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Introduction: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk., Methods and Analysis: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation., Ethics and Dissemination: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309)., Trial Registration Number: NCT05148715., Competing Interests: Competing interests: CL, FDA, FLam, FLau, F-MC and MC are recipients of research career awards from the Fonds de recherche du Québec-Santé. AFT is the chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. FDA, MW and PC received stipends for their role at Transplant Québec MaS holds research grants from the Canadian Institute of Health Research and the New Frontiers in Research Fund related to organ donation research and received a stipend for his role as the Regional Medical Lead (Donation) from Ontario Health (Trillium Gift of Life Network). MSe, RB, M-HM, MMa, A-JF, BB, AD, EC, SHo, LB, HT, PL, JGB, MKS, KEAB, JZ, SE, GK, AH, SHa, BR, SJWO, DT and MMe declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Patients with advanced chronic kidney disease (CKD) have the best chance for a longer and healthier life if they receive a kidney transplant. However, many barriers prevent patients from receiving a transplant., Objectives: To evaluate the effect of a multicomponent intervention designed to target several barriers that prevent eligible patients from completing key steps toward receiving a kidney transplant., Design, Setting, and Participants: This pragmatic, 2-arm, parallel-group, open-label, registry-based, superiority, cluster randomized clinical trial included all 26 CKD programs in Ontario, Canada, from November 1, 2017, to December 31, 2021. These programs provide care for patients with advanced CKD (patients approaching the need for dialysis or receiving maintenance dialysis)., Interventions: Using stratified, covariate-constrained randomization, allocation of the CKD programs at a 1:1 ratio was used to compare the multicomponent intervention vs usual care for 4.2 years. The intervention had 4 main components, (1) administrative support to establish local quality improvement teams; (2) transplant educational resources; (3) an initiative for transplant recipients and living donors to share stories and experiences; and (4) program-level performance reports and oversight by administrative leaders., Main Outcomes and Measures: The primary outcome was the rate of steps completed toward receiving a kidney transplant. Each patient could complete up to 4 steps: step 1, referred to a transplant center for evaluation; step 2, had a potential living donor contact a transplant center for evaluation; step 3, added to the deceased donor waitlist; and step 4, received a transplant from a living or deceased donor., Results: The 26 CKD programs (13 intervention, 13 usual care) during the trial period included 20 375 potentially transplant-eligible patients with advanced CKD (intervention group [n = 9780 patients], usual-care group [n = 10 595 patients]). Despite evidence of intervention uptake, the step completion rate did not significantly differ between the intervention vs usual-care groups: 5334 vs 5638 steps; 24.8 vs 24.1 steps per 100 patient-years; adjusted hazard ratio, 1.00 (95% CI, 0.87-1.15)., Conclusions and Relevance: This novel multicomponent intervention did not significantly increase the rate of completed steps toward receiving a kidney transplant. Improving access to transplantation remains a global priority that requires substantial effort., Trial Registration: ClinicalTrials.gov Identifier: NCT03329521.

Background: The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy., Methods: In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1-2 months (M) apart 4-18M posttransplant. Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2., Results: Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post-dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups., Conclusions: RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose., Clinical Trials Registration: NCT02058589., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Purpose: Although intraoperative anaphylaxis during surgery is a rare event, we describe five patients who experienced perioperative anaphylactic reactions during renal transplantation and were referred for investigation., Clinical Features: Skin-prick and intradermal skin tests were done to investigate potential allergies to drugs given perioperatively prior to the development of anaphylaxis, including basiliximab, propofol, cefazolin, cis-atracurium, fentanyl, latex, remifentanil, and chlorhexidine. In addition, in vitro serologic testing for specific IgE was done in patients suspected to have had chlorhexidine anaphylaxis. All five patients were male, with a mean age of 48 yr (range 30-69). Skin testing for all drugs was non-reactive except for chlorhexidine, which was positive in four of five patients (one patient refused intradermal testing). In vitro test results for chlorhexidine-specific IgE were positive in all of the patients. Anesthetic records showed that intraoperative anaphylaxis had occurred immediately after insertion of a chlorhexidine-coated central venous catheter., Conclusions: Intraoperative insertion of chlorhexidine-coated central venous catheters can trigger life-threatening anaphylaxis in susceptible patients undergoing renal transplantation.

A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Surgical thrombectomy in the context of acute renal vein thrombosis (RVT) post-transplantation has had limited success, with considerable variation in the surgical techniques used. Unfortunately, it is usually followed by allograft nephrectomy within a few days if rapid allograft recovery does not ensue. We report a case of acute RVT in which nephrectomy was not performed despite a prolonged requirement for dialysis post-thrombectomy, but with recovery of renal function 2 weeks later. We also report the findings of serial MRI with diffusion-weighted imaging (DW-MRI) throughout the patient's recovery, which provided novel insights into allograft microvascular perfusion changes post-thrombectomy., Case Presentation: A 65-year old patient underwent living-unrelated kidney transplantation complicated by acute RVT. Surgical thrombectomy and irrigation led to a delayed, but significant, recovery of renal function. Serial non-contrast DW-MRI scanning was used to non-invasively assess microvascular renal blood flow post-operatively. Unlike standard Doppler ultrasonography, DW-MRI documented reduced microvascular perfusion initially, with gradual but incomplete recovery that mirrored the partial improvement in renal function., Conclusions: Our findings suggest that surgical thrombectomy may be more effective than previously described if followed by careful patient observation. Moreover, diffusion-weighted MRI appears to provide important insights into the pathophysiology of delayed graft function and deserves further investigation.

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 m 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.

Background: Establishment of a national kidney paired donation (KPD) program represents a unique achievement in Canada's provincially organized health care system., Methods: Key factors enabling program implementation included consultation with international experts, formation of a unique organization with a mandate to facilitate interprovincial collaboration, and the volunteer efforts of members of the Canadian transplant community to overcome a variety of logistical barriers., Results: As of December 2013, the program had facilitated 240 transplantations including 10% with Calculated panel reactive antibody (cPRA) ≥97%. Unique features of the Canadian KPD program include participation of n = 55 nondirected donors, performance of only donor specific antibody negative transplants, the requirement for donor travel, and nonuse of bridge donors., Conclusion: The national KPD program has helped maintain the volume of living kidney donor transplants in Canada over the past 5 years and serves as a model of inter-provincial collaboration to improve the delivery of health care to Canadians.

Importance: BK virus infection is a significant complication of modern immunosuppression used in kidney transplantation. Viral reactivation occurs first in the urine (BK viruria) and is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies., Objective: To determine if levofloxacin can prevent BK viruria in kidney transplant recipients., Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial involving 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers between December 2011 and June 2013., Interventions: Participants were randomly assigned to receive a 3-month course of levofloxacin (500 mg/d; n = 76) or placebo (n = 78) starting within 5 days after transplantation., Main Outcomes and Measures: The primary outcome was time to occurrence of BK viruria (detected using quantitative real-time polymerase chain reaction) within the first year after transplantation. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival., Results: The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51-1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76-49.95)., Conclusions and Relevance: Among kidney transplant recipients, a 3-month course of levofloxacin initiated early following transplantation did not prevent BK viruria. Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance. These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection., Trial Registration: clinicaltrials.gov Identifier: NCT01353339.

Canada has a marked shortfall between the supply and demand for kidneys for transplantation. Median wait times for deceased donor kidney transplantation vary from 5.8 years in British Columbia, 5.2 years in Manitoba and 4.5 years in Ontario to a little over 2 years in Quebec and Nova Scotia. Living donation provides a viable option for some, but not all people. Consequently, a small number of people travel abroad to undergo kidney transplantation by commercial means. The extent to which they are aware of the potential risks to their health and the health of the kidney vendors is unclear. Travel abroad to obtain a kidney commercially i.e. transplant tourism (TT), raises ethical issues which include the exploitation of the poor, uncertainty of donor informed consent to nephrectomy, poor clinical care and lack of follow up for the donor, commodification of the body and inequity of access to medical care for donors. Also, TT widens socioeconomic disparities in access to transplantation, differing from the Canadian system of universal coverage for healthcare. The Canadian transplant community has discussed how to respond to patients who plan to travel abroad for TT or return with a purchased kidney. Unease rests in the tension between the duty to care for legitimate Canadian residents and the unwillingness to enable TT. This paper discusses three anonymized cases and the Canadian responses to TT as recorded in academic literature and a formal statement by relevant professional bodies.

Background: BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection., Methods/design: The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol., Discussion: Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition., Trial Registration: This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).

Purpose: The aim of this study was to explore donor and recipient outcomes from organ donation after cardiac death (DCD) in Ontario and to examine the impact of DCD on deceased donation rates in Ontario since its implementation., Methods: Donor data were obtained from the Trillium Gift of Life Network (TGLN) TOTAL database from June 1, 2006 until May 31, 2009. All DCDs were tracked, including unsuccessful DCD attempts during that time. For the first 36 months after DCD implementation, all Ontario solid organ transplant programs that utilized organs from DCD provided clinical outcome data at one year. Total DCD activity until December 1, 2010 was also tracked. In addition, we compared organ donation and DCD rates across all Canadian jurisdictions and the USA., Results: For the first 36 months of DCD activity in Ontario, June 1, 2006 to May 31, 2009, there were 67 successful DCDs out of 87 attempted DCDs in 18 Ontario hospitals, resulting in 128 kidney, 41 liver, and 21 lung transplants. The one-year kidney patient and death-censored allograft survivals were 96 and 97%, respectively. Mean (SD) creatinine at 12 months was 150 (108) μmol·L(-1). In 26 (20%) extended criteria donors (ECD-DCD), the one-year creatinine was 206 (158) μmol·L(-1) vs 137 (80) μmol·L(-1) in 102 standard criteria donors (SCD-DCD) (P = 0.002). The one-year liver and lung allograft survivals were 78% and 70%, respectively. Since its implementation four and a half years ago, DCD has accounted for 10.9% of deceased donor activity in Ontario. In 2009, Ontario had a record number of organ donors. Of the 221 deceased donors, 37 (17%) donors were DCD. By December 1, 2010 there were 121 DCD Ontario donors resulting in > 300 solid organ transplants and accounting for 90% of all DCD activity in the country., Conclusion: The rapid update of DCD in Ontario can be attributed to strong proponents in the critical care and transplantation communities with continued support from Trillium Gift of Life Network (TGLN). Ontario is the only province to demonstrate growth in deceased donor rates over the last decade (25% over the last four years), which can be attributed primarily to the success of its DCD activity.

Aim: New-onset diabetes after renal transplantation (NODAT) adversely affects graft and patient survival. However, NODAT risk based on pre-transplant blood glucose (BG) levels has not been defined. Our goal was to identify the best pre-transplant testing method and cut-off values., Materials and Methods: We performed a case-control analysis of non-diabetic recipients who received a live donor allograft with at least 6 months post-transplant survival. Pre-transplant glucose abnormalities were excluded through 75 g oral glucose tolerance testing (OGTT) and random BG (RBG) measurement. NODAT was defined based on 2003 Canadian Diabetes Association criteria. Multivariate logistic and Cox regression analysis was performed to determine independent predictor variables for NODAT. Receiver-operating-characteristic (ROC) curves were constructed to determine threshold BG values for diabetes risk., Results: 151 recipients met initial entry criteria. 12 had pre-transplant impaired fasting glucose and/or impaired glucose tolerance, among who 7 (58%) developed NODAT. In the remaining 139, 24 (17%) developed NODAT. NODAT risk exceeded 25% for those with pre-transplant RBG > 6.0 mmol/l and 50% if > 7.2 mmol/l. Pre-transplant RBG provided the highest AUC (0.69, p = 0.002) by ROC analysis. Increasing age (p = 0.025), acute rejection (p = 0.011), and RBG > 6.0 mmol/l (p = 0.001) were independent predictors of NODAT., Conclusion: Pre-transplant glucose testing is a specific marker for NODAT. Patients can be counseled of their incremental risk even within the normal BG range if the OGTT is normal.

Nocturnal home hemodialysis (NHD) is a novel dialysis strategy associated with multiple advantages over conventional hemodialysis (CHD). Short- and long-term clinical outcomes of NHD patients after kidney transplantation are unknown. We hypothesized that the incidence of delayed graft function (DGF), patient and graft survival, and post-transplant estimated glomerular filtration rate (eGFR) is better among CHD-transplanted individuals than among those having received NHD. Of 231 NHD patients, 36 underwent renal transplantation between 1994 and 2006 and were matched to 68 transplanted CHD patients with a maximum follow-up of 11.7 yr. The incidence of DGF was not different between the two groups [NHD: 15/35 (42.9%) vs. CHD: 25/68 (36.8%) p = 0.43]. In modeling eGFR pre-transplant weight, donor age and recipient race were most predictive. Dialysis modality prior to transplantation influenced neither the level of eGFR post-transplantation (p = 0.34), nor the rate of eGFR decline. Patient survival was comparable between NHD and CHD groups (log-rank p = 0.91). Based on this analysis, it appeared that the incidence of DGF was similar between NHD- and CHD-transplanted patients and that pre-transplant modality did not impact on the level or rate of deterioration of post-transplant eGFR.

Background/aims: Periodic limb movements are common in patients with end-stage renal disease. Kidney transplantation significantly improves renal function and may therefore reduce periodic limb movements. We evaluated the effect of kidney transplantation on periodic limb movements in a group of patients with end-stage renal disease., Methods: Eighteen patients (aged 27-65) who were receiving dialysis and were candidates for living donor or deceased donor kidney transplantation (n = 12) or were predialysis with a suitable living donor arranged (n = 6) were recruited from the transplant clinic. Attended overnight polysomnography was performed before and after kidney transplantation. Patients were divided based on a periodic limb movement index >15 events/h during sleep., Results: Kidney transplantation was associated with a significant reduction in periodic limb movement index in all patients (8 (0-110) events/h vs. 2 (0-80) events/h) and this reduction was greatest in 7 patients with a periodic limb movement index >15 events/h (40 (24-110) events/h to 14 (1-80) events/h, p < 0.005)., Conclusion: Successful kidney transplantation improves periodic limb movements in patients with end-stage renal disease. This may improve sleep quality and sleep-related quality of life in kidney transplant recipients, which should have a beneficial impact on clinical outcomes., (Copyright 2008 S. Karger AG, Basel.)

Background: Sleep apnoea is common in patients with end-stage renal disease. Although individual case reports have described an improvement in sleep apnoea following kidney transplantation, there have been no longitudinal studies of a case series to determine what proportion of patients with sleep apnoea improve., Methods: Dialysis-dependent patients awaiting kidney transplantation and pre-dialysis patients with an identified living donor kidney had overnight polysomnography, which was repeated several months after successful kidney transplantation. Patients were divided into apnoeic and non-apnoeic groups based on an apneoa-hypopnoea index (AHI) > 10/h during pre-transplant polysomnography and, following transplantation, apnoeic patients were further divided into responders and non-responders based on >50% reduction in AHI and/or AHI < 10/h., Results: Eighteen patients (11 men, 7 women), aged 27-65, were studied. Pre-transplant sleep apnoea was present in 11 of 18 (61%) patients. Although transplantation was associated with a significant reduction in blood urea nitrogen and serum creatinine, there were no significant changes in AHI (pre vs post: 20.2 +/- 15.1 vs 23.5 +/- 21.3). Among the 11 apnoeic patients, only three met the criteria for a significant improvement ('responder'). There were no patient characteristics, sleep apnoea indices or renal function changes that distinguished responders from non-responders., Conclusions: Sleep apnoea improves in a minority of patients with end-stage renal disease following successful kidney transplantation. Specific determinants of improvement were not identified.

Tacrolimus extended-release (XL) is a once-daily formulation recently developed to reduce the frequency of dosing for patients currently using the twice-a-day formulation of tacrolimus (TAC). As reported previously, 67 kidney transplant recipients were safely converted (1:1 mg basis, total daily dose) from TAC twice-a-day to XL once-daily in the morning and were maintained on an am dosing regimen of XL using the same therapeutic monitoring and patient care techniques currently employed with TAC. The 2-year postconversion patient (100%) and graft (98.5%) survival, incidence of biopsy-confirmed acute rejection (6.0%), incidence of multiple rejections (1.5%), and safety profile (posttransplant diabetes, hyperlipidemia, hypertension, infections, renal dysfunction, hepatic dysfunction, and malignancies) were consistent with or more favorable than those previously reported for TAC twice-a-day.

Dietary salt is an important contributor to hypertension in the general population. While its role in cyclosporine-induced hypertension is minimal, its role in tacrolimus-based immunosuppression has not been defined. We measured the 24-hour urine sodium excretion as an estimate of intake in a group of stable renal transplant recipients on tacrolimus (N = 143) who had serum creatinine fluctuations <20% during the preceding 3 months. Average clinic-measured blood pressure (BP) from before and after the 24-hour urine collection was computed. Patients with recent changes in antihypertensive medications were excluded. Average systolic BP was 126 +/- 14 and diastolic BP 76 +/- 7 mm Hg. Urine sodium was 162.6 +/- 70 mmol/d (range 50 to 351), and the sodium/creatinine ratio was 15.4 +/- 6.4. There was no correlation between urine sodium excretion and either systolic or diastolic BP (R = 0.07 and R = 0.05, P = NS) or the sodium/creatinine and systolic/diastolic BP (R = 0.13, R = 0.11, P = NS). By multiple linear regression only weight and urine protein were independently associated with both systolic BP (P < .0001 for each) and diastolic BP (P < .05 for each). In conclusion, there is no appreciable influence of dietary salt intake on BP under tacrolimus-based immunosuppression. Restricting dietary salt intake in these patients cannot be recommended at the current time.

Unlabelled: Modified release (MR) tacrolimus is an extended release formulation administered once daily (qD). The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable kidney transplant recipients converted from Prograf twice a day to MR tacrolimus qD., Methods: This was an open-label, multicenter study with a crossover design. Eligible patients were 18 to 65 years of age, more than 6 months posttransplant with stable renal function, and received stable Prograf doses more than 2 weeks prior to enrollment. Patients received Prograf twice a day through day 7; 24-hour PK profiles were obtained on days 1 and 7. Patients were converted to the same milligram-for-milligram daily dose of MR tacrolimus qD in the morning on day 8; 24-hour PK profiles were obtained for MR tacrolimus on days 8, 14, and 21. Laboratory and safety parameters were also evaluated., Results: Most patients (67 of 70) completed all 5 PK profiles. The 90% confidence intervals (CI) for the MR tacrolimus vs Prograf comparison at steady state (days 14 and 21 vs days 1 and 7) were 90.7 and 99.4 for AUC0-24 and 82.7 and 91.9 for Cmin. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 1, r = 0.80; day 7, r = 0.84) and MR tacrolimus (day 14, r = 0.92; day 21, r = 0.86). Renal function remained stable after conversion to MR tacrolimus., Conclusion: The steady state PK of MR tacrolimus are equivalent to Prograf after a milligram-for-milligram conversion in stable kidney transplant recipients. The results provide evidence to support a safe 1:1 conversion from Prograf twice a day to MR tacrolimus.

Survival after kidney transplantation is better than on the waiting list, even in the elderly. However, the effects of a prolonged waiting time for an organ on death with graft function have not been critically examined in this patient group. We conducted a single-center retrospective analysis of our cadaveric renal transplant experience in patients older than 60 years who received a kidney between January 1, 1990 and December 31, 2003. Besides waiting time, the effects of recipient age, gender, and diabetes were also examined. Cox proportional hazards analysis using patient death as a time-dependent outcome was used to estimate the hazard ratio of death posttransplantation. Using Kaplan-Meier survival methodology, patients with waiting times < or =5 years had significantly better survival times posttransplantation compared with those with waiting times >5 years (6.2 vs 2.8 years; P <.001). Each year of waiting was associated with hazard ratio 1.16 (95% confidence interval [CI], 1.06-1.27) for death. Prolonged waiting time on dialysis is deleterious to patient survival in recipients older than 60 years at transplantation. Early transplantation thus should be strongly encouraged in this group of patients.

Background: Calcium channel blockers are widely used in the treatment of post-transplant hypertension but have the potential for drug interaction with calcineurin inhibitors. Renal allograft outcomes when diltiazem is used with cyclosporine have been reported, but similar data with tacrolimus are not available., Methods: We performed a retrospective analysis of all our renal transplant recipients from March 1997 to March 2002 who were given tacrolimus, mycophenolate mofetil and prednisone. Patients were divided into two groups based on whether diltiazem was started in the first postoperative week. Outcome measures included renal function up to 2 years post-transplant, blood pressure (BP) control, tacrolimus exposure, and costs related to tacrolimus monitoring., Results: Sixty-four patients constituted the diltiazem group and 32 the control group. Their baseline characteristics were similar. The mean average daily dose of diltiazem used was 213.95 mg/day. There was no difference in renal function, graft survival, or patient survival over 2 years. BP control was similar although the diltiazem group required more medication. Diltiazem was discontinued in four patients due to side-effects. There was no difference in tacrolimus-related side-effects between the two groups. There was also no difference in tacrolimus exposure, cost related to tacrolimus monitoring, or combined costs when the expense of diltiazem was added., Conclusion: Diltiazem use is acceptably safe and efficacious in renal transplant recipients treated with tacrolimus-based immunosuppressive therapy. It can be considered as a first-line antihypertensive in these patients and is cost neutral for tacrolimus use.

Background: Nocturnal haemodialysis (NHD) is a novel form of haemodialysis therapy that is associated with improved blood pressure control when compared to conventional haemodialysis (CHD). Current studies suggest that NHD lowers blood pressure through a decrease in peripheral resistance. The graft and blood pressure outcomes of NHD patients who undergo renal transplantation are unknown., Methods: We reviewed the renal allograft and blood pressure outcomes of 15 NHD patients who underwent renal transplantation. An age and vintage matched cohort of 29 CHD patients was used as controls., Results: The rate of delayed graft function (DGF) tended to be higher in the NHD group compared to the CHD group (64 vs 41%, P = 0.15), however the 1-year graft function (53+/-6 vs 59+/-5 ml/min, P = 0.426) and graft survival (92 vs 95%, P = 0.751) were similar. Intra-operatively, NHD patients had lower minimum systolic (92+/-5 vs 109+/-4, P = 0.03) and diastolic (48+/-3 vs 64+/-2, P = 0.02) blood pressures in comparison to the CHD cohort. Pathologically, acute tubular necrosis accounted for 100% of DGF in the NHD group in contrast to 75% in the CHD population (P = 0.01). Pre-transplant mean systolic BP (sBP) was significantly lower in the NHD group compared to the CHD group (113+/-6 vs 145+/-10 mmHg, P<0.001). At 12 months post-transplant, mean sBP increased from baseline in the NHD group ( triangle up sBP 22+/-7 mmHg, P = 0.009) while in the CHD group mean sBP fell (Delta sBP -14+/-5 mmHg, P = 0.014). Mean arterial and diastolic BP exhibited similar changes. These trends persisted after 24 months of post-transplant follow-up., Conclusions: One-year graft outcomes and blood pressures are similar for NHD and CHD patients who undergo renal transplantation. Unlike CHD patients, NHD patients experienced a significant fall in their intra-operative blood pressures, which likely contributed towards the delayed graft function in this cohort of patients. Further prospective studies are needed to examine the underlying differences in haemodynamics and long-term graft survival between the two renal replacement modalities.

Allograft nephropathy leads to progressive renal injury and ultimate graft loss. In native kidney disease, the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is beneficial in retarding the decline of renal function. We reviewed a cohort of renal transplant recipients who were prescribed either an ACEi or ARB for biopsy-proven allograft nephropathy. Patients were followed from time of initiation of ACEi/ARB and were stratified based on biopsy findings. Outcomes of interest included safety, allograft survival, renal function, and rate of renal function decline pre- and post-ACEi/ARB. The 5-year allograft survival after biopsy was 83%. Mean serum creatinine was 2.2 +/- 1.1 mg/dL (range 1.0 to 4.3) at time of biopsy and 2.6 +/- 1.2 mg/dL (1.2 to 6.5) at last follow-up. The mean slope of the creatinine versus time (SD) was 2.43 (7.93) in the 12 months prior to therapy and 1.45 (3.66) following therapy, with the absolute difference in slope -3.38 (6.06) (P =.0004). We conclude that treatment with ACEi/ARB is beneficial in the management of allograft nephropathy.

Seasonal variation in blood pressure (BP) has been described in the general and dialysis populations, with higher recordings noted in the winter than in the summer. This difference has been attributed to changes in weight, ambient temperature, and length of daylight. In this study, we sought to determine whether such seasonal differences exist in renal transplant recipients, a group with a high prevalence of hypertension. We reviewed our outpatient population of 652 adult renal transplant recipients and identified primary allograft recipients with graft survival >1 year, stable renal function, on both cyclosporine and prednisone, and who had >1 pair of post-first year "winter" (defined as the months of January and February) plus "summer" (defined as the months of July and August) outpatient BP measurements from the same year. One hundred sixty-three patients met entry criteria, from whom 432 BP pairs were obtained. When the most recent pair from each patient was analyzed (n=163), diastolic and mean BP were found to be higher in winter than summer (by 2.5 and 2.3 mmHg, respectively, P<0.01 for each) by a paired Student t test. In a separate analysis using all BP pairs (n=432), systolic, diastolic, and mean BP were found to be significantly higher in winter (by 5.3, 2.7, and 3.5 mmHg, respectively, P<0.001 for each). An effect of season was confirmed in a multiple regression model of common predictors for hypertension, controlling for number of BP pairs per patient. In conclusion, renal transplant recipients demonstrate higher BP in the winter than in the summer. This effect is independent of known predictors of hypertension in this population and may be, at least, partly related to changes in length of daylight and temperature.

Background: Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids., Methods: Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts., Results: At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149+/-58 micromol/L, compared with 158+/-102 micromol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density., Conclusions: On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.

Angiotensin-converting enzyme inhibitors (ACEi) are a class of antihypertensive agents that decrease mortality in congestive heart failure and have established efficacy in the treatment of hypertension and the slowing of established diabetic nephropathy and other proteinuria-associated glomerulonephritides. These drugs have not gained wide acceptance in the treatment of hypertension in renal transplant recipients (RTRs) because of a potential for decreased renal blood flow and glomerular filtration rate associated with a single kidney and concomitant cyclosporine use. Experimental animal models suggest that ACEi may be of benefit in slowing the progression of chronic renal allograft rejection. We undertook a retrospective chart analysis of all RTRs in our institution who had been treated with an ACEi or an angiotensin II (AT II) antagonist, with the objectives of determining the safety, efficacy, and side effect profile of these medications. The minimum follow-up period was 6 months. One hundred seventy-seven of 642 RTRs were prescribed an ACEi or AT II antagonist. Forty-seven patients discontinued therapy, with the most common causes of discontinuation being cough (8 patients) and hyperkalemia (6 patients). The mean arterial blood pressure at each follow-up period was lower than that at the time of initiation of ACEi or AT II antagonist therapy, with a decrease from 92 +/- 12 mm Hg to 86 +/- 9 mm Hg (P < 0.05) after 3 years of treatment. The serum creatinine concentrations did not change throughout the follow-up period. There was a nonsustained increase from the baseline serum potassium of 4.4 +/- 0.5 to 4.6 +/- 0.6 mEq/L at 3 months (P < 0.05), but no further increases in potassium beyond this time. The mean hemoglobin concentration for the cohort did not change, but 13 RTRs given an ACEi for posttransplantation erythrocytosis (PTE) had a decrease in hemoglobin from 17.1 +/- 1.0 g/dL at the start of ACEi therapy to 14.8 +/- 2.2 g/dL at 3 years (P < 0.05). ACEi and AT II antagonists were generally effective antihypertensives, and were safe and well-tolerated agents in this cohort of RTRs. ACEi were also effective in the treatment of PTE.

Nephritis has been a recognized complication of systemic lupus erythematosus since the early 1900s. Almost all lupus patients have some degree of renal involvement related to their condition, but a considerably smaller proportion of these patients actually progress to end-stage renal disease (ESRD). However, lupus patients are also susceptible to other primary renal insults that may significantly contribute to the deterioration in their renal function. We present a case of a patient with clinical and pathological evidence of lupus nephritis that progressed to ESRD and subsequently developed "recurrent" focal segmental glomerulosclerosis in her transplant kidney. Retrospective clinicopathologic correlation suggested the possibility of more than 1 primary renal process that eventually led to her dialysis-dependent state. This case illustrates the importance of meticulously examining both clinical and renal biopsy data in patients with lupus nephritis and considering the presence of co-existing renal pathologies to resolve an otherwise discordant picture of disease progression. These considerations may have important therapeutic and prognostic implications.

Method: Despite the need to expand the donor pool, it is unclear what parameters should be used. The value of donor renal pathology and calculated creatinine clearance (CrCl) in determining recipient outcome was assessed in 57 kidney transplants from 34 donors in whom pretransplant renal biopsies were performed because of age > or =60, hypertension, and/or vascular disease. We retrospectively compared clinical outcomes in these recipients and 57 control recipients selected to have the same baseline demographics but receiving transplants from low risk donors who were significantly younger (32+/-13.9 vs. 61+/-7.3 years) and lighter weight (71+/-18.1 vs. 84+/-20.2 kg) than the high-risk donors (P<.001 for both)., Results: Recipients of high-risk kidneys had a higher incidence of delayed graft function, defined by a <10% fall in serum creatinine (Cr) in the first 24 hr, (56% vs. 30%, P<.01), a higher incidence of rejection (60% vs. 37%, P = .02) and a higher Cr level (197+/-64 vs. 144+/-54 micromol/L at 18 months, P<.005). Graft and patient survival were similar; 12% and 5% vs. 91% and 9% in high-risk vs. control groups, respectively (P = NS). Donor renal pathology was scored 0-3 (none to severe disease) in four areas: glomerulosclerosis, interstitial fibrosis, tubular atrophy, and vascular disease. A donor vessel score of 3/3 was associated with a 100% incidence of delayed graft function and a mean 1-year Cr level of 275+106 micromol/L (compared with 43% and 192+54 micromol/L in those with lower vessel scores, P<.05). Calculated donor CrCl <100 ml/min was associated with higher recipient Cr levels at 1 year, 240+/-95 micromol/L vs. 180+/-54 micromol/L in recipients of kidneys from donors with CrCl levels >100 ml/min (P<.05). The mean 1-year Cr level was 320+/-102 micromol/L in recipients with both a vascular score of 3/3 and a donor CrCl <100 ml/min and 184+/-63 micromol/L in those with neither factor (P = .001)., Conclusion: Calculated donor CrCl and donor vascular pathology predict recipient graft function and may be helpful in selecting high-risk donors for single kidney transplantation.

Objective: To develop a set of comprehensive, standardized, evidence-based guidelines for the use of antiviral therapy to prevent cytomegalovirus disease in adult patients having undergone renal transplantation., Options: The use of medication, at the time of induction therapy or at the earliest sign of viremia. Treatments were evaluated by patient and donor serologic groups and the induction regimen used., Outcomes: The control of symptoms and features of cytomegalovirus disease over the first 6 mo to 1 yr after transplantation., Evidence: Articles, compiled using a MEDLINE search from 1976 to July 1997, were reviewed by representatives of nephrology, microbiology, pharmacy, and epidemiology. Additional information was obtained from recent review articles and conference abstracts, and from experts in the field., Values: The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examinations were used. High value was placed on studies with a randomized controlled design and blinded outcome observers. Study quality was classified as poor when cointervention was present (especially with regard to immunosuppressive regimens), when more than 20% of patients were lost to follow-up, and when intention to treat analysis was not performed. Recommendations were made with a graded system (grades A and B: Use of the intervention advised, based on high or fair quality evidence, respectively; grades D and E: Use of the intervention not advised, based on high or fair quality evidence, respectively: grade C: No recommendation made because of insufficient or conflicting evidence)., Recommendations: (1) Seropositive recipient; donor seropositive or seronegative; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation). (2) Seronegative recipient; seropositive donor; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation) (3) Seronegative recipient; seropositive donor; conventional immunosuppression. Prophylaxis with antiviral therapy recommended (grade B recommendation). (4) Seronegative recipient; seronegative donor; any immunosuppressive regimen. No prophylaxis with antiviral therapy required (grade D/E recommendation). (5) Seropositive recipient: donor seropositive or seronegative; conventional immunosuppression. Prophylaxis left to the discrimination of the physician in charge (grade C recommendation).

Background: Gingival hyperplasia (GH) is a common side effect of cyclosporine . Azithromycin (Zithromax; AZI) is a macrolide antibiotic reported in case studies to reduce cyclosporine-induced gingival hyperplasia (CIGH) in renal transplant recipients (RTR)., Methods: The efficacy of AZI to treat CIGH in RTR was examined in a double-blind, randomized crossover trial. Patients (n=17) with CIGH were randomized to receive AZI and a matching placebo in alternate order for 5 days, separated by a 2-week washout period. Follow-up visits were conducted at week 6 and week 12. Changes in GH were evaluated by measuring the clinical gingival sulcus depths, tooth length, and the length of the interdental papillae to the cementum-enamel junction of two teeth in each of the four quadrants., Results: Significant improvements were observed in all three types of periodontal measurements, representing reductions of gingival tissue above the medial aspect of the tooth, of the gingival sulcus depth, and of the length of the interdental papillae. Patients reported an improvement in gum bleeding. AZI was well tolerated, and 67% of the patients reported that the treatment was at least somewhat useful., Conclusions: AZI should be considered for RTR with CIGH.

Background: Cytomegalovirus (CMV) associated with thrombotic microangiopathy (TMA) in transplant patients has not been extensively described. This case illustrates an association between CMV and TMA in a transplant patient with resolution of the latter after treatment of the CMV., Methods and Results: At 6 weeks after renal transplantation, a 57-year-old woman presented with TMA. Cyclosporine was discontinued, and plasmapheresis was started. However, the patient continued to deteriorate and developed CMV pneumonitis. Plasmapheresis was discontinued, and intravenous ganciclovir was initiated. Both the TMA and the CMV resolved after initiation of the ganciclovir., Conclusion: This case identifies another potential etiological factor in the development of TMA after renal transplantation. It is the first reported case of TMA being cured with treatment of CMV.

Background: There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events., Methods: The long-term safety and tolerability of conventional cyclosporine (CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up., Results: No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine > or = 20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035)., Conclusions: Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

Thrombotic microangiopathy is an uncommon but well described complication of renal transplantation. This study is a review of the case records of 18 patients with biopsy proven post transplant thrombotic microangiopathy, without cellular rejection. There was no single characteristic underlying cause of renal failure in native kidneys. Although only two (11%) patients had undergone previous transplantation, 16 (89%) had panel reactive antibodies (PRA). All patients received prophylactic antilymphocyte globulin, a single patient had cyclosporin A (CSA) at the time of transplant and in 16 patients CSA was introduced when graft function was established. On this protocol 16 (89%) patients had early graft function. All patients developed acute renal failure and 16 (89%) required dialysis. Nine (50%) patients developed hematological abnormalities. All patients were treated aggressively with anti-rejection therapy, CSA was temporarily withdrawn, and 2 (11%) patients received plasmapheresis. Seven (39%) patients lost their grafts. Renal function in the remaining patients recovered to serum creatinine levels ranging from 104 mumol/l to 430 mumol/l (1.2 mg% to 4.8 mg%). All patients with surviving grafts had CSA successfully reintroduced. This study indicates that there is an association between patients who develop posttransplant thrombotic microangiopathy after CSA administration and high PRA levels. The condition appears to respond to anti-rejection therapy and stopping CSA in the majority of cases. The safe reintroduction of CSA suggests that endothelial cell damage in the posttransplant period may be multifactorial and not solely due to CSA therapy.

In normal kidneys, alpha-smooth muscle actin and collagen type III expression is restricted to vascular smooth muscle cells and perivascular fibrous tissues, respectively, but in pathological conditions their expression or deposition is more extensive. Using immunohistochemistry, we examined the expression of alpha-smooth muscle actin and type III collagen in 31 human renal transplant biopsy specimens obtained from patients with graft dysfunction. We found that dysfunctional renal transplants have increased alpha-smooth muscle actin and collagen III expression in the glomerulus and interstitium, but only glomerular alpha-smooth muscle actin expression correlates with graft function and prognosis.

Background: The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study., Methods: Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons., Results: The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA)., Conclusions: MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

Fifty-five renal transplant recipients were studied prospectively for changes in monoclonal antibody-defined mononuclear cell subsets (MCS) over the first 45 days posttransplant. Patients received induction immunotherapy with either monoclonal OKT2(n = 29) or polyclonal RATS (n = 26) preparation. Sequential examinations showed characteristic patterns of MCS depletion, which differed according to the type of therapy received and which subset was examined. In general, induction therapy with RATS resulted in greater and more sustained reduction of most MCS than was seen with OKT3 therapy. In recipients who received OKT3 induction there was a correlation between allograft rejection and an increase in lymphocytes expressing pan-T cell markers and in natural-killer cells. In contrast, rejection episodes in patients receiving RATS were associated with increases in subpopulations of T cells including helper, inducer and suppressor/cytotoxic T-cell subsets. There was no correlation of rejection with B cells or T-cell activation markers. The different patterns of MCS depletion with different antilymphocyte preparations and the association between changes in different MCS and rejection warrant further investigation.

Recombinant human erythropoietin (rHuEPO) is effective in correcting anemia in hemodialysis, peritoneal dialysis, and predialysis patients. Limited studies in patients with failing renal allografts suggest a similar efficacy but provide little information concerning benefits, dose requirements, or adverse events. This study examined these considerations in a group of 40 patients (18 men; 22 women) aged 40.3 +/- 13.8 yr with stable, chronic renal allograft failure. All patients had a hemoglobin < 95 g/L and a serum creatinine > 250 mumol/L at baseline. Patients received rHuEPO (50 U/kg sc) three times weekly for 24 wk along with iron po if serum ferritin was < 100 micrograms/L. Mean hemoglobin rose from 78.9 +/- 10.4 to 102.6 +/- 18.4 g/L after 24 wk. Mean rHuEPO dose at 24 wk was 129.8 +/- 81.9 U/kg per week. With oral iron supplementation only, serum ferritin fell throughout the 24 wk, whereas serum iron, transferrin saturation, and total iron-binding capacity remained stable. Quality of life was assessed by use of the general Sickness Impact Profile and the disease-specific Transplant Disease Questionnaire measures at baseline and every 8 wk during rHuEPO therapy. Significant improvement was noted in global Sickness Impact Profile scores and in four of five dimensions of the Transplant Disease Questionnaire. Serious adverse events were infrequent. No change in mean systolic or diastolic blood pressure was noted, although there was a significantly increased need for antihypertensive drugs in 18 patients (P = 0.0002). A significant inverse correlation was noted between baseline renal function and maintenance rHuEPO dose (r = -0.45; P < 0.05). Twelve patients returned to dialysis during the study.(ABSTRACT TRUNCATED AT 250 WORDS)