Lynne Senécal

BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches.

Abstract BK polyomavirus is ubiquitous, with a seropositivity rate of over 75% in the adult population. Primary infection is thought to occur in the respiratory tract, but asymptomatic BK virus latency is established in the urothelium. In immunocompromised host, the virus can reactivate but rarely compromises kidney function except in renal grafts, where it causes a tubulointerstitial inflammatory response similar to acute rejection. Restoring host immunity against the virus is the cornerstone of treatment. This review covers the virus-intrinsic features, the posttransplant microenvironment as well as the host immune factors that underlie the pathophysiology of polyomavirus-associated nephropathy. Current and promising therapeutic approaches to treat or prevent this complication are discussed in relation to the complex immunopathology of this condition.

Eculizumab for the Treatment of Severe Antibody-Mediated Rejection: A Case Report and Review of the Literature.

In renal transplantation, treatment options for antibody-mediated rejection are limited. Here, we report a case of severe AMR treated with eculizumab. A 50-year-old woman known for end stage kidney disease secondary to IgA nephropathy received a kidney transplant from a 50-year-old deceased donor. At 5 months after transplantation, she presented with acute graft dysfunction and biopsy showed a severe antibody-mediated rejection associated with thrombotic microangiopathy. Despite an aggressive conventional immunosuppressive regimen, signs of rejection persisted and the patient was treated with 3 doses of eculizumab. Following the therapy, markers of TMA improved and graft function stabilized. However, ongoing signs of rejection remained in the repeated biopsy. In kidney transplantation, eculizumab is an expensive treatment and its role in the treatment of antibody-mediated rejection remains to be determined.

The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients

Conversion from a calcineurin‐inhibitor‐based immunosuppression to a rapamycin‐based immunosuppression may preserve kidney graft function. The side effects of rapamycin can limit its usefulness, but their management and evolution are rarely reported in clinical trials. We performed a retrospective cohort study in patients transplanted before December 31, 2008 and who received rapamycin to replace calcineurin inhibitors. In 219 patients studied, 98% presented ≥1 side effects after starting rapamycin. Side effects occurring in ≥10% of patients were dyslipidemia (52%, 95% confidence interval (CI): 45–59%), peripheral edema (37%, 95%CI: 31–43%), cytopenia (36%, 95% CI: 30–42%), acne (29%, 95% CI: 23–35%), proteinuria (23%, 95% CI: 17–29%), and oral ulcers 14% (95% CI: 10–18%). Proteinuria, ulcers, and edema were difficult to manage and were more likely to cause cessation of rapamycin. Rapamycin was discontinued in 46% of patients (95% CI: 40–52%). Age (odds ratio [OR] per 10‐yr increase: 1.29, 95% CI: 1.05–1.59) and obesity (OR: 2.57, 95% CI: 1.10–6.01) were independently associated with cessation of rapamycin. We conclude that successful control of dyslipidemia and cytopenia can be achieved without discontinuing rapamycin. Most other side effects are harder to manage. Leaner and younger patients are less likely to discontinue rapamycin due to side effects.

Efficacy of Acute Cellular Rejection Treatment According to Banff Score in Kidney Transplant Recipients: A Systematic Review.

Background The poor prognosis classically associated with Banff grade 2 acute cell-mediated rejection (CMR) may be due to unrecognized antibody-mediated damage. We thus performed a systematic review of the literature to determine the rate of response to treatment in kidney transplant recipients with pure CMR, stratified by Banff class. Methods In addition to a manual search, databases interrogated included Excerpta Medica Database (EMBASE), Medical Literature Analysis and Retrieval System Online (MEDLINE), Evidence-Based Medicine (EBM) databases, Central, PubMed and CINAHL. Studies providing functional and/or histological response rates to the treatment of CMR rejection by Banff class (1997 or more recent) were included. Results Among the 746 articles identified, 5 articles were included in the final review. Two studies excluded some, and 2 excluded all features of antibody-mediated rejection, while providing data on functional recovery. The absence of functional recovery was reported in 4% of borderline, 15% for Banff grade 1A and IB pooled, 0% to 25% of Banff grade 1B alone, 11% to 20% of Banff grade 2A, and 38% of Banff grade 2B rejections. Conclusions The rate of functional recovery of pure Banff IIA CMR overlapped with that of Banff grade 1 CMR, whereas Banff grade 2B showed worse prognosis. There was important heterogeneity in the definition of response to treatment and paucity of data describing the histological response to treatment stratified by Banff class. There is a pressing need to standardize outcome metrics for the reversibility of rejection in kidney transplant recipients in order to design high-quality trials for novel therapeutic alternatives.

High mortality after pelvis and lower limb fractures in ESRD

Sir, The high mortality rate associated with hip fracture in the general population, as well as in the end-stage renal disease (ESRD) population, is well described. However, the mortality associated with pelvis and lower limb fractures in ESRD patients remains unknown. We reviewed the medical records of all chronic haemodialysis or peritoneal dialysis patients hospitalized at Maisonneuve-Rosemont Hospital for a fracture from 1 July 1995 to 1 February 2007. Femoral neck, pelvis, femoral condyle, tibial plateau, patella, tibia and malleolus fractures were considered. Femoral neck and pelvis fractures were analysed separately, while the other fractures were analysed together as lower limb fractures. All patients who died during the study period were identified and mortality rates were calculated. During the 127-month-long study period, 60 dialysis patients were hospitalized for a total of 68 fractures. Seven patients had two fracture episodes, and one patient had three fracture episodes. The three most common fracture sites were hip (40 cases), pelvis (13 cases) and malleolus (8 cases) (Table 1). The 1-year mortality rate after a hip fracture was 42.5% (17 patients), with an in-hospital mortality rate of 20%. Two patients died during their hospitalization for a pelvis or lower limb fracture. One-year mortality rates were 30.8% after a pelvis fracture and 20% after a lower limb fracture. Median survival during the observation period was 427 days after a pelvis fracture and 581 days after a lower limb fracture. Hip fracture is associated with a 1-year mortality rate of 24% in the general population [1]. In ESRD, the 1-year mortalityrateafterahipfractureapproximates50%[2].Our results are consistent with previously reported mortality rates. Few studies have described the mortality associated with pelvis or lower limb fractures in the general population. In a British study, the 1-year mortality rates were 8.7% after pelvis fracture and 2.4% after a lower limb fracture [3]. In our ESRD cohort, the 1-year mortality rates for pelvis and lower limb fractures were increased 3.5- and 8.3-fold, respectively. In fact, the impact of pelvis and lower limb fractures on mortality in ESRD patients appears very similar to the impact of hip fracture in the general population. Like hip fractures [4,5], pelvis and lower limb fractures are probably markers of poor nutritional and general health status in this population. With a 1-year mortality rate similar to that of hip fracture in the general population, our data delineate for the first time the poor outcomes associated with pelvis and lower limb fractures in ESRD patients. The incidence, risk factors, clinical and functional outcomes of such fractures in ESRDpatientsneedtobeevaluatedinlarger,registry-based studies.

Practice Patterns in the Treatment and Monitoring of Acute T Cell–Mediated Kidney Graft Rejection in Canada:

Background: One of the goals of the Canadian National Transplant Research Program (CNTRP) is to develop novel therapies for acute rejection that could positively affect graft outcomes with greater efficacy or less toxicity. To develop innovative management strategies for kidney graft rejection, new modalities need to be compared with current clinical practices. However, there are no standardized practices concerning the management of acute T cell–mediated rejection (TCMR). Objectives: To describe clinicians’ practice patterns in the diagnosis, treatment, and monitoring of acute TCMR in Canada. Design: Survey. Setting, Patients/Participants: Canadian transplant nephrologists and transplant surgeons involved in the management of acute TCMR. Methods and Measurements: We developed an anonymous, web-based survey consisting of questions related to the diagnosis, treatment, and monitoring of TCMR. The survey was disseminated on 3 occasions between June and October 2016 through the Canadian Society of Transplantation (CST) kidney group electronic mailing list. Results: Forty-seven respondents, mostly transplant nephrologists (97%), originating from at least 18 of the 25 Canadian centers offering adult or pediatric kidney transplantation, participated in the study. Surveillance biopsies were used by 28% of respondents to screen for kidney graft rejection. High-dose steroids were used by most of the respondents to treat clinical and subclinical Banff grade 1A and 1B rejections. Nine percent (95% confidence interval [CI]: 1-17) of practitioners used lymphocyte-depleting agents as the first-line approach for the treatment of Banff grade 1B acute rejection. Eighteen percent (95% CI: 7-29) and 36% (95% CI: 8-65) of respondents reported that they would not use high-dose steroids for treating clinical and subclinical borderline rejections, respectively. Seventy percent (95% CI: 54-83) of respondents answered that there was no indication to assess histological response to treatment independent of the change in kidney function. Limitations: The limitations of this study are its limited sample size and the low representation of pediatric specialists. Conclusions: There is heterogeneity regarding the use of surveillance biopsies, treatment of borderline rejection, and modalities to monitor treatment response among transplant physicians. Our results illustrate the current state of practice patterns across Canada and can be used to inform the design of future trials.

Conversion from twice-daily to once-daily extended-release tacrolimus in renal transplant recipients: 2-year results and review of the literature.

OBJECTIVES Tacrolimus extended-release formulation has been approved for use in Canada since October 2008. In initial studies, efficacy and safety profile were demonstrated as similar for both formulations (twice-daily tacrolimus and extended-release formula tacrolimus). To validate the safety and efficacy of extended-release formula tacrolimus, we conducted a prospective observational study. MATERIALS AND METHODS At our institution, between January 2009 and January 2010, the switch from tacrolimus to extended-release formula tacrolimus was done in 130 stable kidney recipients. Clinical data were accessed at baseline (data before conversion), 1 to 2 weeks, 1 month, 3 months, 6 months, 12 months, and 24 months after conversion. RESULTS One hundred thirty renal transplant recipients were included in the current study. During the observation period, we saw no acute rejection and no change in graft function (mean serum creatinine levels remained stable). However, compared with baseline, mean tacrolimus trough levels were significantly reduced at 1 to 2 weeks, at 1 month, 6 months, 12 months, and at 24 months after conversion. Regarding the safety profile, no significant changes were noted in blood glucose, potassium, and magnesium. Approximately 35% of recipients preferred the extended-release formula tacrolimus to twice-daily tacrolimus. CONCLUSIONS Conversion from twice-daily tacrolimus to extended-release once-daily tacrolimus appears to be safe and convenient up to 2 years after conversion in some recipients.

Difficulty of patient selection in a combined heart-kidney transplant: a case report.

Combined heart-kidney transplant has become an alternative for heart transplant candidates with significant chronic kidney disease. However, it is not clear which patients will benefit most from such intervention, and in whom cardiac transplant alone will be sufficient to restore adequate renal function. We report the case of a man with ischemic cardiomyopathy and chronic kidney disease who was wait-listed for heart-kidney transplant after acute decompensated heart failure and renal failure requiring hemodialysis. Because of unexpected circumstances, the kidney transplant was cancelled, and only a heart transplant was performed. Nonetheless, the kidney function rapidly improved beyond the levels before hospitalization and remains stable months after transplant. This case illustrates the difficulties in assessing the reversibility of kidney damage in the context of heart failure requiring transplant. This issue is primordial to improve selection of patients who will benefit most from combined heart-kidney transplant in a context of scarce organ allocation resources.