Randomized open-label crossover assessment of Prograf vs Advagraf on immunosuppressant pharmacokinetics and pharmacodynamics in simultaneous pancreas-kidney patients.

INTRODUCTION: We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf). METHODS: In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4 + ATP levels were taken at specified intervals in addition to standard blood work. RESULTS: Twenty-one patients, who were a minimum of 1 year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study. CONCLUSIONS: It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients.

Effect of Coaching to Increase Water Intake on Kidney Function Decline in Adults With Chronic Kidney Disease: The CKD WIT Randomized Clinical Trial.

Importance: In observational studies, increased water intake is associated with better kidney function. Objective: To determine the effect of coaching to increase water intake on kidney function in adults with chronic kidney disease. Design, Setting, and Participants: The CKD WIT (Chronic Kidney Disease Water Intake Trial) randomized clinical trial was conducted in 9 centers in Ontario, Canada, from 2013 until 2017 (last day of follow-up, May 25, 2017). Patients had stage 3 chronic kidney disease (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73 m2 and microalbuminuria or macroalbuminuria) and a 24-hour urine volume of less than 3.0 L. Interventions: Patients in the hydration group (n = 316) were coached to drink more water, and those in the control group (n = 315) were coached to maintain usual intake. Main Outcomes and Measures: The primary outcome was change in kidney function (eGFR from baseline to 12 months). Secondary outcomes included 1-year change in plasma copeptin concentration, creatinine clearance, 24-hour urine albumin, and patient-reported overall quality of health (0 [worst possible] to 10 [best possible]). Results: Of 631 randomized patients (mean age, 65.0 years; men, 63.4%; mean eGFR, 43 mL/min/1.73 m2; median urine albumin, 123 mg/d), 12 died (hydration group [n = 5]; control group [n = 7]). Among 590 survivors with 1-year follow-up measurements (95% of 619), the mean change in 24-hour urine volume was 0.6 L per day higher in the hydration group (95% CI, 0.5 to 0.7; P < .001). The mean change in eGFR was -2.2 mL/min/1.73 m2 in the hydration group and -1.9 mL/min/1.73 m2 in the control group (adjusted between-group difference, -0.3 mL/min/1.73 m2 [95% CI, -1.8 to 1.2; P = .74]). The mean between-group differences (hydration vs control) in secondary outcomes were as follows: plasma copeptin, -2.2 pmol/L (95% CI, -3.9 to -0.5; P = .01); creatinine clearance, 3.6 mL/min/1.73 m2 (95% CI, 0.8 to 6.4; P = .01); urine albumin, 7 mg per day (95% CI, -4 to 51; P = .11); and quality of health, 0.2 points (95% CI, -0.3 to 0.3; P = .22). Conclusions and Relevance: Among adults with chronic kidney disease, coaching to increase water intake compared with coaching to maintain the same water intake did not significantly slow the decline in kidney function after 1 year. However, the study may have been underpowered to detect a clinically important difference. Trial Registration: clinicaltrials.gov Identifier: NCT01766687.

Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events.

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 µM; interquartile range [IQR]: 12.82-32.70 µM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of glomerulonephritis in adults.

The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of adult nephrologists reviewed the guideline statements for management of glomerular disease in adults and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas for which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the choice of second-line agents, are discussed in more detail. Existing practice variation also is addressed. The relevance of treatment recommendations to the Canadian practitioner is discussed.

Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic syndrome in children.

The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of pediatric nephrologists reviewed the guideline statements for management of childhood nephrotic syndrome and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas in which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the length of corticosteroid therapy for the initial presentation and relapses, definitions of steroid resistance, and choice of second-line agents, are discussed in more detail. Existing practice variation is also addressed.

Biomarkers of inflammation, fibrosis, cardiac stretch and injury predict death but not renal replacement therapy at 1 year in a Canadian chronic kidney disease cohort.

BACKGROUND: Newer biomarkers, reflective of biological processes, such as inflammation and fibrosis, cardiac stretch or damage and vascular health may be useful in understanding clinical events in chronic kidney disease (CKD). We assessed whether these newer biomarkers, alone or as a panel, improve risk prediction for renal replacement therapy or death, over and above conventional clinical, demographic and laboratory variables. METHODS: We conducted a prospective observational Canadian cohort study in 2544 CKD patients with estimated glomerular filtration rate (eGFR) of 15-45 mL/min/1.73 m(2), under nephrology care, in urban and rural centers. We measured traditional clinical and laboratory risk factors, as well as newer biomarkers: cystatin C, high sensitivity c-reactive protein (hsCRP), interleukin 6 (IL6), transforming growth factor ß1 (TGFß1), fibroblast growth factor 23 (FGF23), N-terminal probrain natriuretic peptide (NT-proBNP), troponin I and asymmetric dimethylarginine (ADMA). Key outcomes were renal replacement therapy (RRT, dialysis or transplantation) and death, during the first year follow-up after enrollment: a time point important for clinical decision-making for patients and providers. RESULTS: Newer biomarkers do not improve the prediction of RRT, when added to conventional risk factors such as eGFR, urine albumin to creatinine ratio, hemoglobin, phosphate and albumin. However, in predicting death within 1 year, cystatin C, NT-proBNP, hsCRP and FGF23 values significantly improved model discrimination and reclassification: c statistic increased by absolute 4.3% and Net Reclassification Improvement for categories of low, intermediate and high risk at 11.2%. CONCLUSIONS: Our findings suggest that the addition of newer biomarkers may be useful in predicting death in patients with established CKD within a 1-year timeframe. This information may be useful in informing prognosis and redirect resources to serve patients at higher risk to improve outcomes and sustainability of the nephrology care system.

Similar MPA exposure on modified release and regular tacrolimus.

Concomitant immunosuppression may affect the mycophenolate mofetil exposure. Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) with the potential to reduce the likelihood of nonadherence. It is unknown whether mycophenolic acid (MPA) area under the concentration-time curve (AUC) differs between the 2 tacrolimus (Tac) formulations. In a 2-by-2 crossover design, 20 stable renal transplant recipients on twice-daily Tac either continued their usual Tac therapy (n = 10, group 1) or switched to TacMR for a 12-week period (n = 10, group 2), after which the patients crossed over to the other formulation for another 12-week period. Pharmacokinetic profiles using limited sampling strategies were obtained before randomization (visit 1), and at 12 (visit 2) and 24 weeks (visit 3) at steady state. MPA AUC was calculated using the Pawinski formula. When analyzing visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16.69) mg·h·L(-1), respectively, which was not statistically significant using repeated measures (P = 0.1327, R(2) = 0.1109). We conclude that MPA pharmacokinetic profiles are not altered when converting patients from Tac to TacMR.

Cohort profile: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT).

BACKGROUND: The Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events (CanPREDDICT) is a large, prospective, pan-Canadian, cohort study designed to improve our understanding of determinants of renal and cardiovascular (CV) disease progression in patients with chronic kidney disease (CKD). The primary objective is to clarify the associations between traditional and newer biomarkers in the prediction of specific renal and CV events, and of death in patients with CKD managed by nephrologists. This information could then be used to better understand biological variation in outcomes, to develop clinical prediction models and to inform enrolment into interventional studies which may lead to novel treatments. METHODS/DESIGNS: Commenced in 2008, 2546 patients have been enrolled with eGFR between 15 and 45 ml/min 1.73m2 from a representative sample in 25 rural, urban, academic and non academic centres across Canada. Patients are to be followed for an initial 3 years at 6 monthly intervals, and subsequently annually. Traditional biomarkers include eGFR, urine albumin creatinine ratio (uACR), hemoglobin (Hgb), phosphate and albumin. Newer biomarkers of interest were selected on the basis of biological relevance to important processes, commercial availability and assay reproducibility. They include asymmetric dimethylarginine (ADMA), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), troponin I, cystatin C, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6) and transforming growth factor beta 1 (TGFß1). Blood and urine samples are collected at baseline, and every 6 monthly, and stored at -80°C. Outcomes of interest include renal replacement therapy, CV events and death, the latter two of which are adjudicated by an independent panel. DISCUSSION: The baseline distribution of newer biomarkers does not appear to track to markers of kidney function and therefore may offer some discriminatory value in predicting future outcomes. The granularity of the data presented at baseline may foster additional questions.The value of the cohort as a unique resource to understand outcomes of patients under the care of nephrologists in a single payer healthcare system cannot be overstated. Systematic collection of demographic, laboratory and event data should lead to new insights. The mean age of the cohort was 68 years, 90% were Caucasian, 62% were male, and 48% had diabetes. Forty percent of the cohort had eGFR between 30-45 mL/min/1.73m², 22% had eGFR values below 20 mL/min/1.73m²; 61% had uACR < 30. Serum albumin, hemoglobin, calcium and 25-hydroxyvitamin D (25(OH)D) levels were progressively lower in the lower eGFR strata, while parathyroid hormone (PTH) levels increased. Cystatin C, ADMA, NT-proBNP, hsCRP, troponin I and IL-6 were significantly higher in the lower GFR strata, whereas 25(OH)D and TGFß1 values were lower at lower GFR. These distributions of each of the newer biomarkers by eGFR and uACR categories were variable.

Bone and mineral metabolism and fibroblast growth factor 23 levels after kidney donation.

BACKGROUND: Living kidney donation offers a unique setting to study changes in phosphate and vitamin D homeostasis attributable to mild isolated decreases in estimated glomerular filtration rate (eGFR). STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 198 living kidney donors and 98 nondonor controls from 9 transplant centers across 3 countries. For donors, median time after donation was 5.3 years. At assessment, donors had a lower eGFR than controls (73 vs 98 mL/min/1.73 m(2)). PREDICTOR: Living kidney donation (mildly decreased eGFR). OUTCOMES: Biochemical markers of chronic kidney disease-mineral and bone disorder. MEASUREMENTS: Serum creatinine, total serum calcium, serum and urine inorganic phosphate, plasma intact parathyroid hormone, serum calcidiol and calcitriol, renal fractional excretion of inorganic phosphate, and intact serum fibroblast growth factor 23 (FGF-23). RESULTS: Serum FGF-23 levels were significantly higher in donors (38.1 vs 29.7 pg/mL; P < 0.001). For every 10-mL/min/1.73 m(2) decrease in eGFR, FGF-23 level was higher by 3.2 (95% CI, 2.0-4.4) pg/mL. Compared with controls, donors showed higher renal tubular fractional excretion of inorganic phosphate (17.8% vs 12.3%; P < 0.001), lower serum phosphate (0.97 vs 1.02 mmol/L; P = 0.03), and lower serum calcitriol values (63 vs 77 pmol/L; P < 0.001). Serum calcium levels were not significantly different between the 2 groups. Plasma intact parathyroid hormone levels were significantly higher in donors (5.7 vs 5.0 pmol/L; P = 0.03), but were not correlated with FGF-23 or calcitriol levels. LIMITATIONS: Enrollment of a small proportion of past donors at participating centers; assessment of only postdonation values; unable to assess seasonal variation or other temporal patterns in biochemical markers; assessment of kidney function was based on eGFR, not measured GFR. CONCLUSIONS: The FGF-23 pathway may be activated in living kidney donors who show early biochemical changes compatible with chronic kidney disease-mineral and bone disorder. Whether these changes influence bone mineral density and fracture rates warrants consideration.

Supramaximal dose of candesartan in proteinuric renal disease.

High levels of proteinuria predict renal deterioration, suggesting that interventions to reduce proteinuria may postpone the development of severe renal impairment. This multicenter Canadian trial evaluated whether supramaximal dosages of candesartan would reduce proteinuria to a greater extent than the maximum approved antihypertensive dosage. The authors randomly assigned 269 patients who had persistent proteinuria (> or =1 g/d) despite 7 wk of treatment with the highest approved dosage of candesartan (16 mg/d) to 16, 64, or 128 mg/d candesartan for 30 wk. The median serum creatinine level was 130.0 micromol/L (1.47 mg/dl), and the median urinary protein excretion was 2.66 g/d; most (53.9%) patients had diabetic nephropathy. The mean difference of the percentage change in proteinuria for patients receiving 128 mg/d candesartan compared with those receiving 16 mg/d candesartan was -33.05% (95% confidence interval -45.70 to -17.44; P < 0.0001). Reductions in BP were not different across the three treatment groups. Elevated serum potassium levels (K+ > 5.5 mEq/L) led to the early withdrawal of 11 patients, but there were no dosage-related increases in adverse events. In conclusion, proteinuria that persists despite treatment with the maximum recommended dosage of candesartan can be reduced by increasing the dosage of candesartan further, but serum potassium levels should be monitored during treatment.

Kidney and liver transplants from donors after cardiac death: initial experience at the London Health Sciences Centre.

BACKGROUND: The disparity between the number of patients waiting for an organ transplant and availability of donor organs increases each year in Canada. Donation after cardiac death (DCD), following withdrawal of life support in patients with hopeless prognoses, is a means of addressing the shortage with the potential to increase the number of transplantable organs. METHODS: We conducted a retrospective, single-centre chart review of organs donated after cardiac death to the Multi-Organ Transplant Program at the London Health Sciences Centre between July 2006 and December 2007. In total, 34 solid organs (24 kidneys and 10 livers) were procured from 12 DCD donors. RESULTS: The mean age of the donors was 38 (range 18-59) years. The causes of death were craniocerebral trauma (n = 7), cerebrovascular accident (n = 4) and cerebral hypoxia (n = 1). All 10 livers were transplanted at our centre, as were 14 of the 24 kidneys; 10 kidneys were transplanted at other centres. The mean renal cold ischemia time was 6 (range 3-9.5) hours. Twelve of the 14 kidney recipients (86%) experienced delayed graft function, but all kidneys regained function. After 1-year follow-up, kidney function was good, with a mean serum creatinine level of 145 (range 107-220) micromol/L and a mean estimated creatinine clearance of 64 (range 41-96) mL/min. The mean liver cold ischemia time was 5.8 (range 5.5-8) hours. There was 1 case of primary nonfunction requiring retransplantation. The remaining 9 livers functioned well. One patient developed a biliary anastomotic stricture that resolved after endoscopic stenting. All liver recipients were alive after a mean follow-up of 11 (range 3-20) months. Since the inception of this DCD program, the number of donors referred to our centre has increased by 14%. CONCLUSION: Our initial results compare favourably with those from the transplantation of organs procured from donors after brain death. Donation after cardiac death can be an important means of increasing the number of organs available for transplant, and its widespread implementation in Canada should be encouraged.

Using dalteparin in quotidian and nocturnal hemodialysis patients: A prospective study.

INTRODUCTION: Low-molecular weight heparin, such as dalteparin, is an alternative anticoagulation method in conventional hemodialysis (HD). However, there are limited studies on its use in quotidian and nocturnal HD. We assessed the optimal dose, treatment efficacy, and patient safety of dalteparin in quotidian and nocturnal HD populations. METHODS: This study included 10 quotidian (7 in-center and 3 home) and 8 nocturnal home HD patients. Dalteparin was initiated and titrated based on clotting score in these patients. Trough anti-Xa levels were measured. The dalteparin dose, the dialyzer and HD circuit clotting scores, and bleeding episodes were recorded at 4 weeks. Patients who continued dalteparin were followed to 12 months. FINDINGS: For the 10 quotidian HD patients, the median dalteparin dose was 1875 units [1250, 2500] after 4 weeks. For nocturnal HD patients, five of the eight patients switched back to heparin due to high clotting scores while on dalteparin within 4 weeks. However, three patients continued on dalteparin at 4 weeks. After 12 months, one maintained on 5000 units and the other two maintained on 7500 units of dalteparin. All the clotting scores at month 12 were ≤2. One patient died due to an unrelated cause. For all patients who continued on dalteparin, only 9% of the HD treatments had circuit clotting score >2 after reaching stable dose. All trough anti-Xa levels were <0.1 IU/mL. There were no episodes of bleeding. Fistula compression times were not increased. DISCUSSION: This small pilot study suggests that dalteparin can be used effectively and relatively safety in quotidian HD. However, its use in nocturnal HD was only successful in a small proportion of patients. Alternative methods, including second dalteparin bolus after 4 hours of HD treatment, should be assessed for efficacy and practicality.

Transfusion Management of Incident Dialysis Patients in Canada: A Prospective Observational Study.

BACKGROUND: Several studies have demonstrated harm associated with using erythropoiesis-stimulating agents (ESA) to achieve higher hemoglobin (Hb) levels. Subsequently, more conservative use of ESAs has changed anemia therapy in patients with chronic renal failure. OBJECTIVE: The objectives were to identify transfusion rates in hemodialysis (HD) patients during the first year of therapy, to identify factors associated with the probability of transfusion, describe reasons for the transfusions, and identify the Hb values associated with each transfusion. An exploratory objective was to describe the age of red blood cell transfusions. DESIGN: This was a multicenter prospective observational cohort study. SETTING: There were 12 study sites in 5 Canadian provinces. The study was performed from 2012 to 2014. METHODS: The study patients were adult incident chronic HD patients in these centers. Patients with acute kidney injury, peritoneal dialysis, and planned transfer to satellite units were excluded. Patients had to receive at least 1 month of chronic HD to be eligible. Data for 3 months prior to HD were obtained by retrospective chart review. Prospectively, charts were reviewed monthly for 12 months for data abstraction. RESULTS: There were 314 patients enrolled and 79.9% completed 12 month follow-up. Ninety-four (29.9%) patients received at least 1 unit of blood. During the first 90 days, the transfusion episode rate was 148.4 per 100 patient-years compared with 62.6 per 100 patient-years post 90 days. The most frequent indication was a low Hb value (92%) with gastrointestinal bleeding, surgical blood loss, and fatigue accounting for 9.9%, 8.6%, and 4.5%, respectively. Some patients had >1 indication. The mean Hb values prior to transfusion episodes ranged from 75.3 to 78.6 g/L. Cox regression analysis on time to first transfusion and time to first hospitalization/death both showed an association with inpatient initiation of HD. Some 37.5% initiated HD as an inpatient and differed from those starting as an outpatient. They had less predialysis care and laboratory data suggested more inflammation. The mean and median ages of the blood units transfused were 24.9 (SD = 10.0) and 23 days (interquartile range = 17-33). CONCLUSIONS: This work reported the blood transfusion rate in incident HD patients in Canada during a period associated with conservative ESA prescription. The major indication for transfusion was a low Hb rather than clinical symptoms. Initiation of HD as an inpatient was independently associated with the probability of receiving a blood transfusion. These findings require further investigation.

CONTEXTE: Plusieurs études ont fait état de lésions associées à l'utilisation d'agents stimulant l'érythropoïèse (ASE) pour hausser le taux d'hémoglobine (Hb). Dès lors, une utilisation plus conservatrice des ASE a modifié le traitement de l'anémie chez les patients atteints d'insuffisance rénale chronique. OBJECTIFS DE L'ÉTUDE: L'étude visait à i) établir les taux de transfusion sanguine chez les patients hémodialysés au cours de la première année de traitement; ii) cerner les facteurs associés à la probabilité de recourir à une transfusion sanguine; iii) connaître les raisons de la transfusion; et iv) caractériser le taux d'hémoglobine au moment de l'intervention. En outre, un objectif exploratoire consistait à déterminer l'âge des érythrocytes transfusés. TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte observationnelle prospective multicentrique. CADRE DE L'ÉTUDE: L'étude s'est tenue entre 2012 et 2014 sur douze sites répartis dans cinq provinces canadiennes. MÉTHODOLOGIE: Les patients adultes hémodialysés des centres participants ont été recrutés pour l'étude. Ont été exclus les patients atteints d'insuffisance rénale aiguë, les patients traités par dialyse péritonéale et les patients à être transférés vers une unité satellite. Pour être admissible, le patient devait recevoir un traitement d'hémodialyse continu pendant au moins un mois. On a rétrospectivement tiré des dossiers médicaux les données des trois mois précédant l'hémodialyse, puis on a extrait les données des dossiers médicaux chaque mois sur un an. RÉSULTATS: Un total de 314 patients a participé à l'étude et 79,9 % d'entre eux ont complété les 12 mois de suivi. Sur cette période, 94 patients (29,9 %) ont reçu au moins une transfusion sanguine. Au cours des 90 premiers jours, le taux d'épisodes transfusionnels était de 148,4 pour 100 années-patients, comparativement à 62,6 pour 100 années-patients pour le reste de l'étude. La raison la plus fréquente de recourir à une transfusion était un faible taux d'Hb (92 % des cas); les cas de saignements gastro-intestinaux, de perte de sang périchirurgicale et de fatigue comptaient quant à eux pour 9,9 %, 8,6 % et 4,5 % respectivement. Certains patients cumulant plus d'une indication. Le taux d'Hb moyen prétransfusion variait de 75,3 à 78,6 g/L. Une analyse de régression de Cox sur le temps écoulé jusqu'à la première transfusion et jusqu'à la première hospitalisation (ou le décès) du patient a montré une corrélation avec l'initiation d'un traitement d'hémodialyse chez les patients hospitalisés. Les sujets qui avaient initié leur traitement d'hémodialyse alors qu'ils étaient hospitalisés (37,5 %) ont reçu moins de soins prédialyse et présentaient davantage d'inflammation que les sujets qui avaient commencé leurs traitements d'hémodialyse en tant que patient externe. Enfin, l'âge moyen et l'âge médian des érythrocytes transfusés étaient de 24,9 jours (ÉT : 10,0) et de 23 jours (EIQ : 17 à 23). CONCLUSION: Notre étude a permis de connaître le taux de transfusions sanguines dans une population de patients hémodialysés canadiens au cours d'une période correspondant à une prescription conservatrice d'ASE. On a observé que la principale raison de transfusion était un faible taux d'Hb et non des symptômes cliniques. Enfin, une hémodialyse amorcée en cours d'hospitalisation a été associée à une probabilité accrue de transfusion sanguine. Nos constatations devraient faire l'objet d'études plus approfondies.

An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study).

BACKGROUND: Dalteparin sodium, a low-molecular-weight heparin, is indicated for prevention of clotting in the extracorporeal circuit during hemodialysis (HD). Product labeling recommends a fixed single-bolus dose of 5000 international units (IU) for HD sessions lasting up to 4 hours, but adjustable dosing may be beneficial in clinical practice. OBJECTIVE: The aim of the PARROT study was to investigate the safety and efficacy of an adjustable dose of dalteparin in patients with end-stage renal disease requiring 3 to 4 HD sessions per week. DESIGN: A 7-week, open-label, multicenter study with a single treatment arm, conducted between October 2013 and March 2016. SETTING: Ten sites in Canada. PATIENTS: A total of 152 patients with end-stage renal disease requiring 3 to 4 HD sessions per week. MEASUREMENTS: The primary outcome was the proportion of HD sessions completed without premature termination due to inadequate anticoagulation. METHODS: All participants initially received a dose of 5000 IU dalteparin, which could be adjusted at subsequent HD sessions when clinically indicated, by increment or decrement of 500 or 1000 IU, with no specified dose limits. RESULTS: Patients were followed for 256 patient-months. Nearly all (99.9%; 95% confidence interval [CI]: 99.7-100) evaluable HD sessions were completed without premature clotting. Dose was adjusted for more than half (52.3%) of participants, mostly owing to clotting or access compression time >10 minutes. Median dalteparin dose was 5000 IU (range: 500-13 000 IU). There were no major bleeds, and minor bleeding was reported in 2.3% of all HD sessions. There was no evidence of bioaccumulation. LIMITATIONS: This short-term study, with a single treatment arm, was designed to optimize dalteparin dose using a flexible dosing schedule; it was not designed to specifically evaluate dalteparin dose minimization, provide a direct comparison of dalteparin versus unfractionated heparin, or provide information on long-term safety for flexible dalteparin dosing. Patients were excluded if they were at high risk of bleeding, including those on anticoagulants and those on antiplatelet agents other than aspirin <100 mg/d. CONCLUSIONS: Overall, an adjustable dalteparin sodium dose regimen allowed safe completion of HD, with clinical benefits over fixed dosing. TRIAL REGISTRATION: ClinicalTrials.gov NCT01879618, registered June 13, 2013.

CONTEXTE: La daltéparine sodique, une héparine de faible poids moléculaire, est indiquée pour prévenir la formation de caillots dans le circuit extracorporel durant l'hémodialyse (HD). Pour une séance de dialyse d'une durée maximale de quatre heures, l'étiquette du produit recommande une dose fixe de 5 000 unités internationales (U.I.) administrée en bolus. Cependant, il est possible qu'il puisse être bénéfique d'ajuster la dose en pratique. OBJECTIF: Le but de l'étude PARROT était d'analyser l'innocuité et l'efficacité d'une dose ajustable de daltéparine chez des patients atteints d'insuffisance rénale terminale (IRT) et nécessitant trois à quatre séances d'HD par semaine. TYPE D'ÉTUDE: Il s'agit d'une étude ouverte et multicentrique à traitement unique d'une durée de sept semaines couvrant la période entre octobre 2013 et mars 2016. CADRE: L'étude a eu lieu dans dix centres de dialyse au Canada. SUJETS: L'étude a inclus 152 patients atteints d'IRT et nécessitant trois à quatre séances d'HD par semaine. MESURES: Le résultat principal était la proportion de séances d'HD complétées, non interrompues de manière prématurée en raison d'une anticoagulation inadéquate. MÉTHODOLOGIE: Tous les participants ont initialement reçu 5000 U.I. de daltéparine, dose qui a pu être ajustée lors des séances subséquentes, lorsqu'indiqué par le contexte clinique, à raison d'augmentation ou de réduction de 500 ou 1 000 U.I., sans spécification quant aux doses limites. RÉSULTATS: Les patients ont été suivis sur une période de 256 mois-patients. Pratiquement toutes les séances d'HD évaluables (99,9 %; IC 95 % : 99,7-100) ont été complétées sans coagulation prématurée. La dose de daltéparine a été ajustée pour plus de la moitié (52,3 %) des participants, essentiellement en raison de coagulation ou d'un besoin de procéder à une compression de l'accès vasculaire au-delà de 10 minutes. La dose médiane de daltéparine était de 5 000 U.I. (entre 500 et 13 000 U.I.). Aucune hémorragie majeure n'a été rapportée, mais une hémorragie mineure est survenue dans 2,3 % de toutes les séances d'HD analysées. Aucune bioaccumulation n'a été détectée. LIMITES: Cette étude de courte durée à traitement unique a été conçue pour optimiser le dosage de daltéparine à l'aide d'un schéma de posologie flexible. Elle ne visait pas à évaluer spécifiquement la minimisation de la dose ou à fournir des informations sur l'innocuité à long terme d'une posologie flexible pour la daltéparine. Également, les patients à haut risque d'hémorragie ont été exclus de l'étude, notamment ceux qui prenaient des anticoagulants ou des antiplaquettaires autres qu'une dose quotidienne de moins de 100 mg d'aspirine. CONCLUSION: Dans l'ensemble, un schéma posologique flexible pour la daltéparine sodique a permis de compléter les séances d'HD de façon sécuritaire, en plus de fournir des avantages cliniques par rapport à une dose fixe.

Re-exposure to mismatched HLA class I is a significant risk factor for graft loss: multivariable analysis of 259 kidney retransplants.

BACKGROUND: Kidney retransplants carry increased immunologic risk. One possible contributor to this risk may be re-exposure to human leukocyte antigens (HLA) common to a previous donor but foreign to the recipient. Conflicting publications have assessed this risk, so to examine our experience 259 kidney retransplants were analyzed. METHODS: A retrospective cohort of retransplant patients from 1973 to 2005 with minimum 12 months follow up was examined. Using multivariable modeling, important confounders were controlled for identifying factors significantly affecting graft survival. RESULTS: Re-exposure to HLA class I (HLA-A or B) antigens, peak panel reactive antibodies and donor source were the most important determinants of allograft survival, despite a negative conventional or anti-human globulin-augmented T cell crossmatch. We failed to demonstrate that recipient re-exposure to HLA class II (HLA-DR) or positive B cell crossmatch were associated with adverse outcomes. Sample size and molecular versus serologic methods may have influenced the former, while inability to determine antibody specificities may have influenced the latter. Controlling for other variables, the adjusted risk of graft loss associated with re-exposure to HLA class I increased by 71% (P=0.006) and occurred early, consistent with recall of memory cytotoxic T lymphocyte or antibody responses. CONCLUSIONS: Kidney recipients re-exposed to mismatched HLA class I antigens appear to be at heightened risk of early graft loss. Such patients may benefit from pretransplant identification of donor specific antibodies using solid phase methods and heightened vigilance for acute rejection. Future studies may indicate whether more intensive immunosuppression for these patients is warranted.

Cost-effectiveness of irbesartan 300 mg given early versus late in patients with hypertension and a history of type 2 diabetes and renal disease: a Canadian perspective.

BACKGROUND: The Irbesartan in Reduction of Microalbuminuria trial and the Irbesartan in Diabetic Nephropathy Trial found that irbesartan is renoprotective in patients having hypertension with type 2 diabetes. OBJECTIVE: The objective of this study was to assess whether treatment with irbesartan is cost-effective in Canada relative to conventional care in this patient population and whether it is more cost-effective to treat patients early rather than later in the development of renal disease from the perspective of the Canadian health and social care system. METHODS: The analysis compared 3 alternative strategies for the management of hypertension in patients with type 2 diabetes and early renal disease: (1) conventional hypertensive treatment excluding the use of angiotensin II receptor antagonists (AIIRAs); (2) the early addition of irbesartan (an AIIRA) to conventional treatment; and (3) the late addition of irbesartan to conventional treatment. A Markov model was used to simulate the progression of renal disease (microalbuminuria to death) in hypertensive patients with type 2 diabetes over a 25-year time horizon. Transition probabilities were derived from the 2 randomized controlled trials. A cost-effectiveness analysis was conducted with outcome measured in life-years gained (LYGs). RESULTS: The early addition of irbesartan during microalbuminuria was cost-saving and more effective than both delaying irbesartan treatment until advanced overt nephropathy (AON) (0.45 LYG, Can $54,100 saved) and conventional antihypertensive use (0.62 LYG, $68,400 saved). This was due to the increased drug costs associated with the use of irbesartan being offset by savings arising from delays in the development of overt nephropathy and the subsequent delay to end-stage renal disease (ESRD). Sensitivity analyses confirmed the robustness of the study results. CONCLUSIONS: The early use of irbesartan for patients with hypertension and type 2 diabetes who have yet to develop overt nephropathy is both more effective and less costly than delaying irbesartan treatment until AON and conventional antihypertensive use. Analysis suggests that the earlier irbesartan is added to conventional antihypertensive treatment, the greater the delays in the onset of ESRD and the overall savings in health care resource utilization from the perspective of the Canadian health and social care system.

Meta-analysis: risk for hypertension in living kidney donors.

BACKGROUND: The risk for hypertension after kidney donation remains uncertain. PURPOSE: To see whether normotensive adults who donate a kidney develop higher blood pressure and risk for hypertension compared with nondonor adults acting as control participants. DATA SOURCES: MEDLINE, EMBASE, and Science Citation Index were searched from 1966 until November 2005 for articles published in any language. Reference lists of pertinent articles were also reviewed. STUDY SELECTION: The authors selected studies involving 10 or more healthy normotensive adults who donated a kidney and in whom blood pressure was assessed at least 1 year later. DATA EXTRACTION: Two reviewers independently abstracted data on study and donor characteristics, blood pressure measurements, outcomes, and prognostic features. Comparison data were abstracted from donor studies with control participants. Thirty primary authors provided additional data. DATA SYNTHESIS: Forty-eight studies from 28 countries followed a total of 5145 donors. Before surgery, the average age of donors was 41 years, the average systolic blood pressure was 121 mm Hg, and the average diastolic blood pressure was 77 mm Hg for all studies. In controlled studies in which the average follow-up was at least 5 years after donation (range, 6 to 13 years), blood pressure was 5 mm Hg higher in donors than in control participants (the weighted mean for systolic blood pressure using 4 studies involving 157 donors and 128 control participants was 6 mm Hg [95% CI, 2 to 11 mm Hg], and the weighted mean for diastolic blood pressure using 5 studies involving 196 donors and 161 control participants was 4 mm Hg [CI, 1 to 7 mm Hg]). There was statistical heterogeneity among the 6 controlled studies that assessed hypertension; an increase in risk was noted in 1 study (relative risk, 1.9 [CI, 1.1 to 3.5]). LIMITATIONS: Most studies were retrospective and did not include control groups that were assembled and followed along with donors. Approximately one third of the donors had incomplete follow-up information. CONCLUSIONS: On the basis of the limited studies conducted to date, kidney donors may have a 5-mm Hg increase in blood pressure within 5 to 10 years after donation over that anticipated with normal aging. Future controlled, prospective studies with long periods of follow-up will better delineate safety and identify donors at lowest risk for long-term morbidity.

Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients.

BK virus associated nephropathy (BKVAN) has emerged as an important cause of renal allograft dysfunction and graft loss. Although several treatment strategies have been proposed, the rate of graft loss remains high. We studied the outcome of renal transplant patients with BKVAN treated with IVIG. After 11.4 +/- 3.9 months (mean +/- SEM) from the time of transplantation, 8 renal allograft recipients were diagnosed with BKVAN. In addition to a reduction of immunosuppressive therapy, patients received 2 g/kg IVIG. After a mean follow-up of 15 months, all except one patient are currently off dialysis. In summary, after IVIG therapy, 88% of patients still have functioning grafts, although renal function continues to be impaired. The benefit of concomitant IVIG and reduction of immunosuppressive therapy in BKVAN needs to be further addressed in randomized, multicentered trials.