Background: BK virus-associated nephropathy (BKVAN), caused by infection with or reactivation of BK virus, remains a challenge in kidney transplantation. Screening is recommended for all kidney transplant recipients. For those with clinically significant infection, reduction of immunosuppression is the cornerstone of management. There is no specific antiviral or immunomodulatory therapy sufficiently effective for routine use. Objectives: This review aimed to examine the benefits and harms of interventions for BK virus infection in kidney transplant recipients. Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 5 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria: All randomised controlled trials (RCTs) and cohort studies investigating any intervention for the treatment or prevention of BKVAN for kidney transplant recipients. Data collection and analysis: Two authors independently assessed the study quality and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results: Twelve RCTs (2669 randomised participants) were included. Six studies were undertaken in single centres, and six were multicentre studies; two of these were international studies. The ages of those participating ranged from 44 to 57 years. The length of follow-up ranged from three months to five years. All studies included people with a kidney transplant, and three studies included people with signs of BK viraemia. Studies were heterogeneous in terms of the type of interventions and outcomes assessed. The overall risk of bias was low or unclear. Intensive screening for the early detection of BK viraemia or BK viruria prevents graft loss (1 study, 908 participants: RR 0.00, 95% CI 0.00 to 0.05) and decreases the presence of decoy cells and viraemia at 12 months (1 study, 908 participants: RR 0.06, 95% CI 0.03 to 0.11) compared to routine care (high certainty evidence). No other outcomes were reported. Compared to placebo, fluoroquinolones may slightly reduce the risk of graft loss (3 studies, 393 participants: RR 0.37, CI 0.09 to 1.57; I2 = 0%; low certainty evidence), probably makes little or no difference to donor-specific antibodies (DSA), may make little or no difference to BK viraemia and death, had uncertain effects on BKVAN and malignancy, but may increase the risk of tendonitis (2 studies, 193 participants: RR 5.66, CI 1.02 to 31.32; I2 = 0%; low certainty evidence). Compared to tacrolimus (TAC), cyclosporin (CSA) probably makes little or no difference to graft loss and death, may make little or no difference to BKVAN and malignancy, but probably decreases BK viraemia (2 studies, 263 participants: RR 0.61, 95% CI 0.26 to 1.41; I2 = 38%) and probably reduces the risk of new-onset diabetes after transplantation (1 study, 200 participants: RR 0.41, 95% CI 0.12 to 1.35) (both moderate certainty evidence). Compared to azathioprine, mycophenolate mofetil (MMF) probably makes little or no difference to graft loss and BK viraemia but probably reduces the risk of death (1 study, 133 participants: RR 0.43, 95% CI 0.16 to 1.16) and malignancy (1 study, 199 participants: RR 0.43, 95% CI 0.16 to 1.16) (both moderate certainty evidence). Compared to mycophenolate sodium (MPS), CSA has uncertain effects on graft loss and death, may make little or no difference to BK viraemia, but may reduce BKVAN (1 study, 224 participants: RR 0.06, 95% CI 0.00 to 1.20; low certainty evidence). Compared to immunosuppression dose reduction, MMF or TAC conversion to everolimus or sirolimus may make little or no difference to graft loss, BK viraemia or BKVAN (low certainty evidence). TAC conversion to sirolimus probably results in more people having a reduced BK viral load (< 600 copies/mL) than immunosuppression reduction (1 study, 30 participants: RR 1.31, 95% CI 0.90 to 1.89; moderate certainty evidence). Compared to MPS, everolimus had uncertain effects on graft loss and BK viraemia, may reduce BKVAN (1 study, 135 participants: 0.06, 95% CI 0.00 to 1.11) and may increase the risk of death (1 study, 135 participants: RR 3.71, 95% CI 0.20 to 67.35) (both low certainty evidence). Compared to CSA, everolimus may make little or no difference to BK viraemia, has uncertain effects on graft loss and BKVAN, but may increase the risk of death (1 study, 185 participants: RR 3.71, 95% CI 0.42 to 32.55; low certainty evidence). Compared to immunosuppression reduction, the leflunomide derivative FK778 may make little or no difference to graft loss, probably results in a greater reduction in plasma BK viral load (1 study, 44 participants: -0.60 copies/µL, 95% CI -1.22 to 0.02; moderate certainty evidence), but had uncertain effects on BKVAN and malignancy. Aggravated hypertension may be increased with KF778 (1 study, 46 participants: RR 8.23, 95% CI 0.50 to 135.40; low certainty evidence). There were no deaths in either group. Authors' conclusions: Intense monitoring early after transplantation for BK viruria and BK viraemia is effective in improving BK virus infection outcomes as it helps with early detection of the infection and allows for a timely reduction in immunosuppression reduction. There is insufficient evidence to support any other intervention for BK virus infection in kidney transplant recipients.
BACKGROUND: Kidney transplantation is the therapy of choice for many patients with end-stage kidney disease (ESKD) with an improvement in survival rates and satisfactory short term graft survival. However, there has been little improvement in long-term survival. The place of target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus), which have different modes of action from other commonly used immunosuppressive agents, in kidney transplantation remains uncertain. This is an update of a review first published in 2006.
OBJECTIVES: To evaluate the short and long-term benefits and harms of TOR-I (sirolimus and everolimus) when used in primary immunosuppressive regimens for kidney transplant recipients.
SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 20 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs in which drug regimens, containing TOR-I commenced within seven days of transplant, were compared to alternative drug regimens, were included without age restriction, dosage or language of report.
DATA COLLECTION AND ANALYSIS: Three authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. The certainty of the evidence was assessed using GRADE MAIN RESULTS: Seventy studies (17,462 randomised participants) were included; eight studies included two comparisons to provide 78 comparisons. Outcomes were reported at six months to three years post transplant. Risk of bias was judged to be low for sequence generation in 25 studies, for allocation concealment in 23 studies, performance bias in four studies, detection bias in 65 studies, attrition bias in 45 studies, selective reporting bias in 48 studies, and for other potential bias in three studies. Risk of bias was judged to be at high risk of bias for sequence generation in two studies, allocation concealment in two studies, performance bias in 61 studies, detection bias in one study, attrition bias in four studies, for selective reporting bias in 11 studies and for other potential risk of bias in 46 studies. Compared with CNI and antimetabolite, TOR-I with antimetabolite probably makes little or no difference to death (RR 1.31, 95% CI 0.87 to 1.98; 19 studies) or malignancies (RR 0.86, 95% CI 0.50 to 1.48; 10 studies); probably increases graft loss censored for death (RR 1.32, 95% CI 0.96 to 1.81; 15 studies), biopsy-proven acute rejection (RR 1.60, 95% CI 1.25 to 2.04; 15 studies), need to change treatment (RR 2.42, 95% CI 1.88 to 3.11; 14 studies) and wound complications (RR 2.56, 95% CI 1.94 to 3.36; 12 studies) (moderate certainty evidence); but reduces CMV infection (RR 0.43, 95% CI 0.29 to 0.63; 13 studies) (high certainty evidence). Compared with antimetabolites and CNI, TOR-I with CNI probably makes little or no difference to death (RR 1.06, 95% CI 0.84 to 1.33; 31 studies), graft loss censored for death (RR 1.09, 95% CI 0.82 to 1.45; 26 studies), biopsy-proven acute rejection (RR 0.95, 95% CI 0.81 to 1.12; 24 studies); and malignancies (RR 0.83, 95% CI 0.64 to 1.07; 17 studies); probably increases the need to change treatment (RR 1.56, 95% CI 1.28 to 1.90; 25 studies), and wound complications (RR 1.56, 95% CI 1.28 to 1.91; 17 studies); but probably reduces CMV infection (RR 0.44, 95% CI 0.34 to 0.58; 25 studies) (moderate certainty evidence). Lower dose TOR-I and standard dose CNI compared with higher dose TOR-I and reduced dose CNI probably makes little or no difference to death (RR 1.07, 95% CI 0.64 to 1.78; 9 studies), graft loss censored for death (RR 1.09, 95% CI 0.54 to 2.20; 8 studies), biopsy-proven acute rejection (RR 0.87, 95% CI 0.67 to 1.13; 8 studies), and CMV infection (RR 1.42, 95% CI 0.78 to 2.60; 5 studies) (moderate certainty evidence); and may make little or no difference to wound complications (RR 0.95, 95% CI 0.53 to 1.71; 3 studies), malignancies (RR 1.04, 95% CI 0.36 to 3.04; 7 studies), and the need to change treatments (RR 1.18, 95% CI 0.58 to 2.42; 5 studies) (low certainty evidence). Lower dose of TOR-I compared with higher doses probably makes little or no difference to death (RR 0.84, 95% CI 0.67 to 1.06; 13 studies), graft loss censored for death (RR 0.92, 95% CI 0.71 to 1.19; 12 studies), biopsy-proven acute rejection (RR 1.26, 95% CI 1.10 to 1.43; 11 studies), CMV infection (RR 0.87, 95% CI 0.63 to 1.21; 9 studies), wound complications (RR 0.92, 95% CI 0.66 to 1.29; 7 studies), and malignancy (RR 0.84, 95% CI 0.54 to 1.32; 10 studies) (moderate certainty evidence); and may make little or no difference to the need to change treatments (RR 0.91, 95% CI 0.78 to 1.05; 10 studies) (low certainty evidence). It is uncertain whether sirolimus and everolimus differ in their effects on kidney function and lipid levels because the certainty of the evidence is very low based on a single small study with only three months of follow-up.
AUTHORS' CONCLUSIONS: In studies with follow-up to three years, TOR-I with an antimetabolite increases the risk of graft loss and acute rejection compared with CNI and an antimetabolite. TOR-I with CNI potentially offers an alternative to an antimetabolite with CNI as rates of graft loss and acute rejection are similar between interventions and TOR-I regimens are associated with a reduced risk of CMV infections. Wound complications and the need to change immunosuppressive medications are higher with TOR-I regimens. While further new studies are not required, longer-term follow-up data from participants in existing methodologically robust RCTs are needed to determine how useful immunosuppressive regimens, which include TOR-I, are in maintaining kidney transplant function and survival beyond three years.
CONTEXTO: La tromboprofilaxis farmacológica consiste en equilibrar un menor riesgo de tromboembolismo venoso (TEV) frente a un mayor riesgo de sangrado, un compromiso que depende críticamente de los riesgos de ETV y de sangrado en ausencia de profilaxis (riesgo basal). OBJETIVO: Proporcionar estimaciones del riesgo basal de TEV sintomática y hemorragia que requiera reoperación en cirugía oncológica urológica. ADQUISICIÓN DE EVIDENCIAS: Se identificaron estudios observacionales contemporáneos que informaron TEV sintomática o sangrado después de procedimientos urológicos. Se utilizaron los estudios con el menor riesgo de sesgo y se explicó el uso de la tromboprofilaxis y la duración del seguimiento para obtener las mejores estimaciones de los riesgos iniciales dentro de las 4 semanas de la cirugía. Utilizamos el enfoque GRADE para evaluar la calidad de la evidencia. SÍNTESIS DE EVIDENCIA: Se incluyeron 71 estudios que informaron sobre 14 procedimientos de cáncer urológico. La calidad de la evidencia fue generalmente moderada para prostatectomía y cistectomía, y baja o muy baja para otros procedimientos. La duración de la tromboprofilaxis fue muy variable. El riesgo de TEV en las cistectomías fue alto (2.6-11.6% entre los grupos de riesgo), mientras que el riesgo de sangrado fue bajo (0.3%). El riesgo de TEV en las prostatectomías varió según el procedimiento, de 0,2-0,9% en prostatectomía robótica sin disección de ganglios linfáticos pélvicos (PLND) a 3,9-15,7% en prostatectomía abierta con PLND prolongada. El riesgo de sangrado fue del 0,1-1,0%. El riesgo de TEV después de los procedimientos renales fue de 0,7-2,9% para los pacientes de bajo riesgo y de 2,6-11,6% para los pacientes de alto riesgo; El riesgo de sangrado fue de 0,1-2,0%. CONCLUSIONES: La tromboprofilaxis extendida se justifica en algunos procedimientos (p. Ej., Cistectomía abierta y robótica), pero no en otros (por ejemplo, prostatectomía robótica sin PLND en pacientes de bajo riesgo). Para los procedimientos de "llamada cercana", las decisiones dependerán de valores y preferencias con respecto a TEV y sangrado. RESUMEN DEL PACIENTE: Los médicos a menudo dan adelgazadores de sangre a los pacientes para prevenir coágulos de sangre después de la cirugía para el cáncer urológico. Desafortunadamente, los anticoagulantes también aumentan el sangrado. Este estudio proporciona información sobre el riesgo de coágulos y hemorragia que es crucial para decidir por o contra la administración de anticoagulantes.
OBJECTIVE: The aim of this meta-analysis was to evaluate the efficacy of basiliximab versus antithymocyte globulin for induction therapy in renal allograft.
METHODS: Medline (PubMed), Embase, Ovid, Cochrane, and the Chinese Biomedical Literature databases were searched to identify prospective randomized controlled trials that compared basiliximab with antithymocyte globulin (ATG) for induction therapy in renal transplantation. RevMan 5.1 software and Stat Manager V4.1 software were used for the meta-analysis.
RESULTS: Eight RCTs were included, including a total of 1153 patients. Of these, 547 (47%) had received basiliximab, and 606 (53%) had received ATG. The pooled results revealed that the basiliximab had a lower rate of neoplasm compared with ATG [odds ratio (OR) 0.26; 95% confidence interval (CI) 0.08-0.78; P = 0.02]. There were no significant differences between the two drugs regarding 1-year acute rejection rate (OR 1.32; 95% CI 0.93-1.87; P = 0.13), 1-year graft survival rate (OR 0.73; 95% CI 0.45-1.18; P = 0.20), 1-year patient survival rate (OR 0.52; 95% CI 0.27-1.02; P = 0.06), 1-year infection rate (OR 0.90; 95% CI 0.48-1.68; P = 0.73).
CONCLUSION: Induction therapy of basiliximab has similar short-time effects on the recipients in renal transplantation compared with that of ATG. However, regarding the long-term effect, as represented by the rate of neoplasm, basiliximab has a significant advantage.
BACKGROUND: Rejection and infection can occur after kidney transplantation and are important factors in preserving graft kidney function. The use of immunosuppressant agents in transplantation is therefore important, and the question of which induction therapy should be used as an immunosuppressant is controversial.
OBJECTIVE: The goal of this study was to assess the comparative benefits and harms of various maintenance immunosuppressive induction agents in adults undergoing kidney transplantation by using a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy.
METHODS: CENTRAL, MEDLINE, EMBASE, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers were searched until May 2017 to identify randomized controlled trials on immunosuppression for kidney transplantation.
RESULTS: Twenty-seven studies involving 4484 participants were eligible for analysis. Induction and maintenance treatments were administered for 12 months. There was no evidence of differences in outcomes between therapies on all-cause mortality, graft loss, cytomegalovirus, BK virus, neutropenia, thrombocytopenia, and biopsy-proven acute rejection. However, compared with intravenous basiliximab (an interleukin-2 receptor antagonist [IL-2RA]), the most effective treatments to decrease biopsy-proven acute rejection were intravenous alemtuzumab and rabbit antithymocyte globulin (rATG). The odds ratios were 0.45 (95% confidence interval [CI], 0.29-40.78) and 0.63 (95% CI, 0.42-0.95), respectively. As a side effect, rATG was accompanied by more bacterial infection than the IL-2RA (OR, 1.8 [95% CI, 1.01-2.8]).
CONCLUSIONS: The determination of induction in kidney transplantation is important for future prognosis of the graft kidney. Alemtuzumab and rATG exhibited lower biopsy-proven acute rejection than the IL-2RA. As a side effect, rATG produced frequent bacterial infections.
BACKGROUND: mTOR-Is positively influence the occurrence and course of certain tumors after solid organ transplantation. The effect of mTOR-Is on the overall incidence of tumors irrespective of their origin is not entirely clear. Furthermore, conflicting data have been shown on mortality under mTOR-Is.
METHODS: The current literature was searched for prospective randomized controlled renal transplantation trials. There were 1415 trials screened of which 13 could be included (pts. = 5924). A minimum follow-up of 24 months was mandatory for inclusion. Incidence of malignancies and patient survival was assessed in meta-analyses.
RESULTS: The average follow-up of all trials was 40.6 months. Malignancy was significantly reduced under mTOR-Is compared to CNIs (RR 0.70, CI 0.49-0.99, p = 0.046). This effect remained stable when combined with CNIs (RR 0.58, CI 0.34-1.00, p = 0.05). When NMSCs were excluded the risk for malignancy remained significantly reduced under mTOR-I therapy (mono and combi) (RR 0.43, CI 0.24-0.77, p = 0.0046). Graft survival was minimally decreased under mTOR-Is (RR 0.99, CI 0.98-1.00, p = 0.054). This effect was abrogated when mTOR-Is were combined with CNIs (RR 0.99, CI 0.97-1.02, p = 0.50). Patient survival was not different (RR 1.00, CI 0.99-1.01, p = 0.54).
CONCLUSIONS: Posttransplant patients have a lower incidence of malignancy when treated with an mTOR-I no matter if it is used in combination with CNIs or not. This beneficial effect remains significant even when NMSCs are excluded. With currently used mTOR-I-based regimen patient and graft survival is not different compared to CNI therapies.
BACKGROUND: Conversion to everolimus is often used in kidney transplantation to overcome calcineurin inhibitor (CNI) nephrotoxicity but there is conflicting evidence for this approach.
OBJECTIVES: To investigate the benefits and harm from randomized clinical trials (RCTs) involving the conversion from CNI to everolimus after kidney transplantation.
METHODS: Databases were searched up to March 2016. Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).
RESULTS: Eleven RCTs, with a total of 1,633 patients, met the final inclusion criteria. Patients converted to everolimus had improved renal function at 1 year posttransplant with an estimated glomerular filtration rate (eGFR) of 5.36 mL/min per 1.73 m2 greater than patients remaining on CNI (p = 0.0005) and the longer-term results (> 1 year) of renal function was identical to that of 1 year. There was not a substantial difference in graft loss, mortality, and the occurrence of adverse events (AEs) or serious AEs. However, the risks of acute rejection and trial termination due to AEs with everolimus are respectively 1.82 and 2.63 times greater than patients staying on CNI at 1 year posttransplant (p = 0.02, p = 0.03, respectively). Further, those patients who converted to everolimus had a substantially greater risk of anemia, hyperlipidemia, hypercholesterolemia, hypokalemia, proteinuria, stomatitis, mouth ulceration, and acne.
CONCLUSIONS: Conversion from CNI to everolimus after kidney transplantation is associated with improved renal function in the first 5 years posttransplant but increases the risk of acute rejection at 1 year posttransplant and may not be well endured.
AIM: To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin (mTOR) inhibitors with or without calcineurin inhibitors (CNIs) in renal transplant recipients.
METHODS: We analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, mTOR inhibitors as an alternative to CNI within six months of renal transplant by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus using MeSH terms.
RESULTS: Six articles of early withdrawal of CNI and introduction of mTOR-inhibitors within six months of renal transplantation were sought. Glomerular filtration rate (GFR) and serum creatinine were significantly better in mTOR inhibitor group with equivalent survival at 12 mo, even though Biopsy Proven Acute rejection was significantly higher in mTOR-inhibitor group.
CONCLUSION: The evidence reviewed in this meta-analysis suggests that early introduction mTOR-inhibitors substantial CNI minimization. The mTOR inhibitors such as everolimus and sirolimus, due to their complementary mechanism of action and favourable nephrotoxicity profile; better glomerular filtration, lower serum creatinine with equivalent survival. Having said that, due to the higher rejection rate, may influence the use of these regimens to patients with moderate to high immunological risk patients.
JUSTIFICATIVA Y OBJETIVOS: El objetivo de este metaanálisis es comparar las incidencias de citomegalovirus y las infecciones por virus de polioma BK en receptores de trasplante renal que reciben un objetivo de mamífero del régimen basado en inhibidores de rapamicina (mTOR) en comparación con un régimen basado en inhibidores de calcineurina. DISEÑO, AJUSTE, PARTICIPANTES Y MEDIDAS: Realizamos una búsqueda exhaustiva de ensayos controlados y aleatorios hasta enero de 2016 que abordan nuestro objetivo. Otros resultados incluyeron rechazo agudo, pérdida de injerto, eventos adversos graves, proteinuria, complicaciones de cicatrización de la herida, y eGFR. Dos revisores seleccionaron los estudios elegibles, los datos resumidos y evaluaron el riesgo de sesgo. Evaluamos la calidad de la evidencia utilizando la metodología de evaluación, desarrollo y evaluación de calificación de recomendaciones. Resultados Se incluyeron 28 ensayos controlados aleatorios con 6211 participantes clasificados en comparación 1: inhibidor de mTOR frente a inhibidor de calcineurina y comparación 2: inhibidor de mTOR más dosis reducida de inhibidor de calcineurina frente a dosis regular de inhibidor de calcineurina. Los resultados mostraron una menor incidencia de infección por citomegalovirus en el grupo con inhibidores de mTOR, tanto en la comparación 1 (relación de riesgo, 0,54; intervalo de confianza del 95%: 0,41 a 0,72), con alta calidad de la evidencia y comparación 2 (razón de riesgo de 0,43; Intervalo de confianza, 0,24 a 0,80), con una calidad moderada de la evidencia. La evidencia disponible no confirmó ni descartó una reducción de la infección por el virus del polioma BK en el grupo con inhibidores de mTOR en ambas comparaciones. Los resultados secundarios revelaron eventos adversos más graves y rechazos agudos en el grupo con inhibidores de mTOR en comparación 1 y ninguna diferencia en la comparación 2. No hubo diferencias en la pérdida de injerto en ambas comparaciones. La eGFR fue mayor en el grupo basado en el inhibidor de mTOR en comparación 1 (diferencia media = 4,07 ml / min por 1,73 m (2), intervalo de confianza del 95%, 1,34 a 6,80) y similar al grupo con inhibidores de la calcineurina en comparación 2. Se produjeron más proteinuria y complicaciones de curación de heridas en los grupos basados en inhibidores de mTOR. Conclusiones. Se encontró evidencia de moderada a alta calidad de riesgo reducido de infección por citomegalovirus en receptores de trasplante renal en el inhibidor basado en mTOR en comparación con el régimen basado en inhibidores de calcineurina. Nuestra revisión también sugirió que una combinación de un inhibidor mTOR y una dosis reducida de inhibidor de la calcineurina puede estar asociada con eGFR similar y las tasas de rechazos agudos y eventos adversos graves en comparación con un régimen estándar basado en inhibidores de la calcineurina a expensas de una mayor incidencia de proteinuria Y complicaciones de cicatrización de heridas.
Los inhibidores de la calcineurina (CNI) pueden reducir el rechazo agudo del trasplante y la pérdida inmediata del injerto, pero están asociados con efectos adversos significativos como la hipertensión y la nefrotoxicidad que pueden contribuir al rechazo crónico. La toxicidad de la CNI ha conducido a numerosos estudios que investigan la retirada de la CNI y las estrategias de reducción progresiva. A pesar de esto, la incertidumbre permanece sobre la minimización o retirada de CNI. OBJETIVOS: Esta revisión tuvo como objetivo analizar los beneficios y los daños de la disminución o retirada de la CNI en términos de función y pérdida del injerto, incidencia de episodios de rechazo agudo, efectos secundarios relacionados con el tratamiento (hipertensión, hiperlipidemia) y muerte. Métodos de búsqueda: Se realizaron búsquedas en el registro especializado de riñones y trasplantes Cochrane a 11 de octubre de 2016 a través del contacto con el especialista en información utilizando los términos de búsqueda relevantes para esta revisión. Los estudios contenidos en el Registro Especializado se identifican a través de estrategias de búsqueda diseñadas específicamente para CENTRAL, MEDLINE y EMBASE; Procedimientos de conferencia de mano; Y buscar en el portal de búsqueda del International Clinical Trials Register (ICTRP) y ClinicalTrials.gov. Se incluyeron todos los ensayos controlados aleatorios (ECA) en los que se incluyeron los regímenes de fármaco que contenían CNI en comparación con regímenes de fármacos alternativos (retirada de CNI, disminución o dosis baja) en el período posterior al trasplante, sin restricción de edad ni dosis. Dos autores evaluaron de forma independiente los estudios de elegibilidad, riesgo de sesgo y datos extraídos. Los resultados se expresaron como razón de riesgo (RR) o diferencia de medias (MD) con intervalos de confianza del 95% (IC). Se incluyeron 83 estudios en los que participaron 16.156 participantes. La mayoría fueron estudios abiertos; Menos del 30% de los estudios informaron el método de asignación al azar y el ocultamiento de la asignación. Los estudios se analizaron como intención de tratar en el 60% y todos los resultados pre-especificados se informaron en 54 estudios. El sesgo de deserción y notificación no estaban claros en el resto de los estudios, ya que los factores utilizados para juzgar el sesgo se informaron de manera inconsistente. También se observó que el 50% (47 estudios) de los estudios fueron financiados por la industria farmacéutica. Se clasificaron los estudios en cuatro grupos: retirada o evitación de la CNI con o sin sustitución con el objetivo mamífero de los inhibidores de la rapamicina (mTOR-I); Y una dosis baja de CNI con o sin mTOR-I. La retirada de ICC puede conducir al rechazo (RR 2,54; IC del 95%: 1,56 a 4,12; evidencia de certeza moderada), puede tener poca o ninguna diferencia con respecto a la muerte (RR 1,09, 95 % CI 0,96 a 1,24, certidumbre moderada), y probablemente reduce ligeramente la pérdida del injerto (RR 0,85; IC del 95%: 0,74 a 0,98; evidencia de baja calidad). La disminución de la hipertensión se redujo probablemente en el grupo de retirada de CNI (RR 0,82, IC del 95%: 0,71 a 0,95, baja certeza), mientras que la retirada de la CNI puede hacer poca o ninguna diferencia en la neoplasia maligna (RR 1,10, IC 95% (RR 0,87; IC del 95%: 0,52 a 1,45; baja certeza) la evitación de la CNI puede resultar en un mayor rechazo agudo (RR 2,16, IC del 95%: 0,85 a 5,49, baja certeza) pero poco O ninguna diferencia en la pérdida del injerto (RR 0,96; IC del 95%: 0,79 a 1,16; baja certeza). La retirada tardía de la CNI aumentó el rechazo agudo (RR 3,21, IC del 95%: 1,59 a 6,48, certidumbre moderada), pero probablemente redujo la pérdida del injerto (RR 0,84, IC del 95%: 0,72 a 0,97, certezas bajas). Con la introducción de mTOR-I; Probablemente el rechazo agudo aumentó (RR 1,43, IC del 95%: 1,15 a 1,78, certeza moderada) y probablemente hubo poca o ninguna diferencia en la mortalidad (RR 0,96; IC del 95%: 0,69 a 1,36, certeza moderada). La sustitución de mTOR-I puede hacer poca o ninguna diferencia en la pérdida de injerto (RR 0,94, IC del 95%: 0,75 a 1,19, baja certeza), probablemente no hace ninguna diferencia con la hipertensión (RR 0,86; IC del 95%: 0,64 a 1,15; Y probablemente redujo el riesgo de citomegalovirus (RR 0,60, IC del 95%: 0,44 a 0,82, certeza moderada) y malignidad (RR 0,69, IC del 95%: 0,47 a 1,00, baja certeza). Los linfoceles se incrementaron con la sustitución de mTOR-I (RR 1,45, IC del 95%: 0,95 a 2,21, baja certeza) .La baja dosis de CNI combinada con mTOR-I probablemente aumentó la tasa de filtración glomerular (DF) (MD 6,24 ml / min, IC del 95% (RR 0,75; IC del 95%: 0,55 a 1,02; certeza moderada), e hizo poca o ninguna diferencia con el rechazo agudo (RR 1,13; IC del 95%: 0,91 a 1,40; certeza moderada). La hipertensión se redujo (RR 0,98, IC del 95%: 0,80 a 1,20, baja certeza), como fue CMV (RR 0,41, IC del 95%: 0,16 a 1,06, baja certeza). Las dosis bajas de CNI más mTOR-I hacen probablemente poco de diferencia en la malignidad (RR 1,22, IC del 95%: 0,42 a 3,53, baja certeza) y pueden hacer muy poca diferencia con la muerte (RR 1,16, IC del 95%: 0,71 a 1,90; Certidumbre moderada). CONCLUSIONES DE LOS AUTORES: La evitación de CNI aumentó el rechazo agudo y la retirada de la CNI aumentó el rechazo agudo, pero redujo la pérdida del injerto al menos a corto plazo. La dosis baja de CNI con regímenes de inducción redujo el rechazo agudo y la pérdida del injerto sin eventos adversos importantes, también a corto plazo. El uso de mTOR-I redujo las infecciones por CMV pero aumentó el riesgo de rechazo agudo. Estas conclusiones deben atenuarse por la falta de datos a largo plazo en la mayoría de los estudios, particularmente en lo que respecta al rechazo crónico mediado por anticuerpos, y la calidad metodológica subóptima de los estudios incluidos.
Background: BK virus-associated nephropathy (BKVAN), caused by infection with or reactivation of BK virus, remains a challenge in kidney transplantation. Screening is recommended for all kidney transplant recipients. For those with clinically significant infection, reduction of immunosuppression is the cornerstone of management. There is no specific antiviral or immunomodulatory therapy sufficiently effective for routine use. Objectives: This review aimed to examine the benefits and harms of interventions for BK virus infection in kidney transplant recipients. Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 5 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria: All randomised controlled trials (RCTs) and cohort studies investigating any intervention for the treatment or prevention of BKVAN for kidney transplant recipients. Data collection and analysis: Two authors independently assessed the study quality and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results: Twelve RCTs (2669 randomised participants) were included. Six studies were undertaken in single centres, and six were multicentre studies; two of these were international studies. The ages of those participating ranged from 44 to 57 years. The length of follow-up ranged from three months to five years. All studies included people with a kidney transplant, and three studies included people with signs of BK viraemia. Studies were heterogeneous in terms of the type of interventions and outcomes assessed. The overall risk of bias was low or unclear. Intensive screening for the early detection of BK viraemia or BK viruria prevents graft loss (1 study, 908 participants: RR 0.00, 95% CI 0.00 to 0.05) and decreases the presence of decoy cells and viraemia at 12 months (1 study, 908 participants: RR 0.06, 95% CI 0.03 to 0.11) compared to routine care (high certainty evidence). No other outcomes were reported. Compared to placebo, fluoroquinolones may slightly reduce the risk of graft loss (3 studies, 393 participants: RR 0.37, CI 0.09 to 1.57; I2 = 0%; low certainty evidence), probably makes little or no difference to donor-specific antibodies (DSA), may make little or no difference to BK viraemia and death, had uncertain effects on BKVAN and malignancy, but may increase the risk of tendonitis (2 studies, 193 participants: RR 5.66, CI 1.02 to 31.32; I2 = 0%; low certainty evidence). Compared to tacrolimus (TAC), cyclosporin (CSA) probably makes little or no difference to graft loss and death, may make little or no difference to BKVAN and malignancy, but probably decreases BK viraemia (2 studies, 263 participants: RR 0.61, 95% CI 0.26 to 1.41; I2 = 38%) and probably reduces the risk of new-onset diabetes after transplantation (1 study, 200 participants: RR 0.41, 95% CI 0.12 to 1.35) (both moderate certainty evidence). Compared to azathioprine, mycophenolate mofetil (MMF) probably makes little or no difference to graft loss and BK viraemia but probably reduces the risk of death (1 study, 133 participants: RR 0.43, 95% CI 0.16 to 1.16) and malignancy (1 study, 199 participants: RR 0.43, 95% CI 0.16 to 1.16) (both moderate certainty evidence). Compared to mycophenolate sodium (MPS), CSA has uncertain effects on graft loss and death, may make little or no difference to BK viraemia, but may reduce BKVAN (1 study, 224 participants: RR 0.06, 95% CI 0.00 to 1.20; low certainty evidence). Compared to immunosuppression dose reduction, MMF or TAC conversion to everolimus or sirolimus may make little or no difference to graft loss, BK viraemia or BKVAN (low certainty evidence). TAC conversion to sirolimus probably results in more people having a reduced BK viral load (< 600 copies/mL) than immunosuppression reduction (1 study, 30 participants: RR 1.31, 95% CI 0.90 to 1.89; moderate certainty evidence). Compared to MPS, everolimus had uncertain effects on graft loss and BK viraemia, may reduce BKVAN (1 study, 135 participants: 0.06, 95% CI 0.00 to 1.11) and may increase the risk of death (1 study, 135 participants: RR 3.71, 95% CI 0.20 to 67.35) (both low certainty evidence). Compared to CSA, everolimus may make little or no difference to BK viraemia, has uncertain effects on graft loss and BKVAN, but may increase the risk of death (1 study, 185 participants: RR 3.71, 95% CI 0.42 to 32.55; low certainty evidence). Compared to immunosuppression reduction, the leflunomide derivative FK778 may make little or no difference to graft loss, probably results in a greater reduction in plasma BK viral load (1 study, 44 participants: -0.60 copies/µL, 95% CI -1.22 to 0.02; moderate certainty evidence), but had uncertain effects on BKVAN and malignancy. Aggravated hypertension may be increased with KF778 (1 study, 46 participants: RR 8.23, 95% CI 0.50 to 135.40; low certainty evidence). There were no deaths in either group. Authors' conclusions: Intense monitoring early after transplantation for BK viruria and BK viraemia is effective in improving BK virus infection outcomes as it helps with early detection of the infection and allows for a timely reduction in immunosuppression reduction. There is insufficient evidence to support any other intervention for BK virus infection in kidney transplant recipients.
