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Aims/hypothesis Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA 1c , systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA 1c , SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. Methods We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 30–300 mg/g; n  = 636) or macroalbuminuria (UACR > 300 mg/g; n  = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. Results After controlling for clinical confounders including baseline log-transformed UACR, HbA 1c , SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (−32% vs placebo; p  < 0.001) or macroalbuminuria (−41% vs placebo; p  < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA 1c , SBP or weight. Conclusions/interpretation In patients with type 2 diabetes and either micro- or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes. Trial registration: Clinicaltrials.gov NCT01177813 (study 1); NCT01159600 (study 2); NCT01159600 (study 3); NCT01210001 (study 4); and NCT01164501 (study 5).

Aims/hypothesisGalectin-3 has been implicated in cardiac and renal fibrosis and serves as a prognostic clinical indicator in heart failure. The aim of the present study was to evaluate whether serum galectin-3 level is associated with progressive kidney disease in type 2 diabetes.MethodsGalectin-3 was measured in baseline samples by ELISA in 1320 participants with type 2 diabetes with eGFR ≥30 ml min−1 1.73 m−2. The primary outcome was defined as doubling of serum creatinine and/or initiation of renal replacement therapy during follow-up. The secondary outcome was progression to macroalbuminuria in individuals with normo- or microalbuminuria at baseline.ResultsSerum galectin-3 levels were significantly increased in a random subgroup of 270 type 2 diabetic individuals with eGFR >60 ml min−1 1.73 m−2 compared with an age- and sex-matched non-diabetic control group (7.58 ± 2.29 ng/ml vs 6.10 ± 1.91 ng/ml, respectively, p < 0.01). In the whole diabetic cohort, after a mean follow-up of 9 years, galectin-3 was independently associated with doubling of serum creatinine (HR 1.19; 95% CI 1.14, 1.24, p < 0.001) and incident macroalbuminuria (HR 1.20; 95% CI 1.12, 1.30, p < 0.001), even after adjusting for traditional risk factors, baseline eGFR and albuminuria status. Individuals with galectin-3 levels in the highest quartile had a fourfold risk of renal function loss and threefold risk of incident macroalbuminuria.Conclusions/interpretationSerum galectin-3 was independently associated with progressive renal disease in type 2 diabetes. Further mechanistic studies are warranted to determine whether galectin-3 is simply a disease biomarker or is also a mediator of the development and progression of diabetic nephropathy.

Altered plasma levels of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) may predict the development of insulin resistance and other type 2 diabetes mellitus (T2DM) associated comorbidities. To elucidate the role of plasma free amino acids (PFAAs) profile as a biomarker for early detection of diabetic kidney disease, quantitative measurement of PFAAs profile was determined for 90 T2DM subjects, 30 were free of nephropathy, 30 with microalbuminuria, 30 with macroalbuminuria, and in addition to 30 healthy controls. The plasma levels of valine, leucine, isoleucine, phenylalanine, citrulline, and total BCAAs were significantly increased in diabetic normoalbuminuria group when compared to controls. However, the total BCAAs level was significantly decreased in diabetic patients with micro and macroalbuminuria. Other amino acid plasma levels as tyrosine, arginine, ornithine, glycine, and the total AAAs level were significantly decreased in all diabetic subgroups compared to controls. Significant positive correlations between total BCAAs, valine, leucine, isoleucine, serum insulin, glucose, and HOMA-IR values in the diabetic normoalbuminuria group were found. The use of altered PFAAs profile as a prognostic factor in T2DM patients at risk for microalbuminuria or macroalbuminuria might reduce or prevent the incidence of end-stage diabetic renal disease.

INTRODUCTION: Macroalbuminuria in people with type 2 diabetes is common among Pasifika peoples and is associated with end-stage kidney disease and major cardiovascular disease.AIM: In a primary care practice catering for Pasifika people, to determine the time after first recognition of macroalbuminuria to the occurrence of major cardiovascular and renal events, and to examine the relationship with retinopathy status.METHODS: In a retrospective observational cohort study, we documented the occurrence of major cardiovascular events and amputations, end-stage kidney disease and death in 115 people with type 2 diabetes reviewed by a specialist diabetes physician at the Langimalie Tongan Health practice between 2005 and 2018. The follow up was 1–19 (median 9.5) years from the first recognition of macroalbuminuria (albumin:creatinine ratio of >30 g/mol). Survival was described by using Kaplan–Meier analysis.RESULTS: Macroalbuminuria was detected a mean of 9 years after the diagnosis of diabetes, at a mean age of 52 (standard deviation 12) years. Within 6 years of macroalbuminuria detection, 4% of people had died, 15% had reached end-stage kidney disease, 15% had cardiovascular events or amputations and 30% had the composite outcome of any of these. Within 12 years, the respective proportions were: 24%, 29%, 20% and 48%. The composite outcome was less frequent (P < 0.002) in patients without retinopathy at the time macroalbuminuria was recognised. Compared to patients with retinopathy, this group were younger (P = 0.025), more obese (P < 0.0001), had better baseline renal function (P = 0.018) and a shorter interval between the diagnosis of diabetes and recognition of macroalbuminuria (P < 0.0001).DISCUSSION: In this Pasifika population, macroalbuminuria was a marker for serious adverse cardiovascular and renal disease, and mortality, but in the 29% of patients without retinopathy at the time of recognition of macroalbuminuria, the natural history was more benign. The management of such comorbid patients is a substantial challenge for primary health-care services.

BackgroundEsaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine).MethodsWe conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin–angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline.ResultsUACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was − 8.3 mL/min/1.73 m2 at week 24.ConclusionsEsaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine.Clinical trial registrationJapicCTI-173696

Background/Aims: Whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) could benefit patients with diabetes and albuminuria remains controversial. A systematic review and meta-analysis were conducted to answer this question by comparing ACE inhibitors or ARB with placebo among these patients. Methods: In this meta-analysis, electronic data sources (Medline, the Cochrane Collaboration, and EMBASE) were searched. Randomized controlled trials (RCTs) comparing ACE inhibitors or ARB with placebo in subjects with diabetes and albuminuria (defined as urinary albumin-to-creatinine ratio, UACR≥30mg/g Cr) were included. Outcomes parameters were all-cause mortality, end stage renal disease (ESRD), doubling of serum creatinine levels, and cardiovascular events (CV). Results: Twenty-six RCTs (including 20 for ACE inhibitors and 6 for ARB) were included, comprising 10378 participants with diabetes and albuminuria. Compared to placebo, treatment with ACE inhibitors or ARBs did not reduce all-cause mortality or CV. For renal outcomes, ARBs significantly reduced the risk of ESRD by 23% (odds ratio 0.77, 95%CI 0.65-0.92), while ACE inhibitors were not associated with a decreased risk of ESRD (0.69, 0.43-1.10). Both ACE inhibitors and ARBs reduced the risk of doubling of the serum creatinine level (0.60, 0.39-0.91 for ACE inhibitors; 0.75, 0.64-0.88 for ARBs), and subgroup analyses for patients with macroalbuminuria or microalbuminuria showed similar results. Conclusion: In patients with diabetes and albuminuria, ARBs reduced risks of ESRD and doubling of the serum creatinine level. ACE inhibitors and ARBs failed to reduce all-cause mortality and CV. Based on the renoprotective effects, ARBs may be preferred for diabetic patients with albuminuria.

Abstract Background Shenzhuo Formula (SZF), a modified Didang Tang, is used for diabetic kidney disease (DKD), though high-quality evidence is limited. Methods In a randomized, double-blind, double-dummy, active-controlled, multicenter trial, irbesartan (IRB) was the control. A Bayesian model assessed efficacy. Mechanistic studies included Olink inflammation proteomics, single-cell RNA sequencing (scRNA-seq) of KK-Ay mouse kidneys, and in vivo experiments. Results A total of 120 DKD patients with macroalbuminuria were randomized (SZF n = 57, IRB n = 63). At 24 weeks, 24 h urinary total protein change was −0.03 (−0.24 to 0.18) g/24 h in the SZF group and 0.08 (−0.30 to 0.14) g/24 h in the IRB group (P = 0.61). Estimated glomerular filtration rate improved with SZF by 5.91 (1.80 to 10.01) mL/min/1.73m² but declined with IRB by −1.67 (−5.18 to 1.84) mL/min/1.73m² (P < 0.01). Serum creatinine decreased with SZF by −5.15 (−9.73 to −0.56) μmol/L but increased with IRB by 3.39 (−0.84 to 7.61) μmol/L (P < 0.01). Traditional Chinese medicine syndrome response was higher with SZF (89.47% vs. 63.49%, P < 0.01). Safety and metabolic parameters were comparable. Bayesian analysis favored SZF for renal benefit. Mechanistically, SZF downregulated CX3CL1 in endothelial cells and MCP-1 in mesangial and tubular cells, suggesting anti-inflammatory effects restoring endothelial function and attenuating fibrosis. Conclusions SZF matched IRB in proteinuria reduction but was superior in preserving renal function and improving traditional Chinese medicine symptoms in DKD, with good safety. Benefits may involve suppression of CX3CL1/MCP-1-mediated inflammation.

Biochemical markers play a crucial role in the early diagnosis of diabetic nephropathy (DN), a common complication of type 2 diabetes mellitus (T2DM). This study aims to assess the plasma atherogenic index (AIP) in patients with T2DM who have DN, and evaluate the relationship between this parameter and other metabolic parameters, to determine its effectiveness in predicting the development and severity of DN. This retrospective study included 1,902 adult patients diagnosed with T2DM and 455 healthy controls. The T2DM group was further classified based on the albumin/creatinine ratio (UACR) into 770 patients without microalbuminuria, 701 patients with microalbuminuria, and 431 patients with macroalbuminuria. In the T2DM group, levels of creatinine, uric acid, HbA1c, cholesterol, triglycerides, UACR, and AIP increased in the microalbuminuria group compared to the normoalbuminuria group, with the highest levels observed in the macroalbuminuria group (р =0.000 for each). AIP showed a significant positive correlation with HbA1c and triglycerides. Binary logistic regression analysis indicated that AIP and triglyceride levels had a significant impact on the likelihood of having T2DM with microalbuminuria. According to our findings, AIP is associated with the presence and severity of DN in patients with T2DM and serves as an independent risk factor for DN. Therefore, we believe that AIP is a reliable biomarker that can be used additionally to assess risk, determine severity, monitor progression, and guide DN treatment in patients with T2DM.

Purpose: This study aimed to examine the corneal endothelial morphology and thickness in patients with Type 2 diabetes mellitus (T2DM) and compare them with age and sex-matched nondiabetic controls. Methods: This hospital-based cross-sectional observational study was conducted in the ophthalmology department of a tertiary hospital consisting of 262 patients (131 with T2DM as cases and 131 without diabetes who served as controls). All patients underwent a comprehensive ocular examination including visual acuity, slit-lamp biomicroscopy, intraocular pressure measurement. Central corneal thickness (CCT), endothelial cell density (ECD), coefficient of variance (CV), and percentage of hexagonal cells (HEX) were compared between the cases and controls. Predictors of corneal endothelial dysfunctions were analyzed. Data analysis was done by Statistical Package for the Social Sciences (SPSS) version 17.0. Chi-square test, Fisher's exact test, and Spearman's rho correlation analysis were used as appropriate. Results: Patients with T2DM showed poorer visual acuity and higher intraocular pressure. As compared to controls, patients with T2DM had thicker CCT, lesser ECD, decreased HEX, and higher CV but the differences were statistically nonsignificant. HbA1c levels showed a significant positive correlation with CCT and CV and a negative correlation with ECD. Macroalbuminuria and higher albumin creatinine ratio was associated with an increase in CV in patients with T2DM. Conclusion: Our study showed that poorly controlled patients with T2DM and those with macroalbuminuria have corneal endothelial abnormalities.

Aims/hypothesis This meta-analysis aimed to compare the renal outcomes between ACE inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and other antihypertensive drugs or placebo in type 2 diabetes. Methods Publications were identified from Medline and Embase up to July 2011. Only randomised controlled trials comparing ACEI/ARB monotherapy with other active drugs or placebo were eligible. The outcome of end-stage renal disease, doubling of serum creatinine, microvascular complications, microalbuminuria, macroalbuminuria and albuminuria regression were extracted. Risk ratios were pooled using a random-effects model if heterogeneity was present; a fixed-effects model was used in the absence of heterogeneity. Results Of 673 studies identified, 28 were eligible ( n  = 13–4,912). In direct meta-analysis, ACEI/ARB had significantly lower risk of serum creatinine doubling (pooled RR = 0.66 [95% CI 0.52, 0.83]), macroalbuminuria (pooled RR = 0.70 [95% CI 0.50, 1.00]) and albuminuria regression (pooled RR 1.16 [95% CI 1.00, 1.39]) than other antihypertensive drugs, mainly calcium channel blockers (CCBs). Although the risks of end-stage renal disease and microalbuminuria were lower in the ACEI/ARB group (pooled RR 0.82 [95% CI 0.64, 1.05] and 0.84 [95% CI 0.61, 1.15], respectively), the differences were not statistically significant. The ACEI/ARB benefit over placebo was significant for all outcomes except microalbuminuria. A network meta-analysis detected significant treatment effects across all outcomes for both active drugs and placebo comparisons. Conclusions/interpretation Our review suggests a consistent reno-protective effect of ACEI/ARB over other antihypertensive drugs, mainly CCBs, and placebo in type 2 diabetes. The lack of any differences in BP decrease between ACEI/ARB and active comparators suggest this benefit is not due simply to the antihypertensive effect.