Predictors of One-Year Renal Function Decline in Type 2 Diabetes: Implications for Metabolic Target Management.

Serum haptoglobin levels are associated with renal function decline in type 2 diabetes mellitus patients in a Chinese Han population

Background and Aim: Some large clinical trials using SGLT2 inhibitor revealed the superiority in the renal outcome in patients with type 2 diabetes mellitus (T2DM) patients. We already reported that SGLT2 inhibitor improved urinary albumin-creatinine ratio at baseline (ACR) in Japanese T2DM patients with CKD and revealed some factors that influence to the renoprotective effects of SGLT2 inhibitor. The aim of this study is to clarify how the concomitant insulin treatment with SGLT2 inhibitor influence the renal composite outcome. Research Design and Methods: We retrospectively assessed 624 patients with Japanese T2DM patients with CKD who underwent SGLT2 inhibitor treatment for more than 1 year. We set the renal composite endpoint that was the progression of the stage of albuminuria or the decrease in eGFR by ≥15% per year. For comparative analyses, we performed the cohort model of patients with or without insulin treatment that was used propensity score (PS) matching methods. The PS matching was using the following algorithm: 1:1 nearest neighbor match with a ±0.04 caliper and no replacement. Further, all patients were stratified into quintiles based on the corresponding PS and included in the analyses. Results: The comparison of 149 PS-matched patients in each group were performed. The incidence of renal composite outcome was significantly higher in patients with insulin treatment than without it (n=23[15.4%] and n=10[6.7%], respectively, p=0.033). The results from the analysis depending on the quintiles of all patients by the Mantel-Haenszel method, there was a significant difference between the two groups (p=0.021) and the odds ratio for the renal composite outcome was 2.09 (95%CI,1.15, 3.80, p=0.016) in patients with insulin treatment. Conclusion: The concomitant insulin treatment with SGLT2 inhibitor influenced the renal composite outcome in Japanese T2DM patients with CKD. Disclosure K. Kobayashi: None. M. Toyoda: None. H. Sakai: None. K. Tamura: Research Support; Self; AstraZeneca K.K., Ono Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; AstraZeneca K.K., Ono Pharmaceutical Co., Ltd. N. Hatori: None.

Cigarette smoking predicts faster progression of type 2 established diabetic nephropathy despite ACE inhibition.

Low HDL cholesterol and the risk of rapid renal function decline in type 2 diabetes

Background/Objective: Evidence of cardiovascular and renal outcomes has already been shown for SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1Ras); therefore, combination therapy with these drugs is of clinical interest. This study aimed to evaluate the effect of the preceding drug for patients with the combination treatment of SGLT2i and GLP1Ra on renal outcomes. Methods: We retrospectively extracted data of patients with type 2 diabetes mellitus who had received both SGLT2i and GLP1Ra treatment for at least 1-year at 18 medical facilities in Japan. Finally, 341 patients in the GLP1Ra-preceding group and 319 in the SGLT2i-preceding group were analyzed. The renal composite outcome was progression of the albuminuria stage, ≥30% decrease in eGFR, or both. The multiple imputation method for missing values and an inverse probability weighting method using the propensity score were used for the comparison of outcome. Results: The median observation period and the incidence of the renal composite outcome in the SGLT2i-preceding group and the GLP1Ra-preceding group was 55.1months, 26.9% and 58.7months, 25.6%, respectively, with an odds ratio (OR) [95% confidence interval] of 1.50 [0.89, 2.53] (p=0.13). The ORs for the ≥30% decrease in eGFR and the progression of albuminuria stage were 0.96 [0.47, 2.00] (p=0.93) and 1.76 [0.97, 3.69] (p=0.06), respectively. Compared to the GLP1Ra-preceding group, the annual change in eGFR and change in the logarithmic value of urine albumin-to-creatinine ratio (LnACR) was 0.27mL/min/1.73 m2/year [-0.60, 1.14], and 0.18 [-0.10, 0.43] respectively. LnACR at baseline, pioglitazone use, and baseline mean arterial blood pressure were independent factors for renal composite outcome with ORs [95% CI] of 1.15 [1.01, 1.31], 0.47 [0.23, 0.96], and 1.03 [1.01, 1.05], respectively. Conclusion: In combination therapy with SGLT2i and GLP1Ra, the difference in the preceding drug did not affect the renal composite outcome. Disclosure K.Kobayashi: None. M.Toyoda: None.

Background and objective: Serum beta-2 microglobulin (β2M) has been used as a useful clinical marker of chronic kidney dysfunction. The current study aims to evaluate the diagnostic accuracy of β2M for the early detection of diabetic nephropathy among Iraqi patients with type II diabetes mellitus. Methods: The study included 84 participants divided into four groups, three of them were type II diabetics and the fourth is the healthy individuals’ (control) group. The diabetic’ subgroups were named according to the Micral test as: normoalbuminuria (21 patients), microalbuminuria (21 patients), and macroalbuminuria group (21 patients). The control group included 21, age- and sex-matched, healthy participants. Biochemical markers for diabetes mellitus as well as β2M were determined for each participant and then were analyzed statistically. Results: The serum β2M of normoalbuminuria group was (2.86±0.95 µg/mL), microalbuminuria group was (5.06±1.97 µg/mL) and macroalbuminuria group (3.6±1.59 µg/mL). The results showed significant increase (p˂0.05) in the β2M level of microalbuminuria group when compared with that of normoalbuminuria and macroalbuminuria groups. In addition, a highly significant increase (p˂0.01) in β2M concentration was observed in microalbuminuria group when compared with that of the control group. Conclusions: β2M can be used as a useful biomarker for the early detection of diabetic nephropathy.

One third of patients with type 1 diabetes and microalbuminuria experience an early, progressive decline in renal function that leads to advanced stages of chronic kidney disease and ESRD. We hypothesized that the urinary proteome may distinguish between stable renal function and early renal function decline among patients with type 1 diabetes and microalbuminuria. We followed patients with normal renal function and microalbuminuria for 10 to 12 yr and classified them into case patients (n = 21) with progressive early renal function decline and control subjects (n = 40) with stable renal function. Using liquid chromatography matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we identified three peptides that decreased in the urine of patients with early renal function decline [fragments of alpha1(IV) and alpha1(V) collagens and tenascin-X] and three peptides that increased (fragments of inositol pentakisphosphate 2-kinase, zona occludens 3, and FAT tumor suppressor 2). In renal biopsies from patients with early nephropathy from type 1 diabetes, we observed increased expression of inositol pentakisphosphate 2-kinase, which was present in granule-like cytoplasmic structures, and zona occludens 3. These results indicate that urinary peptide fragments reflect changes in expression of intact protein in the kidney, suggesting new potential mediators of diabetic nephropathy and candidate biomarkers for progressive renal function decline.

We investigated associations of quantitative levels of N-glycans with hemoglobin A1c (HbA1c), renal function and renal function decline in type 1 diabetes. We measured 46 total N-glycan peaks (GPs) on 1565 serum samples from the Scottish Diabetes Research Network Type 1 Bioresource Study (SDRNT1BIO) and a pool of healthy donors. Quantitation of absolute abundance of each GP used 2AB-labeled mannose-3 as a standard. We studied cross-sectional associations of GPs and derived measures with HbA1c, albumin/creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR), and prospective associations with incident albuminuria and final eGFR. All GPs were 1.4 to 3.2 times more abundant in SDRTN1BIO than in the healthy samples. Absolute levels of all GPs were slightly higher with higher HbA1c, with strongest associations for triantennary trigalactosylated disialylated, triantennary trigalactosylated trisialylated structures with core or outer arm fucose, and tetraantennary tetragalactosylated trisialylated glycans. Most GPs showed increased abundance with worsening ACR. Lower eGFR was associated with higher absolute GP levels, most significantly with biantennary digalactosylated disialylated glycans with and without bisect, triantennary trigalactosylated trisialylated glycans with and without outer arm fucose, and core fucosylated biantennary monogalactosylated monosialylated glycans. Although several GPs were inversely associated prospectively with final eGFR, cross-validated multivariable models did not improve prediction beyond clinical covariates. Elevated HbA1c is associated with an altered N-glycan profile in type 1 diabetes. Although we could not establish GPs to be prognostic of future renal function decline independently of HbA1c, further studies to evaluate their impact in the pathogenesis of diabetic kidney disease are warranted.

Faculty Opinions recommendation of A panel of novel biomarkers representing different disease pathways improves prediction of renal function decline in type 2 diabetes.

Objective: We aimed to evaluate the efficacy of canagliflozin for the treatment of specific cardiovascular and renal outcomes in Type 2 diabetes mellitus (T2DM) patients by means of a systematic review and meta-analysis. Methods: We performed comprehensive searches of PubMed, the Cochrane Library, and Embase for randomized, placebo-controlled trials of the treatment of T2DM with canagliflozin that were published to 28 September 2020. The cardiovascular outcomes recorded were cardiovascular mortality, heart failure, myocardial infarction, and stroke. The renal composite outcomes recorded were end-stage renal disease (ESRD), renal death. The data for the principal cardiovascular outcomes, ESRD, and renal death were pooled and expressed as Hazard ratios (HRs) with 95% confidence intervals (CIs). Two reviewers independently selected the trials and extracted the data. Results: We identified a total of 1,741 publications, leaving 96 for their titles, abstracts and full-text review. Of these, 10 trials met the inclusion criteria and were finally included in our meta-analysis. The meta-analysis showed that canagliflozin significantly reduced the risk of heart failure in T2DM by 36% (HR 0.64, 95% CI 0.53 to 0.77, p = 0.000). The effects of canagliflozin on non-fatal myocardial infarction or non-fatal stroke (HR 0.84, 95% CI: 0.76 to 0.93, p = 0.001), cardiovascular mortality (HR 0.84, 95% CI 0.72 to 0.97, p = 0.021), and myocardial infarction (HR 0.84, 95% CI 0.70 to 1.00, p = 0.045) in patients with T2DM were relatively small, reducing the risks by 16%. In addition, canagliflozin reduced the risk of stroke in T2DM patients by 13% (HR 0.87, 95% CI 0.71 to 1.06, p = 0.166). Moreover, canagliflozin significantly reduced the risk of the composite renal event of ESRD or renal death by 36% (HR 0.64, 95% CI 0.54 to 0.75, p = 0.000). Conclusion: This meta-analysis suggests that canagliflozin protects against cardiovascular and renal outcomes in patients with T2DM. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero], identifier [CRD42020210315]

Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in older white adults, with an incidence of 12 cases per millions of people per year. Primary MN (PMN, 75%-80% of MNs) is an organ-specific autoimmune disease caused by antibodies anti-PLA2R and anti-THSD7A. Regardless of treatment one third of patients progresses to end-stage renal disease and two third develop non-progressive chronic kidney disease. Renal biopsy is the gold standard for MN diagnosis. Several clinical and biochemical markers have been associated with the risk of progressive loss of kidney function while contrasting results have been obtained by the few studies which have examined the prognostic value of histologic findings. In this study the clinical outcome of patients with PMN has been considered based on the prognostic value of histological findings. Method Forty-nine patients with PMN of our Nephrology Unit at Padova University Hospital from 2003 to 2018 were considered. 16 patients were excluded from the study due to missing data. Age, comorbidities, proteinuria (g/day) and renal function (eGFR, CKD-EPI) were collected. eGFR decline and decrease of proteinuria were used as clinical outcomes. The follow-up was considered from renal biopsy to the last visit (in absence of GFR decline or decrease in proteinuria). Histological grading (0-3) was assigned to parameters (glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis (IF), vascular hyalinosis (VH)) and were evaluated separately or in combination (as GSTIV score). Morphometric analysis was used to quantify IF and expressed in percentage as the mean of area covered by pixel. Statistical analysis was performed using Fisher’s exact test and Mann-Whitney U-test where appropriate. Cox regression analyses (univariate and multivariate) were performed to identify variables associated with both renal outcomes and p<0.05 was considered as significant. ROC curves were used to determine interstitial fibrosis cut-off values predictive for both outcomes. Area under the curve (AUC) between 0.8 and 1.0 was considered as significant. Diagnostic accuracy was assessed by Specificity (Sp), Sensibility (Se), positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios. Results Patients with no decrease of proteinuria had a greater degree of IF vs those with a full response (p=0.006). Univariate Cox analyses identified age ≥65 years (HR 4.92), pre-existing CKD (HR 12.98) and IF (HR3.05) as significant predictors of renal function decline in all patients. Multivariate Cox analysis confirmed these variables (age ≥65 years HR 3.05, CKD HR 6.35, IF HR 3.03). In patients without CKD only IF was significantly associated with eGFR decline in both Cox univariate and multivariate analysis (HR 4.34 and 5.05 respectively). ROC analysis showed that IF threshold of 17.80% identified patients with eGFR reduction (AUC 0.65, Se 0.50, Sp 0.79, PPV 0.75, NPV 0.45, LR+ 2.38, LR-0.63) and IF threshold of 18.04% the lack of proteinuria reduction (AUC 0.78, Se 0.70, Sp 0.83, PPV 0.67, NPV 0.80, LR+ 4.12, LR- 0.36). Conclusion Our study shows that IF could be used as a histologic predictor of renal and proteinuria outcomes. Biopsy report should therefore also include quantitative IF data that could be helpful for the choice of a more appropriate therapeutic approach.

Predicting Post-Heart Transplant Composite Renal Outcome Risk in Adults: A Machine Learning Decision Tool

Background : The prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents is increasing in both poor and rich countries. Epidemiologic studies have reported significant and continuous associations between HbA1c level and diabetes-related vascular complications. Younger adults with early exposure to hyperglycemia are at high risk for end-organ damage. Few studies have reported the relationship of age to glycemic control in patients with T2DM world-wide and little comparison among young adults and elderly patients especially in the Asian population. This study investigates the relationship of age and glycemic control in Asian patients with T2DM attending primary care clinics in Singapore. Methods : We included T2DM patients who had at least 2 visits to the public-sector primary care clinic for diabetes treatment in 2009 . Demographic characteristics, medical records and laboratory results were extracted from the enterprise-wide chronic disease registry . The mean HbA1c, blood pressure and LDL-cholesterol were trended by age. Multivariate logistic regression was used to identify the factors predicting “poor” glycemic control. Results : There were 58,057 T2DM patients and both the mean HbA1c and LDL-cholesterol were lower among elderly than adult patients. Mean HbA1c was 8.08 ± 1.62% for patients ± 0.99% for patients 85+ years old. Mean LDL-cholesterol levels were 2.84 ± 0.81 and 2.55 ± 0.73 mmol/L for the respective age groups. The Malay and Indian groups had significantly poorer glycemic control compared to the Chinese, AdjOR 1.65 (95% CI: 1.54 - 1.77) and 1.50 (95% CI: 1.40 - 1.61) respectively. Other significant predictors of poor glycemic control included the male gender, presence of maculopathy or retinopathy, peripheral vascular disease, coronary heart disease, heart failure, and being on insulin therapy (AdjOR 8.00; 95% CI: 7.54 - 8.48). Patients with poor LDL-c (4.1+ mmol/L) were 4.2 times more likely to have poor glycemic control (95% CI: 3.78 - 4.66) while those with Grade 2 hypertension were 1.5 times (95% CI: 1.35 - 1.76) more likely than those without hypertension. Conclusions : Younger T2DM patients had poorer glycemic and cholesterol control than older patients in Singapore and they should have targeted interventions to achieve “optimal” glycemic and cholesterol control. doi:10.4021/jem13e

The relationship between glycaemic control and coronary artery disease (CAD) in type 2 diabetes mellitus (T2DM) is controversial. In the current cross-sectional study, we addressed the relationship between Hemoglobin A1c (HbA1c) values and the need for revascularization among diabetic patients undergoing coronary angiography. A total of 301 consecutive patients with known T2DM (age 61.8±10.1 years, 46.2 % women) requiring coronary angiography due to CAD symptoms were included. T2DM patients were categorized into two groups based on their HbA1c values: 93 (30.9%) diabetics with good glycaemic control (HbA1c≤7 %), and 208 (69.1%) diabetics with poor glycaemic control (HbA1c>7 %). A total of 123 patients (40.9%) required revascularization. The revascularization rate was 28.0% among T2DM patients with good glycaemic control and 46.6% among T2DM patients with poor glycaemic control, respectively (p=0.002). In a logistic regression analysis, the need for revascularization was predicted by poor glycaemic control (Odds Ratio [OR] 2.26, 95% Confidence Interval [CI] 1.32-3.82; p=0.003) adjusted for age, gender, Body-Mass-Index and diabetes duration. Moreover, there was a linear relationship between HbA1c values and number of affected coronary arteries (r= 0.169; p=0.003). Our data suggest that there is a close association between poor glycaemic control and increased revascularization rate in T2DM, which should be considered in primary and secondary prevention models.

Previous studies in HIV-infected individuals have demonstrated serum albumin to be strongly associated with kidney function decline, independent of urine albumin and inflammatory markers. Lower serum albumin concentrations may be an under-appreciated risk factor for kidney function decline in elders. We performed a cohort analysis in the Health Aging and Body Composition Study, a cohort of well-functioning, bi-racial, community-dwelling elders between the age of 70 and 79 years. We examined the associations of serum albumin concentration with longitudinal kidney function decline by estimated glomerular filtration rate (eGFR). Outcomes included linear eGFR decline, rapid kidney function decline defined as >30% decrease in eGFR, defined as a final eGFR <60 mL/min/1.73 m2 in those with an eGFR >60 mL/min/1.73 m2 at baseline. Cystatin C-based eGFR was calculated at baseline, Year 3 and Year 10. Mean age was 74 years, and mean eGFR was 73 mL/min/1.73 m2 at baseline. The mean rate of eGFR change was 1.81 mL/min/1.73 m2 per year. After multivariate adjustment, lower serum albumin concentrations were strongly and independently associated with kidney function decline (-0.11 mL/min/1.73 m2 per year for each standard deviation decrease serum albumin; -0.01 to - 0.20) with no attenuation after adjustment for urine albumin and inflammatory markers (-0.12, -0.03 to - 0.22). When divided into quartiles, serum albumin levels ≤3.80 g/dL were associated with increased odds of rapid kidney function decline (odds ratio 1.59; 1.12-2.26) and increased risk of incident chronic kidney disease (incident rate ratio 1.29; 1.03-1.62) relative to levels >4.21g/dL. Urine albumin to creatinine ratio (ACR) was also significantly and independently associated with kidney function decline (-0.08 mL/min/1.73 m2 per year for urine ACR >30 mg/g; -0.82 to - 0.13). Lower serum albumin levels are strongly and independently associated with kidney function decline in elders, independent of clinical risk factors, urine albumin and measured inflammatory markers.