Diabetic Kidney Disease Phenotypes Research Articles

Assessment of cardiovascular risk in patients with type 2 diabetes and albuminuric diabetic kidney disease phenotype

Introduction. The aim of this study is analysis of cardiovascular risk in non-albuminuric and albuminuric patients with type 2 diabetes and diabetic kidney disease. Material and Methods. The study included 136 patients with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate <90 ml/ min/1.73 m2). Patients were divided into two groups: Group A (patients without albuminuria) and Group B (patients with albuminuria). The cardiovascular risk was assessed through a retrospective analysis of data from electronic medical records. Results. We found statistically significantly more patients with stage 3a (Group A: 10% vs. Group B: 54%) and stage 3b (Group A: 7% vs. Group B: 13%; p<0.05) chronic kidney disease in the albuminuric group. These patients also had a longer duration of diabetes (Group A: 13.43?9.56 vs. Group B: 17.14?9.17 years; p<0.05), a higher frequency of male subjects (Group A: 44% vs. Group B: 63.9%; p<0.05) and a higher prevalence of smokers. The presence of hypertension was significantly more frequent in Group B (Group A: 89% vs. Group B: 97.2%; p<0.05). There was no significant difference between the groups in terms of age and metabolic control. However, coronary heart disease (Group A: 36% vs. Group B: 55.6%; p<0.05), peripheral artery disease (Group A: 16% vs. Group B: 22.2%; p<0.05), and stroke (Group A: 5% vs. Group B: 22.2%; p<0.05) were significantly more common in patients with type 2 diabetes and albuminuria. Conclusion. The albuminuric phenotype of diabetic kidney disease is associated with greater kidney function impairment, a longer duration of diabetes, and a higher prevalence in men. The presence of albuminuria significantly increases cardiovascular risk in people with type 2 diabetes and chronic kidney disease. Using renoprotective antihyperglycemic agents is essential in this group of patients, as they have an increased mortality risk.

Diabetic Kidney Disease Phenotypes and Cardiovascular Outcomes

Diabetic Kidney Disease Phenotypes and Cardiovascular Outcomes

FG-4592 relieves diabetic kidney disease severity by influencing metabolic profiles via gut microbiota reconstruction in both human and mouse models.

Objective: Diabetic kidney disease (DKD) is one of the most prevalent complications of diabetes mellitus (DM) and is highly associated with devastating outcomes. Hypoxia-inducible factor (HIF), the main transcription factor that regulates cellular responses to hypoxia, plays an important role in regulating erythropoietin (EPO) synthesis. FG-4592 is the HIF stabilizer that is widely used in patients with renal anemia. We investigated the effect of FG-4592 on DKD phenotypes and the pharmacologic mechanism from the perspective of gut microbiota and systemic metabolism. Design: We collected the clinical data of 73 participants, including 40 DKD patients with combined renal anemia treated with FG-4592, and 33 clinical index-matched DKD patients without FG-4592 treatment from The First Affiliated Hospital of Zhengzhou University at the beginning and after a 3-6-month follow-up period. We established DKD mouse models treated by FG-4592 and performed fecal microbiota transplantation from FG-4592-treated DKD mice to investigate the effects of FG-4592 on DKD and to understand this mechanism from a microbial perspective. Untargeted metabolome-microbiome combined analysis was implemented to globally delineate the mechanism of FG-4592 from both microbial and metabolomic aspects. Result: DKD phenotypes significantly improved after 3-6 months of FG-4592 treatment in DKD patients combined with renal anemia, including a decreased level of systolic blood pressure, serum creatinine, and increased estimated glomerular infiltration rate. Such effects were also achieved in the DKD mouse model treated with FG-4592 and can be also induced by FG-4592-influenced gut microbiota. Untargeted plasma metabolomics-gut microbiota analysis showed that FG-4592 dramatically altered both the microbial and metabolic profiles of DKD mice and relieved DKD phenotypes via upregulating beneficial gut microbiota-associated metabolites. Conclusion: FG-4592 can globally relieve the symptoms of DKD patients combined with renal anemia. In the animal experiment, FG-4592 can reconstruct the intestinal microbial profiles of DKD to further upregulate the production of gut-associated beneficial metabolites, subsequently improving DKD phenotypes.

424-P: Diabetic Kidney Disease (DKD) Worsens CV Outcomes after First-Ever Major Cardiovascular Event in Type 2 Diabetes (T2D)

Aim: CV prognosis worsens in T2D after a first CV event. We assessed impact of DKD on mortality and subsequent CV events after a first CV event. Methods: Death rate was recorded over a median 14.1 (IQR 13.8-14.5) years follow-up in 961 T2D subjects. Vital status (Italian Health Card Database) was censored on December 31, 2017 (major CV events available for 947 participants). Effect of DKD (ACR <30/≥30 mg/g) and/or CKD-EPI eGFR ≥60/<60 ml/min/1.73 m2) was determined by Kaplan-Meier (K-M) curves and hazard ratios (HR, 95% CI) by unadjusted and adjusted Cox regression models (age, diabetes duration (DD), sex, smoking, retinopathy, hypertension, dyslipidemia, prior CVD; no-DKD as reference). Results: At census, 229 subjects were dead (23.8%) and 298 participants out of 947 (31.5%) had a first CV event during a median 13.8 year pre-event follow-up. Compared with free-CV event subjects, those with CVD were older, more often men, with longer diabetes duration, worse CV risk profile, more microvascular complications and CVD before recruitment. During a median 6 yr post-first CV event follow-up 99 subjects died: 57 (27.4%) no DKD, 42 (46.7%) DKD (K-M, p=0.005). Compared to no DKD the latter had an unadjusted HR of 1.76 (1.18-2.63, p=0.005; adjusted 1.69, 1.13-2.52, p=0.011). Death rate increased with DKD worsening with statistically significant HR (unadjusted 3.31, 1.73-6.31, p<0.0001; adjusted 3.32, 1.65-6.64, p=0.001) for ACR≥30/eGFR<60. During a median 3.1 post-first CV event follow-up, a new CV event occurred in 124 subjects: 82 (39.4%) no DKD and 42 (46.7%) DKD (K-M, p=0.019) with unadjusted HR for a new CV event in DKD of 1.40 (0.96-2.03, p=0.077). Rate of a secondary CV event increased across DKD phenotypes with unadjusted (HR 3.42, 95% CI 1.76-6.65, p<0.0001) and adjusted HR of 3.18 (1.57-6.44; p=0.001) for ACR≥30/eGFR<60, respectively. Conclusions: In T2D subjects, DKD still worsens the risk of mortality and secondary CV events after the occurrence of a first CV event. Disclosure M.Garofolo: Consultant; Novo Nordisk, Employee; Eli Lilly and Company. D.Lucchesi: None. M.Giambalvo: None. M.Capobianco: None. P.Francesconi: None. G.Penno: Advisory Panel; Eli Lilly and Company, Bayer Inc., Consultant; Novo Nordisk, AstraZeneca, Boehringer Ingelheim Inc. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi.

Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk.

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m2, absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.

Impact of Baseline Clinical Variables on SGLT2i's Antiproteinuric Effect in Diabetic Kidney Disease.

Proteinuria is a major risk factor for the progression of chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated a nephroprotective and antiproteinuric effect in people with type 2 diabetes (T2DM) and proteinuric CKD. We conducted a retrospective study to evaluate clinical and laboratory variables that can help predict proteinuria reduction with SGLT2i therapy. Patients affected by T2DM and CKD who started any SGLT2i were included in the study. Patients were stratified into two subgroups, Responder (R) and non-Responder (nR), based upon the response to the therapy with SGLT2i, namely the reduction in a 24 h urine proteins test (uProt) of ≥30% from baseline levels. The aim of the study is to analyse differences in baseline characteristics between the two groups and to investigate the relationship between them and the proteinuria reduction. A Kruskal-Wallis test, unpaired t-test and Chi2 test were used to test the difference in means and the percentage (%) between the two groups. Linear and logistic regressions were utilized to analyse the relationship between proteinuria reduction and basal characteristics. A total of 58 patients were enrolled in the study: 32 patients (55.1%) were in the R group and 26 patients (44.9%) in the nR group. R's patients had a significant higher uProt at baseline (1393 vs. 449 mg/24 h, p = 0.010). There was a significant correlation between baseline uProt and proteinuria reduction with SGLT2i in both univariate (β = -0.43, CI -0.55 to -031; p < 0.001) and multivariate analyses (β = -0.46, CI -0.57 to -0.35, p < 0.001). In the multivariate analysis, there was a significant positive correlation between the estimated glomerular filtration rate (eGFR) and proteinuria reduction (β = -17, CI -31 to -3.3, p = 0.016) and a significant negative correlation with body mass index (BMI) (β = 81, CI 13 to 50, p = 0.021). The multivariate logistic regressions show a positive correlation of being in the R group with diabetic retinopathy at baseline (Odds Ratio (OR) 3.65, CI 0.97 to 13.58, p = 0.054), while the presence of cardiovascular disease (CVD) at baseline is associated with being in the nR group (OR 0.34, CI 0.09 to 1.22, p = 0.1), even if these statements did not reach statistical significance. In this real-life experience, following the administration of SGLT2i, a reduction of more than 30% in proteinuria was observed in more than half of the patients, and these patients had a significantly higher baseline proteinuria value. Variables such as eGFR and BMI are variables that, considered in conjunction with proteinuria, can help predict treatment response before therapy initiation. Different phenotypes of diabetic kidney disease may have an impact on the antiproteinuric response.

Sex differences in risk factors for end-stage kidney disease and death in type 2 diabetes: A retrospective cohort study.

This study investigated the sex differences in the risk of end-stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. During a median follow-up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02-1.75; p=.034) and death (HR 1.64; 95% CI 1.24-2.16; p=.001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo- and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.

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.

Nonalbuminuric Diabetic Kidney Disease and Risk of All-Cause Mortality and Cardiovascular and Kidney Outcomes in Type 2 Diabetes: Findings From the Hong Kong Diabetes Biobank

Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing DKD phenotype. We compared the risks of adverse outcomes among patients with this phenotype compared with other DKD phenotypes. Multicenter prospective cohort study. 19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank. DKD phenotypes defined by baseline estimated glomerular filtration rate (eGFR) and albuminuria: no DKD (no decreased eGFR or albuminuria), albuminuria without decreased eGFR, decreased eGFR without albuminuria, and albuminuria with decreased eGFR. All-cause mortality, cardiovascular disease (CVD) events, hospitalization for heart failure (HF), and chronic kidney disease (CKD) progression (incident kidney failure or sustained eGFR reduction≥40%). Multivariable Cox proportional or cause-specific hazards models to estimate the relative risks of death, CVD, hospitalization for HF, and CKD progression. Multiple imputation was used for missing covariates. Mean participant age was 61.1 years, 58.3% were male, and mean diabetes duration was 11.1 years. During 54,260 person-years of follow-up, 438 deaths, 1,076 CVD events, 298 hospitalizations for HF, and 1,161 episodes of CKD progression occurred. Compared with the no-DKD subgroup, the subgroup with decreased eGFR without albuminuria had higher risks of all-cause mortality (hazard ratio [HR], 1.59 [95% CI, 1.04-2.44]), hospitalization for HF (HR, 3.08 [95% CI, 1.82-5.21]), and CKD progression (HR, 2.37 [95% CI, 1.63-3.43]), but the risk of CVD was not significantly greater (HR, 1.14 [95% CI, 0.88-1.48]). The risks of death, CVD, hospitalization for HF, and CKD progression were higher in the setting of albuminuria with or without decreased eGFR. A sensitivity analysis that excluded participants with baseline eGFR<30 mL/min/1.73 m2 yielded similar findings. Potential misclassification because of drug use. Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR.

Features of chronic complications in latent autoimmune diabetes in adults

Purpose of the work. To find out the features of the course of chronic kidney disease in patients with latent autoimmune diabetes in adults (LADA) compared with the classic types of diabetes. Materials and methods. 145 patients with diabetes mellitus (DM) were examined (70 patients with LADA, 40 with type 1 DM — T1DM, 35 with type 2 DM — T2DM. Antibodies to glutamic acid decarboxylase and to tyrosine phosphatase were determined in all patients. Features of chronic kidney disease (CKD) were studied on the basis of anamnesis, clinical examination, glomerular filtration rate, microalbuminuria and the of albumin-creatinine ratio in urine. Results and discussion. According to the anamnesis, the diagnosis of CKD in patients with LADA was established on average up to 3 years from the manifestation of diabetes (in 30 % — already in the onset of the disease), while in T1DM — after 7.2 years, in T2DM — after 1.9 years. The most common stage of CKD in LADA patients was III (in 49 % of people). At the same time, the majority of patients had a nonalbuminuric phenotype of diabetic kidney disease (NARI). In terms of the characteristics of the course of CKD, LADA occupied an intermediate position, combining the signs of both main types of diabetes. Conclusions. The diagnosis of CKD in patients with LADA was established much earlier than in T1DM which indicates the incorrect use of the same recommendations for screening this complication in these patients. There was a predominance of NARI in patients with LADA. CKD in LADA requires the development of special approaches to screening, diagnosis and treatment.

Dyslipidemia in diabetic kidney disease classified by proteinuria and renal dysfunction: A cross-sectional study from a regional diabetes cohort.

ABSTRACTAims/IntroductionDiabetic kidney disease (DKD) exacerbates dyslipidemia and increases the incidence of atherosclerotic cardiovascular disease. DKD is a concept that includes typical diabetic nephropathy and an atypical phenotype without proteinuria. We investigated dyslipidemia in different DKD phenotypes that have not been fully studied.Materials and MethodsFasting plasma was obtained from 1,073 diabetes patients enrolled in the regional diabetes cohort (ViNA cohort). Non‐proteinuric and proteinuric DKD were defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 in the absence or presence of urinary albumin‐to‐creatinine ratio >300 mg/g. Novel lipid risk factors, low‐density lipoprotein (LDL) triglyceride (TG) and small dense LDL cholesterol were measured using our established homologous assay.ResultsThe proportion of atherosclerotic cardiovascular disease patients was higher in non‐proteinuric DKD and even higher in proteinuric DKD than in non‐DKD. Increased estimated glomerular filtration rate grade and albuminuric stage were independently correlated with higher TG, TG‐rich lipoprotein cholesterol and apolipoprotein CIII. Therefore, proteinuric DKD had the highest of these levels. Small dense LDL cholesterol and LDL‐TG were higher in the proteinuria without renal dysfunction group in the lipid‐lowering drug‐free subset. Lipoprotein(a) was higher in DKD regardless of proteinuria.ConclusionsProteinuria was associated with an atherogenic subspecies of LDL, whereas renal dysfunction was associated with increased lipoprotein(a). Proteinuria and renal dysfunction independently exacerbated TG‐rich lipoprotein‐related dyslipidemia. This is in good agreement with the results of large‐scale clinical studies in which proteinuria and renal dysfunction synergistically increased the risk of atherosclerotic cardiovascular disease in populations with diabetes.

Фенотипы диабетической болезни почек (обзор литературы и собственные данные)

В статье приведены современные сведения о диабетической болезни почек (ДБП) с учетом ее фенотипов. Представлены данные литературы об эпидемиологии, факторах и механизмах развития фенотипов этого осложнения при сахарном диабете (СД), а также возможностях его диагностики и лечения. Описаны варианты течения ДБП в зависимости от типа СД, основанные на собственных исследованиях. Представлены данные анализа 1576 пациентов с СД 1-го, 2-го типов и латентным аутоиммунным диабетом взрослых (LADA), описано распределение больных по стадиям ХБП и фенотипам ДБП. По данным лабораторных и инструментальных исследований установлено, что неальбуминурическое нарушение функции почек является доминирующим фенотипом среди пациентов с СД (60 % — с СД 1-го типа, 43 % — с СД 2-го типа, 53 % — с LADA). Выявленные различия в зависимости от типа СД, вероятно связаны с особенностями механизмов поражения почек при разных типах СД. Поскольку СД 2-го типа обычно диагностируется спустя длительное время после манифестации, все патогенетические звенья возникновения ДБП, включая феномен глюкозотоксичности, эндотелиальной дисфункции, оксидативного стресса и т.д., приводят к более масштабным изменениям, чем у пациентов с СД 1-го типа, который диагностируется сразу же после начала заболевания. Также частота альбуминурической формы ДБН при СД 2-го типа может быть связана с отягчающим влиянием артериальной гипертензии, дислипидемии и инсулинорезистентности, которые способствуют прогрессированию ДБП. Снижение распространенности альбуминурического фенотипа связано как с совершенствованием нефропротекторного действия сахароснижающих препаратов, что не только позволяет остановить развитие протеинурии, но и способствует регрессированию уже имеющихся поражений почек, так и с ростом количества пациентов со снижением скорости клубочковой фильтрации без протеинурии, что, по мнению авторов, может быть следствием более ранней диагностики основного заболевания и его осложнений.

Trajectories of kidney function in diabetes: a clinicopathological update.

Diabetic nephropathy has been traditionally diagnosed based on persistently high albuminuria and a subsequent decline in glomerular filtration rate (GFR), which is widely recognized as the classical phenotype of diabetic kidney disease (DKD). Several studies have emphasized that trajectories of kidney function in patients with diabetes (specifically, changes in GFR and albuminuria over time) can differ from this classical DKD phenotype. Three alternative DKD phenotypes have been reported to date and are characterized by albuminuria regression, a rapid decline in GFR, or non-proteinuric or non-albuminuric DKD. Although kidney biopsies are not typically required for the diagnosis of DKD, a few studies of biopsy samples from patients with DKD have demonstrated that changes in kidney function associate with specific histopathological findings in diabetes. In addition, various clinical and biochemical parameters are related to trajectories of GFR and albuminuria. Collectively, pathological and clinical characteristics can be used to predict trajectories of GFR and albuminuria in diabetes. Furthermore, cohort studies have suggested that the risks of kidney and cardiovascular outcomes might vary among different phenotypes of DKD. A broader understanding of the clinical course of DKD is therefore crucial to improve risk stratification and enable early interventions that prevent adverse outcomes.

Insulin resistance, diabetic kidney disease, and all-cause mortality in individuals with type 2 diabetes: a prospective cohort study

BackgroundIt is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study.MethodsThis observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006–2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35 mg/kg/min) to T3 (≤ 4.14 mg/kg/min, highest IR).ResultsCVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate [eGFR]) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p < 0.0001, and hazard ratio [HR] adjusted for multiple confounders including DKD, 1.140 [95% confidence interval [CI], 1.049–1.238], p = 0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 [95% CI, 1.072–1.375], p = 0.002) and in those with nonalbuminuric DKD (1.276 [1.034–1.575], p = 0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age.ConclusionsThe proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria.Trial registrationClinicalTrials.gov, NCT00715481, retrospectively registered 15 July 2008.

Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.

Consistent effects of empagliflozin on cardiovascular and kidney outcomes irrespective of diabetic kidney disease categories: Insights from the EMPA-REG OUTCOME trial.

To explore the cardiovascular (CV) and kidney effects of empagliflozin in patients with different clinical phenotypes of diabetic kidney disease (DKD) (i.e. with the presence or absence of overt albuminuria) participating in the EMPA-REG OUTCOME trial. EMPA-REG OUTCOME randomized participants (1:1:1) to empagliflozin 10 mg, 25 mg or placebo, added to standard of care. Post hoc, patients with different clinical phenotypes of DKD at baseline were categorized in three subgroups: (a) overt DKD (overt albuminuria [urinary albumin-to-creatinine ratio of >300 mg/g] with any estimated glomerular filtration rate [eGFR]; n = 769); (b) non-overt DKD (kidney impairment [eGFR < 60 mL/min/1.73 m2 ] without overt albuminuria [urinary albumin-to-creatinine ratio of ≤300 mg/g]; n = 1290); and (c) 'all others' (eGFR ≥ 60 mL/min/1.73 m2 without overt albuminuria; n = 4893). Analyses included CV (death, hospitalization for heart failure, all-cause hospitalization) and selected kidney outcomes, change in eGFR and kidney safety. Cox proportional hazards models assessed the consistency of treatment effect across subgroups. Empagliflozin significantly reduced the risk of CV and kidney outcomes across all subgroups (P-values for interaction >.05), consistent with the overall trial population findings. Empagliflozin also significantly reduced the yearly loss of eGFR, assessed by chronic slopes, in all subgroups. The adverse event profile of empagliflozin was similar across all subgroups. Empagliflozin may improve CV and kidney outcomes and slow the progression of kidney disease in type 2 diabetes patients with DKD, irrespective of its clinical form, both with or without the presence of overt albuminuria.

Features of phenotypes of diabetic kidney disease depending on the type of underlying disease

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Associations Between Day-by-Day Home Blood Pressure Variability and Renal Function and Albuminuria in Patients With and Without Diabetes.

The phenotype of diabetic kidney disease represents a lower estimated glomerular filtration rate (eGFR) and albuminuria. We investigated the association between day-by-day home blood pressure (BP) variability and the eGFR in subjects with diabetes and compared this association with that in subjects without diabetes. We then attempted to determine whether the association is present in albuminuria. We analyzed 4,231 patients with risk factors of cardiovascular disease (24.4% with diabetes) from the J-HOP (Japan Morning Surge-Home Blood Pressure) study. Home BP was measured in the morning and evening for 14 days. We calculated the SD, coefficient of variation, average real variability (ARV), and variation independent of the mean of the subjects' morning and evening home systolic BP (SBP) as the indexes of day-by-day home BP variability. A multiple linear regression analysis adjusted for covariates showed both average morning and evening SBP were associated with the log-transformed urine albumin-to-creatinine ratio (UACR) with and without diabetes (all P < 0.05), but not with the eGFR except for an association of average evening SBP in the no-diabetes group. None of the indexes of day-by-day morning and evening home SBP variability were associated with the log-transformed UACR except for the association between the ARV of home morning SBP in the diabetes group. All of the indexes of day-by-day morning and evening home SBP variability were associated with the eGFR only in the diabetes group (all P < 0.05). The association between increased day-by-day home BP variability and impaired renal function was unique in diabetes.

Distribution of phynotypes of diabetic kidney disease in latent autoimmune diabetes in adults

Objective – to determine the prevalence of diabetic kidney disease phenotypes in latent adult autoimmune diabetes compared to other types of diabetes mellitus.Material and methods. A comprehensive examination of 96 patients with chronic kidney disease and diabetes mellitus: 40 (main group) with latent autoimmune diabetes in adults (LADA), 28 - with type 1 diabetes mellitus(T1DM), 28 - with type 2 diabetes mellitus (T2DM) – comparison groups. Complaints, anamnesis, objective examination, the results of general clinical laboratory tests, carbohydrate metabolism, glomerular filtration rate, albuminuria, albumin-creatinine ratio have evaluated.Results. The classical albuminuric phenotype was diagnosed in 7.1% of patients with T1DM, in 10.7% of patients with T2DM and in 13% of patients with LADA, respectively. The proportion of patients with non-albuminuric renal impairment was 85.7% with T1DM, 53.6% with T2DM and 70.4% with LADA. Progressive decline in renal function was found in 7.1% of cases of T1DM, 35.7% of T2DM and 16.7% of LADA.Conclusions. The prevalence of phenotypes of diabetic kidney disease in LADA differs from that in classical types of diabetes, which requires a differential approach to the management of this diabetic complication.

Nephroprotective potential of glucagon-like peptide-1 receptor agonists

Patients with diabetes mellitus (DM), which is a key factor in the development of kidney diseases, are increasingly competing for limited healthcare resources. Diabetic kidney disease (DKD) remains a significant cause of end-stage renal failure in the patients of many countries and is also associated with a high risk of cardiovascular pathology and mortality. The variety of clinical phenotypes of DKD in patients with type 2 diabetes mellitus (DM2) occurring due to a variety of pathogenetic factors and the characteristics of the evolution of complications under the influence of contemporary therapeutic methods, has been a special subject of discussion in recent years. Optimal control of the level of glycaemia and hypertension and timely blockade of the reninangiotensinaldosterone system do not provide sufficient protection for the kidneys. Over the recent decade, the nephroprotective potential of a group of modern anti-hyperglycaemic agents, i.e., glucagon-like peptide 1 receptor agonists (GLP1 RA) has been actively discussed. GLP1 RA have proven to be quite effective in controlling glycaemia and metabolic syndrome components (weight, systolic blood pressure and lipid profile) and in significantly reducing the risk of the primary, three-component endpoint (major adverse cardiac events: cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) according to large studies on cardiovascular safety. The renal effects of GLP1 RA are attributed to a wide range of direct and indirect effects of glucagon-like peptide-1 on renal structures and functions owing to their anti-inflammatory, anti-oxidant and anti-apoptotic properties.