This review employs a systematic literature review approach aimed at exploring the effects of exercise on diabetic kidney disease (DKD). We prioritize high-quality study designs, including randomized controlled trials (RCTs) and prospective cohort studies, to enhance the credibility of the findings.

Data were systematically retrieved from electronic databases such as PubMed, Embase, and Cochrane Library using relevant keywords, including “diabetic kidney disease,” “exercise,” and “blood glucose stability.” The study selection and data extraction were conducted by two independent researchers to ensure the accuracy of the results.

Inclusion Criteria: (i) Study Population: Participants must be diagnosed with diabetic kidney disease (DKD) according to the diagnostic criteria set by the International Diabetes Federation (IDF) or other authoritative guidelines. (ii) Study Design: We included randomized controlled trials (RCTs), prospective cohort studies, systematic reviews, and meta-analyses to ensure a comprehensive and high-quality assessment. (iii) Intervention Content: Studies must include an exercise intervention with clearly described types of exercise (e.g., aerobic, resistance training), frequency, and duration. (iv) Related Disease Studies: Research that includes other chronic diseases related to DKD (e.g., diabetes with heart disease, hypertension) to provide broader context. (v) Outcome Assessment: Studies should report specific effects of exercise on DKD patients, including blood glucose stability, renal function indicators (such as creatinine and urine protein), and related pathological mechanisms.

Exclusion Criteria: (i) Comorbid Patients: Studies focusing on patients with severe unrelated diseases (e.g., end-stage renal disease, active cancer) will be excluded to reduce confounding factors. (ii) Healthy Individuals: Exclude studies that involve healthy individuals as participants without mentioning DKD patients. (iii) Insufficient Sample Size: Exclude studies with fewer than 100 participants to ensure the validity of statistical analyses. (iv) Lack of Long-term Follow-up: Exclude studies that do not provide at least 6 months of follow-up data to assess the long-term effects of exercise.

We prefer studies with larger sample sizes to ensure statistical significance and representativeness. The selected literature included studies with sample sizes exceeding 100 participants, providing sufficient statistical support.

Quantitative analyses were conducted on the results of the included studies, employing appropriate statistical methods to evaluate the impact of exercise on DKD patients and further explore the effects of different exercise interventions on the underlying pathological mechanisms.

Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease. Its pathogenesis is complex, involving various molecular and cellular pathways, with hyperglycemia and hemodynamic disturbances being the primary driving factors for its onset and progression (Figure 1).

In DKD, dysfunction of the afferent and efferent arterioles is a key factor leading to increased glomerular filtration rate (GFR). Under normal conditions, the afferent arteriole, located at the entrance of the glomerulus, delivers blood to the glomerulus. Its dilation increases blood flow and pressure within the glomerulus, thereby enhancing the filtration rate. The efferent arteriole, situated at the exit, carries filtered blood away from the glomerulus; its constriction further increases glomerular pressure, leading to a rise in GFR (12). Metabolic disturbances in DKD, along with oxidative stress, inhibit nitric oxide (NO) production, which typically reduces vasodilation. However, in a hyperglycemic environment, the activation of the local renin-angiotensin system (RAS) elevates angiotensin II levels, causing efferent arteriole constriction. As a compensatory mechanism, afferent arteriole dilation occurs to maintain glomerular filtration. This combination of afferent dilation and efferent constriction significantly increases intraglomerular pressure, thereby raising GFR, exacerbating kidney damage, and leading to proteinuria (13–15).

In the early stages of DKD, persistent hyperglycemia induces changes in vascular factors, such as NO and endothelin-1, leading to the aforementioned vascular dysfunction. As intraglomerular pressure continues to rise, hyperfiltration develops, laying the foundation for subsequent kidney damage. These hemodynamic changes also cause phenotypic alterations in endothelial cells, increasing the permeability of the glomerular basement membrane, eventually resulting in proteinuria (13). In addition to hemodynamic changes, hyperglycemia exacerbates oxidative stress through the activation of aldose reductase (AR) in the polyol pathway. This pathway converts excess glucose into sorbitol, which accumulates within cells, consuming NADPH and inhibiting glutathione (GSH) regeneration. Since NADPH is an essential cofactor for GSH reduction, its depletion weakens the cells ability to scavenge reactive oxygen species (ROS), thereby intensifying oxidative stress (16). Moreover, sorbitol and vitamin C share the same cellular transport channel, so elevated sorbitol levels can inhibit vitamin C uptake, impairing the cell’s antioxidant defense capacity (17). Studies have shown that increased AR activity is closely linked to enhanced ROS production and the progression of DKD (18). Thus, AR not only compromises antioxidant defenses by depleting NADPH but also directly increases ROS production through sorbitol metabolism (17, 19). Consequently, the use of aldose reductase inhibitors has been considered a potential therapeutic strategy for DKD intervention, as they effectively reduce ROS levels (19, 20). As DKD progresses, alterations in intracellular glucose metabolism lead to the formation of advanced glycation end products (AGEs), further driving DKD progression. In a hyperglycemic environment, non-enzymatic glycation produces AGEs that cross-link with collagen and elastin in the extracellular matrix, altering their molecular structure and elasticity, thereby increasing matrix stiffness (21). This stiffening is a major cause of glomerular basement membrane thickening and tubulointerstitial fibrosis, disrupting normal kidney architecture and contributing to chronic kidney disease (CKD) (22). These structural changes play a key role in the pathophysiology of diabetes-related complications. Matrix stiffening limits the normal expansion and contraction of renal tubules, leading to impaired filtration and reabsorption functions, thereby accelerating DKD progression (23, 24). Furthermore, the cross-linking of AGEs with collagen and elastin not only affects the mechanical properties of renal tubules but also activates fibrotic pathways in the kidneys through oxidative stress and inflammatory responses (25). This fibrosis is a key factor in the pathological progression of DKD, further impairing normal kidney structure and function (25, 26). Research indicates that transforming growth factor-β1 (TGF-β1) is a key mediator of renal fibrosis in DKD. TGF-β1 primarily activates the Smad signaling pathway, promoting the transdifferentiation of renal intrinsic cells, including tubular epithelial cells, mesangial cells, and fibroblasts, into myofibroblasts. These myofibroblasts are the main source of excessive extracellular matrix (ECM) synthesis, producing and secreting ECM components like type I and IV collagen, fibronectin, and laminin (27, 28). Additionally, TGF-β1 inhibits the activity of matrix metalloproteinases (MMPs), reducing ECM degradation and resulting in ECM accumulation in kidney tissue (29, 30). This excessive ECM deposition ultimately leads to structural disorganization of the kidney, forming scar tissue that restricts normal kidney function (28, 29). Therefore, TGF-β1 serves as a crucial driver of fibrosis in DKD. Aside from hyperglycemia-induced pathological changes, lipid metabolism disorders can further worsen the condition by promoting ROS production through increased lipid peroxidation products. This process leads to glomerulosclerosis and tubulointerstitial fibrosis, aggravating DKD severity (31, 32). Moreover, AGEs enhance the expression of various NF-κB-related pro-inflammatory mediators, activated by ROS produced in high-glucose environments. Podocyte exposure to AGEs results in the upregulation of pro-inflammatory cytokines, infiltration of inflammatory cells, and stimulation of adhesion molecules and profibrotic factors (33). With the accumulation of AGEs and persistent hyperglycemia, the renin-angiotensin-aldosterone system (RAAS) is activated. RAAS activation results in the production of angiotensin II (Ang II), which primarily induces oxidative stress via NADPH oxidase and promotes inflammation and fibrosis through pro-inflammatory and profibrotic cytokines (34, 35). The pathogenesis of DKD is complex, involving interactions at multiple biological levels. At the molecular level, genetic and epigenetic regulation plays a significant role in DKD progression. Studies indicate that changes in gene expression and epigenetic modifications, such as DNA methylation, histone changes, and non-coding RNA activity, are closely associated with inflammation and fibrosis-related signaling pathways (36, 37). These mechanisms are influenced by hyperglycemia-induced oxidative stress and AGE formation, accelerating the pathological process of DKD. At the cellular level, mitochondrial dysfunction, along with disturbances in energy metabolism and excessive ROS production, are key contributors to DKD (36, 38). Furthermore, dysregulation of the autophagy process worsens cellular damage and compromises the integrity of the glomerular filtration barrier, leading to proteinuria (36, 38). At the tissue level, renal fibrosis is a hallmark of advanced DKD, where ongoing inflammation and ECM accumulation lead to tubulointerstitial fibrosis, causing irreversible damage to kidney structure and function (36). These insights provide a more comprehensive understanding of the mechanisms underlying DKD.

Exercise serves as a crucial intervention in the management of diabetic kidney disease (DKD), particularly in stabilizing blood glucose levels, a key factor in the progression of DKD in patients with Type 2 diabetes mellitus (T2DM). The mechanistic role of exercise in improving DKD, as illustrated in Figure 2, is multifaceted, involving various pathways that collectively contribute to better blood glucose stability. These pathways include the CaMKII, AMPK, mTOR, and IRS1/PI3-K/AKT/GLUT4 pathways, each playing a unique role in glucose metabolism and insulin sensitivity.

By engaging in regular physical activity, patients with DKD can activate these pathways, leading to improved insulin sensitivity, enhanced glucose uptake by skeletal muscles, and reduced blood glucose levels. For instance, the AMPK pathway, a well-known energy sensor, is particularly responsive to exercise. Activation of this pathway through physical activity improves insulin sensitivity and glucose uptake, crucial for maintaining stable blood glucose levels. Similarly, exercise-induced activation of the IRS1/PI3-K/AKT/GLUT4 pathway enhances the efficiency of glucose transport into cells, further contributing to blood glucose stability.

Moreover, exercise influences the regulation of blood glucose homeostasis by affecting muscle contraction and energy utilization. For example, muscle contractions during exercise stimulate the translocation of glucose transporters to the cell membrane, facilitating glucose entry into cells. This process is crucial for maintaining blood glucose levels within a normal range, especially in individuals with T2DM, who are at a higher risk of developing DKD.

In summary, the role of exercise in improving DKD extends beyond physical fitness. It involves a complex interplay of metabolic pathways that work together to stabilize blood glucose levels. This stabilization is key in managing DKD, as it directly impacts the progression of kidney disease in patients with T2DM. The beneficial effects of exercise on these pathways underscore its importance as a therapeutic strategy in the treatment and management of DKD. This section provides a comprehensive review of the mechanistic role of exercise in improving DKD.

Numerous clinical studies have demonstrated the benefits of exercise in helping diabetic patients control blood sugar, lipids, and weight, improving insulin sensitivity, enhancing cardiovascular and pulmonary function, and reducing the risk of cardiovascular and microvascular complications. This section reviews key studies that have focused specifically on the impact of exercise interventions on diabetic kidney disease (DKD) outcomes (139). Additionally, meta-analyses have shown that exercise has a beneficial effect on improving the renal function of diabetic patients, effectively reducing the incidence of microalbuminuria and renal failure (140). The results of a large randomized controlled trial, T2D Patients with Intensive Glucose Control and Vascular Complications showed that patients who performed moderate to high-intensity exercise had a lower risk of microvascular events compared to those who did not exercise or only performed light physical activity during a median follow-up period of 5 years (141). The FinnDiane study in Finland found that physical activity was related to DKD in T1D patients, and compared to patients with normal urinary albumin excretion rates, those with microalbuminuria had a higher frequency of low-intensity physical activity. After adjusting for confounding factors, higher frequencies and intensities of physical activity were found to reduce the risk of DKD in T1D patients (142). A recent large-sample study in elderly patients with diabetes found that regular physical activity (at least 2 times per week) was significantly associated with lower ESKD and proteinuria rates, as well as a slower decline in GFR (143). In a 39-month prospective follow-up study conducted by Tamiya et al. on a cohort of 173 patients with DKD, it was found that sedentary behavior of ≥525 min/day increases the risk of kidney and cardiovascular events and/or all-cause mortality among DKD patients (144).

The latest studies have shown that a combination of aerobic exercise and quadriceps muscle strengthening training for 6 months can reduce the risk of peritoneal/hemodialysis, cardiovascular disease, and all-cause mortality in DKD patients, while also increasing high-density lipoprotein cholesterol levels and improving lip metabolism (145). These clinical studies have proven the beneficial effects of exercise on DKD, but currently, most studies on exercise intervention in DKD are small clinical trials with short durations, and more large-sample, long-term randomized controlled studies are needed to provide evidence for the exercise guidance of DKD patients.

Despite the abundant evidence showing the benefits of regular exercise for diabetic patients, the majority of diabetic patients have not developed a regular exercise habit. A large cross-sectional study in Europe on 18,028 adult T1D patients showed that less than 20% of patients were able to perform aerobic exercise at least twice a week (146). The results of a self-reported exercise study in American T2D patients showed that only 42.6–65.1% of patients met the American Diabetes Association (ADA) guideline-recommended exercise duration (147).

There is currently a lack of research on the current status of exercise in DKD patients, but epidemiological studies on CKD show that CKD patients average 9 days of exercise per month, and 45% of ESKD patients do not exercise (148). The reasons for the decreased exercise in DKD patients may include difficulty in controlling blood sugar, decreased muscle function, co-morbidities such as cardiovascular disease, and reduced hemoglobin levels due to decreased erythropoietin production. In addition, inadequate exercise counseling by healthcare providers, lack of exercise prescriptions, and incentives are also contributing factors to the lack of exercise in DKD patients (139).

In general, regular exercise has been proven to have numerous benefits for individuals with diabetes, including helping to control blood sugar, lipids, and weight, improving insulin sensitivity, and enhancing cardiovascular and pulmonary function. It also improves overall health and reduces the risk of cardiovascular and microvascular complications and mortality. Exercise has also been shown to have beneficial effects on improving renal function, reducing microalbuminuria, and decreasing the incidence of renal failure. Please refer to Table 1 for clinical research on the improvement of diabetic kidney disease through exercise.

According to the American Diabetes Association (ADA)’s Lifestyle and Healthcare Guidelines released in 2023, patients with diabetes should engage in diversified exercises including aerobic exercise, resistance exercise, combination exercise, and flexibility exercise (139). The specific recommendations are as follows: children and adolescent diabetes patients should engage in 60 min of moderate to vigorous intensity aerobic exercise daily, and at least 3 sessions of high-intensity resistance exercise per week; adults should engage in at least 150 min of moderate to vigorous intensity aerobic exercise per week and perform resistance exercise 2–3 times per week; elderly individuals should participate in 2–3 sessions of flexibility training and balance training per week (139). Resistance exercise and high-intensity interval training (HIIT) are not recommended for elderly patients (149). It is worth noting that ADA’s guidelines on physical activity/exercise do not restrict the exercise modalities for diabetes patients (150) but recommend individuals with microalbuminuria to participate in moderate to vigorous intensity exercise. For individuals with macroalbuminuria, exercise should start with low-intensity, low-impact activities and gradually increase intensity and duration. In 2022, the Kidney Association released clinical practice guidelines for exercise and lifestyle management in patients with chronic kidney disease (CKD), providing relevant recommendations for non-dialysis CKD patients, dialysis patients, and kidney transplant patients, encouraging them to break sedentary behavior and gradually increase exercise intensity, performing 150 min of moderate-intensity aerobic exercise per week or 75 min of moderate to vigorous intensity exercise (149).

A large body of research has confirmed the efficacy and safety of exercise in DKD patients, and thus, the guidelines recommend that dialysis patients with no contraindications engage in 150 min of moderate-intensity exercise or 75 min of high-intensity exercise per week (150). Early studies have demonstrated the benefits of different forms of exercise in diabetic kidney disease (DKD), with aerobic training being the most effective for enhancing cardiorespiratory fitness, improving insulin sensitivity, reducing weight, and improving glycemic and lipid metabolism; resistance exercise and HIIT can increase skeletal muscle mass and decrease the risk of exercise-induced hypoglycemia in individuals with type 1 diabetes (T1D) (151). Interestingly, comparing the effects of different exercise modalities, including aerobic, resistance, combination, and HIIT, on DKD, it was found that they can improve microvascular vasodilation in patients with type 2 diabetes (T2D), with aerobic and combination exercise having the most significant improvement on endothelial function (118); HIIT and moderate-intensity continuous aerobic exercise can significantly enhance activation of the renin-angiotensin-aldosterone system (RAAS) regulatory axis, with the latter having a more pronounced effect (152). However, the optimal exercise modality and regimen for DKD have not been established globally, and healthcare professionals should actively encourage patients to participate in exercise, select appropriate exercise modalities based on individual conditions, and gradually increase exercise intensity.

When prescribing exercise for patients with diabetic kidney disease (DKD), healthcare professionals need to carefully consider the patient’s overall health status and any potential complications to tailor appropriate exercise recommendations. In certain cases, exercise may not be suitable for all patients, particularly for those with proliferative diabetic retinopathy or severe non-proliferative diabetic retinopathy (88), cardiovascular disease including myocardial ischemia, heart failure, or peripheral arterial disease, patients with autonomic neuropathy resulting in impaired regulation of heart rate and blood pressure (153), as well as those with peripheral neuropathy and foot ulcers. In such cases, the type and intensity of exercise should be carefully considered, and it may be necessary to avoid or reduce exercise intensity.

Additionally, patients with type 1 diabetes (T1D) are at a higher risk of experiencing fluctuations in blood glucose levels during and after exercise, which increases the risk of hypoglycemia. To minimize this risk, patients should select appropriate types of exercise, control the intensity and duration of exercise, adjust insulin doses, consume additional carbohydrates, and continuously monitor blood glucose levels before, during, and after exercise to enhance glycemic control (154).

Exercise recommendations for DKD patients also vary depending on their age and health status. For children and adolescents with diabetes, it is recommended to engage in 60 min of moderate to vigorous aerobic exercise daily, with at least three sessions of high-intensity resistance exercise per week. Adults are advised to engage in at least 150 min of moderate to vigorous aerobic exercise per week, along with 2–3 sessions of resistance exercise. For older adults, 2–3 sessions of flexibility and balance training per week are recommended. Dialysis patients are advised to engage in 150 min of moderate-intensity exercise or 75 min of vigorous-intensity exercise per week. Healthcare professionals should select suitable exercise modalities based on the patient’s specific health status and physical condition and gradually increase exercise intensity to ensure safety and effectiveness. In conclusion, exercise recommendations for DKD patients should be individualized to meet the needs of different patients while minimizing the risk of complications and other potential hazards. These potential exercise prescription recommendations for patients with DKD are represented in Table 2.

In conclusion, exercise has shown promising potential as a therapeutic approach to alleviate DKD. Exercise can improve blood glucose stability associated with DKD, RAAS, reduce renal oxidative stress and inflammation, enhance the crosstalk between muscle and kidney, and improve endothelial cell function. These mechanisms contribute to the overall improvement of DKD. Exercise offers several advantages over traditional treatment methods, including its safety, effectiveness, and lack of apparent side effects. It can be used as an adjunct treatment to medication, blood glucose control, protein-restricted diet, and blood pressure management. Despite the clear benefits of exercise in DKD management, there is still a lack of large-scale, long-term randomized controlled trials to provide more evidence and establish exercise guidelines specific to DKD. Healthcare professionals should actively encourage DKD patients to engage in exercise and prescribe personalized exercise regimens based on individual conditions.

Future research should focus on exploring optimal exercise modalities, intensities, and durations for DKD patients, as well as investigating the long-term effects of exercise on DKD outcomes. Additionally, efforts should be made to address the barriers and challenges that prevent DKD patients from engaging in regular exercise, such as lack of awareness, motivation, and guidance. Therefore, exercise holds great potential as a non-pharmacological intervention for DKD and can significantly improve the quality of life for DKD patients. By integrating exercise into the management of DKD, we can reduce the burden on families and societies and ultimately improve the overall clinical outcomes of DKD patients.