Hypomagnesemia and the Risk of New-Onset Diabetes Mellitus after Kidney Transplantation.

Several studies suggest a link between post-transplant hypomagnesemia and new-onset diabetes after transplantation (NODAT), but this relationship remains controversial. We conducted a retrospective cohort study of 948 nondiabetic kidney transplant recipients from January 1, 2000, to December 31, 2011, to examine the association between serum magnesium level and NODAT. Multivariable Cox proportional hazards models were fitted to evaluate the risk of NODAT as a function of baseline (at 1 month), time-varying (every 3 months), and rolling-average (i.e., mean for 3 months moving at 3-month intervals) serum magnesium levels while adjusting for potential confounders. A total of 182 NODAT events were observed over 2951.2 person-years of follow-up. Multivariable models showed an inverse relationship between baseline serum magnesium level and NODAT (hazard ratio [HR], 1.24 per 0.1 mmol/L decrease; 95% confidence interval [95% CI], 1.05 to 1.46; P=0.01). The association with the risk of NODAT persisted in conventional time-varying (HR, 1.32; 95% CI, 1.14 to 1.52; P<0.001) and rolling-average models (HR, 1.34; 95% CI, 1.13 to 1.57; P=0.001). Hypomagnesemia (serum magnesium <0.74 mmol/L) also significantly associated with increased risk of NODAT in baseline (HR, 1.58; 95% CI, 1.07 to 2.34; P=0.02), time-varying (HR, 1.78; 95% CI, 1.29 to 2.45; P<0.001), and rolling-average models (HR, 1.83; 95% CI, 1.30 to 2.57; P=0.001). Our results suggest that lower post-transplant serum magnesium level is an independent risk factor for NODAT in kidney transplant recipients. Interventions targeting serum magnesium to reduce the risk of NODAT should be evaluated.

Outcomes of early hospital readmission after kidney transplantation: Perspectives from a Canadian transplant centre.

BACKGROUND: Early hospital readmissions (EHRs) after kidney transplantation range in incidence from 18%-47% and are important and substantial healthcare quality indicators. EHR can adversely impact clinical outcomes such as graft function and patient mortality as well as healthcare costs. EHRs have been extensively studied in American healthcare systems, but these associations have not been explored within a Canadian setting. Due to significant differences in the delivery of healthcare and patient outcomes, results from American studies cannot be readily applicable to Canadian populations. A better understanding of EHR can facilitate improved discharge planning and long-term outpatient management post kidney transplant. AIM: To explore the burden of EHR on kidney transplant recipients (KTRs) and the Canadian healthcare system in a large transplant centre. METHODS: This single centre cohort study included 1564 KTRs recruited from January 1, 2009 to December 31, 2017, with a 1-year follow-up. We defined EHR as hospitalizations within 30 d or 90 d of transplant discharge, excluding elective procedures. Multivariable Cox and linear regression models were used to examine EHR, late hospital readmissions (defined as hospitalizations within 31-365 d for 30-d EHR and within 91-365 d for 90-d EHR), and outcomes including graft function and patient mortality. RESULTS: In this study, 307 (22.4%) and 394 (29.6%) KTRs had 30-d and 90-d EHRs, respectively. Factors such as having previous cases of rejection, being transplanted in more recent years, having a longer duration of dialysis pretransplant, and having an expanded criteria donor were associated with EHR post-transplant. The cumulative probability of death censored graft failure, as well as total graft failure, was higher among the 90-d EHR group as compared to patients with no EHR. While multivariable models found no significant association between EHR and patient mortality, patients with EHR were at an increased risk of late hospital readmissions, poorer kidney function throughout the 1st year post-transplant, and higher hospital-based care costs within the 1st year of follow-up. CONCLUSION: EHRs are associated with suboptimal outcomes after kidney transplant and increased financial burden on the healthcare system. The results warrant the need for effective strategies to reduce post-transplant EHR.

What Are the Burden, Causes, and Costs of Early Hospital Readmissions After Kidney Transplantation?

INTRODUCTION: Kidney transplant recipients are at risk for complications resulting in early hospital readmission. This study sought to determine the incidences, risk factors, causes, and financial costs of early readmissions. DESIGN: This single-centre cohort study included 1461 kidney recipients from 1 Jul 2004 to 31 Dec 2012, with at least 1-year follow-up. Early readmission was defined as hospitalization within 30 or 90-days postdischarge from transplant admission. Associations between various parameters and 30 and 90-days posttransplant were determined using multivariable Cox proportional hazards models. The hospital-associated costs of were assessed. RESULTS: The rates of early readmission were 19.4% at 30 days and 26.8% at 90 days posttransplant. Mean cost per 30-day readmission was 11 606 CAD. Infectious complications were the most common reasons and resulted in the greatest cost burden. Factors associated with 30 and 90-days in multivariable models were recipient history of chronic lung disease (hazard ratio or HR 1.78 [95%CI: 1.14, 2.76] and HR 1.68 [1.14, 2.48], respectively), median time on dialysis (HR 1.07 [95% CI: 1.01, 1.13]and HR 1.06 [95% CI: 1.01, 1.11], respectively), being transplanted preemptively (HR 1.75 [95% CI: 1.07, 2.88] and HR 1.66 [95% CI: 1.07, 2.57], respectively), and having a transplant hospitalization lasting of and more than 11 days (HR 1.52 [95% CI: 1.01, 2.27] and HR 1.65 [95% CI: 1.16, 2.34], respectively). DISCUSSION: Early hospital readmission after transplantation was common and costly. Strategies to reduce the burden of early hospital readmissions are needed for all patients.

A Systematic Review of the Effect of N-Acetylcysteine on Serum Creatinine and Cystatin C Measurements.

INTRODUCTION: N-acetylcysteine (NAC) is an antioxidant that can regenerate glutathione and is primarily used for acetaminophen overdose. NAC has been tested and used for preventing iatrogenic acute kidney injury or slowing the progression of chronic kidney disease, with mixed results. There are conflicting reports that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, we conducted a systematic review of the literature to determine whether there is an effect of NAC on kidney function as measured with serum creatinine and cystatin C. METHODS: A literature search was conducted to identify all study types reporting a change in serum creatinine after NAC administration. The primary outcome was change in serum creatinine after NAC administration. The secondary outcome was a change in cystatin C after NAC administration. Subgroup analyses were conducted to assess effect of creatinine assay (Jaffe vs. non-Jaffe and intravenous vs. oral). RESULTS: Six studies with a total of 199 participants were eligible for the systematic review and meta-analysis. There was a small but significant decrease in serum creatinine after NAC administration overall (weighted mean difference [WMD], -2.80 µmol/L [95% confidence interval {CI} -5.6 to 0.0]; P = 0.05). This was greater with non-Jaffe methods (WMD, -3.24 µmol/L [95% CI -6.29 to -0.28]; P = 0.04) than Jaffe (WMD, -0.51 µmol/L [95% CI -7.56 to 6.53]; P = 0.89) and in particular with intravenous (WMD, -31.10 µmol/L [95% CI -58.37 to -3.83]; P = 0.03) compared with oral NAC (WMD, -2.5 µmol/L [95% CI -5.32 to 0.32]; P = 0.08). There was no change in cystatin C after NAC administration. DISCUSSION: NAC causes a decrease in serum creatinine but not in cystatin C, suggesting analytic interference rather than an effect on kidney function. Supporting this, the effect was greater with non-Jaffe methods of creatinine estimation. Future studies of NAC should use the Jaffe method of creatinine estimation when kidney outcomes are being reported. Even in clinical settings, the use of an enzymatic assay when high doses of intravenous NAC are being used may result in underdiagnosis or delayed diagnosis of acute kidney injury.

Mapping multicenter randomized controlled trials in anesthesiology: a scoping review.

BACKGROUND: Evidence suggests that there are substantial inconsistencies in the practice of anesthesia. There has not yet been a comprehensive summary of the anesthesia literature that can guide future knowledge translation interventions to move evidence into practice. As the first step toward identifying the most promising interventions for systematic implementation in anesthesia practice, this scoping review of multicentre RCTs aimed to explore and map the existing literature investigating perioperative anesthesia-related interventions and clinical patient outcomes. METHODS: Multicenter randomized controlled trials were eligible for inclusion if they involved a tested anesthesia-related intervention administered to adult surgical patients (≥ 16 years old), with a control group receiving either another anesthesia intervention or no intervention at all. The electronic databases Embase (via OVID), MEDLINE, and MEDLINE in Process (via OVID), and Cochrane Central Register of Control Trials (CENTRAL) were searched from inception to February 26, 2021. Studies were screened and data were extracted by pairs of independent reviewers in duplicate with disagreements resolved through consensus or a third reviewer. Data were summarized narratively. RESULTS: We included 638 multicentre randomized controlled trials (n patients = 615,907) that met the eligibility criteria. The most commonly identified anesthesia-related intervention theme across all studies was pharmacotherapy (n studies = 361 [56.6%]; n patients = 244,610 [39.7%]), followed by anesthetic technique (n studies = 80 [12.5%], n patients = 48,455 [7.9%]). Interventions were most often implemented intraoperatively (n studies = 233 [36.5%]; n patients = 175,974 [28.6%]). Studies typically involved multiple types of surgeries (n studies = 187 [29.2%]; n patients = 206 667 [33.5%]), followed by general surgery only (n studies = 115 [18.1%]; n patients = 201,028 [32.6%]) and orthopedic surgery only (n studies = 94 [14.7%]; n patients = 34,575 [5.6%]). Functional status was the most commonly investigated outcome (n studies = 272), followed by patient experience (n studies = 168), and mortality (n studies = 153). CONCLUSIONS: This scoping review provides a map of multicenter RCTs in anesthesia which can be used to optimize future research endeavors in the field. Specifically, we have identified key knowledge gaps in anesthesia that require further systematic assessment, as well as areas where additional research would likely not add value. These findings provide the foundation for streamlining knowledge translation in anesthesia in order to reduce practice variation and enhance patient outcomes.

Approach to treatment of cicatricial ectropion: a systematic review and meta-analysis comparing surgical and minimally invasive options.

Cicatricial ectropion can involve the skin, subcutaneous tissue, muscle, and septum to result in chronic tearing and keratopathy. Surgery involving the orbital rim or eyelid is a common cause. Minimally invasive techniques may provide alternative options for correction, but the comparative benefit to surgery is unknown. To compare the efficacy of surgical and minimally invasive minimally invasive treatment options for cicatricial ectropion. A comprehensive literature search of Medline, EMBASE, and the Cochrane Library published from 1960 to August 2019 was performed for studies that described any treatment of cicatricial ectropion. 1391 studies were found, of which 31 had extractable data for 299 patients. Pooling of outcome data occurred for the primary and secondary outcomes. The complete and partial response rates to treatment (primary outcomes) as well as the recurrence rate and physician global assessment of cosmesis (secondary outcomes) were analyzed. Surgical correction resulted in complete correction in 79% of patients compared to 63% of hyaluronic acid treated patients. Hyaluronic acid injection had a better aesthetic outcome, but a higher recurrence rate overall. Hyaluronic acid filler with a high G' along with delayed dissolution trended toward a lower recurrence rate. Other minimally invasive treatments had little data. The literature found was limited to mostly single-center, observational studies. Hyaluronic acid may be a viable alternative for cicatricial ectropion in those patients who cannot undergo surgery. Further prospective studies are required to routinely recommend minimally invasive techniques.

A systematic review on the efficacy and safety of low molecular weight heparin as an anticancer therapeutic in preclinical animal models.

OBJECTIVE: The therapeutic effects of low molecular weight heparins (LMWH) may extend past thrombosis prevention, with preclinical evidence demonstrating anti-metastatic properties. Clinical evidence on the topic, however, remains controversial. A systematic review of preclinical evidence may help elucidate reasons for this contradictory evidence. The objective of our systematic review is to assess the anti-metastatic properties of LMWHs in solid tumour animal models. METHODS: MEDLINE, Embase, Web of Science and PubMed were searched from inception to May 12th, 2020. All articles were screened independently and in duplicate. Studies that compared LMWH to a placebo or no treatment arm in solid tumour animal models were included. The primary outcome was the burden of metastasis. Secondary outcomes included primary tumour growth and mortality. The risk of bias was assessed in duplicate using a modified Cochrane Risk of Bias tool. RESULTS: Forty-two studies were included in the review. Administration of a LMWH was associated with a significant decrease in the burden of metastasis (SMD -2.18; 95% CI -2.66 to -1.70). Additionally, the administration of a LMWH was also associated with a significant reduction in primary tumour growth (SMD -1.95; 95% CI -2.56 to -1.34) and risk of death (RR 0.39; 95% CI 0.16-0.97). All included studies were deemed to be at an unclear risk of bias for at least one methodological criterion. CONCLUSIONS: Our results demonstrate that LMWH can effectively reduce metastatic burden and reduce tumour growth in preclinical animal models of solid tumour malignancies. Reasons for the contradiction with clinical evidence require further exploration.

The Effect of N-Acetylcysteine on Creatinine Measurement: Protocol for a Systematic Review.

BACKGROUND: N-acetylcysteine (NAC) is an antioxidant which can regenerate glutathione and is primarily used for acetaminophen overdose. It is also a potential therapy to prevent iatrogenic acute kidney injury or slow the progression of chronic kidney disease. It has been considered in this context by many studies with mixed results. Notably, a biological-mechanism rationale for a protective effect of NAC has never been adequately reported. Among conflicting reports, there appears to be evidence that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, a systematic review of the literature will be conducted to determine whether there is an effect of NAC on kidney function measured with serum creatinine. OBJECTIVE: To determine the effect of NAC on kidney function. DESIGN: A systematic review and meta-analysis. SETTINGS: Prospective studies, with administration of NAC, in the absence of any other change in kidney function (such as contrast administration or surgery). PATIENTS: Adult humans aged 18 years old or more, either healthy volunteers or with chronic kidney disease, were administered with NAC. Populations having little to no kidney function such as in end-stage kidney disease will be excluded. MEASUREMENTS: Serum creatinine and/or cystatin C measurements before and after NAC administration. METHODS: An information specialist will assist in searching MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify all study types including randomized controlled trials, and prospective cohort studies reporting change in serum creatinine after NAC administration. Two reviewers will independently screen the titles and abstracts of the studies obtained from the search using predefined inclusion criteria and will then extract data from the full texts of selected studies. The weighted mean difference will be calculated for change in creatinine with NAC, using random-effects analysis. Quality assessment will be done with the Cochrane Risk of Bias tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. RESULTS: The outcome of interest is kidney function as reported by either change in serum creatinine and/or serum cystatin C measurement for randomized trials or comparing baseline (pre-NAC dose) values and those following the NAC dose. LIMITATIONS: Possible heterogeneity and publication bias and lack of mechanistic data. CONCLUSIONS: This systematic review will provide a synthesis of current evidence on the effect of NAC on serum creatinine measurement. These findings will provide clinicians with guidelines and serve as a strong research base for future studies in this field. SYSTEMATIC REVIEW REGISTRATION: This review is registered with PROSPERO, CRD42017055984.

CONTEXTE: La N-acétylcystéine (NAC) est un antioxydant capable de régénérer le glutathion et principalement utilisé pour traiter les cas de surdose d'acétaminophène. La NAC pourrait également s'avérer efficace comme traitement préventif de l'insuffisance rénale aiguë iatrogénique ou pour ralentir la progression de l'insuffisance rénale chronique. Cette substance a fait l'objet de plusieurs études dans ce contexte, mais les résultats demeurent mitigés. Notamment, il reste toujours à rapporter adéquatement une justification de l'effet protecteur de la NAC sur la base d'un mécanisme biologique. Parmi les rapports contradictoires, certaines données montreraient que la NAC abaisse artificiellement les valeurs de créatinine sérique mesurées sans améliorer la fonction rénale, potentiellement par interférence de l'essai. À la lumière de ces résultats divergents, une revue systématique de la littérature sera effectuée pour déterminer si la NAC produit un effet sur la fonction rénale mesurée par la créatinine sérique. OBJECTIF: Mesurer l'effet de l'administration de NAC sur la fonction rénale. TYPE D'ÉTUDE: Une revue systématique de la littérature et une méta-analyse. CADRE: Les études prospectives avec administration de NAC sans autres changements dans la fonction rénale; l'administration d'un produit de contraste ou une intervention chirurgicale, par exemple. SUJETS: Des adultes, volontaires sains ou atteints de néphropathie chronique, ayant reçu de la NAC. Seront exclues les populations dont la fonction rénale est faible ou inexistante; notamment, les cas d'insuffisance rénale terminale. MESURES: Des mesures de la créatinine sérique et/ou de la cystatine C faites avant et après l'administration de NAC. MÉTHODOLOGIE: Un documentariste spécialisé assistera les recherches dans les bases de données MEDLINE, EMBASE et Cochrane CENTRAL afin de répertorier tous les types d'essais, y compris les essais contrôlés à répartition aléatoire, et toutes les études de cohorte prospectives faisant état d'une variation de la créatinine sérique à la suite de l'administration de NAC. À l'aide de critères d'inclusion prédéfinis, deux réviseurs seront indépendamment chargés de trier les titres et abrégés des études répertoriées lors de la revue de la littérature. Ils devront ensuite extraire les données des textes des études qui auront été retenues. Une analyse des effets aléatoires sera utilisée pour calculer la moyenne pondérée des écarts pour les variations observées dans les mesures de créatinine en présence de NAC. La qualité des essais aléatoires sera évaluée à l'aide de l'outil Cochrane sur le risque de biais, et celle des études observationnelles sera mesurée avec l'échelle de Newcastle-Ottawa. RÉSULTATS: Le principal résultat d'intérêt est la fonction rénale telle que rapportée soit par un changement dans les mesures de créatinine sérique et/ou de la cystatine C dans les essais à répartition aléatoire, soit en comparant les valeurs mesurées avant et après l'administration d'une dose de NAC. LIMITES: L'hétérogénéité des données, de possibles biais de publication et un manque de données mécanistiques. CONCLUSION: Cette revue systématique offrira une synthèse des données probantes actuelles sur l'effet de la NAC sur les mesures de créatinine sérique. Ces résultats fourniront des lignes directrices aux cliniciens et serviront de bases solides pour les recherches futures dans ce domaine.

Cancer recurrence after solid organ transplantation: A systematic review and meta-analysis.

Solid organ transplant recipients (SOTR) with a pre-transplant malignancy (PTM) have been thought to be at high risk of cancer recurrence. However, recent population-based studies report cancer recurrence rates in SOTR similar to those of non-transplant patients. A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library to identify studies reporting cancer recurrence in SOTR with PTM. Quality assessment was performed using a validated tool for assessing the quality of an observational study with no control group designed by the Institute of Health Economics. Overall and site-specific recurrence rates per person-year were pooled using generalized linear random/mixed-effects meta-analysis models and an exact likelihood approach based on a binomial and Poisson distribution. Meta-regressions, subgroup and sensitivity meta-analyses were used to explore sources of heterogeneity. Fifty-seven eligible studies were identified and 39 were included in the meta-analysis. The pooled recurrence rate was 1.6 (95% CI 1.0-2.6) per 100 person-year for all studies, and 1.1 (95% CI 0.5-2.7) when restricted to population-based studies. The recurrence rate was higher for kidney (2.4 per 100 person-year, 95% CI 1.0-5.6) compared with liver (1.0 per 100 person-year, 95% CI 0.4-2.6), and cardiothoracic recipients (1.3 per 100 person-year, 95% CI 0.6-2.7). Time from cancer diagnosis to transplantation (TCT) ≤ 5 years was associated with greater risk of cancer recurrence compared to TCT > 5 years (risk ratio: 2.80, 95% CI 1.12-7.01). In conclusion, the risk of cancer recurrence in recipients with PTM is considerably lower than historic reports used to establish recommendations for listing patients with PTM. Evidence to support minimum cancer remission times before transplantation is limited.

Outcomes of Solid Organ Transplant Recipients With Preexisting Malignancies in Remission: A Systematic Review and Meta-Analysis.

BACKGROUND: Solid organ transplant recipients (SOTR) with a pretransplant malignancy (PTM) are at increased risk for cancer recurrence. However, it is unclear whether differences in survival and incidence of posttransplant de novo malignancies exist between recipients with PTM and those without PTM. We designed a systematic review to synthesize all available evidence assessing these outcomes. METHODS: A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library to identify studies comparing the following outcomes in SOTR by PTM status: (1) all-cause mortality, (2) cancer-specific mortality, and (3) incidence of posttransplant de novo malignancy. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Thirty-two cohort studies were included. Recipients with PTM were at increased risk of all-cause mortality compared to recipients without PTM (pooled hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.27-1.81). Similarly, recipients with PTM were 3 times more likely to die of cancer (pooled HR, 3.13; 95% CI, 2.29-4.27). The pooled HR for developing posttransplant de novo malignancy was also increased (HR, 1.92; 95% CI, 1.52-2.42). The association of all-cause mortality and SOTR with PTM did not vary by transplanted organ. CONCLUSIONS: Pretransplant malignancy is associated with increased risk of all cause-mortality, cancer-specific mortality and of developing de novo malignancies after transplantation compared with those without PTM. These results reaffirm the need for careful selection of transplant recipients with PTM. Tailored screening and management strategies should be developed for this group of patients.