Evolving strategies for nephroprotection in diabetic kidney disease: From established therapies to novel interventions

Abstract

The prevalence of diabetes mellitus is increasing worldwide, and diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease. DKD is characterized by progressive albuminuria and decline in kidney function driven by chronic hyperglycemia, glomerular hypertension, inflammation, and structural renal damage. Traditionally, DKD management has relied on lifestyle modification, glycemic control, blood pressure reduction, and renin–angiotensin–aldosterone system inhibition, with clinical trials demonstrating delayed disease progression. Despite these measures, substantial residual renal risk persists. Recent randomized trials have established the nephroprotective role of newer therapies. Sodium–glucose co-transporter 2 inhibitors, including canagliflozin, dapagliflozin, and empagliflozin, reduce the risk of sustained kidney function decline, kidney failure, and renal or cardiovascular death. Glucagon-like peptide-1 receptor agonists such as liraglutide, semaglutide, and dulaglutide lower albuminuria and slow renal function loss. In addition, the non-steroidal mineralocorticoid receptor antagonist finerenone provides further renal and cardiovascular protection when added to renin–angiotensin system blockade in patients with albuminuric DKD. This review summarizes clinical trial evidence supporting established and emerging therapies for nephroprotection in DKD, highlighting the shift toward earlier and combined treatment strategies to improve long-term kidney outcomes in patients with diabetes.

Key Words: Diabetic kidney disease; Sodium-glucose co-transporter 2 inhibitors; Diabetic nephropathy; Diabetes mellitus; Albuminuria

Core Tip: Diabetic kidney disease (DKD) is a complex and leading cause of end-stage renal disease, traditionally managed through glycemic and blood pressure control. However, recent advances, including sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and mineralocorticoid receptor antagonists, offer renoprotective benefits beyond glucose lowering, marking a significant shift in DKD treatment strategies and providing new hope for improved kidney outcomes in diabetes care.

INTRODUCTION

Diabetes mellitus (DM) is a chronic disease characterized by metabolic abnormalities that affect multiple organs and tissues, most notably the eyes, kidneys, and nerves, leading to reduced life expectancy and quality of life. According to the International Diabetes Federation, 537 million individuals were living with diabetes in 2021, a number projected to rise to 783 million by 2045[1]. Despite the benefits of lifestyle modification and current therapies, DM remains a major global healthcare concern[2]. Diabetic kidney disease (DKD), a microvascular complication affecting approximately one-third of individuals with diabetes, is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. This is particularly evident in industrialized countries such as the United States, where DKD accounts for nearly 40% of new dialysis cases[3,4]. Although impaired renal function is a frequent comorbidity in diabetes, the precise etiology of renal damage is often difficult to determine due to the presence of multiple comorbidities that can contribute to renal failure. Despite advances in diabetes management, many patients still develop DKD and progress to ESRD, ultimately requiring hemodialysis or kidney transplantation[5]. Given these challenges, early detection and effective management of DKD are crucial to prevent progression to advanced kidney disease and associated complications. This review aims to provide an updated overview of DKD pathophysiology and clinical manifestations, and to evaluate both established and emerging nephroprotective strategies aimed at reducing the risk of DKD progression in diabetic patients.

PATHOPHYSIOLOGY OF DKD

DKD, also known as diabetic nephropathy, is clinically diagnosed by the presence of persistent albuminuria and/or a reduced glomerular filtration rate (GFR). DKD, primarily resulting from microvascular complications, is the leading cause of ESRD and affects approximately 30%-40% of individuals with DM[6]. The pathophysiology of DKD is multifactorial, involving complex hemodynamic and metabolic disturbances induced by chronic hyperglycemia[7]. Sustained elevations in plasma glucose activate several pathogenic pathways, including increased production of advanced glycation end-products (AGEs), oxidative stress, and proinflammatory signaling, all of which contribute to progressive renal structural and functional decline[8]. A key early event in the pathogenesis of DKD is glomerular hyperfiltration, which results primarily from afferent arteriolar vasodilation and increased intraglomerular pressure. This functional alteration is often asymptomatic and may precede the onset of microalbuminuria. Over time, thickening of the glomerular basement membrane and expansion of the mesangium occur due to the accumulation of extracellular matrix proteins[9]. Among the earliest cellular changes are injury and depletion of podocytes, specialized epithelial cells that, under high glucose conditions, experience increased production of reactive oxygen species (ROS), mitochondrial DNA damage, and peroxidation of proteins and lipids. These processes collectively contribute to podocyte injury and the progression of DKD[10]. In addition, ongoing inflammation and activation of profibrotic pathways, such as transforming growth factor-beta (TGF-β) signaling, promote interstitial fibrosis and tubular atrophy, both of which are strong predictors of renal function decline[11].

Emerging evidence indicates that the progression of DKD does not always follow a linear trajectory but may fluctuate through overlapping histological and clinical phases. In the context of CKD progression, three main functional stages are commonly described[12]: (1) Early stage (hyperfiltration phase): Characterized by increased GFR, normal blood pressure, and absence of proteinuria. Despite normal serum creatinine, structural changes, like basement membrane thickening, begin to emerge; (2) Incipient nephropathy: Microalbuminuria becomes detectable (30-300 mg/day) and is often associated with rising blood pressure. GFR may still be in the normal range, but mesangial expansion and podocyte injury are progressing; and (3) Overt nephropathy: Characterized by persistent macroalbuminuria (> 300 mg/day), hypertension, and declining GFR. The main histological changes are glomerulosclerosis, tubulointerstitial fibrosis, and arteriolar hyalinosis. This stage significantly raises the risk of ESRD and cardiovascular events.

However, not all diabetic patients have identical progression rates of DKD. Older patients, particularly those with multiple comorbidities, may show reduced GFR without albuminuria, or non-diabetic renal pathology superimposed on diabetic background. A combination of clinical, laboratory, and histopathologic evaluation is required to differentiate DKD from other nephropathies, for a correct diagnosis[13].

Because the pathophysiology of DKD involves a cascade of metabolic, hemodynamic, and inflammatory insults that progressively damage glomerular and tubular structures, early identification of these changes and timely intervention during the subclinical phase are essential to maximize the preservation of renal function.

LIFESTYLE MODIFICATION

Lifestyle modification is a cornerstone in the management of DKD and is strongly recommended in both primary and secondary prevention strategies. Several modifiable risk factors influence the development and progression of DKD, and addressing them can significantly delay renal function decline.

Smoking

Cigarette smoking is a well-established independent risk factor, not only for cardiovascular disease but also for the progression of CKD, particularly in patients with DM[14]. Tobacco smoke is a toxic mixture of harmful components, which have been shown to play a role in processes involved in the pathogenesis of DKD, such as endothelial dysfunction, oxidative stress, systemic inflammation and increased sympathetic activity[15]. These mechanisms, in turn, promote glomerular injury, podocyte loss, increased albumin permeability, and ultimately glomerulosclerosis[16]. Recent longitudinal data further reinforce this association, as shown by a 2024 cohort study by Matsumoto et al[17] which demonstrated that cigarette smoking significantly accelerated estimated glomerular filtration rate (eGFR) decline, even after adjusting for confounders. Moreover, a comprehensive systematic review including 17 cross-sectional studies, confirmed that smoking increases the incidence of CKD, suggesting a causal relationship[18].

Given that this effect has been shown to be more pronounced in diabetic subjects, smoking must be considered a modifiable risk factor in DKD progression[17]. In people with diabetes, the CKD progression associated with smoking has been shown to be mainly caused by oxidative stress, amplification of inflammatory signaling, impaired glycemic control, and worsening of hypertension[19], whereas, smoking cessation leads to a reduction in albuminuria and a slower decline in renal function. A reversible impact of smoking on renal hemodynamics and glomerular pathology has also been highlighted by Orth, who supported the positive effect of cessation on long-term nephroprotection[19].

In any case, all international guidelines advocate for smoking cessation as a fundamental component of kidney protection strategies in diabetic care[20].

Physical activity

Current guidelines recommend at least 150 minutes per week of moderate to vigorous physical activity, to improve insulin sensitivity, lipid profile and glycemic control, and to reduce blood pressure[21]. A combined strength and aerobic training program have been shown to significantly reduce albuminuria, systemic inflammation, and cardiovascular risk[22].

Different types of exercise have been shown to affect primary DKD parameters through multiple pathways: Regulating the renin-angiotensin-aldosterone system (RAAS), minimizing oxidative stress and inflammatory processes, improving endothelial cell function, and facilitating muscle-kidney tissue interactions[21].

In an observational study including 6739 diabetic/prediabetic adults, physical activity (≥ 150 minute/week) was found to be associated with a 28% lower risk of albuminuria (OR = 0.72; 95%CI: 0.57-0.92), with the greatest benefit observed at ≥ 300 minute/week (OR = 0.66)[23]. A Japanese cohort study of CKD stage G3b-G5 patients showed that physical activity reduced the risk of ≥ 40% decline in eGFR or need for dialysis/kidney transplant, with active diabetic patients showing HR = 0.68 in early-stage CKD[24].

Thus, both albuminuria and systemic inflammation have been shown to be reduced by regular aerobic or resistance exercise, which can therefore be considered a non-pharmacological adjunct treatment in DKD management.

Weight reduction

Obesity is an independent risk factor for the development of renal dysfunction. Obesity-related kidney damage is primarily driven by chronic inflammation, oxidative stress, dysregulated adipokine signaling, and ectopic lipid accumulation[25]. These factors disrupt key intracellular pathways and contribute to glomerular and tubular endothelial dysfunction, cellular injury, and activation of the RAAS, thereby promoting progressive renal injury and fibrosis[26]. In addition, weight reduction, particularly in obese individuals, contributes to lower intraglomerular pressure and improved insulin resistance. Weight loss has been associated with improvements in insulin sensitivity, lipid metabolism, and decreases in proteinuria, blood pressure, systemic inflammation and oxidative stress[27]. Evidence from this 2024 comprehensive review further indicates that weight loss achieved through diet, exercise, pharmacotherapy, or bariatric surgery significantly improves renal outcomes among obese individuals with and without diabetes, underscoring benefits such as reduced proteinuria, better blood pressure control, and improved metabolic profiles[27]. These findings suggest that weight reduction may be an important component of nephroprotection in DKD.

Sodium and potassium restriction

There is clear evidence that high sodium intake represents a significant modifiable risk factor in DKD, since it has been shown to exacerbate arterial hypertension, disrupt fluid balance, and reduce the effectiveness of RAAS inhibitors, accelerating the decline in kidney function[28]. On the other hand, meta-analyses and randomized controlled trials have shown that reduction of sodium intake (< 2 g/day) can help lower and control high blood pressure levels and proteinuria in individuals with DKD, thereby reducing the progression of kidney failure[29]. A post-hoc analysis of the RENAAL and IDNT trials showed that patients with DKD, who consumed a low-sodium diet (as indicated by the lowest tertile of 24-hour urinary sodium excretion), experienced a 43% reduction in the risk of renal events, such as doubling of serum creatinine or progression to ESRD, when they were treated with angiotensin receptor blockers (ARBs), compared to those on higher sodium diets[30].

In contrast, in patients with higher sodium intake, the renoprotective effects of ARB therapy were significantly reduced or even absent[20,30]. Consequently, current clinical guidelines advocate sodium restriction as a core strategy in DKD management, to optimize both blood pressure control and the effectiveness of kidney-protective therapy[20].

Vegetarian diets

Plant-based diets constitute a nutrient-dense approach, characterized by a high antioxidant capacity and anti-inflammatory potential. Indeed, in both diabetic and non-diabetic populations, plant-based diets with lower acid load and reduced inflammation have been associated with slower CKD progression[31]. In a prospective analysis by Thompson et al[32], including 7747 diabetes patients, the associations between healthy and less healthy plant-based diets and the risk of CKD among those with diabetes were evaluated. Although the risk of hyperkalemia in patients on plant-rich diets represents a significant clinical concern, adherence to a healthy plant-based diets was shown to be associated with a lower CKD risk (24 vs 35; P = 0.002)[32]. Therefore, careful monitoring of dietary potassium is recommended, as well as the use of intestinal potassium binders, to achieve a modest reduction in potassium levels[33].

Nonetheless, evidence from a randomized controlled trial shows that whole-food plant-based diets can be safely implemented without increased serum potassium, likely due to improved fiber intake and reduced potassium bioavailability[34].

Planetary health diet

The planetary health diet, which emphasizes plant-based foods, limits animal product consumption, and minimizes ultra-processed foods, has been associated with a reduced prevalence of DKD[35]. Recent evidences indicate that higher adherence to this dietary regime correlates with a decreased likelihood of both CKD and DKD, with a 10-point increase in Planetary Health Diet Index associated with an OR of 0.86 (95%CI: 0.76-0.97) for DKD. This association is partially mediated by improvements in body composition, particularly central lean mass distribution, which is crucial for metabolic health in individuals with diabetes[35].

Low-protein diets

A protein intake restricted to 0.6-0.8 g/kg/day is recommended in CKD management to reduce nitrogenous waste products, decrease glomerular hyperfiltration, and improve uremic symptoms. However, every dietary intervention must be personalized to prevent malnutrition and maintain good health, considering individual variations in biochemistry, metabolism, genetics, and microbiota. Combined with ketoacid analogues (KAs), low-protein diets have demonstrated benefits in delaying dialysis initiation[36]. The latest Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, focusing on CKD evaluation and management, confirmed that protein intake of 0.6-0.8 g/kg/day is appropriate for CKD stages 3-5 (non-dialysis), including patients with diabetes, to balance renal protection and nutritional adequacy[20]. Furthermore, when supplemented with KAs, low-protein diets have demonstrated added renoprotective effects and metabolic benefits. A 2022 meta-analysis by Bellizzi et al[37] examined the effects of KA-supplemented low- or very-low-protein diets in patients with non-dialysis DKD. The review included 11 studies and found that the combination of KAs with dietary protein restriction led to significant reductions in proteinuria (P = 0.037)[37]. Recent evidence from Garneata et al[38] reinforced this approach. In a prospective, interventional study on 92 patients with advanced DKD (eGFR < 30 mL/minute/1.73 m² and proteinuria > 3 g/day), a low-protein diet (0.6 g/kg/day, mostly plant-based) supplemented with KAs led to a threefold reduction in proteinuria and a fivefold slower decline in eGFR over 12 months, compared to the pre-intervention slope. In this high-risk population, the mean annual eGFR decline was just 1.5 mL/minute, significantly slower than the expected rate[38].

In conclusion, lifestyle modifications, though often underemphasized, remain powerful interventions that can synergistically enhance pharmacological therapies in DKD. Their integration into daily care should be actively promoted and tailored to individual patient needs and comorbidities.

Blood glucose control

Optimal blood glucose control has always been one of the main strategies for reducing the risk of developing micro- and macrovascular complications secondary to DM. Glycated hemoglobin (HbA1c) is a nonenzymatic glycation product of hemoglobin, whose measurement reflects the long-term glycemic levels in diabetic patients. Several studies have shown that, in both type 1 diabetes (T1D) or type 2 diabetes (T2D), improved glycemic control reduces the risk or delays the progression of both microvascular complications, including nephropathy and retinopathy, and macrovascular complications, such as cardiovascular events[39-41]. The Diabetes Chronic Complications Trial (DCCT) evaluated a total of 1441 T1D patients, 726 with no retinopathy and 715 with mild retinopathy, who were randomized to the intensive therapy group vs the conventional therapy group. The mean follow-up was 6.5 years. The results showed that the intensive therapy group, achieving HbA1c of 7.0% (53 mmol/mol), reduced the risk of retinopathy, nephropathy and neuropathy by 35%-70% compared with the conventional therapy group[42]. At the end of the DCCT, all participants continued receiving intensive treatment and were included in an observational study called Epidemiology of Diabetes Interventions and Complications (EDIC), with a maximum follow-up of 18 years. The results showed a lower risk of developing microalbuminuria (risk reduction = 45%, 95%CI: 26-59) and macroalbuminuria (risk reduction = 61%, 95%CI: 41-74). Furthermore, at year 17-18 of EDIC, the prevalence of albumin excretion rate ≥ 30 mg per 24 hours was 18.4% in the intensive treatment group during the DCCT, compared with 24.9% in the conventional treatment group (P = 0.02) and the incidence of eGFR lower than 60 mL/minute/1.73 m² was lower in the intensive treatment group (risk reduction = 44%, 95%CI: 12-64)[43]. In addition, in T2D, the United Kingdom Prospective Diabetes Study, showed that intensive therapy with an HbA1c of 7.0% (53 mmol/mol), compared with standard therapy, led to a 25% risk reduction in microvascular, but not macrovascular, outcomes[44]. Furthermore, tight glycemic control may provide greater benefits if started early rather than when organ damage is already present[45]. Monami et al[46] showed in a meta-analysis that patients with better glycemic control were at lower risk of major cardiovascular events (OR = 0.89, 95%CI: 0.85-0.94) and renal adverse events (OR = 0.73, 95%CI: 0.65-0.82), but not all-cause mortality (OR = 0.95, 95%CI: 0.88-1.01) or ocular complications (OR = 0.94, 95%CI: 0.72-1.22). Within the subgroups, for glucose-lowering drugs inducing hypoglycemia, there was a lower risk of microvascular complications (HbA1c ≤ 6.5%), but not of major cardiovascular events or all-cause mortality, with a higher risk of severe hypoglycemia (OR = 2.72, 95%CI: 1.79-4.13). Conversely, drugs not inducing hypoglycemia were associated with a reduction of major cardiovascular events, renal adverse events, and all-cause mortality, for HbA1c < 7%[46]. The ADVANCE-ON studies evaluated 8,494 diabetic patients of the ADVANCE trial to provide long-term evidence for renal protection in T2D. The median follow-up was 9.9 years and intensive glucose control (HbA1c ≤ 6.5%) resulted in a 46% reduction in end-stage kidney disease risk, compared to standard therapy (HR = 0.54, P < 0.01), particularly in patients with earlier-stage CKD and lower baseline systolic blood pressure[47]. Another meta-analysis to evaluate the effect of intensive glycemic control in older (age ≥ 60 years) or frail adults with T2D, including 7528 studies, showed that intensive glycemic control was associated with reductions in microvascular (HR = 0.73, 95%CI: 0.68-0.79) and macrovascular complications (HR = 0.84, 95%CI: 0.79-0.89), but no differences in all-cause mortality (HR = 0.96, 95%CI: 0.90-1.03) with an increased risk of severe hypoglycemia (HR = 2.45, 95%CI: 2.22-2.72)[48]. Thus, an important element to be considered is that lower glycemic targets result in an increased risk of hypoglycemia, which can be harmful. The Action to Control Cardiovascular Risk in Diabetes Study Group performed a randomized study on 10251 patients with T2D (mean age = 62.2 years), to evaluate the effect of intensive glycemic control (HbA1c target 6.4%) in reducing the cardiovascular risk. The study was discontinued after 3.5 years of follow-up due to higher mortality in the intensive-therapy group and more frequent cases of severe hypoglycemia (P < 0.001)[49]. Thus, HbA1c targets should be individualized for each patient, considering the type of diabetes, comorbidities, risk of hypoglycemia and life expectancy[45]. In patients with CKD, particularly in advanced stages, certain conditions can alter HbA1c concentrations either by increasing or decreasing them. Indeed, increased inflammation and oxidative stress and the presence of metabolic acidosis, typical of these patients may contribute to the formation of AGEs. On the other hand, CKD patients show an increased risk of anemia, transfusions, and use of erythropoiesis-stimulating agents or iron-replacement therapies, which could shorten the red blood cell half-life and, consequently, reduce HbA1c levels[50]. Thus, the measurement of HbA1c is less accurate in CKD patients, particularly in the more advanced stages. Consequently, a target < 6.5% or < 7% is recommended for CKD patients in the earlier stages with high risk for cardiovascular disease and development/increase of albuminuria, since they can easily achieve glycemic targets and are at a low risk of hypoglycemia. A target < 7.5% or < 8% is recommended for patients with high risk of hypoglycemia, stage 4-5 CKD, multiple comorbidities, and with low life expectancy. Altogether, the HbA1c measurement has limited reliability in evaluating long-term glycemic control in advanced CKD, due to analytic imprecision and bias[20,51]. Consequently, these patients are at increased risk of hypoglycemia if treated with traditional therapy, and stringent glycemic targets might not be suitable or even potentially harmful[52]. In conclusion, optimal glycemic targets to improve clinical outcomes in these patients remain uncertain and further studies are needed to evaluate the role of new glucose-lowering agents.

PHARMACOLOGICAL TREATMENTS

Despite the introduction of new adjunctive medications in diabetes therapy, many patients with DKD continue to experience worsening kidney function over time, underscoring the limitations of traditional management strategies, typically focused on monitoring average glucose levels and blood pressure. Although these traditional approaches remain essential, they are often not capable of fully addressing the complex pathophysiological processes associated with DKD, which include not only metabolic and hemodynamic disorders but also inflammation, oxidative stress, and fibrosis. As a result, new targeted pharmacological interventions may help to go beyond glucose regulation to directly protect kidney structure and function. The synergistic effects of lifestyle interventions, combined with pharmacological treatment, represent a pivotal shift in the treatment landscape of DKD, addressing an urgent need for more effective interventions to delay or prevent kidney failure in diabetic patients[53] (Table 1).

Table 1 Stepwise pharmacological approach to nephroprotection in diabetic kidney disease.

Risk/disease stage	Therapeutic focus	Pharmacological choice	Expected nephroprotective effect
Diabetes with preserved estimated GFR, no albuminuria	Early risk reduction	Metformin	Slows early kidney function decline
DKD with confirmed albuminuria	Hemodynamic and albuminuria control	ACEi or ARB	Reduces albuminuria and rate of estimated GFR loss
DKD at any stage with albuminuria	Kidney-protective core therapy	SGLT2i	Slows progression of kidney disease and reduces risk of kidney failure
Persistent albuminuria despite core therapy	Residual renal risk reduction	Finerenone	Further attenuates DKD progression
DKD with metabolic and cardiovascular risk	Metabolic-renal risk modulation	GLP-1 receptor agonist	Lowers albuminuria and slows kidney function decline
Advanced DKD with persistent albuminuria despite monotherapy	Comprehensive multi-target nephroprotection	SGLT2i + Finerenone ± RAS blockade	Additive reduction in kidney failure risk through complementary mechanisms
When preferred agents are not tolerated	Alternative glucose-lowering strategy	DPP-4 inhibitor	Renally safe glucose-lowering option
Marked albuminuria, evolving strategies	Enhanced albuminuria control	Tirzepatide	Dose-dependent reduction in albuminuria

ACEi: Angiotensin-converting enzyme inhibition; ARB: Angiotensin receptor blocker; DKD: Diabetic kidney disease; GFR: Glomerular filtration rate; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; RAS: Renin-angiotensin system; SGLT2i: Sodium-glucose co-transporter 2 inhibitor; DPP-4: Dipeptidyl peptidase-4.

Metformin

Metformin, an oral agent belonging to the class of drugs called biguanides, and the first-line option for oral therapy in T2D, is considered an “essential medicine” by the World Health Organization, owing to its beneficial pleiotropic effects and its rare induction of hypoglycemia[54]. Its mechanism of action is not completely understood, but its effectiveness is mostly mediated by the inhibition of hepatic gluconeogenesis, decreased intestinal absorption and increased peripheral uptake of glucose, reduced fatty acid oxidation and lowered levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides. Furthermore, it can promote weight loss in patients with obesity[55].

Beyond its metabolic effects, metformin has shown potential nephroprotective and vasculoprotective properties. Several preclinical studies have shown that metformin can attenuate renal inflammation and fibrosis, through the activation of AMP protein kinase and inhibition of TGF-β, which together inhibit profibrotic signaling[56,57]. In addition, metformin has been shown to reduce oxidative stress, by limiting mitochondrial ROS production, improving endothelial function and preserving podocyte integrity[58]. Furthermore, treatment with metformin has shown a lower incidence of microvascular complications, including nephropathy, compared to sulfonylureas or insulin[44].

Observational studies also indicated that metformin therapy in the early stages slows the progression of CKD, despite the risk of lactic acidosis in advanced stages. Current guidelines allow metformin use in patients with eGFR > 30 mL/minute/1.73 m², emphasizing careful monitoring[59].

Renin angiotensin system inhibitors

The renin-angiotensin system (RAS) plays a central role in the development and progression of DKD. Its activation promotes glomerular hypertension, endothelial dysfunction, podocyte injury, and stimulation of profibrotic and proinflammatory pathways. Consequently, pharmacological inhibition of RAS with angiotensin-converting enzyme inhibition (ACEi) remains a cornerstone of nephroprotection in diabetic patients[60]. The mechanism of action of ACEi is characterized by a reduction in intraglomerular pressure, proteinuria and the rate of GFR decline[61].

Previously, a meta-analysis has shown that ACEi can reduce the risk of kidney failure and cardiovascular events. Although in patients with CKD 3-5, ACEi-based therapy has been associated with some side effects, such as hyperkaliemia, hypotension, and cough, these drugs are currently among the most beneficial treatments to reduce both the risk factors and comorbidities associated with kidney diseases, such as cardiovascular outcomes, and all-cause mortality in non-dialysis CKD 3-5 patients[62].

Patients with microalbuminuria or proteinuria

In DM patients with established microalbuminuria (urinary albumin excretion 30-300 mg/day) or proteinuria (> 300 mg/day), ACEi and ARBs have shown renoprotective effects beyond their ability to reduce blood pressure, intraglomerular pressure, and proteinuria, and to slow the decline in GFR.

In the IRMA-2 trial study, the ARB irbesartan was shown to significantly reduce the risk of progression from microalbuminuria to overt nephropathy, in patients with T2D and early renal involvement (70% relative risk reduction with 300 mg/day)[63,64].

These findings support preferential prescribing of ARBs as first-line agents for patients with T2D and proteinuric kidney disease, as an alternative therapy in case of ACEi intolerance. Despite both classes provide the same clinical benefits, combination therapy is not recommended, due to the increased risk of hyperkalemia and acute kidney injury[65].

Patients without microalbuminuria

In normoalbuminuric diabetic patients, the benefit of RAS inhibition is less clear-cut and must be individualized. While ACEi and ARBs are widely used in diabetic patients with hypertension, there is limited evidence supporting their use for primary renal protection in normotensive individuals without albuminuria[66]. The BENEDICT trial investigated whether ACEi therapy could prevent microalbuminuria in T2D patients with normal albumin excretion. The ACEi trandolapril has been found to significantly reduce the incidence of new-onset microalbuminuria, compared to placebo, with the greatest benefits on hypertensive patients[67]. However, in normotensive, normoalbuminuric patients, the benefits were more limited, and the risk-benefit ratio should be carefully evaluated. Importantly, in these patients, RAS inhibitors should not be used solely for nephroprotection, unless other compelling indications, such as hypertension or left ventricular dysfunction are present[20].

Overall, RAS inhibition remains a reference point for nephroprotective therapy in diabetes, in patients with early or overt signs of kidney damage, although their use must be carefully monitored to avoid the risk of side effects, such as hyperkalemia and acute GFR decline.

Sodium glucose cotransporter 2 inhibitor

Sodium-glucose co-transporter 2 (SGLT2), encoded by the SLC5A2 gene, is predominantly expressed in proximal tubular cells and is responsible for reabsorbing about 90% of the filtered glucose load. Pharmacological inhibition of SGLT2 promotes glucose excretion and reduces blood glucose levels by blocking the reabsorption of filtered glucose, without causing hypoglycemia[68]. Of note, in both diabetic and non-diabetic CKD patients, proximal tubule hypertrophy, associated with SGLT2 overexpression and enhanced proximal reabsorption of glucose and sodium, leads to deactivation of tubulo-glomerular feedback and a consequent reduction in GFR[69]. SGLT2 inhibitors (SGLT2is) are characterized by a multifactorial mechanism of action, as they exert natriuretic, glycosuric, anti-inflammatory, and antifibrotic effects, through lowering glomerular pressure, improving of neurohumoral balance, and reducing of nephron workload. These processes lead to stabilization of the GFR, with reduction of albuminuria and intraglomerular pressure and a slowing of disease progression. Thus, the activity carried out by gliflozins is simultaneously nephro- and cardioprotective[53,70]. Additionally, SGLT2is have also been shown to modestly reduce blood pressure and weight, contributing to further protection. Like ACEi, an early reduction in GFR and proteinuria is considered a marker of therapeutic benefit. Unlike drugs targeting the RAAS, however, SGLT2i are associated with a lower risk of hyperkalemia and a reduced incidence of acute renal failure (AKI)[71,72].

Several studies have analyzed the major cardiovascular and renal outcomes associated with the use of SGLT2i in diabetic and non-diabetic patients[72].

The first study evaluating the efficacy and safety of SGLT2i in patients with T2D and albuminuric CKD, was CREDENCE. The primary outcome was a composite of ESRD, a doubling of the serum creatinine level, or death from renal or cardiovascular causes. It showed that canagliflozin, at a dose of 100 mg daily, reduced the relative risk of the primary outcome of 30% compared to the control group[73].

Three major studies EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58, on empagliflozin, canagliflozin and dapagliflozin, respectively, which analyzed more than 30000 diabetic patients, with or without atherosclerotic disease showed that SGLT2i could reduce major cardiovascular adverse events by 11% and the risk of cardiovascular death or hospitalization for heart failure by 23%. Furthermore, SGLT2i reduced renal disease progression by 45% and the greatest benefit was seen in patients with more advanced CKD[74-77].

DAPA-CKD was the first renal outcome trial showing efficacy and safety of dapagliflozin in patients with CKD with or without T2D. More specifically, the study had as primary outcomes: 50% decline in GFR, ESRD, and death from cardiovascular or renal causes. Patients receiving dapagliflozin had a 39% reduction in outcomes compared with placebo. The finding was present in patients with T2D and non-diabetic CKD. In the first month, the fall in GFR is part of the drug's mechanism of action, and at 3 years the decline in GFR was 1.60 mL/minute per year, compared with 3.59 mL/minute per year in the placebo group. There was also a 35% reduction in proteinuria and a 15% reduction in urine albumin-creatinine ratio (UACR)[78]. Again, SGLT2i were well tolerated, with reduced risk of hyperkalemia and AKI.

EMPA-KIDNEY evaluated the efficacy of empagliflozin in patients with CKD, regardless of diabetes status. The trial enrolled over 6600 participants with eGFR between 20 and 90 mL/minute/1.73 m² and elevated albuminuria. Notably, nearly half of the participants did not have diabetes, making EMPA-KIDNEY the most inclusive SGLT2i trial to date. The study demonstrated a 28% relative risk reduction in the primary composite outcome of CKD progression or cardiovascular death, compared to the placebo group. Additionally, empagliflozin significantly slowed eGFR decline and reduced hospitalization rates. The trial confirmed the broad renal and cardiovascular benefits of SGLT2i, extending their use to patients with non-diabetic CKD[79].

Recently, the use of SGLT2i in kidney transplant recipients has been explored. Their antifibrotic effect could help prevent recurrence and limit the development of interstitial fibrosis and tubular atrophy, by reducing the incidence of post-transplant DM and cardiovascular events. Nevertheless, evidence in this field is still limited, although it is of great interest.

Moreover, due to their action on podocytes and their antiproteinuric effect, SGLT2i may also have a potential role in proteinuric glomerulonephritis, although current data are still scarce.

Interestingly, a recent study has reported the ability of these drugs to slow progression in Alport disease[80].

Mineralocorticoids receptors antagonist

These drugs act by targeting the mineralocorticoid receptor, a key mediator of aldosterone-driven inflammation, fibrosis, and vascular remodeling. Originally developed as antihypertensive and heart failure agents, mineralocorticoid receptor antagonists (MRAs) have gained increasing relevance in nephrology due to their potential to slow CKD and DKD progression[81]. MRAs can be broadly categorized into steroidal and non-steroidal agents. The traditional steroidal MRAs, such as spironolactone and eplerenone, have been clinically used for decades and have been shown to reduce proteinuria and cardiovascular events. However, their utility in CKD is often limited by adverse effects, particularly hyperkalemia or, endocrine-related side effects due to non-selective receptor binding[82]. Spironolactone, the first MRA developed, has been shown to significantly reduce albuminuria by up to 30%-40%, when added to RAAS inhibitors in patients with DKD[83]. However, its use is limited by dose-dependent side effects, including gynecomastia, menstrual irregularities, and hyperkalemia, mainly observed in patients with advanced CKD or concurrent RAAS blockade[84]. Eplerenone, a more selective agent, with a favorable hormonal side effect profile due to higher specificity for the mineralocorticoid receptor and lower affinity for androgen and progesterone receptors, is also associated with similar potassium-related risks and, unfortunately, there are no clear data on the prevention and treatment of DKD[85-87].

On the other hand, the non-steroidal MRA finerenone is currently the most important advancement in this class. In the FIDELIO-DKD trial, involving over 5700 patients with T2D and CKD randomized to finerenone or placebo, after a median follow-up of 2.4 years, finerenone significantly reduced the risk of the composite renal outcome (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) compared to placebo (HR = 0.82; 95%CI: 0.73-0.93; P = 0.001). All patients were treated with maximally tolerated RAAS blockade. In this trial, finerenone also reduced the risk of cardiovascular events, particularly heart failure hospitalization and cardiovascular death[88].

The FIGARO-DKD, a double-blind trial conducted in a complementary population of 7437 diabetic patients with earlier-stage CKD, confirmed cardiovascular benefit in the finerenone group (HR = 0.87; 95%CI: 0.76-0.98; P = 0.03) even though there were no significant differences between-the two groups in the incidence of the secondary composite outcome (kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes)[89]. These trials firmly established finerenone as the first MRA with dedicated and robust evidence in DKD. Even though these trials showed an increased risk of hyperkaliemia, routine potassium monitoring and hyperkalemia management strategies can reduce this event, and it is now recommended in international guidelines as an add-on to ACEi or ARB in patients with albuminuric DKD.

In recent years, attention has shifted toward novel steroidal and non-steroidal MRAs with improved selectivity and safety profiles. Recent developments, this class of drugs includes promising new molecules. The first one is esaxerenone (CS-3150), which was previously used to treat hypertension and has now shown encouraging results in the management of DKD[90]. Indeed, several studies have confirmed that this molecule is more effective than placebo in inducing remission of UACR in patients with T2D, with levels below 30 mg/g upon completion of treatment[90,91].

Wada et al[92] tested Aparenone (MT-3995) in patients with DKD, showing that after 24 weeks of treatment the drug was able to reduce UACR by 54 % and to cause remission in 28 % of the study subjects taking the 10 mg daily dose[93].

AZD-9977 has already been successfully tested in healthy subjects and in patients with renal failure and heart failure in phase I studies[94]. The randomized phase II study is ongoing and assess the significance of this drug. The aim of this study is to compare escalating doses of AZD-9977 in combination with dapagliflozin vs dapagliflozin alone or placebo, to evaluate its antiproteinuric effect in patients with stable symptomatic heart failure (New York Heart Association 2-3) with a left ventricular ejection fraction < 55%, stage 3 CKD, and micro-macroalbuminuria[95].

Two other drugs in development that have ongoing phase two studies are KBP-5074 and BI690517. The former is being tested in cardiorenal diseases[96,97].

Incretin-based medication

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors and glucose-dependent insulinotropic polypeptide (GIP) analogs, have gained prominence in managing hyperglycemia, while offering extra-glycemic benefits[98,99].

GLP-1 RAs

This category of drugs, including liraglutide, semaglutide, and dulaglutide, have emerged as an important option not only for glycemic control, but also for renal and cardiovascular protection in patients with T2D. Their nephroprotective effects are increasingly recognized to occur independently of HbA1c lowering and are believed to act through a variety of mechanisms, such as anti-inflammatory, anti-atherogenic, natriuretic, and endothelial-protective actions. These pathways contribute to reducing albuminuria and slowing the progression of DKD through improved renal hemodynamics and metabolic modulation[100]. Furthermore, they directly activate glucagon-like peptide-1 (GLP-1) receptors, resulting in delayed gastric emptying, increased satiety, and reduced food intake, which translates into clinically significant weight loss[101].

In the LEADER trial, a total of 9340 patients underwent randomization to the liraglutide group and the placebo group. In exploratory outcomes nephropathy, defined as the new onset of macroalbuminuria or a doubling of the serum creatinine level and an eGFR of ≤ 45 mL/minute/1.73 m², the need for continuous renal-replacement therapy, or death from renal disease, was lower in the liraglutide group (HR = 0.84; 95%CI: 0.73-0.97; P = 0.02)[102]. The SUSTAIN-6 trial randomly assigned 3297 patients with T2D once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. Interestingly, it demonstrated that semaglutide lowered the incidence of new or worsening nephropathy that includes persistent macroalbuminuria, doubling of the serum creatinine level and a creatinine clearance of less than 45 mL/minute/1.73 m² of body-surface area (HR = 0.64; 95%CI: 0.46-0.88; P = 0.005), primarily by decreasing macroalbuminuria[103]. Similarly, in the REWIND trial 9901 participants were enrolled and randomized dulaglutide (n = 4949) or placebo (n = 4952). The results showed a significant reduction in the composite renal outcome (sustained decline in eGFR, new macroalbuminuria, or renal replacement therapy) in the dulaglutide group, despite enrolling patients with a lower cardiovascular risk profile[104]. Finally, the FLOW trial provided the first dedicated renal outcomes data for GLP-1 RAs in diabetic patients with CKD (eGFR 25-75 mL/minute/1.73 m², UACR 200-5000 mg/g). The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of < 15 mL/minute/1.73 m²), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. A total of 3533 participants were randomized to the semaglutide and the placebo group. After a median of 3.4 years, the risk of a primary-outcome event was 24% lower in the semaglutide group (HR = 0.76; 95%CI: 0.66-0.88; P = 0.0003). Moreover, the mean annual eGFR slope was significantly slower in the semaglutide group (P < 0.001)[105]. These effects were consistent across subgroups and independent of SGLT2i use. Unlike SGLT2is, GLP1 RAs do not induce acute eGFR dips and are generally well tolerated in moderate CKD. Their additional benefits, as weight loss, modest blood pressure reduction, and lipid profile improvement, further support their role in comprehensive cardiorenal protection.

DPP-4 inhibitors

This class of agents which include sitagliptin, linagliptin, vildagliptin, and alogliptin, lower blood glucose by inhibiting the degradation of endogenous incretin hormones (GLP-1 and GIP). This inhibition enhances glucose-dependent insulin secretion while simultaneously suppressing glucagon release. DPP-4 inhibitors are generally weight-neutral and do not promote weight loss. Although they modestly increase circulating GLP-1 and GIP concentrations through inhibition of the DPP-4 enzyme, the levels achieved are insufficient to induce appetite suppression or to elicit more pronounced metabolic effects observed with GLP-1 RAs[106]. The SAVORTIMI 53 was a randomized trial of 16492 patients with T2D, randomized to saxagliptin or placebo with a median follow-up of 2.1 years. The study was designed to evaluate if saxagliptin had a protective effect in diabetic nephropathy. The results showed that mean change in albumin/creatinine ratio (ACR) was better in the saxagliptin compared to placebo (-34.3 mg/g; P < 0.004), but the change in eGFR was similar in both groups[107]. In the TECOS study, 14671 diabetic patients were randomized to sitagliptin or placed in addition to standard therapy. After a median follow-up of 3 years, the sitagliptin group showed modest eGFR declines (-4.0 mL/minute/1.73 m² vs -2.8 mL/minute/1.73 m² over 4 years) and a slight UACR reduction (approximately 0.18 mg/g), compared to placebo (P < 0.001)[108].

Among these molecules, linagliptin is unique for its non-renal clearance, permitting fixed dosing across all CKD stages without dose adjustments[109]. In the CARMELINA study, a randomized placebo-controlled multicenter trial, 6991 diabetic patients with high cardiovascular e renal risk were randomized to linagliptin or placebo. After a median follow-up of 2.2 years, the study showed that kidney outcomes (death due to renal failure, ESRD, or sustained ≥ 40% decrease in eGFR from baseline) was not significantly different between the linagliptin group (9.4%; 4.89 per 100 person-years) and placebo groups (8.8%; 4.66 per 100 person-years; HR = 1.04; 95%CI: 0.89-1.22; P = 0.62). However, progression of albuminuria category (from normoalbuminuria to microalbuminuria/macroalbuminuria or from microalbuminuria to macroalbuminuria) occurred less frequently in the linagliptin group [763/2162 (35.3%); 21.4 per 100 person-years] than in the placebo group [819/2129 (38.5%); 24.5 per 100 person-years; HR = 0.86; 95%CI: 0.78-0.95; P = 0.003][110]. Recently, systematic review and meta-analysis have confirmed a significant reduction in albuminuria in patients treated with DPP-4 inhibitors. A 2024 systematic review of 23 randomized controlled trials involving over 16378 diabetic patients showed that DPP4 inhibitors significantly lowered urine ACR (SMD = -0.23; 95%CI: -0.41 to -0.06; P = 0.001). On the other hand, no significant changes were found in eGFR or serum creatinine[111]. Another 2024 meta-analysis including 17 randomized controlled trials confirmed modest reductions in ACR (MD = -2.76 mg/g, 95%CI: -5.23 to -0.29, I² = 0%, P = 0.03) but no significant effect on eGFR, with similar safety profiles in T2D patients[112]. In conclusion, DPP4 inhibitors remain valuable for albuminuria reduction, especially when more potent agents are contraindicated or poorly tolerated[113].

GIP analogs

This class of compounds includes dual GIP/GLP1 receptor agonists such as tirzepatide and represent a novel class with robust effects on metabolic parameters and weight loss. Tirzepatide is the first molecule of this class. It is a novel incretin-based therapy with potent effects on glycemic control, weight reduction, and emerging evidence of nephroprotection[114]. Preclinical data support this hypothesis, showing that tirzepatide exerts direct renal effects by activating the PI3K-AKT survival pathway, decreasing inflammation and oxidative stress, and protecting glomerular podocytes in mouse models[115].

The SURPASS1-5 pooled post-hoc analysis evaluated the effect of tirzepatide on kidney function. The results showed that, at week 40/42, the adjusted mean percentage reductions in UACR from baseline with tirzepatide 5 mg, 10 mg, and 15 mg doses were 19.3%, 22.0%, and 26.3%, respectively, compared with all pooled comparators. These reductions were consistent across comparator groups, including placebo, other active treatments, and insulin-based regimens. Moreover, these effects were partly independent of weight and HbA1c changes[116].

A recent meta-analysis including fifteen randomized trials showed that the use of tirzepatide at doses of 10 mg and 15 mg resulted in a significant reduction in UACR compared with placebo, while the 5 mg dose did not demonstrate a statistically significant effect. Specifically, UACR reductions for the 10 mg and 15 mg doses were -26.95% (P < 0.0001) and -18.03% (P = 0.0008), respectively. Subgroup analyses revealed that tirzepatide (all doses combined) was more effective than placebo in lowering UACR in both individuals with and without T2D, though the effect was more pronounced in those with T2D (-33.25% vs -7.93%; P = 0.001 for subgroup comparison). Further subgroup analysis based on kidney function, showed consistent UACR improvements with tirzepatide in T2D patients, regardless of whether baseline eGFR was above or below 90 mL/minute/1.73 m². No significant difference was observed between eGFR groups (P = 0.62), suggesting that the effect is independent of renal function status[117]. Finally, the ongoing TREASURE-CKD trial is evaluating tirzepatide’s long-term impact on renal outcomes in patients with CKD with or without diabetes and is expected to clarify its potential role in delaying progression to kidney failure[116]. Taken together, these findings position tirzepatide as a promising nephroprotective agent: It significantly lowers albuminuria, slows eGFR decline, and shows no detrimental effects on kidney function over the short term.

NEW PERSPECTIVE OF NEPHROPROTECTION IN DKD

Certainly, the progressive understanding of the pathogenetic mechanisms of DKD has allowed research to be directed toward the study of new targeted therapeutic frontiers. Promising new therapies are being developed including key mechanisms and optimal targets to slow or even stop DKD progression[72,118].

Endothelin receptor antagonists

High levels of circulating endothelin-1 (ET-1) have been observed in patients with DKD. ET-1 is involved in salt-water homeostasis, but in DKD, via the activation of its receptors ETA and ETB, it promotes endothelial dysfunction, vasoconstriction, fibrosis and inflammation[119,120]. In light of this, a number of studies have been started over the years to analyze the efficacy of ET-1 antagonists in DKD. In 2020, Zhang et al[121] performed a meta-analysis of seven studies with 5271 participants, and found that ER antagonists showed greater antiproteinuric action, up to a 40% reduction in UACR, and significant reductions in blood pressure, compared with the control group.

Vitamin D supplementation

One of the characteristic changes in diabetic nephropathy is podocyte injury, which is responsible for the reduced renal filtering capacity associated with the development of proteinuria. In this regard, the homeostasis of podocytes is regulated by the system of their degradation and intracellular recycling by autophagy[122]. Several studies have shown a close correlation between autophagy and vitamin D, which together with its receptor can maintain this function stable even under pathological conditions, such as diabetic nephropathy[123-125]. One study investigated the nephroprotective ability of calcitriol in mice with laboratory-induced diabetes. After administration of the active form of vitamin D, a progressive activation of vitamin D receptors was observed, associated with a reduction of glomerular sclerosis and proteinuria[126]. Consequently, the use of vitamin D receptor activators such as paracalcitol or calcitriol can be considered valuable agents against DKD progression. Furthermore, vitamin D in its hormonal form (1,25-Dihydroxyvitamin D3) also acts by reducing the expression of risk factors for DKD progression, including FGF-23 and RAS[127,128].

Inflammation antagonists

Since both the pathogenesis and progression of DKD have been shown to be heavily influenced by inflammatory compounds, some therapeutic frontiers aim to counteract inflammation[129]. For example, treatment with carnosine showed, in a murine study model, a reduction in renal inflammation and fibrosis, through its ability to bind to glycine N-methyltransferase (GNMT), increasing its expression. Low levels of GNMT are indeed associated with reduced availability of methyl groups, such as S-adenosylmethionine or S-adenosyl homocysteine to the cellular pool, as also observed in the kidneys of DKD mice[130,131]. Other biological drug strategies for targeting inflammatory cytokines have been developed, such as AF2838 compound, a selective protein inhibitor able to promote monocyte recruitment, and monoclonal antibodies like gevokizumab and canakinumab, which target interleukin-1β (IL-1β). AF2838 compound has shown anti-inflammatory effects in preclinical models, but clinical data on renal outcomes are still lacking. The monoclonal antibody gevokizumab, an angiogenesis inhibitor in early-phase trials, showed a modest effect in DKD patients in counteracting both inflammation and renal parameter decline and was discontinued. Similarly, canakinumab, assessed in the CANTOS trial, reduced cardiovascular events but had no significant impact on eGFR decline or progression to kidney failure[132].

Altogether, among the anti-inflammatory strategies, monoclonal antibodies have been shown to reduce cardiovascular and, potentially, renal adverse outcomes in diabetic patients, although nephropathy-specific trials remain limited. Gevokizumab, another IL-1β inhibitor, has shown promise in glycemic and inflammatory control, in phase II trials[133]. Experimental inhibitors, such as AF2838, targeting monocyte recruitment, and dual chemokine blockade (e.g., CCL2 and CXCL12), have also demonstrated synergistic protection in animal models of DKD[134]. These studies support inflammation as a pivotal target for future therapies, despite clinical validation still being required.

Antioxidant therapy

The hyperglycemic condition characteristic of DKD represents a continuous stimulus for oxidative stress, which is responsible for the production of ROS. Normally, the body cells produce both enzymatic antioxidants, such as superoxide dismutase or glutathione peroxidase, and non-enzymatic ones, such as vitamins C and E, glutathione and β-carotene[135]. Given the importance of antioxidant management, several drugs have already been studied for their ability to slow renal function decline associated with diabetes, by acting on oxidative pathways, among which SGLT2is, GLP-1 RAs, AGE formation inhibitors, xanthine oxidase[136]. Pharmacological inhibition of NADPH oxidase showed nephroprotective action in subjects with long-standing DKD. In addition, GKT137831, a specific inhibitor for Nox 4, has been revealed to reduce inflammation, renal fibrosis, and albuminuria levels[137]. Among the flavonoids, which have also been investigated for their antioxidant properties, hydrosmin, a synthetic molecule derived from hesperidin, has been evaluated in a trial, in an experimental DKD model, showing itself to be capable of delaying renal damage by inhibiting cellular aging associated with inflammation and oxidative stress[138] (Figure 1 and Supplementary Table 1).

Figure 1 Pathophysiological progression and management strategies in diabetic kidney disease. This schematic illustrates the pathogenesis, clinical progression, and current therapeutic approaches in diabetic kidney disease. Created in BioRender (Supplementary material). T1D: Type 1 diabetes; T2D: Type 2 diabetes; GFR: Glomerular filtration rate; RAAS: Renin-angiotensin-aldosterone system; SGLT2: Sodium-glucose co-transporter 2; MRA: Mineralocorticoid receptor antagonist; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; DPP-4: Dipeptidyl peptidase-4; GIP: Glucose-dependent insulinotropic polypeptide.

PRESENT AND FUTURE DIRECTIONS

The contemporary management of DKD has undergone a fundamental reconceptualization, moving beyond glucose-centric approaches toward integrated nephroprotective strategies. Central to this evolution is the recognition that SGLT2i and RAS inhibitor (RASi) operate through complementary yet mechanistically distinct pathways: SGLT2i reduce intraglomerular pressure primarily through afferent arteriolar constriction and restoration of tubuloglomerular feedback[139], whereas RASis achieve similar hemodynamic benefits via efferent arteriolar dilation[72]. The KDIGO 2022 guidelines have codified this understanding by positioning both agent classes alongside metformin as foundational first-line therapy[20], a departure from traditional sequential prescribing patterns that reflects accumulating evidence favoring early combination strategies.

This therapeutic paradigm assumes greater clinical significance when one considers the expanding recognition of cardiovascular vulnerability in earlier disease stages. Cardiovascular risk does not initiate at the microalbuminuric threshold but rather demonstrates a continuous relationship with albuminuria from substantially lower levels, specifically, UACR values exceeding 5 mg/g Cr have been associated with measurable increases in cardiovascular events despite falling within the conventionally defined normoalbuminuric range[140]. Such observations underscore that the traditional binary classification of albuminuria status may inadequately capture the continuum of risk, particularly in younger patients or those with multiple metabolic risk factors.

The natural history of diabetic albuminuria, characterized by progressive worsening in the absence of intervention, provides compelling justification for proactive therapeutic intensification in high-risk subgroups. Patients demonstrating obesity, inadequate glycemic regulation, or suboptimal blood pressure control warrant consideration for dual SGLT2i and RAS inhibitor therapy even at the normoalbuminuric stage[141]. When UACR trajectories reveal upward trends despite initial dual therapy, clinicians should pursue prompt escalation rather than protracted observation. The addition of MRAs or GLP-1 receptor agonists at this juncture may prevent transitions to more advanced albuminuria categories that prove recalcitrant to subsequent intervention[72].

Regular UACR monitoring serves not merely as disease surveillance but as the cornerstone of risk-adapted therapeutic decision-making, given that even modest incremental elevations portend both renal and cardiovascular adverse outcomes[142]. The clinical challenge lies in achieving remission at earlier stages: Whereas microalbuminuria may prove reversible with timely intervention at lower UACR levels, delays in therapeutic intensification substantially diminish the probability of complete remission. Similarly, regression from overt albuminuria to microalbuminuria becomes progressively more difficult as absolute UACR values increase and histologic changes advance[10]. These observations emphasize that nephroprotection in diabetes may benefit from proactive UACR reduction rather than passive monitoring, and a UACR-guided treatment intensification strategy could be considered an important approach.

Within the diabetic population exists a particularly vulnerable subset termed “rapid decliners”, characterized by accelerated GFR loss that substantially exceeds typical rates of decline[143]. Early identification of this phenotype through systematic UACR and eGFR surveillance enables targeted therapeutic intensification before irreversible nephron loss occurs. These high-risk individuals require comprehensive intervention with what has been aptly termed the “fantastic four” of diabetic nephropathy: The synergistic combination of SGLT2is, RAS inhibitors, MRAs, and GLP-1 receptor agonists, complemented by intensive lifestyle modification encompassing dietary sodium restriction, weight optimization, and structured physical activity[144].

Cardiorenal protection extends beyond albuminuria and GFR preservation to encompass comprehensive metabolic risk factor management, with dyslipidemia representing a critical yet sometimes underemphasized target. Contemporary guidelines advocate aggressive LDL-C reduction to below 1.4 mmol/L (55 mg/dL) in diabetic patients with target organ damage, whether manifested as albuminuria, reduced eGFR, or both[145]. The KDIGO 2022 framework positions statins as essential first-line lipid-lowering therapy in this population, and their integration with nephroprotective agents should be considered standard of care rather than optional adjunctive treatment[20]. Achieving these stringent lipid targets may confer benefits extending beyond cardiovascular protection to include direct renoprotective effects, potentially through mechanisms involving reduced inflammation and endothelial dysfunction.

This integrated paradigm, characterized by early detection through systematic biomarker surveillance, risk stratification based on albuminuria trajectories and decline phenotypes, and comprehensive multi-drug regimens targeting complementary pathophysiologic pathways, represents the contemporary standard for optimizing long-term outcomes in DKD. Future investigations will need to define optimal sequences for therapeutic escalation, identify biomarkers beyond albuminuria and eGFR that predict treatment responsiveness, and determine whether even more aggressive early intervention strategies can fundamentally alter disease trajectories in the highest-risk populations.

CONCLUSION

The management of DKD has entered a transformative phase, marked by the integration of traditional therapies with novel pharmacological agents that provide cardiovascular and renal protection beyond glycemic control. While glucose and blood pressure optimization remain crucial objectives, agents such as SGLT2is, GLP-1 receptor agonists, nonsteroidal MRAs, and endothelin receptor blockers have demonstrated independent nephroprotective effects, by slowing the progression of kidney function decline in DKD patients. Moreover, the understanding of pathogenic mechanisms involved in inflammation, oxidative stress, and autophagy has unveiled new therapeutic targets. Future strategies will likely rely on a multifactorial approach tailored to individual risk profiles, comorbidities, and stages of CKD. Ongoing trials and precision medicine will be essential to define optimal combinations and sequencing of these interventions. Ultimately, early identification and comprehensive management are key to mitigating the burden of DKD and its systemic complications.