The intestinal microbiome plays a critical role in maintaining kidney homeostasis through complex bidirectional interactions within the gut–kidney axis (84, 85). Emerging evidence implicates gut microbial dysbiosis as an active contributor to the pathophysiology of DKD. Characteristic alterations in gut microbial composition in DKD include a marked reduction in short-chain fatty acid (SCFA)-producing bacteria—particularly butyrate-producing members of the Lachnospiraceae family and genera such as Blautia and Faecalibacterium—alongside an overgrowth of potentially pathogenic taxa, including Enterobacteriaceae and other gamma-proteobacteria (86). Mounting evidence indicates that patients with DKD commonly exhibit gut microbiota dysbiosis, altered bile acid pool composition, and aberrant expression of bile acid receptors—particularly Farnesoid X Receptor (FXR) and Takeda G protein–coupled receptor 5. These disruptions may exacerbate renal injury by activating pro-inflammatory signaling cascades, notably the NF-κB pathway and NLRP3 inflammasome, thereby enhancing cytokine production (87). This microbial imbalance contributes to disease progression through several mechanisms. Aberrant protein fermentation enhances the generation of nephrotoxic metabolites, such as indoxyl sulfate, p-cresol sulfate, and trimethylamine N-oxide (TMAO) (88–90). As renal function declines, these uremic toxins accumulate and exacerbate kidney injury by promoting oxidative stress, disrupting cellular metabolism, and activating inflammatory signaling pathways (90–92). Intestinal barrier dysfunction further amplifies renal damage. During DKD progression, hyperglycemia and microbial dysbiosis disrupt epithelial tight junctions, increasing gut permeability and enabling translocation of endotoxins—particularly lipopolysaccharide (LPS)—into the systemic circulation (93, 94). LPS activates the Toll-like receptor 4 (TLR4)/NF-κB pathway, sustaining systemic inflammation and accelerating renal decline (95). A reciprocal relationship exists between kidney dysfunction and gut microbial alterations: renal impairment, influenced by dietary restrictions, antibiotic exposure, slowed gastrointestinal transit, altered luminal pH, and urea accumulation, reshapes the intestinal environment, further promoting dysbiosis and perpetuating kidney injury (96). While DKD shares many features of gut dysbiosis observed in other forms of CKD, it exhibits unique microbial patterns driven by diabetes-specific metabolic disturbances (92, 97). Compared with non-diabetic kidney disease, DKD is associated with more profound depletion of SCFA-producing bacteria, resulting in reduced levels of beneficial microbial metabolites such as butyrate, propionate, and acetate (98). These SCFAs exert anti-inflammatory effects via activation of G-protein–coupled receptors and inhibition of histone deacetylases; their deficiency aggravates renal inflammation and fibrosis (99). Additionally, DKD is characterized by aberrant amino acid metabolism. Enhanced microbial degradation of tryptophan and phenylalanine increases production of nephrotoxic derivatives—such as phenyl sulfate and indole compounds—which contribute to fibrosis through oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activation (100–102). Hyperglycemia itself directly alters the gut microbiota, favoring expansion of pathogenic species while suppressing beneficial taxa (103, 104). AGEs further modify microbial metabolic outputs and promote uremic toxin production (105). Diabetes-related gastrointestinal complications, including gastroparesis and altered motility, contribute to small intestinal bacterial overgrowth, exacerbating microbial imbalance (106). Elevated TMAO levels in DKD also downregulate tight junction proteins, increasing intestinal permeability (107, 108). This “leaky gut” phenotype—driven by hyperglycemia, uremia, and microbial toxins—establishes a destructive cycle of barrier dysfunction in both the intestine and kidney. Given the central role of gut–kidney interactions in DKD pathogenesis, microbiota-targeted interventions—including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation—represent promising therapeutic strategies. A more refined understanding of diabetes-specific dysbiosis may facilitate the development of precision microbiota-based interventions for DKD prevention and treatment.

Exosomes—first characterized in 1982—are membrane-bound extracellular vesicles that have emerged as pivotal mediators of intercellular communication and key contributors to disease pathogenesis. In DKD, recent evidence indicates that hyperglycemia and albuminuria stimulate increased exosome production from glomerular endothelial cells and tubular epithelial cells (109–111). These vesicles actively propagate proinflammatory and profibrotic signals within the renal microenvironment (109, 112). Under hyperglycemic conditions, mesangial cell–derived exosomes have been shown to upregulate transforming growth factor-beta (TGF-β) expression and activate the TGF-β1/PI3K–Akt signaling pathway, ultimately promoting podocyte injury and fibrotic remodeling (113). Additionally, exosomes serve as carriers of microRNAs (miRNAs) that modulate mesangial cell proliferation and interstitial fibrosis—two key pathological features of progressive DKD (114–116). These findings underscore the role of exosomes not merely as passive biomarkers, but as active participants in the molecular signaling networks that drive diabetic kidney injury.

Autophagy is a fundamental cellular process responsible for the degradation and recycling of damaged organelles and misfolded proteins, playing a vital role in maintaining renal homeostasis. In DKD, impaired autophagy has been identified as a central pathogenic mechanism contributing to podocyte injury, albuminuria, and tubulointerstitial damage (117). Experimental studies demonstrate that enhancing autophagic flux ameliorates structural and functional renal injury, reduces proteinuria, and delays disease progression (118–120). These findings support the concept that autophagy dysregulation is involved throughout the course of DKD—from early glomerular changes to advanced stages of kidney failure. Given its essential role in cellular quality control, the autophagy pathway represents a promising therapeutic target (121). Interventions aimed at restoring autophagic function may provide a novel approach to disrupt the pathological cascade underlying DKD, offering potential to slow or halt the progression of renal injury in diabetic patients.

Ferroptosis is a regulated, iron-dependent form of cell death distinct from apoptosis, necrosis, and autophagy. Characterized by excessive lipid peroxidation and impaired antioxidant defenses, ferroptosis has been increasingly implicated in the pathogenesis of DKD (122–124). Experimental evidence from diabetic animal models and human kidney tubular epithelial cells exposed to hyperglycemic conditions demonstrates hallmark features of ferroptosis, including mitochondrial shrinkage and disrupted redox homeostasis (122, 125, 126). Inhibition of ferroptosis has been shown to confer renoprotective effects and attenuate DKD progression (122). Renal biopsy specimens from DKD patients reveal elevated expression of ferroptosis-associated proteins—such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2—accompanied by marked downregulation of glutathione peroxidase 4 (GPX4), a key suppressor of ferroptosis (127). These molecular signatures support the contribution of ferroptotic cell death to DKD pathogenesis and identify ferroptosis as a promising therapeutic target. Interventions aimed at restoring redox balance, chelating iron, or directly inhibiting ferroptosis-related enzymes may offer novel strategies for renal protection in diabetic patients.

Epigenetic regulation—including DNA methylation, histone modifications, and non-coding RNA-mediated gene silencing—plays a crucial role in the initiation and progression of DKD (128). These heritable yet reversible modifications influence gene expression without altering the underlying DNA sequence, thereby modulating cellular responses to hyperglycemia and inflammatory stimuli (129, 130). Among epigenetic mechanisms, histone methylation has garnered particular attention for its role in shaping chromatin structure and regulating transcription of key profibrotic genes such as transforming growth factor-beta 1 (TGF-β1) and type I collagen (131, 132). Aberrant histone methylation patterns have been linked to persistent inflammation, fibrogenesis, and activation of programmed cell death pathways in renal tissues, contributing to progressive loss of kidney function in DKD (133). Importantly, the reversible nature of epigenetic modifications renders them attractive targets for therapeutic intervention. Pharmacological modulation of histone methyltransferases, DNA methyltransferases, and chromatin-binding proteins may enable reprogramming of disease-associated gene expression patterns (134). As such, targeting epigenetic dysregulation represents a promising strategy to halt or potentially reverse DKD progression in clinical settings.

Achieving and maintaining optimal glycemic control is fundamental to both the prevention and progression attenuation of DKD. The ADVANCE trial demonstrated that reducing hemoglobin A1c (HbA1c) levels below 6.5% was associated with a 21% reduction in nephropathy risk and a 30% reduction in proteinuria (135, 136). Similarly, in type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) established that intensive glucose control reduced the risk of DKD progression by ~60% (137). These findings are supported by meta-analyses of multiple clinical trials, which show significant reductions in the incidence of both microalbuminuria (relative risk 0.86) and macroalbuminuria (relative risk 0.74) with improved glycemic management (138). However, individualized treatment remains essential. Patients with advanced kidney dysfunction may derive limited renal benefit from intensive glucose lowering and are at heightened risk of hypoglycemia (139). Recent studies also suggest that glycemic variability—fluctuations in glucose levels—may be as important as mean glycemia in predicting adverse renal outcomes. Thus, therapeutic strategies should balance glycemic targets with safety considerations, particularly in patients with reduced renal reserve (140).

Blood pressure regulation is a cornerstone of DKD management. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend maintaining blood pressure below 130/80 mmHg, with more stringent targets advised for individuals with albuminuria, due to their heightened risk of renal and cardiovascular events (141, 142). Evidence from the UK Prospective Diabetes Study (UKPDS) demonstrated that effective blood pressure control significantly reduces both microvascular and macrovascular complications in patients with diabetes (143). Among antihypertensive agents, inhibitors of the renin–angiotensin–aldosterone system (RAAS)—particularly Cs (ACEIs)—have shown superior renal benefits. A subanalysis of the African American Study of Kidney Disease and Hypertension (AASK) highlighted ramipril's efficacy, demonstrating a 22%−38% reduction in composite renal endpoints compared to other antihypertensive agents (144). These findings have firmly established RAAS blockade as the foundational antihypertensive strategy in DKD. Selection of additional agents—such as calcium channel blockers or diuretics—should be guided by comorbid conditions, volume status, and patient-specific factors to achieve individualized and sustained blood pressure targets (145, 146).

Dyslipidemia is a significant modifiable risk factor for cardiovascular disease in patients with DKD, and its effective management is essential to reduce overall morbidity and mortality (147). The Study of Heart and Renal Protection (SHARP), which enrolled 9,270 individuals with moderate-to-advanced CKD, demonstrated that combination lipid-lowering therapy with simvastatin and ezetimibe reduced the incidence of major atherosclerotic events by 17% (148). A meta-analysis of 33 randomized controlled trials (RCTs) further confirmed the renoprotective effects of statins, showing reductions in urinary albumin excretion [weighted mean difference (WMD): −2.04 mg/24 h], proteinuria (WMD: −0.58 g/24 h), and modest improvements in creatinine clearance (WMD: +0.86 ml/min) (149). Based on these findings, current clinical guidelines recommend maintaining low-density lipoprotein cholesterol (LDL-C) levels below 100 mg/dl, with lower targets for individuals at elevated cardiovascular risk (150). Lipid-lowering therapy, particularly with statins and combination regimens, thus plays a central role in the comprehensive management of DKD.

Lifestyle modification represents a critical adjunct to pharmacologic therapy in DKD management, offering substantial benefits for blood pressure control, metabolic regulation, and renal outcomes (151). Among dietary interventions, sodium restriction has the strongest evidence base. A Cochrane systematic review reported mean reductions of 6.15 mmHg in systolic and 3.41 mmHg in diastolic blood pressure following dietary sodium restriction (152). Current international guidelines recommend limiting sodium intake to 2.0–2.3 g/day (153). Observational data consistently demonstrate a strong correlation between sodium intake and albuminuria severity (154). Weight management also exerts important renoprotective effects. Mendelian randomization studies have identified a causal relationship between increased body mass index (BMI) and heightened kidney disease risk, with each standard deviation increase in BMI nearly doubling disease probability (odds ratio: 2.00) (155). Bariatric and metabolic surgeries have been associated with marked improvements in renal function and reductions in albuminuria among obese patients with DKD (156). Physical activity offers additional benefit. Structured exercise programs, particularly those incorporating resistance training, have been shown to improve glomerular filtration rates and reduce proteinuria (157). Current clinical guidelines recommend that DKD patients engage in at least 150 min per week of moderate-intensity aerobic exercise to support cardiorenal health (158).

The contemporary pharmacologic framework for DKD emphasizes the use of four core medication classes, each contributing distinct yet complementary cardiorenal protective effects. These include: (1) RAASi—such as ACEIs and ARBs; (2) SGLT2i; (3) GLP-1 RAs; and (4) ns-MRAs (159, 160). Each class targets different pathogenic mechanisms—hemodynamic dysregulation, hyperglycemia, inflammation, and fibrosis—and has independently demonstrated benefits for renal and cardiovascular outcomes in randomized controlled trials. When used in combination, these agents exhibit additive and, in some cases, synergistic effects, offering a robust strategy for mitigating DKD progression and associated cardiovascular morbidity (161). The integration of these therapies into routine clinical practice represents a paradigm shift from glucose-centric models toward a comprehensive cardiorenal-metabolic treatment approach.

Optimal management of DKD requires a multidisciplinary, team-based approach that leverages the expertise of various healthcare professionals. Primary care providers play a foundational role in screening, risk stratification, early intervention, and referral of high-risk individuals (162). Endocrinologists contribute specialized expertise in glycemic management, particularly in selecting agents with proven cardiorenal benefits, such as SGLT2i and GLP-1 RAs (163). As DKD advances, nephrologists take on a central role in managing progressive renal function decline, persistent albuminuria, complex electrolyte disturbances, and planning for renal replacement therapy when appropriate (164). Given the elevated cardiovascular burden in DKD, cardiologists are increasingly integral to the care team (165). However, data suggest that SGLT2 inhibitors and GLP-1 receptor agonists remain underutilized in cardiology practice despite their established benefits (166). Reframing these agents as foundational cardiorenal protective therapies, rather than merely glucose-lowering drugs, is essential to enhance their uptake across disciplines. Implementation of patient-centered care models—featuring integrated electronic health records, effective inter-provider communication, and collaborative clinical decision-making—remains critical to achieving therapeutic goals. Both the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and the American Diabetes Association (ADA) endorse multidisciplinary care coordination as a central pillar of comprehensive DKD management (167).

Blockade of the RAAS remains the foundational therapy for DKD, supported by robust evidence from landmark randomized controlled trials. The Collaborative Study Group (CSG) trial enrolled 409 patients with type 1 diabetes and persistent proteinuria (≥500 mg/day), randomizing them to captopril or placebo (168). Captopril reduced the risk of serum creatinine doubling by 48% (P = 0.007), with a more pronounced 76% risk reduction observed in patients with baseline serum creatinine >2.0 mg/dl. Moreover, captopril therapy halved the combined risk of mortality, dialysis initiation, or kidney transplantation. In patients with type 2 diabetes, the RENAAL trial evaluated 1,513 participants with overt nephropathy (169). Losartan treatment resulted in a 16% relative reduction in the composite outcome of doubling of serum creatinine, end-stage renal disease (ESRD), or death (P = 0.02). Notably, losartan decreased the risk of serum creatinine doubling and ESRD by 25 and 28%, respectively, and reduced proteinuria by 35%, compared to a 4% increase in the placebo group. The Irbesartan Diabetic Nephropathy Trial (IDNT) compared irbesartan to amlodipine and placebo in 1,715 patients with type 2 DKD (170). Irbesartan reduced the primary composite endpoint by 23% vs. amlodipine and 20% vs. placebo (both P < 0.01), while also slowing the rate of renal function decline (171, 172). Despite the strength of these findings, several limitations must be acknowledged. Differences in blood pressure between treatment arms may confound interpretation of direct renoprotective effects. Sample sizes limited secondary endpoint analysis, and pharmaceutical sponsorship introduces the possibility of selective outcome reporting. Additionally, composite endpoints combining irreversible outcomes with surrogate markers complicate interpretation. Nevertheless, these trials provide compelling and consistent evidence that RAAS inhibition reduces the progression of DKD and underpins current clinical guideline recommendations.

SGLT2i represent a transformative advance in the management of CKD, including DKD, with efficacy demonstrated across multiple large-scale randomized trials. The CREDENCE trial enrolled 2,627 patients with type 2 diabetes and albuminuric kidney disease [urinary albumin-to-creatinine ratio (UACR) 300–5,000 mg/g; estimated glomerular filtration rate (eGFR) 30–90 ml/min/1.73 m²], randomizing participants to canagliflozin (100 mg daily) or placebo (173). Over a median 2.6-year follow-up, canagliflozin reduced the risk of the primary composite outcome—ESRD, doubling of serum creatinine, or death from renal or cardiovascular causes—by 30% (HR 0.70; 95% CI 0.59–0.82). The DAPA-CKD trial extended these findings to both diabetic and non-diabetic CKD populations. Among 4,304 participants (67.5% with diabetes), dapagliflozin (10 mg daily) reduced the primary composite outcome by 39% (HR 0.61; 95% CI 0.51–0.72) (174). Similarly, the EMPA-KIDNEY trial, which included 6,609 participants across various CKD etiologies and stages, demonstrated that empagliflozin reduced the risk of kidney disease progression or renal death by 28% (HR 0.72; 95% CI 0.64–0.82) (175). Despite their robust benefits, several caveats apply. All three trials were industry-sponsored, raising the potential for reporting bias. Importantly, patients with advanced renal impairment (eGFR < 20–30 ml/min/1.73 m²) were excluded, limiting generalizability to this high-risk subgroup. Moreover, long-term safety data in patients with severely reduced kidney function remain incomplete. Nonetheless, these studies firmly establish SGLT2 inhibitors as cornerstone therapy for DKD and broader CKD management. Their renoprotective effects—largely independent of glycemic control—have redefined treatment paradigms, expanding their role from antidiabetic agents to central components of cardiorenal protection across diverse patient populations.

MRAs have emerged as a novel and promising class of therapeutic agents for DKD. Finerenone, a selective non-steroidal MRA, has led this advancement by targeting aldosterone-mediated inflammatory and fibrotic signaling pathways—key drivers of DKD progression. Its mechanism of action complements those of SGLT2 inhibitors and RAAS blockers, contributing to a multifaceted therapeutic approach (176). The FIDELIO-DKD trial provided pivotal evidence supporting the efficacy of finerenone in patients with type 2 diabetes and CKD (177). In this randomized, placebo-controlled study of 5,734 participants (UACR 30–5,000 mg/g; eGFR 25–75 ml/min/1.73 m²), finerenone (10–20 mg daily) significantly reduced the primary composite renal outcome—defined as kidney failure, sustained eGFR decline ≥40%, or renal death—by 18% compared to placebo (HR 0.82; 95% CI 0.73–0.93; P = 0.001) over a median follow-up of 2.6 years. The FIGARO-DKD trial, which enrolled patients with earlier-stage DKD and preserved eGFR, demonstrated a 13% relative reduction in major adverse cardiovascular events (MACE; HR 0.87; 95% CI 0.76–0.98; P = 0.03), primarily driven by a 29% reduction in heart failure hospitalizations (178). The FIDELITY pooled analysis (n = 13,026) integrated data from both trials, confirming consistent cardiorenal benefits: a 23% reduction in the composite kidney outcome (HR 0.77; 95% CI 0.67–0.88) and an 18% reduction in all-cause mortality (HR 0.82; 95% CI 0.70–0.95) (179). Despite these encouraging findings, several limitations warrant consideration. All three trials were sponsored by the manufacturer (Bayer), raising the possibility of reporting bias. Hyperkalemia was a notable adverse event, occurring in 21.4% of finerenone-treated patients vs. 9.1% in the placebo group, necessitating close monitoring of serum potassium levels. Furthermore, the exclusion of patients with symptomatic heart failure may restrict the generalizability of results to this particularly vulnerable subgroup. Nevertheless, finerenone has firmly established itself as a critical component of contemporary DKD therapy. When combined with SGLT2 inhibitors, it enables a complementary, mechanism-based approach that targets multiple pathogenic pathways. These developments underscore a paradigm shift toward multi-targeted precision therapy in DKD, aligning with the broader goals of individualized medicine in nephrology.

GLP-1 RAs have emerged as promising agents in the management of DKD, exerting multifaceted benefits through improved glycemic control, weight reduction, anti-inflammatory effects, and modulation of renal hemodynamics (1). An expanding body of evidence from both cardiovascular outcome trials and kidney-specific studies supports their implementation in DKD care. In the LEADER trial, which enrolled 9,340 individuals with type 2 diabetes and elevated cardiovascular risk, liraglutide treatment resulted in a 22% reduction in a secondary composite renal outcome (HR 0.78; 95% CI 0.67–0.92), primarily due to reduced incidence of new-onset macroalbuminuria (180–182). Similarly, the SUSTAIN-6 trial (n = 3,297) reported a 36% relative reduction in kidney disease progression with semaglutide (HR 0.64; 95% CI 0.46–0.88) (183). Although both trials evaluated renal outcomes as secondary endpoints, the results provided compelling early evidence of renoprotection. The FLOW trial was the first randomized controlled trial specifically designed to evaluate renal outcomes with GLP-1 RA therapy (184). Among 3,534 participants with DKD (eGFR 25–75 ml/min/1.73 m²; UACR 100–5,000 mg/g), once-weekly semaglutide (1.0 mg) reduced the risk of the primary composite renal endpoint—defined as kidney failure, sustained ≥50% eGFR decline, or death from renal or cardiovascular causes—by 24% (HR 0.76; 95% CI 0.66–0.88) (185). Additionally, semaglutide reduced all-cause mortality by 20% (HR 0.80; 95% CI 0.67–0.95). The trial was terminated early due to clear efficacy, marking a major advancement in renal protection through incretin-based therapy. However, subgroup analyses from FLOW raised important questions regarding combination therapy. Among 550 participants concurrently receiving SGLT2 inhibitors, semaglutide conferred no significant renal benefit (HR 1.07; 95% CI 0.69–1.67), in contrast to substantial protection observed in those not on SGLT2i therapy (HR 0.73; 95% CI 0.63–0.85). These findings suggest a potential therapeutic ceiling when combining agents with overlapping mechanisms—including natriuresis, afferent arteriolar constriction, and anti-inflammatory effects—and underscore the need for further investigation into optimal sequencing and drug combinations. Several caveats must be considered when interpreting these data. All major GLP-1 RA trials—including LEADER, SUSTAIN-6, and FLOW—were sponsored by pharmaceutical companies (Novo Nordisk or Eli Lilly), raising the possibility of reporting bias. Except for FLOW, renal outcomes were evaluated as secondary endpoints, with limited statistical power for definitive conclusions. Moreover, patients with advanced kidney dysfunction (eGFR < 25 ml/min/1.73 m²) were consistently excluded, limiting applicability to this high-risk population. Long-term safety and efficacy in patients with severe renal impairment remain to be fully characterized. In summary, GLP-1 receptor agonists now represent a key therapeutic option in the comprehensive management of DKD. Their distinct mechanisms of action complement those of RAASi and SGLT2i, offering additional opportunities for personalized care. Future research should focus on identifying optimal therapeutic combinations and addressing unmet needs in underrepresented and high-risk patient groups.

Dipeptidyl peptidase-4 (DPP-4) inhibitors exert their effects by blocking DPP-4 enzymatic activity, thereby preventing the degradation of endogenous incretin hormones—primarily glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). This prolongs the bioactivity of incretins, contributing to glucose-dependent insulin secretion and suppression of glucagon release. Beyond their glycemic effects, DPP-4 inhdiabetic kidney diseaseibitors have shown potential renoprotective properties, including improved renal perfusion, attenuation of oxidative stress, reduced proinflammatory signaling, and enhanced tubular epithelial cell viability (186). In a clinical study by Kim and colleagues involving 414 patients with DKD, treatment with DPP-4 inhibitors led to a 28.4% reduction in UACR, compared with only an 8.2% reduction in the control group (P < 0.01) (186). The annual rate of decline in estimated glomerular filtration rate (eGFR) was also slower among treated individuals (1.24 vs. 2.01 ml/min/1.73 m²; P = 0.03), indicating modest renoprotective benefit. DPP-4 inhibitors offer distinct clinical advantages, particularly in high-risk populations. They are weight-neutral, carry a low risk of hypoglycemia, and are well-tolerated, with rare gastrointestinal side effects (187). These features make them suitable for elderly patients, those with impaired renal function, and individuals intolerant to other glucose-lowering agents. However, their cardiorenal efficacy is modest compared with that of SGLT2i and GLP-1 receptor agonists. As a result, current treatment guidelines position DPP-4 inhibitors as secondary options—primarily for patients who cannot tolerate or are ineligible for first-line renoprotective therapies (1). Although they do not offer the same magnitude of benefit as newer agents, DPP-4 inhibitors remain valuable in individualized DKD management. Further studies are warranted to evaluate their role in combination regimens alongside other evidence-based therapies. An overview of these pivotal trials, including inclusion criteria and primary/secondary endpoints, can be found in Table 1.

Pentoxifylline, a non-selective phosphodiesterase inhibitor, has shown modest clinical benefit in patients with moderate to advanced stages (3, 4) of DKD. Its therapeutic effects are attributed to multiple mechanisms, including upregulation of the renoprotective Klotho protein, suppression of proinflammatory cytokines, attenuation of tissue fibrosis, and reduction of proteinuria (188). These actions collectively contribute to the preservation of renal function and deceleration of disease progression. Pentoxifylline is generally well-tolerated. The most frequently reported adverse effects are gastrointestinal in nature—nausea, vomiting, and abdominal discomfort (189). Although bleeding complications are rare, caution is warranted in patients with recent cerebral or retinal hemorrhage due to its potential antiplatelet activity (190). Given its low cost, pleiotropic effects, and favorable safety profile, pentoxifylline may serve as a valuable adjunctive treatment in select patients with progressive DKD. It offers a cost-effective therapeutic addition, particularly in resource-limited settings or among patients unable to access newer agents. However, broader clinical adoption will require further validation through large-scale, randomized trials.

AGEs comprise harmful compounds formed when proteins and lipids undergo non-enzymatic glycation in hyperglycemic environments. These molecules promote tissue damage by inducing oxidative stress and chronic inflammatory responses, significantly contributing to DKD progression and other diabetic complications, including cardiovascular disorders (191). Emerging research suggests that dietary modifications aimed at limiting AGEs consumption can improve insulin sensitivity, reduce glycemic parameters, and decrease systemic inflammatory markers (192). While pharmaceutical agents that inhibit AGEs formation remain in early developmental stages, nutrition-based interventions to minimize AGEs exposure represent practical, economical, and beneficial therapeutic approaches that complement comprehensive DKD management (193). Future investigations should focus on defining recommended dietary AGEs intake limits and thoroughly assessing their long-term clinical effects, facilitating the incorporation of targeted nutritional strategies into routine clinical recommendations.

Active vitamin D (calcitriol) and related synthetic analogs function as steroid-like hormones that regulate mineral homeostasis, immune function, and cellular differentiation. CKD patients frequently exhibit vitamin D insufficiency, which strongly correlates with accelerated renal function decline and increased albuminuria (194, 195). Administration of active vitamin D consistently improves endothelial function, reduces albuminuria, and inhibits progression of renal fibrosis (196–198). Mechanistic studies demonstrate that vitamin D receptor (VDR) activation reduces podocyte apoptosis by suppressing NF-κB signaling cascades (199, 200). Paricalcitol, a selective vitamin D receptor activator, has shown promising results in preclinical research by modulating Wnt signaling pathways, reducing glucose-induced podocyte injury, and markedly decreasing albumin excretion (201). In a controlled clinical trial involving 45 patients with persistent albuminuria despite optimal renin-angiotensin-aldosterone system blockade, paricalcitol treatment achieved significant additional reductions in albuminuria compared with placebo (202). These observations support VDR targeting as a promising adjunctive therapeutic strategy for DKD, particularly among high-risk individuals with residual albuminuria, offering an innovative approach beyond conventional management.

A recent actuarial modeling study assessed the potential clinical benefits of combining three major pharmacologic classes—SGLT2 inhibitors, GLP-1 receptor agonists, and the non-steroidal MRA finerenone—using data from large-scale randomized trials (161). The analysis integrated findings from the CANVAS and CREDENCE trials (n = 14,543) for SGLT2i (203), a meta-analysis of eight cardiovascular outcome trials for GLP-1 RAs (n = 60,080) (204), and the FIDELIO-DKD and FIGARO-DKD studies for finerenone (n = 13,026) (179). Results were striking. The three-drug combination was projected to reduce major adverse cardiovascular events (MACE) by 35% (HR 0.65; 95% CI 0.55–0.76), decrease hospitalization for heart failure by 68%, and slow CKD progression by 58% (HR 0.42; 95% CI 0.31–0.56). In hypothetical patients aged 50 years, this regimen could extend MACE-free survival by 3.2 years and delay kidney disease progression by 5.5 years. Despite the compelling projections, several important limitations must be acknowledged. No clinical trial to date has directly evaluated triple therapy vs. single or dual combinations; these findings are derived from indirect comparisons that assume independent and additive effects across agents. All source studies were industry-sponsored, introducing potential bias due to selective reporting. Additionally, the simulation relied on clinical trial populations that may not fully reflect real-world patient heterogeneity, possibly overestimating effectiveness. Furthermore, mechanistic overlap—particularly in anti-inflammatory and natriuretic effects—raises the possibility of diminishing returns when combining these agents. Nevertheless, this analysis offers robust support for advancing comprehensive, multi-target treatment strategies in DKD. As therapeutic options expand and evidence accumulates, structured combination therapy—especially when guided by biomarker-driven risk stratification—has the potential to redefine DKD management and optimize long-term cardiorenal protection.

The therapeutic strategy combining RAASi, SGLT2i, and ns-MRAs—collectively referred to as Renal Triple Therapy (RTT)—offers synergistic, mechanism-based protection in the management of DKD. This multi-drug approach concurrently targets intraglomerular hypertension, tubular inflammation, and fibrotic remodeling (1, 177, 178, 205). A recent network meta-analysis reported that RTT reduced the risk of cardio-renal composite outcomes by 46% compared to RAASi monotherapy (HR 0.54; 95% CI 0.50–0.58) (206). The FIDELITY analysis, which pooled data from the FIDELIO-DKD and FIGARO-DKD trials (n = 13,026; median follow-up: 3.0 years), demonstrated that finerenone reduced cardiovascular events by 14% (HR 0.86; P = 0.0018), kidney events by 23% (HR 0.77; P = 0.0002), and all-cause mortality by 18% (HR 0.82; P = 0.014) (179, 207). Importantly, patients receiving concurrent SGLT2i therapy experienced even greater renoprotection, with a 58% reduction in kidney composite outcome risk (HR 0.42) (208). Despite these compelling findings, several barriers hinder widespread clinical adoption of RTT. Hyperkalemia remains a primary safety concern. In FIDELIO-DKD, mild hyperkalemia (serum potassium ≥5.5 mmol/L) occurred in 21.4% of finerenone-treated patients compared to 9.2% in the placebo group (209). While SGLT2 inhibitors may help mitigate this risk, implementation of rigorous potassium monitoring protocols remains essential when combining agents (210). Real-world applicability is another limitation. Pivotal trials systematically excluded certain patient populations: 43.2% of individuals with CKD without albuminuria and 6.9% with eGFR below 25 ml/min/1.73 m²—two cohorts frequently encountered in clinical practice (211). Future research should focus on determining the optimal sequencing of these agents, characterizing long-term safety and tolerability in diverse populations, and developing personalized, biomarker-driven treatment algorithms. Such efforts will be critical to fully realize the therapeutic potential of Renal Triple Therapy and integrate it effectively into standard care pathways for DKD.

The progression of DKD arises from intricate interactions between metabolic dysregulation, chronic inflammation, and renal fibrosis. Advances in pathophysiological understanding have revealed several promising molecular targets within these interrelated pathways, offering potential avenues for innovative therapeutic development. Endothelin receptor antagonists (ERAs) have shown renoprotective efficacy by inhibiting endothelin-mediated vasoconstriction and suppressing pro-inflammatory and pro-fibrotic signaling cascades (236). These effects translate into reductions in albuminuria, mitigation of fibrotic remodeling, and preservation of renal function (236–238). Similarly, inverse agonists of the cannabinoid-1 receptor have demonstrated favorable metabolic and structural outcomes in preclinical models, improving insulin sensitivity and maintaining renal architecture (239, 240). The transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) plays a central role in redox homeostasis and inflammation (241). Pharmacological activation of Nrf2 enhances the expression of cytoprotective genes, conferring resistance against oxidative injury and fibrogenesis in DKD models (242). Another emerging target is ceramide synthase 6 (CerS6), a key regulator of sphingolipid metabolism implicated in sterile inflammation. CerS6 promotes mitochondrial DNA release and activates the cGAS–STING pathway, amplifying inflammatory responses and aggravating kidney damage (243, 244). Inhibition of CerS6 has been shown to attenuate renal injury in experimental models, underscoring its therapeutic potential (244). Collectively, these mechanistic insights highlight the feasibility of multi-targeted therapeutic approaches that concurrently address metabolic abnormalities, inflammation, and fibrosis. Future efforts should focus on translating these findings into clinically viable interventions, with an emphasis on long-term efficacy, safety, and personalized application.

Emerging evidence supports the intestinal microbiome as a novel and modifiable target in the treatment of DKD. Accumulating data from clinical trials and meta-analyses suggest that probiotic supplementation may confer renoprotective benefits through modulation of gut microbial communities, metabolic regulation, and suppression of systemic inflammation. A meta-analysis of seven randomized controlled trials involving 456 patients demonstrated that probiotics significantly improved renal outcomes: eGFR increased [standardized mean difference (SMD) = 6.03; 95% CI: 0.84–11.21; P = 0.020], while serum creatinine and blood urea nitrogen levels declined (P < 0.05) (245). Oxidative stress markers also improved, with significant increases in glutathione and total antioxidant capacity (P < 0.001), and decreased malondialdehyde concentrations (P = 0.020) (245). Inflammatory markers such as high-sensitivity C-reactive protein were significantly reduced (P < 0.001) (245). Further support comes from a randomized, double-blind, controlled trial involving 60 DKD patients, in which daily administration of 8 × 10⁹ CFU probiotics for 12 weeks improved fasting glucose, HOMA-IR, and lipid profiles (P < 0.01) (246). A comprehensive 2023 Cochrane review evaluating 45 trials (n = 2,266) confirmed the safety of probiotic interventions, with most adverse events being mild gastrointestinal symptoms (247). According to GRADE methodology, evidence for improvements in blood urea nitrogen, total cholesterol, and LDL-C was of moderate quality, whereas data on serum creatinine, UACR, fasting glucose, and HbA1c were rated low quality (248). Despite promising findings, several limitations constrain the clinical applicability of existing data. Notably, there is substantial heterogeneity among trials in terms of DKD diagnostic criteria, probiotic strains, dosages, treatment durations, and outcome measures (98). Most studies enrolled small cohorts (30–200 participants) with short follow-up periods (8–24 weeks), precluding evaluation of hard clinical endpoints such as progression to ESKD (98, 247). Furthermore, the geographic concentration of study populations—primarily among Asian, particularly Chinese, patients—raises concerns regarding generalizability (98, 249). Mechanistic studies suggest that probiotics exert their effects through microbial rebalancing, augmentation of short-chain fatty acid-producing bacteria (e.g., Faecalibacterium, Roseburia), and reduction in uremic toxin production (98, 250). Moving forward, high-quality multicenter clinical trials with larger sample sizes, longer follow-up, and standardized endpoints are essential to validate efficacy. Personalized approaches based on host–microbiome interactions may further enhance therapeutic outcomes. Current evidence supports the adjunctive use of multi-strain probiotic formulations (≥4 × 10⁹ CFU daily for 8–12 weeks) in DKD management, provided they are administered under appropriate clinical supervision and integrated within a broader therapeutic framework.

Stem cell–based interventions, particularly those utilizing mesenchymal stem cells (MSCs), hold considerable promise for the treatment of DKD, although clinical translation remains at an early stage. A meta-analysis of 40 preclinical studies involving 992 diabetic rodent models demonstrated that MSC-based therapies markedly improved renal function and attenuated key pathological features, including fibrosis, inflammation, apoptosis, and oxidative stress (251). Focused analysis of MSCs revealed potent glucose-lowering effects [standardized mean difference (SMD) = −1.954; 95% CI: −2.389 to −1.519; P < 0.001], as well as significant reductions in serum creatinine (SMD = −4.838; P < 0.001) and blood urea nitrogen (SMD = −4.912; P < 0.001), indicating substantial renoprotective benefits (252). The NEPHSTROM trial remains the most advanced human study to date. This phase 1b/2a randomized, placebo-controlled trial enrolled 16 patients with type 2 diabetes and progressive DKD, who were allocated in a 3:1 ratio to receive either a single intravenous infusion of 80 × 106 ORBCEL-M cells (CD362-selected, allogeneic bone marrow–derived MSCs) or placebo (253). The treatment exhibited a favorable safety profile, with no serious treatment-related adverse events reported. In terms of efficacy, the MSC-treated group exhibited a slower annual decline in eGFR. However, measured GFR did not differ significantly between groups, raising questions about the clinical relevance of this finding. Notably, MSC therapy preserved circulating regulatory T cells and stabilized inflammatory monocyte subsets, suggesting immunomodulatory effects. Despite encouraging preclinical and early clinical data, multiple translational hurdles remain. Considerable heterogeneity across animal studies (I² = 85.1%−90.8%) arises from variability in cell sources, administration routes, dosing protocols, and outcome measures (252). The limited sample size in NEPHSTROM reduces statistical power and precludes definitive conclusions regarding efficacy (253). Furthermore, most animal models of DKD rely on chemically induced diabetes, which may inadequately reflect the multifactorial pathophysiology of human DKD (254). Mechanistic studies suggest that MSCs exert their benefits predominantly via paracrine signaling, including anti-inflammatory (e.g., downregulation of IL-6, IL-1β, and TNF-α), anti-fibrotic, and pro-angiogenic effects, as well as preservation of mitochondrial function (254–257). However, MSCs derived from patients with type 2 diabetes exhibit functional impairments, including accelerated senescence, impaired proliferation, and reduced therapeutic efficacy, thereby limiting the feasibility of autologous cell therapies (254). Critical barriers to clinical translation include the lack of standardized manufacturing protocols, variability in quality control, uncertainty regarding optimal delivery methods, and the absence of consensus on therapeutic dosing regimens. To advance MSC-based therapy toward routine clinical application in DKD, future research must prioritize large, well-powered, rigorously designed late-phase clinical trials, along with the development of predictive biomarkers for therapeutic responsiveness. Additionally, combination strategies that integrate MSCs with established pharmacological agents—such as SGLT2i—warrant exploration as potentially synergistic treatment modalities.

This comprehensive review underscores several critical considerations for improving the clinical management of DKD. First, compelling evidence now supports a shift from traditional monotherapy toward multi-targeted combination regimens. Rather than incremental escalation, clinicians should consider early initiation of dual or triple therapy in patients with persistent albuminuria despite optimized RAAS inhibition. The FIDELITY pooled analysis demonstrated that Renal Triple Therapy (RTT) reduced the risk of composite kidney outcomes by 23%, reinforcing the rationale for such strategies. Second, adopting a cardio-kidney-metabolic framework represents a major paradigm shift from glucose-centric management to a more holistic, risk-based approach. The substantial cardiovascular benefits observed with SGLT2 inhibitors (55% reduction in heart failure hospitalization) and GLP-1 receptor agonists (35% reduction in major adverse cardiovascular events) highlight the need to align treatment with broader cardiorenal-metabolic risk profiles, rather than focusing exclusively on glycemic control. Third, integrative approaches, including TCM, offer additional therapeutic value. For example, the combination of Huangkui capsules and irbesartan significantly reduced proteinuria (by 262.3 mg/g), suggesting that culturally tailored integrative strategies may benefit select patient populations. However, implementing such approaches requires careful evaluation of evidence quality and vigilant monitoring for herb–drug interactions. Finally, emerging insights into novel disease mechanisms—including ferroptosis, gut microbiota dysbiosis, and epigenetic regulation—provide a foundation for precision medicine. Incorporating biomarkers derived from these pathways may enable personalized therapy selection and dynamic treatment monitoring, accelerating the transition from empirical regimens to mechanism-driven care in DKD.

To improve both clinical outcomes and translational progress in DKD, future research should prioritize the following six domains.