Marcelo Cantarovich

Cyclosporine Reduction in the Presence of Everolimus : 3-Month Data From a Canadian Pilot Study of Maintenance Cardiac Allograft Recipients

BACKGROUNDnConcentration-controlled everolimus with concomitant cyclosporine (CsA) dose reduction in renal transplantation permits preservation of kidney function without loss of efficacy. Data are lacking regarding everolimus with reduced-dose CsA in maintenance cardiac transplant patients.nnnMETHODSnIn a multicenter, open-label, single-arm pilot study, concentration-controlled everolimus was initiated in patients receiving CsA microemulsion (Neoral) with/without mycophenolate mofetil (MMF) or azathioprine, and with/without corticosteroids. On the day of everolimus initiation, MMF/azathioprine was discontinued and CsA dose was reduced by 25% with further reductions as required in response to decreasing calculated glomerular filtration rate (cGFR).nnnRESULTSnOf the 36 patients enrolled (intent-to-treat [ITT]), 27 underwent CsA dose reduction as planned (per protocol [PP]). During Week 1, the CsA dose was reduced by 23.3 +/- 7.3% in the ITT population (p < 0.0001) and 26.9 +/- 2.9% in the PP population (p < 0.0001). Mean cGFR (Nankivell) was 68.9 +/- 14.5 ml/min at baseline and 64.4 +/- 14.3 ml/min at Week 12 in the ITT population (p = 0.021), and 69.5 +/- 14.4 ml/min and 66.6 +/- 8.6 ml/min in the PP cohort (p = 0.132). cGFR at Week 12 met the criterion for non-inferiority vs baseline. One case of acute rejection of Grade >or=3A occurred (2.7%). There was no graft loss or death. Hemoglobin and hematocrit levels decreased significantly, whereas cholesterol and triglyceride levels increased (all p < 0.0001).nnnCONCLUSIONSnThis pilot study suggests that initiation of concentration-controlled everolimus with a concomitant 25% reduction in CsA dose in maintenance heart transplant patients is associated with no significant decline in renal function, and no indication of increased rejection to Month 3 post-conversion. Evaluation of more substantial CsA dose reductions is required.

Reduction of cyclosporine following the introduction of everolimus in maintenance heart transplant recipients: a pilot study

Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48‐week, multicenter, single‐arm pilot study in heart transplant patients >12u2003months post‐transplant, everolimus was started at 1.5u2003mg/day (subsequently adjusted to target C0 5–10u2003ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C0 and C2, respectively. Mean cGFR was 68.9u2003±u200314.5u2003ml/min at baseline and 61.6u2003±u200311.5u2003ml/min at week 48 (Pu2003=u20030.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease ≤25% of cGFR from baseline. Two patients experienced biopsy‐proven acute rejection Grade 3A (5.6%). Between baseline and week 48, there were significant increases in total cholesterol, LDL‐cholesterol and triglycerides, and small but significant elevations in liver enzymes. This 1‐year pilot study suggests that CsA dose reduction of ca. 40% after initiation of everolimus was associated with a decrease in cGFR, however, based on the prespecified criteria stable renal function was attained.

Canadian Society of Transplantation and Canadian Society of Nephrology Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

KDIGO (Kidney Disease: Improving Global utcomes) is an international initiative to deelop and implement clinical practice guideines. In November 2009, KDIGO published ts guideline for the management of kidney ransplant recipients. This guideline was exremely comprehensive and spanned more than 50 pages. The Canadian Society of Transplanation (CST) and the Canadian Society of Nehrology (CSN) congratulate KDIGO, memers of the guideline work group, and the vidence review team for producing such a horough and exhaustive document. This guideine will be of great value to health professionls involved in the management of kidney ransplant recipients. KDIGO is an international organization and hus its guidelines have international scope. To ave practical applicability, the various recomendations and suggestions will need adaptation o suit individual countries or jurisdictions. As uch, the CST and CSN formed a joint work roup to review the KDIGO guideline and make uggestions about its applicability and relevance n a Canadian context. This commentary was ritten acknowledging the unique nature of our ransplant population with its ethnic diversity, ur health care system that has variable funding nd access to different medications and services, nd our geography, which has transplant care ocused in larger urban areas, requiring many atients to travel considerable distances. Our ommentary provides supplementary informaion regarding the care of kidney transplant recipints in a Canadian context and should be viewed n conjunction with the full KDIGO document hen making clinical decisions.

Reduced dose Thymoglobulin, tacrolimus, and mofetil mycophenolate results in excellent solitary pancreas transplantation outcomes.

Abstract:u2002 Background:u2002 Graft survival following solitary pancreas transplantation has traditionally lagged behind that of simultaneous pancreas–kidney transplants. Thymoglobulin® (TMG), a polyclonal rabbit‐derived antilymphocyte antibody was originally introduced as treatment for acute rejection of renal allografts. However, data regarding the efficacy of TMG induction in solitary pancreas transplants is lacking. We present the 1‐yr graft survival and acute rejection rate of 22 solitary pancreas transplants performed at the McGill University Health Centre using reduced dose TMG induction with lower dose tacrolimus and mophetil mycophenolate.

Vascular Access-Related Bloodstream Infections in First Nations, Community and Teaching Canadian Dialysis Units, and Other Centre-Level Predictors

Background/Aims: Vascular access-related bloodstream infection (BSI) is frequent among patients undergoing hemodialysis increasing their morbidity and mortality, but its occurrence across various dialysis centre types is not known. The aims of this study were to describe the incidence rates and assess the variability in BSI risk between dialysis centre types and other centre-level variables. Methods: We conducted a retrospective cohort study of 621 patients initiating hemodialysis in 7 Canadian dialysis centres. Cox regression models, where access type was continuously updated, were used to identify predictors of BSI occurrence. Results: During follow-up of the cohort (median age 68.1 years, 41.7% female, and 76.7% initiating with a central venous catheter, CVC), 73 patients had a BSI (rate: 0.21/1000 person-days). The BSI risk was not different in First Nation units (adjusted relative risk: 0.47, 95% confidence interval: 0.06–3.72) and teaching hospitals (1.33, 0.70–2.54) compared to community hospitals. No other centre-related variables were associated with the risk of BSI. Conclusion: We did not find differences in the BSI risk among dialysis unit types, or any other centre-related variables. The rates of BSI in our population were lower than those observed in other settings, but the high proportion of patients using CVCs is concerning.

Tricuspid valve replacement after cardiac transplantation.

Abstract:u2002 Background:u2002 Tricuspid regurgitation (TR) occurs commonly in transplanted hearts. Although theoretically attractive, tricuspid valve replacement (TVR) has not been widely investigated as a possible therapy in post‐transplant patients. The purpose of this study was to determine the safety of TVR in heart transplant patients and its effects on measurable clinical endpoints.

Canadian Forum on Combined Organ Transplantation.

Abstract The Canadian Society of Transplantation and Canadian Blood Services conducted a consensus forum on combined renal/nonrenal transplants, as they are not part of Canadian organ-specific allocation models at present. The purpose of this initiative was to make recommendations, develop eligibility criteria, and a decision-making model on listing and allocation. Forty-two participants with expertise in combined transplantation participated in the consensus forum. The United States and Canadian data were reviewed. The consensus forum made recommendations regarding the following: (1) investigation of etiology, severity, duration, and level of renal dysfunction; (2) documentation of degree of nonreversible kidney injury; (3) eligibility for combined (either simultaneous or staged) transplantation; (4) research. Key recommendations were: (1) patients with end-stage nonrenal disease with estimated glomerular filtration rate less than 30 mL/min per 1.73 m2 for longer than 1 month or on dialysis less than 3 months, who fulfill criteria for nonreversibility of renal dysfunction (by level and duration of renal dysfunction, imaging, and pathology findings), would be eligible for combined renal/nonrenal transplantation; (2) patients on dialysis longer than 3 months would be eligible for combined renal/nonrenal transplantation; (3) staged renal after nonrenal transplantation with subsequent prioritized allocation of renal transplant was endorsed in selected cases. The validation and impact of these recommendations on allocation will require further studies.

Early renal function recovery and long‐term graft survival in kidney transplantation

Following kidney transplantation (KTx), renal function improves gradually until a baseline eGFR is achieved. Whether or not a recipient achieves the best‐predicted eGFR after KTx may have important implications for immediate patient management, as well as for long‐term graft survival. The aim of this cohort study was to calculate the renal function recovery (RFR) based on recipient and donor eGFR and to evaluate the association between RFR and long‐term death‐censored graft failure (DCGF). We studied 790 KTx recipients between January 1990 and August 2014. The last donor SCr prior to organ procurement was used to estimate donor GFR. Recipient eGFR was calculated using the average of the best three SCr values observed during the first 3 months post‐KTx. RFR was defined as the ratio of recipient eGFR to half the donor eGFR. 53% of recipients had an RFR ≥1. There were 127 death‐censored graft failures (16%). Recipients with an RFR ≥1 had less DCGF compared with those with an RFR <1 (HR 0.56; 95% CI 0.37–0.85; P = 0.006). Transplant era, acute rejection, ECD and DGF were also significant determinants of graft failure. Early recovery of predicted eGFR based on donor eGFR is associated with less DCGF after KTx.

Long-term immunosuppression with anti-CD25 monoclonal antibodies in heart transplant patients with chronic kidney disease.

BACKGROUNDnChronic kidney disease (CKD), a frequent and serious complication after heart transplantation, is associated with increased mortality. Current strategies include dose reduction or conversion from calcineurin inhibitors (CNIs) to either mycophenolate mofetil and/or rapamycin, with variable results and side-effect profiles.nnnMETHODSnWe evaluated the effectiveness of long-term anti-CD25 monoclonal antibody (MAb)-based immunosuppression in 17 adult heart transplant recipients with CKD at 10 +/- 5 years post-transplant. Seven patients had previously been switched to rapamycin but had untreatable side-effects and 10 patients were still on a CNI. The latter were matched with 10 control heart transplant patients whose renal function had remained stable over a similar post-transplant follow-up period, on CNI.nnnRESULTSnAnti-CD25 MAb were given over 13 +/- 10 months and were well tolerated with CD25 saturation monitoring (target <2% expression). Side-effects secondary to rapamycin resolved in 6 patients. The slope change of the creatinine clearance improved in patients in whom CNIs were discontinued (+0.335 ml/min/month vs -0.124 ml/min/month in controls, p = 0.03). Four patients died. Three died after 2, 6 and 7 months of follow-up, respectively, with the following diagnoses: acute renal failure (the patient refused dialysis); acute rejection (the patient had refused protocol endomyocardial biopsy); and perforated diverticulitis. The fourth patient died of pneumonia, 3 months after conversion from anti-CD25 MAb to rapamycin, because of poor venous access.nnnCONCLUSIONSnThe use of long-term anti-CD25 MAb therapy as a potential replacement for CNI- and rapamycin-based immunosuppression is feasible. It is crucial that rejection surveillance be intensified. A randomized, controlled trial is required to confirm the benefits and safety of this strategy.

Immunosuppression with budesonide for liver transplant recipients with severe infections

When a liver transplant recipient develops a lifethreatening infection, the tendency is to decrease or withhold immunosuppression. However, the risk of infection must be balanced against the risk of organ rejection in this context. Here we report 3 patients with fungal infections after liver transplantation whose immunosuppression was switched to a budesonide-based regimen by our transplant team. Budesonide is an oral corticosteroid with a high rate of firstpass metabolism by the isoenzyme cytochrome P450 3A4, so high intrahepatic concentrations and low systemic concentrations are achieved. This decreases the glucocorticoid activity of the parent compound to approximately a hundredth and leaves very little available systemically; thus, the risk of infection and other adverse steroid effects is potentially decreased. We chose budesonide because it has recently been shown to be a successful treatment for autoimmune hepatitis and to both prevent rejection and provide control over severe fungal infections. The first case was a 60-year-old man who underwent liver transplantation for hepatitis C in 2001 and underwent retransplantation for ischemic cholangiopathy in November 2010 with a Model for End-Stage Liver Disease score of 23. He developed a Saccharomyces cerevisiae infection according to peritoneal fluid and blood cultures 5 days after transplantation, and this infection was treated with caspofungin. The patient also developed Enterobacter aerogenes sepsis, which was treated with imipenem. Because of these infections, mycophenolate mofetil and tacrolimus were discontinued, and oral budesonide was initiated at 9 mg once a day. This dosage was chosen because it is the standard dose for Crohn’s disease. The liver enzyme levels and the liver function remained stable with budesonide monotherapy 3 months later, and follow-up liver biopsy revealed cholestasis but no evidence of acute rejection (Fig. 1). The second case was a 63-year-old man who underwent liver transplantation for hepatitis B cirrhosis and developed pericardial tamponade 4 days after transplantation, which required a pericardial window. He was diagnosed with fungal pericarditis due to Aspergillus flavus and was started on voriconazole and caspofungin. He was switched from tacrolimus and prednisone to budesonide monotherapy (3 mg by mouth 3 times a day). The patient developed a hemorrhagic stroke a few months after transplantation and died because of acute aspiration pneumonia. During his autopsy, extensive pericardial fibrosis was found with occasional fungal hyphae consistent with his history of Aspergillus pericarditis. The liver showed no evidence of cellular rejection, but mild hemosiderosis was seen. The third case was a 34-year-old woman with liver failure secondary to steroid-resistant autoimmune hepatitis with a Model for End-Stage Liver Disease score of 38. After liver transplantation, she was given corticosteroids, tacrolimus, and mycophenolate mofetil as immunosuppression. Magnetic resonance imaging of the brain was performed because of decreased