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.

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.

Adequate early cyclosporin exposure is critical to prevent renal allograft rejection: patients monitored by absorption profiling.

This study used receiver operating characteristic analysis to investigate the properties of area under the concentration-time curve during the first 4h after cyclosporin-microemulsion dosing (AUC0-4) and cyclosporin (CyA) levels immediately before and at 2 and 3h after dosing (C0, C2 and C3) to predict the risk of biopsy-proven acute rejection (AR) at 6 months. Ninety-eight kidney transplant recipients treated with CyA-microemulsion-based triple therapy immunosuppression were studied on post-transplant days 3, 5, and 7, and at increasing intervals thereafter. The most sensitive and specific predictor of AR was AUC0-4. Of the single time-point measurements, the measurement properties of C2 were closest to those of AUC0-4, and superior to those of C3. The relationship between C0 and subsequent AR was weak and did not reach statistical significance. On day 3, CyA AUC0-4 > or = 4,400 ng.h/mL and C2 > or = 1,700 ng/mL were each associated with a 92% negative predictive value for rejection in the first 6months. Pharmacokinetic measurements on or after day 5, and measurements on day 3 in patients with delayed graft function, were not predictive of AR. Adequate exposure within the first 3days post transplantation may be critically important in preventing subsequent rejection.

Systematic finger guided transrectal needle biopsies of the prostate--alternative to TRUS guided biopsies in clinical practice.

OBJECTIVE: To prospectively evaluate the efficacy of a Systematic Finger Guided (SFG) approach to transrectal Prostate Needle Biopsy (PNB). PATIENTS AND METHODS: One hundred and eighty-nine sets of SFG PNB were performed on 145 men. At least four biopsy cores were taken systematically from apex to base on each side of the prostate, including suspicious areas if present. The SFG experience was compared to a literature cohort and to 14 patients who had both SFG and TRUS guided PNB. RESULTS: Of 111 SFG biopsy sets taken from 88 men with suspicious DRE, 53% were positive; 25%, 43% and 84% of men had a PSA of 0-4, 4.1-10 and >10 ng/ml respectively. With benign DRE's, positive biopsies were seen in 22% and 28% of those with a PSA 4.1-10 and >10 ng/ml respectively. Of 22 patients with two or more sets of SFG PNB's, 11 (50%) were positive on repeat PNB. Of the 14 patients with a mix of TRUS and SFG PNB's, six were concordant, four were positive on SFG only, and one on TRUS only (p=n.s.). CONCLUSION: Results of SFG PNB's and TRUS PNB's are equivalent in patients with and without suspicious prostates on DRE, probably due to the systematic nature of the sampling and number of the samples taken.

Kidney transplantation in children with urinary diversion or bladder augmentation.

PURPOSE: Urinary tract anomalies or dysfunction leaves the bladder unsuitable for urine drainage in a significant proportion of children presenting for kidney transplantation. We reviewed a multi-institutional experience to determine the ramifications of kidney transplantation in children with bladder augmentation or urinary diversion. MATERIALS AND METHODS: During a 28-year period 18 boys and 12 girls 1.7 to 18 years old (mean age 12.1) received 31 kidney transplants. Cause of end stage renal disease was renal dysplasia in 8 cases, posterior urethral valves in 5, obstructive uropathy in 5, neurogenic bladder/chronic pyelonephritis in 4, spina bifida/chronic pyelonephritis in 3, prune belly syndrome in 3 and reflux in 2. RESULTS: Of the patients 17 had augmented bladder (ileum 9, ureter 5, sigmoid 2 and stomach 1), 12 had incontinent urinary conduits (8 ileum, 6 colon) and 1 had a continent urinary reservoir. Surgical complications included 1 case each of stomal stenosis, stomal prolapse, renal artery stenosis, urine leak, enterovesical fistula and wound dehiscence. Medical complications included urinary tract infection in 21 cases and metabolic acidosis in 5. A bladder stone developed in 1 patient. There was no correlation between the incidence of symptomatic urinary tract infections and type of urinary drainage. Acidosis was more common in patients with augmented bladder (4 of 17 versus 1 of 14) but there was no correlation between the bowel segment used and the occurrence of acidosis. Graft survival was 90% at 1 year, 78% at 5 years and 60% at 10 years. Etiology of graft loss included chronic rejection in 6 cases, noncompliance in 4 and acute rejection in 1. There were no deaths. CONCLUSIONS: Drainage of transplanted kidneys into an augmented bladder or urinary conduit is an appropriate management strategy when the native bladder is unsuitable or absent. Patients with kidney transplants drained into augmented bladder or urinary conduit are at increased risk for urine infection. Graft survival is not adversely affected compared to historical controls when a kidney transplant is drained into a urinary conduit or augmented bladder.

Progress in renal transplantation.

PURPOSE: The improvements in renal transplantation over the last 10 years have been one of the great success stories in medicine. We reviewed these successes with a focus on the following: changes in demographics of donors and recipients in Canada, the benefits of new immunosuppressive regimes and the efforts to minimize their toxicity and finally, our understanding of measures to circumvent chronic rejection. MATERIALS AND METHODS: A review of current transplantation literature was performed and pertinent data presented. As well, information from the Canadian Organ Replacement Register was selected to provide an overview of changes in renal transplantation in Canada. RESULTS: Despite the stable rate of transplantation in Canada, the number of new patients starting dialysis each year roughly equals the entire national renal transplant waiting list. These patients are older and have more complex co-morbidities mandating prudent use of immunosuppression so as to minimize toxicity. Standard triple therapy consists of a calcineurin inhibitor, an antimetabolite and corticosteroids. Antibody therapy is indicated in sensitized recipients and newer monoclonal humanized antibodies offer less toxicity. Nonspecific therapies are less favorable due to unwanted side effects and we can now identify subsets of patients who are most likely to benefit from specific therapy. Newer non-nephrotoxic agents hold promise for future regimens. However a paucity of large, multicenter, randomized trials, tested against standard protocols, limits their current indications. Many immunologic and non-immunologic factors influence the outcome of renal transplantation and play a role in the development in acute and chronic rejection. CONCLUSIONS: The challenges of renal transplantation over the next 10 years are: 1) in the development of specific therapies that can be altered according to patient co-morbidities and other factors influencing outcome; 2) minimizing toxicity; 3) preventing chronic rejection; and 4) improving our national organ donation network.

Perinephric abscess presenting as chronic diarrhea.

Perinephric abscess is an uncommon diagnosis with a variable presentation and high mortality. We report an unusual case of a patient with a perinephric abscess who presented with chronic diarrhea and weight loss.

Impact of absorption profiling on efficacy and safety of cyclosporin therapy in transplant recipients.

The optimisation of cyclosporin therapy remains a challenge because of the very narrow therapeutic window and the highly variable pharmacokinetics of the drug. Therefore, there has been a concerted effort in the clinical transplant community to explore and test cyclosporin monitoring tools and techniques that will allow blood concentrations of cyclosporin to be maintained within the narrow therapeutic window in order to maximise efficacy and minimise toxicity. Absorption profiling is a simple and accurate technique for adjusting dosages of cyclosporin microemulsion that utilises an estimation of the rate and extent of cyclosporin absorption in order to optimise immunosuppression in the individual patient. Two estimation tools in particular are an abbreviated area under the concentration-time curve (AUC) for the first 4 hours postdose and a single sampling point at 2 hours postdose. These 2 monitoring strategies have not only been validated as an accurate estimation of cyclosporin bioavailability but have been demonstrated to significantly improve clinical outcomes in patients compared with traditional trough concentration monitoring. The evidence presented in this review demonstrates that absorption profiling results in the following clinical benefits compared with trough concentration monitoring: (i) reduced incidence of acute rejection; (ii) reduced severity of rejection episodes; (iii) reduced nephrotoxicity; and (iv) a rational basis for dosage adjustments. The optimisation of immunosuppressive therapy continues to be a major priority in the management of the organ transplant recipient. Absorption profiling is a sensitive and practical approach for optimising the dosage of cyclosporin microemulsion, and can further extend the benefits of cyclosporin immunosuppression in the individual patient.

Is routine ureteric stenting needed in kidney transplantation? A randomized trial.

BACKGROUND: Whether routine ureteric stenting in low-urological-risk patients reduces the risk of urological complications in kidney transplantation is not established. METHODS: Eligible patients were recipients of single-organ renal transplants with normal lower urinary tracts. Patients were randomized intraoperatively to receive either routine stenting or stenting only in the event of technical difficulties with the anastomosis. All patients underwent Lich-Gregoire ureteroneocystostomy. RESULTS: Between June 1994 and December 1997, 331 kidney transplants were performed at a single center, 305 patients were eligible, and 280 patients were enrolled and randomized. Donor and recipient age, sex, donor source, whether first or subsequent grafts, ureteric length, native renal disease, and immunosuppression were similar in each group. In the no-routine-stenting group 6 of 137 patients (4.4%) received stents after randomization for intraoperative events that in the surgeon's opinion required use of a stent. In an intention-to-treat analysis there was no difference between groups in the primary outcome cluster of obstruction or leak [routine stenting 5 of 143 (3.5%) vs. no routine stenting 9 of 137 (6.6%); P=0.23], or in either of these complications analyzed separately. All urological complications were successfully managed without major morbidity. Living donor organs and shorter ureteric length (after trimming) were univariate risk factors for leaks, although increasing donor age was associated with obstruction. CONCLUSIONS: Routine ureteric stenting is unnecessary in kidney transplantation in patients at low risk for urological complications. Careful surgical technique with selective stenting of problematic anastomoses yields similar results.

Effect of recipient sensitization (peak PRA) on graft outcome in haploidentical living related kidney transplants.

OBJECTIVE: To evaluate the influence of pre-transplant recipient sensitization on the outcome of 1-haploidentical live related donor (LRD) kidney transplants. METHOD: We reviewed 141 consecutive cyclosporine-treated adult haploidentical first transplants for which panel reactive antibody (PRA) levels were available. Patients were divided into three groups according to their peak PRA levels: group I, PRA = 0 (n = 97); group II, PRA = 1-50% (n = 24); and group III, PRA = 51-100% (n = 20). RESULTS: Differences in PRA were associated with significant differences in short- and longer-term graft survival, unrelated to patient survival. Graft survival at 1, 3, and 5 yr was only 74, 40, and 27% in group III, compared to 92, 87, and 52% in group II, and 96, 91, and 85% in group I (p < 0.001). Increasing PRA was associated with shorter time-to-graft failure. In group III, 20% lost their transplant from acute rejection in the first 6 months, versus 4% in group II and 3% in group I (p < 0.01). Graft survival in group II diverged from that of group I only after 3 yr, due to an increase in loss from chronic rejection. Hospitalization was longer in group III, in association with a significantly higher incidence of acute rejection during the first 3 months after transplantation (p < 0.02). Serum creatinine was higher in sensitized than nonsensitized patients at all time points. CONCLUSIONS: Sensitization has a significant negative impact on the outcome of haploidentical LRD kidney transplants. Sensitized potential recipients and their potential donors should be aware of this in arriving at informed decision-making for transplantation. These patients may benefit from more sensitive cross-match testing, more intense or more novel immunosuppression, or immunomodulation to modify their immune responsiveness.

Neoral use in the renal transplant recipient.

This review and critical analysis of current trends of immunosuppression management in pediatric transplantation provides evidence and support for the continued role of Neoral as an indispensable part of immunosuppressive protocols. CyA formulation influences clinical outcomes such as acute rejection, as confirmed by several multicenter studies. The CyA microemulsion formulation reduces pharmacokinetic variability and its consequent impact on outcomes over the long term. An advanced TDM strategy can improve the effectiveness and safety of immunosuppression in both de novo and maintenance renal transplant patients. There are potential risks resulting from CyA withdrawal strategies. Neoral is an indispensable part of combination protocols in renal transplantation.

Is 3-hour cyclosporine blood level superior to trough level in early post-renal transplantation period?

PURPOSE: Cyclosporine dose is traditionally based on trough blood levels. Cyclosporine trough blood level correlates poorly with acute rejection and cyclosporine nephrotoxicity after renal transplantation. We determined whether cyclosporine blood level at any other time point is superior to cyclosporine trough blood level as a predictor of acute rejection and cyclosporine nephrotoxicity. MATERIALS AND METHODS: Cyclosporine blood level was measured before (trough), and 1, 2, 3 and 4 hours after the dose in 156 initial renal transplant cases 2 to 4 days after the initiation of cyclosporine micro-emulsion formula administration. The cylosporine micro-emulsion dose was based on cyclosporine trough blood level targeting 250 to 400 microg./l. RESULTS: Regression analysis revealed that only delayed graft function (p = 0.007) and cyclosporine blood level after 3 hours (p = 0.008) predicted acute rejection. Mean cyclosporine trough blood level plus or minus standard error was not significantly different in patients with and without acute rejection (293+/-21 versus 294+/-11 microg./l.). Mean cyclosporine blood level after 3 hours was significantly lower in patients with acute rejection (1,156+/-90 versus 1,421+/-50, p = 0.008). Cases were divided into tertiles at levels after 3 hours (1,100 and 1,500 microg./l.). The group in which the level after 3 hours was less than 1,100 microg./l. had the highest acute rejection rate (22 of 50 patients, 44%) and a cyclosporine nephrotoxicity rate of 13% (7 of 52 patients). The group in which the level after 3 hours was 1,100 to 1,500 microg./l. had the lowest acute rejection rate (5 of 46 patients, 11%) without increased cyclosporine nephrotoxicity (7 of 52 patients, 13%). A level after 3 hours of greater than 1,500 microg./l. was associated with a rejection rate of 15% (7 of 47 patients) but significantly higher cyclosporine nephrotoxicity (16 of 52 patients, 30%). CONCLUSIONS: Cyclosporine blood level after 3 hours in the early post-transplantation period is associated with acute rejection and cyclosporine nephrotoxicity. A cyclosporine blood level range after 3 hours of 1,100 to 1,500 microg./l. is associated with an optimal outcome. Our data suggest that cyclosporine blood level after 3 hours may represent a better method of monitoring cyclosporine micro-emulsion dose than cyclosporine trough blood level. This hypothesis must be further studied in randomized trials.

Neoral monitoring by simplified sparse sampling area under the concentration-time curve: its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation.

BACKGROUND: Cyclosporine (CsA) dosing is traditionally based on trough blood levels (C0) rather than area under the concentration-time curve (AUC), although AUC correlates better with posttransplantation clinical events. For Neoral, AUC based on limited sampling correlates closely with full 12-hr AUC. The purpose of our study was to correlate C0 with AUC based on CsA levels at 0, 1, 2, 3, and 4 hr after dose (PK0-4) and to compare this AUC with C0 in predicting acute rejection (AR) and acute cyclosporine nephrotoxicity (CsANT) in de novo first kidney transplant patients. METHODS: PK0-4 was done 2-4 days after starting Neoral for 156 patients. All received CsA-based triple-drug immunosuppression without antibody induction. AUC was calculated as projected 12-hr (AUC0-12) and actual 4-hr (AUC0-4) from the PK0-4 using the parallel trapezoid rule. Neoral dosing was based on C0 not AUC. AUC was retrospectively compared with C0 as a predictor of AR and CsANT during the first 90 days. RESULTS: C0 correlated poorly with AUC0-12 and AUC0-4 (r=0.61 and r=0.42). C0 (mean+/-SEM) levels were not significantly different in 34 patients with and 109 without AR (293+/-21 vs. 294+/-11 microg/L, P=0.95). AUC0-12 and AUC0-4 were significantly lower in patients with than without AR (AUC0-12 9090+/-598 vs. 10608+/-336 microg x h/L, P=0.01; AUC0-4 3934+/-306 vs. 4802+/-166 microg.h/L, P=0.006). In stepwise regression analysis only AUC0-12 or AUC0-4 (P=0.03/P=0.02) and delayed graft function (P=0.007) predicted AR. AUC0-12, AUC0-4, and C0 were all significantly higher in patients with CsANT than without CsANT (AUC0-12 11746+/-650 vs. 10023+/-301 microg x h/L, P=0.01; AUC0-4 5270+/-358 vs. 4474+/-150 microg x h/L, P=0.01; C0 343+/-18 vs. 287+/-10 microg/L, P=0.01), but in stepwise regression analysis C0 was not an independent predictor of CsANT. Patients with AUC0-12 in the range of 9500 to 11500 microg x h/L or AUC0-4 between 4400 and 5500 microg x h/L had the lowest incidence of AR (13% and 7%, respectively) without significantly higher risk for CsANT. CONCLUSION: C0 correlates poorly with AUC based on PK0-4. Early AUC based on PK0-4 is more closely associated with AR and CsANT than is C0. Our data suggest that a target AUC0-12 of 9500-11500 or AUC0-4 of 4400-5500 microg x h/L may provide optimal Neoral immunosuppression.