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Background Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated. Methods Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure < 130/80 mmHg, glycated haemoglobin < 7%, LDL, HDL and total cholesterol < 100 mg/dL, > 40/50 mg/dL for men/women and < 175 mg/dL, respectively). Primary endpoint was MACEs occurrence by end of follow-up phase. Secondary endpoints included single components of primary endpoint and all-cause death. Results At the end of intervention period (median 3.84 and 3.40 years in MT and SoC group, respectively), targets achievement was significantly higher in MT. During 13.0 years (IQR 12.4–13.3) of follow-up, 262 MACEs were recorded (116 in MT vs. 146 in SoC). The adjusted Cox shared-frailty model demonstrated 53% lower risk of MACEs in MT arm (adjusted HR 0.47, 95%CI 0.30–0.74, P  =  0.001 ). Similarly, all-cause death risk was 47% lower (adjusted HR 0.53, 95%CI 0.29–0.93, P  =  0.027 ). Conclusion MT induces a remarkable benefit on the risk of MACEs and mortality in high-risk DKD patients. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925

Aims/hypothesesWe aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes.MethodsWe performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid.ResultsIn models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p < 0.001) and microvascular events (continuous NRI +14.4%, p = 0.012).Conclusions/interpretationWe report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.

Inflammation is a main mechanism for the pathogenesis and progression of diabetic kidney disease (DKD). Interleukin-6 (IL-6) is an important inflammatory mediator that is suggested to be involved in the pathogenesis of DKD. The aim of our study was to evaluate the association between IL-6 levels and progression of DKD in patients with type 2 diabetes mellitus. Materials an methods: IL-6 levels were measured at baseline and after 4 and 12 months in 70 patients included in a multi-center, randomized controlled clinical trial designed to compare the effect of RAS blockers in monotherapy to dual blockade for slowing the progression of DKD. The primary composite endpoint was > 50% increase in baseline serum creatinine, end-stage kidney disease (ESKD), or death. The median follow-up was 36 months, during which 27 patients (38.6%) reached the primary endpoint. Baseline IL-6 levels correlated with TNF-α, C-reactive protein, and PTH levels. Survival analysis showed that patients with the highest IL-6 levels (> 4.84 pg/mL) reached the primary endpoint faster than the other two groups. Multivariate Cox regression analysis showed that baseline IL-6 levels > 4.84 pg/mL (HR 4.10, 95% CI 1.36 - 12.31) were a risk factor for reaching the primary endpoint adjusted for eGFR and proteinuria. Generalized linear mixed model analysis showed no effect on subsequent IL-6 levels either with RAS blockade monotherapy or dual blockade. These results suggest that treatment with RAS blockade does not influence IL-6 levels. IL-6 is independently associated with an increased risk for progression of DKD.

Background Individuals with diabetic kidney disease (DKD) often suffer cardiac and kidney events. We sought to develop an accurate means by which to stratify risk in DKD. Methods Clinical variables and biomarkers were evaluated for their ability to predict the adjudicated primary composite endpoint of CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) by 3 years. Using machine learning techniques, a parsimonious risk algorithm was developed. Results The final model included age, body-mass index, systolic blood pressure, and concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, insulin-like growth factor binding protein-7 and growth differentiation factor-15. The model had an in-sample C-statistic of 0.80 (95% CI = 0.77–0.83; P  < 0.001). Dividing results into low, medium and high risk categories, for each increase in level the hazard ratio increased by 3.43 (95% CI = 2.72–4.32; P  < 0.001). Low risk scores had negative predictive value of 94%, while high risk scores had positive predictive value of 58%. Higher values were associated with shorter time to event (log rank P  < 0.001). Rising values at 1 year predicted higher risk for subsequent DKD events. Canagliflozin treatment reduced score results by 1 year with consistent event reduction across risk levels. Accuracy of the risk model was validated in separate cohorts from CREDENCE and the generally lower risk Canagliflozin Cardiovascular Assessment Study. Conclusions We describe a validated risk algorithm that accurately predicts cardio-kidney outcomes across a broad range of baseline risk. Trial registration CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; NCT02065791) and CANVAS (Canagliflozin Cardiovascular Assessment Study; NCT01032629/NCT01989754). Graphical abstract Persons with diabetic kidney disease (DKD) are at riskfor progressive kidney failure and cardiovascular (CV) events. Using datafrom the CREDENCE trial of patients with type 2 diabetes and DKD,machine learning techniques were applied to create a highly accuratealgorithm to predict progressive DKD and adverse CV outcomes. Thealgorithm was validated both within an internal CREDENCE cohort andexternally in the CANVAS trial.

Background Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. Methods Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ 2 -test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. Results Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097–0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). Conclusions Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. Clinical trial registration : http://clinicaltrials.gov.uniqueidentifier :NCT00153101.

Persons with diabetes are at high risk of developing diabetic kidney disease (DKD), which is associated with high morbidity and mortality. Current drug therapies for DKD, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are not entirely satisfactory. This study aimed to evaluate the additional benefit and safety of the Chinese herbal granule Tangshen Formula (TSF) in treating DKD. The study was designed as a six-center randomized, double-blind, placebo-controlled trial. From April 2007 through December 2009, 180 patients with DKD were enrolled. In addition to conventional treatment with ACEIs or ARBs, 122 participants were randomly assigned to receive TSF and 58 participants to receive placebo for 24 weeks. Primary outcome was urinary protein level, measured by urinary albumin excretion rate (UAER) for participants with microalbuminuria, 24-hour urinary protein (24h UP) for participants with macroalbuminuria. Secondary outcomes included renal function, serum lipids, quality of life, symptoms, and adverse events. After 24 weeks of treatment, no statistically significant difference in UAER (TSF -19.53 μg/min compared with placebo -7.01 μg/min, with a mean difference of -12.52 μg/min; 95%CI, -68.67 to 43.63, P = 0.696) was found between TSF and placebo groups. However, TSF displayed a statistically significant decrease in 24h UP (TSF-0.21 g compared with placebo 0.36 g, with a mean difference of -0.57g; 95%CI, -1.05 to -0.09, P = 0.024). Estimated glomerular filtration rate (eGFR) was improved in both patients with microalbuminuria and macroalbuminuria, with a mean difference of 15.51 ml/min/1.73 m2 (95%CI, 3.71 to 27.31), 9.01 ml/min/1.73 m2 (95%CI, -0.10 to 18.13), respectively. Other secondary outcomes showed no statistically significant difference between groups or in the incidence of adverse events. Based on conventional treatments, TSF appears to provide additional benefits compared with placebo in decreasing proteinuria and improving eGFR in DKD patients with macroalbuminuria. Nevertheless, further study is needed to evaluate TSF treating patients with microalbuminuria. Chinese Clinical Trial Registry ChiCTR-TRC-10000843.

To estimate whether a mix of pre- and probiotics would strengthen the gut barrier and protect the kidneys in individuals with type 1 diabetes and albuminuria. Randomized, placebo-controlled, crossover study. Forty-one participants received synbiotic (pre- and probiotics) mix or placebo for 12 weeks with 6 weeks washout. Primary endpoint was change from baseline to end-of-period in UACR. Secondary endpoints were changes in endothelial glycocalyx thickness, inflammatory and intestinal barrier dysfunction markers, glomerular filtration rate (GFR) and ambulatory systolic blood pressure. Thirty-five participants completed the study. Mean age was 58 (SD 10) years, 73 % (n = 30) were male, median UACR was 134 (IQR 63–293) mg/g, estimated GFR was 75 (30) ml/min/1.73m2. There was no significant difference in UACR with a mean relative change (CI 95 %) from baseline to end-of-treatment of −3.0 (−18.4; 15.5) % in the synbiotic group and −12.0 (−29.6; 9.6) % in the placebo group with no significant difference between treatment periods (9.37 (−25.2; 44.0) percentage points; p = 0.60). No significant beneficial difference in the secondary end points was demonstrated. Twelve weeks treatment with synbiotic mix had no effect on UACR or on any of the secondary endpoints in subjects with type 1 diabetes and albuminuria. •There is need for treatment of CKD in type 1 diabetes. Alterations in the gut microbiota is linked to CKD and diabetes.•Can synbiotics be an intervention to prevent development and progression of CKD in type 1 diabetes?•Treatment with synbiotics had no effect on UACR in subjects with type 1 diabetes and albuminuria.•Unfortunately our study could not find support of using synbiotics as additional treatment.

BackgroundWe conducted exploratory analyses to identify distinct trajectories of estimated glomerular filtration rate (eGFR) and their relationship with hyperfiltration, subsequent rapid eGFR decline, and albuminuria in participants with youth-onset type 2 diabetes enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.MethodsAnnual serum creatinine, cystatin C, urine albumin, and creatinine measurements were obtained from 377 participants followed for ≥ 10 years. Albuminuria and eGFR were calculated. Hyperfiltration peak is the greatest eGFR inflection point during follow-up. Latent class modeling was applied to identify distinct eGFR trajectories.ResultsAt baseline, participants’ mean age was 14 years, type 2 diabetes duration was 6 months, mean HbA1c was 6%, and mean eGFR was 120 ml/min/1.73 m2. Five eGFR trajectories associated with different rates of albuminuria were identified, including a “progressive increasing eGFR” group (10%), three “stable eGFR” groups with varying starting mean eGFR, and an “eGFR steady decline” group (1%). Participants who exhibited the greatest peak eGFR also had the highest levels of elevated albuminuria at year 10. This group membership was characterized by a greater proportion of female and Hispanic participants.ConclusionsDistinct eGFR trajectories that associate with albuminuria risk were identified, with the eGFR trajectory characterized by increasing eGFR over time associating with the highest level of albuminuria. These descriptive data support the current recommendations to estimate GFR annually in young persons with type 2 diabetes and provide insight into eGFR-related factors which may contribute to predictive risk strategies for kidney disease therapies in youth with type 2 diabetes.Trial registrationClinicalTrials.gov Identifier: NCT00081328, date registered 2002.

Background Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA ® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. Methods CARMELINA ® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5–10.0% (48–86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA ® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. Results Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m 2 , and eGFR 55 ± 25 mL/min/1.73 m 2 . A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m 2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. Conclusions CARMELINA ® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier—NCT01897532; registered July 9, 2013

Background Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. Methods Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. Results Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both p adjust  < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (R A ) (p = 0.116), but diminished resistance of efferent arterioles (R E ) (p = 0.001). In M+I group R A was increased (p = 0.006) and R E remained unchanged (p = 0.538). The effects on R A (p adjust  < 0.05) and on R E (p adjust  < 0.05) differed between the groups. Conclusions In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing R A and E+L predominantly decreasing R E , which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. Trial registration : The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016