Point-of-care-ultrasound for the assessment of post-renal transplant recipients.

INTRODUCTION: Postoperative imaging for deceased donor renal transplants is often delayed, as these surgeries occur after-hours. These delays can be critical in identifying immediate complications. To our knowledge, there are no formal training programs for point-of-care ultrasound (POCUS) in this setting; therefore, we aimed to develop and evaluate a feasible and practical POCUS curriculum for the assessment of a renal transplant graft. METHODS: Urology and nephrology transplant physicians completed a three-hour online course, followed by a five-hour hands-on seminar for sonographic scanning. Simulated patients with transplanted kidneys were used. Course material was developed with licensed ultrasound technologists based on Sonography Canada national competency profiles. Pre- and post-course surveys focused on user confidence, while pre- and post-course multiple-choice questionnaires assessed theoretical knowledge. RESULTS: Twelve participants were included, six of whom were urologists. Theoretical knowledge in POCUS improved significantly (p<0.001). Confidence in manipulation of ultrasound controls, Doppler imaging, and POCUS of the transplant kidney also improved (all p<0.001, d>2.0). Participants indicated an increased likelihood of POCUS use in clinical practice and that training should be integrated into a transplant fellowship. CONCLUSIONS: We introduced a novel and guideline-based POCUS curriculum that leveraged local ultrasound educators and found improved theoretical knowledge and skill confidence in our cohort of transplant physicians. This course will serve as the first step toward a validated competency-based training system for POCUS use in the immediate post-renal transplant setting, and likely will be incorporated into the training of the modern transplant physician.

Combined preoperative plasma exchange and red blood cell exchange transfusion in a renal transplant patient with protein S deficiency and hemoglobin SC disease.

BACKGROUND: Protein S deficiency is associated with increased risk of venous thromboembolism, complicating the perioperative management of such patients. We present a patient with sickle cell disease (Hb SC genotype) and inherited protein S deficiency who underwent a living-donor renal transplant. To minimize thrombotic risk and sickle cell complications, both plasma exchange and red blood cell (RBC) exchange transfusion were performed pre-operatively. METHODS AND MATERIALS: Plasma exchange was utilized to increase protein S levels and to reduce the risk of post-operative venous thromboembolism, including allograft thrombosis, while RBC exchange was performed to reduce the risk of acute post-operative sickle cell disease complications. RESULTS: With the use of combined pre-operative plasma exchange and RBC exchange transfusion, this patient with protein S deficiency and Hb SC underwent a successful renal transplant without acute sickle cell complications or thrombotic complications. CONCLUSIONS: This case demonstrates the potential use of pre-operative plasma exchange in patients with protein S deficiency undergoing high thrombotic risk procedures.

Impact of Bioelectrical Impedance-Guided Fluid Management and Vitamin D Supplementation on Left Ventricular Mass in Patients Receiving Peritoneal Dialysis: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Hypervolemia and vitamin D deficiency occur frequently in patients receiving peritoneal dialysis and may contribute to left ventricular (LV) hypertrophy. The effect of bioelectrical impedance analysis (BIA)-guided volume management or vitamin D supplementation on LV mass among those receiving peritoneal dialysis is uncertain. STUDY DESIGN: Two-by-two factorial randomized controlled trial. SETTING & PARTICIPANTS: Sixty-five patients receiving maintenance peritoneal dialysis. INTERVENTION: BIA-guided volume management versus usual care and oral cholecalciferol 50,000 U weekly for 8 weeks followed by 10,000 U weekly for 44 weeks or matching placebo. OUTCOME: Change in LV mass at 1 year measured by cardiac magnetic resonance imaging. RESULTS: Total body water decreased by 0.9 + 2.4 (SD) L in the BIA group compared with a 1.5 ± 3.4 L increase in the usual care group (adjusted between-group difference: -2.4 [95% CI, -4.1 to -0.68] L, P = 0.01). LV mass increased by 1.3 ± 14.3 g in the BIA group and decreased by 2.4 ± 37.7 g in the usual care group (between-group difference: +2.2 [95% CI, -13.9 to 18.3] g, P = 0.8). Serum 25-hydroxyvitamin D concentration increased by a mean of 17.2 ± 30.8 nmol/L in the cholecalciferol group and declined by 8.2 ± 24.3 nmol/L in the placebo group (between-group difference: 28.3 [95% CI, 17.2-39.4] nmol/L, P < 0.001). LV mass decreased by 3.0 ± 28.1 g in the cholecalciferol group and increased by 2.0 ± 31.2 g in the placebo group (between-group difference: -4.5 [95% CI, -20.4 to 11.5] g, P = 0.6). LIMITATIONS: Relatively small sample size with larger than expected variation in change in LV mass. CONCLUSIONS: BIA-guided volume management had a modest impact on volume status with no effect on the change in LV mass. Vitamin D supplementation increased serum vitamin D concentration but had no effect on LV mass. FUNDING: Unrestricted Baxter International extramural grant and the Kidney Foundation of Canada. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01045980.

Circulating heparin-like anticoagulants: Case report and review of literature.

We report a case of a 56-year-old woman with a history of idiopathic thrombocytopenic purpura (ITP) following splenectomy on mycophenolate mofetil (MMF), who developed moderate bleeding after stopping MMF. Her laboratory testing suggested the presence of an abnormal circulating heparin-like anticoagulant with demonstrable anti-Xa activity. She was initially treated with antifibrinolytic therapy and was subsequently started on MMF alongside intravenous immunoglobulin, which significantly improved her bleeding symptoms. The presence of abnormal circulating heparin-like anticoagulants is a rare cause of coagulopathy. Few cases exist in the literature, with nearly all occurring in the setting of hematologic or solid-organ malignancy. The mechanism by which these endogenous anticoagulants develop is unclear. Clinical manifestations range from mild bleeding and bruising to life-threatening hemorrhage refractory to conventional therapy. Diagnosis of a heparin-like anticoagulant is based on coagulation testing as well as exclusion of other exogenous anticoagulants, acquired inhibitors, and/or factor deficiencies.

Using bioimpedance analysis to assess intensive care unit patients with sepsis in the post-resuscitation period: a prospective multicentre observational study.

PURPOSE: Clinicians lack well-validated, non-invasive, objective tools to guide volume management in the post-resuscitative period. Bioimpedance analysis (BIA) represents a novel method for guiding fluid management. We studied the relationship of BIA vector length (VL), an indicator of volume status, to the need for mechanical ventilation in patients with sepsis. METHODS: This is a multicentre prospective observational study at four Canadian ICUs. We examined adult patients admitted to the ICU within 72 hr of a sepsis diagnosis. Patients underwent daily BIA measurements for 30 days, until discharge from the ICU, or until death. Our primary outcome was the ongoing need for invasive mechanical ventilation, and we examined the association with VL using a generalized estimating equation. Our secondary analyses were targeted to determine an association between VL and other measures of volume status and acute kidney injury (AKI). RESULTS: We enrolled 159 patients from four centres over 27 months. The mean (standard deviation [SD]) age was 64 (15) yr with a mean (SD) APACHE (acute physiology, age, chronic health evaluation) II score of 25 (10); 57% (n = 91) were male. A 50-unit (ohm·m) increase in VL over any time period was associated with a 30% decrease in the probability of requiring invasive mechanical ventilation (P < 0.03). Volume expansion, indicated by a shorter VL, correlated with higher edema scores (r = - 0.31; P < 0.001) and higher net 24-hr fluid balance (r = - 0.27, P < 0.001). Patients with AKI had a shorter overall VL (r = - 0.23; P = 0.003). CONCLUSIONS: An increase in VL over time is associated with a decrease in probability of requiring invasive mechanical ventilation. Vector length correlates with other commonly used volume assessment methods in post-resuscitation patients with sepsis.

Efficacy and safety of non-vitamin K antagonist oral anticoagulants post-kidney transplantation.

BACKGROUND: Novel oral anticoagulants (NOACs) were developed as alternatives to vitamin K antagonists, primarily warfarin, as they do not require routine monitoring and have limited drug-drug and drug-food interactions. However, the efficacy and safety of these agents in kidney transplantation are not well studied. AIM: To assess the profile and safety of NOACs for patients who had kidney transplantation, and to provide recommendations and guidelines on therapeutic strategies in these patients. METHODS: This was a retrospective study carried out among adult patients who were actively on the following NOACs (apixaban, rivaroxaban or dabigatran) in our renal transplantation program from December 2015 to December 2016. The patients were identified primarily through electronic medical record system (patient data linkage). Data on the clinical and laboratory profile of the patients were retrieved and analyzed with SPSS 22.0. RESULTS: Complete data on 42 renal transplant patients were retrieved: 59.5% males, 90.5% were whites and 66.7% were older than 60 years old. The mean duration since renal transplantation of the patients was 8.8 ± 7.4 years. The most common risk factors for the development of end-stage renal disease in the subjects were hypertension (19.0%), polycystic kidney disease (19.0%), followed by diabetic nephropathy (16.7%) and chronic glomerulonephritis (16.7%). The main indications for NOACs use in the cohort were atrial fibrillation in 25 patients (59.5%) and venous thromboembolism in 10 patients (23.8%). Overall, 29 patients (69%) were treated with apixaban, 10 patients (23.8%) with rivaroxaban and 3 patients (7.14%) with dabigatran. No (0%) thromboembolic events were observed during the one-year period, but 3 (7.1%) bleeding events occurred in the cohort consisting of 1 patient treated with rivaroxaban 15 mg daily and 2 patients who received apixaban 2.5 mg twice daily. There were no significant changes in serum tacrolimus level three days after the initiation of NOACs among patients treated with tacrolimus (pre- and post-NOACs tacrolimus levels were 7.2516 and 7.8867 ng/mL, P = 0.55, respectively). Also, after one-year of treatment with NOACs there were no significant changes in the pre- and post-NOACs serum creatinine level (P = 0.772) and estimated glomerular filtration rates (P = 0.232). CONCLUSION: No thromboembolic events or significant changes in renal profile were observed in our cohort of kidney transplant recipients who were treated with NOACs for at least a year. However, a few bleeding events were observed. This calls for further well-planned randomized controlled trials to assess the efficacy and safety of NOACs among renal transplant recipients.

Circulating microvesicle protein is associated with renal transplant outcome.

Renal transplantation is an effective therapy with improved long-term outcomes compared with other therapies for end stage renal disease. Present methods for evaluating kidney allograft function, such as serum creatinine or allograft biopsy, are not sensitive and identify pathological changes only after any potential intervention would be effective. Thus, there is a necessity for biomarkers that would provide early prognostic information about kidney transplant outcomes. Circulating microvesicles represent an attractive source of biomarkers for different diseases including renal failure. We have studied the proteins of the circulating microvesicles from two populations of kidney transplant recipients (n = 20) with poor transplant outcomes (n = 10) or good transplant outcome (n = 10), according to their estimated glomerular filtration rate (eGFR). Microvesicles from age-matched healthy subjects (n = 10) were used as a control. Also, we performed a pilot study to assess the microvesicle protein in kidney transplant recipients before and six months after kidney transplant (n = 6), compared to healthy subjects. Proteomic analysis of microvesicles could discriminate between transplant recipients and healthy subjects, and between transplant patients based on eGFR. Our results shed light on the potential of blood microvesicles to provide a novel tool for the prediction of the outcome of kidney transplants.

Crusted scabies in a renal transplant recipient treated with daily ivermectin: A case report and literature review.

Crusted scabies is a rare disease variant associated with T-cell dysregulation. Transplant patients are at risk of developing crusted scabies as a consequence of their immunosuppressive regimens. We report a case of crusted scabies presenting with recurrent septicemia in a 65-year-old renal transplant recipient, treated with daily ivermectin for 7 days after initial failure of weekly ivermectin dosing. A literature review of crusted scabies in transplant recipients consisting of 19 cases reports was summarized. Pruritus was common, and initial misdiagnosis was frequent. Most were treated with topical therapy, with one-third receiving ivermectin. Three of seven cases presenting with a concomitant infection died. Crusted scabies is commonly misdiagnosed in transplant recipients owing to its rarity, varied appearance, and different skin distributions. It should be considered in the differential diagnosis of transplant recipients presenting with rash and pruritus, given its association with secondary infection and subsequent mortality.

Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts.

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

WNT signaling is required for peritoneal membrane angiogenesis.

The wingless-type mouse mammary tumor virus integration site family (WNT) signaling pathway is involved in wound healing and fibrosis. We evaluated the WNT signaling pathway in peritoneal membrane injury. We assessed WNT1 protein expression in the peritoneal effluents of 54 stable peritoneal dialysis (PD) patients and WNT-related gene expression in ex vivo mesothelial cell cultures from 21 PD patients. In a transforming growth factor-ß (TGF-ß)-mediated animal model of peritoneal fibrosis, we evaluated regulation of the WNT pathway and the effect of WNT inhibition on peritoneal fibrosis and angiogenesis. WNT1 and WNT2 gene expression were positively correlated with peritoneal membrane solute transport in PD patients. In the mouse peritoneum, TGF-ß-induced peritoneal fibrosis was associated with increased expression of WNT2 and WNT4. Peritoneal ß-catenin protein was significantly upregulated after infection with adenovirus expressing TGF-ß (AdTGF-ß) along with elements of the WNT signaling pathway. Treatment with a ß-catenin inhibitor (ICG-001) in mice with AdTGF-ß-induced peritoneal fibrosis resulted in attenuation of peritoneal angiogenesis and reduced vascular endothelial growth factor. Similar results were also observed with the WNT antagonist Dickkopf-related protein (DKK)-1. In addition to this, DKK-1 blocked epithelial-mesenchymal transition and increased levels of the cell adhesion protein E-cadherin. We provide evidence that WNT signaling is active in the setting of experimental peritoneal fibrosis and WNT1 correlates with patient peritoneal membrane solute transport in PD patients. Intervention in this pathway is a possible therapy for peritoneal membrane injury.

Study of Cardiovascular Outcomes in Renal Transplantation: A Prospective, Multicenter Study to Determine the Incidence of Cardiovascular Events in Renal Transplant Recipients in Ontario, Canada.

BACKGROUND: Renal transplant recipients (RTRs) are at significantly higher risk for morbidity and mortality compared with the general population, largely attributed to cardiovascular disease (CVD). Previous estimates of CVD events have come from health care databases and retrospective studies. OBJECTIVE: The objective of this study was to prospectively determine the prevalence of risk factors and incidence of CVD events in a Canadian cohort of RTRs. DESIGN: Study of Cardiovascular Outcomes in Renal Transplantation (SCORe) was a prospective, longitudinal, multicenter observational study. SETTING: Adult RTRs were recruited from 6 participating transplant sites in Ontario, Canada. PATIENTS: Eligible patients were those receiving a living or deceased donor renal transplant. Patients who received simultaneous transplant of any other organ were excluded. MEASUREMENTS: Primary outcomes included myocardial infarction (MI) defined by American College of Cardiology (ACC-MI) criteria, and major adverse cardiac events (MACE), defined as cardiovascular (CV) death, ACC-MI, coronary revascularization, and nonhemorrhagic stroke. CV events were adjudicated by a single, independent cardiologist. METHODS: CV and transplant-specific risk factors that predict MACE and ACC-MI were identified by stepwise regression analysis using the Cox proportional hazards model. RESULTS: A total of 1303 patients enrolled across 6 transplant centers were followed for 4.5 ± 1.6 years (mean ± SD). Incidence of MACE was 7.0%, with significant independent predictors/risk factors including age, diabetes, coronary revascularization, nonhemorrhagic stroke, and renal replacement therapy (RRT). ACC-MI incidence was 4.0%, with significant independent predictors/risk factors including age, coronary revascularization, and duration of RRT in excess of the median value (2.91 years). LIMITATIONS: Patients were recruited from a single province, so may not reflect the experience of RTRs in other areas of Canada. CONCLUSIONS: Using a prospective design and rigorous methodology, this study found that the incidence of CV events after renal transplantation was elevated relative to the general Canadian population and was comparable with that reported in patient registries, thus helping validate the utility of retrospective analysis in this field. SCORe highlights the importance of monitoring RTRs for traditional cardiac and transplant-specific CV risk factors to help prevent CV morbidity and mortality. Further research is needed to investigate a broader range of potential risk factors and their combined effects on incident CV events.

CONTEXTE: Les receveurs d'une greffe rénale présentent un risque significativement plus élevé de morbidité et de mortalité que l'ensemble de la population, ceci est en grande partie attribuable aux maladies cardiovasculaires. Les estimations antérieures du nombre d'événements cardiovasculaires proviennent des bases de données du système de santé et des résultats d'études rétrospectives. OBJECTIF DE L'ÉTUDE: L'étude visait à mesurer de manière prospective la prévalence des facteurs de risque et l'incidence des événements cardiovasculaires dans une cohorte de patients receveurs d'une greffe rénale au Canada. TYPE D'ÉTUDE: L'étude SCORe consistait en une étude observationnelle longitudinale menée de façon prospective au sein de plusieurs centres hospitaliers. CADRE DE L'ÉTUDE: Les patients adultes receveurs d'une greffe rénale ont été recrutés dans six hôpitaux de la province de l'Ontario, au Canada. PATIENTS: Les patients qui avaient reçu une greffe rénale provenant d'un donneur vivant ou décédé ont été inclus dans l'étude. Les patients qui avaient reçu une greffe simultanée de tout autre organe ont été exclus. MESURES: Les principaux critères retenus incluaient un infarctus du myocarde répondant aux critères établis par l'American College of Cardiology (ACC-MI), des événements cardiaques majeurs indésirables (MACE) tels que le décès d'origine cardiovasculaire, l'ACC-MI, la revascularisation coronarienne et l'AVC non hémorragique. Ces événements cardiovasculaires ont été constatés par un cardiologue indépendant. MÉTHODOLOGIE: Les facteurs de risque, cardiovasculaires ou spécifiques à la transplantation, qui permettent de prédire les MACE et l'ACC-MI ont été identifiés à l'aide du modèle de risques proportionnels de Cox pour l'analyse de régression en étapes. RÉSULTATS: Les 1 303 patients recrutés au sein des six centres hospitaliers ont été suivis sur une moyenne de 1,6 an (SD ± 4,5). L'incidence de MACE était de 7,0%, avec des indicateurs prévisionnels indépendants et des facteurs de risque significatifs incluant l'âge, le diabète, la revascularisation coronarienne, l'AVC non hémorragique et la thérapie de remplacement rénale. L'incidence d'ACC-MI était de 4,0%, avec des indicateurs prévisionnels indépendants et des facteurs de risque significatifs incluant l'âge, la revascularisation coronarienne et une durée pour la thérapie de remplacement rénal excédant la valeur médiane (2,91 ans). LIMITES DE L'ÉTUDE: Les patients ont été recrutés dans une seule province, les résultats sont susceptibles de ne pas être représentatifs de la situation des receveurs d'une greffe rénale ailleurs au Canada. CONCLUSIONS: Grâce à un plan d'étude prospectif et à une méthodologie rigoureuse, nous avons déterminé que l'incidence des événements cardiovasculaires chez les receveurs d'une greffe rénale a été plus élevée que dans la population canadienne en général. Nous avons également constaté qu'elle était comparable à l'incidence rapportée dans les registres de patients, ce qui vient confirmer l'utilité des études rétrospectives dans ce domaine. Les résultats obtenus lors de l'étude SCORe mettent en lumière l'importance de faire un suivi auprès des receveurs d'une greffe rénale afin de détecter les facteurs de risque cardiovasculaires ou spécifiques à l'intervention, et ainsi aider à prévenir la mortalité et la morbidité liées aux maladies cardiovasculaires. D'autres recherches sont nécessaires afin d'examiner un plus large éventail de facteurs de risques potentiels et leurs effets concomitants sur les événements cardiovasculaires.

Matrix metalloproteinase 9 is associated with peritoneal membrane solute transport and induces angiogenesis through ß-catenin signaling.

Background: For patients using peritoneal dialysis (PD), the peritoneal membrane can develop fibrosis and angiogenesis, leading to ultrafiltration failure, chronic hypervolemia and increased risk of technique failure and mortality. Matrix metalloproteinases (MMPs), and specifically the gelatinases (MMP2 and MMP9), may be involved in peritoneal membrane injury. Methods: From stable PD patients, mesothelial cells were assayed for MMP gene expression. MMP9 was overexpressed in mouse peritoneum by adenovirus, and MMP9 -/- mice were subjected to transforming growth factor ß (TGF-ß)-induced peritoneal fibrosis. Results: MMP9 mRNA expression correlated with peritoneal membrane solute transport properties. Overexpression of MMP9 in the mouse peritoneum induced submesothelial thickening and angiogenesis. MMP9 induced mesothelial cell transition to a myofibroblast phenotype measured by increased alpha smooth muscle actin and decreased E-cadherin expression. Angiogenesis was markedly reduced in MMP9 -/- mice treated with an adenovirus expressing active TGF-ß compared with wild-type mice. TGF-ß-mediated E-cadherin cleavage was MMP9 dependent, and E-cadherin cleavage led to ß-catenin-mediated signaling. A ß-catenin inhibitor blocked the angiogenic response induced by AdMMP9. Conclusions: Our data suggest that MMP9 is involved in peritoneal membrane injury possibly through cleavage of E-cadherin and induction of ß-catenin signaling. MMP9 is a potential biomarker for peritoneal membrane injury and is a therapeutic target to protect the peritoneal membrane in PD patients.

Assessment of Postresuscitation Volume Status by Bioimpedance Analysis in Patients with Sepsis in the Intensive Care Unit: A Pilot Observational Study.

Background. Bioimpedance analysis (BIA) is a novel method of assessing a patient's volume status. Objective. We sought to determine the feasibility of using vector length (VL), derived from bioimpedance analysis (BIA), in the assessment of postresuscitation volume status in intensive care unit (ICU) patients with sepsis. Method. This was a prospective observational single-center study. Our primary outcome was feasibility. Secondary clinical outcomes included ventilator status and acute kidney injury. Proof of concept was sought by correlating baseline VL measurements with other known measures of volume status. Results. BIA was feasible to perform in the ICU. We screened 655 patients, identified 78 eligible patients, and approached 64 for consent. We enrolled 60 patients (consent rate of 93.8%) over 12 months. For each 50-unit increase in VL, there was an associated 22% increase in the probability of not requiring invasive mechanical ventilation (IMV) (p = 0.13). Baseline VL correlated with other measures of volume expansion including serum pro-BNP levels, peripheral edema, and central venous pressure (CVP). Conclusion. It is feasible to use BIA to predict postresuscitation volume status and patient-important outcomes in septic ICU patients. Trial Registration. This trial is registered with clinicaltrials.gov NCT01379404 registered on June 7, 2011.

Coronary artery calcification, cardiovascular events, and death: a prospective cohort study of incident patients on hemodialysis.

BACKGROUND: Coronary calcification in patients with end-stage renal disease (ESRD) is associated with an increased risk of cardiovascular outcomes and death from all causes. Previous evidence has been limited by short follow-up periods and inclusion of a heterogeneous cluster of events in the primary analyses. OBJECTIVE: To describe coronary calcification in patients incident to ESRD, and to identify whether calcification predicts vascular events or death. DESIGN: Prospective substudy of an inception cohort. SETTING: Tertiary care haemodialysis centre in Ontario (St Joseph's Healthcare Hamilton). PARTICIPANTS: Patients starting haemodialysis who were new to ESRD. MEASUREMENTS: At baseline, clinical characterization and spiral computed tomography (CT) to score coronary calcification by the Agatston-Janowitz 130 scoring method. A primary outcome composite of adjudicated stroke, myocardial infarction, or death. METHODS: We followed patients prospectively to identify the relationship between cardiac calcification and subsequent stroke, myocardial infarction, or death, using Cox regression. RESULTS: We recruited 248 patients in 3 centres to our main study, which required only biochemical markers. Of these 164 were at St Joseph's healthcare, and eligible to participate in the substudy; of these, 51 completed CT scanning (31 %). Median follow up was 26 months (Q1, Q3: 14, 34). The primary outcome occurred in 16 patients; 11 in the group above the median and 5 in the group below (p = 0.086). There were 26 primary outcomes in 16 patients; 20 (77 %) events in the group above the coronary calcification median and 6 (23 %) in the group below (p = 0.006). There were 10 deaths; 8 in the group above the median compared with 2 in the group below (p = 0.04). The hazard ratios for coronary calcification above, compared with below the median, for the primary outcome composite were 2.5 (95 % CI 0.87, 7.3; p = 0.09) and 1.7 (95 % CI 0.55, 5.4; p = 0.4), unadjusted and adjusted for age, respectively. For death, the hazard ratios were 4.6 (95 % CI 0.98, 21.96; p = 0.054) and 2.4 (95 % CI 0.45, 12.97; p = 0.3) respectively. LIMITATIONS: We were limited by a small sample size and a small number of events. CONCLUSIONS: Respondent burden is high for additional testing around the initiation of dialysis. High coronary calcification in patients new to ESRD has a tendency to predict cardiovascular outcomes and death, though effects are attenuated when adjusted for age.

CONTEXTE: La calcification de l'artère coronaire chez les patients atteints d'insuffisance rénale terminale (IRT) est associée à un risque accru de troubles cardiovasculaires et de mortalité, toutes causes confondues. Les données précédemment recueillies se limitaient à un suivi de courte durée, de même qu'à l'inclusion de séries d'accidents non liés lors de l'analyse préliminaire. OBJECTIFS: Décrire la calcification de l'artère coronaire chez les patients atteints d'IRT et déterminer si la calcification de l'artère coronaire peut prédire des accidents vasculaires et la mort. TYPE D'ÉTUDE: Sous-étude prospective de cohorte selon le mode d'installation. CADRE: Une unité de soins tertiaires en dialyse, en Ontario (St Joseph's Healthcare Hamilton). PARTICIPANTS: Des patients qui sont nouvellement atteints d'IRT et qui entament une hémodialyse. MESURES: En début de traitement, une caractérisation clinique et une tomodensitométrie (TDM) hélicoïdale qui permettent de mesurer la calcification de l'artère coronaire sur 130, selon l'échelle d'Agatston-Janowitz. L'indicateur principal des résultats comprend l'AVC, l'infarctus du myocarde ou la mort. MÉTHODES: Nous avons suivi les patients de manière prospective, afin de cibler la relation entre la calcification de l'artère coronaire et l'AVC, l'infarctus du myocarde ou la mort subséquente, en utilisant la régression de Cox. RÉSULTATS: Nous avons recruté 248 patients dans trois unités, dans le cadre de l'étude principale, qui ne requérait que des biomarqueurs chimiques. De ces patients, 164 étaient de St Joseph's Healthcare, et étaient admissibles à la sous-étude; 51 avaient effectué une tomographie par ordinateur (31 %). Le suivi médian s'étendait sur 26 mois (Q1, Q3: 14, 34). L'indicateur principal a été observé chez 16 patients; 11 dans le groupe se trouvant au-dessus de la médiane, et 5 dans le groupe inférieur (p?=?0,086). On a observé 26 indicateurs principaux chez 16 patients; 20 (77 %) accidents dans le groupe se trouvant au-dessus de la médiane en ce qui a trait à la calcification et 6 (23 %) dans le groupe inférieur (p?=?0,006). Il y a eu 10 décès; 8 dans le groupe se trouvant au-dessus de la médiane et 2 dans le groupe inférieur (p?=?0,04). Les taux de risque de calcification de l'artère coronaire se trouvant au-dessus et sous la médiane, pour les indicateurs principaux, étaient respectivement de 2,5 (95 % IC 0,98; 21,96; p?=?0,054) et 2,4 (95 % IC 0,45, 12,97; p?=?0,3). LIMITES DE L'ÉTUDE: Nous avons été limités par la taille restreinte de l'échantillon, de même que par le petit nombre d'accidents. CONCLUSION: Le fardeau du répondant repose sur des examens supplémentaires au moment de commencer la dialyse. Un fort taux de calcification de l'artère coronaire chez les patients nouvellement atteints d'IRT tend à prédire des accidents cardiovasculaires et la mort, bien que les effets soient atténués après révision en fonction de l'âge.

Plasma exchange to remove HIT antibodies: dissociation between enzyme-immunoassay and platelet activation test reactivities.

Repeated therapeutic plasma exchange (TPE) has been advocated to remove heparin-induced thrombocytopenia (HIT) IgG antibodies before cardiac/vascular surgery in patients who have serologically-confirmed acute or subacute HIT; for this situation, a negative platelet activation assay (eg, platelet serotonin-release assay [SRA]) has been recommended as the target serological end point to permit safe surgery. We compared reactivities in the SRA and an anti-PF4/heparin IgG-specific enzyme immunoassay (EIA), testing serial serum samples in a patient with recent (subacute) HIT who underwent serial TPE precardiac surgery, as well as for 15 other serially-diluted HIT sera. We observed that post-TPE/diluted HIT sera-when first testing SRA-negative-continue to test strongly positive by EIA-IgG. This dissociation between the platelet activation assay and a PF4-dependent immunoassay for HIT antibodies indicates that patients with subacute HIT undergoing repeated TPE before heparin reexposure should be tested by serial platelet activation assays even when their EIAs remain strongly positive.

Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients.

The peritoneal membrane becomes damaged in patients on peritoneal dialysis (PD). Gremlin 1 (GREM1) inhibits bone morphogenic proteins (BMPs) and plays a role in kidney development and fibrosis. We evaluated the role of gremlin in peritoneal fibrosis and angiogenesis. In a cohort of 32 stable PD patients, GREM1 concentration in the peritoneal effluent correlated with measures of peritoneal membrane damage. AdGrem1, an adenovirus to overexpress gremlin in the mouse peritoneum, induced submesothelial thickening, fibrosis, and angiogenesis in C57BL/6 mice, which was associated with decreased expression of BMP4 and BMP7. There was evidence of mesothelial cell transition to a mesenchymal phenotype with increased α smooth muscle actin expression and suppression of E-cadherin. Some of the GREM1 effects may be reversed with recombinant BMP7 or a pan-specific transforming growth factor ß (TGF-ß) antibody. Neovascularization was not inhibited with a TGF-ß antibody, suggesting a TGF-ß-independent angiogenic mechanism. Swiss/Jackson Laboratory (SJL) mice, which are resistant to TGF-ß-induced peritoneal fibrosis, responded in a similar fashion to AdGrem1 as did C57BL/6 mice with fibrosis, angiogenesis, and mesothelial-to-mesenchymal transition. GREM1 was associated with up-regulated TGF-ß expression in both SJL and C57BL/6 mice, but SJL mice demonstrated a defective TGF-ß-induced GREM1 expression. In summary, GREM1 induces fibrosis and angiogenesis in mouse peritoneum and is associated with increased solute transport in these PD patients.

Programmatic variation in home hemodialysis in Canada: results from a nationwide survey of practice patterns.

BACKGROUND: Over 40% of patients with end stage renal disease in the United States were treated with home hemodialysis (HHD) in the early 1970's. However, this number declined rapidly over the ensuing decades so that the overwhelming majority of patients were treated in-centre 3 times per week on a 3-4 hour schedule. Poor outcomes for patients treated in this fashion led to a renewed interest in home hemodialysis, with more intensive dialysis schedules including short daily (SDHD) and nocturnal (NHD). The relative infancy of these treatment schedules means that there is a paucity of data on 'how to do it'. OBJECTIVE: We undertook a systematic survey of home hemodialysis programs in Canada to describe current practice patterns. DESIGN: Development and deployment of a qualitative survey instrument. SETTING: Community and academic HHD programs in Canada. PARTICIPANTS: Physicians, nurses and technologists. MEASUREMENTS: Programmatic approaches to patient selection, delivery of dialysis, human resources available, and follow up. METHODS: We developed the survey instrument in three phases. A focus group of Canadian nephrologists with expertise in NHD or SDHD discussed the scope the study and wrote questions on 11 domains. Three nephrologists familiar with all aspects of HHD delivery reviewed this for content validity, followed by further feedback from the whole group. Multidisciplinary teams at three sites pretested the survey and further suggestions were incorporated. In July 2010 we distributed the survey electronically to all renal programs known to offer HHD according to the Canadian Organ Replacement Registry. We compiled the survey results using qualitative and quantitative methods, as appropriate. RESULTS: Of the academic and community programs that were invited to participate, 80% and 63%, respectively, completed the survey. We observed wide variation in programmatic approaches to patient recruitment, human resources, equipment, water, vascular access, patient training, dialysis prescription, home requirements, patient follow up, medications, and the approach to non-adherent patients. LIMITATIONS: Cross-sectional survey, unable to link variation to outcomes. Competition for patients between HHD and home peritoneal dialysis means that case mix for HHD may also vary between centres. CONCLUSIONS: There is wide variation between programs in all domains of HHD delivery in Canada. We plan further study of the extent to which differences in approach are related to outcomes.

PROBLÉMATIQUE: Au début des années 70, plus de 40% des patients en insuffisance rénale terminale aux États-Unis étaient traités par hémodialyse à domicile (HDD). Cette proportion a décliné rapidement au cours des décennies suivantes, de sorte que le mode de suppléance pour la majorité des patients est maintenant l'hémodialyse 3 fois par semaine à raison de 3 à 4 heures par séance. Les mauvais résultats obtenus avec cette méthode ont renouvelé l'intérêt pour l'HDD, notamment pour les dialyses intensives incluant la dialyse quotidienne courte (DQC) et l'hémodialyse nocturne (HDN). Étant donné leur nouveauté, il y a peu de données sur les façons de faire avec ces modes de suppléance. OBJECTIF: Afin de décrire les pratiques actuelles, nous avons réalisé un questionnaire systématique auprès des programmes d'HDD au Canada. DESIGN: Développement et déploiement d'un outil qualitatif. CADRE: Programmes d'HDD académiques et communautaires au Canada. PARTICIPANTS: Médecins, infirmières et technologues. VARIABLES MESURÉES: Approches pour la sélection des patients, le mode de suppléance, les ressources humaines disponibles et le mode de suivi pour chaque programme. MÉTHODOLOGIE: Nous avons développé un outil en trois phases. Un groupe de discussion composé de néphrologues canadiens ayant une expertise en DQC ou HDN ont échangé sur le contenu de l'étude et ont rédigé des questions sur 11 domaines. Trois néphrologues familiers avec tous les aspects de l'HDD ont révisé la validité des questions, puis ont demandé un nouvel avis à tout le groupe de discussion. Des équipes multidisciplinaires provenant de trois sites ont ensuite évalué le questionnaire et ont apporté des suggestions. En juillet 2010, le questionnaire a été distribué électroniquement à tous les programmes qui offrent l'HDD d'après le Registre canadien des insuffisances et des transplantations d'organes. Les résultats ont été compilés au moyen de méthodes qualitatives ou quantitatives, le cas échéant. RÉSULTATS: 80% des centres académiques et 63% des centres communautaires invités ont répondu au questionnaire. Nous avons observé des variations importantes entre les programmes quant au recrutement des patients, aux ressources humaines, à l'équipement, à l'eau, aux accès vasculaires, à l'entraînement des patients, à la prescription de dialyse, aux exigences du domicile, au suivi des patients, à la médication et à l'approche face aux patients non-adhérents. LIMITATIONS: Étude transversale, incapacité d'associer les variations aux issues cliniques. La compétition entre l'HDD et la dialyse péritonéale pour le recrutement des patients entraîne peut-être une variabilité entre les centres dans la composition des groupes de patients en HDD. CONCLUSIONS: Il y a de grandes variations entre les programmes dans tous les domaines concernant l'HDD au Canada. Nous planifions d'étudier dans le futur jusqu'à quel point ces différences sont reliées aux issues cliniques.

Estimated GFR reporting influences recommendations for dialysis initiation.

Automated reporting of estimated GFR (eGFR) with serum creatinine measurement is now common. We surveyed nephrologists in four countries to determine whether eGFR reporting influences nephrologists' recommendations for dialysis initiation. Respondents were randomly allocated to receive a survey of four clinical vignettes that included either serum creatinine concentration only or serum creatinine and the corresponding eGFR. For each scenario, the respondent was asked to rank his or her likelihood of recommending dialysis initiation on a modified 8-point Likert scale, ranging from 1 ("definitely not") to 8 ("definitely would"). Analysis of the 822 eligible responses received showed that the predicted likelihood of recommending dialysis increased by 0.55 points when eGFR was reported (95% confidence interval, 0.33 to 0.76), and this effect was larger for eGFRs >5 ml/min per 1.73 m(2) (P<0.001). Subgroup analyses suggested that physicians who had been in practice ≥13 years were more affected by eGFR reporting (P=0.03). These results indicate that eGFR reporting modestly increases the likelihood that dialysis is recommended, and physicians should be aware of this effect when assessing patients with severe CKD.

Vascular access for intensive maintenance hemodialysis: a systematic review for a Canadian Society of Nephrology clinical practice guideline.

BACKGROUND: Practices in vascular access management with intensive hemodialysis may differ from those used in conventional hemodialysis. STUDY DESIGN: We conducted a systematic review to inform clinical practice guidelines for the provision of intensive hemodialysis. SETTING & POPULATION: Adult patients receiving maintenance (>3 months) intensive hemodialysis (frequent [≥5 hemodialysis treatments per week] and/or long [>5.5 hours per hemodialysis treatment]). SELECTION CRITERIA FOR STUDIES: We searched EMBASE and MEDLINE (1990-2011) for randomized and observational studies. We also searched conference proceedings (2007-2011). INTERVENTIONS: (1) Central venous catheter (CVC) versus arteriovenous (AV) access, (2) buttonhole versus rope-ladder cannulation, (3) topical antimicrobial cream versus none in buttonhole cannulation, and (4) closed connector devices among CVC users. OUTCOMES: Access-related infection, survival, hospitalization, patency, access survival, intervention rates, and quality of life. RESULTS: We included 23, 7, and 5 reports describing effectiveness by access type, buttonhole cannulation, and closed connector device, respectively. No study directly compared CVC with AV access. On average, bacteremia and local infection rates were higher with CVC compared with AV access. Access intervention rates were higher with more frequent hemodialysis, but access survival did not differ. Buttonhole cannulation was associated with bacteremia rates similar to those seen with CVCs in some series. Topical mupirocin seemed to attenuate this effect. No direct comparisons of closed connector devices versus standard luer-locking devices were found. Low rates of actual or averted (near misses) air embolism and bleeding were reported with closed connector devices. LIMITATIONS: Overall, evidence quality was very low. Limited direct comparisons addressing main review questions, small sample sizes, selective outcome reporting, publication bias, and residual confounding were major factors. CONCLUSIONS: This review highlights several differences in the management of vascular access in conventional and intensive hemodialysis populations. We identify a need for standardization of vascular access outcome reporting and a number of priorities for future research.

Mercury-associated nephrotic syndrome: a case report and systematic review of the literature.

Kidney injury from mercury is known to cause dose-related tubular dysfunction and idiosyncratic nephrotic syndrome according to various case reports. Motivated by a patient with subacute-onset nephrotic syndrome, histologic features of secondary focal segmental glomerulosclerosis, and concurrent mercury toxicity, we conducted a systematic review to explore renal histologic changes in patients with toxic mercury exposures and nephrotic syndrome. Data were extracted from a patient's clinical record. MEDLINE/Ovid was searched from 1950 to November 2010 using a prespecified search strategy. Two nephrology textbooks and the UpToDate online database also were searched. Inclusion criteria were studies of humans with nephrotic syndrome, nephrotic-range proteinuria, or kidney biopsy results reported. There were no exclusion criteria. We identified 27 other reports of 42 patients with nephrotic syndrome or nephrotic-range proteinuria. Of the 26 individuals, including our patient, who underwent kidney biopsy, histology showed glomerular disease in 21. Of these 20 biopsies, 4 showed minimal change disease and 15 showed membranous glomerulonephritis. Mercury exposure can lead to various glomerular lesions; we emphasize the importance of a careful occupational and dietary history in elucidating a cause for the undetermined nephrotic syndrome.