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New insights in the treatment of DKD: recent advances and future prospects

BMC Nephrology volume 26, Article number: 72 (2025) Cite this article

Abstract

Diabetic kidney disease (DKD) represents the predominant and severe microvascular complication associated with diabetes, frequently culminating in End-Stage Kidney Disease (ESKD). The escalating prevalence of diabetes has correspondingly led to a rise in DKD incidence, imposing significant challenges on both individuals and society. The etiology of DKD is multifaceted and remains devoid of definitive therapeutic interventions. This article examines the pharmacological actions and mechanisms of different drugs used for the prevention and treatment of DKD that are currently in clinical use or undergoing development. The goal is to offer insights for early intervention based on therapeutic combinations to potentially slow kidney disease progression.

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Background

Diabetes represents a significant global public health concern, with its prevalence steadily rising each year. According to the International Diabetes Federation (IDF), it is observed that by 2021, diabetes will affect 10.5% of the adult population worldwide, a figure that is anticipated to increase to 12.2% by the year 2045 [1]. DKD is a prevalent complication of diabetes, with approximately 40% of individuals with diabetes developing DKD. DKD is the primary etiology of ESKD in diabetic patients, accounting for 30–50% of ESKD cases globally [2]. In the context of chronic kidney disease (CKD) burden, DKD represents approximately one third of cases [3, 4]. DKD not only poses a significant threat to public health, but also has implications for economic growth and development [5]. In recent years, advancements in the understanding of the pathogenesis of DKD have led to the emergence of several new diabetes medications that have demonstrated promising efficacy in clinical settings. Consequently, the protective effects of these medications on kidney function and their underlying molecular mechanisms have garnered increasing attention in research. This review explores the pharmacological treatments currently employed in the management of DKD, elucidating their respective mechanisms of action. Additionally, potential strategies and therapeutic targets for the prevention and treatment of DKD that are currently undergoing investigation are discussed. The objective is to provide insights for early intervention through therapeutic combinations, with the potential to decelerate the progression of kidney disease.

Pathological features and mechanisms of kidney fibrosis

The primary pathological alterations observed in DKD encompass thickening of the glomerular basement membrane, dilation of mesangial cells, development of nodular glomerular sclerosis, transformation of the outer and entering arterioles into hyalinoid structures, injury to podocytes, transition of tubular epithelial cells into mesenchymal cells, progressive accumulation of extracellular matrix, as well as the presence of tubular interstitial vacuoles and loose arrangement, ultimately culminating in kidney fibrosis [6,7,8]. The estimated glomerular filtration rate (eGFR) and urinary albumin excretion are commonly utilized as diagnostic markers for DKD in diabetic patients who have not undergone kidney biopsy [9].

The pathogenesis of DKD is multifaceted, with prolonged hyperglycemia playing a significant role as an inducer (Fig. 1). Elevated blood glucose levels in patients can result in metabolic disorders, hemodynamic abnormalities, activation of the renin-angiotensin-aldosterone system (RAAS), accumulation of fatty acids, oxidative stress, and the secretion of inflammatory factors, ultimately leading to increased levels of growth factors, vasoactive hormones, cytokines, and chemokines in the kidneys [10, 11]. Genetic predisposition and epigenetic alterations are implicated in the pathogenesis and progression of DKD [12]. Studies have demonstrated significant associations between various microRNAs, long non-coding RNAs (lncRNAs), DNA methylation, and histone modifications with key clinical parameters such as urinary albumin excretion rate, eGFR, glycated hemoglobin A1c (HbA1c), and creatinine levels in individuals with DKD [13,14,15]. Diets characterized by elevated levels of sugar, fat, and protein, along with imbalances in intestinal microbiota—specifically a reduction in beneficial bacteria such as Lactobacillus, Bifidobacterium, and Faecalibacterium, coupled with an increase in pathogenic genera including Enterococcus, Enterobacteriaceae, Clostridaceae, and Klebsiella—can contribute to metabolic dysfunction [16,17,18]. These dietary and microbial alterations may impair intestinal barrier integrity, enhance intestinal permeability, and provoke systemic inflammation, resulting in the production of reactive oxygen species. Consequently, these factors may lead to kidney cell damage, inflammation, and fibrosis [19,20,21]. β-arrestin impedes autophagy by down-regulating the expression of specific genes associated with the autophagic process, thereby exacerbating podocyte injury. This exacerbation can subsequently result in diminished glomerular function and the development of proteinuria [22]. Hyperglycemia has been shown to induce mitochondrial dysfunction and elevate the electron transport chain burden, leading to an overproduction of superoxide that can activate endothelial nitric oxide synthase phosphorylation. This subsequently triggers the NF-κB mediated inflammatory pathway, resulting in vascular dysfunction and ultimately contributing to kidney injury [23, 24].

Fig. 1
figure 1

The major mechanisms of DKD

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Drug treatment for DKD

Renin-angiotensin system (RAS) inhibitors

The RAAS is integral to the pathogenesis of diabetic nephropathy. Conventional therapeutic approaches, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are extensively utilized in managing this condition, and for approximately two decades, inhibitors of the RAS represented the sole class of pharmacological agents available for renal protection [25]. These pharmacological agents confer nephroprotective effects by attenuating the activity of the renin-angiotensin system, thereby mitigating elevated glomerular pressure. This mechanism not only effectively decelerates the progression of CKD in individuals with diabetes but also diminishes the incidence of cardiovascular events [26]. Research indicates that ACEIs and ARBs can significantly decelerate the progression of proteinuria by effectively reducing urinary protein excretion, thereby mitigating the risk of renal damage [27]. This dual protective mechanism is particularly crucial for patients with concomitant hypertension and diabetes. Recent advancements have demonstrated that the combination of ACEIs and ARBs, or their integration with other RAAS inhibitors such as aldosterone receptor antagonists, can achieve more effective blood pressure control and further reduce proteinuria [28]. Consequently, this approach contributes to a more pronounced delay in the deterioration of renal function. However, ACEIs and ARBs are associated with potential adverse effects, including hyperkalemia and acute renal failure [29]. Consequently, it is imperative for healthcare professionals to meticulously monitor patients’ serum potassium levels and renal function parameters during treatment, and to promptly adjust the therapeutic regimen as necessary.

Sodium-glucose cotransporter-2(SGLT2) inhibitors

SGLT2 inhibitors represent a novel category of hypoglycemic agents that enhance normal tubuloglomerular feedback, alleviate glomerular filtration pressure, mitigate hyperfiltration, and decrease urinary protein excretion by inhibiting sodium and glucose reabsorption in the proximal convoluted tubules [30, 31]. These effects are believed to underlie the kidney protective properties of SGLT2 inhibitors. Furthermore, the kidney protective mechanisms of SGLT2 inhibitors may involve modulation of inflammation and oxidative stress, as well as enhancement of kidney energy metabolism [32, 33]. Recent large-scale clinical studies have demonstrated that SGLT2 inhibitors have shown efficacy in controlling blood sugar levels, reducing proteinuria in patients with DKD, and delaying the decline of kidney function [34,35,36]. Based on previous findings, the 2022 KDIGO guidelines recommend that SGLT-2 inhibitors be initiated in type 2 diabetes mellitus (T2DM) and CKD patients at eGFR ≥ 20mL (/ min•1.73m2). SGLT-2 inhibitor therapy should be carried out for as long as possible if tolerated, and should be continued even if eGFR falls below 20mL (/ min•1.73m2) until kidney replacement therapy is started [37]. Dapagliflozin received approval from the Food and Drug Administration (FDA) on April 30, 2022, for the purpose of mitigating the risk of renal decline, renal failure, cardiovascular mortality, and hospitalization due to heart failure in adult patients diagnosed with CKD [38]. However, SGLT2 inhibitors are contraindicated for individuals with type 1 diabetes mellitus (T1DM) or those experiencing diabetic ketoacidosis (DKA). Additionally, the presence of glycosuria associated with this medication may elevate the risk of developing infections in the reproductive and urinary systems [39].

Glucagon-like Peptide-1 (GLP-1) receptor agonist

GLP-1 receptor agonists (GLP-1 RAs) have been shown to provide kidney protection through mechanisms that are independent of their hypoglycemic effects, including the inhibition of oxidative stress and inflammatory responses, improvement of endothelial function, inhibition of kidney fibrosis, promotion of urinary sodium excretion, and enhancement of kidney hemodynamics [40, 41]. The utilization of GLP-1RAs has been demonstrated to correlate with a reduced risk of adverse renal outcomes, including macroalbuminuria, doubling of serum creatinine, end-stage renal disease, and mortality due to nephropathy. These agents offer significant benefits in decreasing glomerular filtration rates and urinary albumin excretion in patients with T2DM, thereby reducing the risk of complex renal outcomes by 18%, indicating potential renal protective effects [42, 43]. Among the available GLP-1RAs options, dulaglutide, semaglutide, and the long-acting liraglutide have exhibited notable renal protective properties and are suitable for use as hypoglycemic agents in T2DM patients with renal impairment [44, 45]. From the standpoint of renal and cardiovascular protection, as well as enhanced glycemic control, patients with T2DM who also have kidney disease may benefit from treatment with GLP-1RAs, such as liraglutide, dulaglutide, and semaglutide, which offer renal and cardiovascular advantages. However, GLP-1RAs are primarily utilized in the management of T2DM. Their efficacy is limited in patients with T1DM or those experiencing severe islet cell dysfunction. Additionally, the use of GLP-1RAs is associated with adverse effects, including nausea and vomiting [46].

Nonsteroidal mineralocorticoid receptor antagonist (ns-MRA)

Mineralocorticoid receptors (MR) are cytoplasmic receptors extensively expressed in the heart, kidneys, and various components of the vascular system [47, 48]. Hyperglycemia induces the over-activation of MR, which subsequently facilitates the release of nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and other pro-inflammatory cytokines and pro-fibrotic mediators [49]. This cascade of events culminates in fibrosis within the cardiac, renal, and vascular systems. Finerenone, the inaugural selective mineralocorticoid receptor antagonist endorsed for DKD, functions by inhibiting mineralocorticoid receptor-mediated sodium reabsorption and overactivation in the kidney system, while exhibiting no binding affinity for androgen, progesterone, estrogen, and glucocorticoid receptors [50, 51]. Recent years have witnessed a plethora of extensive clinical trials showcasing the enhanced efficacy of DKD therapy [52, 53]. Notably, the FIDELITY Asian subgroup analysis revealed that Finerenone yielded a 34% reduction in the incidence of kidney complex endpoint events among Asian cohorts. Finerenone demonstrated a significant reduction in the risk of kidney failure by 35% for a single kidney event and by 31% for kidney adverse events, maintaining a sustained reduction of ≥ 40% from baseline eGFR [54]. In comparison to conventional MRA, Finerenone exhibits a shorter half-life, a balanced distribution between kidney and cardiac tissues, and a lower prevalence of hyperkalemia [55]. The 2023 European Society of Cardiology (ESC) Diabetes Guidelines endorse the use of Finerenone at the highest level for mitigating cardio- kidney risk in patients with T2DM and CKD based on robust medical evidence [56]. MRA inhibit the binding of aldosterone to the mineralocorticoid receptor, thereby disrupting the Na+-K + exchange process, which may result in hyperkalemia. In patients with CKD, it is imperative to assess serum potassium levels prior to initiating Finerenone therapy. Finerenone treatment is contraindicated if serum potassium exceeds 5.0 mmol/L or if the eGFR is below 25 mL/min/1.73 m² [57].

Dipeptidyl peptidase-4 (DPP-4) inhibitors

DPP-4 inhibitors have been demonstrated to extend the duration of endogenous GLP-1 activity through the inhibition of DPP-4 enzyme, thereby facilitating hypoglycemic outcomes [58]. Research findings indicate that in addition to enhancing glycemic regulation, DPP-4 inhibitors exhibit a protective impact on kidney function, particularly evident in the reduction of proteinuria and attenuation of kidney function deterioration [59, 60]. CARMELINA’s international, multicenter, randomized, double-blind, placebo-controlled clinical trial of linagliptin revealed that while linagliptin demonstrated efficacy in delaying the progression of proteinuria classification, it did not significantly reduce the risk of kidney complex endpoint events [61]. A meta-analysis of four randomized, double-blind, placebo-controlled Phase III clinical trials demonstrated that the combination therapy of linagliptin and an angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist over a 24-week period effectively decreases urinary albumin levels in patients with T2DM, independent of systolic blood pressure and glycosylated hemoglobin levels. However, changes in eGFR before and after treatment were found to be clinically insignificant [62]. A meta-analysis of 13 randomized controlled trials demonstrated that treatment with linagliptin resulted in a 16% reduction in the incidence of clinically significant kidney adverse events in individuals with T2DM [63]. However, there is a dearth of extensive, multicenter, randomized controlled clinical trials focusing on DPP-4 inhibitors with kidney outcomes as the primary endpoint event.

Anti-inflammatory

The activation of inflammatory signaling pathways leading to kidney injury is a significant pathological mechanism in the onset and progression of DKD [64]. Advanced glycosylation end products, generated through non-enzymatic glycosylation following hyperglycemia, accumulate in the glomerular basement membrane and mesangial cells, thereby facilitating the advancement of DKD [65]. The accumulation of advanced glycosylation end products can trigger the activation of NF-κB, leading to an increase in the transcription levels of pro-inflammatory factors and chemokines, including TNF-α, interleukin (IL)-1β, and IL-6, exacerbating kidney inflammation injury in patients with DKD [66]. Pentoxifylline, a methylxanthine derivative, acts as a non-specific phosphodiesterase inhibitor that activates protein kinase A (PKA) and suppresses the production of inflammatory factors such as IL-6 and TNF-α [67]. Baricitinib, a targeted inhibitor of JAK1 and JAK2, has been shown to decrease proteinuria and plasma levels of the inflammatory factor TNF-α in a clinical trial (NCT01683409). The JAK/STAT pathway is being explored as a potential therapeutic target for ameliorating progressive decline in kidney function [68]. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that interacts with two distinct receptors, ETA and ETB, with ETA promoting vasoconstriction, inflammation, fibrosis, and cell proliferation [69]. A Phase III clinical trial demonstrated that atrasentan, an ETA antagonist, significantly decreased proteinuria by 35% in individuals with T2DM. However, it also resulted in an elevated incidence of cardiovascular events and mortality. Further investigation is warranted to determine the potential efficacy of endothelin-1 receptor A antagonists in the treatment of DKD [70].

Anti fibrosis

Kidney tubulointerstitial fibrosis plays a significant role in the advancement of DKD. Antifibrotic medications are anticipated to impede the progression of kidney function decline by obstructing the fibrotic process. Pirfenidone, an oral anti-fibrotic small-molecule drug commonly utilized for idiopathic pulmonary fibrosis, is believed to mitigate mesenchymal cell transformation and kidney fibrosis by antagonizing TGF-β both in vivo and in vitro, although its precise mechanism of action remains uncertain [71]. Participants who were administered pirfenidone in a small-scale, randomized, double-blind controlled trial exhibited a notably elevated average glomerular filtration rate following 6 months of treatment compared to those who received a placebo (NCT00063583) [72]. As of October 2021, ClinicalTrials.gov documents three Phase 1 and/or 2 trials investigating the impact of pirfenidone on kidney disease. Overall, there were no statistically significant variances observed in blood pressure, proteinuria, or projected initiation of kidney replacement therapy, although this lack of significance may be attributed to constraints such as a restricted sample size [73, 74]. A Phase 2 clinical trial of pirfenidone, the largest conducted thus far and the sole trial of a kidney fibrosis drug to assess kidney fibrosis using imaging or urine markers as the primary endpoint, is currently ongoing and is expected to conclude in December 2024 [75]. Roscovitine, a purine analogue that acts as an inhibitor of cyclin-dependent kinases, has been shown to mitigate kidney tubulointerstitial fibrosis by impeding the MAPKp38 pathway in DKD [76]. Selonsertib, a highly selective and potent oral inhibitor of apoptosis signal-regulating kinase 1 (ASK1), has demonstrated the ability to decelerate kidney fibrosis by targeting ASK1 and subsequently inhibiting the downstream JNK pathway. The findings of a Phase II clinical trial indicate that selonsertib decreased the rate of decline in glomerular filtration rate by 18%, implying a potential slowing of the progression of DKD (NCT02177786) [77]. While the utilization of these medications in DKD remains at the clinical trial phase, the outlook appears promising.

Potential treatments for DKD

Recently, there has been significant interest in the involvement of microRNA (miRNA) and lncRNA in DKD. Certain miRNA and lncRNA have been found to modulate gene expression associated with DKD and contribute to pathological mechanisms such as inflammation and oxidative stress [78, 79]. Research indicates a strong association between miR-21 and the progression of DKD, as it is recognized as a pro-inflammatory factor capable of activating multiple inflammatory pathways and worsening kidney injury [80]. A study investigating the efficacy of the miR-21 antagonist Lademirsen in individuals with Alport syndrome revealed that while the treatment demonstrated favorable tolerability and safety outcomes, it did not result in a significant improvement in the rate of eGFR decline among adult patients at high risk for rapid disease progression [81].

The research on stem cell therapy in the context of DKD has garnered considerable attention in recent years, with stem cells being noted for their robust self-renewal capacity, remarkable plasticity, and ability to differentiate into various cell types within specific microenvironments [82, 83]. Researchers hypothesized that following kidney tissue injury, the transplantation and localization of stem cells in the kidney exhibit characteristics of differentiation towards kidney tissue, contributing to cell regeneration and tissue repair. Chronic inflammation is a crucial factor in the pathogenesis of DKD, and Mesenchymal Stem Cells (MSC) have the potential to mitigate DKD progression by ameliorating systemic and local kidney inflammation [84]. In vitro investigations have validated the ability of MSC to attenuate the upregulation of pro-inflammatory cytokines in proximal kidney duct epithelial cells exposed to elevated glucose levels [85]. Furthermore, MSC have been shown to markedly decrease the expression of interleukin-16 in both kidney tissue and systemic circulation, thereby ameliorating inflammation in the kidneys and throughout the body [86]. The development of kidney fibrosis in DKD is closely linked to pro-fibrotic alterations in kidney cell phenotype during the process of epithelial-mesenchymal transition. Stem cells were found to reduce the expression levels of pro-fibrotic molecules, type I collagen, and fibronectin, as well as decrease extracellular matrix deposition, resulting in a significant improvement in kidney fibrosis [87, 88]. Additionally, MSC have been shown to not only decrease blood glucose levels but also protect vascular endothelium from diabetic damage through a paracrine mechanism mediated by MAPK/ERK signaling. This suggests that MSC therapy holds promise for the treatment of diabetic vascular complications [89]. A study conducted by researchers at the University of Melbourne, Australia, involved the treatment of 30 patients with DKD using bone marrow-derived mesenchymal precursor cells (MPCs), resulting in improved stability of plasma clearance (mGFR) and eGFR over a 12-week follow-up period [90]. The findings suggest that stem cell therapy holds promise for the management of DKD. Multiple clinical trials registered on ClinicalTrials.gov and the Chinese Clinical Trial Registry have been undertaken to further investigate the effectiveness and safety of stem cell therapy for DKD. The application of MSC in DKD has a broad prospect, which brings new hope and possibility for the treatment of DKD.

Conclusion

The etiology of diabetic nephropathy is multifaceted, encompassing numerous signaling pathways that can be targeted for therapeutic intervention. Additionally, there exist correlations and interactions among these pathways, leading to the identification of various pharmacological agents for the prevention and management of diabetic nephropathy (Table 1). DKD is a significant complication of diabetes that presents a substantial health risk to affected individuals. Advances in research have enhanced our comprehension of the etiology, early detection, and therapeutic approaches for DKD. Despite the numerous challenges that persist in the treatment of diabetic nephropathy, it is noteworthy that the majority of commercially available pharmacological interventions are not accessible to patients with T1DM. However, recent advancements in novel therapeutics, stem cell therapies, and related fields provide promising new avenues for treatment (Fig. 2). In a study published in Circulation in 2024, it was determined that among patients with T2DM and moderate albuminuria (urinary albumin creatinine ratio UACR ≥ 30 mg/g), the three-drug combination of SGLT2i, GLP-1 RA, and ns-MRA resulted in a significant reduction in the risk of cardiovascular and kidney events, as well as an improvement in overall survival when compared to conventional treatment methods [91]. The anticipation of further rigorous clinical investigations holds the potential to expand therapeutic options and enhance the well-being of DKD patients in the future. Through sustained dedication and innovative approaches, we are optimistic that significant advancements will be achieved in the prevention and management of DKD, ultimately benefiting diabetic individuals globally.

Table 1 Summary of representative drugs for prevention and treatment of DKD
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Fig. 2
figure 2

Current treatment strategies and potential targets for DKD

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Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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Funding

This work was supported as follows: the National Natural Science Foundation of China (Grant No: 82074221), the National High Level Hospital Clinical Research Funding (2023-NHLHCRF-DJMS-04).

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  1. Department of Clinical Laboratory, China-Japan Friendship Hospital, Beijing, China

    Meimei Zhao, Yongtong Cao & Liang Ma

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  1. Meimei Zhao
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The manuscript was created, written, and edited by M. Zhao. The manuscript was read, edited, and amended by L.M. The manuscript was read and modified by YT.C.All authors reviewed the manuscript.

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Zhao, M., Cao, Y. & Ma, L. New insights in the treatment of DKD: recent advances and future prospects. BMC Nephrol 26, 72 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12882-025-03953-3

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BMC Nephrology

ISSN: 1471-2369

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