Int J App Pharm, Vol 17, Issue 1, 2025, 68-81Original Article
PREVENTING DIABETIC KIDNEY DISEASE: A SYSTEMATIC REVIEW OF CURRENT PHARMACOLOGICAL APPROACHES
B. DHARANI*, STEPHY SEBASTIAN, S. NAZRIN, SUBA A.
1*A. C. S. Medical College and Hospital, Dr. M. G. R. Educational and Research Institute, Chennai, India
*Corresponding author: B. Dharani; *Email: doctordharanibhaskaran@gmail.com
Received: 17 Oct 2024, Revised and Accepted: 05 Dec 2024
ABSTRACT
Objective: This review examines the growing global burden of Diabetic Nephropathy (DN), a major complication of Diabetes Mellitus (DM) and a leading cause of Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD). With diabetes rates increasing, DN presents a significant health challenge. Current treatments manage established DN, but preventive strategies targeting high-risk individuals are urgently needed. This review evaluates current and emerging therapies for DN prevention.
Methods: A comprehensive literature search was conducted across multiple databases (PubMed, Web of Science, SCOPUS and others) to identify studies on the treatment and prevention of DN in DM patients. Eligible studies included Randomized Controlled Trials (RCT), cohort studies and meta-analyses published upto 2024, focusing on outcomes like albuminuria, Glomerular Filtration Rate (GFR) and ESRD incidence.
Results: Current treatments, including Sodium Glucose Co-transporter 2 (SGLT2) inhibitors, Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blocker (ARB), effectively reduce albuminuria and slow progression. Emerging therapies, such as antioxidants (Alpha-Lipoic Acid (ALA), Resveratrol), Mineralocorticoid Receptor Antagonists (MRA) and Endothelin Receptor Antagonists (ERA), show promise in improving kidney function and reducing inflammation. Other potential therapies targeting Oxidative Stress (OS), inflammation and fibrosis, such as Advanced Glycation End products(AGE) inhibitors and Tumor Necrosis Factor-α (TNF-α) inhibitors, have demonstrated preclinical efficacy but require further validation.
Conclusion: While current therapies slow DN progression, they do not offer definitive prevention. Emerging treatments targeting oxidative stress, inflammation and fibrosis show promise in reducing kidney damage. However, challenges like side effects and long-term safety remain. Further research is needed to establish the efficacy of these therapies and develop personalized strategies for preventing DN in high-risk populations.
Keywords: Diabetic kidney disease, Diabetic nephropathy, DN, DKD, Preventive therapy, Preventing diabetic nephropathy, Preventing DKD, Diabetes complications
© 2025 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2025v17i1.52956 Journal homepage: https://innovareacademics.in/journals/index.php/ijap
INTRODUCTION
Diabetes mellitus (DM) is a global metabolic disorder with a rapidly increasing incidence, rising from 108 million cases in 1980 to 451 million in 2017 and projected to affect 693 million people by 2045 [1, 2]. This alarming trend presents a major healthcare challenge worldwide. Among the chronic complications of DM, Diabetic Nephropathy (DN) is one of the most serious and feared. Affecting approximately 40% of individuals with diabetes, DN significantly contributes to the burden of Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD), making diabetes the leading cause of ESRD globally [3]. Cardiovascular complications also present a major concern for individuals with DN, with cardiovascular disease being the primary competing risk before patients reach stage 4 CKD [4].
DN is a long-term, progressive kidney condition that typically manifests after 10 to 20 years of diabetes, initially characterized by microalbuminuria and progressing to macroalbuminuria and eventual renal impairment [5, 6]. Early intervention is crucial, as strict control of blood glucose and Blood Pressure (BP) has been shown to slow disease progression [7]. However, despite advances in treatment, including the use of ACE Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB) and newer therapies like Sodium Glucose co-Transporter (SGLT2) inhibitors, the majority of current interventions focus on managing the condition after it has already developed rather than preventing its onset.
This presents a critical gap in diabetes care. While existing therapies help control blood glucose and mitigate renal and cardiovascular complications, there is a pressing need for preventive strategies that can specifically target high-risk diabetic individuals before DN develops. Identifying and developing preventive therapies is essential to reduce the incidence of DN, ESRD and the need for Renal Replacement Therapy (RRT). By shifting focus toward early prevention, we can significantly improve patient outcomes, reduce healthcare costs and alleviate the growing burden of diabetes-related kidney disease. This review will explore the current landscape of drug treatments for DN and examine emerging preventive approaches that could transform the management of Diabetic Kidney Disease (DKD).
MATERIALS AND METHODS
Literature search strategy
A comprehensive literature search was performed to identify relevant studies examining treatment and preventive strategies for DN and DKD in individuals with DM. The search was conducted in multiple electronic databases, including Springer, Wiley, Web of Science, PubMed, Google Scholar, SCOPUS, Embase and Cochrane Library, with no restriction on publication date up to 2024. To further enhance the breadth of the review, references cited within included articles were also manually searched.
The following keywords and Boolean operators were used in the search: "Diabetic Nephropathy" OR "Diabetic Kidney Disease", "Diabetes Mellitus" AND "Treatment" OR "Prevention", "SGLT2 inhibitors" OR "ACE inhibitors" OR "Angiotensin Receptor Blockers", "Investigational drugs to prevent Diabetic Kidney disease", "Investigational drugs to prevent Nephropathy". The search strategy was refined using these terms in combination to ensure inclusion of studies relevant to both the treatment and prevention of DN/DKD.
Inclusion and exclusion criteria
Articles were considered for inclusion if they met the following criteria: Published in peer-reviewed journals, investigated the treatment or prevention of DN/DKD in patients with Type 1 Diabetes Mellitus (T1DM) or Type 2 Diabetes Mellitus (T2DM), reported clinical outcomes related to albuminuria, Glomerular Filtration Rate (GFR) or the incidence of ESRD, involved Randomized Controlled Trials (RCT), cohort studies or meta-analyses and published between 2000 and 2024.
Studies were excluded if: They focused on non-diabetic kidney disease, the population consisted exclusively of patients without diabetes, they did not report relevant outcomes for DN/DKD or lacked sufficient clinical data, they were not published in peer-reviewed journals (e. g., conference abstracts) and the full text was unavailable or did not provide usable data for analysis.
Data extraction and evaluation
Data from the included studies were extracted and evaluated based on the quality of the evidence and the relevance of the findings. Key variables extracted included study design, patient population, type of intervention or preventive measure, outcomes related to renal function (e.g., albuminuria progression, GFR) and any reported adverse events.
Risk of bias assessment
The risk of bias for each included study was assessed using the Cochrane Risk of Bias Tool for RCT and the Newcastle-Ottawa Scale for observational studies. Bias was evaluated across several domains: Selection bias (e.g., random sequence generation, allocation concealment), Performance bias (e.g., blinding of participants and personnel), Detection bias (e.g., blinding of outcome assessment), Reporting bias (e.g., selective reporting of outcomes).
Studies were categorized as having low, moderate or high risk of bias in each domain. Any disagreements regarding bias assessments were resolved through discussion among the authors. Sensitivity analyses were conducted to assess the robustness of the review findings, especially in studies with a high risk of bias.
RESULTS AND DISCUSSION
Pathophysiology of DKD
The mechanisms underlying DKD arise from the interplay of three primary processes: hemodynamic, metabolic, and inflammatory factors. Each process contributes differently depending on an individual's genetic background, which explains variability in disease progression.
Hemodynamic factors
A crucial element of the hemodynamic aspect of DKD is the Renin-Angiotensin-Aldosterone System (RAAS). Renin, secreted by juxtaglomerular cells near the afferent arterioles, is pivotal for RAAS activation. Angiotensin II, produced through this pathway, binds to AT1 and AT2 receptors: AT1 receptor activation leads to increased resistance in efferent arterioles and elevated intraglomerular pressure maintaining renal filtration rates and AT2 receptor activation promotes vasodilatory Prostaglandin (PG) release, which offers a protective counterbalance [8].
Elevated angiotensin II levels contribute to renal injury through non-hemodynamic mechanisms: Stimulates aldosterone secretion and Promotes release of inflammatory chemokines, such as MCP-1 and TGF-β [9, 10].
Metabolic factors
Hyperglycemia, Insulin Resistance (IR) and dyslipidemia contribute to the progression of DKD. Excess glucose load in the proximal tubule upregulates SGLT-1 and SGLT-2, enhancing glucose and sodium reabsorption. This leads to decreased sodium delivery to the distal nephron and impaired tubuloglomerular feedback, disrupting normal glomerular hemodynamics [11-13].
Local factors
Factors like Endothelin-1, Reactive Oxygen Species (ROS) and Thromboxane A2 (TXA2) increase the tone of efferent arterioles contributing to glomerular hypertension. IR increases the production of Cyclooxygenase-2 (COX-2), prostanoids and the kallikrein-kinin system, resulting in the dilation of the afferent arterioles.
Activation of the Renin-Angiotensin System (RAS) can damage Glomerular Endothelial Cells (GEC), increasing fenestrations and triggering apoptosis. Hyperglycemia promotes the formation of Advanced Glycation End products (AGE), which attach to their RAGE receptors that reduces Nitric Oxide (NO) availability and increase activity of Transforming Growth Factor-Beta (TGF-β), a fibrotic factor. Diabetes accelerates the aging of Endothelial Progenitor Cells (EPC), diminishing their reparative capabilities.
Podocyte dysfunction
Podocytes exhibit dysregulated production of Vascular Endothelial Growth Factor (VEGF). Damage to podocytes results in foot process effacement and podocyte loss, which is a key mechanism in the development of albuminuria in diabetic patients [14-17].
Inflammation and fibrosis
Inflammation and fibrosis play crucial roles in the development of DKD. Infiltration of renal tissue by macrophage is a significant characteristic of DKD. Hyperglycemia and angiotensin II contribute to the recruitment of macrophages, which amplify inflammation through cytokine release. Activation of Mineralocorticoid Receptors (MR) intensifies the inflammatory response and contributes to glomerular damage by promoting sodium reabsorption and potassium excretion [18-20].
Fig. 1: Pathophysiology of DKD
Drugs to prevent DKD
Preventing DKD involves a multifaceted approach aimed at managing the underlying risk factors associated with diabetes. First and foremost, maintaining tight blood glucose control through diet, exercise and medications is essential to prevent damage to the kidneys. Monitoring and managing BP is equally critical, as high BP can accelerate kidney damage. Keeping BP within target levels (typically<130/80 mm Hg) through lifestyle changes and medications like ACE inhibitors or ARB is recommended. Reducing excess weight, avoiding smoking and limiting alcohol intake are also key lifestyle modifications that improve overall kidney health. Additionally, controlling cholesterol levels with statins can help reduce the cardiovascular risk that often accompanies diabetes and contributes to kidney dysfunction. Regular screening for early signs of kidney damage, such as albuminuria (protein in the urine) allows for early intervention and monitoring. In some cases, medications like SGLT2 inhibitors may be prescribed to further protect the kidneys. By addressing these modifiable risk factors along with a focus on diet, exercise and regular medical check-ups, individuals with diabetes can significantly reduce their risk of developing diabetic kidney disease.
Current treatment options
Glycemic control
Glycemic control is fundamental in managing DKD. The American Diabetes Association (ADA) recommends an A1C target of<7% for most adults with diabetes, while the American College of Physicians (ACP) suggests a target range of 7-8% for patients with long-standing diabetes or limited life expectancy [21, 22]. Studies show that aggressive glycemic control (e.g., A1C<6%) can reduce DKD incidence, but it may increase the risk of hypoglycemia, especially in older adults or those with cardiovascular disease [23]. Therefore, treatment should be individualized based on the patient's risk profile.
DPP-4 Inhibitors (e.g., Sitagliptin, Saxagliptin) reduce albuminuria independently of glucose control and are generally well tolerated. However, they may increase the risk of Heart Failure (HF) and have uncertain long-term benefits in preventing ESRD [24-26].
GLP-1 Receptor Agonists (e.g., Semaglutide, Liraglutide) protect renal endothelial cells and reduce Oxidative Stress (OS), improving kidney function and albuminuria. However, gastrointestinal side effects and risks of pancreatitis may limit their use [27-29].
SGLT2 Inhibitors (e.g., Empagliflozin, Canagliflozin) are a breakthrough in DKD management, significantly reducing renal disease progression and the need for RRT, as shown in the EMPA-REG OUTCOME trial [30, 31]. They can cause urinary and genital infections and dehydration and their long-term renal benefits in broader populations are still under study.
Thiazolidinediones (e.g., Pioglitazone) can reduce albuminuria but are limited by side effects such as weight gain and edema, with unclear benefits in preventing ESRD [32].
BP control
Control of BP is crucial in preventing the progression of DKD. While a target BP of<140/90 mm Hg is generally recommended, achieving this may not be appropriate for all patients [33, 34].
ACE Inhibitors (e.g., Enalapril, Ramipril) are effective in reducing albuminuria and mortality in DKD but can cause hyperkalemia, hypotension and renal impairment, especially in patients with existing kidney dysfunction [35, 36].
Aldosterone Antagonists (e.g., Spironolactone) lower proteinuria and BP, particularly in patients already on ACE inhibitors or ARB. However, they carry risks of hyperkalemia and gynecomastia and their benefit in advanced DKD remains unclear [37, 38].
ARB (e. g., Losartan, Valsartan) also reduce albuminuria and slow DKD progression. Like ACE inhibitors, they can cause hyperkalemia and hypotension and their long-term efficacy in advanced CKD is still under investigation [39].
MRA such as Spironolactone, Eplerenone and nonsteroidal MRAs like Finerenone have shown promise in reducing albuminuria and improving renal outcomes in DKD. Nonsteroidal MRAs, including Finerenone have a lower incidence of hyperkalemia and may offer a safer alternative to traditional therapies. Similarly, esaxerenone and KBP-5074, other nonsteroidal MRAs have also been found to significantly reduce Urine Albumin to Creatinine Ratio (UACR) in patients with diabetes and CKD [40-53]. These agents, especially when combined with ACE inhibitors or ARB, provide cardiorenal protection, though potassium monitoring is essential.
Table 1: Current treatment options to prevent DKD
| Drug category | Drug | Mechanism of action | Dose | Side effects | Cost | Reference number |
| Glycemic control | DPP-4 Inhibitors | Inhibit DPP-4, increasing incretin hormones, improving insulin secretion, and reducing albuminuria | Sitagliptin (100 mg daily), Saxagliptin (5 mg daily) | Nasopharyngitis, heart failure risk, hypoglycemia (rare) | Moderate | [24-26] |
| GLP-1 Receptor Agonists | Increase insulin secretion, decrease glucagon secretion, and reduce renal oxidative stress, improving albuminuria | Semaglutide (0.25 mg weekly), Liraglutide (0.6 mg daily) | Nausea, vomiting, pancreatitis risk, Hypoglycemia | High | [27-29] | |
| SGLT2 Inhibitors | Block sodium-glucose cotransporter 2 (SGLT2), reducing glucose reabsorption in the kidney, improving albuminuria, and slowing renal disease progression | Empagliflozin (10 mg daily), Canagliflozin (100 mg daily) | UTIs,Mycotic genital infections, dehydration, DKA (rare) | High | [30, 31] | |
| Thiazolidinediones | Activate PPAR-γ receptors, improving insulin sensitivity and reducing albuminuria | Pioglitazone (15-45 mg daily) | Weight gain, edema, heart failure risk | Moderate | [32] | |
| BP control | ACE Inhibitors | Inhibit angiotensin-converting enzyme, reducing aldosterone, promoting vasodilation, and lowering proteinuria | Enalapril (5-40 mg daily), Ramipril (2.5-10 mg daily) | Hyperkalemia, hypotension, Cough, Increase serum creatinine level, Teratogenicity | Low | [35, 36] |
| Aldosterone Antagonists | Block aldosterone receptors, reducing sodium retention, proteinuria, and BP | Spironolactone (25-100 mg daily) |
|
Low | [37, 38] | |
| ARB | Block angiotensin II receptors, reducing vasoconstriction and aldosterone release, improving albuminuria | Losartan (25-100 mg daily), Valsartan (40-160 mg daily) | Hyperkalemia, hypotension, Increase in serum creatinine | Moderate | [39] | |
| MRA | Block mineralocorticoid receptors, reducing proteinuria, blood pressure, and kidney damage | Spironolactone (25-100 mg daily), Finerenone (10-20 mg daily) | Hyperkalemia, hyponatremina, gynecomastia, hypovolemia (Spironolactone) | High | [40-53] |
Critical analysis
Despite the availability of various pharmacological agents to control glycemia and blood pressure in DKD, several key limitations remain. First, while ACE inhibitors, ARB and SGLT2 inhibitors have demonstrated efficacy in slowing the progression of renal disease, none of these therapies are curative. They predominantly serve as disease-modifying agents, with benefits primarily in reducing albuminuria and delaying the progression to more severe stages of DKD. However, in many patients, particularly those with advanced disease these agents provide only limited protection.
Furthermore, side effects are a significant concern. ACE inhibitors and ARBs may cause hyperkalemia and renal dysfunction, while SGLT2 inhibitors increase the risk of urinary and genital infections. Thiazolidinediones, while effective in some cases, can exacerbate heart failure, weight gain and edema, limiting their use in certain patient populations.
As a result, there is an urgent need for individualized treatment approaches in managing DKD. Treatment regimens should be tailored to the patient’s specific stage of disease, comorbid conditions and risk factors. A more personalized approach incorporating factors such as age, underlying cardiovascular risk and co-morbidities may optimize therapeutic outcomes and minimize adverse effects.
Experimental treatment
Antioxidants
Alpha-lipoic acid (ALA)
A potent antioxidant that neutralizes ROS and reduces OS, ALA protects against DKD. It improves renal function, reduces fibrosis and decreases inflammatory cytokines (IL-6, TNF-α) by modulating pathways like p38 MAPK and NF-κB [54-56]. Clinical trials show ALA reduces urinary albumin excretion, a key marker of kidney dysfunction in diabetes. Typical dosages range from 600–1,200 mg/day [57-59].
Resveratrol
This polyphenol regulates oxidative stress, inflammation and autophagy in DN. It reduces ROS, enhances antioxidant defenses and improves kidney function through the AMPK/SIRT1/Nrf2 and Keap1/Nrf2 pathways [60, 61]. Studies show it also reduces proteinuria and improves renal structure [62, 63]. Combined with other treatments, Resveratrol may enhance DN management [64]. Network pharmacology highlights therapeutic targets for Resveratrol in DKD [65].
Curcumin
Known for anti-inflammatory, antioxidant and anti-apoptotic effects, curcumin protects the kidneys by activating Nrf2 and inhibiting NF-κB. It reduces OS, inflammation and fibrosis, particularly in DN [66-70]. Curcumin nanoparticles (nCUR) have shown promise in delaying DKD progression, even without controlling hyperglycemia [71]. It also modulates inflammation in CKD patients [72-75].
Sulbutiamine
It is a synthetic vitamin B1 derivative. Sulbutiamine reduces OS, improves kidney function and suppresses inflammatory markers in DN models [76].
Schisandrin B (Sch B)
It isa plant-derived lignan that targets mitochondrial dysfunction and Epithelial-Mesenchymal Transition (EMT) in renal tubular cells, reducing fibrosis and improving mitochondrial function in DKD. Sch B acts through the TGF-β1, PI3K/Akt, and AMPK pathways [77].
AGE formation inhibitors
Diphlorethohydroxycarmalol (DPHC) is found in brown seaweed. DPHC inhibits the AGE-RAGE interaction, preventing MGO-induced renal damage and regulating apoptosis [78]. Other AGE inhibitors like Aminoguanidine show promise, although clinical trials have been limited due to side effects [79-81].
Aldose reductase inhibitors (ARIs)
WJ-39andEpalrestatare ARI that inhibit the polyol pathway to protect against diabetic kidney damage. WJ-39 improves mitochondrial function and reduces fibrosis in preclinical models [82]. Epalrestat has beneficial effects on renal function and interacts with key pathways (AGE-RAGE, TNF, HIF-1) [83], though gastrointestinal side effects limit its clinical use.
MRA
Esaxerenone is an MR blocker. Esaxerenone reduces albuminuria in DN independent of BP-lowering effects [84].
Endothelin-1 receptor A (ETA) antagonists
Atrasentan and Zibotentan are ETA-selective antagonists that reduce glomerular permeability and proteinuria, showing potential for DN and CKD. Atrasentan has shown promise in reducing renal events and albuminuria [85-91]. However, side effects like fluid retention and hepatotoxicity are concerns with long-term use.
mTOR inhibitors
mTOR signaling, activated by high glucose and cytokines in diabetes, promotes cell proliferation and fibrosis in kidney cells, contributing to DKD. mTOR activation impairs autophagy and promotes OS, inflammation and podocyte damage. Rapamycin, an mTOR inhibitor, shows promise in preclinical models but has side effects, including proteinuria and IR [92-105]. Other mTOR-targeting agents, like thiazolidinediones (Rosiglitazone), aldosterone antagonists (Spironolactone) and plant compounds (e.g., Tripterygium glycoside), show protective effects in DKD [106-114]. Vitamin D Receptor (VDR) activation, through DDIT4 upregulation, inhibits mTOR, mitigating kidney injury and fibrosis. These findings support mTOR inhibition as a potential DKD therapy, though further research is needed [115-121].
TNF-α inhibitors
TNF-α and its receptors, TNFR1 and TNFR2, play a role in the progression of DKD. Inhibiting TNF activity in diabetic models reduces proteinuria, sodium retention and kidney hypertrophy. Soluble TNF receptors like TNFR: Fc and Etanercept show promise in mitigating renal damage, suggesting TNFR as a key therapeutic target in DKD [122-126].
Pentoxifylline (PTX)
PTX has shown benefits in DKD by reducing proteinuria, improving kidney function (creatinine clearance), controlling inflammation and OS. PTX also improves lipid profiles, lowering LDL-C and Triglycerides (TGL) and reduces TNF-α levels. These multifactorial effects underscore its potential in DKD management [127-134]. Large-scale studies are needed to confirm PTX's therapeutic potential.
Protein kinase C inhibitors (PKCI)
PKC β overactivity contributes to DN via collagen production and fibrosis. Ruboxistaurin, a selective PKC β inhibitor, reduces glomerular hyperfiltration and proteinuria in diabetic rats [135, 136]. Echinochrome A (EchA), derived from sea urchins, also inhibits PKC and improves renal function in diabetic models by reducing OS and fibrosis [137].
Nox1/4 inhibitors
NOX1 and NOX4 enzymes generate ROS, promoting inflammation and fibrosis in DKD. GKT137831, a dual NOX1/4 inhibitor, shows protective effects in preclinical DN models. The NOX-E36 inhibitor reduced albuminuria in DN patients, suggesting its potential for preventing kidney damage [138-140].
Nrf2 activators
Nrf2 activation enhances antioxidant capacity, reduces inflammation and prevents fibrosis, critical in DN. Bardoxolone Methyl, an Nrf2 activator, improved GFR in diabetic patients, though cardiovascular concerns led to trial termination [141, 142].
Table 2: Experimental treatment to prevent DKD
| Drug category | Drug | Mechanism of action | Study model | Study outcome | Challenges in development | Reference number | Why it can be used in preventing DKD? |
| Antioxidants | ALA | Neutralizes ROS, reduces OS, modulates inflammatory and fibrotic pathways | Animal (Preclinical), Human (Clinical) | Preclinical studies showed protective effects on kidney function, reduced hyperglycemia, prevented glomerulosclerosis and fibrosis. Clinical trials showed decreased albumin excretion. | Mild side effects (GI discomfort, hypoglycemia), optimal dosage and long-term safety need further study | [54-59] | OS is a key driver of DKD and ALA targets this pathway, offering potential for kidney protection. |
| Resveratrol | Modulates AMPK/SIRT1/Nrf2 and Keap1/Nrf2 pathways, reduces ROS, enhances antioxidant enzymes, improves kidney function. | Animal (Preclinical), Human (Clinical) | Reduced proteinuria, improved kidney structure, decreased inflammatory markers. Subgroup analyses showed beneficial effects with or without co-treatment with other medications. | Long-term efficacy and optimal dosage still under investigation. | [60-65] | Given the role of inflammation and oxidative stress in DKD, resveratrol could help reduce these factors, slowing kidney damage. | |
| Curcumin | Reduces OS, prevents renal damage, enhances mitochondrial function, modulates Nrf2 and NF-κB. | Animal (Preclinical), Human (Clinical) | Reduced renal inflammation and fibrosis, improved kidney function in diabetic rat models. In human trials, reduced inflammation in CKD patients. | More research needed for precise mechanisms and clinical application. | [62-66, 103-106] | Curcumin offers antioxidant, anti-inflammatory, and antifibrotic properties, essential for combating DKD progression. | |
| Sulbutiamine | Reduces OS, suppresses inflammatory markers, improves kidney function. | Animal (Preclinical) | Reduced fasting blood glucose, improved kidney function (decreased urea, creatinine), reduced inflammation, and improved histopathological changes in kidneys of diabetic rats. | Limited human data on long-term effects. | [76] | Targets OS and inflammation, core contributors to DKD, with promising effects in early studies. | |
| Sch B | Inhibits EMT, improves mitochondrial function, reduces ROS, enhances ATP production. | Animal (Preclinical) | Prevented EMT in renal tubular cells, improved mitochondrial function, reduced fibrosis and OS. | Limited human studies and clinical validation. | [77] | Inhibiting EMT and improving mitochondrial function may help prevent fibrosis and functional decline in DKD. | |
| AGE formation inhibitors | DPHC | Inhibits AGE-RAGE interaction, regulates apoptosis, enhances Nrf2 pathway. | Animal (Preclinical) | Prevented AGE-related kidney damage, suppressed RAGE protein expression, reduced renal damage in diabetic rats. | Limited clinical data, need for larger trials. | [78] | AGE accumulation accelerates DKD progression; targeting AGE-RAGE interactions may slow down this process. |
| Aminoguanidine | Inhibits AGE formation by trapping reactive carbonyl compounds and preventing glycoxidation. | Animal (Preclinical), Human (Clinical) | Reduced renal AGE accumulation and mesangial expansion in diabetic rats, but minimal benefits in human trials for overt nephropathy | Discontinued due to toxicity and adverse effects in humans. | [79-81] | AGEs contribute to fibrosis and inflammation in DKD, making their inhibition crucial for slowing disease progression. | |
| Aldose Reductase Inhibitors (ARIs) | WJ-39 | Inhibits aldose reductase, reducing polyol pathway activation, improves mitochondrial function, reduces fibrosis. | Animal (Preclinical) | Protected against renal tubular damage in diabetic rats, improved mitochondrial function and reduced fibrosis. | Long-term safety and efficacy in humans remain to be confirmed. | [82] | The polyol pathway is linked to DKD progression, and inhibition could reduce kidney damage and fibrosis. |
| Epalrestat | Inhibits aldose reductase, reducing renal metabolic disturbances and inflammatory pathways. | Human (Clinical), Animal (Preclinical) | Reduced renal dysfunction and metabolic disturbances in DN patients, decreased inflammation. | Gastrointestinal side effects and liver enzyme abnormalities limit use. | [83] | Inhibition of aldose reductase could provide a direct therapeutic benefit in addressing metabolic disturbances in DKD. | |
| MRA | Esaxerenone | Blocks MR, reduces albuminuria independent of BP reduction. | Human (Clinical) | Reduced Urine Albumin-to-Creatinine Ratio (UACR) in patients with DN, independent of BP effects. | Further research needed to clarify mechanisms and efficacy across different populations. | [84] | Blocking MR can reduce albuminuria, a key marker of kidney damage in DKD. |
| ETA | Ambrisentan, Macitentan, Sitaxentan, BQ-123, Darusentan, Avosentan, Atrasentan, Zibotentan | Selective antagonism of ETA receptors, reducing vasoconstriction, inflammation and renal damage | Preclinical, Clinical | Reduced glomerular permeability, lower BP, potential for treating resistant hypertension, DN | Side effects: hepatotoxicity, fluid retention, anemia, particularly with long-term use of Sitaxentan, Avosentan | [85-91] | ETA can mitigate vasoconstriction and inflammation, both of which contribute to DKD progression. |
| Bosentan, Tezosentan, Aprocitentan | Dual antagonism of ETA and ETB receptors, vasodilation, renal protection | Preclinical, Clinical | Bosentan approved for PAH; Tezosentan does not reduce cardiovascular events; Aprocitentan lowers BP in resistant hypertension | Liver dysfunction, fluid retention, lack of cardiovascular event reduction in clinical trials | [163-169] | Dual antagonism of endothelin receptors can help combat renal vasoconstriction and improve kidney outcomes in DKD. | |
| mTOR Inhibitor | Rapamycin, Thiazolidinediones (e. g., Rosiglitazone), Aldosterone antagonists (e. g., Spironolactone) | Inhibition of mTOR signaling pathway, preventing podocyte damage and glomerular hypertrophy | Preclinical, Clinical | Reduced kidney injury, improved glomerular function, reduced fibrosis and inflammation | Side effects: proteinuria, renal tubular necrosis, insulin resistance, immune suppression | [92-105] | mTOR inhibitors can protect glomerular integrity and prevent kidney injury, crucial for preventing DKD. |
| Tripterygium Glycoside, Triptolide, Radix Astragali, Paecilomyces Cicadidae, Dihydromyricetin, Ginsenoside Rg1, Kaempferol | Modulation of mTOR signaling, enhancing autophagy, reducing epithelial-mesenchymal transition and apoptosis | Preclinical, In vitro | Protection of renal function, delayed DKD progression, improved autophagic processes | Limited clinical data, potential safety concerns, unclear mechanisms of action | [106-114] | Modulating mTOR signaling could enhance kidney function and delay DKD progression by promoting autophagy and reducing fibrosis. | |
| TNF-α Inhibitors | Infliximab, Etanercept | Inhibition of TNF signaling, reduction of inflammation, sodium retention and renal hypertrophy | Preclinical (STZ rats), Clinical (human) | Reduced urinary TNF excretion, attenuated kidney damage, decreased albuminuria | Limited understanding of TNFR1 vs TNFR2 contributions, variable outcomes across models | [122-126] | TNF-α is a major pro-inflammatory mediator in DKD; its inhibition could help reduce kidney inflammation and damage. |
| PTX | PTX | Anti-inflammatory, reduces oxidative stress, improves lipid profile and enhances kidney function | Clinical (human), Preclinical | Reduced UACR, improved creatinine clearance, reduced inflammation and OS | Need for large-scale, longitudinal studies to confirm findings, safety profile concerns | [127-134] | PTX’s anti-inflammatory and antioxidant effects make it a potential therapy to reduce kidney damage in DKD patients. |
| PKCI | Ruboxistaurin, EchA | Inhibition of PKC β and downstream pathways, reducing fibrosis and oxidative stress | Preclinical (rat, mouse), Clinical | Reduced glomerular hyperfiltration, proteinuria, improved renal function in DN models | Limited human trials, efficacy and safety concerns, need for long-term data | [135-137] | PKC activation plays a role in DKD progression; inhibiting it could help reduce fibrosis and renal damage in diabetes. |
| Nox1/4 Inhibitor | GKT137831, NOX-E36 | Inhibition of NOX1 and NOX4, reducing ROS production and kidney damage | Preclinical (mouse), Clinical (human) | Significant reduction in albuminuria, potential efficacy in preventing kidney damage | Lack of long-term clinical data, variable response across patient populations | [138-140] | NOX enzymes contribute to OS in DKD; inhibiting them may prevent kidney injury and slow disease progression. |
| Nrf2 Activator | Bardoxolone Methyl | Activation of Nrf2 pathway, enhancing antioxidant capacity and reducing inflammation | Clinical (human) | Increased glomerular filtration rate (GFR), but trial terminated early due to cardiovascular events | Safety concerns (cardiovascular risks), need for further trials to confirm long-term benefits | [141, 142] | Activating Nrf2 enhances kidney antioxidant defenses, which is critical in managing OS in DKD. |
| JAK-STAT Inhibitor | Baricitinib | Inhibits JAK1 and JAK2, suppresses inflammation and reduces albuminuria. | Phase II clinical trial in type 2 diabetic patients with DKD. | Significant reduction in albuminuria (40%), reduction in pro-inflammatory biomarkers (e. g., CXCL10, CCL2). Common AE: anemia. | Potential safety concerns with long-term use (e. g., anemia, infection). Further large-scale trials needed. | [143-154] | Shows promising results in reducing inflammation, albuminuria, and fibrosis in DKD patients. |
| Ruxolitinib | It blocks JAK1 and JAK2, leading to a decrease in inflammation and fibrosis while also regulating podocyte autophagy. | Preclinical animal models (STZ-induced Wistar rats, HG-induced MPC-5 cell model). | Reduced proteinuria, decreased levels of inflammatory markers (TNF-α, TGF-β1, NF-κB), and fibrosis markers (vimentin). | No clinical trials yet for DKD, limited full animal studies. | Potential for reducing kidney fibrosis and inflammation in DKD, though further research needed. | ||
| Nifuroxazide | Inhibits JAK2 and Tyk2, suppresses STAT3 phosphorylation, reduces oxidative stress and inflammation. | Preclinical studies in STZ-induced SD rats, UUO rats. | Reduced oxidative stress, inflammation, and renal fibrosis. Improved glucose metabolism. | Lack of clinical trials for DKD, but long-term safety in clinical use suggests promise. | High oral safety promising anti-inflammatory and antioxidative effects could be useful in DKD treatment. | ||
| Sinomenine | Inhibits JAK2/STAT3/SOCS1 pathway, reduces inflammation, fibrosis, and apoptosis. | Preclinical studies in STZ-induced SD rats. | Reduced apoptosis of renal cells, along with decreased inflammation and fibrosis. Skin lesions and gastrointestinal discomfort noted. |
Potential side effects such as skin lesions and gastrointestinal issues. | Potential therapeutic option for inflammation and fibrosis in DKD through JAK/STAT modulation. | ||
| Silymarin | It blocks the JAK2/STAT3/SOCS1 and TGF-β/Smad signaling pathways, leading to a reduction in inflammation, oxidative stress, and fibrosis. | Preclinical studies in STZ-induced SD rats. | Improved podocyte injury, reduced oxidative stress, and renal fibrosis. Gastrointestinal discomfort reported as AE. | Teratogenicity concerns in animal studies, limited clinical data. | May help reduce oxidative stress and renal fibrosis in DKD patients with favorable safety profile in clinical use. | ||
| Total Glucosides of Paeony (TGP) | Inhibits JAK2/STAT3 pathway, suppresses macrophage activation, reduces renal inflammation and fibrosis. | Preclinical studies in Wistar rats with STZ-induced DKD. | Inhibited macrophage infiltration and fibrosis, reduced progression of DKD. | No clinical data yet for DKD. | Potential anti-inflammatory and fibrosis-reducing effects make it promising for DKD management. | ||
| Paeoniflorin | Inhibits JAK2/STAT3 pathway, reduces macrophage infiltration and inflammatory responses. | Preclinical studies in STZ-induced C57BL/6J mice. | Alleviated kidney inflammation and fibrosis, improved kidney protection. | No significant adverse reactions in clinical trials. | May provide effective anti-inflammatory and protective effects against DKD. | ||
| Isoliquiritigenin | Inhibits JAK2/STAT3 pathway, reduces inflammation and oxidative stress, protects against renal fibrosis. | Preclinical studies in HFD/STZ-induced SD rats. | Reduced renal fibrosis and inflammation, decreased IL-6 and ICAM-1 levels. | Minimal side effects reported. | Promising in alleviating oxidative stress and fibrosis, potential for DKD prevention. | ||
| Momordica Charantia | Inhibits JAK2/STAT3/STAT5/SOCS3/4 pathways, reduces renal inflammation and fibrosis. | Preclinical studies in STZ-induced Wistar rats. | Reduced renal inflammatory response, modulated JAK/STAT pathways, reduced kidney damage. | No major adverse effects, but further studies on long-term use are needed. | Potential for modulating inflammatory pathways, a promising candidate for DKD prevention. | ||
| Danzhi Jiangtang Capsule | Inhibits JAK/STAT pathway, reduces oxidative stress and inflammation in DKD. | Preclinical studies in HFD/STZ-induced SD rats and AGE-induced GMC model. | Reduced renal dysfunction, alleviated inflammatory injury in rats, associated with JAK/STAT inhibition. | Limited clinical data, but in vitro and animal studies suggest efficacy. | Potential as a complementary treatment for DKD by targeting oxidative stress and inflammation. | ||
| ErHuang Formula | Inhibits CXCL6/JAK/STAT3 pathway, reduces inflammation fibrosis, and improves kidney function. | Preclinical studies in HFD/STZ-induced SD rats and HG-induced NRK-49F cells. | Reduced fibrosis, decreased inflammation and renal dysfunction. | Need for more extensive clinical trials. | Potential to reduce renal fibrosis and inflammation, useful in DKD management. | ||
| Adhesion and chemokine molecule inhibitors | ASP8232 (VAP-1 inhibitor), Emapticap Pegol (CCL2-CCR2 inhibitor), NOX-A12 (CXCL12 inhibitor) | Blockade of adhesion molecules and chemokines, reducing immune cell migration and kidney inflammation | Clinical (Phase II), Preclinical | Reduced proteinuria, renal protection, slowed progression of kidney injury | Limited options for targeting adhesion molecules need for additional clinical research | [155-161,162] | Targeting adhesion molecules can block immune cell migration to the kidneys, reducing inflammation and fibrosis in DKD. |
JAK-STAT inhibitors
JAK inhibitors, such as tofacitinib (JAK1/3) and baricitinib (JAK1/2), have shown effectiveness in treating inflammatory and autoimmune diseases, including rheumatoid arthritis [143]. Ruxolitinib, another JAK1/2 inhibitor, is approved for myelofibrosis [144] and has also been studied in autoimmune diseases like Crohn’s disease and psoriasis [145, 146]. In early clinical trials, JAK inhibitors have demonstrated potential in treating DKD by improving renal function and reducing inflammatory markers [147, 148]. Baricitinib, for instance, has reduced albuminuria and inflammation in type 2 diabetic patients with DKD (NCT01683409). However, the long-term safety of these treatments, especially concerning anemia and infection risks, requires further investigation. Additionally, Ruxolitinib and Nifuroxazide, which inhibit the JAK/STAT pathway, have shown promise in experimental models for DKD treatment by reducing fibrosis and inflammation [149, 150]. Natural products like Sinomenine, Silymarin and Paeoniflorin have also been studied for their ability to modulate the JAK/STAT pathway and offer potential therapeutic benefits for DKD [151, 152]. Other medications, such as liraglutide and vitamin D, have been found to inhibit the JAK/STAT pathway and alleviate DKD-related inflammation and fibrosis, although further clinical trials are needed to confirm their long-term efficacy and safety [153, 154].
Adhesion and chemokine molecule inhibition in DKD
Adhesion molecules (ICAM-1, VCAM-1, VAP-1) and chemokines (e. g., CCL2) contribute to kidney inflammation and damage in DKD. Targeting adhesion molecules with VAP-1 inhibitors like ASP8232 and blocking the CCL2-CCR2 pathway with Emapticap Pegol reduced proteinuria in Phase II trials [155-161]. CXCL12 inhibition also alleviated kidney damage in diabetic mice [162].
Critical analysis
The development of experimental drugs for DKD has been notably slow despite promising preclinical results and the urgent need for effective therapies. One significant reason for this lag is the high attrition rate during clinical trials, often due to issues related to safety, efficacy and side effects. Many drugs that show potential in animal models fail to replicate these outcomes in human trials. For example, while antioxidants like ALA and curcumin show positive effects in preclinical studies, they often have limited bioavailability or cause mild side effects in humans which hampers their clinical adoption. Similarly, AGE formation inhibitors like Aminoguanidine, despite showing promise in animal models, were discontinued in human trials due to toxicity concerns. Additionally, the complexity of DKD’s pathophysiology, involving multiple pathways such as OS, inflammation, fibrosis and metabolic dysregulation, makes it difficult to pinpoint a single therapeutic target. As a result, clinical trials frequently fail to achieve the desired outcomes, slowing the development of effective treatments.
Moreover, regulatory and financial hurdles further delay the introduction of new DKD therapies. Clinical trials, particularly those for chronic conditions like DKD, require long follow-up periods to assess long-term safety and effectiveness, which increases both time and cost. This is particularly challenging for drugs targeting multiple pathways, such as mTOR inhibitors or ETA, where potential side effects like fluid retention or cardiovascular risks must be carefully managed. Limited funding, especially for phase III trials and a lack of consensus on optimal biomarkers for disease progression, also contribute to the slow pace of drug development. As a result, while the number of experimental drugs in the DKD pipeline is growing, many faces significant obstacles before they can be approved for widespread clinical use, further delaying advances in treatment for this progressive and debilitating disease.
Table 3: Comparison of current drugs Vs experimental drugs to prevent DKD
| Criteria | Current treatment options | Experimental treatment options |
| Therapeutic efficacy | -DPP-4 Inhibitors: Improve insulin secretion and reduce albuminuria. Proven efficacy in DKD management. -SGLT2 Inhibitors: Reduce glucose reabsorption and albuminuria, slow progression of kidney disease. -ACE Inhibitors/ARBs: Reduce proteinuria, control BP and protect kidney function. |
-Antioxidants (ALA, Resveratrol, Curcumin, Sulbutiamine, Schisandrin B): Show promising effects on reducing OS, improving kidney function and preventing fibrosis in preclinical and early clinical trials. -AGE Formation Inhibitors (DPHC, Aminoguanidine): Show potential in reducing kidney damage by preventing AGE-RAGE interaction. -ARI: Potential to reduce kidney damage by inhibiting the polyol pathway. -MRA (Esaxerenone): Show efficacy in reducing albuminuria independent of BP. -Endothelin-1 Receptor Antagonist (Ambrisentan, Macitentan, Bosentan): Potential to reduce glomerular permeability and inflammation. -mTOR Inhibitors (Rapamycin, Tripterygium Glycoside): Demonstrate efficacy in reducing kidney injury, improving glomerular function and decreasing inflammation and fibrosis. -TNF-α Inhibitors (Infliximab, Etanercept): Show potential in reducing kidney inflammation and albuminuria. -PTX: Demonstrates potential in improving kidney function and reducing inflammation. -Nox1/4 Inhibitors (GKT137831, NOX-E36): Show potential to reduce ROS production and kidney damage. -Nrf2 Activators (Bardoxolone Methyl): Demonstrated increased glomerular filtration rate, though concerns over cardiovascular safety exist. -JAK-STAT Inhibitors (Baricitinib): Reduced proteinuria in early-phase trials, suggesting efficacy in DKD management. -Adhesion and Chemokine Molecule Inhibitors: Target adhesion molecules to reduce inflammation and kidney damage. |
| Cost | -Moderate to High: SGLT2 inhibitors, GLP-1 agonists, and other medications like ACE inhibitors or ARBs can be expensive, especially newer drugs like SGLT2 inhibitors. | -Varies: Many experimental treatments are still in clinical trials and are not yet commercially available, making the cost difficult to determine. Some therapies might be cost-effective if they enter the market but others, especially novel biologics or small molecules, may be expensive. |
CONCLUSION
In conclusion, while significant progress has been made in identifying and implementing strategies to prevent DKD, many of the current interventions primarily focus on slowing disease progression rather than offering definitive prevention. Lifestyle modifications such as weight loss, physical activity and dietary changes remain foundational in reducing the risk of DKD and pharmacological treatments such as ACE inhibitors, ARB and SGLT2 inhibitors have demonstrated efficacy in mitigating the onset of kidney complications. However, these interventions are not without limitations and while they can delay the progression of kidney damage, they do not fully prevent the disease in all patients.
Given the promising yet early-stage nature of many emerging therapies such as antioxidants (e. g., ALA, Resveratrol, Curcumin), MRA and novel agents like JAK-STAT inhibitors, the urgency for more extensive and rigorous clinical trials becomes evident. Early clinical data may suggest potential benefits, but they are not sufficient to justify the optimistic outlook that some of these therapies might prevent DKD in the long term. Therefore, a key priority is the acceleration of clinical studies to validate these promising treatments, particularly for high-risk populations who may benefit most from early intervention.
Additionally, as DKD is a complex and multifactorial disease, a more personalized approach to prevention by incorporating individual risk factors such as age, comorbid conditions and underlying cardiovascular risk will be essential in optimizing prevention strategies. Tailoring interventions to the specific needs of each patient has the potential to prevent the onset of DKD while minimizing adverse effects. Ultimately, a concerted effort to advance clinical trials and refine prevention strategies will be crucial in reducing the burden of DKD and improving outcomes for those at risk.
ACKNOWLEDGEMENT
In writing this review article, I wish to express my sincere appreciation to everyone who supported and contributed to its development. I am especially grateful to my colleagues and mentors, whose insightful feedback and constructive critiques were instrumental in guiding this work. I also want to acknowledge the researchers whose groundbreaking studies laid the groundwork for this systematic review; their dedication and innovative approaches have greatly enhanced this field.
FUNDING
No financial support, grants, or other assistance was provided.
AUTHORS CONTRIBUTIONS
All authors played a role in the conception and design of the study. B. Dharani, S. Nazrin, and Stephy Sebastian handled data collection and analysis. The initial draft of the manuscript was prepared by B. Dharani and S. Nazrin, while Suba A. assisted in gathering articles. Each author reviewed earlier drafts, provided feedback, and approved the final version.
CONFLICTS OF INTERESTS
The authors declare that there is no conflict of interest.
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