Belatacept Conversion in Kidney After Liver Transplantation.

BACKGROUND: Costimulatory blockade with belatacept has demonstrated long-term benefits in renal transplantation, but de novo use in liver transplant recipients has resulted in increased rejection, graft loss, and death. However, belatacept conversion as a calcineurin inhibitor (CNI) avoidance strategy has not been studied and may be of benefit in liver transplantation where CNI-induced renal dysfunction and toxicity are barriers to improved outcomes. METHODS: Using clinical data extracted from our institutional medical record, we report on 8 patients who underwent kidney after liver transplantation and were treated with belatacept-based immunosuppression and transient CNI therapy. RESULTS: All patients tolerated belatacept therapy without any patient deaths or graft losses. No episodes of rejection, de novo donor-specific antibody formation, or major systemic infections were observed, and all patients demonstrated preserved liver and excellent renal allograft function. Patients received belatacept for a median duration of 13.2 mo, and at a median follow-up of 15.9 mo post-kidney transplant, 6 of 8 patients continued on belatacept with 3 completely off and 3 poised to transition off CNI. CONCLUSIONS: These findings are the first evidence that in liver transplant recipients requiring subsequent kidney transplantation, belatacept-based therapy can potentially facilitate CNI-free maintenance immunosuppression. This supports the possibility of belatacept conversion in stand-alone liver transplant recipients as a viable method of CNI avoidance.

Space Radiation Protection Countermeasures in Microgravity and Planetary Exploration.

BACKGROUND: Space radiation is one of the principal environmental factors limiting the human tolerance for space travel, and therefore a primary risk in need of mitigation strategies to enable crewed exploration of the solar system. METHODS: We summarize the current state of knowledge regarding potential means to reduce the biological effects of space radiation. New countermeasure strategies for exploration-class missions are proposed, based on recent advances in nutrition, pharmacologic, and immune science. RESULTS: Radiation protection can be categorized into (1) exposure-limiting: shielding and mission duration; (2) countermeasures: radioprotectors, radiomodulators, radiomitigators, and immune-modulation, and; (3) treatment and supportive care for the effects of radiation. Vehicle and mission design can augment the overall exposure. Testing in terrestrial laboratories and earth-based exposure facilities, as well as on the International Space Station (ISS), has demonstrated that dietary and pharmacologic countermeasures can be safe and effective. Immune system modulators are less robustly tested but show promise. Therapies for radiation prodromal syndrome may include pharmacologic agents; and autologous marrow for acute radiation syndrome (ARS). CONCLUSIONS: Current radiation protection technology is not yet optimized, but nevertheless offers substantial protection to crews based on Lunar or Mars design reference missions. With additional research and human testing, the space radiation risk can be further mitigated to allow for long-duration exploration of the solar system.

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial.

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2 . One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).

Partial vs. radical nephrectomy and the risk of all-cause mortality, cardiovascular, and nephrological outcomes.

INTRODUCTION: The study's objective was to examine the effects of renal-preservation surgery on long-term mortality, cardiovascular outcomes, and renal-related outcomes. METHODS: We performed a retrospective cohort study of all partial (n=575) and radical nephrectomies (n=882) for tumors ≤7 cm in diameter between 2002 and 2010 across three academic centers in Ontario, Canada. We linked records from provincial databases to assess patient characteristics and outcomes (median seven years' followup using retrospective data). A weighted propensity score was used to reduce confounding. The primary outcome was all-cause mortality. Secondary outcomes included hospitalization with major cardiovascular events, non-cancer related mortality, kidney cancer-related mortality, and dialysis. RESULTS: Mean one-year postoperative estimated glomerular filtration rate (eGFR) was 71 mL/min/1.73 m2 in the partial group and 52 mL/min/1.73 m2 in the radical group. Partial nephrectomy was associated with a lower risk of all-cause mortality in the first five years after surgery (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.27-0.66), which did not extend beyond five years (HR 1.01, 95% CI 0.68-1.49). Kidney cancer-related mortality was lower in the partial compared to the radical group for the first four years after surgery (HR 0.16, 95% CI 0.04-0.72). There were no significant differences between the groups for cardiovascular outcomes or non-cancer related deaths. CONCLUSIONS: Overall survival and cancer-specific survival was reduced in radical nephrectomy patients. However, despite reduced renal function in the radical nephrectomy group, non-cancer-related death, cardiovascular events, and dialysis were not significantly different between groups. Long-term benefits of partial nephrectomy may be less than previously believed.

Transplanting kidneys from donors with small renal masses - a strategy to expand the donor pool.

INTRODUCTION: Renal transplantation is the optimal treatment for end-stage renal disease, but organ demand continues to outstrip supply. The transplantation of kidneys from donors with small renal masses (SRMs) represents a potential avenue to expand the donor pool. We reviewed all published cases of transplants from donors with SRMs and we present followup data, best practices, and outline an actionable series of steps to guide the implementation of such transplants at individual centers. METHODS: A detailed literature search of the MEDLINE/PubMed and SCOPUS databases was performed. Thirty unique data sets met inclusion criteria and described the transplantation of tumor-ectomized kidneys; nine data sets described the transplantation of contralateral kidneys from donors with SRMs. RESULTS: A total of 147 tumorectomized kidneys have been transplanted. Pathology revealed 120 to be renal cell carcinomas (RCCs), of which 116 were stage T1a (0.3-4 cm). The mean followup time was 44.2 months (1-200). A single suspected tumor recurrence occurred in one patient nine years post-transplantation and it was managed with active surveillance. Twenty-seven kidneys have been transplanted from deceased donors with contralateral renal masses. Pathology revealed 25 to be RCCs, of which 19 were confirmed to be stage T1 (<7 cm). The mean followup time was 46.7 months (0.5-155). One recipient developed an RCC and underwent curative allograft nephrectomy. CONCLUSIONS: Careful use of kidneys from donors with SRMs is feasible and safe, with an overall recurrence rate of less than 1.5%. The use of such kidneys could help alleviate the organ shortage crisis.

Active surveillance in Canadian men with low-grade prostate cancer.

BACKGROUND: Recent guidelines recommend against routine screening for prostate cancer, partly because of the risks associated with overtreatment of clinically indolent tumours. We aimed to determine the proportion of patients whose low-grade prostate cancer was managed by active surveillance instead of immediate treatment. METHODS: We reviewed data for patients who were referred to the Ottawa regional Prostate Cancer Assessment Clinic with abnormal results for prostate-specific antigen (PSA) or prostate examination between Apr. 1, 2008, and Jan. 31, 2013. Patients with subsequent biopsy-proven low-grade (Gleason score 6) cancer were included. Active surveillance was defined a priori as monitoring by means of PSA, digital rectal examination and repeat biopsies, with the potential for curative-intent treatment in the event of disease progression. RESULTS: Of 477 patients with low-grade cancer, active surveillance was used for 210 (44.0%), and the annual proportion increased from 32% (11/34) in 2008 to 67% (20/30) in 2013. Factors associated with immediate treatment were palpable tumour, PSA density above 0.2 ng/mL(2) and more than 2 positive biopsy cores. Factors associated with surveillance were age over 70 years and higher Charlson comorbidity index. Of 173 men who received immediate surgical treatment, 103 (59.5%) had higher-grade or advanced-stage disease on final pathologic examination. Of the 210 men with active surveillance, 62 (29.5%) received treatment within a median of 1.3 years, most commonly (52 [84%]) because of upgrading of disease on the basis of surveillance biopsy. INTERPRETATION: Active surveillance has become the most common management strategy for men with low-grade prostate cancer at our regional diagnostic centre. Factors associated with immediate treatment reflected those that increase the risk of higher-grade tumours.

Maximal kidney length predicts need for native nephrectomy in ADPKD patients undergoing renal transplantation.

INTRODUCTION: Native nephrectomy in patients with autosomal dominant polycystic kidney disease (ADPKD) is performed on a case-by-case basis. We determine if pre-transplant maximal kidney length (MKL) can be used to predict ultimate nephrectomy status. METHODS: We performed a retrospective review of ADPKD patients who underwent renal transplantation at our centre between January 2000 and December 2012. Pre-transplant measurements of MKL alone, MKL adjusted for height (HtMKL), weight (WtMKL) and body mass index (BMI-MKL) were each assessed for their predictive ability via a receiver operating characteristic (ROC) curve analysis. RESULTS: In total, 84 patients met our inclusion criteria, of which 17 (20.2%) underwent native nephrectomy. An MKL ROC curve analysis revealed an area under the curve (AUC) of 0.867 (95% confidence interval [CI] 0.775-0.931; p < 0.001). An optimal cutoff criterion of >21.5 cm revealed a sensitivity of 94.1% (95% CI 71.3-99.9) and specificity of 70.1% (95% CI 57.7-80.7) for eventual nephrectomy. The AUC of HtMKL, WtMKL and BMI-MKL ROC curves did not differ significantly from MKL alone. HtMKL improved specificity, but not overall test performance. The determination of the cut-off MKL may be influenced by the single-centre retrospective nature of this analysis, as well as the fact that renal size was determined by ultrasound and not computerized tomography or magnetic resonance imaging. CONCLUSION: MKL in patients with ADPKD is associated with the eventual need for nephrectomy and may be a useful clinical tool to risk stratify these patients and therefore guide patient conversations to a decision to leave the native kidneys in situ.

Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction?

While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.

Debilitating lower urinary tract symptoms in the post-renal transplant population can be predicted pretransplantation.

BACKGROUND: Overactive bladder and benign prostatic hyperplasia commonly cause lower urinary tract symptoms (LUTS) in the renal transplant (RTx) population. These LUTS may be masked by low urine output and may pose risk to renal allografts after RTx. Our purpose was to determine the frequency and severity of LUTS in RTx patients and to determine if patients at highest risk for LUTS could be predicted by validated questionnaires or other pre-RTx characteristics. METHODS: All patients who underwent RTx between 2005 and 2010 were asked to complete the validated Overactive Bladder Questionnaire based on patient symptoms before RTx and at 6 and 12 months after RTx. Male patients also completed the International Prostate Symptom Score survey. Patient, donor, and RTx characteristics and outcome data were collected. RESULTS: Of 466 RTx recipients, 23.8% responded and 89 patients were eligible for participation in the study. LUTS were common both before and after RTx as measured by the Overactive Bladder Questionnaire and International Prostate Symptom Score. Pre-RTx survey scores were predictive of moderate to severe post-RTx LUTS (relative risk, 4.1-18.0; P≤0.05). Low urine output of less than 250 mL per day was also predictive of moderate to severe post-RTx LUTS (relative risk, 2.9-5.9; P<0.02). CONCLUSIONS: Validated questionnaires and low urine output before transplantation may be used to identify patients at highest risk for LUTS after RTx. Identification of at risk patients would allow earlier initiation of treatment strategies to improve patient quality of life.

Learning surgically oriented anatomy in a student-run extracurricular club: an education through recreation initiative.

Didactic and laboratory anatomical education have seen significant reductions in the medical school curriculum due, in part, to the current shift from basic science to more clinically based teaching in North American medical schools. In order to increase medical student exposure to anatomy, with clinical applicability, a student-run initiative called surgically oriented anatomy prosectors (SOAP) club was created within the extracurricular program at the Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada. SOAP invites surgeons and residents from various surgical specialties to demonstrate, on a cadaver, a surgical procedure of their choosing. During the demonstration, the anatomy, as it relates to the surgical procedure, is discussed. The students then break into smaller groups to examine the relevant anatomy on the cadavers, during which time the discussion is broadened. The group continues the conversation in a social environment with refreshments. SOAP is one of the most popular extracurricular clubs with 65% of first and second year medical students registered as members. The high demand for SOAP, along with the positive participant feedback, may be due to its utilization of the principle of education through recreation, which seeks to provide opportunities for learning seamlessly throughout all facets of life. It also demonstrates the desire, amongst certain medical students, to learn applied anatomy, particularly within a surgical context.

Combination stem cell therapy for heart failure.

Patients with congestive heart failure (CHF) that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. Therefore, one of the important next steps in the field is optimization. In this paper we discuss three ways to approach this issue: a) increasing stem cell migration to the heart; b) augmenting stem cell activity; and c) combining existing stem cell therapies to recapitulate a "therapeutic niche". We conclude by describing a case report of a heart failure patient treated with a combination stem cell protocol in an attempt to augment beneficial aspects of cord blood CD34 cells and mesenchymal-like stem cells.