Estimated Impact of Deemed Consent Legislation for Organ Donation on Individuals With Kidney Failure: A Dynamic Decision Analytic Model.

Background: There is little data modeling the impact of deemed consent legislation (eligible individuals who do not register their decision to decline to be a donor are presumed to consent after death) on outcomes for individuals with kidney failure. Objective: To estimate the change in life-years (LYs) and quality-adjusted life-years (QALYs) resulting from different changes in the rate of deceased donor kidney transplantation associated with deemed consent legislation and health system transformation. Design: Dynamic Decision Analytic Model. Setting: This modeling study included kidney failure patients in Atlantic Canada (all of whom receive their kidney transplants in Halifax, Nova Scotia). The adoption of deemed consent legislation was the intervention, and opt-in (the status quo) was the reference comparator. Patients: Prevalent kidney failure patients at the end of 2019 in all of Atlantic Canada (N = 3615) served as the starting population. Methods: We compared expected outcomes between the intervention and comparator. Changes in QALYs and total LYs were modeled under different changes to the proportion of patients receiving a deceased donor kidney transplant (from -10% to 20%) resulting from deemed consent relative to the status quo. Changes in QALYs and LYs were reported for 3 different time horizons (5, 10, and 30 years). Uncertainty around QALYs and total LYs was reported using 95% confidence intervals (CIs) constructed from a probabilistic sensitivity analysis using 1000 Monte Carlo Simulations. Results: The increase in QALYs ranged from 7 QALYs (95% CI: 5-10) with a 5% increase using a 5-year time frame to 882 QALYs (95% CI: 619-1144) with a 20% increase over a 30-year time frame. Parallel changes in total LYs were also observed. In contrast, decreases in deceased donor kidney transplantation resulted in a loss of QALYs (for example, -463 QALYs; 95% CI: -633 to -306 for a 10% decrease over a 30-year time frame). Using the most optimistic scenario (a 20% increase), there was an 18% increase in the cumulative number of deceased donor kidney transplant recipients over a 30-year observation period. Limitations: The results are subject to uncertainty depending on changes to the dialysis or transplant population that were not modeled and that may not be fully captured with probabilistic sensitivity analysis. Conclusions: Deemed consent legislation will lead to variable changes in QALYs and total LYs for the kidney failure population, depending on the degree to which deceased donor transplantation rates change and the time horizon of observation. This modeling study may serve as a baseline to monitor the future impact of deemed consent legislation.

Contexte: Il existe peu de données modélisant l'impact d'une loi sur le consentement présumé (les personnes admissibles qui n'enregistrent pas leur décision de refuser d'être un donneur sont présumées consentir après leur décès) sur les résultats des personnes atteintes d'insuffisance rénale. Objectif: Estimer les variations dans les années de vie (AV) et les années de vie corrigées en fonction de leur qualité (AVCQ) résultant de changements dans les taux de transplantation rénale provenant d'un donneur décédé; changements qui seraient associés à la loi sur le consentement présumé et à la transformation du système de santé. Conception: Modèle dynamique d'analyse décisionnelle. Cadre: L'étude a été modélisée avec des patients du Canada atlantique atteints d'insuffisance rénale terminale (tous avaient reçu leur greffe de rein à Halifax, en Nouvelle-Écosse). L'intervention consistait en l'adoption d'une loi sur le consentement présumé, alors que le statu quo représentait le comparateur de référence. Sujets: La population de départ était constituée des patients atteints d'insuffisance rénale terminale à la fin de 2019 dans l'ensemble du Canada atlantique (N=3615). Méthodologie: Nous avons comparé les résultats attendus pour l'intervention et le comparateur. Les variations dans les AVCQ et les AV totales ont été modélisées en fonction de divers changements résultant du consentement présumé par rapport au statu quo dans la proportion de patients recevant une transplantation rénale d'un donneur décédé (de -10 à 20 %). Les variations dans les AVCQ et les AV ont été rapportées pour trois horizons temporels (5, 10 et 30 ans). L'incertitude entourant les AVCQ et les années de vie totales a été rapportée avec des intervalles de confiance à 95 % établis à partir d'une analyse de sensibilité probabiliste réalisée par la méthode de Monte Carlo. Résultats: En ce qui concerne les AVCQ, la variation passait de 7 AVCQ (IC 95 % : 5, 10), avec une augmentation de 5 % sur une période de 5 ans, à 882 AVCQ (IC 95 % : 619, 1 144) avec une augmentation de 20 % sur une période de 30 ans. Des variations parallèles ont été observées pour les AV totales. En revanche, la diminution du taux de transplantations rénales provenant d'un donneur décédé a entraîné une perte d'AVCQ (par ex. - 463 AVQ; IC à 95 % : -633, -306 pour une diminution de 10 % sur une période de 30 ans). Dans le scénario le plus optimiste (augmentation de 20 %), on a observé une augmentation de 18 % du nombre cumulatif de transplantations rénales provenant de donneurs décédés au cours d'une période d'observation de 30 ans. Limites: Les résultats sont sujets à des incertitudes en fonction de variations dans la population de patients sous dialyse ou greffés qui n'auraient pas été modélisées et qui pourraient ne pas être entièrement prises en compte par une analyse de sensibilité probabiliste. Conclusion: La loi sur le consentement présumé entraînera des changements variables dans les AV totales et les AVCQ des patients atteints d'insuffisance rénale terminale, selon le degré d'évolution des taux de transplantation provenant de donneurs décédés et de l'horizon d'observation. Cette étude de modélisation peut servir de référence pour surveiller les impacts futurs d'une loi sur le consentement présumé.

Donor-Recipient Matching in Kidney Transplant: We're Not There Yet.

BACKGROUND: Strategic organ allocation is expected to prolong patient and graft survival after transplant. This study explored differences in graft survival when kidneys are allocated based on strategic donor-recipient (D-R) pairing vs with the existing Kidney Allocation System (KAS). METHODS: Using the Scientific Registry of Transplant Recipients from 2000 to 2014, we used a multivariable Cox model to assess the hazard ratios (HRs) for death or graft failure among 3 hypothetical donor kidneys transplanted into 3 hypothetical recipients, relative to an ideally matched D-R pair. Median predicted survival for each of the 9 possible D-R pairing combinations was determined, and outcomes for strategic D-R pairing were compared with those obtained using the KAS for allocation. RESULTS: A total of 31,607 patients (29.7%) died or developed graft loss over the study period. Strategic allocation of kidneys resulted in HRs for graft loss of 1.74 (95% confidence interval [CI], 1.41-2.14), 1.82 (95% CI, 1.46-2.26), and 1.74 (95% CI 1.38-2.19) for recipients 1, 2 and 3 respectively, whereas by following the KAS, HRs were 1.93 (95%, CI 1.63-2.28), 2.06 (95% CI, 1.74-2.44), and 1.93 (95% CI, 1.58-2.37); corresponding to 3.84, 11.39, and 7.40 months longer predicted patient or graft survival for recipients 1, 2 and 3 with strategic D-R pairing compared with the KAS. CONCLUSIONS: Allocation of kidneys by strategic D-R pairing may improve graft survival relative to allocation using the KAS.

Hepatitis C virus-infected kidney waitlist patients: Treat now or treat later?

Currently many but not all centers transplant hepatitis C virus (HCV) viremic positive (+) donor kidneys into HCV+ recipients. Directed donation of HCV+ organs reduces the wait time to transplantation for HCV+ patients. Direct-acting antiviral (DAA) therapy can cure HCV in virtually all who are infected. Some have suggested that treatment of HCV+ waitlisted patients be deferred with the hope that earlier transplantation will provide better outcomes than early DAA therapy. However, there are not enough organs to guarantee prompt transplantation for the current waitlist of infected candidates. A Markov medical decision analysis model was created to compare the overall outcomes of delayed DAA therapy (Option 1) to immediate DAA therapy (Option 2) in waitlisted HCV+ patients. Option 1 patients were modeled to be transplanted 1 year earlier, with a higher cumulative transplant incidence (54% at 5 years post-listing vs 45% for Option 2). Despite this, Option 2 provided 0.43 (95% confidence interval [CI] 0.38-0.49) more life years than Option 1. However, Option 1 was preferred for regions with much greater access to HCV+ organs or in patients with very low HCV+-associated mortality. The best option from an individual patient's perspective will differ by region and candidate.

De Novo Donor-Specific Human Leukocyte Antigen Antibody Screening in Kidney Transplant Recipients After the First Year Posttransplantation: A Medical Decision Analysis.

Screening for de novo donor-specific antibodies (dnDSA) in stable kidney transplant recipients is routine practice in some centers. Patients with DSA are at increased risk of graft loss and early intervention may improve outcomes. However, the costs and benefits of dnDSA surveillance are unknown. A medical decision analysis to examine a screening strategy was developed for kidney transplant recipients who had stable graft function and were DSA negative 1 year posttransplant. In the base case, a modest 25% reduction in graft loss in dnDSA-positive patients treated with increased immunosuppression resulted in 0.04618 quality-adjusted years (QALYs) gained. However, benefits from reduced graft loss were eliminated if there was a small increased risk of death from added therapy. The incremental cost effectiveness was marginal at approximately $120 000-250 000 per QALY, but could be more or less favorable depending on several key variables such as efficacy of treatment, screening costs, incidence rate of subclinical dnDSA, and patient survival. Screening performed the best in patients with lower mortality rates and higher baseline incidence rates of dnDSA. Further study is warranted to gather the necessary high-quality evidence to justify screening.

Nucleic acid testing (NAT) of organ donors: is the 'best' test the right test? A consensus conference report.

Nucleic acid testing (NAT) for HIV, HBV and HCV shortens the time between infection and detection by available testing. A group of experts was selected to develop recommendations for the use of NAT in the HIV/HBV/HCV screening of potential organ donors. The rapid turnaround times needed for donor testing and the risk of death while awaiting transplantation make organ donor screening different from screening blood-or tissue donors. In donors with no identified risk factors, there is insufficient evidence to recommend routine NAT, as the benefits of NAT may not outweigh the disadvantages of NAT especially when false-positive results can lead to loss of donor organs. For donors with identified behavioral risk factors, NAT should be considered to reduce the risk of transmission and increase organ utilization. Informed consent balancing the risks of donor-derived infection against the risk of remaining on the waiting list should be obtained at the time of candidate listing and again at the time of organ offer. In conclusion, there is insufficient evidence to recommend universal prospective screening of organ donors for HIV, HCV and HBV using current NAT platforms. Further study of viral screening modalities may reduce disease transmission risk without excessive donor loss.

Screening to prevent polyoma virus nephropathy in kidney transplantation: a cost analysis.

Polyoma virus nephropathy is an important cause of graft dysfunction in kidney transplant recipients and screening to prevent disease has been advocated. Although screening incurs new costs, our hypothesis is that savings from less immunosuppression in those with positive screening tests could pay for overall costs of screening. In 134 consecutive recipients, polyoma virus (positive decoy cells) was detected in the urine of 34 (25.4%) individuals over a 2-year follow-up. Of these 34, 11 had a plasma BK PCR of >7700 copies/mL. Immunosuppression was reduced stepwise in these patients until viral loads fell <1000/mL. Overall screening costs (including extra plasma PCR testing) were estimated at $33,450. Those with positive PCR had greater reductions in annual immunosuppression costs by year 2 ($6452 vs. $2799, p = 0.0015) compared to those with negative screens. At the end of the 2-year period, 61% of the screening costs were covered by less immunosuppressant costs. At the end of 30 months there were net savings. In summary, reductions in immunosuppression cover the cost of screening for polyoma viral infection. Longer-term follow-up is needed to ensure patient outcomes remain acceptable.

Cancer mortality in kidney transplantation.

Immunosuppression is associated with an increased risk of cancer in kidney transplant recipients compared to the general population. It is less clear whether standardized cancer mortality ratios (SMRs) are also increased. This study's hypothesis is that SMRs are not increased because of competing risks of death. During the median follow-up of 5.05 years (Q1-Q3: 2.36-8.62), there were 1937 cancer deaths and 36 619 noncancer deaths among 164 078 first kidney-only transplant recipients captured in the United States Renal Data System between January 1990 and December 2004. The observed cancer death rate was 206 per 100 000 patient-years compared to an expected rate of 215 per 100,000 patient-years in the general population. The overall age- and sex-adjusted SMR was only 0.96 (95% CI 0.92-1.00). However, patients <50 years had SMRs significantly greater than unity while patients >60 had SMRs lower than unity. Up to 25% of cancer-related deaths occurred after allograft failure. These findings challenge the notion that cancer is a major cause of premature death in all kidney transplant recipients and has implications for design of cancer prevention strategies in kidney transplant recipients.

MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the multidrug resistance (MDR1) gene correlate with the intestinal function of P-glycoprotein (PGP). PGP serves as a hydrophobic export pump that extrudes cyclosporine (CsA) across the luminal membrane thus preventing CsA absorption. These genetic variants may predict CsA exposure levels in the early posttransplantation period. METHODS: CsA absorption profiles were established in 75 renal transplant patients using total daily dose and body weight adjusted 4-hour area under the time-concentration curve, AUC(0-4)/mg dose/kg body weight, on posttransplant day 3. These patients were subsequently genotyped for C3435T and G2677T polymorphisms using real-time polymerase chain reaction. An analysis was conducted to assess the independent impact of C3435T and G2677T SNPs on CsA bioavailability. RESULTS: C3435T polymorphisms were found to be an independent predictor of CsA AUC(0-4)/mg dose/kg levels on postoperative day 3. An inverse correlation was found between the number of T alleles and AUC values such that every T allele was associated with an approximate 15% decrement in AUC(0-4)/mg dose/kg (P = .034). A similar nonsignificant trend was observed for G2677T polymorphisms. CONCLUSIONS: MDR1 SNPs are correlated with CsA exposure in the early post-transplant period. Polymorphisms, in conjunction with other criteria, may become a useful tool to optimize initial drug dosing in renal transplantation.

Access to the kidney transplant wait list.

The study examines selection for kidney transplantation and determines who are referred, how many had contraindications and whether comorbidity indices predict transplant status. Of 113 consecutive adult incident end-stage renal disease (ESRD) patients at this single center 47 (41.6%) were referred. Using published guidelines, 48 (42.5%) had a specific contraindication. However 26 (23%) were neither referred nor had contraindications. An ESRD mortality score, acute renal failure status and albumin were independent predictors of referral but only the mortality score was predictive of contraindication status. The Charlson and ESRD comorbidity indices were less predictive of contraindication or referral status. In a comparison of patients who were Candidates (referred and no contraindication, n = 39) compared to those who were Neither (not referred and no contraindications, n = 26), age was the most discriminating factor (c = 0.99, 95% CI 0.97-1.00). Comorbidity and mortality indices were inferior. Neither patients were older (75 +/- 7 years) and had comorbidity scores that were higher than Candidates but similar to those with contraindications (ESRD index; Neither 3.3 +/- 2.5, Candidate 1.4 +/- 1.8, and contraindication 4.1 +/- 3.4). Comorbitity indices do not help explain selection practices whereas age is an important discriminator. How many Neither patients would benefit from transplantation is not known.

BK virus nephropathy in a heart transplant recipient: case report and review of the literature.

The human polyomavirus BK virus (BKV) remains latent in the urinary tract and may be reactivated in immunocompromised states. BKV is noted to be the etiologic agent of polyomavirus-associated nephropathy (PVAN), which is a significant cause of allograft failure in renal transplant patients. Renal dysfunction following non-renal solid organ transplantation is common and is typically attributed to drug toxicity or patient comorbidities. In this article we describe a case of PVAN in the native kidneys of a heart transplant recipient and review the literature. Although this is only the fourth case reported, BKV nephropathy should be considered in the differential diagnosis of new renal failure following non-kidney solid organ transplantation, as early diagnosis of PVAN is necessary to prevent irreversible renal damage.

Polyoma virus-induced hemorrhagic cystitis in renal transplantation patient with polyoma virus nephropathy.

We report a biopsy proven case of hemorrhagic cystitis in a cadaveric renal transplant patient with hematuria. Because more and more polyoma virus infection is being diagnosed in kidney transplant recipients, clinicians should be aware that gross hematuria in a recent transplant recipient may represent polyoma virus-induced hemorrhagic cystitis.

Impact of mycophenolate mofetil loading on drug exposure in the early posttransplant period.

UNLABELLED: Achieving adequate therapeutic levels of immunosuppressive medications is important in rejection prevention. This study examined exposure to mycophenolic acid (MPA) in kidney transplant patients within the first 5 days posttransplantation. METHODS: This single-center, nonrandomized study of first solitary kidney allograft recipients receiving cyclosporine (n = 116) or tacrolimus (n = 50) included patients who received either 1 g or 1.5 g of mycophenolate mofetil twice daily starting postoperatively. Exposure to MPA was measured at days 3 and 5 posttransplant using published limited sampling time equations. RESULTS: There were no significant differences in exposure in the cyclosporine-treated patients receiving 3-g (n = 22) compared to 2-g (n = 94) daily doses (AUC([0-12]) 33.8 +/- 10.0 mg*h/L versus 30.1 +/- 9.7 mg*h/L, P = .20, respectively). About half the patients in both groups had AUC([0-12]) <30 mg*h/L on days 3 and 5 posttransplant. On the other hand, there was significantly greater exposure on day 3 in the tacrolimus-treated patients receiving 3 g (n = 21) compared to 2 g (n = 29) daily (AUC([0-12]) 43.1 +/- 9.0 mg*h/L versus 36.8 +/- 11.1 mg*h/L, P = .016, respectively). On day 3 one (4.8%) patient receiving 3 g had an AUC([0-12]) of <30 mg*h/L; whereas, eight (27.5%) receiving 2 g were below this level (P = .068). The AUC([0-12]) levels were not different on day 5. CONCLUSIONS: Loading with higher doses of mycophenolate mofetil results in greater exposure and a trend toward more patients in the therapeutic window within the first week for tacrolimus- but not for cyclosporine-treated patients.

Hypertension-based clinical risk strategies for detecting microalbuminuria in diabetes.

BACKGROUND: Microalbuminuria screening to identify patients at risk of diabetic nephropathy is widely accepted. AIM: To investigate whether blood-pressure-based strategies can identify such patients without the need for microalbuminuria testing. METHODS: Spot urine for albumin/creatinine ratios was performed in all patients over an 18-month period. The performance of four combinations of clinical models, based on existing triggers for anti-hypertensive intervention (prior use and/or existing systolic BP exceeding 140 or 160 mmHg and/or dipstick proteinuria exceeding 1+ or 2+) was evaluated at microalbuminuria thresholds of 3.5 and 10 mg/mmol. The models were ranked 1 to 4, based on their escalating relative strengths in predicting need for intervention. RESULTS: Of 3748 patients, 1257 (34%) or 739 (20%) exceeded microalbuminuria thresholds of 3.5 or 10 mg/mmol. All four models predicted microalbuminuria risk (areas under ROC curves 0.60-0.77, all p < 0.001). The models (1-4) identified 2220, 2465, 2803 or 2937 for intervention, respectively, irrespective of microalbuminuria status, and missed 368, 232, 194 or 126 at 3.5 mg/mmol and 164, 87, 81 or 45 at 10 mg/mmol. DISCUSSION: Clinical models using routinely measured parameters reduced the target population for microalbuminuria screening by 60-80%, missing 3-10% of patients with albumin/creatinine ratios exceeding 3.5 mg/mmol or 1-4% of those exceeding 10 mg/mmol.

Treatment of hypercholesterolemia with ezetimibe in the kidney transplant population.

BACKGROUND: Given the high incidence of lipid abnormalities, high burden of cardiovascular disease, and high proportion who do not achieve target levels despite therapy in the kidney transplant population, additional lipid lowering strategies are needed. METHODS: This was a nonrandomized, open-label, single-cohort evaluation of ezetimibe, a novel cholesterol absorption inhibitor, in 40 stable kidney transplant recipients with hypercholesterolemia. RESULTS: After 4 weeks of therapy total and LDL cholesterol were reduced by 23 +/- 13% (P < .0001) and 33 +/- 15% (P < .0001), respectively. The drug was equally effective in patients on cyclosporine (19), tacrolimus (13), or sirolimus (8), but more effective (P = .0006) when used in combination with a statin (41 +/- 13% reduction in LDL, n = 22) compared with monotherapy (24% +/- 13%, n = 18). There were no significant effects on serum creatinine, drug levels, body weight, or liver function tests. CONCLUSIONS: Ezetimibe is an effective LDL cholesterol-lowering agent in the kidney transplant population. Further studies are warranted in a larger population not only to examine the extent of cardiovascular risk reduction but also to detect unwarranted toxicity.

Basiliximab lowers the cyclosporine therapeutic threshold in the early post-kidney transplant period.

Early adequate cyclosporine exposure has been shown to predict low acute rejection rate in kidney transplantation. The aim of this study is to determine the importance of exceeding the early cyclosporine therapeutic exposure threshold with basiliximab induction. A retrospective analysis of 166 first cadaveric and non-identical live donor transplant recipients treated with or without basiliximab induction, Neoral, mycophenolate mofetil and prednisone, was performed. Adequate exposure was defined as a 2-h post-Neoral dose cyclosporine level (C2) >1700 ng/mL at day 3. The primary outcome was acute rejection within the first 6 months. In the no basiliximab (control) group (n = 74), rejection occurred in 23% (17 of 74) of recipients and was strongly associated with low cyclosporine exposure on day 3. Acute rejection occurred in 38% (11 of 29) with C2 <1700 ng/mL compared with 13% (six of 45) with C2 >/=1700 ng/mL (p = 0.014). In the basiliximab group (n = 92), rejection occurred in only 11% (10 of 92) of recipients and did not correlate with cyclosporine exposure. Acute rejection occurred in 10% (four of 40) with C2 <1700 ng/mL compared with 12% (six of 52) with C2 >/=1700 ng/mL (p = 0.81). Therefore achieving cyclosporine therapeutic targets by day 3 may not be required when anti-IL2 receptor antibody induction is used.

Therapeutic monitoring of cyclosporine in kidney transplantation: the Halifax experience.

Appropriate dosing of an immunosuppressive agent is critical to its efficacy and tolerability. Finding a simple and effective method of monitoring cyclosporine (CsA/CyA) has been formidable despite a long history of widespread usage. Earlier reports linked CsA dosing to trough levels (C0), whereas later more elaborate systems have evaluated efficacy linked to 12-hour area-under-the-curve (AUC(0-12)) as a measure of total drug exposure. Recent work done at our center and elsewhere has shown that the 2-hour postdose concentration (C2) to be simple and more effective than the C0 or the AUC. With C2 monitoring as a guide to CsA dosing, acute rejection (AR) and nephrotoxicity (NT) can be effectively reduced. Furthermore, absorption profile as per C2 levels further emphasizes the importance of achieving the targeted peak concentration in the first week of transplantation. The C2 concentration strategy is discussed in light of newer induction agents and other immunosuppression.

Importance of peak PRA in predicting the kidney transplant survival in highly sensitized patients.

Do patients with high historic peak panel-reactive antibodies (PRA) remain high risk if their PRA levels fall before transplantation? We examined retrospectively 406 first and repeat kidney recipients with a peak PRA of >50%, who were transplanted from our center between January 1990 and December 2001. Univariate analysis by log-rank test was performed for variables that affect graft survival. The factors tested included current PRA, peak PRA, difference between peak and current PRA (DeltaPRA), HLA mismatch, gender, age, transplant number, and donor source. Receiver operator characteristic curves (ROC) were generated to obtain the best cutpoints for current PRA and DeltaPRA. Current PRA (P < .0001), peak PRA (P = .0004), and DeltaPRA (P = .0015) were significant predictors by univariate analysis. However, in a multivariate model, peak PRA was not significant. Current PRA (P < .0001) was significantly associated with graft survival, while DeltaPRA showed a strong trend to significance (P = .05). Current PRA of <26% and DeltaPRA of >37% were the best cutpoints for separating good and poor outcomes. This study shows that current PRA and DeltaPRA impact on graft survival in highly sensitized (>50%) patients. Sensitized patients with peak PRA >50% who subsequently have a drop in PRA to <26% are at lower risk of graft loss than those with a persistently high PRA. A fall in peak PRA of >37% at the time of transplant appears to be of benefit only in those patients who achieve a current PRA of <26%.

Basiliximab widens the therapeutic window for AUC-monitored neoral therapy early after kidney transplantation.

Early adequate cyclosporine exposure has been shown to predict low acute rejection. Recently basiliximab induction has been added to immunosuppressive regimens to further reduce rejection. The aim of this study was to determine the importance of achieving the early cyclosporine therapeutic threshold with basiliximab induction. A retrospective analysis of first cadaver and nonidentical living donor transplant recipients treated with or without basiliximab induction was performed. All patients (n = 170) received neoral, mycophenolate mofetil, and prednisone. The cyclosporine absorption profile was measured on day 3. Adequate cyclosporine exposure was defined as area under the curve (AUC) 0-4: >4400 microg x h/L at day 3. The primary outcome was acute rejection (AR) within the first 6 month. In the no basiliximab (control) group, AR occurred in 22% (17/78) of recipients and was strongly associated with low cyclosporine exposure on day 3. AR occurred in 39% (9/23) with cyclosporine AUC0-4 < 4400 microg x h/L compared with 15% (8/55) with AUC0-4 > 4400 microg x h/L (P =.016). In the basiliximab group, AR occurred in only 9% (8/92) of recipients and did not correlate with cyclosporine exposure. AR occurred in 8% (2/24) with cyclosporine AUC0-4 < 4400 microg x h/L compared with 9% (6/68) with AUC0-4 > 4400 microg x h/L (P =.94). Achieving cyclosporine therapeutic targets by day 3 may not be required when anti-IL2 induction is used.

Tacrolimus monitoring by simplified sparse sampling under the concentration time curve.

The purpose of this study was to determine which tacrolimus pharmacokinetic parameters best predicted efficacy in kidney transplantation. Blood tacrolimus levels at 0, 1, 2, 3, and 4 hours postdose were measured in 28 kidney transplants. All received tacrolimus-based triple-drug therapy with mychophenolate mofetil and prednisone. Associations between blood concentrations at each sampling time point and the area under the curve (AUC) 0-4 were measured by Pearson's correlation coefficients. Tacrolimus dosing was based on C0 not AUC. AUC and blood concentrations at each sampling time were retrospectively compared with C0 as predictor of acute rejection and nephrotoxicity. Although tacrolimus C0 correlated with AUC0-4 (r =.86), correlations were higher with C2 and C3 (r =.96 and r =.94, respectively). C0 levels were not significantly different in six patients with acute rejection and 23 patients without. There was a trend toward lower tacrolimus C3 in patients with AR than without AR (P =.06). C2 and C3 correlate better with AUC0-4 than C0. Early tacrolimus C3 levels may be a better than C0 as a predictor of efficacy.