Impact of Renin-Angiotensin System Blockade on Mortality and Allograft Loss among Renal Transplant Recipients: A Systematic Review and Meta-Analysis.

The blockade of the renin-angiotensin system (RAS) has a beneficial effect on reducing the levels of proteinuria and blood pressure in patients with chronic kidney disease (CKD) and reduces the risk of developing end-stage kidney disease in CKD patients. Nonetheless, a debate persists regarding the impact of RAS inhibitors on outcomes such as mortality and graft survival in renal transplant patients. To assess the effect of RAS inhibitors on graft recipients in the past decade, we conducted a systematic review and meta-analysis. We searched Embase, PubMed, and the Cochrane Central Register of Clinical Trials from January 1, 2012, to August 1, 2022. We included 14 articles, comprising 5 randomized controlled trials (RCTs) and 9 cohort studies, including 45,377 patients. These studies compared patient or graft survival between an RAS inhibitor treatment arm and a control arm. The meta-analysis revealed that RAS blockade was significantly associated with lower mortality in cohort studies (risk ratio [RR] = 0.66, 95% confidence interval [CI]: 0.55-0.79), reduced allograft loss in cohort studies (RR = 0.62, 95% CI: 0.54-0.71), and significant changes in systolic blood pressure in RCTs. Subgroup analysis of the groups of interest (interventions involving RAS blockade, follow-up period of ≥5 years) showed consistently reduced mortality (RR = 0.67, 95% CI: 0.56-0.81) and reduced allograft loss (RR = 0.61, 95% CI: 0.54-0.70). Our results demonstrated that the application of RAS blockade among renal transplant recipients was associated with lower mortality and allograft loss in cohort studies but not in RCTs. More powered clinical trials are needed to evaluate the effects of RAS blockade in renal transplant recipients.

Kung CW ，Lin YC ，Tseng CS ，Chou YH ... -  《-》

Sex and gender as predictors for allograft and patient-relevant outcomes after kidney transplantation.

Sex, as a biological construct, and gender, defined as the cultural attitudes and behaviours attributed by society, may be associated with allograft loss, death, cancer, and rejection. Other factors, such as recipient age and donor sex, may modify the association between sex/gender and post-transplant outcomes. We sought to evaluate the prognostic effects of recipient sex and, separately, gender as independent predictors of graft loss, death, cancer, and allograft rejection following kidney or simultaneous pancreas-kidney (SPK) transplantation. We aimed to evaluate this prognostic effect by defining the relationship between recipient sex or gender and post-transplantation outcomes identifying reasons for variations between sexes and genders, and then quantifying the magnitude of this relationship. We searched MEDLINE and EMBASE databases from inception up to 12 April 2023, through contact with the Cochrane Kidney and Transplant Information Specialist, using search terms relevant to this review and no language restrictions. Cohort, case-control, or cross-sectional studies were included if sex or gender were the primary exposure and clearly defined. Studies needed to focus on our defined outcomes post-transplantation. Sex was defined as the chromosomal, gonadal, and anatomical characteristics associated with the biological sex, and we used the terms "males" and "females". Gender was defined as the attitudes and behaviours that a given culture associates with a person's biological sex, and we used the terms "men" and "women". Two authors independently assessed the references for eligibility, extracted the data and assessed the risk of bias using the Quality in Prognosis Studies (QUIPS) tool. Whenever appropriate, we performed random-effects meta-analyses to estimate the mean difference in outcomes. The outcomes of interest included the Standardised Outcomes in Nephrology-Kidney Transplant (SONG-Tx) core outcomes, allograft loss, death, cancer (overall incidence and site-specific) and acute or chronic graft rejection. Fifty-three studies (2,144,613 patients; range 59 to 407,963) conducted between 1990 and 2023 were included. Sixteen studies were conducted in the Americas, 12 in Europe, 11 in the Western Pacific, four in the Eastern Mediterranean, three in Africa, two in Southeast Asia, and five across multiple regions. All but one study focused on sex rather than gender as the primary exposure of interest. The number identified as male was 54%; 49 studies included kidney transplant recipients, and four studies included SPK transplant recipients. Twenty-four studies included adults and children, 25 studies included only adults, and four studies included only children. Data from 33 studies were included in the meta-analyses. Among these, six studies presented unadjusted hazard ratios (HRs) that assessed the effect of recipient sex on kidney allograft loss. The other studies reported risk ratios (RRs) for the pre-defined outcomes. Notably, the decision to restrict the meta-analyses to unadjusted estimates arose from the variation in covariate adjustment methods across studies, lacking a common set of adjusted variables. Only three studies considered the modifying effect of recipient age on graft loss or death, which is likely crucial to evaluating sex differences in post-transplant outcomes. No studies considered the modifying effect of recipient age on cancer incidence or allograft rejection risk. In low certainty evidence, compared with male recipients, being female may make little or no difference in kidney allograft loss post-transplantation (7 studies, 5843 patients: RR 0.91, 95% CI 0.73 to 1.12; I2 = 73%). This was also observed in studies that included time-to-event analyses (6 studies, 238,937 patients; HR 1.07, 95% CI, 0.95 to 1.20; I2 = 44%). Two recent large registry-based cohort studies that considered the modifying effects of donor sex and recipient age showed that female recipients under 45 years of age had significantly higher graft loss rates than age-matched male recipients in the setting of a male donor. In contrast, female recipients 60 years and older had lower graft loss rates than age-matched male recipients, regardless of donor sex. Compared with male recipients, being female may make little or no difference in death up to 30 years post-transplantation; however, the evidence is very uncertain (13 studies, 60,818 patients: RR 0.94, 95% CI 0.81 to 1.09; I2 = 92%). Studies that considered the modifying effect of recipient age and donor sex showed that female recipients had a higher excess death risk than males under 45 years of age in the setting of a male donor. Compared with male recipients, being female may make little or no difference in cancer incidence up to 20 years post-transplantation; however, the evidence is very uncertain (7 studies, 25,076 patients; RR 0.84, 95% CI 0.70 to 1.01; I2 = 60%). Compared with male recipients, being female may make little or no difference in the incidence of acute and chronic kidney allograft rejection up to 15 years post-transplantation (9 studies, 6158 patients: RR 0.89, 95% CI 0.75 to 1.05; I2 =54%; low certainty evidence). One study assessed gender and reported that when compared with men, women experienced better five-year survival in high (HR 0.71, 95% CI 0.59 to 0.87) and middle-income areas (HR 0.82, 95% CI 0.74 to 0.92), with no difference in low-income areas (HR 0.85, 95% CI 0.72 to 1.01). There was considerable uncertainty regarding any association between sex or gender and post-transplant patient-relevant outcomes. This was primarily due to clinical and methodological heterogeneity. The observed clinical heterogeneity between studies could be attributed to diverse patient characteristics within sample populations. As a result of limited sex-stratified demographic data being provided, further investigation of this heterogeneity was constrained. However, factors contributing to this finding may include recipient age, donor age, types, and sex. Methodological heterogeneity was noted with the interchangeable use of sex and gender, outcome misclassification, the use of different measures of effects, inconsistent covariate profiles, and disregard for important effect modification. There is very low to low certainty evidence to suggest there are no differences in kidney and pancreas allograft survival, patient survival, cancer, and acute and chronic allograft rejection between male and female kidney and SPK transplant recipients.

Jayanti S ，Beruni NA ，Chui JN ，Deng D ，Liang A ，Chong AS ，Craig JC ，Foster B ，Howell M ，Kim S ，Mannon RB ，Sapir-Pichhadze R ，Scholes-Robertson NJ ，Strauss AT ，Jaure A ，West L ，Cooper TE ，Wong G ... -  《Cochrane Database of Systematic Reviews》

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction.

Martin N ，Manoharan K ，Davies C ，Lumbers RT ... -  《Cochrane Database of Systematic Reviews》

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction.

Martin N ，Manoharan K ，Thomas J ，Davies C ，Lumbers RT ... -  《Cochrane Database of Systematic Reviews》

Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD. Strategies to enable persistent use of renin-angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated. We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups. During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials ( P -heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P -heterogeneity = 0.009). In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade. ClinicalTrials.gov, NCT02065791 and NCT03036150 . This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_11_21_JASN0000000000000248.mp3.

Fletcher RA ，Jongs N ，Chertow GM ，McMurray JJV ，Arnott C ，Jardine MJ ，Mahaffey KW ，Perkovic V ，Rockenschaub P ，Rossing P ，Correa-Rotter R ，Toto RD ，Vaduganathan M ，Wheeler DC ，Heerspink HJL ，Neuen BL ... -  《-》