Medication adherence in renal transplant recipients: A latent variable model of psychosocial and neurocognitive predictors.

OBJECTIVE: Estimates indicate that 20-70% of renal transplant recipients are medication non-adherent, significantly increasing the risk of organ rejection. Medication adherence is negatively impacted by lower everyday problem solving ability, and associations between depressive symptoms, self-efficacy, and adherence are reported in renal transplant recipients. Nonetheless, to date, these associations have not been examined concurrently. Given the relationship between non-adherence and organ rejection, it is critical to gain a better understanding of the predictors of adherence in renal transplant recipients. To this end, we modeled relationships among cognitive abilities, depressive symptoms, self-efficacy, and adherence in this group. METHODS: Participants (N = 211) underwent renal transplant at least one year prior to participation. Adherence was measured via self-report, medication possession ratio, and immunosuppressant blood-level. Traditionally-measured neurocognitive and everyday problem-solving abilities were assessed. Depressive symptoms were measured via self-report, as were general and medication adherence related self-efficacy. Structural equation modeling was used to assess the fit of the model to available data. RESULTS: Everyday problem solving and self-efficacy had direct positive associations with adherence. Depressive symptoms were negatively associated with self-efficacy, but not adherence. Traditionally-measured neurocognitive abilities were positively associated with self-efficacy, and negatively associated with depressive symptoms. CONCLUSIONS: We present a comprehensive investigation of relationships between cognitive and psychosocial factors and adherence in medically stable renal transplant recipients. Findings confirm the importance of everyday problem solving and self-efficacy in predicting adherence and suggest that influences of depressive symptoms and neurocognitive abilities are indirect. Findings have important implications for future development of interventions to improve medication adherence in renal transplant recipients.

Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: The hematological side effects associated with mycophenolic acid (MPA) are relatively common and have severe consequences. The majority of literature data have not shown clear consistency in the MPA exposure-neutropenia relationship. We hypothesized that (i) adult de novo kidney transplant recipients who develop neutropenia have relatively higher dose-normalized MPA exposure than patients without neutropenia, and (ii) the observed neutropenia may be explained by polymorphisms in metabolism and/or transporter genes responsible for MPA disposition. METHODS: Adult kidney transplant recipients on steady-state tacrolimus and MPA, not receiving a corticosteroid, and with stable renal function were recruited for investigation at three periods post-transplant (1, 3, and 12 months; n = 21, 17, and 13, respectively). Clinical variables (age, weight, MPA daily dose, albumin, serum creatinine, absolute neutrophil count), tacrolimus and MPA concentrations (for exposure calculation), and genotypes (UGT2B7 G211T, UGT2B7 C802T, UGT1A9 T-275A, UGT1A9 T98C, MRP2 C-24T, MRP2 G1249A, OATP1B1 A388G, OATP1B1 C463A) were characterized. RESULTS: A significant inverse association between dose-normalized MPA exposure (a surrogate marker for apparent MPA clearance) and absolute neutrophil count in all three study periods (r2 ~ 0.3-0.7) was observed. No associations between characterized single nucleotide polymorphisms and MPA exposure or absolute neutrophil count were established. However, significant alterations in the minor allele frequencies of UGT2B7*2 C802T, UGT1A9 T275A, and MRP2 G1249A were evident. CONCLUSION: These findings support the clinical strategy for conducting MPA therapeutic drug monitoring in adult kidney transplant patients on steroid-free immunosuppressant therapy. The novel population genomic analysis data warrant further epidemiological investigations in a larger study sample.

Posttransplant Lymphoproliferative Disorder in Adults Receiving Kidney Transplantation in British Columbia: A Retrospective Cohort Analysis.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a major complication following kidney transplantation. OBJECTIVE: We undertook this study to characterize PTLD in kidney transplant patients in British Columbia with regard to incidence, patient and graft survival, histological subtypes, treatment modalities, and management of immunosuppression. DESIGN: Retrospective cohort analysis. SETTING: British Columbia. PATIENTS: All adult patients who underwent kidney transplantation in British Columbia between January 1, 1996, and December 31, 2012, were included. Patients less than 18 years of age at the time of first transplant and multiple organ transplant recipients were excluded from analysis. MEASUREMENTS: Patients with lymphoproliferative disorders that occurred subsequent to kidney transplantation were considered to have developed PTLD. METHODS: Cases of PTLD were identified by cross-referencing data abstracted from the provincial transplant agency's clinical database with the provincial cancer agency's lymphoma registry. Patients were followed up for the development of PTLD until December 31, 2012, and for outcomes of death and graft failure until December 31, 2014. Data collection was completed via an electronic chart review. RESULTS: Of 2217 kidney transplant recipients, 37 (1.7%) developed PTLD. Nine cases were early-onset PTLD, occurring within 1 year of transplant; of these cases, 6 were known/presumed Epstein-Barr virus mismatch, compared with only 2 of 28 late-onset cases. Patient survival for early-onset PTLD was 100% at 2 years post diagnosis. Late-onset PTLD had survival rates of 71.4% and 67.9% at 1 and 2 years, respectively. PTLD was associated with significantly decreased patient survival (P = .031) and graft survival (uncensored for death, P = .017), with median graft survival of PTLD and non-PTLD patients being 9.5 and 16 years, respectively. Immunosuppressant therapy was reduced in the majority of patients; additional therapies included rituximab monotherapy, CHOP-R, radiation, and surgery. LIMITATIONS: Limitations to this study include its retrospective nature and the unknown adherence of patients to prescribed immunosuppressant regimens. In addition, cumulative doses of immunosuppression received and the degree of immunosuppression reduction for PTLD management were not effectively captured. CONCLUSIONS: The incidence of PTLD in British Columbia following kidney transplantation was low and consistent with rates reported in the literature. The incidence of late-onset PTLD and its association with reduced patient and graft survival warrant further analysis of patients' long-term immunosuppression.

CONTEXTE: Le syndrome lymphoprolifératif post-greffe (SLPG) est une complication grave survenant à la suite d'une transplantation rénale. OBJECTIF DE L'ÉTUDE: Nous avons mené cette étude afin de caractériser le SLPG chez les receveurs d'une greffe rénale en Colombie-Britannique en ce qui a trait à son incidence, à la survie du patient et du greffon, aux sous-types histologiques, aux modalités de traitement et à la gestion de l'immunosuppression. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte rétrospective effectuée en Colombie-Britannique. SUJETS: Ont été inclus dans l'étude tous les patients adultes ayant subi une transplantation rénale entre le 1er janvier 1996 et le 31 décembre 2012 en Colombie-Britannique. Les patients âgés de moins de 18 ans au moment de l'intervention et les patients receveurs de greffe de multiples organes ont été exclus. MESURES: Tout cas de SL apparu après une greffe rénale étaient considérés comme un SLPG. MÉTHODOLOGIE: Les cas de SLPG ont été répertoriés en recoupant les données extraites de la base de données cliniques de l'agence provinciale de transplantation avec les données du registre des lymphomes tenu par l'agence provinciale de lutte contre le cancer. Les participants ont été suivis jusqu'au 31 décembre 2012 pour l'apparition du SLPG et jusqu'au 31 décembre 2014 pour les issues défavorables telles que la mort du patient ou le rejet du greffon. L'examen du dossier électronique des patients a complété la collecte des données. RÉSULTATS: Des 2 217 receveurs d'une greffe rénale répertoriés, seuls 37 (1,7 %) ont développé un SLPG. L'apparition du SLPG s'est faite de façon précoce, soit dans la première année post-greffe, pour neuf de ces patients, dont six représentaient un cas connu ou présumé de non-concordance pour le virus d'Epstein Barr (EBV). En comparaison, seuls deux des 28 patients ayant expérimenté un développement tardif du SLPG étaient présumés non-concordants pour l'EBV. Deux ans après le diagnostic, 100 % des patients ayant eu une apparition précoce du SLPG avaient survécu. Dans les cas de développement tardif de la maladie, le taux de survie passait à 71,4 % après un an et à 67,9 % après deux ans pour les patients. Le développement du SLPG a été associé avec une réduction significative de la chance de survie du patient (p = 0,031) et du greffon (p = 0,017, cas de décès non censurés). La survie médiane du greffon était de 9,5 ans pour les patients ayant développé un SLPG alors qu'elle était de 16 ans pour les autres. L'intensité du traitement immunosuppresseur a pu être réduite pour la majorité des patients. Les traitements additionnels incluaient la monothérapie au rituximab, le R-CHOP, la radiation et la chirurgie. LIMITES DE L'ÉTUDE: La nature rétrospective de l'étude est un facteur limitant la portée de nos résultats, de même que l'absence de données sur l'adhérence des patients au traitement immunosuppressif. De plus, nous n'avons pu mesurer précisément les doses cumulatives d'immunosuppresseurs reçues, ni le degré de réduction de ces derniers dans la prise en charge du SLPG. CONCLUSION: En Colombie-Britannique, l'incidence du SL post-greffe rénale s'est avérée faible et cohérente avec les taux rapportés dans la littérature. L'incidence de l'apparition tardive du SLPG et son association à un taux et une durée de survie amoindris (à la fois pour le patient et pour le greffon) justifient une analyse plus poussée de l'immunosuppression à long terme dans la population en question.

An observational study of health literacy and medication adherence in adult kidney transplant recipients.

BACKGROUND: There is a high prevalence of non-adherence to immunosuppressants in kidney transplant recipients. Although limited health literacy is common in kidney recipients and is linked to adverse outcomes in other medical populations, its effect on medication adherence in kidney transplant recipients remains poorly understood. The objective was to investigate the effect of lower health literacy on immunosuppressant adherence. METHODS: Kidney recipients who were at least 6 months post-transplant and outpatients of Vancouver General Hospital in B.C., Canada were recruited through invitation letters. A total of 96 recipients completed the Health Literacy Questionnaire, which provides a multifactorial profile of self-reported health literacy and the Transplant Effects Questionnaire-Adherence subscale measuring self-reported immunosuppressant adherence. Hierarchical linear regression was used to analyze the association between health literacy and adherence after controlling for identified risk factors of non-adherence. RESULTS: Our sample was on average 53 years old, 56% male and 9 years post-transplant. Kidney recipients reported low levels of health literacy on scales measuring active health management and critical appraisal of information and 75% reported non-perfect adherence. Worse adherence was associated with poorer overall health literacy (ΔR2 = 0.08, P = 0.004) and lower scores on six of nine of the health literacy factors. CONCLUSIONS: Poorer health literacy is associated with lower immunosuppressant adherence in adult kidney transplant recipients suggesting the importance of considering a recipient's level of health literacy in research and clinical contexts. Medication adherence interventions can target the six factors of health literacy identified as being risk factors for lower medication adherence.

Assessing medication adherence in solid-organ transplant recipients.

OBJECTIVES: We sought to determine and compare the prevalence of nonadherence in lung, kidney, and liver transplant recipients, and identify potential risk factors for nonadherence. MATERIALS AND METHODS: This cross-sectional, single-center, retrospective cohort study, evaluated 225 outpatient lung, kidney, and liver transplant recipients' adherence to immunosuppressant medication. Based on immunosuppressant dosages and dispensing records, medication possession ratio (days of medication supplied/actual days) and gaps in prescription refills (> 30-day lapse between expected depletion of supply and next refill) were used as surrogate markers in assessing adherence for 2 years. Patients were adherent to their immunosuppressant medication regimens if their medication possession ratio was ≥ 80%. RESULTS: The mean age of the subjects was slightly greater than 50 years of age, and they were a median of 2.0, 1.3, and 1.1 years posttransplant at the start of data collection for lung, kidney, and liver recipients. Overall medication possession ratios were 95.4% ± 7.5%, 95.9% ± 7.6%, and 92.7% ± 12.3% in our lung, kidney, and liver recipients. Only 7.1% of patients had a medication possession ratio lower than 80%, which was the cutoff for nonadherence. No statistical analyses were performed to identify potential factors for nonadherence because of the small number of nonadherent patients. CONCLUSIONS: Immunosuppressant medication adherence at our center was high for all 3 organ cohorts, as measured by a medication possession ratio of 80% or better. Further study is needed to evaluate immunosuppressant adherence over time after transplant, and confirm the clinical factors that optimize adherence in high-risk patients.

Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen.

PURPOSE: The pharmacokinetics of both tacrolimus and mycophenolic acid in renal transplant recipients on a corticosteroid-free regimen was evaluated. METHODS: Upon administration of steady-state morning tacrolimus and mycophenolate mofetil doses, 28 patients for whom at least three months had passed after renal transplantation underwent serial blood sample collection over a 12-hour dosing period. Whole blood concentrations of tacrolimus were measured, as were mycophenolic acid, mycophenolic acid 7-0-glucuronide (MPAG), and acyl glucuronide MPAG (AcMPAG) concentrations. Pharmacokinetic parameters were then analyzed by conventional noncompartmental modeling. RESULTS: The mean ± S.D. pharmacokinetic parameters for tacrolimus, normalized to a dose of 1 mg, were as follows: area under the concentration-time curve (AUC), 52.6 ± 24.8 µg · hr/L/mg; maximum concentration (C(max)), 8.0 ± 3.3 µg/L/mg; time to C(max) (t(max)), 1.8 ± 1.0 hr; and minimum concentration (C(min)), 2.6 ± 1.4 µg/L/mg. The mean ± S.D. pharmacokinetic parameters for mycophenolic acid, normalized to a mycophenolate mofetil dose of 1 g, were AUC, 26.9 ± 13.2 µg ·hr/mL/g; C(max), 17.5 ± 5.4 µg/mL/g; t(max), 0.9 ± 0.6 hr; and C(min), 1.5 ± 1.1 µg/mL/g. The free fraction of mycophenolic acid was 1.8% ± 0.7%. AUC ratios of MPAG:mycophenolic acid and AcMPAG:mycophenolic acid were 13.0 ± 5.8 and 0.1 ± 0.2, respectively. CONCLUSION: Overall exposure and C(min) values for tacrolimus were similar but C(max) values were higher than those documented in renal transplant patients treated with corticosteroid-based regimens. This may have clinical implications in corticosteroid-free patients experiencing symptoms of tacrolimus toxicity despite trough levels within target ranges. Mycophenolic acid exposure increased with time, but AUC values fell within the range expected for patients receiving concurrent corticosteroids.

Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy.

BACKGROUND: The effect of islet cell transplantation (ICT) on the progression of diabetic microvascular complications is not well understood. METHODS: We have conducted a prospective, crossover, cohort study comparing ICT with intensive medical therapy on the progression of diabetic nephropathy, retinopathy, and neuropathy. RESULTS: The rate of decline in glomerular filtration rate is slower after ICT than on medical therapy. There was significantly more progression of retinopathy in medically treated patients than post-ICT. There was a nonsignificant trend for improved nerve conduction velocity post-ICT. CONCLUSIONS: ICT is associated with less progression of microvascular complications than intensive medical therapy. Multicenter, randomized trials are needed to further study the role of ICT in slowing the progression of diabetic complications.

Development and validation of limited sampling strategies for tacrolimus and mycophenolate in steroid-free renal transplant regimens.

PURPOSE: 1) To develop and validate limited sampling strategies (LSSs) for tacrolimus (TAC) and mycophenolic acid (MPA) in renal transplant recipients not receiving corticosteroids; and 2) to evaluate predictive performance of published LSSs (for steroid-based regimens) in a steroid-free population. METHODS: On administration of steady-state morning TAC and mycophenolate mofetil doses, 12-hour serial blood samples from 28 stable renal transplant recipients were collected and measured by validated high-performance liquid chromatography methods and area under the curve (AUC) by trapezoidal rule. TAC LSSs were developed and validated by multiple regression analysis by a two-group method (index n = 18; validation n = 10) and MPA LSSs by the jackknife method (n = 28). Potential LSSs were those with r ≥ .8 (TAC) or r ≥ 0.7 (MPA) and < 3 time points within 2 hours (TAC) or 4 hours (MPA) postdose. Predictive performance was calculated and other published TAC and MPA LSSs tested using preset criteria for bias and precision of within ± 15%. RESULTS: For TAC, three three-concentration, one two-concentration, and one one-concentration model met preset criteria. The best equations were: TAC AUC = 10.338 + 7.739C0 + 3.589C2 (r = 0.956, bias = -3.4%, precision = 4.7%) and TAC AUC = 29.479 + 5.016C2 (r = 0.862, bias = 3.2%, precision = 9.7%). For MPA, only one model was identified: MPA AUC = 9.328 + 1.311C1 + 1.455C2 + 2.901C4 (r = 0.838, bias = -3.8%, precision = 14.9%). One published TAC (and no MPA) LSS in renal transplant recipients on steroid-based regimens met criteria. CONCLUSIONS: To the authors' knowledge, these LSSs are the first to be developed and validated in steroid-free renal transplant recipients and can be used to accurately predict TAC and MPA AUCs for steroid-free regimens. Because the commonly used MPA LSS is based on a steroid regimen and not predictive for steroid-free patients, the newly derived MPA LSS is being applied at the authors' institution. Other renal transplant centers may also wish to validate this equation in their own patients.

Similar outcomes for Canadian renal transplant recipients followed up in transplant centers and satellite clinics.

BACKGROUND: A significant proportion of long-term care for renal transplant recipients (RTRs) in Canada is provided by community nephrologists in satellite clinics (SCs). The outcomes of RTRs followed up in SCs have not been formally compared with those followed up in transplant centers (TCs). METHODS: This multicenter retrospective study from 13 TCs and SCs across Canada compared patient and graft outcomes in RTRs with a functioning graft more than or equal to 18 months. Data were abstracted at 6 to 18 months posttransplantation, and at last visit (if >18 months). Patients were stratified in a 1:1 ratio between TCs and SCs, and by a 3:1 ratio between cyclosporine A and tacrolimus. The primary outcome was change (Δ) in Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR) from 6 to 18 months posttransplantation (ΔeGFRM18-6). Secondary outcomes included the prevalence of hyperlipidemia, diabetes, and hypertension. RESULTS: A total of 264 RTRs followed at TCs and SCs demonstrated broad similarity in baseline recipient and donor characteristics. ΔeGFRM18-6 were similar for TCs versus SCs and better for tacrolimus versus cyclosporine A (P=0.022). There was no difference in lipid levels between TCs and SCs during 6 to 18 months, although low-density lipoprotein cholesterol was lower in SCs versus TCs at most recent visit (2.6 vs. 2.3 mmol/L; P=0.003). Fasting blood glucose levels were similar in TCs and SCs. Comparable target blood pressure levels were achieved, and the prevalence of hypertension was similar for both TCs and SCs at all time points. CONCLUSION: Short-term graft and patient outcomes are similar in TC and SC RTRs, supporting the feasibility of follow-up patient care outside major TCs.

Pharmacokinetics of mycophenolic acid and its glucuronidated metabolites in stable islet transplant recipients.

Given the paucity of data on pharmacokinetics of mycophenolic acid (MPA) in islet transplant, the aim of this study was to characterize pharmacokinetic parameters of MPA and its 2 glucuronidated metabolites in stable islet transplant recipients. Sixteen subjects were entered into this open-label study after written informed consent. Upon administration of a steady-state morning mycophenolate mofetil dose, 12-hour serial concentrations of MPA and its phenolic glucuronide (MPAG) and acyl-glucuronide (AcMPAG) were measured by a validated high-performance liquid chromatography method and pharmacokinetic parameters analyzed by noncompartmental modeling. Subjects included 11 women and 5 men who had received 2.7 +/- 0.8 islet transplants. Age was 50 +/- 8 years, weight 64 +/- 11 kg, serum albumin 4.2 +/- 0.3 g/dL, and serum creatinine 1.1 +/- 0.4 mg/dL. All patients were also on tacrolimus-based steroid-free immunosuppressant regimens. Mycophenolate mofetil dosage ranged from 1 to 2 g daily (25.4 +/- 6.1 mg/kg/d). Pharmacokinetic parameters for MPA were area under the curve 42.9 +/- 21.6 microg h/mL; dose-normalized AUC 52.9 +/- 25.4 microg h/mL/g; maximal concentration (Cmax) 13.0 +/- 6.2 microg/mL; time to Cmax (tmax) 1.2 +/- 0.4 hours; minimum concentration (Cmin) 1.4 +/- 1.0 microg/mL; and MPA-free fraction 1.2% +/- 1.0%. Area under the curve ratios of MPAG/MPA and AcMPAG/MPA were 17.8 +/- 12.4 and 0.1 +/- 0.1, respectively. The wide interpatient variability in all pharmacokinetic parameters of MPA and metabolites are consistent with results from the only other published pharmacokinetic study in islet transplant recipients. A population model and a search for significant covariates may help reduce this variability. Pharmacokinetic parameters calculated in the present study, coupled with findings from the only other published MPA study in islet transplant, form a preliminary base on which to build a population model for future multicenter studies of this little-studied transplant subpopulation.

A quality of life comparison in cyclosporine- and tacrolimus-treated renal transplant recipients across Canada.

BACKGROUND: Many Canadian renal transplant recipients receive either cyclosporine or tacrolimus as a long-term immunosuppressive agent. We investigated the effect of these drugs on quality of life (QoL) in Canadian transplant recipients. METHODS: We included adult single-organ recipients undergoing a transplant between July 1997 and March 2005, whose graft function was =18 months, recruited across 13 Canadian sites including 5 transplant centers (TCs) and 8 satellite centers (SCs). Patients were stratified 3:1 by cyclosporine vs. tacrolimus based on calcineurin inhibitor(s) (CNIs) received at 6 months posttransplant and matched 1:1 by TC vs. SC. Physical (PCS) and mental component summary (MCS) scores measured by the SF-12 scale for cyclosporine- and tacrolimus-treated recipients were compared. Patient opinions about their perceived CNI-related side effects captured by categorical questions or a numerical Likert scale (1-10) were compared by chi-square test or ANOVA, respectively. RESULTS: There were 231 participants (124 cyclosporine, 43 tacrolimus and 64 with dual experience) who responded to both questionnaires. Their SF-12-measured PCS and MCS scores were similar (PCS 42.0, 43.0 and 41.4, p=0.705; MCS 50.3, 47.8 and 47.1, p=0.115; respectively). However, patients receiving tacrolimus more strongly preferred to continue on this CNI than those receiving cyclosporine (67.4% vs. 44.4%, p=0.009), while more patients on cyclosporine wished to stop taking it (23.4 vs. 2.3%, p=0.004). Patient preference for CNI did not differ by center type. CONCLUSION: QoL among Canadian renal transplant recipients receiving cyclosporine or tacrolimus is similar. Although Canadian recipients prefer tacrolimus, CNI type does not significantly affect their QoL.

Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection.

BACKGROUND: The purpose of this study was to determine whether screening for anti-human leukocyte antigen (HLA) antibodies (Abs) could predict development of acute rejection (AR) before clinical evidence of kidney allograft dysfunction in nonsensitized recipients. METHODS: Eighty-four non-HLA identical kidney transplant recipients were prospectively tested for anti-HLA Abs (FlowPRA analysis and anti-HLA Ab specificity determination) at 0, 10, 20, 30, 60, 90, 180 and 365 posttransplantation, and at the time of clinical suspicion of AR. Allograft biopsies were performed at the time of engraftment, 3 and 12 months posttransplantation, when patients developed new anti-HLA Abs, or when clinically indicated. RESULTS: Among the 70 patients without preformed anti-HLA Abs, 11 developed de novo anti-HLA Abs (8 donor-specific Abs) at a median of 30 days (q1-q3=10-180 days) after transplantation. Patients with de novo anti-HLA Abs had a shorter time to AR than patients without de novo anti-HLA Abs, P=0.06. However, in all cases, de novo anti-HLA Abs developed concomitantly or after a clinically evident AR. CONCLUSIONS: Although de novo anti-HLA Abs were associated with AR, routine screening for anti-HLA Abs was not useful in identifying patients at risk for AR before clinical evidence of allograft dysfunction.

Limited sampling strategies for predicting area under the concentration-time curve of mycophenolic acid in islet transplant recipients.

BACKGROUND: Mycophenolate mofetil is widely used in islet transplant recipients and its active metabolite, mycophenolic acid (MPA), exhibits wide pharmacokinetic variability. However, to our knowledge, no limited sampling strategy (LSS) exists for monitoring MPA in this subpopulation. OBJECTIVE: To define optimal LSSs for MPA monitoring and to test their predictive performance in islet transplant recipients. METHODS: After written informed consent was obtained and upon administration of a steady-state morning mycophenolate mofetil dose, blood samples were collected at 0, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours from 16 stable islet transplant recipients. MPA concentrations were measured by a validated high-performance liquid chromatography method with ultraviolet detection and pharmacokinetic parameters analyzed by noncompartmental modeling. All 16 patients' profiles were used to develop the LSSs via multiple regression analysis. Potential LSSs were restricted to ones having R(2) 0.90 or greater and 3 or fewer time points within the first 4 hours postdose. Resulting equations were validated for their predictive performance using the jackknife method, with acceptable criteria for bias and precision preset to within +/-15%. In addition, 14 published LSSs (in the renal transplant population) were tested in our islet transplant patients. RESULTS: Five LSSs met preset criteria and had conventional sampling times: AUC = 1.783 + 1.248C1 + 0.888C2 + 8.027C4 (R2 = 0.98, bias = -3.09%, precision = 9.53%) AUC = 2.778 + 1.413C1 + 0.963C3 + 7.511C4 (R2 = 0.97, bias = -3.22%, precision = 11.02%) AUC = 1.448 + 1.239C1 + 0.271C1.5 + 9.108 C4 (R2 = 0.96, bias = -1.90%, precision = 11.46) AUC = 1.410 - 0.259C0 + 1.443C1 + 9.622C4 (R2 = 0.96, bias = -2.68%, precision = 11.53%) AUC = 1.547 + 1.417C1 + 9.448C4 (R2 = 0.96, bias = -2.46%, precision = 11.14%) where AUC = area under the concentration-time curve. None of the other published LSSs in the renal transplant population met the preset criteria for bias and precision. CONCLUSIONS: To our knowledge, these are the first precise and accurate LSSs for predicting MPA AUC developed specifically for islet transplant recipients. The LSS that we recommend is the one utilizing 2 concentrations: AUC = 1.547 + 1.417C1 + 9.448C4. This equation is convenient and clinically feasible. Other islet transplant centers may wish to validate our equation in their population or use our template as a guide to develop accurate and precise LSSs specific to their patient population.

Factors associated with progression of interstitial fibrosis in renal transplant patients receiving tacrolimus and mycophenolate mofetil.

BACKGROUND: We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed. METHODS: Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study. RESULTS: At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)-ci + ct more than or equal to 2-increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies. CONCLUSIONS: A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.

Probabilistic modeling of cytomegalovirus infection under consensus clinical management guidelines.

BACKGROUND: Cytomegalovirus (CMV) is the most common viral pathogen after renal transplantation and remains a major therapeutic challenge with important clinical and economic implications from both direct and indirect consequences of infection. METHODS: This 5-year study modeled the relationship between CMV infection and biopsy-proven graft rejection, graft loss, or death after renal transplantation in an inception cohort using Canadian consensus guidelines for CMV management as a component of a detailed cost-analysis of viral infection. RESULTS: Probabilities of CMV viremia and syndrome/disease among 270 sequential graft recipients were 0.27 and 0.09, respectively; 91% of cases occurred in the first 6 months. Probability of CMV infection as the first event was 0.29, with a probability of subsequent biopsy-proven acute rejection (BPAR) of 0.05 (mean: 62+/-26 days, range: 32-85 days), whereas the probability of BPAR as the first event was 0.18, with a probability of subsequent CMV infection of 0.38 (mean: 63+/-31, range: 27-119 days). Probability of freedom from both CMV infection and BPAR throughout the period of observation was 0.53. Time-dependent Cox analysis showed that neither donor/recipient CMV risk stratum nor CMV infection influenced the risks of BPAR (P=0.24; P=0.74) or of graft loss or death (P=0.26; P=0.34). In contrast, BPAR significantly increased the risk of both subsequent CMV infection (hazard ratio=1.77, P=0.03) and of graft loss or death (hazard ratio=8.31, P<0.0001). CONCLUSIONS: Although current antiviral therapy seems to mitigate the reported deleterious effects of CMV infection on BPAR or graft survival, BPAR remains a significantly risk factor for both CMV infection and functional graft survival.

A matched cohort pharmacoepidemiological analysis of steroid free immunosuppression in renal transplantation.

BACKGROUND: This longitudinal, sequential, matched closed-cohort design pharmacoepidemiological analysis examined the influence of maintenance steroid therapy in 380 first graft recipients after renal transplantation under conditions of normal clinical practice. METHODS: Nonexposed (steroid avoidance, n=190) and exposed (steroid treated, n=190) cohorts were matched 1:1 for key demographic factors, including donor source (living or deceased), diabetic status, panel reactive antibody level, recipient age (by decade), and sex. RESULTS: Cohorts were comparable for all variables except median human leukocyte antigen mismatch (4 vs. 3, P=0.03), use of tacrolimus (90.0% vs. 59.5%, P

Probability, predictors, and prognosis of posttransplantation glomerulonephritis.

Glomerulonephritis (GN) is the leading cause of chronic kidney disease among recipients of renal transplants. Because modern immunosuppressive regimens have reduced the incidence of rejection-related graft loss, the probability and clinical significance of posttransplantation GN (PTGN) requires reevaluation. In this Canadian epidemiologic study, we monitored 2026 sequential renal transplant recipients whose original renal disease resulted from biopsy-proven GN (36%), from presumed GN (7.8%), or from disorders other than GN (56%) for 15 yr without loss to follow-up. Kaplan-Meier estimates of PTGN in the whole population were 5.5% at 5 yr, 10.1% at 10 yr, and 15.7% at 15 yr. PTGN was diagnosed in 24.3% of patients whose original renal disease resulted from biopsy-proven GN, compared with 11.8% of those with presumed GN and 10.5% of those with disorders other than GN. Biopsy-proven GN in the native kidney, male gender, younger age, and nonwhite ethnicity predicted PTGN. Current immunosuppressive regimens did not associate with a reduced frequency of PTGN. Patients who developed PTGN had significantly reduced graft survival (10.2 versus 69.7%; P < 0.0001). In summary, in the Canadian population, PTGN is a common and serious complication that causes accelerated graft failure, despite the use of modern immunosuppressive regimens.

A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes.

BACKGROUND: We hypothesized that transplantation of islets into type 1 diabetics could improve outcomes of glucose metabolism, renal function, retinopathy, and neuropathy compared with intensive medical therapy. METHODS: We conducted a prospective, crossover, cohort study of intensive medical therapy (group 1) versus islet cell transplantation (group 2) in 42 patients. All were enrolled in group 1 then 31 crossed over with group 2 when islet donation became available. Transplantation was performed by portal venous embolization of more than 12,000 islet equivalents/kg body weight under cover of immunosuppression with antithymocyte globulin, tacrolimus, and mycophenolate. Outcome measures were HbA1c, change in glomerular filtration rate (GFR), progression of retinopathy, and change in nerve conduction velocity. This report details interim analysis of outcomes after 34+/-18 months (group 1) and 38+/-18 months (group 2). RESULTS: HbA1c (%) in group 1 was 7.5+/-0.9 versus 6.6+/-0.7 in group 2 (P<0.01). GFR (mL/min/month) declined in both groups (group 1 -0.45+/-0.7 vs. group 2 -0.12+/-0.7, P=0.1). Slope of the GFR decline in group 1 was significantly more than 0. Retinopathy progressed in 10 of 82 eyes in group 1 versus 0 of 51 in group 2 (P<0.01). Nerve conduction velocity (m/sec) remained stable in group 1 (47.8+/-5 to 47.1+/-5 m/sec) and group 2 (47.2+/-4.5 to 47.7+/-3.5). CONCLUSION: Islet transplantation yields improved HbA1c and less progression of retinopathy compared with intensive medical therapy during 3 years follow-up.

Reduced progression of diabetic retinopathy after islet cell transplantation compared with intensive medical therapy.

BACKGROUND: Diabetic retinopathy is a major complication of type 1 diabetes and remains a leading cause of visual loss. There have been no comparisons of the effectiveness of intensive medical therapy and islet cell transplantation on preventing progression of diabetic retinopathy. METHODS: The British Columbia islet transplant program is conducting a prospective, crossover study comparing medical therapy and islet cell transplantation on the progression of diabetic retinopathy. Progression was defined as the need for laser treatment or a one step worsening along the international disease severity scale. An interim data analysis was performed after a mean 36-month follow-up postislet transplantation and these results are presented. RESULTS: The medical and postislet transplant groups were similar at baseline. Subjects after islet transplantation had better glucose control than the medically treated subjects (mean HbA1c 6.7%+/-0.9% vs. 7.5+/-1.2, P<0.01) and were C-peptide positive. Progression occurred significantly more often in all subjects in the medical group (10/82 eyes, 12.2%) than after islet transplantation (0/51 eyes, 0%) (P<0.01). Considering only subjects who have received transplants, progression occurred in 6/51 eyes while on medical treatment and 0/51 posttransplant (P<0.02). CONCLUSIONS: Progression of diabetic retinopathy was more likely to occur during medical therapy than after islet cell transplantation.