Advanced Diabetic Kidney Disease Research Articles

Effectiveness and safety of finerenone in diabetic kidney disease patients: a real-world observational study from China

Aims Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin–angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Methods Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. Results The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300–5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9–11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. Conclusions This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.

Healthcare Costs Across Diabetic Kidney Disease Stages: A Veterans Affairs Study

In the United States, diabetic kidney disease (DKD) affects about one-third of individuals with type 2 diabetes, causing significant economic burdens on the health care system and affecting patients' quality of life. The aim of the study was to quantify the burden of care in patients at different stages of DKD and to monitor shifts in healthcare costs throughout these stages. This study used data from the Veterans Affairs National database, focusing on US veterans diagnosed with DKD between January 2016 and March 2022. Aggregated all-cause health care costs per month were summarized using descriptive statistics. We used a generalized linear model to calculate the cost of DKD patent care based on the stages, dialysis phase, and kidney replacement therapy. The cohort of 685,288 patients with DKD was predominantly male (96.51%), White (74.42%), and non-Hispanic (93.54%). The mean (SD) per-patient per-month costs were $1,597 ($3,178), $1,772 ($4,269), $2,857 ($13,072), $3,722 ($12,134), $5,505 ($14,639), and $6,999 ($16,901) for stages 1, 2, 3a, 3b, 4 and 5 respectively. The average monthly expenditure for patients receiving long-term dialysis was $12,299. Costs peaked sharply during the first month of kidney replacement therapy at $38,359 but subsequently decreased to $6,636 after 1 year. The economic implications of DKD are profound, emphasizing the need for efficient early detection and disease management strategies. Preventing patients from progressing to advanced DKD stage will minimize the economic repercussions of DKD and will assist health care systems in optimizing resource allocation.

Low-Protein Diets Could Be Effective and Safe in Elderly Patients with Advanced Diabetic Kidney Disease.

Low-protein diets (LPDs) seem to improve metabolic complications of advanced CKD, thus postponing kidney replacement therapy (KRT) initiation. However, the nutritional safety of LPDs remains debatable in patients with diabetic kidney disease (DKD), especially in the elderly. This is a sub-analysis of a prospective unicentric interventional study which assessed the effects of LPD in patients with advanced DKD, focusing on the feasibility and safety of LPD in elderly patients. Ninety-two patients with DKD and stable CKD stage 4+, proteinuria >3 g/g creatininuria, good nutritional status, with confirmed compliance to protein restriction, were enrolled and received LPD (0.6 g mixed proteins/kg-day) supplemented with ketoanalogues of essential amino acids for 12 months. Of the total group, 42% were elderly with a median eGFR 12.6 mL/min and a median proteinuria 5.14 g/g creatininuria. In elderly patients, proteinuria decreased by 70% compared to baseline. The rate of kidney function decline was 0.1 versus 0.5 mL/min-month before enrolment. Vascular events occurred in 15% of cases, not related to nutritional intervention, but to the severity of CKD and higher MAP. LPDs seem to be safe and effective in postponing KRT in elderly patients with advanced DKD while preserving the nutritional status.

Low Protein Diet Reduces Proteinuria and Decline in Glomerular Filtration Rate in Advanced, Heavy Proteinuric Diabetic Kidney Disease.

Low protein diet (LPD) seems beneficial in ameliorating the complications of chronic kidney disease (CKD), in reducing proteinuria and the decline in kidney function, thus postponing the need for kidney replacement therapy (KRT). However, this type of intervention was less investigated in diabetic kidney disease (DKD). This is a single-center, prospective, interventional study that aims to assess the efficacy of reducing proteinuria and the rate of decline in the estimated glomerular filtration rate (eGFR). Patients with advanced DKD (stable proteinuria > 3 g/g and eGFR < 30 mL/min) with a good nutritional status and accepting a LPD were evaluated for inclusion. Ninety-two of the 452 screened patients (66% males, median age 61 years, proteinuria 4.8 g/g creatininuria, eGFR 11.7 mL/min/1.73 m2) completed the study. Intervention consisted of LPD supplemented with ketoanalogues of essential amino acids (KA) along with conventional nephroprotective therapy. Efficacy parameters were the variation in proteinuria and in eGFR from baseline to the end of the study. Proteinuria decreased 3-fold, and the rate of decline in eGFR decreased 5-fold in the intervention phase. No patient initiated KRT or died. LPD supplemented with KA seems effective in safely postponing KRT by reducing proteinuria and the decline in kidney function in advanced DKD.

#1076 DNA hypomethylation of Syk induces oxidative stress and apoptosis via the PKCβ/ P66shc signaling pathway in diabetic kidney disease

Abstract Background and Aims Epigenetic alterations, especially DNA methylation, have been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications, including diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) is known to be involved in immune and inflammatory disorders. We, therefore, investigated the possible involvement of Syk promoter methylation in DKD, and the mechanisms underlying this process. Method Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. A diabetic mouse model (ApoE−/−DM) was generated from ApoE knockout (ApoE−/−) mice using a high fat and high glucose diet combined with low-dose streptozocin (STZ) intraperitoneal injection. We also established an in vitro model using HK2 cells. Results A marked elevation in the expression levels of Syk, PKCβ, and P66shc in renal tubules was observed in patients with DKD. In ApoE−/− DM mice, Syk expression and the binding of Sp1 to the Syk gene promoter were both increased in the kidney. In addition, the promoter region of the Syk gene exhibited hypomethylation. Syk inhibitor (R788) intervention improved renal function and alleviated pathologic changes in ApoE−/− DM mice. Moreover, R788 intervention alleviated oxidative stress and apoptosis and down-regulated the expression of PKCβ/ P66shc signaling pathway proteins. In HK2 cells, oxLDL combined with high glucose stimulation upregulated Sp1 expression in the nucleus (compared with control and oxLDL groups), and this was accompanied by an increase in the binding of Sp1 to the Syk gene promoter. SP1 silencing down-regulated the expression of Syk and inhibited the production of reactive oxygen species and cell apoptosis. Finally, PKC agonist intervention reversed the oxidative stress and apoptosis induced by Syk inhibitor (R406). Conclusion In DKD, hypomethylation at the Syk gene promoter was accompanied by an increase in Sp1 binding at the promoter. As a consequence of this enhanced Sp1 binding, Syk gene expression was upregulated. Syk inhibitors could attenuate DKD-associated oxidative stress and apoptosis via down-regulation of PKCβ/ P66shc signaling pathway proteins. Together, our results identify Syk as a promising target for intervention in DKD.

#1071 The effect and mechanism of SGLT2 inhibitor on improving inflammatory injury of glomerular endothelial cells in diabetes

Abstract Background and Aims ATP-binding cassette transporter A1 (ABCA1), which reduces intracellular cholesterol accumulation, is highly expressed in the kidney. Studies have shown that sodium-glucose co-transporter 2 inhibitors (SGLT2) inhibitors promote ABCA1 expression in multiple tissues and organs. However, the effect of SGLT2 inhibitors on ABCA1 expression in diabetic kidney disease (DKD) is unclear. In this study, the effect of empagliflozin, an SGLT2 inhibitor, on ABCA1 in glomerular endothelial cells(GECs) of DKD and the possible mechanisms linking ABCA1 to GECs inflammatory injury were investigated. Method Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. db/db mice were used as animal models of type 2 diabetes and the effects of SGLT2 inhibitors on ABCA1 were analyzed by treatment with empagliflozin. The effects of ABCA1 overexpression on glomerular lipid deposition and kidney injury were examined in a type 2 diabetic mouse model with ABCA1 overexpression (db/db + ABCA1 mice), and human renal glomerular endothelial cells (HRGECs) cultured in high glucose and high cholesterol conditions, which simulated type 2 diabetes in vitro. Results The expression of ABCA1 in the glomeruli of DKD patients and db/db mice was significantly decreased. Enhancing ABCA1 expression in the kidney tissue of diabetic mice by adenovirus transduction improved renal cholesterol deposition, inhibited the overactivation of C3a/C5a, and improved renal inflammatory injury. In addition, in cultured HRGECs under high glucose and high cholesterol conditions, ABCA1 deficiency increased the deposit of cellular cholesterol, contributed to overactivation of C3a/C5a, and induced inflammatory injury. Overexpression of ABCA1 enhancing cholesterol efflux or inhibition of C3a/C5a activation in vitro significantly protected against glomerular endothelial injury stimulated by high glucose and high cholesterol. Moreover, SGLT2 inhibitor empagliflozin up-regulated the expression of ABCA1 and down-regulated the levels of cholesterol, C3a/C5a and inflammatory cytokines in diabetic mice and HRGECs. Conclusion SGLT2 inhibitor (empagliflozin) might play a renal protective role by up-regulating ABCA1-mediated cholesterol outflow, inhibiting the activation of C3a/C5a, and then ameliorating the inflammatory injury of GECs.

#1910 Echocardiographic findings in patients with advanced diabetic kidney disease and obstructive sleep apnea

Abstract Background and Aims Obstructive sleep apnea (OSA) is associated with accelerated development of cardiovascular disease. The prevalence of OSA is increased in both type 2 diabetes (DM2) and in chronic kidney disease, and is very high in patients with diabetic kidney disease. However, the contribution of OSA to alterations in cardiac structure and function in diabetic kidney disease remains unknown. We therefore compared cardiac structure and function in diabetic kidney disease patients with or without OSA. Method In a cross-sectional study, 120 patients with DM2, a urine albumin-creatinine ratio (UACR) &amp;gt; 30 mg/g and an estimated glomerular filtration rate (eGFR) &amp;lt; 60 ml/min/1.73 m2 were tested for OSA. OSA severity was quantified by the apnea-hypopnea-index (AHI). Patients without OSA (AHI &amp;lt; 5 events/hour) were compared to patients with moderate (AHI 15-29 events/hour) or severe OSA (AHI ≥30 events/hour). Transthoracic echocardiography was conducted in all patients to evaluate cardiac structure and function. Linear regression analyses were used to assess the associations between OSA and echocardiographic parameters. Results AHI-data were available for 114 patients; 43 had no OSA, 33 had mild OSA and 38 had moderate-severe OSA. A total of 74 patients (73% men), 39 with no OSA and 35 with moderate-severe OSA, had complete data for both echocardiography and OSA. Their mean age was 71.5 ± 9.4 years, mean eGFR was 32.2 ± 12.3 mL/min/1.73 m2 and the median UACR of 533 (192–1707) mg/g. Age, smoking status, diabetes duration, eGFR, blood pressure, antihypertensive medicine, chronic obstructive pulmonary disease and atrial fibrillation were not significantly different between patients with and without OSA. Patients with moderate-severe OSA had significantly larger left atrial volume index (LAVI) (39.0 ± 19.6 vs. 28.1 ± 10.5 mL/m2, P = 0.0035), left ventricular mass index (LVMI) (49.2 ± 12.0 vs. 41.8 ± 9.7, g/m2, P = 0.0043), and right ventricular diameter (34.3 ± 5.8 vs. 28.4 ± 4.4 mm, P &amp;lt; 0.0001) compared to those without OSA (Fig. 1). Global longitudinal strain (GLS) was significantly reduced in OSA patients (−14.9 ± 3.1 vs. −16.6 ± 2.8, P = 0.0196), while no difference was observed in LV ejection fraction (54.4 ± 8.1 vs. 56.5 ± 6.2, p = 0.21). The association between OSA and LAVI, LVMI, right ventricular diameter and GLS remained significant after adjustment for age, sex, eGFR and mean arterial pressure. Conclusion Moderate-severe OSA is independently associated with alterations in cardiac structure and function in patients with diabetic kidney disease and reduced renal function. OSA could be an independent contributor to the development of heart failure in patients with diabetic kidney disease.

Systemic administration of miR-451 improves autophagy response in an accelerated mouse model of diabetic kidney disease

Diabetic kidney disease (DKD) is a common and severe microvascular complication of both type 1 and type 2 diabetes mellitus. It is the most common cause of end stage renal disease in the United States. Autophagy is a highly conserved pathway that recycles damaged organelles and macromolecules to maintain intracellular homeostasis. There is mounting evidence highlighting the role of autophagy in diabetic kidney disease. MicroRNAs (miRNA) affect the transcription of several genes involved in the development and progression of DKD, regulating key pathways and processes, including fibrotic signaling and autophagy. Thus, the dysregulation of miRs exacerbates kidney injury in the diabetic setting. Previous work from our group suggests that chronic systemic inhibition of miR-451 exacerbates fibrosis in the kidney of an obese insulin resistant mouse model (tallyHo/Jng), indicating a potential renoprotective role for miR-451 in the diabetic kidney. However, few studies have investigated this protective role of miR-451 in the diabetic kidney. This study aimed to understand the renoprotective effects of miR-451 in an accelerated mouse model of DKD. BTBR ob/ob mice rapidly develop morphological renal lesions characteristic of both early and advanced human DKD, with proteinuria typically beginning at 4-weeks of age. 12-week old male black and tan, brachyuric (BTBR) ob/ob mice and BTBR wild-type mice were treated with commercially available miR-451 mimics (2mg/kg/bw; n=3/treatment group; treatment groups: WT, BTBR ob/ob, WT+miR-451, and BTBR ob/ob+miR-451) 1X per week for 3-consective weeks. Spot urine was collected weekly until the end of study. Random blood glucose was measured by tail prick weekly. Mice were humanely euthanized, and kidneys and blood harvested at the end of the treatment period. Western blotting of whole kidney homogenate was performed following a standard protocol. Data was analyzed using students t-test or ANOVA, where appropriate, p&lt;0.05 considered significant. Albumin: creatinine ratio was four times higher (p=0.01) in BTBR ob/ob mice beginning at 5 weeks. Treatment with miR-451 mimics had no significant effect on body weight in either group. Blood glucose was significantly higher in miR-451 treated and untreated BTBR ob/ob mice at 12-weeks (425± 33.1 mg/dL; p=0.04) and 13-weeks (383± 25.3 mg/dL; p=0.007). However, blood glucose decreased significantly from week 13 (554.7± 10.8 mg/dL) to week 14(289± 13.3 mg/dL; p=0.0002) in BTBR ob/ob miR-451 treated mice. Western blot analysis of MiR-451 mimic treated BTBR ob/ob and WT mice whole kidney homogenate revealed a 91% (p=0.02) and 95% (p=0.01) reduction, respectively, in YWHAZ (a predicted miR-451 target). Conversely, western blot analysis of autophagy related proteins revealed a 68% (p=0.01) increase in ATG101 and a 44% increase in Beclin-1 in miR-451 mimic treated BTBR ob/ob mice. Collectively, the findings of this study suggest that miR-451 may offer protection in the diabetic kidney via autophagic signaling and improved blood glucose control. GHUCCTS KL2 Scholar Program (Award Number: KL2TR001432) The Charles and Mary Latham Fund Howard University Department of Medicine Start-Up Funds; Howard University Bridge Fund and Pilot Study Awards. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Epidemiology of Diabetic Kidney Disease among US Veterans.

With a large number of patients and high mortality, diabetic kidney disease (DKD) imposes a significant burden on US health care. Although diabetes is the leading cause of chronic kidney disease and complications, the epidemiology of DKD in the contemporary US veteran population is generally unknown. We aimed to estimate the rate of DKD progression and to measure the general epidemiology of DKD in the United States veteran population. We performed a retrospective observational research using electronic health-care records and administrative databases. The DKD patient cohort was abstracted from the Veterans Health Administration health-record data from January 2016 to March 2022. We defined DKD patients using the laboratory test data based on Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines. Summary statistics include the five-year cumulative incidence of progression to an advanced stage from the DKD stage at the cohort entry date and prevalence at a series of single time points. A total of 685,288 patients (male [96%], mean age 62 years, Caucasian [64%], non-Hispanic [87%]) met our eligibility criteria. The 5-year cumulative incidence of progression to an advanced DKD stage or all-cause death from DKD stages G1 A2/A3, G2 A2/A3, G3a, and G3b were 52.0%, 47.4%, 50.5%, and 60.9%, respectively. In sum, 594,082 patients were classified as moderate or high risk as per KDIGO guidelines in 2021, and stages G3a and G3b accounted for 51.2% and 25.3%, respectively, of cases. More than half of DKD patients underwent a stage progression or death within 5 years. A substantial number of DKD patients at an earlier stage might be left undetermined. The study findings warrant a revision of DKD patient identification and management in US veterans.

DNA hypomethylation of Syk induces oxidative stress and apoptosis via the PKCβ/P66shc signaling pathway in diabetic kidney disease.

Epigenetic alterations, especially DNA methylation, have been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications, including diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) is known to be involved in immune and inflammatory disorders. We, therefore, investigated the possible involvement of Syk promoter methylation in DKD, and the mechanisms underlying this process. Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. A diabetic mouse model (ApoE-/- DM) was generated from ApoE knockout (ApoE-/-) mice using a high-fat and high-glucose diet combined with low-dose streptozocin intraperitoneal injection. We also established an invitro model using HK2 cells. A marked elevation in the expression levels of Syk, PKCβ, and P66shc in renal tubules was observed in patients with DKD. In ApoE-/- DM mice, Syk expression and the binding of Sp1 to the Syk gene promoter were both increased in the kidney. In addition, the promoter region of the Syk gene exhibited hypomethylation. Syk inhibitor (R788) intervention improved renal function and alleviated pathologic changes in ApoE-/- DM mice. Moreover, R788 intervention alleviated oxidative stress and apoptosis and downregulated the expression of PKCβ/P66shc signaling pathway proteins. In HK2 cells, oxLDL combined with high-glucose stimulation upregulated Sp1 expression in the nucleus (compared with control and oxLDL groups), and this was accompanied by an increase in the binding of Sp1 to the Syk gene promoter. SP1 silencing downregulated the expression of Syk and inhibited the production of reactive oxygen species and cell apoptosis. Finally, PKC agonist intervention reversed the oxidative stress and apoptosis induced by Syk inhibitor (R406). In DKD, hypomethylation at the Syk gene promoter was accompanied by an increase in Sp1 binding at the promoter. As a consequence of this enhanced Sp1 binding, Syk gene expression was upregulated. Syk inhibitors could attenuate DKD-associated oxidative stress and apoptosis via downregulation of PKCβ/P66shc signaling pathway proteins. Together, our results identify Syk as a promising target for intervention in DKD.

Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model.

Diabetic kidney disease (DKD) is characterized by histological changes including fibrosis and inflammation. Evidence supports that DKD is mediated by the innate immune system and more specifically by the complement system. Using Ins2Akita T1D diabetic mice, we studied the connection between the complement cascade, inflammation, and fibrosis in early DKD. Data were extracted from a previously published quantitative-mass-spectrometry-based proteomics analysis of kidney glomeruli of 2 (early DKD) and 4 months (moderately advanced DKD)-old Ins2Akita mice and their controls A Spearman rho correlation analysis of complement- versus inflammation- and fibrosis-related protein expression was performed. A cross-omics validation of the correlation analyses' results was performed using public-domain transcriptomics datasets (Nephroseq). Tissue sections from 43 patients with DKD were analyzed using immunofluorescence. Among the differentially expressed proteins, the complement cascade proteins C3, C4B, and IGHM were significantly increased in both early and later stages of DKD. Inflammation-related proteins were mainly upregulated in early DKD, and fibrotic proteins were induced in moderately advanced stages of DKD. The abundance of complement proteins with fibrosis- and inflammation-related proteins was mostly positively correlated in early stages of DKD. This was confirmed in seven additional human and mouse transcriptomics DKD datasets. Moreover, C3 and IGHM mRNA levels were found to be negatively correlated with the estimated glomerular filtration rate (range for C3 rs = -0.58 to -0.842 and range for IGHM rs = -0.6 to -0.74) in these datasets. Immunohistology of human kidney biopsies revealed that C3, C1q, and IGM proteins were induced in patients with DKD and were correlated with fibrosis and inflammation. Our study shows for the first time the potential activation of the complement cascade associated with inflammation-mediated kidney fibrosis in the Ins2Akita T1D mouse model. Our findings could provide new perspectives for the treatment of early DKD as well as support the use of Ins2Akita T1D in pre-clinical studies.

Sixteen prescribed Chinese herbal medicines provide time-dependent cardiorenal and survival benefits in patients with overall and advanced diabetic kidney disease: a real-world study in Taiwan.

A causal connection between oxidative stress and inflammation in diabetes, along with its associated renal and cardiovascular complications, has been established. Sixteen prescribed potentially renoprotective Chinese herbal medicines for diabetic kidney disease (PRCHMDKD), which are scientific Chinese medicine (botanical drug) and categorized into five classes (clearing heat, nourishing yin, dampness dispelling, tonifying qi, and harmonizing formulas), exhibit shared antioxidative properties and target multiple oxidative stress pathways. However, the time-response, cumulative effects, and safety (hyperkalemia risk) of these sixteen PRCHMDKD on cardiorenal and survival outcomes in patients with overall and advanced DKD remain unresolved. This retrospective cohort study analyzed national health insurance claims data in 2000-2017. Four statistical methods, including Cox proportional hazards models, complementary restricted mean survival time (RMST), propensity score matching, and competing risk analysis for end-stage renal disease (ESRD), were employed to investigate this relationship. The study included 43,480 PRCHMDKD users and an equal number of matched nonusers within the overall DKD patient population. For advanced DKD patients, the cohort comprised 1,422 PRCHMDKD users and an equivalent number of matched nonusers. PRCHMDKD use in overall and advanced, respectively, DKD patients was associated with time-dependent reductions in adjusted hazard ratios for ESRD (0.66; 95% CI, 0.61-0.70 vs. 0.81; 0.65-0.99), all-cause mortality (0.48; 0.47-0.49 vs. 0.59; 0.50-0.70), and cardiovascular mortality (0.50; 0.48-0.53 vs. 0.61; 0.45-0.82). Significant differences in RMST were observed in overall and advanced, respectively, DKD patients, favoring PRCHMDKD use: 0.31 years (95% CI, 0.24-0.38) vs. 0.61 years (0.13-1.10) for ESRD, 2.71 years (2.60-2.82) vs. 1.50 years (1.03-1.98) for all-cause mortality, and 1.18 years (1.09-1.28) vs. 0.59 years (0.22-0.95) for cardiovascular mortality. Additionally, hyperkalemia risk did not increase. These findings remained consistent despite multiple sensitivity analyses. Notably, the cumulative effects of utilizing at least four or five classes and multiple botanical drugs from the sixteen PRCHMDKD provided enhanced renoprotection for patients with both overall and advanced DKD. This suggests that there is involvement of multiple targets within the oxidative stress pathways associated with DKD. This real-world study suggests that using these sixteen PRCHMDKD provides time-dependent cardiorenal and survival benefits while ensuring safety for DKD patients.

Bacterial infection-related glomerulonephritis in patients with diabetes.

Diabetic patients are prone to infections, thus making them a unique cohort at risk of developing bacterial infection-related glomerulonephritis (IRGN). In total, 1693 adult diabetic patients underwent kidney biopsy between 2005 and 2021 at our tertiary care hospital in South India. Of these, 121 consecutive cases which met criteria of bacterial IRGN were included in this study. The mean age of the cohort was 53.1 ± 10.1 years and 83/121 (68.5%) were males. Majority (98.3%) had type 2 diabetes for a median duration of 6 (IQR, 2-12) years. The most common sites of infection were skin (47/121, 38.8%) and urinary tract (15/121, 12.4%). Fifty percent (58/121) of patients had underlying advanced diabetic kidney disease (DKD). Isolated C3 deposits (without immunoglobulin) occurred in 66/121 (54.5%) patients predominantly in advanced DKD patients. IgA-dominant glomerulonephritis occurred in only 9/121 (7.4%) patients. Short-course oral steroid was given to 86/121 (71.1%) patients. Steroid related dysglycemia and immunosuppression related infections occurred in 9/61 (14.8%) and 16/61 (26.2%) patients respectively. Of the 90 patients with follow up details >3 months, 46 (51.1%) progressed to kidney failure over a median period of 0.5 (IQR, 0-7.2) months. Patients diagnosed in the latter half of our study period (2013-2021) were older, less commonly presented with fever, had more pronounced hypocomplementemia and severe renal histology predominantly with a 'starry sky' immunofluorescence pattern. Superimposed bacterial IRGN on underlying DKD is associated with poor renal outcomes. Use of short course steroid was associated with significant toxicity.

#6423 LONG-TERM PROGNOSIS OF HYPOPROTEIC DIET SUPPLEMENTED WITH KETOANALOGUES IN PATIENTS WITH ADVANCED DIABETIC KIDNEY DISEASE AND SEVERE PROTEINURIA

Abstract Background and Aims Studies support the role of low-protein regimens in managing chronic kidney disease (CKD). In addition, some data emphasize the role of low-protein diets (LPDs) in postponing kidney replacement therapy (KRT) in patients with CKD, even in diabetic patients with heavy proteinuria. Although most results seem to be in favor of a LPD in CKD, even in patients with advanced diabetic kidney disease (DKD), there is insufficient data on long-term kidney and patient outcomes. This is a follow-up study aimed to determine the outcomes in kidney survival and patient survival in patients with DKD and severe proteinuria. Method The follow-up study included all patients with advanced DKD and severe proteinuria who previously participated in a twelve-month uni-centric prospective study looking to assess variations in kidney function and proteinuria. At baseline, 97 patients with DKD, with stable stage 4+ CKD and proteinuria of nephrotic-range, who proved adherent to protein restriction were enrolled and received LPD (0.6 g mixed protein/kg-day) supplemented with ketoanalogues of essential amino acids (Ketosteril®, Bad Homburg, Germany, 1 tb/10 kg dry ideal body weight per day) for 12 months. Ninety-two patients completed the study (5 patients received kidney transplant). The efficacy outcomes were assessed by the decline of kidney function and proteinuria. Safety parameters were evaluated by anthropometric measurements (Body Mass Index), Subjective Global Assessment score and serum albumin. Compliance to the LPD was assessed by urinary urea from a 24-hour urine collection to estimate protein intake (ePI) and a 3-day food diary to estimate the energy intake. After the end of the study, the patients continued to remain compliant to the nutritional intervention. The primary composite endpoint was the need for KRT or patient death. The census moment was either the occurrence of the primary endpoint or the 31st of January, 2023. Results At baseline, patients had a median age of 61 years (95% CI 58 to 67), 66% were men, with poorly controlled diabetes assessed by the level of the glycated hemoglobin [8.1% (95% CI 8.0 to 8.3)]. All patients had a good nutritional status (SGA A). The median estimated glomerular filtration rate (eGF) was 12.6 mL/min (95% CI 11.7 to 13.1) and the median proteinuria was 5.2 g/g creatininuria (95% CI 5.0 to 5.2). After 12 months, a significant reduction in proteinuria was observed (67%), as well as a reduction in the kidney function decline by almost 80% compared to the period before the inclusion and a preserved good nutritional status (SGA A). The median follow-up was 105 months (95% CI 103 to 106). After almost 9 years of follow-up, 83.7% of patients remained alive, despite significant comorbidities. The median survival was 62 months (95% CI 47 to 85). Seventy-six percent of patients required KRT, with a predilection for hemodialysis. The median period of time until KRT was 26 months (95% CI 24 to 29). In a Kaplan-Meier survival analysis, the compliance to the sLPD was associated with better kidney survival (p = 0.03). Conclusion Low-protein diets supplemented with ketoanalogues of essential amino acids seem to be associated with a better kidney outcome on long-term in patients with advanced diabetic kidney disease and heavy proteinuria.

#6375 HYPOPROTEIC DIET SUPPLEMENTED WITH KETOANALOGUES VERSUS CONVENTIONAL DIET IN PATIENTS WITH ADVANCED DIABETIC KIDNEY DISEASE AND SEVERE PROTEINURIA

Abstract Background and Aims Low-protein diets seem to have an important role in the management of advanced chronic kidney disease (CKD). In addition, this type of nutritional regimen may defer kidney replacement therapy by improving metabolic abnormalities. However, low-protein diets (LPDs) may be more difficult to integrate in patients with diabetic kidney disease (DKD), because of the already complex dietary intervention in these patients. This is a comparative study that aimed to assess the effects of a ketoanalogue-supplemented low-protein diet (sLPD) versus a conventional diet on the progression of CKD and proteinuria in patients with advanced DKD. Method Ninety-seven adult patients with DKD and heavy proteinuria (&amp;gt;3g/g creatininuria) who proved to be compliant to protein restriction in a 3-month run-in phase were enrolled to receive a LPD (0.6g mixed protein/kg-day) supplemented with ketoanalogues of essential amino acids (Ketosteril®, Bad Homburg, Germany, 1 tb/10 kg dry ideal body weight per day) for 12 months. Ninety-two patients completed the study (5 patients received preemptive kidney transplant). The control group was made up of seventy-four adult patients with DKD and heavy proteinuria who received a conventional diet for 12 months. Efficacy outcomes were variation of the estimated glomerular filtration (eGF) and variation of proteinuria. Results At baseline, patients from the sLPD group had a median age of 61 years (95% CI 58 to 67), were mostly male (66%) and predominantly on insulin (68%). Patients in the control group had a median age of 60 years (95% CI 56 to 61), 62% were male and, similarly, the majority were on insulin (62%). All patients had poorly controlled diabetes, with a glycated hemoglobin of 8.1% (95% CI 8.0 to 8.3) in the sLPD group and 8.2% (95% CI 7.9 to 8.6) in the conventional-diet group respectively (P = .84). Although the median eGF was different between groups: 24.78 mL/min (95% CI 20.00 to 30.00) in sLPD patients versus 12.61 mL/min (95% CI 11.70 to 13.11) in conventional diet patients (p&amp;lt;0.0001), proteinuria was similar at baseline: 5.26 g/g creatininuria (95% CI 4.98 to 5.22) in sLPD patients and 4.05 g/g creatininuria (95% CI 3.70 to 5.80) in control group patients (P = .44). After 12 months, the decline of eFG (mL/min/month) was four-times slower in the sLPD group versus the control group [0.11 (95% CI 0.1 to 0.14) versus 0.43 (95% CI 0.30 to 0.57), p&amp;lt;0.0001]. A twofold reduction in proteinuria (g/month) was observed in sLPD patients compared to conventional diet patients [0.29 (95% CI 0.28 to 0.32) versus 0.12 (95% CI 0.09 to 0.15), p&amp;lt;0.0001]. Conclusion Low-protein diets supplemented with ketoanalogues of essential amino acids seem to be more efficient in reducing kidney function decline and proteinuria than conventional diets.

#5826 NEPHROPROTECTIVE EFFECTS OF SEMAGLUTIDE IN A MOUSE MODEL OF HYPERTENSION-ACCELERATED DIABETIC KIDNEY DISEASE

Abstract Background and Aims Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of long-acting GLP-1R agonist semaglutide alone and in combination with an ACE inhibitor in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female db/db mice. Method Seven weeks after ReninAAV administration and six weeks post-UNx, db/db UNx-ReninAAV mice were administered (q.d.) vehicle, semaglutide (30 nmol/kg, s.c.) or semaglutide (30 nmol/kg, s.c.) + lisinopril (30 mg/kg, p.o.) for 11 weeks. Endpoints included tail-cuff blood pressure evaluation at week 1 and 10, plasma/urine biochemistry, kidney histopathology as well as RNA sequencing. Results Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, urine/renal kidney injury molecule-1 (KIM-1) levels. Furthermore, semaglutide suppressed gene expression markers of extracellular matrix modelling and immune system activation. Co-administration of lisinopril further ameliorated hypertension, glomerulosclerosis as well as markers of fibrogenesis and inflammation. Conclusion Semaglutide improves disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD. Renal outcomes were further improved by combined antihypertensive standard-of-care. These data display the translatability of the db/db UNx-ReninAAV mouse model of DKD.

#3938 THE ASSOCIATION BETWEEN HEMOGLOBIN A1C LEVEL AND COMPLICATIONS IN PATIENTS WITH DIABETES AND ADVANCED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Although the global prevalence of advanced diabetic kidney disease is increasing, the optimum glycemic target remains uncertain. Specifically, data pertaining to the association of hemoglobin A1c (HbA1c) level with micro- and macrovascular outcomes in patients with advanced diabetic kidney disease remain inconclusive. We examined the association between HbA1c levels and complications in patients with diabetes and chronic kidney disease (CKD) stage 4 and 5. Method In a Danish nationwide registry-based retrospective cohort study, we included persons ≥18 years of age with diabetes, an estimated glomerular filtration rate (eGFR) &amp;lt;30 mL/min/1.73m2 and a concurrent measured HbA1c between 2010 and 2022. Complications were categorized as 1) major adverse cardiovascular events (MACE) defined as a composite endpoint of acute myocardial infarction, stroke, and all-cause mortality; 2) microvascular complications defined as a composite endpoint of diabetic retinopathy, major lower extremity amputation, and start of dialysis; 3) hospitalization with hypoglycemia. Multiple outcome-specific Cox regressions stratified by HbA1c levels were performed to calculate the 1-year risk of complications standardized to the distribution of risk factors of all patients in the sample. The analyses regarding the risk of hypoglycemia were further stratified according to insulin treatment at baseline. Results In total, 34,046 patients were included. The median age was 76.2 (IQR 69.1-82.7) years and 54.6% were men. The median eGFR and HbA1c level was 26.4 (IQR 21.9-28.5) mL/min/1.73m2 and 53 (IQR 46-63) mmol/mol, respectively. Figure 1 depicts the 1-year risks of MACE and microvascular complications stratified by HbA1c level. We found a U-shaped association between HbA1c level and MACE where patients with an HbA1c level between 45-50 mmol/mol had the lowest risk. The risk increased significantly with an HbA1c level below 45 mmol/mol or above 65 mmol/mol compared with 45-50 mmol/mol (P&amp;lt;0.001). The risk of microvascular complications was lowest at an HbA1c level between 35-40 mmol/mol. The risk increased significantly with increasing levels of HbA1c above 50 mmol/mol compared with 35-40 mmol/mol (P&amp;lt;0.05). The 1-year risks of hospitalization with hypoglycemia stratified according to HbA1c level and insulin treatment are illustrated in Figure 2. For both groups, the risk was lowest at an HbA1c level between 30-40 mmol/mol and increased with increasing HbA1c levels. Conclusion In patients with diabetes and CKD stage 4 and 5, HbA1c levels &amp;gt;65 mmol/mol and &amp;lt;45 mmol/mol were associated with an increased risk of MACE, whereas HbA1c levels &amp;gt;50 mmol/mol were associated with a higher risk of microvascular complications. Our findings suggest that appropriate glycemic control can reduce adverse outcomes in patients with advanced CKD without increasing the risk of hypoglycemia, but also suggest that intensive glycemic control (HbA1c &amp;lt;45 mmol/mol) might be associated with an increased risk of MACE.

The cardiovascular and renal effects of glucagon-like peptide 1 receptor agonists in patients with advanced diabetic kidney disease

BackgroundTo determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular and renal protective effects in patients with advanced diabetic kidney disease (DKD) with an estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m2.MethodsIn this cohort study, patients with type 2 diabetes mellitus and eGFR < 30 mL/min per 1.73 m2 with a first prescription for GLP-1RAs or dipeptidyl peptidase 4 inhibitors (DPP-4is) from 2012 to 2021 (n = 125,392) were enrolled. A Cox proportional hazard model was used to assess the cardiorenal protective effects between the GLP-1RA and DDP-4i groups.ResultsA total of 8922 participants [mean (SD) age 68.4 (11.5) years; 4516 (50.6%) males; GLP-1RAs, n = 759; DPP-4is, n = 8163] were eligible for this study. During a mean follow-up of 2.1 years, 78 (13%) and 204 (13.8%) patients developed composite cardiovascular events in the GLP-1RA and DPP-4i groups, respectively [hazard ratio (HR) 0.88, 95% confidence interval CI 0.68–1.13]. Composite kidney events were reported in 134 (38.2%) and 393 (44.2%) patients in the GLP-1RA and DPP-4i groups, respectively (subdistribution HR 0.72, 95% CI 0.56–0.93).ConclusionsGLP-1RAs had a neutral effect on the composite cardiovascular outcomes but reduced composite kidney events in the patients with advanced DKD compared with DPP-4is.

Urinary N‐acetyl‐β‐d‐glucosaminidase‐creatine ratio is a valuable predictor for advanced diabetic kidney disease

Many biomarkers show high diagnostic values for diabetic kidney disease (DKD), but fewer studies focus on the predictive assessment of DKD progression by blood and urinary biomarkers. This study aims to find powerful risk predictors and identifying biomarkers in blood and urine for DKD progression. A total of 117 patients with type 2 DKD including early and advanced stages and their laboratory parameters were statistically assessed. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the significance of discriminating between early and advanced DKD, and the predictive power for advanced DKD was analyzed by regression analysis and trisector grouping. N-acetyl-β-d-glucosaminidase-creatine (NAG/CR) level in advanced DKD was statistically higher than that in early DKD (p < 0.05), and there was a higher incidence of advanced DKD (72% vs. 56%) and high odds ratio (OR: 3.917, 95% CI: 1.579-10.011) of NAG/CR with ≥2.79 U/mmol compared with <2.79 U/mmol (p < 0.05). NAG/CR ratio also showed a higher area under the ROC curve of 0.727 (95% CI: 0.616-0.828, p=0.010) with a high sensitivity (0.75) and a moderate specificity (0.66) when 1.93 U/mmol was set as the optimal cutoff value. The adjusted-multivariable analysis revealed that NAG/CR had an OR of 1.021 (95% CI: 1.024-1.038) and 2.223 (95% CI: 1.231-4.463) based on a continuous and categorical variable, respectively, for risk of advanced DKD. Moreover, the prevalence of advanced DKD exhibited an increasing tendency by an increment of the trisector of NAG/CR. This study suggests that NAG/CR ratio is an independent predictor for advanced DKD, and it also can be used as a powerful identifying marker between early and advanced DKD.

The harmful intestinal microbial community accumulates during DKD exacerbation and microbiome-metabolome combined validation in a mouse model.

Diabetic kidney disease (DKD) is one of the most prevalent complications of diabetes mellitus (DM) and is associated with gut microbial dysbiosis. We aim to build a diagnostic model to aid clinical practice and uncover a crucial harmful microbial community that contributes to DKD pathogenesis and exacerbation. A total of 528 fecal samples from 180 DKD patients and 348 non-DKD populations (138 DM and 210 healthy volunteers) from the First Affiliated Hospital of Zhengzhou University were recruited and randomly divided into a discovery phase and a validation phase. The gut microbial composition was compared using 16S rRNA sequencing. Then, the 180 DKD patients were stratified into four groups based on clinical stages and underwent gut microbiota analysis. We established DKD mouse models and a healthy fecal microbiota transplantation (FMT) model to validate the effects of gut microbiota on DKD and select the potential harmful microbial community. Untargeted metabolome-microbiome combined analysis of mouse models helps decipher the pathogenetic mechanism from a metabolic perspective. The diversity of the gut microbiome was significantly decreased in DKD patients when compared with that of the non-DKD population and was increased in the patients with more advanced DKD stages. The DKD severity in mice was relieved after healthy gut microbiota reconstruction. The common harmful microbial community was accumulated in the subjects with more severe DKD phenotypes (i.e., DKD and DKD5 patients and DKD mice). The harmful microbial community was positively associated with the serum injurious metabolites (e.g., cholic acid and hippuric acid). The fecal microbial community was altered markedly in DKD. Combining the fecal analysis of both human and animal models selected the accumulated harmful pathogens. Partially recovering healthy gut microbiota can relieve DKD phenotypes via influencing pathogens' effect on DKD mice's metabolism.