reduction in eGFR in EMPEROR REDUCED) [47, 49]. One study, eValuation of ERTugliflozin effIcacy and safety – CardioVascular outcomes (VERTIS-CV) [48], reported no significant difference in their secondary kidney disease outcome (death due to kidney disease, kidney replacement therapy, or doubling of serum creatinine) between those randomized to ertugliflozin versus placebo (HR=0.80 [95% CI: 0.61–1.05] )[48].

GLP-1 RA agents (Table 4)

Cardiovascular outcome trials have also examined GLP-1 RA in people with T2D with kidney disease outcomes as secondary outcomes; to date, there are no published studies of GLP-1 RAs with kidney outcomes as a primary outcome. Randomized, placebo-controlled trials including Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) [51]; Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND) [42]; Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes (Harmony Outcomes) [52]; Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) [53]; Exenatide Study of Cardiovascular Event Lowering (EXSCEL) [54]; Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) [58]; Assessment of Weekly Administration of dulaglutide in Diabetes (AWARD 7) [56]; and Effect of Efpeglenatide on Cardiovascular Outcomes (AMPLITUDE-O) [60] all reported significantly lower rates of kidney disease outcomes in participants assigned to the active drug as compared with those assigned to placebo, or active drug as compared to insulin in AWARD-7. LEADER, REWIND, and AMPLITUDE-O report significantly lower risk of composite kidney disease outcomes among those assigned to study drug versus placebo (LEADER HR=0.78 [95% CI: 0.67–0.92]; REWIND HR=0.85 [95% CI: 0.77–0.93]; AMPLITUDE-O HR=0.68 [95% CI: 0.57–0.79]) [42, 51, 60]. EXSCEL found no significant difference in risk of their composite outcome (HR=0.43 [95% CI: 0.15–1.22]) [54].

Other GLP-1RA studies reported on individual kidney disease measures. In Harmony Outcomes, there was a between-group difference (albiglutide vs. placebo) in change in eGFR at 8 months (mean difference=−1.11 [95% CI: −1.84 to 0.39]) and at 16 months (mean difference=−0.43 [95% CI: −1.26 to 0.41]) [52]. SUSTAIN-6 reported significantly lower risk of new or worsening nephropathy (HR=0.64 [95% CI: 0.46–0.88]) or persistent macroalbuminuria (HR=0.54 [95% CI: 0.37–0.77]) among those assigned to semaglutide as compared with placebo [53]. In ELIXA, participants assigned to lixisenatide had a 24% increase in UACR from baseline to study week 108 while those assigned to placebo had a 34% increase, a significant difference (p=0.004) [58]. In AWARD 7, participants assigned to dulaglutide had higher eGFR at 52 weeks than those assigned to insulin glargine (eGFR least square means = 34.0 mL/min/1.73m2, p=0.005 for dulaglutide 1.5 mg, eGFR least square means = 33.8 mL/min/1.73 m2, p=0.009 for dulaglutide 0.75mg) [56]. More details of these studies are provided in Table 4. As the kidney outcomes mentioned here were all secondary outcomes from cardiovascular outcomes or glycemic lowering trials, there is a clear need for studies with primary kidney disease outcomes in participants with T2D and DKD [55]. The Effect of Semaglutide Versus Placebo on the Progression of Renal Impairment in Subjects With Type 2 Diabetes and Chronic Kidney Disease (FLOW, NCT03819153) trial is investigating a GLP-1RA with a primary kidney disease outcome (≥50% eGFR decline, kidney failure, and death from kidney or CV disease) [65]. A companion study, Renal Mode of Action of Semaglutide in Patients With Type 2 Diabetes and Chronic Kidney Disease (REMODEL, NCT04865770), is examining the effect of semaglutide on kidney inflammation, perfusion, and oxygenation [66].

MRA agents (Table 5)

Two recent clinical trials report on the effects of a non-steroidal MRA, finerenone, on kidney disease outcomes. Finerenone demonstrated positive results in FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) with kidney disease endpoints as primary outcomes [67]. In this study, participants assigned to finerenone had an 18% lower risk of the primary composite outcome (ESKD or eGFR <15 mL/min/1.73 m2, sustained decrease of ≥40% in eGFR from baseline for ≥4 weeks, or kidney disease death) as compared with those assigned to placebo (HR=0.82 [95% CI=0.73–0.93]) [67]. FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease (FIGARO-DKD) [68] included kidney disease endpoints as secondary outcomes. Participants assigned to finerenone had a 23% lower risk of the composite kidney disease outcome of first occurrence of kidney failure, sustained decrease from baseline eGFR ≥57% for ≥4 weeks, or kidney disease death as compared to the placebo arm (HR=0.77 [95% CI: 0.60–0.99]) [68]. Both of these clinical trials included participants with T2D and DKD who were on a maximally tolerated dose of an ACE inhibitor or ARB [67, 68]. The FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analYsis (FIDELITY) [57] prespecified meta-analysis reported that finerenone significantly reduced risk of kidney disease outcomes (kidney failure, sustained ≥57% decrease in eGFR, or kidney disease death) by 23% and the risk of cardiovascular endpoints (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) by 14% versus placebo in >13,000 participants. Finerenone was well tolerated, but investigator-reported hyperkalemia (serum potassium concentration >5.5 mmol/l) was more common versus placebo (14.0% versus 6.9%, respectively) [57].

Conclusions

DKD is a frequent and serious complication in people with T2D and diabetes is the most common cause of ESKD and kidney failure worldwide [59]. Glycemic control and blood pressure management, with preferential use of agents that attenuate the renin-angiotensin aldosterone system, have traditionally represented the cornerstone for prevention and treatment of DKD. Even though these measures may reduce albuminuria, their beneficial effects on GFR decline or progression to ESKD are modest [63, 64, 69, 70].

In recent studies, treatment with SGLT-2i and GLP-1 RA proved to reduce the risk for a combined major adverse cardiovascular event endpoint (including cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) [60, 71]. In the CREDENCE and the DAPA-CKD trials, treatment with canagliflozin and dapagliflozin were shown to reduce risks of substantial eGFR decline or kidney failure with a primary kidney disease outcome in adults with T2D who had DKD. These findings have inspired many organizations that produce clinical practice guidelines across the world to recommend these agents over other treatments in people with T2D and DKD and/or cardiovascular disease.

Despite these new therapeutic opportunities for treating people with T2D, the risk of DKD progression remains [11, 72]. There is evidence to support the role of the mineralocorticoid receptor through inflammation and fibrosis in the progression of DKD [72]. Treatment of DKD with older steroidal MRAs has not been widely implemented because of their high rate of unfavorable side effects such as hyperkalemia [72]. However, finerenone is a new non-steroidal MRA with less side effects and more potent anti-inflammatory and antifibrotic effects as compared with steroidal MRAs [73, 74]. Finerenone was shown to evoke kidney and cardiovascular protective effects in people with T2D and DKD [57, 67]. Therefore, promising new pharmacological drugs are available to be used in people with DKD.

Drugs like phosphodiesterase inhibitors, 5-hydroxytrytamine 2a receptor antagonists, aldosterone synthesis inhibitors, anti-inflammatory agents, and others are under clinical development. Such additional classes of agents might further increase the armamentarium in the treatment of DKD in the future [33, 75]. Even though new drugs will help to improve the prognosis of people with DKD, it becomes more and more a challenge for physicians to choose the most beneficial medication or combination of medications for an individual patient. There is a need to evaluate the kidney-protective effects of different treatment modalities based on individual characteristics. For example, it would be important to evaluate if different drugs might have a distinct efficacy in patients with DKD with and without albuminuria. Combination therapy with SGLT-2is and MRAs also need to be better explored to understand if benefits are additive. Additional clinical and real-world studies are warranted to elucidate best clinical practices.

It is important to emphasize the intention of this review, along with its limitations. We aimed to provide an overview on recent renal data of SGLT-2i, GLP-1 RAs, and MRAs. Most of the studies included in the review were cardiovascular outcome trials, with kidney outcomes as secondary outcomes. As such, they may not have sufficient power to provide confirmative answers on kidney-related endpoints, especially when examined by subgroups. Furthermore, for composite secondary kidney outcomes, examining each individual component of the composite outcome provided interesting information, but again, these results were underpowered to be considered confirmatory. With the composite renal outcomes of studies examining GLP-1 RAs driven primarily by reductions in albuminuria, the studies do not prove any beneficial effect of GLP-1 RA on kidney outcomes. Even though many of the results are not confirmatory, they are of interest to discuss potential effects in an exploratory sense. Results of these trials are thesis generating and should not be interpreted in a confirmatory sense. This highlights the need for future trials with kidney outcomes as primary outcomes of interest.