Serum Proenkephalin A as a Marker of Renal Dysfunction and Glycemic Status in Diabetic Nephropathy.

Aims: Hospital readmissions due to recurrent fluid overload in diabetes and diabetic kidney disease can be avoided with evidence-based interventions. We aimed to identify at-risk patients who can benefit from these interventions by developing risk prediction models for readmissions for fluid overload in people living with diabetes and diabetic kidney disease. Methods: This was a single-center retrospective cohort study of 1,531 adults with diabetes and diabetic kidney disease hospitalized for fluid overload, congestive heart failure, pulmonary edema, and generalized edema between 2015 and 2017. The multivariable regression models for 30-day and 90-day readmission for fluid overload were compared with the LACE score for discrimination, calibration, sensitivity, specificity, and net reclassification index (NRI). Results: Readmissions for fluid overload within 30 days and 90 days occurred in 8.6% and 17.2% of patients with diabetes, and 8.2% and 18.3% of patients with diabetic kidney disease, respectively. After adjusting for demographics, comorbidities, clinical parameters, and medications, a history of alcoholism (HR 3.85, 95% CI: 1.41–10.55) and prior hospitalization for fluid overload (HR 2.50, 95% CI: 1.26–4.96) were independently associated with 30-day readmission in patients with diabetic kidney disease, as well as in individuals with diabetes. Additionally, current smoking, absence of hypertension, and high-dose intravenous furosemide were also associated with 30-day readmission in individuals with diabetes. Prior hospitalization for fluid overload (HR 2.43, 95% CI: 1.50–3.94), cardiovascular disease (HR 1.44, 95% CI: 1.03–2.02), eGFR ≤45 mL/min/1.73 m2 (HR 1.39, 95% CI: 1.003–1.93) was independently associated with 90-day readmissions in individuals with diabetic kidney disease. Additionally, thiazide prescription at discharge reduced 90-day readmission in diabetic kidney disease, while the need for high-dose intravenous furosemide predicted 90-day readmission in diabetes. The clinical and clinico-psychological models for 90-day readmission in individuals with diabetes and diabetic kidney disease had better discrimination and calibration than the LACE score. The NRI for the clinico-psychosocial models to predict 30- and 90-day readmissions in diabetes was 22.4% and 28.9%, respectively. The NRI for the clinico-psychosocial models to predict 30- and 90-day readmissions in diabetic kidney disease was 5.6% and 38.9%, respectively. Conclusion: The risk models can potentially be used to identify patients at risk of readmission for fluid overload for evidence-based interventions, such as patient education or transitional care programs to reduce preventable hospitalizations.

ASIAN PACIFIC SOCIETY OF NEPHROLOGY CLINICAL PRACTICE GUIDELINE ON DIABETIC KIDNEY DISEASE.

To evaluate whether serum Gasdermin D (GSDMD) levels are associated with diabetic kidney disease (DKD) and renal function impairment, and to assess its potential diagnostic value. This cross-sectional observational study included 111 patients with DKD, 100 patients with non-diabetic kidney diseases, and 135 healthy controls. Serum GSDMD levels were measured using a chemiluminescence assay. Associations between GSDMD and clinical parameters were analyzed using Spearman correlation and binary logistic regression. Receiver operating characteristic (ROC) curves were constructed to evaluate diagnostic performance. Serum GSDMD levels were significantly higher in patients with DKD than in healthy controls (P < 0.05). GSDMD levels were positively correlated with glucose (GLU), creatinine (CREA), blood urea nitrogen (BUN), and urinary albumin-to-creatinine ratio (UACR), and negatively correlated with estimated glomerular filtration rate (eGFR) (all P < 0.01). Multivariate logistic regression identified GSDMD as an independent factor associated with DKD. The area under the ROC curve (AUC) for GSDMD in identifying DKD was 0.847 (95% CI: 0.808-0.886), which increased to 0.933 (95% CI: 0.904-0.962) when combined with conventional indicators. Serum GSDMD levels are significantly associated with diabetic kidney disease and renal dysfunction. These findings suggest that GSDMD may serve as a complementary biomarker for DKD assessment; however, longitudinal and multicenter studies are required to confirm its prognostic value and clinical applicability.

Role of Kidney Biopsies for Biomarker Discovery in Diabetic Kidney Disease.

ObjectiveThis study aims to investigate the relationship between urinary creatinine (UCr) and the risk and severity of Diabetic Kidney Disease (DKD) in patients with Type 2 Diabetes Mellitus (T2DM). The goal is to establish UCr as a potential biomarker for early DKD detection and severity assessment.MethodsA retrospective cross-sectional analysis was conducted using medical records of T2DM patients. Patients were classified into groups with and without DKD, and relevant clinical data, including demographic, blood, and urine parameters, were collected. Logistic regression and receiver operating characteristic (ROC) curve analysis evaluated the association between UCr levels and DKD. Curve fitting and threshold effect model were used to further evaluate the relationship between UCr and the incidence and severity of DKD.ResultsA total of 302 T2DM patients were analyzed, with 137 diagnosed with DKD. Significant differences in clinical parameters were observed between the DKD and non-DKD groups, particularly in UCr, urine albumin levels, and eGFR. UCr levels demonstrated a strong association with DKD. Moreover, a non-linear relationship was identified, with specific inflection points indicating different correlation patterns of UCr with DKD occurrence and progression.ConclusionThe findings of this study highlight the potential of UCr as a valuable biomarker for early detection and assessment of DKD in T2DM patients. Incorporating UCr measurements into routine clinical practice could enhance early identification of patients at risk for kidney complications, leading to timely intervention and improved patient outcomes.

ObjectiveThis study aimed to investigate the relationship between bone metabolism markers, including serum klotho, fibroblast growth factor 23 (FGF23), 25(OH)D3, iPTH, calcium (Ca), and PHOS and the progression of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Additionally, the predictive value of these markers for DKD progression was evaluated.MethodsThis study involved 126 patients with T2DM between May 2021 and March 2023. DKD staging was assessed based on urinary protein excretion rates and estimated glomerular filtration rate (eGFR). The study evaluated serum concentrations of klotho, FGF23, 25(OH)D3, iPTH, Ca and PHOS across various stages and examined their relationships with clinical parameters. Receiver operating characteristic (ROC) curve analysis was utilized to determine the predictive accuracy of these bone metabolism markers for DKD. Multivariate linear and logistic regression analyses identified risk factors linked to DKD severity.ResultsAmong the 126 participants, 30 had non-DKD with normal proteinuria, while 96 had DKD, categorized as 31 with stage III DKD (microproteinuria), 34 with stage IV DKD, and 31 with stage V DKD (massive proteinuria). With advancing DKD from stage III to V, levels of klotho, 25(OH)D3, and Ca decreased significantly, whereas FGF23, iPTH and PHOS levels increased markedly. Klotho is significantly positively correlated with eGFR (r = 0.285, P = 0.001.) and negative correlations with serum creatinine (Scr) and UACR (r = -0.255, P = 0.004; r = -0.260, P = 0.011). FGF23 was positively related to systolic blood pressure (SBP) (r = 0.224, P = 0.012), but negatively with eGFR (r = -0.294, P = 0.001). Additionally, 25(OH)D3 exhibited significant negative correlations with several adverse clinical biomarkers, and both iPTH, Ca and PHOS were strongly associated with DKD progression (P<0.05). ROC analysis showed high predictive accuracy for DKD using these bone metabolism markers, with a combined area under the curve (AUC) of 0.846. Multivariate logistic regression analysis reinforced the significance of these markers in DKD progression.ConclusionBone metabolism markers, such as klotho, FGF23, 25(OH)D3, iPTH, Ca and PHOS are intricately linked to DKD progression and may function as valuable predictive biomarkers.

Background and Aims Diabetic kidney disease (DKD), occurs in 20–40% of patients with diabetes mellitus (DM), is the leading cause of end-stage renal disease (ESRD). DKD is a clinical diagnosis mainly based on the persistent albuminuria and reduced estimated glomerular filtration rate (eGFR) [1]. However, increased UACR and reduced eGFR are the final consequences due to DKD, novel biomarkers are critical for predicting DKD development. Osteopontin (OPN) is a profibrotic adhesion phosphoprotein that participates in cell chemotaxis, adhesion, migration, and proliferation, as well as extracellular matrix (ECM) hyperplasia. Hyperglycemia could enhance OPN gene expression through the activation of the renin-angiotensin system (RAS), mTOR pathway, NF-κB, and TGF-β pathway and then cause podocyte injury and ECM hyperplasia. Therefore, OPN upregulation is not only the result of various pathophysiological processes in DKD, but also results in kidney injury. Osteopontin (OPN) could predict incident DKD in DM patients [2], N-terminal OPN (ntOPN) has a stronger profibrotic adhesion effect than full-length OPN. This study aims to reveal the clinical benefit of ntOPN as a potential marker to identify DM patients at high risk of DKD, and establish ntOPN-based diagnostic and forecast models for renal outcomes in DM patients. Method We performed a cross-sectional study of 316 adults with Type 1 DM≥ 5 years or Type 2 DM, then followed by a prospective observational cohort study of 143 adult DM patients without renal involvement at baseline and follow-up for at least one year. During the follow-up period, the primary endpoint was “DKD occurrence”, defined as the presence of one of the following conditions in DM patients [3]: (1) repeat UACR ≥30 mg/g at least 2 of 3 measurements within 3 to 6 months; (2) eGFR &amp;lt;60 mL/min/1.73 m2 for more than three months; (3) renal pathological findings were consistent with DKD. The secondary endpoint was “DKD progression”, which included: (1) eGFR sustained decreased by at least 25%; (2) development of ESRD, and/or need for renal replacement therapy; (3) death from the renal cause. Logistic regression analysis was performed to analyze the relationship between parameters and the events of DKD occurrence and progression. Receiver operator characteristic (ROC) analysis was used to assess the predictive ability of established models for clinical endpoints. Results The median value of urinary ntOPN (UntOPN) was 44.15 ng/ml in the cross-sectional cohort, DKD prevalence was significantly higher in the high UntOPN group than in the low UntOPN group. The ROC curves of UntOPN, urinary neutrophil gelatinase-associated lipocalin (UNGAL), and their combination indicated that both combination and ntOPN alone perform better than UNGAL for DKD diagnosis (Fig. 1A). In the prospective cohort, UntOPN was an independent risk factor and further improved the predictive ability for DKD occurrence and DKD progression than UNGAL (Figs. 1B and 1C). Based on the parameters detected as risk factors for DKD occurrence and progression, we set up a series of multi-biomarker panels for DKD prediction using UntOPN, UNGAL, serum cystatin C, serum creatinine (Scr), UACR, and TCH/HDL-C ratio. Compared with the model of Scr + UACR, the area under ROC curve (AUC) of the six-biomarker model was higher, and also ranked the highest among the six ROC curves in predicting 1-year risk of DKD occurrence and DKD progression (Figs. 1B and 1C). Conclusion Our results showed that urinary ntOPN is associated with DKD development, and elevated urinary ntOPN is an independent predictor for DKD occurrence and progression. Compared with the traditional biomarkers of Scr + UACR, our multi-biomarker models based on urinary ntOPN performed better in predicting DKD development, which could provide more accurate tools for DKD risk prediction, thereby improving the renal prognosis in DM patients.

Background: Research on the diagnostic utility of hypoxia-inducible factor-1 alpha (HIF-1α) as an indicator of diabetic kidney disease (DKD) in the Indian population is lacking. We aimed to assess the relationship between the circulating HIF-1α levels and serum creatinine in individuals with DKD. Methods: This observational, analytical case–control study enrolled 80 patients (40 cases and 40 controls) with diabetes mellitus stratified according to serum creatinine (≥1.4 mg/dL and ≤1.4 mg/dL). Data on glycated hemoglobin (HbA1c) and serum creatinine levels were collected. HIF-1α levels were estimated using enzyme-linked immunosorbent assay, and for estimated glomerular filtration rate (eGFR), the chronic kidney disease epidemiology collaboration formula was utilized. Group comparisons were performed using an independent t -test and analysis of variance. Pearson correlation, receiver operating characteristic (ROC) curve analysis, multivariable logistic regression, and multiple linear regression were used to assess associations and diagnostic performance. Results: Circulating HIF-1α levels were significantly higher in cases compared to controls (4.88 ± 2.16 vs. 3.25 ± 0.83 ng/mL, P &lt; 0.001). HIF-1α showed a moderate positive correlation with serum creatinine ( r = 0.436, P &lt; 0.001) and an inverse correlation with eGFR ( r = −0.440, P &lt; 0.001). ROC analysis demonstrated moderate diagnostic accuracy (area under the curve = 0.747; 95% confidence interval: 0.635–0.859), with 60% sensitivity and 92.5% specificity at a cutoff &gt; 4.214 ng/mL. In multiple linear regression analysis, HIF-1α was independently and inversely associated with eGFR after adjustment for age, sex, and HbA1c (β = −5.36; P &lt; 0.001). Conclusions: Circulating HIF-1α levels are significantly associated with markers of renal dysfunction in diabetic patients and may serve as a potential adjunct biomarker of early renal impairment. No significant association was observed between HIF-1α and HbA1c.

This cross-sectional study aimed to evaluate the utility of three surrogate markers of insulin resistance, TyG, TG/HDL, and TyG-BMI in clinical practice by examining their association with diabetic kidney disease (DKD). Results: Of 476 patients with type 2 diabetes (T2DM), 42 (8.8%) had DKD. Patients with DKD showed significantly higher levels of BMI, fasting blood glucose, HbA1c, lipids, markers of renal dysfunction and three IR indices (TyG, TG/HDL and TyG-BMI) than those without DKD compared to those without DKD. Crosstabs/Risk analysis revealed that TyG index (OR = 1.39, 95% CI =1.218-1.587, p= 0.002), TG/HDL (OR =1.356, 1.189-1.545, p= 0.004), and TyG-BMI (OR =1.247, 1.073-1.450, p= 0.043). Based on the receiver operating characteristic curve, the areas under ROC with best cutoff values of TyG index, TG/HDL and TyG-BMI, were 0.762, 0.720 and 0.654, respectively and 9.5, 2.19 and 225, respectively. DKD patients &gt;40 years had a significantly increased TyG index (p = 0.047) of 67.0% compared to patients &lt;40 years of age of 50.0%. Conclusion: Among T2DM patients, the risk of DKD increases with the increase of TyG index, TG/HDL and TyG-BMI, with their respective cut-off values being 9.5, 2.19 and 225. The TyG performed best in predicting DKD, followed by TG/HDL and then TyG-BMI. Age was positively associated with TyG index, indicating a higher prevalence of DND in patients with T2DM.

Objective To elucidate the efficiency lncRNA GAS5 and miR-21 as biomarkers in diabetes mellitus and diabetic nephropathy. Methods The patients were divided into three groups, diabetic nephropathy group (DN group proven by renal biopsy, n=25, 14 males and 11 females), diabetes group (DM group, with normal urine albumin creatinine ratio, n=10, 4 males and 6 females), and normal control group (NC group, n=9, 4 males and 5 females). The expressions of lncRNA GAS5 and miR-21 in serum samples were detected by real-time quantitative PCR. The correlation between serum lncRNA GAS5 and miR-21 expressions and the clinical parameters was analyzed by T-test, Pearson, Spearman test and multivariate linear regression analysis. Differences of lncRNA GAS5 and miR-21 in different groups were analyzed by one-way analysis of variance. The ROC curve was used to analyze the efficacy of lncRNA GAS5 and miR-21 in diabetes and diabetic nephropathy. All data were analyzed by SPSS 20.0 and GraphPad software, with P<0.05 as considered statistically significant. Results (1) The expression of serum lncRNA GAS5 was significantly down-regulated and serum miR-21 was significantly up-regulated in both diabetes mellitus and diabetic nephropathy patients compared to the NC group all (P<0.05). (2) In DN patients, the expression of serum lncRNA GAS5 was gradually up-regulated along with the increment of 24 h urinary protein. The expression of serum miR-21 was gradually up-regulated along with renal biopsy stage IIb-Ⅲ of DN (P<0.05). (3) FBG and HbA1c were all negatively correlated with serum lncRNA GAS5 (P<0.05), and FBG was independently correlated with serum lncRNA GAS5 (P<0.05). Urine microalbumin, Total cholesterol (TC), Scr, Urea and SBP were all positively correlated with serum miR-21(P<0.05). Albumin (ALB) and estimated GFR (eGFR) were negatively correlated with serum miR-21(P<0.05), and ALB was independently correlated with serum miR-21 (P<0.05). (4) The efficiency of serum lncRNA GAS5, miR-21 and lncRNA GAS5/miR-21 as diagnostic for DM were was good (P<0.05). (5) The efficiency of serum miR-21 and lncRNA GAS5/miR-21 as diagnostic for DN were was good (P<0.05). Conclusions (1) Serum lncRNA GAS5 had good efficiency in diabetes mellitus. The sensitivity of lncRNA GAS5/miR-21 for diagnosis of diabetes was 85.71%, and specificity was 88.89%. (2) The level of serum miR-21 can be used as a noninvasive marker for diabetic nephropathy. Key words: Diabetic nephropathies; Diabetes mellitus; MicroRNA; lncRNA growth arrest specific transcript 5; miR-21; Diagnostic signature

In patients with atrial fibrillation, there is an increased risk of stroke associated with diabetes mellitus. There is little known about the association between elevated hemoglobin A1c and stroke risk in these patients. This analysis from Danish registries evaluated the effect of glycemic status measured by hemoglobin A1c on the risk of thromboembolism. Increasing levels of hemoglobin A1c were associated with a higher risk of thromboembolism, suggesting a more graded association of stroke risk and diabetes control; however, no association was found in patients with diabetes mellitus duration 10 years.

BackgroundThe prevalence of type 2 diabetes has grown significantly in China. However, little is known about the survival outcome of people with type 2 diabetes and diabetic kidney disease (DKD). The purpose of this study is to examine the survival of this population and the risk factors for mortality in one suburb cohort of Beijing, China.MethodsFour hundred and forty-five people with DKD (48.8% male, age at onset of diabetes 48.8 ± 11.0 years, age at enrollment 57.5 ± 11.6 years) were enrolled in one suburb of Beijing, China between January 1st, 2003 and December 31st, 2015. Mortality ascertainment was censored by December 31st, 2015. Survival analysis was performed by Kaplan–Meier analysis, and Cox proportional hazards regression models were served for risk factor analysis of mortality. The Chiang method was used to estimate life expectancy by age.ResultsA total of 78 deaths were identified during the 3232 person-years of follow-up. Multivariate Cox regression analysis showed significantly higher risks of mortality with respect to older age, higher systolic blood pressure (SBP), lower body mass index (BMI) and lower estimated glomerular filtration rate (eGFR). The life expectancy at age of 50 was estimated to be 12.3 (95%, CI: 9.0–16.1) years. Circulatory disease was the leading cause of death in this population (accounting for 43.6% of all deaths), followed by diabetic complications (33.3%) and respiratory disease (6.4%).ConclusionsData from one Chinese cohort from 2003 through 2015 showed that people with DKD faced higher risk of death and shorter life expectancy. Factors significantly increasing risk of death included older age, higher SBP, lower BMI and lower eGFR. There is an urgent need to early detection, closely monitoring and effective intervention on DKD.

Markers of and Risk Factors for the Development and Progression of Diabetic Kidney Disease

Apathy in Dementia: An Examination of the Psychometric Properties of the Apathy Evaluation Scale

C4d is a well-known biomarker of the complement cascade. It is derived from cleavage of the labile thioester bond of C4b. This was a retrospective and prospective cross-sectional study, done at our tertiary care hospital. Methods: We evaluated 50 cases and 10 controls to adjudge the significance of C4d deposits in native renal diseases. Majority of the patients (44%) were in the age group of 10-20 years followed by 20% in the age group of 31-40 years. 62% of study population were male. Results: Majority of patients were diagnosed with FSGS (16%), followed by membranous nephropathy (14%), Lupus nephropathy (14%) and IgA nephropathy (12%). All patients diagnosed with Membranous nephropathy, IgA nephropathy and hypertensive nephropathy showed glomerular C4d deposits. All patients diagnosed with IgA Nephropathy, post infectious glomerulonephritis, Lupus Nephritis, minimal change disease, acute/ chronic tubulointerstitial nephritis, diabetic nephropathy, hypertensive nephropathy showed tubular C4d deposits. All patients diagnosed with Diabetic nephropathy and hypertensive nephropathy showed arterial C4d deposits. There was correlation of intensity expression of glomerular C4d deposits with presenting 24 hours urinary protein level at the time of biopsy ( p value=0.027) but no correlation with urea/creatinine. There was significant association (p value 0.019) of tubular C4d positivity with 24 hour protein at the time of biopsy. Tubular C4d deposits showed no significant presenting serum urea and creatinine at the time of biopsy. Conclusion: There was also no correlation noted between presenting 24 hours urinary protein and serum urea and creatinine levels with arterial C4d deposit in diabetic and hypertensive nephropathy patients.