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.

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.

Does pretransplant obesity affect the outcome in kidney transplant recipients?

UNLABELLED: The effect of obesity on renal transplant outcome remains unclear due to conflicting published studies. The purpose of this study was to assess whether obesity affects the outcome in renal transplant patients. METHODS: We retrospectively analyzed 33 obese (BMI >30; mean = 34.1 +/- 3.68; group I) and 35 nonobese (BMI < or = 30; mean = 23.6 +/- 3.18; group II) renal transplants performed at our center between March 1999 to December 2002. These two groups were well matched with respect to age, sex, donor source, hypertension, diabetes, ischemic heart disease, hyperlipidemia, native kidney disease (PCKD, 6 vs 4; diabetic, 5 vs 4; glomerulonephritis, 6 vs 7; FSGS, 2 vs 2 and IgA, 2 vs 7), HLA mismatch and immunosuppressants medications (Neoral, 21 vs 25; tacrolimus, 11 vs 10; Cellcept, 28 vs 31; Prednisone, 33 vs 35; ATG, 7 vs 8; Basiliximab, 14 vs 13 and Rapamycin, 5 vs 2, groups I and II, respectively). Follow-up was from 7 months to 4.4 years. RESULTS: Significant differences were noted in operating time, wound infection, perinephric hematoma, lymphocele, and number of hospital days. There were no significant differences between the two groups in the incidence of wound dehiscence, deep vein thrombosis, pulmonary embolism, atelectasis, urine leak, delayed graft function, acute rejection rate, and the following posttransplant variables: diabetes mellitus, myocardial infarction, hyperlipidemia, hypertension, and incisional hernia. We conclude that obesity significantly increases operating time, wound complications, and hospitalizations.

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.

Third dose of basiliximab in pediatric renal transplantation.

Antibody induction therapy is frequently used in pediatric renal transplantation to reduce risk of early rejection. We previously reported lower rates of human herpes virus type 6 (HHV-6) reactivation in patients receiving monoclonal antibody induction with basiliximab, compared to patients receiving antithymocyte globulin/antilymphocyte globulin treatment. Subclinical rejection events were still present in many patients in the first 6 months after transplantation. This prompted a third dose of basiliximab to be administered at day 21 in addition to the standard two doses given immediately prior to transplantation and on day 4. No significant reduction of subclinical rejections was noted in the 11 patients receiving triple dosing of basiliximab. Two patients developed an allergic reaction responsive to intravenous fluids, steroids, and antihistamines with full resolution within 30 minutes of administration. There was no increase in de novo infection or reactivation of HHV-6 or Epstein-Barr virus in this group compared to patients receiving two doses of basiliximab. The goal of reduction of early subclinical rejection events was not achieved with the third dosing of basiliximab in this initial group of pediatric renal transplant patients. However, 63.6% of patients receiving triple basiliximab remained free of clinical and/or subclinical rejection for the first 6 months posttransplant compared to only 36.4% remaining rejection-free for the same interval in the group who received the conventional two doses of basiliximab.

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.

Bladder perforation during laparoscopic donor nephrectomy.

We present two cases of bladder perforation during laparoscopic donor nephrectomy at our institution. Neither of the surgeries was otherwise complicated, and the diagnoses were made post-operatively. The kidneys were extracted through a Pfannenstiel incision and used blunt dissection to penetrate the peritoneum. Both patients had previous tubal ligations, adhesions from which may have increased the chance of injury. We believe that this is a previously unreported complication that merits attention. Care should be taken with the peritoneal incision and dissection as the bladder may be susceptible to injury.

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%.

Long-term follow-up of pediatric en bloc renal transplantation.

We reviewed the outcomes of pediatric en bloc renal transplantation at two Canadian centers in the cyclosporine era. Between 1984 and 2002, 16 patients received pediatric en bloc renal transplants. Mean recipient age and weight were 45 +/- 17 years and 72.2 +/- 14.4 kg, respectively. En bloc kidneys were procured from donors aged 2.1 +/- 0.8 years (range, 0.7 to 4.0), weighing an average of 14.3 +/- 2.0 kg (range, 12 to 17). All en bloc kidneys were successfully transplanted without thrombosis. All patients received calcineurin inhibitors and corticosteroids. Only three patients received antibody-based induction therapy. Rejection episodes occurring in seven grafts were all successfully treated. Mean follow-up was 3.7 years (range 0.4 to 15.0). Mean serum creatinine values at 3 months and 1 and 3 years were 138.8 +/- 54.5 micromol/L, 118.6 +/- 38.1 micromol/L, and 95.1 +/- 24.4 micromol/L, respectively. The mean creatinine value of five patients with at least 5 years follow-up was 96.8 +/- 12.3 micromol/L. Three-year graft and patient survival rates were 94%. Two deaths with functioning grafts occurred secondary to cardiac and infectious etiologies. None of the grafts were lost independent of death. We conclude that en bloc transplantation has excellent short- and long-term results. Improving graft function after 3 years represented by reduced serum creatinine suggests that these kidneys have excellent renal reserve and growth potential.

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.

Extravesical ureteroneocystostomy with and without internalized ureteric stents in pediatric renal transplantation.

The use of ureteric double-J stents and the Lich-Gregoir (extravesical) technique of ureteroneocystotomy have both been shown to decrease the rate of urologic complications in adult kidney transplantation (Tx). There are, however, few studies of the systematic use of stents in pediatric renal Tx. Between 1991 and 1997, 32 consecutive pediatric renal transplant recipients routinely received a 6F-12 cm indwelling double-J stent and were studied prospectively. These patients were compared with 32 consecutive pediatric recipients in whom a stent was not used. The latter were transplanted between 1987 and 1991 and formed the control group. All patients had a Lich-Gregoir ureteroneocystotomy. Stents were removed under general-anesthetic cystoscopy 2 3 weeks after Tx. Immunosuppression for stented patients was polyclonal antibody induction, delayed (7-10 days) cyclosporin A, azathioprine, and prednisone. The control group received the same triple drug regimen but with no induction in 29 of the 32 patients. All patients were followed-up with at least one ultrasound evaluation in the first month, and a renal scan and repeat ultrasound were performed if there was any rise in serum creatinine. In the stented group there were two patients with urinary leak and no obstructions. In the non-stented group there were no leaks and one obstruction. There was no graft loss owing to urologic complications in either group. There were three cases of stent expulsion (all in girls) and one case of stent migration in the posterior urethra (a boy). The 1-yr graft survival rate was 90.6% in the stented group and 65.6% in the non-stented group. The prophylactic use of an indwelling ureteral stent in pediatric renal Tx did not reduce the risk of urinary leakage or obstruction. Stent migration is a common phenomenon and, while not a serious complication, is traumatic to children. Furthermore, removal of an internalized double-J stent requires a general anesthetic. We recommend using a stent for selected patients only.

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.

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.