Binding Potassium to Improve Treatment With Renin-Angiotensin-Aldosterone System Inhibitors: Results From Multiple One-Stage Pairwise and Network Meta-Analyses of Clinical Trials.

This manuscript presents findings from the first dichotomous data pooling analysis on clinical trials (CT) regarding the effectiveness of binding potassium. The results emanated from pairwise and network meta-analyses aiming evaluation of response to commercial potassium-binding polymers, that is, to achieve and maintain normal serum potassium (n = 1,722), and the association between this response and an optimal dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) needing individuals affected by heart failure (HF) or resistant hypertension, who may be consuming other hyperkalemia-inducing drugs (HKID) (e.g., ß-blockers, heparin, etc.), and frequently are affected by chronic kidney disease (CKD) (n = 1,044): According to the surface under the cumulative ranking area (SUCRA), sodium zirconium cyclosilicate (SZC) (SUCRA >0.78), patiromer (SUCRA >0.58) and sodium polystyrene sulfonate (SPS) (SUCRA <0.39) were different concerning their capacity to achieve normokalemia (serum potassium level (sK+) 3.5-5.0 mEq/L) or acceptable kalemia (sK+ ≤ 5.1 mEq/L) in individuals with hyperkalemia (sK+ >5.1 mEq/L), and, when normokalemia is achieved, patiromer 16.8-25.2 g/day (SUCRA = 0.94) and patiromer 8.4-16.8 g/day (SUCRA = 0.41) can allow to increase the dose of spironolactone up to 50 mg/day in subjects affected by heart failure (HF) or with resistant hypertension needing treatment with other RAASi. The potential of zirconium cyclosilicate should be explored further, as no data exists to assess properly its capacity to optimize dosing of RAASi, contrarily as it occurs with patiromer. More research is also necessary to discern between benefits of binding potassium among all type of hyperkalemic patients, for example, patients with DM who may need treatment for proteinuria, patients with early hypertension, etc. Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42020185614, CRD42020185558, CRD42020191430.

Cholesterol-Lowering Treatment in Chronic Kidney Disease: Multistage Pairwise and Network Meta-Analyses.

Pairwise and network meta-analyses on the relationship between the efficacy of the use of statins with or without ezetimibe and reductions in low-density lipoprotein cholesterol (LDLc) and C-reactive protein (CRP) in patients with chronic kidney disease (CKD) are presented. In the pairwise meta-analysis, statins with or without ezetimibe were shown to be efficacious in reducing major adverse cardiovascular events (MACE) in patients with CKD and an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2, in the context of both primary prevention [odds ratio (OR)/95% confidence interval (95% CI)/I2/number of studies (n): 0.50/0.40-0.64/0%/6] and primary/secondary prevention (0.66/0.57-0.76/57%/18). However, in the Bayesian network meta-analysis, compared to the placebo, only atorvastatin 80 mg daily and atorvastatin and rosuvastatin at doses equivalent to simvastatin 20 mg daily reduced the odds of MACEs in this patient population. The network meta-analysis for LDLc and CRP treatment objectives also showed that, regardless of eGFR and excluding dialysis patients, the number of MACEs decreased in patients with CKD, with reductions in both LDLc and CRP of less than 50% (surface under the cumulative ranking (SUCRA)/heterogeneity (vague)/n: 0.77/0.14/3). The evaluation of the benefits of drugs may lead to individualized therapy for CKD patients: Cholesterol-lowering treatment for CKD patients with high levels of both LDLc and CRP is suggested.

The number of FoxP3 regulatory T cells in the circulation may be a predictive biomarker for kidney transplant recipients: A multistage systematic review.

BACKGROUND: The kinetics of the FoxP3 regulatory T-cell (Treg) population in kidney transplant recipients (KTR) are related to the clinical effect of immunosuppression based on mammalian Target Of Rapamycin inhibitors (mTORi) with/without belatacept (predictive biomarker). METHODS: A multistage systematic review of published and unpublished literature is presented [registration IDs in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017057570, CRD42018085019, CRD42018084941, CRD42018085186]. A multidisciplinary supervision mechanism for contextualizing of search findings was required. The peripheral blood immune cell phenotypes encompassing all regulatory cells in KTRs were assessed in order to suggest new markers of acute rejection-associated acute allograft dysfunction (AR/AAD) events in KTRs treated with mTORi alone or combined to belatacept. Quantitative estimates and evaluation of the body of evidence are provided. RESULTS: An increase in Tregs and other regulatory cell types in the circulation in KTRs under mTORi with/without belatacept were observed. Patients with increased Tregs presented a low frequency of AR/AAD events compared to those in which the number of Tregs remained unchanged or even diminished [Odds Ratio (OR)/95% confidence interval (95% CI)/I2/number of studies (n): 0.31/0.10-0.93/0%/6]. Nevertheless, there are too few trials to consider Tregs in the circulation as a predictive biomarker. Inadequate reporting prevents appreciating clinical relevance in such studies. CONCLUSIONS: Despite advances, clinical qualification of potential predictive biomarkers continues to be difficult. Clinical evidence on Tregs in KTRs needs to be enlarged. Biomarkers should be able to evaluate the effect of medicines targeted to specific patient populations.

Data on a new biomarker for kidney transplant recipients: The number of FoxP3 regulatory T cells in the circulation.

This article presents unrevealed details of the systematic review process of the article "The number of FoxP3 regulatory T cells in the circulation may be a predictive biomarker for kidney transplant recipients: A multistage systematic review" (Herrera-Gómez et al., 2018). Eligibility criteria guiding searches and study selection, the risk of bias assessment, the assessment of medicine-test codependency (evaluation of the body of evidence), and meta-analytic calculations are provided. The data allows other researchers, particularly those involved in experiments on Translational Epidemiology applied to Pharmacology, to corroborate and extend our assessments.

Recuentos de células T reguladoras en sangre periférica como biomarcador predictivo del resultado del trasplante renal: revisión sistemática / Peripheral blood regulatory T cell counts as a predictive biomarker for the outcome of kidney transplant: A systematic review

Fundamento y objetivo: Las células T reguladoras circulantes podrían convertirse en un adecuado biomarcador para los trasplantados renales. El objetivo de este estudio es evaluar el efecto de los inhibidores de la mammalian target of rapamycin (I-mTOR, «diana de rapamicina en células de mamífero») en las células reguladoras, y el interés clínico de este efecto. Material y métodos: Revisión sistemática de trabajos publicados y no publicados. Bases de datos y repositorios del mundo entero. Se buscaron ensayos controlados aleatorizados y estudios de cohortes que compararon recuentos de células reguladoras y episodios de rechazo entre trasplantados tratados con y sin I-mTOR. Los trabajos podían medir la correlación células reguladoras-filtrado glomerular. Se evaluó la codependencia células reguladoras-eficacia de los I-mTOR. Resultados: Se incluyeron 5 ensayos y 9 estudios. Las diferencias clínicas no permitieron una estimación cuantitativa del efecto de la inmunosupresión en el número de células reguladoras. Sin embargo, observamos que hay más células reguladoras con sirolimus o everolimus. El número de episodios de rechazo fue similar con anticalcineurínicos que con I-mTOR, a pesar de las diferencias en el número de células reguladoras. La correlación combinada células reguladoras-filtrado glomerular fue prospectivamente de 0,114, con un intervalo de confianza al 95% (IC 95%) de 0,062-0,406, y retrospectivamente, de 0,13 (IC 95% 0,0-0,361). Existen pruebas directas, aunque de bajo nivel (aleatorización estratificada por el biomarcador), respecto a la codependencia células reguladoras-eficacia de los I-mTOR. Conclusión: El número de células reguladoras puede asociarse a buenos resultados o desenlaces en los tratados con I-mTOR (eficacia antirrechazo), considerando la relación entre estas células y la función del injerto. Registro: PROSPERO (CRD42016046285) (AU)

Background and objective: Circulating regulatory T cells could become a suitable biomarker for kidney recipients. The objective of this study was to evaluate the effect of mammalian target of rapamycin (mTOR) inhibitors on regulatory T cell numbers, and the clinical interest of this effect. Material and methods: Systematic review of published and unpublished studies. Worldwide databases or repositories. Randomised controlled trials and cohort studies comparing regulatory T cell counts and rejection episodes between patients with and without mTOR inhibitors were searched. Correlation of regulatory T cells-glomerular filtration rate might be supplied. Co-dependency regulatory T cells-mTOR inhibitors efficacy was evaluated. Results: Five trials and 9 studies were included. Clinical differences made it difficult to obtain quantitative estimates of the effect of immunosuppression on regulatory T cell numbers. Nevertheless, we found that there are higher regulatory T cell numbers under treatment with sirolimus or everolimus. Rejection episodes were similar under calcineurin inhibitors and mTOR inhibitors despite different regulatory T cell numbers. Pooled correlation regulatory T cells-glomerular filtration rate was, prospectively 0.114 (95% confidence interval [95% CI] 0.062-0.406), and retrospectively 0.13 (95% CI 0.0-0.361). There is direct evidence although of low level (biomarker-stratified randomisation) on the co-dependency regulatory T cells-mTOR inhibitors efficacy. Conclusions: Regulatory T cells counts may be associated with better outcomes under treatment with mTOR inhibitors (anti-rejection efficacy), considering that there is a relationship between these cells and kidney graft function Registration: PROSPERO (CRD42016046285) (AU)

Peripheral blood regulatory T cell counts as a predictive biomarker for the outcome of kidney transplant: A systematic review. / Recuentos de células T reguladoras en sangre periférica como biomarcador predictivo del resultado del trasplante renal: revisión sistemática.

BACKGROUND AND OBJECTIVE: Circulating regulatory T cells could become a suitable biomarker for kidney recipients. The objective of this study was to evaluate the effect of mammalian target of rapamycin (mTOR) inhibitors on regulatory T cell numbers, and the clinical interest of this effect. MATERIAL AND METHODS: Systematic review of published and unpublished studies. Worldwide databases or repositories. Randomised controlled trials and cohort studies comparing regulatory T cell counts and rejection episodes between patients with and without mTOR inhibitors were searched. Correlation of regulatory T cells-glomerular filtration rate might be supplied. Co-dependency regulatory T cells-mTOR inhibitors efficacy was evaluated. RESULTS: Five trials and 9 studies were included. Clinical differences made it difficult to obtain quantitative estimates of the effect of immunosuppression on regulatory T cell numbers. Nevertheless, we found that there are higher regulatory T cell numbers under treatment with sirolimus or everolimus. Rejection episodes were similar under calcineurin inhibitors and mTOR inhibitors despite different regulatory T cell numbers. Pooled correlation regulatory T cells-glomerular filtration rate was, prospectively 0.114 (95% confidence interval [95% CI] 0.062-0.406), and retrospectively 0.13 (95% CI 0.0-0.361). There is direct evidence although of low level (biomarker-stratified randomisation) on the co-dependency regulatory T cells-mTOR inhibitors efficacy. CONCLUSIONS: Regulatory T cells counts may be associated with better outcomes under treatment with mTOR inhibitors (anti-rejection efficacy), considering that there is a relationship between these cells and kidney graft function. REGISTRATION: PROSPERO (CRD42016046285).