Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Evaluation of the predisposition and clinical impact of BK virus replication in kidney transplant patients

ABSTRACT The BK virus (BKV) produces a subclinical kidney infection in immunocompetent individuals. However, viremia may occur in kidney transplant patients with ongoing immunosuppression. BKV-associated nephropathy (BKVN) has no specific treatment and is a leading cause of organ transplant loss. In this study, we evaluated the predisposition and the clinical impact of BKV replication in kidney transplant patients during post-transplant monitoring in a reference institution in Brazil. Demographic, clinical and laboratory data generated during routine outpatient follow-up were retrospectively collected. BK viremia was investigated using real-time polymerase chain reaction. Of the 553 participants, 7.4% (n = 41) presented BKV replication. Of these, 16 (39%) lost their kidney graft and interstitial nephritis was identified on kidney biopsy in 50% of the cases. Among the evaluated variables, only the use of the immunosuppressant mycophenolate sodium was identified as a risk factor for viremia (OR 7.96; 95% CI 2.35 to 26.98). The graft survival estimate in BKV-positive patients was significantly reduced (24.8% vs. 85.6%) after 10 years of transplantation. We concluded that defining predisposing factors remains an important challenge for the prevention and control of BKV activity following kidney transplantation, especially considering the development of BKVN and its strong effect on graft maintenance

A cardioplegia oxigenada na proteção miocárdica durante a cirurgia cardíaca: estudo clínico e enzimático Oxygenated cardioplegia in myocardial protection during cardiac surgery: a clinical and enzymatic study

A cardioplegia tem sido reconhecida como um fator muito importante na proteção oo miocárdio. Sabe-se que, mesmo a 15ºC, o coração consome oxigênio. Testes in vitro demonstraram que a cardioplegia cristalóide libera mais oxigênio que a sangüínea. Neste estudo, foram analisadas as variações hemodinâmicas, eletrocardiográficas e enzimáticas em 26 pacientes divididos em 2 grupos, nos quais a cardiplegia cristalóide de Gomes foi empregada. Grupo I: 12 pacientes (solução não oxigenada); Grupo II: 14 pacientes (solução oxigenada). A avaliação dos pacientes incluiu a recuperação hemodinâmica após a parada cardíaca, o uso de drogas vasoativas, o ritmo e o aspecto do eletrocardiograma (ECG), a freqüência cardíaca (FC), a pressão arterial média (PAM), a pressão venosa central (PVC) e as enzimas TGO e CPK-MB. Estes parâmetros foram medidos nos seguintes tempos: antes, logo após a cirurgia e após 6, 12, 24, 48 e 72 horas de pós-operatório. Os resultados demonstraram que a recuperação hemodinâmica foi similar em ambos os grupos. O uso de drogas vasoativas foi maior no Grupo II. No ECG, observou-se mais bradicardia e fibrilação ventricular no Grupo II do que no Grupo I. A freqüência cardíaca, a pressão arterial média e a pressão venosa central não mostraram diferença significativa em ambos os grupos. As enzimas TGD e CPK-MB mostraram elevação mais acentuada no Grupo I do que no II e essa diferença foi significativa (P Cardioplegia has been recognized as a very important factor in myocardial protection. Today we know that even the arrested heart at 15ºC wastes oxygen. "In vitro" it was already shown that release of oxygen was higher in cristalloid than in blood solution. In this study we analized the hemodinamic, electrocardiographic and enzimatic variations in 26 patients, divided into two groups in whom cardioplegia with the Gomes solution was used. Group I: 12 patients (control group - non oxygenated solution). Grupo II: 14 patients (oxygenated solution). The evaluation of the patients included hemodynamic recovery after arrest, the use of vasoactive drugs, cardiac rhythm and aspect of the ECG, heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP) and enzymes SGOT and CPK-MB in the following times: pre and postoperatory period and after 6, 12, 24, 48 and 72 hours of postoperatory period. Hemodynamic recovery was similar in both groups, the use of vasoactive drugs was greater in Group II. In the ECG was seen more sinus bradycardia in Group II that also needed more electric defibrilation. Heart rate, mean arterial prossure and central venous pressure showed no significant difference between the two groups in the postoperative period. The enzymes SGOT and CPK were higher in Group I than in Group II. In conclusion, data suggested that both solutions had similar results in the hemodynamic recovery end vital parameters. An higher incidence of bradycardia was seen in Group II, probably related to the longer cardiac arrest, with more infusions of the cardioplegic solution. The variation of the enzimes suggested that oxygenated cardioplegia was more effective than the non-oxygenated solution to assure the preservation of the myocardium

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (<60, 60-69, and >_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 & PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and >_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791