Antibiotics versus no therapy in kidney transplant recipients with asymptomatic bacteriuria (BiRT): a pragmatic, multicentre, randomized, controlled trial.

OBJECTIVES: Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB. METHODS: We performed this multicentre, randomized, open-label trial in kidney transplant recipients who had ASB and were ≥2 months post-transplantation. We randomly assigned participants to receive antibiotics or no therapy. The primary outcome was the incidence of symptomatic UTI over the subsequent 12 months. RESULTS: One hundred and ninety-nine kidney transplant recipients with ASB were randomly assigned to antibiotics (100 participants) or no therapy (99 participants). There was no significant difference in the occurrence of symptomatic UTI between the antibiotic and no-therapy groups (27%, 27/100 versus 31%, 31/99; univariate Cox model: hazard ratio 0.83, 95%CI: 0.50-1.40; log-rank test: p 0.49). Over the 1-year study period, antibiotic use was five times higher in the antibiotic group than in the no-therapy group (30 antibiotic days/participant, interquartile range 20-41, versus 6, interquartile range 0-15, p < 0.001). Overall, 155/199 participants (78%) had at least one further episode of bacteriuria during the follow-up. Compared with the participant's baseline episode of ASB, the second episode of bacteriuria was more frequently caused by bacteria resistant to clinically relevant antibiotics (ciprofloxacin, cotrimoxazole, third-generation cephalosporin) in the antibiotic group than in the no-therapy group (18%, 13/72 versus 4%, 3/83, p 0.003). CONCLUSIONS: Applying a screen-and-treat strategy for ASB does not reduce the occurrence of symptomatic UTI in kidney transplant recipients who are more than 2 months post-transplantation. Furthermore, this strategy increases antibiotic use and promotes the emergence of resistant organisms.

Prospective randomized study of conversion from tacrolimus to cyclosporine A to improve glucose metabolism in patients with posttransplant diabetes mellitus after renal transplantation.

Tacrolimus (TAC) increases the risk of posttransplant diabetes (PTDM) compared with cyclosporine A (CYC). The present 12-month, multicenter, investigator-driven, prospective, randomized study was designed to assess whether conversion from tacrolimus to CYC can reverse PTDM after renal transplantation. Predominantly white patients with PTDM according to the 2005 American Diabetes Association criteria were randomized to either replacement of TAC with CYC or continuation of their TAC-based regimen after stratification for type of glucose-lowering therapy, steroid therapy, and hepatitis C status. At 12 months, 14 of 41 patients with complete data in the CYC arm (34%; 95%CI 19%-49%) were free of diabetes, whereas this was the case in only 4 of 39 patients (10%; 95%CI 3%-20%) in the TAC arm (P = .01). At 12 months, 39% of patients in the CYC arm were off glucose-lowering medication vs 13% of patients in the TAC arm (P = .01). The CYC group decreased glycated hemoglobin level during the 12-month follow-up, resulting in significantly lower levels compared with the TAC group (6.0 ± 0.9% vs 7.1 ± 1.7% at 12 months; P = .002). In conclusion, replacement of TAC with CYC significantly improves glucose metabolism and has the potential to reverse diabetes during the first year after conversion. (EU Clinical Trials Register No. 2006-001765-42).

Ticlopidine and clopidogrel, sometimes combined with aspirin, only minimally increase the surgical risk in renal transplantation: a case-control study.

BACKGROUND: Patients undergoing kidney transplantation are sometimes being treated with antiplatelet agents such as ticlopidine or clopidogrel. Some teams refuse to wait-list these patients for fear of bleeding during transplant surgery. METHODS: We retrospectively reviewed the records of 702 adult patients with a kidney transplant alone between 2000 and 2010. Nineteen (2.7%) patients were taking clopidogrel or ticlopidine when called in for transplantation. Furthermore, 10 of these 19 patients were also taking low-dose aspirin (ASA). We compared the risk of bleeding peri- and postoperatively, and the occurrence of cardiovascular complications within 30 days after renal transplantation between 19 cases and 39 controls randomly selected within the cohort. RESULTS: Platelets were administered to 7 cases (37%) versus 0 controls (P<0.001). A single case (5.3%) presented with significant bleeding during surgery following an implantation biopsy, and required 4 red bood cell (RBC) units. During the first day, 3 of the 19 cases (16%) and 1 of the 39 controls required RBC (P=0.1). No reoperation was performed for bleeding. After the transplant, clopidogrel or ticlopidine was resumed in only two patients. The platelet count and haemoglobin were similar between cases and controls at Day 30. No cardiovascular event occurred in cases or controls during the first month post-transplantation. At 5 years, graft and patient survival was similar in cases and controls. CONCLUSIONS: Clopidogrel and ticlopidine, sometimes in combination with ASA, are associated with a low risk of bleeding during renal transplantation and does not seem to be a contraindication for renal transplant surgery.

Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring.

BACKGROUND: With effective agents available to prevent posttransplantation acute organ rejection, medication adherence becomes a key factor for successful treatment outcomes after renal transplantation. A once-daily, modified-release oral formulation of tacrolimus has been developed to simplify dosing and improve medication adherence. METHODS: Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograft to Advagraf is a randomized multicenter controlled trial to evaluate adherence between a tacrolimus once-daily regimen and a tacrolimus twice-daily regimen using an electronic monitor to document drug intake. After enrolment, all patients continued the twice-daily regimen for 3 months and then were randomized 2:1 between the two formulations and followed for 6 months. Adherence was decomposed into patients' persistence and implementation of each regimen. RESULTS: Two hundred nineteen patients (45% male; 3±2 years after transplantation) were analyzed (145 once daily and 74 twice daily). At 6 months after randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group remained persistent with the treatment (P=0.0824). Among patients who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the twice-daily group (P=0.0009) took the prescribed number of daily doses. When the patients took the twice-daily regimen, the average percentage of missed doses was 11.7% in the morning and 14.2% in the evening (P=0.0035). CONCLUSIONS: Regimen implementation of tacrolimus once daily is significantly superior to the twice-daily regimen. There was a residual prevalence of suboptimal adherence that will have to be countered by means other than reformulation and regimen simplification. Electronically compiled dosing histories provide detailed data on patient adherence that can be used for efficient medication management.

Shipping donor kidneys within Eurotransplant: outcomes after renal transplantation in a single-centre cohort study.

BACKGROUND: Shipment of organs during the allocation process aims to improve human leucocyte antigen (HLA) matching but can also have a detrimental effect by prolonging cold ischaemia. The overall effect of organ exchange on post-transplant outcomes in the Eurotransplant (ET) region has not been investigated. METHODS: This is a retrospective single-centre cohort study to investigate the effect of shipment of renal allografts on cold ischaemia times and the incidence of acute rejection (AR) and graft survival in 661 transplantations of deceased donor kidneys. RESULTS: Forty-six per cent (N = 301) of the patients received a locally procured and 54% (N = 360) a shipped donor kidney. Locally procured donors tended to be older, more often hypertensive and had less frequently died from trauma. Recipients of shipped kidneys were at higher immunological risk, being younger, more frequently retransplanted and immunized against HLA antigens. Shipped kidneys had a 2.2-h prolongation of cold ischaemia time (18.0 versus 20.2 h; P < 0.0001) but significantly less HLA A, B and DR mismatches (2.20 versus 2.84; P < 0.0001). Recipients of shipped kidneys had an increased incidence of first-year AR [19 versus 13%; odds ratio 1.62 (1.06-2.49); P = 0.026] and death-censored graft loss [hazard ratio 1.6 (1.1-2.4); P = 0.01] that was no longer statistically significant after adjustments for risk factors by multivariable modelling. CONCLUSIONS: Shipment of kidneys in the ET region is associated with a modest increase in cold ischaemia time and significantly better HLA matching. This allows for successful transplantation of higher risk patients with no significant penalty with regard to AR rates or death-censored graft survival.

Combined introduction of anti-IL2 receptor antibodies, mycophenolic acid and tacrolimus: effect on malignancies after renal transplantation in a single-centre retrospective cohort study.

BACKGROUND: Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen. METHODS: A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD). RESULTS: In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001). CONCLUSION: Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Ineligibility for renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 patients.

Little is known about the proportion of renal transplant candidates who are considered ineligible by the transplant center, the reasons of their ineligibility and their survival during dialysis. In this retrospective, single-center study of 445 adult patients referred between 2001 and 2006, 36 (8%) were deemed ineligible for medical contraindications. The leading reason was cardiovascular (CV) (75%), specifically aorto-iliac, and/or limb vessels atheromatosis or calcifications; ischemic heart disease; or a combination thereof. Nine patients had other contraindications that were absolute for three of them; six patients displayed a combination of relative contraindications. When compared to eligible patients (N = 409), those ineligible were significantly older (60 yr vs. 48), more often diabetics (50% vs. 15%), obese (39% vs. 17%) suffering from coronary artery disease (53% vs. 11%) and peripheral arterial disease (86% vs. 11%). Their primary nephropathy was more often diabetic and/or hypertensive/nephroangiosclerosis (61% vs. 23%), and their median dialysis vintage prior to evaluation was longer (29 months vs. 10, p < 0.0001). The actuarial survival of ineligible patients was significantly lower than that of eligible patients (at five yr: 53% vs. 88%). Adequate control of CV risk factors before dialysis and early referral for transplantation might help to improve eligibility of renal transplant candidates.

Conversion from Prograf to Advagraf among kidney transplant recipients results in sustained decrease in tacrolimus exposure.

BACKGROUND: Advagraf is a slow release form of tacrolimus with once-daily formulation. The potential advantages of Advagraf are better adherence and a safer profile by avoiding toxic peak concentrations. In this study, we evaluated the required daily doses of tacrolimus and subsequent blood levels on conversion from Prograf to Advagraf among kidney transplant recipients. METHODS: We retrospectively reviewed data from 55 patients for whom a switch from Prograf to Advagraf was identified. Tacrolimus daily doses and concomitant blood levels were analyzed at several time points ranging from 3 months before to 6 months after conversion. RESULTS: We observed a significant increase in tacrolimus daily doses, starting with a dose of 0.063 mg/kg of Prograf, increasing up to 0.081 mg/kg of Advagraf at 6 months (P<0.0001). After conversion, we observed a quick and sustained decrease in trough tacrolimus levels, decreasing from 8.05 ng/mL at day 0 to 6.30 ng/mL at day 180 (P=0.0009). At 6 months, 35% of patients experienced a decrease in trough levels of more than 30%. Creatinine values remained stable over time, and no patient experienced an acute rejection episode. CONCLUSIONS: Contrary to the manufacturer instructions, we found a significant decrease in tacrolimus exposure after switching to Advagraf. Therefore, the switch from Prograf to Advagraf should be performed under close medical supervision.