Renal Endpoints Research Articles

Glomerulosclerosis predicts poor renal outcome in patients with idiopathic membranous nephropathy.

This study aimed to investigate the association between the proportion of glomerulosclerosis (focal segmental glomerulosclerosis and/or global glomerulosclerosis) and renal prognosis in patients with idiopathic membranous nephropathy (IMN). A retrospective analysis performed from January 2008 to December 2017 in the First Affiliated Hospital of Shenzhen University by renal biopsy confirmed 200 patients with IMN, and their clinical pathology and prognosis were compared. Patients were divided into three groups on the basis of glomerular sclerosis proportion tertiles: low (Tertile1 group, proportion of glomerulosclerosis, 0-0%), middle (Tertile2 group, proportion of glomerulosclerosis, 0-5.5%) and high (Tertile3 group, proportion of glomerulosclerosis, 5.8-72.7%) tertiles. The follow-up endpoints were decreased estimated glomerular filtration rate (eGFR) by 20%, end-stage renal disease, and all-cause mortality. (1) Both, the Tertile1 and Tertile2, groups had significantly lower albumin level and higher 24-h urine protein level than that in the Tertile3 group. Regarding treatment, as the proportion of glomerulosclerosis increases, a more aggressive treatment with glucocorticoids and immunosuppressants should be provided. (2) Correlation analysis showed that the proportion of glomerulosclerosis was positively associated with age (P < 0.05). However, it was negatively associated with eGFR (P < 0.05). (3) Renal tubular atrophy and renal interstitial inflammatory cell infiltration were considered independent correlative factors for glomerulosclerosis. Kaplan-Meier analysis revealed that renal survival rate was significantly lower in patients with a proportion of glomerulosclerosis ≥ 6.45% than in patients with a proportion of glomerulosclerosis < 6.45%. Cox regression analysis revealed that as the proportion of glomerulosclerosis increases, the risk of renal outcomes increases gradually. Patients in the Tertile3 (higher proportion of glomerulosclerosis) group had more severe renal pathological damage compared to patients in the Tertile1 and Tertile2 groups. Glomerulosclerosis is a risk factor for renal function progression and poor renal prognosis in patients with IMN. As the proportion of glomerulosclerosis increases, the risk of renal endpoint events increases gradually.

Carotid-Femoral Pulse Wave Velocity as a Risk Marker for Development of Complications in Type 1 Diabetes Mellitus.

BackgroundThe value of carotid‐femoral pulse wave velocity (cfPWV) as risk factor for development of complications in type 1 diabetes mellitus remains to be determined. We investigated associations between cfPWV and renal outcomes, cardiovascular events, and all‐cause mortality in people with type 1 diabetes mellitus.Methods and ResultscfPWV was measured with SphygmoCor in 633 people with type 1 diabetes mellitus. Median (interquartile range) follow‐up was 6.2 (5.8−6.7) years. End points included progression in albuminuria group, decline in estimated glomerular filtration rate (eGFR) ≥30%, end‐stage kidney disease, cardiovascular event, mortality, and a composite renal end point. Hazard ratios (HRs) were calculated per 1‐SD increase in cfPWV. Adjustments included age, sex, hemoglobin A1c, mean arterial pressure, body mass index, low‐density lipoprotein cholesterol, smoking, urine albumin excretion rate, and eGFR. The cohort included 45% women, mean (SD) age was 54 (13) years, mean (SD) eGFR was 83.2 (27.9) mL/min per 1.73 m2, and mean (SD) cfPWV was 10.4 (3.3) m/s. Median (interquartile range) albumin excretion rate was 17 (17‐63) mg/24 h. After adjustment, higher cfPWV was associated with increased hazard of progression in albuminuria (HR, 1.59; 95% CI, 1.10−2.32); decline in eGFR ≥30% (HR, 1.38; 95% CI, 1.06−1.79); cardiovascular event (HR, 1.31; 95% CI, 1.01−1.70); mortality (HR, 1.36; 95% CI, 1.00−1.85); and the composite renal end point (HR, 1.30; 95% CI, 1.04−1.63), but not with end‐stage kidney disease (HR, 1.18; 95% CI, 0.62−2.26). Higher cfPWV was associated with steeper yearly increase in albumin excretion and steeper yearly decline in eGFR after adjustment (P=0.002 and P=0.01, respectively).ConclusionscfPWV was associated with increased hazard of renal outcomes, cardiovascular event, and mortality. cfPWV may be suited for risk stratification in type 1 diabetes mellitus.

Development and Internal Validation of a Discrete Event Simulation Model of Diabetic Kidney Disease Using CREDENCE Trial Data.

IntroductionThe Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study showed that compared with placebo, canagliflozin 100 mg significantly reduced the risk of major cardiovascular events and adverse renal outcomes in patients with diabetic kidney disease (DKD). We developed a simulation model that can be used to estimate the long-term health and economic consequences of DKD treatment interventions for patients matching the CREDENCE study population.MethodsThe CREDENCE Economic Model of DKD (CREDEM-DKD) was developed using patient-level data from CREDENCE (which recruited patients with estimated glomerular filtration rate 30 to < 90 mL/min/1.73 m2, urinary albumin to creatinine ratio > 300–5000 mg/g, and taking the maximum tolerated dose of a renin–angiotensin–aldosterone system inhibitor). Risk prediction equations were fit for start of maintenance dialysis, doubling of serum creatinine, hospitalization for heart failure, nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. A micro-simulation model was constructed using these risk equations combined with user-definable kidney transplant event risks. Internal validation was performed by loading the model to replicate the CREDENCE study and comparing predictions with trial Kaplan–Meier estimate curves. External validation was performed by loading the model to replicate a subgroup of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program with patient characteristics that would have qualified for inclusion in CREDENCE.ResultsRisk prediction equations generally fit well and exhibited good concordance, especially for the placebo arm. In the canagliflozin arm, modest underprediction was observed for myocardial infarction, along with overprediction of dialysis, doubling of serum creatinine, and all-cause mortality. Discrimination was strong (0.85) for the renal outcomes, but weaker for the macrovascular outcomes and all-cause mortality (0.60–0.68). The model performed well in internal and external validation exercises.ConclusionCREDEM-DKD is an important new tool in the evaluation of treatment interventions in the DKD population.Trial RegistrationClinicalTrials.gov identifier, NCT02065791.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00923-w) contains supplementary material, which is available to authorized users.

SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials

Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. Boehringer Ingelheim.

Rationale and Design of the ACS-BP Study: Prognostic Value of In-Hospital Blood Pressure and Indices of Atherosclerosis in Acute Coronary Syndromes.

High blood pressure (BP) is a leading risk factor for coronary artery disease and other major cardiovascular events. Blood pressure variability (BPV), ambulatory arterial stiffness index (AASI) and ankle- brachial index (ABI) have been proposed as indices that can improve risk stratification for an adverse cardiac outcome. However, their utility in the setting of acute coronary syndromes (ACS) is unclear. The ACS-BP study is a single-centre observational cohort study designed to investigate the prognostic role of haemodynamic load and arterial stiffness indices for cardio-renal outcomes in patients with acute myocardial infarction (AMI). All consecutive patients admitted with a diagnosis of acute AMI with or without ST segment elevation were screened for inclusion in the study. The management of AMI will follow current guidelines. Data from baseline clinical and laboratory parameters during their hospitalization were collected. The haemodynamic load of each patient was determined by clinical BP values as well as 24-h ambulatory BP monitoring. The AASI was calculated from the raw 24-h BP data and ABI was measured after the third day of hospitalization using a certified device. Patients were followed-up for 12 months in order to collect data for hard cardiovascular and renal endpoints. The study results should clarify the role of these non-invasive tools in secondary risk stratification of such patients.

Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction.

In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction). In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. At randomization, eGFR was 63±19 mL·min-1·1.73 m-2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; P=0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min-1·1.73 m-2 (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (-2.0 [95% CI, -2.2 to -1.9] versus -2.7 [95% CI, -2.8 to -2.5] mL·min-1·1.73 m-2 per year). In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program.

Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes. To assess whether eGFR declines <57% could detect canagliflozin's effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect. Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect. Declines in eGFR <57% may provide robust estimates of canagliflozin's effects on renal outcomes if the analysis controls for the drug's acute hemodynamic effect. CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754.

Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: Expert opinion from a European consensus panel.

The large number of pharmacological agents available to treat type 2 diabetes (T2D) makes choosing the optimal drug for any given patient a complex task. Because newer agents offer several advantages, whether and when sulphonylureas (SUs) should still be used to treat T2D is controversial. Published treatment guidelines and recommendations should govern the general approach to diabetes management. However, expert opinions can aid in better understanding local practices and in formulating individual choices. The current consensus paper aims to provide additional guidance on the use of SUs in T2D. We summarize current local treatment guidelines in European countries, showing that SUs are still widely proposed as second-line treatment after metformin and are often ranked at the same level as newer glucose-lowering medications. Strong evidence now shows that sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with low hypoglycaemia risk, promote weight loss, and exert a positive impact on vascular, cardiac and renal endpoints. Thus, using SUs in place of SGLT-2is and GLP-1RAs may deprive patients of key advantages and potentially important cardiorenal benefits. In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT-2is and/or GLP-1RAs should be used as part of diabetes management, in the absence of contraindications. Routine utilization of SUs as second-line agents continues to be acceptable in resource-constrained settings.

Direct Renin Inhibition in Non-diabetic chronic Kidney disease (DRINK): a prospective randomized trial.

The potential long-term safety and efficacy of aliskiren in nondiabetic chronic kidney disease (CKD) are unknown. We sought to investigate the renoprotective effect of aliskiren on nondiabetic CKD patients. In this open-label, parallel, randomized controlled trial, nondiabetic CKD Stages 3-4 patients were randomized to receive aliskiren added to an angiotensin II receptor blocker (ARB) at the maximal tolerated dose, or ARB alone. Primary outcome was the rate of change in estimated glomerular filtration rate (eGFR). Secondary endpoints included rate of change in urine protein-to-creatinine ratio (UPCR), cardiovascular events and hyperkalemia. Composite renal outcomes of doubling of baseline serum creatinine or a 40% reduction in eGFR or incident end-stage renal disease or death were analyzed as post hoc analysis. Seventy-six patients were randomized: 37 to aliskiren (mean age 55.1 ± 11.1 years) and 39 to control (mean age 55.0 ± 9.4 years). Their baseline demographics were comparable to eGFR (31.9 ± 9.0 versus 27.7 ± 9.0 mL/min/1.73 m2, P = 0.05) and UPCR (30.7 ± 12.6 versus 47.8 ± 2.8 mg/mmol, P = 0.33) for treatment versus control subjects. After 144 weeks of follow-up, there was no difference in the rate of eGFR change between groups. Six patients in the aliskiren group and seven in the control group reached the renal composite endpoint (16.2% versus 17.9%, P = 0.84). The cardiovascular event rate was 10.8% versus 2.6% (P = 0.217). The hyperkalemia rate was 18.9% versus 5.1% with an adjusted hazard ratio of 7.71 (95% confidence interval 1.14 to 52.3, P = 0.04) for the aliskiren arm. Aliskiren neither conferred additional renoprotective benefit nor increased adverse events, except for more hyperkalemia in nondiabetic CKD patients.

Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial

Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. Gilead Sciences.

Decaffeinated Coffee Consumption and Renal Function Impairment in Health and Diabetes: A Paradigm-Shift

Aim: The belief that decaffeinated coffee (DCAF) does not contain a physiologically relevant concentration of caffeine and therefore has no significant adverse effect on renal endpoints makes patients who are vulnerable to renal dysfunction, renal compromised state, medical conditions that contraindicate caffeine intake or those already on prescription medications known to adversely affect the kidney to sometimes substitute DCAF for caffeinated coffee even as the credibility of this paradigm remains disputable. Therefore, the present study aimed to assess the effect of DCAF consumption on markers of renal function and carbohydrate metabolism in health and diabetes. Materials and Methods: Sixty Wistar Albino rats were divided into 12 groups (6pairs) (n=5per group) for male and female animals. Animals in group 1 served as normal control (NCTRL) and were given standard feed and water only. Animals in group 2 received standard feed plus DCAF. Group 3 was the diabetic (DIA) only group while groups 4, 5, and 6 were DIA plus DCAF treatment groups. After 4weeks of treatment, animals were sacrificed and blood obtained and analyzed for the biochemical indices of renal function and carbohydrate metabolism using standard methods. Results: Serum creatinine (SCr) levels increased significantly in all DCAF treated groups compared with the NCTRL group in male and female animals. Serum electrolytes did not show any significant change across groups. Serum Urea (SUr) increased and decreased in DIA alone group and DIA plus DCAF groups respectively. Serum glucose, insulin, and HOMA-IR increased and decreased significantly in DIA alone group and DIA plus DCAF treated groups respectively compared with NCTRL and DCAF control groups. Conclusion: The consumption of DCAF may adversely affect renal endpoints in health and diabetes but improves markers of carbohydrate metabolism in diabetes likely due to the re-enforcement effect of its caffeine and other bioactive constituents.

Thyroid function, renal events and mortality in chronic kidney disease patients: the German Chronic Kidney Disease study.

BackgroundHypothyroidism and low free triiodothyronine (FT3) syndrome [low FT3 levels with normal thyroid-stimulating hormone (TSH)] have been associated with reduced kidney function cross-sectionally in chronic kidney disease (CKD) patients with severely reduced estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD). Results on the prospective effects of impaired thyroid function on renal events and mortality for patients with severely reduced eGFR or from population-based cohorts are conflicting. Here we evaluated the association between thyroid and kidney function with eGFR (cross-sectionally) as well as renal events and mortality (prospectively) in a large, prospective cohort of CKD patients with mild to moderately reduced kidney function.MethodsThyroid markers were measured among CKD patients from the German Chronic Kidney Disease study. Incident renal endpoints (combined ESKD, acute kidney injury and renal death) and all-cause mortality were abstracted from hospital records and death certificates. Time to first event analysis of complete data from baseline to the 4-year follow-up (median follow-up time 4.04 years) of 4600 patients was conducted. Multivariable linear regression and Cox proportional hazards models were fitted for single and combined continuous thyroid markers [TSH, free thyroxine (FT4), FT3] and thyroid status.ResultsCross-sectionally, the presence of low-FT3 syndrome showed a significant inverse association with eGFR and continuous FT3 levels alone showed a significant positive association with eGFR; in combination with FT4 and TSH, FT3 levels also showed a positive association and FT4 levels showed a negative association with eGFR. Prospectively, higher FT4 and lower FT3 levels were significantly associated with a higher risk of all-cause mortality (Nevents = 297). Per picomole per litre higher FT3 levels the risk of reaching the composite renal endpoint was 0.73-fold lower (95% confidence interval 0.65–0.82; Nevents = 615). Compared with euthyroid patients, patients with low-FT3 syndrome had a 2.2-fold higher risk and patients with hypothyroidism had a 1.6-fold higher risk of experiencing the composite renal endpoint.ConclusionsPatients with mild to moderate CKD suffering from thyroid function abnormalities are at an increased risk of adverse renal events and all-cause mortality over time.

142-LB: Very Low Dose SGLT2 Inhibition Is as Effective as Angiotensin II Receptor Blockage for Cardiac and Renal Fibrosis in High Salt 5/6 Nephrectomized Rats

SGLT2 inhibition has beneficial effects on cardiovascular and renal endpoints but the lowest effective dose is unknown. Effects of the SGLT2 inhibitor, empagliflozin (EMPA) were evaluated in nondiabetic, 5/6 nephrectomy (5/6 Nx) rats. Rats were treated for 8 weeks: Sham + normal diet + placebo (PBO); 5/6Nx + 2% high salt diet (HSD) + PBO; 5/6Nx + HSD + EMPA 1.2 mg/kg/day); 5/6Nx + HSD + telmisartan (5 mg/kg/day); 5/6Nx + HSD + linagliptin (3 mg/kg/day). EMPA increased urinary glucose excretion at dosages eight times lower than currently used low doses. 5/6Nx HSD rats treated with EMPA showed significantly (-29.95/-25.00 mmHg, p&amp;lt;0.001) lower blood pressure (BP) and significantly reduced renal (-33.67%; p&amp;lt;0.05) and cardiac (- 34.85%; p&amp;lt;0.05) fibrosis vs. PBO. Effects of EMPA on BP and renal and cardiac fibrosis were comparable to telmisartan (BP: -31.89/-24.24 mmHg, p&amp;lt;0.001; renal fibrosis -43.96%; p&amp;lt;0.01; cardiac fibrosis: -36.37%; p&amp;lt;0.01) and effects on fibrosis were comparable to linagliptin (renal fibrosis -41.54%; p&amp;lt;0.05; cardiac fibrosis: -50.01%; p&amp;lt;0.001). Many genes were differentially regulated among groups, e.g., transferrin receptor (Trfc), A-kinase anchor protein 1 (Akap1) and mitogen-activated protein kinase 9 (Mapk9) were affected by EMPA and telmisartan while Caspase 1 (Casp1) gene expression was altered by EMPA only in the heart. In the kidney, both EMPA and linagliptin led to differential regulation of pleckstrin homology domain-containing family A member 1 (Plekha1), while only EMPA resulted in differential expression of prostaglandin E synthase (Ptges) and G protein-coupled receptor, class C, group 5, member A (Gprc5a) gene expression. Very low dose EMPA was almost as effective as standard dosages of telmisartan or linagliptin in counteracting BP increase and cardiac and renal fibrosis. The underlying mechanism involves regulation of genes involved in cardiac and renal fibrosis. Disclosure S. Zeng: None. A.A. Hasan: Research Support; Self; Boehringer Ingelheim International GmbH. D. Delic: None. Y. Xiong: None. C. Chu: None. L. Yin: None. S. Frankenreiter: Employee; Self; Boehringer Ingelheim Pharma GmbH &amp; Co. KG. Other Relationship; Self; Evotec International GmbH. B. Krämer: Advisory Panel; Self; Boehringer Ingelheim International GmbH. T. Klein: Employee; Self; Boehringer Ingelheim International GmbH. B. Hocher: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Funding Boehringer Ingelheim &amp; Eli Lilly and Company Diabetes Alliance

P0751METFORMIN, A CLASSIC TREATMENT FOR TYPE 2 DIABETES WITH POSSIBLE RENOPROTECTIVE EFFECTS

Abstract Background and Aims Metformin is the antidiabetic of choice in patients with type 2 diabetes mellitus. Experimental studies and clinical observations have shown that metformin could have a beneficial effect on the progression of kidney disease through the activation of cAMP due to its anti-inflammatory, antifibrotic, and anti-oxidative action. The objective was to compare the progression of CKD in diabetic patients with or without metformin as antidiabetic in their treatment and the prevalence of cardiovascular events in both groups. Method Unicentric retrospective observational analysis. Inclusion criteria: outpatients seen in nephrology consultation during the year of 2012 with diabetes mellitus and stage 3 CKD. Renal, cardiovascular outcomes and mortality were analyzed between patients treated with / without metformin. Median follow-up of 76.5 months (41-84). Renal end-point: estimated glomerular filtration rate drop (MDRD-4) by 50% and / or start of dialysis program. Cardiovascular end-point: ischemic heart disease, stroke, arterial revascularization and / or amputation. Cardiovascular or any cause mortality. Results 148 patients (96M, 52W) with a mean age of 75±9 years and an eGFR of 40±9 ml / min / 1.73 m2 were included. In relation to hypoglycemic therapy: 45 received metformin, 61 insulin and 31 DPP4i. 80% received treatment with RAAS blockers. After the follow-up, the progression of the renal disease was greater in patients who did not receive metformin: eGFR fall of -7.0±16 vs -0.15±16 ml / min in those treated with metformin (p = 0.019). 25 patients in the group without metformin suffered a renal event vs. 5 in the metformin group (logRank: 4.186, p = 0.045). In the Cox analysis, metformin treatment decreases the progression of kidney disease in a model adjusted for baseline renal function and treatment with RAASB (HR 0.368, p = 0.043), losing its predictive power in a proteinuria-adjusted model. During the follow-up, 45 patients died (20 metformin, 25 non-metformin) and 45 patients suffered a cardiovascular event (15 metformin, 30 non-metformin), with no differences between the two groups. Conclusion Metformin treatment in patients with stage 3 CKD could slow the progression of CKD, this effect should be demonstrated in randomized studies with larger sample size.

P0109EVALUATION AND COMPARISON OF TWO RENAL HISTOLOGICAL CLASSIFICATIONS OF IGA VASCULITIS

Abstract Background and Aims Primary IgA nephropathy (IgAN) and IgA vasculitis nephritis (IgAVN) share common features e.g. clinical, histological, pathophysiological. Their prognosis assessment is usually considered to be dependent on histological findings which are therefore useful to establish therapeutic intervention. The validated MEST-C classification is widely used for IgAN. Regarding IgAVN, various classifications are used in clinical practice. However, there is no consensus regarding their feasibility, correlations with renal outcome and their usefulness regarding therapeutic decisions. The aim of this study was to compare the Pillebout and Nochy French classification (PNC), created as a specific IgAVN prognosis scoring system MEST-C classification. Method Renal biopsies (RB) of patients with IgAVN were selected from two previous national IGAV cohorts and then reclassified according to the MEST-C and PNC classifications. For both classifications, the primary endpoint was the renal remission defined as a final glomerular filtration rate (GFR) greater than 60 ml / min. We also analyse: a) the renal survival defined as the absence of dialysis or transplantation; b) clinical-pathological correlation between the 2 classifications and c) the interobserver reproducibility. Results 372 RB from 316 patients were analysed, with 240 patients followed for at least 1 year. The median age was 48 yrs (14 to 86), with a sex ratio of 1.76 for men and a median follow-up of 4.3 years (range 1 to 22.7). Renal impairment was more severe over the age of 60 yrs. The presence of general signs, the initial GFR, and hypertension were significantly associated with renal survival. Proteinuria and albuminemia were associated with proliferative lesions (MEST-C score: E, C). The fibrous lesions (MEST-C: T and PNC stage V) were associated with GFR at the end of the follow-up. No significant association was found between the PNC stage and renal survival. Univariate analyses showed significant association with the primary outcome for the MEST-C T variable (p=0.02). However, by multivariate analysis, this association did not persist. The correlation between the observers was better for MEST-C compared with PNC (0.87 vs. 0.75). Conclusion Our results suggest that MEST-C classification has a good clinical and pathological correlation, a good reproducibility, and is interesting to evaluate the long-term renal outcome of patients with IgAVN. However, the correlation is still not perfect. Indeed, fibrosis was the only pathological feature independently associated with renal endpoints. We suggest that MEST-C is a scoring system which is not fully adapted due to the predominant inflammatory mechanism in IgAVN unlike IgAN. PNC should not be used because of the poor interobserver correlation. It is important to identify new specific IgAVN histological markers, taking into account the inflammatory mechanism, to ensure a more accurate prognostic classification, useful to guide therapeutic strategy.

P0397OUTCOMES OF PROTEINASE 3- AND MYELOPEROXIDASE ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY ASSOCIATED VASCULITIS IN DENMARK 2014-2017

Abstract Background and Aims Anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) defines an uncommon group of autoimmune diseases with antibodies directed against proteinase 3 (PR3) or myeloperoxidase (MPO). Incidence rates of PR3- and MPO-AAV differ geographically, and current evidence based on genetic variations and cluster analyses supports discrimination of associated vasculitis based on PR3- and MPO-positivity. Such discrimination could provide insights of scope for clinical trials with ramifications for improvement of treatment. With the aim of comparing patient characteristics and outcomes between PR3- and MPO-AAV, we report on results from a nationwide retrospective cohort study. Method Incident patients positive for PR3- and MPO-anti-neutrophil cytoplasmic antibodies were identified in central laboratories of three of four administrative regions (covering 80% of the population) in Denmark between 1/1-2014 and 31/12-2017. Patient characteristics were identified by cross-referencing of data from multiple national health care registers. Baseline renal function was calculated based on the CKD-EPI equation using plasma creatinine measurements recorded 365 to 7 days prior to index. Incidences of all-cause mortality and end-stage renal disease stratified on baseline eGFR were computed using the Aalen-Johansen estimator. Hazard ratios for specific predictors including strata of baseline eGFR were calculated based on a multiple Cox proportional hazards model adjusted for relevant confounders. Results In total 770 patients were included in the study (PR3 n=399 and MPO n=371). Annual incidence rates of PR3- and MPO-AAV were 22.6 and 21.1 per million, respectively. PR3-AAV was associated with greater preponderance for male gender (54.4% vs. 42.3%, p=0.001), lower patient age (61.9 years [IQR 41.6-73.0 years] vs. 64.9 years [IQR 50.0-74.0 years], p=0.016), and greater baseline renal function (eGFR 87 ml/min [IQR 56-101 ml/min] vs. 75 ml/min [IQR 36-92 ml/min] compared with MPO-AAV. Comorbid burden was comparable; 26% of patients had history of hypertension, 15% of patients had a history of ischemic heart disease, and 12% of patients had a history of cancer. Acute dialysis was initiated in 5.3% and 6.7%, plasmapheresis in 12.8% and 13.7%, and mechanical ventilation in 4.8% and 4.3% of patients with PR3- and MPO-AAV, respectively. Median follow-up was 564 days [234 – 932]. A total of 86 deaths and 25 end-stage renal disease endpoints were recorded during follow-up. Cumulative incidences of all-cause mortality and end-stage renal disease stratified on baseline eGFR are shown in Figure 1. Adjusted hazard ratios for all-cause death and/or end-stage renal disease showed increased risk associated with PR3-AAV, HR 1.51 (95% CI 1.03 – 2.25, p=0.036), non-European descent, HR 3.63 (95% CI 1.29-10.25, p=0.015) and patient age, HR 1.05 (95% CI 1.03-1.07, p&amp;lt;0.001). In both PR3- and MPO-AAV, only baseline eGFR ≤ 20ml/min/1.73m2 was associated with poorer prognosis (ref.: baseline eGFR &amp;gt;90 ml/min/1.73m2); MPO-AAV: eGFR 51-90 ml/min/1.73m2: HR 2.34 (95% CI 0.75 – 7.34, p=0.145), eGFR 21-50 ml/min/1.73m2: HR 2.11 (95% CI 0.60 – 7.47, p=0.246), and eGFR ≤ 20ml/min/1.73m2: 5.05 (95% CI 1.55 – 16.45, p=0.007); PR3-AAV: eGFR 51-90 ml/min/1.73m2: HR 1.54 (95%CI 0.53 – 4.46, p=0.427), eGFR 21-50 ml/min/1.73m2: HR 1.70 (95% CI 0.51 – 5.64, p=0.386), and eGFR ≤ 20ml/min/1.73m2: 8.06 (95% CI 2.83 – 23.0, p=&amp;lt;0.001). Conclusion In a nationwide cohort study comparing PR3- and MPO-AAV, PR3-AAV was associated with poorer 24-month outcomes in spite of superior renal function at baseline. Overall, poor prognosis was limited to patients with severe renal insufficiency (eGFR ≤20ml/min/1.73m2) at time of diagnosis in both PR3- and MPO-AAV.

139-LB: The Redox Balance Predicts Both Cardiovascular (CV) and Renal Outcomes in CANVAS

We tested whether circulating metabolites reflecting cytosolic (lactate/pyruvate) or mitochondrial (β-hydroxybutyrate/acetoacetate [AcAc]) redox balance are associated with major clinical outcomes in patients with type 2 diabetes. The CANVAS study randomized participants to placebo (Plb) or canagliflozin (100mg or 300mg) (Tx) and followed them for up to 6 years. Metabolic markers were measured at baseline (2,373 in Tx [dose combined] and 1,185 in Plb), at year 1 (2,022 in Tx and 949 in Plb) and year 2 (1,793 in Tx and 834 in Plb). By linear mixed model analysis, plasma free fatty acids, AcAc, and β-hydroxybutyrate increased with Tx vs. Plb, whereas plasma pyruvate decreased with Tx while glycerol and lactate did not change significantly. Of note, these changes were independent of the background antihyperglycemic medication (metformin, sulfonylureas, insulin, or combinations thereof). The incidence of hospitalized heart failure or cardiovascular death (HHF/CVD) was 10.2%, the incidence of the renal composite endpoint (CombR; i.e., 40% reduction in eGFR or renal replacement/death) was 3.9%. In Cox models adjusting for sex, age, BMI, HbA1c, baseline systolic blood pressure, diabetes duration, smoking, baseline use of diuretics or statins, history of heart failure, prior CV disease, and Tx, baseline AcAc was a negative predictor of HHF/CVD (HR=0.83 [95%CI 0.75-0.94]), while baseline lactate was a positive predictor (HR=1.42 [95%CI 1.20-1.68]). Adding baseline ACR and eGFR to the same multivariate model for CombR as the outcome, AcAc was still a negative (HR=0.84 [95%CI 0.75-0.94]) and lactate still a positive predictor (HR=1.42 [95%CI 1.20-1.67]). For CV and renal outcomes, higher baseline plasma lactate is an independent positive risk marker potentially reflecting a reducing cytosolic redox shift, but higher baseline plasma AcAc is a protective factor, which may be related to efficient mitochondrial supply/usage of reducing equivalents. Further analysis is needed to test these hypotheses. Disclosure E. Ferrannini: Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Oramed Pharmaceuticals. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. S. Baldi: None. T. Scozzaro: None. F. Tesfaye: Employee; Self; Janssen Research &amp; Development, LLC. W. Shaw: Employee; Self; Janssen Pharmaceuticals, Inc. N. Rosenthal: None. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson &amp; Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research &amp; Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. V. Perkovic: Other Relationship; Self; See Other Relationship field. M.K. Hansen: Employee; Self; Janssen Research &amp; Development, LLC. Funding Janssen Research &amp; Development, LLC

512-P: The Concomitant Insulin Treatment with Sodium–Glucose Cotransporter 2 Inhibitors Influenced the Renal Composite Outcome in Japanese Type 2 Diabetes Patients with Chronic Kidney Disease

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.

P0831HIGH SERUM ALKALINE PHOSPHATASE PREDICTS THE RISK OF CKD PROGRESSION: EFFECT NODIFICATION BY THE GFR

Abstract Background and Aims In the post-hoc analyses of the SUSTAIN and ASSURE trials (Kidney Blood Press Res. 2018;43:449-457), Apabetalone, an epigenetic modulator which lowers serum alkaline phosphatase (AlkPhos), stabilized the GFR in patients with cardiovascular disease and a GFR &amp;lt;60/ml/min/1.73m2. Analyzing the relationship between AlkPhos and renal outcomes in patients with established CKD is useful to preliminarily explore the biological hypothesis that AlkPhos is implicated in CKD progression. Method We investigated the relationship between AlkPhos and the risk for a combined renal end-point (30% GFR loss or dialysis/renal transplantation) in a cohort of 609 stage 3-5 CKD patients with an average GFR of 34.8±12.1ml/min/1.73 m2. Results Median AlkPhos levels were 91 IU/L (Interquartile range 71-117 IU/L) and in the vast majority of patients had values below 147 IU/L (the upper limit of the normal range). Over a median follow up of 3 years, two-hundred patients had the combined renal end-point. In an unadjusted analysis 1 ln increase in AlkPhos entailed a 49% risk excess for the renal end-point (HR: 1.49, 95% CI 1.11-2.01, P=0.008). Adjusting for traditional (age, gender, smoking, diabetes, total cholesterol, BMI, systolic BP, CV comorbidities) and CKD specific risk factors (hemoglobin, albumin, phosphate, and hs-CRP) did not modify the strength of this association (HR:1.48, 95% CI 1.08-2.02, P=0.016). Furthermore, In a fully adjusted analysis testing the GFR as an effect modifier of the AlkPhos - combined renal end point relationship showed a strong GFR- AlkPhos interaction (Figure). Indeed the risk for the combined renal end-point was gradually more pronounced at progressively more severe degrees of renal dysfunction, the HR being 0.94 (CI95% 0.60-1.47) at a GFR of 40 ml/min/m2 and 2.71 (CI95% 1.49-4.93) at 10 ml/min/1.73m2. Conclusion In patients with stage 3-5 CKD alkaline phosphatase within the normal range is associated with the risk for progression to ESRD and the GFR is an effect modifier of this relationship. Findings in this study are compatible with the hypothesis that within the normal range of this biomarker, the risk for CKD progression by alkaline phosphatase is amplified by the severity of CKD. These data are in keeping with post-hoc analyses of the SUSTAIN and ASSURE trials and provide circumstantial support to the hypothesis that interventions lowering serum alkaline phosphatase may mitigate CKD progression.

Blueberries effects in experimental diet-induced prediabetes: a focus on renal impairment

Abstract Introduction Benefits arising from blueberry (BB) consumption are well-described in type 2 diabetes evolution and inherent complications. Lending further support to this thesis, previous work from our group unequivocally demonstrates BB supplementation efficacy to manage prediabetic hepatic liver steatosis. Whether a similar effect also holds truth in early renal impairment is an unsolved issue. Objectives To address blueberry juice (BJ) ability to exert renoprotective effects in experimental prediabetes. Methodology Diet-induced prediabetes [high-sucrose (35% Hsu) and high-fat (60% HF)] was developed in adult male Wistar rats through the ingestion of HSu for 9 weeks supplemented by HF for another 14 weeks (HSuHF, n = 16). On W9, half of the former animals orally received BJ (25g/kg BW, HSuHF+BJ). Control animals (n = 8) received standard diet during the entire protocol. Functional [serum and urinary creatinine, uric acid, glucose; glomerular filtration rate (GFR)], structural [H&amp;E and Oil Red O staining] and molecular [triglycerides content and inflammation (RT-qPCR, WB)] markers of renal injury were assessed along with metabolic profile. Results Even though diet-induced glucose intolerance, insulin insensitivity and plasmatic hypertriglyceridemia were significantly ameliorated upon BJ treatment, this nutraceutical intervention was unable to halt or slow down renal lipidosis and glomerular crescent-like lesions apart from a slight amelioration of both GFR and IL-6 levels in HSuHF-treated rats. Conclusion Unlike previous results clearly demonstrating the ability of BJ nutraceutical intervention to afford protection against metabolic impairment and hepatic steatosis evolution in experimentally diet-induced prediabetes, only a modest renoprotective effect was observed in functional and morphological renal endpoints. Future studies are warranted to dissect the divergent effects of BJ on early liver and kidney impairment.