Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014. OBJECTIVES: To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS: In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 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 Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data.  AUTHORS' CONCLUSIONS: The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.

ANTECEDENTES: Los fármacos estimulantes de la eritropoyesis (FEE) se suelen utilizar para tratar la anemia en personas con nefropatía crónica. Sin embargo, su uso se ha asociado a eventos cardiovasculares. Esta es una actualización de una revisión Cochrane publicada por primera vez en 2014. OBJETIVOS: Comparar la eficacia y la seguridad de los FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi­polietilenglicol epoetina beta y FEE biosimilares) entre sí, con placebo, o ningún tratamiento, para el tratamiento de la anemia en adultos con nefropatía crónica. MÉTODOS DE BÚSQUEDA: En esta actualización, a través del contacto con el documentalista, y con el uso de términos de búsqueda pertinentes para esta revisión, se realizaron búsquedas en el Registro de estudios del Grupo Cochrane de Riñón y trasplante (Cochrane Kidney and Transplant) hasta el 29 de abril de 2022. Los estudios en el registro se identifican mediante búsquedas en CENTRAL, MEDLINE y EMBASE, en resúmenes de congresos, en el portal de búsqueda de la Plataforma de registros internacionales de ensayos clínicos (ICTRP) y en ClinicalTrials.gov. CRITERIOS DE SELECCIÓN: Se consideraron para la inclusión los ensayos controlados aleatorizados (ECA) que incluían una comparación de un FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi­polietilenglicol epoetina beta, una epoetina biosimilar o una darbepoetina alfa biosimilar) con otro FEE, placebo o ningún tratamiento en adultos con NC. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores independientes examinaron los resultados de la búsqueda y extrajeron los datos. La síntesis de los datos se realizó mediante un metanálisis pareado de efectos aleatorios (expresada como odds ratio [OR] y sus intervalos de confianza [IC] del 95%) y un metanálisis en red. Se evaluó la heterogeneidad y la inconsistencia dentro de los metanálisis con técnicas estándares y se planeó crear subgrupos y una metarregresión para explorar las fuentes de heterogeneidad o la inconsistencia. Se evaluó la certeza en las estimaciones del tratamiento para los desenlaces principales (prevención de transfusiones de sangre y muerte [por cualquier causa]) mediante el método Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTADOS PRINCIPALES: En esta actualización se incluyeron 62 nuevos estudios (9237 participantes), por lo que la revisión incluye ahora 117 estudios con 25 237 participantes. La mayoría de los estudios tuvieron riesgo alto o incierto de sesgo en la mayoría de los dominios metodológicos. En general, los resultados siguen siendo similares en esta actualización en comparación con la revisión anterior de 2014. Para prevenir la transfusión de sangre, la epoetina alfa (OR 0,28; IC del 95%: 0,13 a 0,61; evidencia de certeza baja) y la epoetina beta (OR 0,19; IC del 95%: 0,08 a 0,47; evidencia de certeza baja) podrían ser superiores al placebo, y la darbepoetina alfa fue probablemente superior al placebo (OR 0,27; IC del 95%: 0,11 a 0,67; evidencia de certeza moderada). La metoxi­polietilenglicol epoetina beta (OR 0,33; IC del 95%: 0,11 a 1,02; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,34; IC del 95%: 0,11 a 1,03; evidencia de certeza muy baja) y una darbepoetina alfa biosimilar (OR 0,37; IC del 95%: 0,07 a 1,91; evidencia de certeza muy baja) tuvieron efectos inciertos sobre la prevención de la transfusión de sangre en comparación con el placebo. Los efectos comparativos de los FEE comparados con otro FEE sobre la prevención de las transfusiones de sangre fueron inciertos, en evidencia de certeza baja a muy baja. Los efectos sobre la mortalidad (por cualquier causa) fueron inciertos para la epoetina alfa (OR 0,79; IC del 95%: 0,51 a 1,22; evidencia de certeza baja), la epoetina beta (OR 0,69; IC del 95%: 0,40 a 1,20; evidencia de certeza baja), la metoxi­polietilenglicol epoetina beta (OR 1,07; IC del 95%: 0,67 a 1,71; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,80; IC del 95%: 0,47 a 1,36; evidencia de certeza baja) y una darbepoetina alfa biosimilar (OR 1,63; IC del 95%: 0,51 a 5,23; evidencia de certeza muy baja) en comparación con el placebo. Es probable que no hubiera diferencias entre la darbepoetina alfa y el placebo en las probabilidades de muerte (por cualquier causa) (OR 0,99; IC del 95%: 0,81 a 1,21; evidencia de certeza moderada). Los efectos comparativos de los FEE comparados con otro FEE sobre la mortalidad (por cualquier causa) fueron inciertos en evidencia de certeza baja a muy baja. Es probable que la epoetina beta aumentara el riesgo de hipertensión en comparación con el placebo (OR 2,17; IC del 95%: 1,17 a 4,00; evidencia de certeza moderada). En comparación con el placebo, la epoetina alfa (OR 2,10; IC del 95%: 1,22 a 3,59; evidencia de certeza muy baja), la epoetina beta (OR 1,88; IC del 95%: 1,12 a 3,14; evidencia de certeza baja) y la metoxi­polietilenglicol epoetina beta (OR 1,98; IC del 95%: 1,05 a 3,74; evidencia de certeza baja) podrían aumentar las probabilidades de hipertensión, pero una epoetina biosimilar (OR 1,88; IC del 95%: 0,96 a 3,67; evidencia de certeza baja) y una darbepoetina alfa biosimilar (OR 1,98; IC del 95%: 0,84 a 4,66; evidencia de certeza baja) tuvieron efectos inciertos sobre la hipertensión. Los efectos comparativos de todos los FEE comparados con otro FEE, placebo o ningún tratamiento sobre la mortalidad cardiovascular, el infarto de miocardio, el accidente cerebrovascular, la trombosis de acceso vascular, la insuficiencia renal y la disnea fueron inciertos. El análisis en red para el cansancio no fue posible debido a los pocos datos disponibles. CONCLUSIONES DE LOS AUTORES: Los efectos comparativos de los diferentes FEE sobre las transfusiones de sangre, la mortalidad (por cualquier causa y cardiovascular), los eventos cardiovasculares mayores, el infarto de miocardio, el accidente cerebrovascular, la trombosis de acceso vascular, la insuficiencia renal, el cansancio y la disnea fueron inciertos.

Factors associated with functional arteriovenous fistula at hemodialysis start and arteriovenous fistula non-use in a single-center cohort.

BACKGROUND: The gold standard of commencing hemodialysis with a functional arteriovenous fistula (AVF) is challenging. We aim to review factors associated with functional AVF at hemodialysis start at a tertiary hospital. METHODS: We retrospectively reviewed incident hemodialysis patients or who had AVF creation at a single tertiary hospital from 2011 to 2016. Data was extracted for patient comorbidities, duration from referral to AVF creation and hemodialysis start, estimated glomerular filtration rate (eGFR) at surgical referral, referring nephrologist, events accelerating eGFR decline, and revisions for "failing to mature" AVF to assess factors associated with non-functioning AVF or late AVF creation, using multinomial logistic regression. RESULTS: Two hundred two patients received hemodialysis and 51 had AVF creation but did not dialyze (AVF futility rate 20%). Of these, 133 (66%) commenced hemodialysis with a central venous catheter (CVC) and 69 (34%) with an AVF. Patients with functional AVFs at hemodialysis start were referred earlier than those with non-functional AVFs (median 256 vs 66 days before hemodialysis start, p = 0.001). Age, sex, eGFR at surgical referral, and comorbidities were not predictive of patients with functional AVFs. Events accelerating eGFR decline were associated with an increased incidence of CVC at hemodialysis start (risk ratio (RR) 4.21, 95% confidence interval (CI) 1.96-9.03, p < 0.0001). Referring nephrologists external to our renal unit may be associated with non-functional AVF at hemodialysis start (RR 6.60, 95% CI 1.74-25.13, p = 0.006). CONCLUSIONS: We found that functional AVFs required referral a median of 256 days prior to hemodialysis start and events accelerating eGFR decline increase the incidence of CVC at hemodialysis start. Age, sex, eGFR at surgical referral, and comorbidities did not inform the likelihood of timely AVF creation and evaluation of further predictive pre-dialysis factors is necessary to identify patients requiring early AVF creation whilst minimizing the cost of unnecessary procedures.

Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.

BACKGROUND: Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014. OBJECTIVES: To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 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 Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE. MAIN RESULTS: Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists. AUTHORS' CONCLUSIONS: The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.

Interventions for preventing bone disease in kidney transplant recipients.

BACKGROUND: People who have chronic kidney disease (CKD) have important changes to bone structure, strength, and metabolism. Children experience bone deformity, pain, and delayed or impaired growth. Adults experience limb and vertebral fractures, avascular necrosis, and pain. The fracture risk after kidney transplantation is four times that of the general population and is related to Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) occurring with end-stage kidney failure, steroid-induced bone loss, and persistent hyperparathyroidism after transplantation. Fractures may reduce quality of life and lead to being unable to work or contribute to community roles and responsibilities. Earlier versions of this review have found low certainty evidence for effects of treatment. This is an update of a review first published in 2005 and updated in 2007. OBJECTIVES: This review update evaluates the benefits and harms of interventions for preventing bone disease following kidney transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 16 May 2019 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 Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: RCTs and quasi-RCTs evaluating treatments for bone disease among kidney transplant recipients of any age were eligible. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial risks of bias and extracted data. Statistical analyses were performed using random effects meta-analysis. The risk estimates were expressed as a risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous outcomes together with the corresponding 95% confidence interval (CI). The primary efficacy outcome was bone fracture. The primary safety outcome was acute graft rejection. Secondary outcomes included death (all cause and cardiovascular), myocardial infarction, stroke, musculoskeletal disorders (e.g. skeletal deformity, bone pain), graft loss, nausea, hyper- or hypocalcaemia, kidney function, serum parathyroid hormone (PTH), and bone mineral density (BMD). MAIN RESULTS: In this 2019 update, 65 studies (involving 3598 participants) were eligible; 45 studies contributed data to our meta-analyses (2698 participants). Treatments included bisphosphonates, vitamin D compounds, teriparatide, denosumab, cinacalcet, parathyroidectomy, and calcitonin. Median duration of follow-up was 12 months. Forty-three studies evaluated bone density or bone-related biomarkers, with more recent studies evaluating proteinuria and hyperparathyroidism. Bisphosphonate therapy was usually commenced in the perioperative transplantation period (within 3 weeks) and regardless of BMD. Risks of bias were generally high or unclear leading to lower certainty in the results. A single study reported outcomes among 60 children and adolescents. Studies were not designed to measure treatment effects on fracture, death or cardiovascular outcomes, or graft loss.Compared to placebo, bisphosphonate therapy administered over 12 months in transplant recipients may prevent fracture (RR 0.62, 95% CI 0.38 to 1.01; low certainty evidence) although the 95% CI included the possibility that bisphosphonate therapy might make little or no difference. Fracture events were principally vertebral fractures identified during routine radiographic surveillance. It was uncertain whether any other drug class decreased fracture (low or very low certainty evidence). It was uncertain whether interventions for bone disease in kidney transplantation reduce all-cause or cardiovascular death, myocardial infarction or stroke, or graft loss in very low certainty evidence. Bisphosphonate therapy may decrease acute graft rejection (RR 0.70, 95% CI 0.55 to 0.89; low certainty evidence), while it is uncertain whether any other treatment impacts graft rejection (very low certainty evidence). Bisphosphonate therapy may reduce bone pain (RR 0.20, 95% CI 0.04 to 0.93; very low certainty evidence), while it was very uncertain whether bisphosphonates prevent spinal deformity or avascular bone necrosis (very low certainty evidence). Bisphosphonates may increase to risk of hypocalcaemia (RR 5.59, 95% CI 1.00 to 31.06; low certainty evidence). It was uncertain whether vitamin D compounds had any effect on skeletal, cardiovascular, death, or transplant function outcomes (very low certainty or absence of evidence). Evidence for the benefits and harms of all other treatments was of very low certainty. Evidence for children and young adolescents was sparse. AUTHORS' CONCLUSIONS: Bisphosphonate therapy may reduce fracture and bone pain after kidney transplantation, however low certainty in the evidence indicates it is possible that treatment may make little or no difference. It is uncertain whether bisphosphonate therapy or other bone treatments prevent other skeletal complications after kidney transplantation, including spinal deformity or avascular bone necrosis. The effects of bone treatment for children and adolescents after kidney transplantation are very uncertain.