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

Impacto de la bacteriuria asintomática en trasplante renal. Cohorte retrospectiva

Introduction: Asymptomatic bacteriuria (AB) during the first year post-renal transplantation has an incidence higher than 50%. Urinary tract infection (UTI) is the most frequent complication of renal transplantation; its incidence is between 30 and 70 % during the first year. Objective: To analyze the incidence of UTI and AB during the first year post-renal transplantation and their impact on renal function.  Methods: Retrospective study in renal transplantation patients older than 18 between January 2006 and December 2017 in our center. Patients who had received combined renal transplantation, lost renal graft during the first year due to surgical complications (thrombosis, allograft rupture) or medical complications (rejection, underlying disease recurrence) were excluded. Results: A study was performed with 161 adult patients who had undergone kidney transplantation. The incidence of UTI and AB during the first year after receiving transplantation was 32% and 25%, respectively. The mean renal function one year after transplantation was as follows: (n=53) Cr 1.36(±0.44) for UTI patients; (n=30) Cr 1.36(±0.41) for AB non-treated patients; (n=11) Cr 1.39(±0.42) for AB treated patients, and (n=90) Cr 1.31(±0.43) p=0.95 for patients not suffering from UTI or AB. The risk of UTI was 55% for non-treated AB and 57% for treated AB, with RR 0.96 (95% CI: 0.52-1.8). Conclusion: No significant differences in renal function were found in UTI and AB patients one year after transplantation as compared to patients not suffering from these conditions. AB treatment did not reduce UTI risk.  Introducción: La bacteriuria asintomática (BA), en el primer año postrasplante renal, tiene una incidencia mayor al 50%. La infección urinaria (ITU) es la complicación infecciosa más común en trasplante renal, su incidencia oscila entre el 30 y el 70% en el primer año. Objetivo: Analizar la incidencia de ITU y BA en el primer año postrasplante renal y su impacto en la función renal. Material y métodos: Estudio retrospectivo, de pacientes trasplantados renales, mayores de 18 años, en el período comprendido entre enero de 2006 y diciembre de 2017, en nuestro centro. Fueron excluidos pacientes con trasplantes renales combinados, pérdida del injerto renal durante primer año por complicaciones quirúrgicas (trombosis, rotura renal) o médicas (rechazo, recidiva de enfermedad de base). Resultados: Fueron analizados 161 pacientes adultos trasplantados renales. La incidencia en el primer año postrasplante de ITU y BA fue del 32% y del 25%, respectivamente. La función renal promedio al año del trasplante fue: de los pacientes con ITU (n=53) Cr 1,36(±0,44), de los pacientes con BA no tratada (n=30) Cr 1.36(±0,41), de los pacientes con BA tratada (n=11) Cr 1,39(±0,42), y de los pacientes sin ITU ni BA (n=90) Cr 1,31(±0,43) p=0,95. El riesgo de ITU en las BA no tratadas fue del 55% y en las tratadas del 57%, con un RR 0,96 (IC 95% 0,52-1,8). Conclusión: No hubo diferencias significativas en la función renal al año del trasplante en los pacientes que tuvieron ITU y BA en relación a los pacientes que no tuvieron. El tratamiento de las BA no redujo el riesgo de padecer ITU. 

Tratamientos específicos en poliquistosis renal autosómica dominante: Una biología compleja y una enfermedad de larga duración

ADPKD es ocasionada por mutaciones en los genes PKD1 y PKD2. Sus dos proteínas, las policistinas 1 y 2, asientan en el cilium primario inmóvil de cada célula y contribuyen a través de su función mecanosensora a una señalización normal del calcio intracelular (Ca2+). Los quistes renales crecen por un doble proceso epitelial, secreción aumentada de fluidos y mayor proliferación, productos del aumento del AMPc intracelular. En esta línea de hallazgos, se demostró en animales que el uso de un inhibidor del receptor V2 (OPC-31260) de la vasopresina endógena, disminuye el aumento del volumen renal y de los quistes y preserva el filtrado glomerular (FG). Por otro lado, la inhibición de la proteína kinasa mTOR (mamalian target of rapamycin), que regula múltiples funciones celulares e integra la información que llega de vías que incluyen la insulina, factores de crecimiento y mitógenos, también se demostró efectiva en modelos animales. En base a estos datos, se inició un ensayo clínico en fase III (Estudio TEMPO) con el inhibidor OPC-31260 (Tolvaptan) del receptor V2 de la vasopresina. No existen todavía datos preliminares de su influencia sobre el crecimiento del volumen renal y el FG, pero disminuye la reabsorción de agua libre y causa diabetes insípida nefrogénica parcial por su acción sobre el receptor V2. Enfoques similares sobre la inhibición del contenido de AMPc intracelular pueden lograrse en humanos con la somatostatina y su análogo de acción prolongada octeotride. Los estudios en humanos con inhibidores de mTOR (everolimus y sirolimus) mostraron disminución del volumen renal pero con mayor declinación del FG en el primer caso y no diferencias en esos índices en el segundo. En conclusión, si bien los modelos animales han provisto un enfoque racional para los ensayos clínicos en humanos, son necesarios nuevos protocolos que estimen cuándo comenzar el tratamiento, cómo evaluar la “etapa biológica” de la enfermedad y qué marcadores de eficacia son necesarios en una enfermedad de larga duración como ADPKD.ADPKD is caused by mutations in the PKD1 and PKD2 genes. The two codified proteins, polycystins 1 and 2, are localized in the primary non-motil cilium and contribute through its mechanosensorial function to a normal signal process in the intracellular calcium (Ca2+) machinery. Renal cysts grow by a double epithelial process of increase in both fluid secretion and cell proliferation, fuelled both by a high intracellular cAMP. Along all these findings, it was also demonstrated in animal PKD models that an inhibitor of the endogenous vasopressin V2 receptor slowed the increase of renal volume and preserved the glomerular filtration rate (GFR). Besides this, the kinase-protein mTOR (mamalian target of rapamycin), that regulates multiple cellular functions and integrates information coming from a variety of growth factors and mitogens was also effective in ameliorating the course of the disease in animal PKD models. Upon all this data, a double-blind phase III clinical trial was started (TEMPO) with an inhibitor of the V2-vasopressin receptor OPC-31260 (Tolvaptan). No data are available at present on the influence of Tolvaptan on both renal volume and GFR. Similar approaches pointing to inhibit the AMPc intracellular content have been used in humans with somatostatin and its long-acting analogous octeotride, with preliminary benefits. Published results in humans with the mTOR inhibitors everolimus showed a slower pace in the growth rate of renal volume without concurrent changes in GFR. No beneficial changes were observed with the use of sirolimus. In summary, different animal models have provided a rational approach for planning clinical trials with different compounds. It is still necessary to get new data that permit the development of a new stage of carefully designed trials. This should permit to define questions as when to start treatment, how to evaluate the “biological” stage of the disease and which markers should be used to assess treatment effectiveness in a long-life disease as ADPKD.Fil: Martin, Rodolfo Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Austral; ArgentinaFil: Fraga, Adriana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Austral; ArgentinaFil: Fragale, Guillermo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Austral; ArgentinaFil: Cestari, Jorge. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Austral; ArgentinaFil: Martínez, María F.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Austral; ArgentinaFil: Arrizurieta, Elvira. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Austral; ArgentinaFil: Azurmendi, Pablo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Austral; Argentin

Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy

The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study

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

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