Prevention of Diabetic Kidney Disease: the Chennai Experience

The current pandemic of diabetes mellitus will inevitably be followed by an epidemic of chronic kidney disease. It is anticipated that 25-40% of patients with type 1 diabetes and 5-40% of patients with type 2 diabetes will ultimately develop diabetic kidney disease. The control of blood pressure represents a key component for the prevention and management of diabetic nephropathy. There is a strong epidemiological connection between hypertension in diabetes and adverse outcomes in diabetes. Hypertension is closely linked to insulin resistance as part of the 'metabolic syndrome'. Diabetic nephropathy may lead to hypertension through direct actions on renal sodium handling, vascular compliance and vasomotor function. Recent clinical trials also support the utility of blood pressure reduction in the prevention of diabetic kidney disease. In patients with normoalbuminuria, transition to microalbuminuria can be prevented by blood pressure reduction. This action appears to be significant regardless of whether patients have elevated blood pressure or not. The efficacy of ACE inhibition appears to be greater than that achieved by other agents with a similar degree of blood pressure reduction; although large observational studies suggest the risk of microalbuminuria may be reduced by blood pressure reduction, regardless of modality. In patients with established microalbuminuria, ACE inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) consistently reduce the risk of progression from microalbuminuria to macroalbuminuria, over and above their antihypertensive actions. The clinical utility of combining these strategies remains to be established. In patients with overt nephropathy, blood pressure reduction is associated with reduced urinary albumin excretion and, subsequently, a reduced risk of renal impairment or end stage renal disease. In addition to actions on systemic blood pressure, it is now clear that ACE inhibitors and ARBs also reduce proteinuria in patients with diabetes. This anti-proteinuric activity is distinct from other antihypertensive agents and diuretics. Although there is a clear physiological rationale for blockade of the renin angiotensin system, which is strongly supported by clinical studies, to achieve the optimal lowering of blood pressure, particularly in the setting of established diabetic renal disease, a number of different antihypertensive agents will always be needed. In the end, the choice of agents should be individualised to achieve the maximal tolerated reduction in blood pressure and albuminuria. Ultimately, no matter how it is achieved, so long as it is achieved, renal risk can be reduced by agents that lower blood pressure and albuminuria.

Efficient primary prevention of diabetic kidney disease (DKD) is currently lacking. The identification of people at high DKD risk and timely intervention are key to preventing DKD. Therefore, a model to classify people according to their risk for developing DKD was developed previously and used in the current analysis to assess the effect of semaglutide versus placebo on primary DKD prevention. Participants with type 2 diabetes from the randomized, double-blind, placebo-controlled SUSTAIN 6 trial without DKD at baseline who received 0.5/1.0 mg semaglutide or placebo were grouped by baseline DKD risk, calculated using a validated model. The main post hoc outcome was the effect of semaglutide versus placebo on the proportion of participants who developed DKD [urinary albumin/creatinine ratio (UACR) ≥30 mg/g and/or estimated glomerular filtration rate <60 mL/min/1.73 m2]. Additional post hoc outcomes included changes in DKD risk score, UACR and estimated glomerular filtration rate over time. Of the total 1139 participants included in the analysis, 28.7% developed DKD; more participants with a high DKD risk (952/1139) developed DKD. Semaglutide significantly reduced the risk of developing DKD in both the total [odds ratio 0.56 (95% confidence interval: 0.42; 0.74; p < 0.0001)], and high DKD risk population [odds ratio 0.51 (95% confidence interval: 0.38; 0.69; p < 0.0001)] and significantly delayed DKD development versus placebo. The beneficial effects of semaglutide were largely driven by UACR changes. The number needed to treat for semaglutide in the high DKD risk population was 7. This post hoc study indicates that semaglutide may have beneficial effects on primary DKD prevention in people with T2D.

&lt;p&gt; &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Objective&lt;/strong&gt;: In patients with moderate-severe albuminuric kidney disease, sodium-glucose co-transporter-2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type-2 diabetes (T2D), focusing on populations with low kidney risk. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In the DECLARE-TIMI 58 trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was sustained decline ≥40% in estimated glomerular filtration rate (eGFR) to&lt;60mL/min/1.73m², end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6-months to 4-year) or total (baseline to 4-year) eGFR slopes. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; Most participants were in the low-moderate KDIGO risk categories (n=15,201, 90.3%). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction 0.97), including those at low risk (HR 0.54, 95%CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR≥60ml/min/1.73m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HR= 0.52, 0.57, 0.55, and 0.70, respectively, p&lt;0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m²/year; p&lt;0.0001). &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease. &lt;/p&gt;

In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk. In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes. Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001). Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.

&lt;p&gt; &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Objective&lt;/strong&gt;: In patients with moderate-severe albuminuric kidney disease, sodium-glucose co-transporter-2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type-2 diabetes (T2D), focusing on populations with low kidney risk. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In the DECLARE-TIMI 58 trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was sustained decline ≥40% in estimated glomerular filtration rate (eGFR) to&lt;60mL/min/1.73m², end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6-months to 4-year) or total (baseline to 4-year) eGFR slopes. &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; Most participants were in the low-moderate KDIGO risk categories (n=15,201, 90.3%). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction 0.97), including those at low risk (HR 0.54, 95%CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR≥60ml/min/1.73m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HR= 0.52, 0.57, 0.55, and 0.70, respectively, p&lt;0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m²/year; p&lt;0.0001). &lt;/p&gt; &lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease. &lt;/p&gt;

Clinical Challenges in Diagnosis and Management of Diabetic Kidney Disease

Chronic Kidney Disease and Diabetes–A Potential Causal Link

Background: Altered lipid metabolism is increasingly recognized as a key mediator of renal lipid accumulation, inflammation, oxidative stress, and fibrosis. Recent studies indicate a role for ceramides and sphingolipids in the pathogenesis and progression of kidney disease in diabetes and in obesity. Glucosylceramide is a particular species of glycosphingolipid that is synthesized by the addition of sugar to ceramide by glucosylceramide synthase (Ugcg). Further glycosylation pathways result in the formation of over 300 glycosphingolipids, including lactosylceramide, GM1, and GM3. Methods: To address whether glucosylceramide plays a role in the pathogenesis of diabetic kidney disease, we used a db/db mice as a model of type 2 diabetes to examine whether glucosylceramide levels change in diabetic kidneys. To test whether the inhibition of glucosylceramide synthase could mediate the beneficial effects of reduced glucosylceramide level in the kidney, we treated diabetic mice with the FDA-approved UGCG inhibitor eliglustat. Results: Using lipidomics, we have found increased glucosylceramide levels in the kidneys of diabetic db/db mice compared to nondiabetic db/m mice. We further investigated the glucosylceramide synthase UGCG expression and regulation in the diabetic kidney. UGCG is expressed in podocytes and tubular cells of human and mouse kidney, as determined by single nuclei RNA-seq and IHC and IF. We overexpressed UGCG in mouse proximal tubule cells and found that overexpression of UGCG caused significantly increased inflammation and decreased mitochondrial gene expression and mitochondrial membrane potential. Furthermore, we found that short-term treatment of UGCG inhibitor eliglustat successfully decreased the overall glucosylceramide level in diabetic kidneys, decreased urinary albumin, and improved markers of inflammation and fibrosis. Conclusions: Our studies provide evidence to support a novel treatment avenue to use UGCG inhibitor eliglustat in the treatment and prevention of diabetic kidney disease. This work was supported by NIH (NIDDK) award numbers R01 DK139676 (ML) andR01DK127830. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Diabetes continues to be the leading causes of kidney disease in the U.S. and around the world. Despite beneficial interventions implemented in patients with diabetes that mitigate some of its negative effects, kidney disease still progresses in most of these patients because the pathogenesis of diabetic kidney disease remains poorly understood. Recent evidence indicates that impairments in mitochondrial dynamics and function plays an important role in pathogenesis of diabetic kidney disease and brings promise to treatment strategies for improving mitochondrial function and the related pathways that may prevent or slow the progression of kidney disease.We aimed to test the influence of one key mitochondrial protein deacetylase, Sirtuin 3 (SIRT3) as a potential target for therapy in diabetic kidney disease. In kidney biopsies from human patients with diabetic nephropathy, there are decreases in SIRT3 mRNA and protein abundance in glomeruli and tubules. To test the effect of SIRT3 on the prevention of diabetic kidney disease, we conducted a study comparing three groups of mice: A control group, a diabetic group (db/db), and a diabetic group treated with nicotinamide riboside (NR), a precursor for NAD+, which is a co‐substrate required for SIRT3 activity. Treatment of diabetic mice with NR resulted in a) increase in renal SIRT3 activity as determined by significant decreases in total acetylated proteins and acetylated SOD2, significant decreases in b) albuminuria, c) mesangial expansion and glomerular area, d) accumulation of collagen IV protein, e) loss of synaptopodin and f) accumulation of 4‐HNE. In conclusion, SIRT3 plays an important role in diabetic kidney disease and increasing the SIRT3 activity may prevent the progression of diabetic kidney disease.Support or Funding InformationNIHThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic kidney disease (CKD) is the most common cause of end-stage renal disease in patients with type 2 diabetes mellitus (T2DM). CKD increases the risk of cardiovascular diseases; therefore, its prevention and treatment are important. The prevention of diabetic kidney disease (DKD) can be achieved through intensive glycemic control and blood pressure management. Additionally, DKD treatment aims to reduce albuminuria and improve kidney function. In patients with T2DM, renin-angiotensin-aldosterone system inhibitors, sodium glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can delay the progression of DKD. Hence, there is a need for novel treatments that can effectively suppress DKD progression. Finerenone is a first-in-class nonsteroidal mineralocorticoid receptor antagonist with clinically proven efficacy in improving albuminuria, estimated glomerular filtration rate, and risk of cardiovascular events in early and advanced DKD. Therefore, finerenone is a promising treatment option to delay DKD progression. This article reviews the mechanism of renal effects and major clinical outcomes of finerenone in DKD.

To develop a position statement that identifies research priorities in diabetic kidney disease and provides recommendations to researchers and research funders on how best to address them. A one-day research workshop was conducted, bringing together research experts in diabetes and kidney disease, healthcare professionals, and people living with diabetes, to identify and prioritise research recommendations. The following key areas were identified as needing increased focus: Understanding causal mechanisms in diabetic kidney disease Prevention of diabetic kidney disease Addressing health inequalities Improving diagnosis Improving care Supporting self-management CONCLUSIONS: This position statement outlines recommendations to address the urgent need to tackle diabetic kidney disease and calls on the diabetes and kidney research communities to act upon these recommendations to ensure future research works to eliminate unfair and avoidable disparities in health.

MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease

The caveolin-1 regulated protein follistatin protects against diabetic kidney disease

Management of patients with diabetes mellitus and chronic kidney disease (CKD) is a challenging task because multiple factors in each condition may impact the other. Glycemic control offers significant benefits in the prevention of diabetic kidney disease (DKD), but other associated morbidities are also important to address. Patients with diabetes with insufficient glycemic and blood pressure control are at a high risk for developing both cardiovascular disease and progression of nephropathy. This article discusses proper screening, identification, and management in the different stages of DKD, with special considerations for dialysis and transplant patients. We also review information on altered metabolism of medications and the appropriate use of diabetic agents, including recommendations for management of glucose control in CKD.

ObjectiveTo provide a scientific basis for the early prevention of diabetic kidney disease and diabetic retinopathy progression in diabetic patients by systematically evaluating the relationship between glycated hemoglobin (HbA1c) variability and diabetic kidney disease and diabetic retinopathy in these patients.MethodsDatabases including PubMed, Web of Science, Cochrane Library, and Embase were searched for studies investigating the association between HbA1c variability and adverse renal events or retinal diseases in diabetic patients, with data collected from the establishment of each database up to August 5, 2025. Two researchers independently conducted literature screening, data extraction, and assessment of the risk of bias in the included studies. Meta-analysis was performed using the Review Manager 5.3 software, with odds ratio (OR) or hazard ratio (HR) as the effect size indicators.ResultsA total of 45 cohort studies were included in this study, covering 172,111 participants from 20 countries and regions, of which 22 focused on diabetic kidney events and eight on diabetic retinopathy events, and 15 included both outcomes. For the meta-analysis of the association between HbA1c variability and adverse renal events, the standard deviation (SD) of HbA1c was associated with the risk of adverse renal events in patients with type 1 diabetes mellitus (T1DM), with an HR of 0.97 [95% confidence interval (CI): 0.64–1.48, p = 0.90] and an OR of 1.76 (95% CI: 1.12–2.77, p = 0.01); additionally, for each 1% increase in HbA1c-SD, the incidence of adverse renal events in T1DM patients increased, with an HR of 1.40 (95% CI: 1.23–1.59, p< 0.00001). In patients with type 2 diabetes mellitus (T2DM), the coefficient of variation (CV), SD, and high HbA1c variability score (HVS) of HbA1c were all associated with the mortality of adverse renal events, and all HbA1c variability indicators [CV, CV-per 1% increase, SD, SD-per 1% increase, hemoglobin glycation index (HGI), and HVS] were associated with an increased risk of adverse renal events in this population. For the meta-analysis of the association between HbA1c variability and retinopathy, HbA1c-CV was associated with the risk of retinopathy in T1DM patients, with an HR of 1.15 (95% CI: 1.08–1.22, p< 0.0001); HbA1c-SD was also significantly associated with the risk of retinopathy in T1DM, with an HR of 1.83 (95% CI: 1.28–1.63, p = 0.001) and an OR of 4.89 (95% CI: 1.64–14.65, p = 0.005); in T2DM patients, both HbA1c-CV and SD were significantly associated with the risk of retinopathy, with HRs of 1.12 (95% CI: 1.07–1.17, p< 0.00001) and 1.19 (95% CI: 1.06–1.34, p = 0.003), respectively.ConclusionHbA1c variability is positively associated with the risks of adverse renal events and retinal diseases in diabetic patients. Therefore, HbA1c variability may play an important and promising role in guiding blood glucose control targets for diabetic patients and predicting the progression of adverse renal events or retinal diseases.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420251133099.