Calcineurin Inhibitor in NEuRoloGically deceased donors to decrease kidney delayed graft function study: study protocol of the CINERGY Pilot randomised controlled trial.

INTRODUCTION: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk. METHODS AND ANALYSIS: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation. ETHICS AND DISSEMINATION: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309). TRIAL REGISTRATION NUMBER: NCT05148715.

A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Evaluation and comparison of four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy.

BACKGROUND: Semi-quantitative and quantitative immunoassays are the most commonly used methodology to evaluate immunity post immunization. OBJECTIVES: To compare four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy. STUDY DESIGN: 210 serological samples from COVID-19 infection and vaccination cohorts were used to create a serological sample repository. Serological methods from four manufacturers, namely Euroimmun, Roche, Abbott, and DiaSorin, were evaluated for quantitative, semi-quantitative, and qualitative antibody measurements. All four methods measure IgG antibodies against the SARS-CoV-2 spike receptor-binding domain and report the results in Binding Antibody Unit/mL (BAU/mL). A Total Error Allowable (TEa) of ±25% was chosen as the criteria to determine whether two methods are clinically equivalent quantitatively. Semi-quantitative results (titers) were derived using numeric antibody concentration divided by the cut-off value for each method. RESULTS: All paired quantitative comparisons demonstrated unacceptable performance. With ±25% as TEa, the best agreement was 74 (35.2% out of 210 samples) between Euroimmun and DiaSorin, whereas the lowest agreement was 11 (5.2% out of 210 samples) between Euroimmun and Roche. Antibody titers amongst all four methods were significantly different (p < 0.001). The highest titer difference from the same sample is between Roche and DiaSorin with a 1392-fold difference. On qualitative comparison, none of the paired comparison showed acceptable comparison (p < 0.001). CONCLUSIONS: Poor correlation exists between four evaluated assays, quantitatively, semi-quantitatively, and qualitatively. Further harmonization of assays is required to achieve comparable measurements.

Use of Sodium-Glucose Cotransporter-2 Inhibitors in Renal Transplant Patients With Diabetes: A Brief Review of the Current Literature.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents commonly prescribed in type 2 diabetes (T2D). They have been shown to slow the progression of diabetic nephropathy and improve cardiovascular outcomes in high-risk individuals, although major cardiovascular and renal outcome clinical trials have excluded renal transplant patients. The aim of this review was to determine the outcomes and safety with use of SGLT2 inhibitors in renal transplant patients with diabetes. We conducted a review of randomized controlled trials, cohort studies, case series and case reports that assessed use of SGLT2 inhibitors in patients post-renal transplant with either pre-existing T2D or new-onset diabetes after transplant. The outcomes assessed included blood pressure, renal allograft function (estimated glomerular filtration rate), proteinuria (urinary albumin-to-creatinine ratio), glycemic control, body weight and adverse effects. A total of 9 studies, which included 144 patients, were reviewed. SGLT2 inhibitor use in renal transplant patients demonstrates either a small or nonsignificant reduction in blood pressure and results in overall stable renal allograft function. It also results in modest improvement in glycemic control as well as weight reduction. The incidence of adverse effects is low and reversible, as reported in previous nontransplant clinical trials. Overall, our findings suggest beneficial outcomes with no significant adverse effects or complications with the use of SGLT2 inhibitors in renal transplant patients with diabetes; however, these findings are based on small trials, and thus well-designed trials in this population are warranted.

Effect of Bisphosphonates on Bone Health in Adult Renal Transplant Patients: Beyond the First Year Posttransplant-A Systematic Review and Meta-Analysis.

BACKGROUND: Bone mineral density (BMD) decreases postrenal transplantation. Evidence demonstrating the effects of bisphosphonates on BMD and fracture risk beyond 1-year posttransplant is sparse in existing literature, but remains essential to enhance clinical outcomes in this population. OBJECTIVE: Our study aimed to systematically review and meta-analyze the current literature on the use of any bisphosphonate in the adult renal transplant population beyond the first year of renal transplant to determine its effect on BMD and fracture incidence. DESIGN: We conducted a systematic review and meta-analysis of primary research literature that included full-text, English-language, original randomized clinical trials (RCTs) and observational studies. SETTING: Patient data were primarily captured in an outpatient setting across various studies. PATIENTS: Our population of interest was patients older than 18 years who received deceased/living donor kidney transplantation and any bisphosphonate with a follow-up greater than 12 months posttransplantation. MEASUREMENTS: The primary outcome was change in BMD from baseline. Secondary outcomes were the incidence of fractures and effects of other confounders on bone health. METHODS: We included RCTs and observational studies that satisfied our inclusion criteria. Each study was analyzed for risk of bias and data were extrapolated to analyze for overall statistical significance accounting for heterogeneity of studies. RESULTS: Sixteen studies (N = 1762) were analyzed. The follow-up ranged from 12 to 98 months. There was a nonsignificant improvement in BMD with bisphosphonate treatment persisting into the second and third years posttransplant at the lumbar spine. The calculated standardized mean BMD difference was -0.29 (-0.75 to 0.17), P = .22. Only 5 studies reported a total of 43 new fractures. Prednisone (P < .01), low body weight (P < .001), low body mass index (P < .01), and male gender (P < .05) correlated with reduced lumbar and femoral BMD. LIMITATIONS: Limitations of this review include the use of BMD as a surrogate outcome, the bias of the included studies, and the incomplete reporting data in numerous analyzed studies. CONCLUSIONS: We demonstrate no statistically significant benefit of bisphosphonate treatment on BMD beyond the first year postrenal transplantation. Despite heterogeneity of treatment, a differential nonsignificant improvement in lumbar spine BMD was consistent and may be clinically relevant. TRIAL REGISTRATION: PROSPERO CRD42019125593.

CONTEXTE: La densité minérale osseuse (DMO) décroit à la suite d'une greffe rénale. Les données probantes faisant état des effets des bisphosphonates sur la DMO et le risque de fracture au-delà d'un an post-greffe sont rares dans la littérature, mais demeurent essentielles pour améliorer les résultats cliniques pour cette population. OBJECTIF: L'étude actuelle visait à réaliser une revue systématique et une méta-analyse de la littérature faisant état de l'usage des bisphosphonates dans une population de greffés rénaux adultes, au-delà de la première année post-greffe, afin de connaître les effets de cette médication sur la DMO et sur l'incidence de fractures. TYPE D'ÉTUDE: Une revue systématique et une méta-analyse de la littérature ont été réalisées à partir d'articles rédigés en anglais, présentant les résultats d'essais cliniques et d'études observationnelles. CADRE: Dans les différentes études, les données provenaient principalement de patients suivis sur une base externe. SUJETS: Notre population d'intérêt était constituée de patients adultes ayant subi une greffe rénale provenant d'un donneur décédé ou vivant, ayant reçu un traitement par un bisphosphonate et ayant été suivis pendant plus de douze mois post-transplantation. MESURES: L'issue principale était une variation de la DMO par rapport à la valeur initiale. L'incidence de fractures et les effets des autres facteurs de confusion sur la santé osseuse constituaient les issues secondaires. MÉTHODOLOGIE: Ont été inclus les essais cliniques et les études observationnelles qui répondaient à nos critères d'inclusion. Chaque étude a fait l'objet d'une analyse des risques de biais et les données ont été extrapolées pour analyser la signification statistique de l'ensemble en tenant compte de l'hétérogénéité des études. RÉSULTATS: Seize études (n=1762) ont été analysées. La période de suivi variait de 12 à 98 mois. Une amélioration non significative de la DMO du rachis lombaire ayant persisté dans la deuxième et la troisième année post-greffe a été observée à la suite d'un traitement par un bisphosphonate. La moyenne normalisée calculée des variations de la DMO s'établissait à -0,29 (-0,75 à 0,17; p=0,22). Seules cinq études ont rapporté de nouvelles fractures, pour un total de 43 fractures. La prise de prednisone (p<0,01), un faible poids (p<0, 001), un faible IMC (p<0,01) et le fait d'être un homme (p<0,05) ont corrélé avec une DMO lombaire ou fémorale réduite. LIMITES: Le recours à la DMO comme issue intermédiaire, les biais contenus dans les études incluses et le fait que plusieurs des études analysées comportaient des données incomplètes constituent les limites de l'étude. CONCLUSION: Nous n'avons pu démontrer un avantage statistiquement significatif sur la DMO à poursuivre un traitement par les bisphosphonates au-delà de la première année suivant une greffe rénale. Malgré l'hétérogénéité du traitement, une amélioration non significative de la DMO lombaire a été observée et pourrait s'avérer pertinente sur le plan clinique.

Quantifying cognitive dysfunction across the spectrum of end-stage kidney disease: A systematic review and meta-analysis.

Cognitive dysfunction is reportedly highly prevalent among chronic kidney disease (CKD) patients. A variety of screening tools and neuropsychiatric batteries are used to quantify the magnitude and nature of this dysfunction. Our objective is to summarize the neurocognitive testing used, and determine what degree cognitive dysfunction is reported in CKD patients. All study designs published in English that contained participants who were either pre-dialysis patients, haemodialysis (HD) or peritoneal dialysis (PD) patients or renal transplant recipients were considered. Reported comparative non-CKD control data was also collected. All study designs were included. The search period encompassed articles from 1980 to May 2018. This review is registered with PROSPERO (CRD42018096568). Of the 1711 articles screened, 148 articles were relevant and used in the meta-analysis. Commonly used assessments were The Mini-Mental State Examination (MMSE), The Modified Mini-Mental State Examination, the Trails Making Tests (TMT) forms A and B and components of the Wechsler Adult Intelligence Scale: Digit Span and Digit Symbol. Means for all assessments were adjusted using a random effects model to account for the differences in variance. Adjusted mean MMSE scores were significantly lower for both pre-dialysis (26.08, n = 17 073) and HD (26.31, n = 3314) patients when compared to non-CKD controls (28.21, n = 5226). PD (58.01 s, n = 859) and HD (56.04 s, n = 2344) patients also took significantly longer to complete the Trails Making Task A than non-CKD controls (37.62 s, n = 4809). Patients with CKD, especially pre-dialysis and those requiring dialysis, are likely to exhibit impairments in cognition that can be identified with specific screening neuropsychological assessments.

Posttransplantation proteinuria: an approach to diagnosis and management.

Proteinuria is a common problem encountered in the treatment of renal transplant recipients, occurring in up to 45% of patients. Proteinuria from native kidneys falls rapidly after renal transplantation, and persistent or worsening proteinuria is usually indicative of allograft pathology. Biopsy studies of transplant patients with proteinuria have confirmed that transplant-specific diagnoses (transplant glomerulopathy, interstitial fibrosis and tubular atrophy, and acute rejection) are more commonly found than other proteinuric conditions, such as glomerulonephritis. As in the nontransplant setting, proteinuria is associated with worse clinical outcomes, including an increased risk for death, cardiovascular events, and graft loss. Blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers will reduce proteinuria, but the long-term effect of these medications on patient and graft survival remains unknown.

Sudden cardiac death in chronic kidney disease: epidemiology and prevention.

Annual cardiovascular mortality in patients with chronic kidney disease (CKD) is much higher than in the general population. The rate of sudden cardiac death increases as the stage of CKD increases and could be responsible for 60% of cardiac deaths in patients undergoing dialysis. In hemodialysis units treating patients with CKD, cardiac arrest occurs at a rate of seven arrests per 100,000 hemodialysis sessions. Important risk factors for sudden cardiac death in patients with CKD include hospitalization within the past 30 days, a drop of 30 mmHg in systolic blood pressure during hemodialysis, duration of life on hemodialysis, time since the previous dialysis session, and the presence of concomitant diabetes mellitus. As a result of the adverse cardiomyopathic and vasculopathic milieu in CKD, the occurrence of arrhythmias, conduction abnormalities, and sudden cardiac death could be exacerbated by electrolyte shifts, divalent ion abnormalities, diabetes, sympathetic overactivity, in addition to inflammation and perhaps iron deposition. Impaired baroreflex effectiveness and sensitivity, as well as obstructive sleep apnea, might also contribute to the risk of sudden death in CKD. The likelihood of survival following cardiac arrest is very low in dialysis patients. Primary and secondary prevention of cardiac arrest could reduce cardiovascular mortality in patients with CKD. Cardioverter-defibrillator implantation decreases the risk of sudden death in patients with CKD. The decision to implant a cardioverter-defibrillator should be influenced by the patient's age and stage of CKD.

Mechanisms of the cardiorenal syndromes.

The kidney and heart have essential roles in maintaining blood volume homeostasis and in the regulation of systemic blood pressure. Acute or chronic dysfunction in either the heart or kidneys can induce dysfunction in the other organ, resulting in the so-called cardiorenal syndromes, which are classified into five different types. Abrupt worsening of cardiac function predisposes an individual to acute kidney injury from renal hypoperfusion or renal congestion. Progressive, sometimes permanent, chronic kidney impairment can result from chronic renal hypoperfusion or congestion. Heart failure is common in patients with acute kidney injury. Chronic kidney disease predisposes individuals to atherosclerotic, arteriosclerotic and cardiomyopathic disease. Finally, both cardiac and renal disease can also occur secondary to systemic conditions, such as diabetes or autoimmune disease. This Review examines the mechanisms presiding over the first four types of cardiorenal syndromes. These mechanisms provide a template that accounts for the heart-kidney interactions that occur in patients whose concomitant cardiac and renal conditions result from a third cause.