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.

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.

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.

Kidney graft loss in children: implications for program development.

BACKGROUND: Graft survival in children who undergo kidney transplantation is lower than that in adults. The objective of the study was to review the experience of the first 22 years of operation of the regional pediatric kidney transplantation unit for Atlantic Canada, based at the IWK-Grace Health Centre, Halifax, and to use the results to improve graft survival. METHODS: All cases of kidney transplantation performed at the centre from 1971 to 1992 were reviewed and the data compiled with the use of a predetermined database outline. Data for first transplants were analysed and compared with those in North American databases. Of the 40 graft failures, 19 (48%) occurred within the first 3 months after transplantation, a rate similar to that at other centres. The overall survival rates tended to be slightly lower than those of international databases. The introduction of cyclosporine A as an immunosuppressant, in 1985, did not provide the expected marked improvement in survival. Infection frequently accompanied acute rejection, and there was a delay in treatment of infections and rejection after discharge home. On the basis of these preliminary findings, several program changes were made: 1) a sequential immunosuppression protocol was implemented, 2) the intensity of the medical surveillance was increased for the first 3 months after transplantation, with aggressive treatment of infections and rejections, 3) a dedicated pediatric transplantation team was established as a subset of the adult team and 4) pediatric-specific selection criteria for cadaver donors were formulated. After these changes were implemented, data were collected and analysed up to June 30, 1997. RESULTS: Graft survival rates at 1, 2 and 5 years improved dramatically. After the beginning of 1993, there were only 2 graft losses among 22 transplants. Only one of these occurred in the first 3 months, and it was due to recurrent disease. Twenty-four rejection episodes occurred (10 in the first 3 months after transplantation), but all were reversed easily with high-dose steroid therapy. INTERPRETATION: Sequential immunosuppression with close medical surveillance and early aggressive treatment of infection and rejection contribute to a marked improvement in kidney graft survival in children.

Infection concomitant with pediatric renal allograft rejection.

Renal allograft rejection episodes are frequent in children and often lead to allograft failure. Frequent association of fever with rejection in our transplant program provoked a prospective evaluation of concurrent infection during rejection episodes. Because cytomegalovirus has an established role in rejection and allograft survival, evaluation of cytomegalovirus and other herpes viruses (human simplex virus type 1, varicella, Epstein-Barr virus, and human herpes virus type 6 [HHV-6]) was undertaken in addition to standard bacterial investigation. A total of 37 patients were followed over a 30-month period. Six of eight rejection episodes were associated with herpes viruses (HHV-6, n = 6, and Epstein-Barr virus, n = 1). Three of the herpes-group-associated rejection episodes were treated with antiviral therapy in addition to pulse steroid treatment, with full recovery. The three patients with HHV-6-associated rejection episodes who were treated with pulse steroids, but no antiviral therapy, developed chronic allograft rejection. The recipient's response to allograft antigens may be influenced by concomitant herpes infection, and specific antiviral therapy appears to be indicated when infection is confirmed in association with rejection. An antiviral treatment program coupled with modulation of standard antirejection immunotherapy has the potential to improve morbidity and mortality in the pediatric renal transplant population.

In vitro correlates of in vivo therapy with cyclosporine to immunosuppress rejection of heterotopic rat cardiac allografts across strong (RT-1) plus weak (non-RT-1) histocompatibility differences.

This study correlated different oral cyclosporine doses with in vivo graft survival, blood and tissue drug levels, and in vitro immune performances. Wistar-Furth (WFu, RT-1u) hosts engrafted with heterotopic cardiac transplants from strongly histoincompatible Buffalo (BUF, RT-1b) rats were treated postoperatively with 14-day courses of different doses of CsA delivered per gavage. There was a graded prolongation of graft survival--namely, no effect at the 1.5 mg/kg dose; a modest effect at 3 mg/kg; a therapeutic effect at 5 mg/kg; and long-term unresponsiveness at 10 mg/kg. Whole blood, serum, and tissue CsA concentrations correlated with drug dose. On day 7 posttransplantation--that is, during the peak of the immune response of untreated recipients and midway during the period of daily CsA therapy--in vitro immune performances were examined in each experimental group. On the one hand, the mixed lymphocyte reaction of WFu host splenic T cells toward donor-type BUF stimulators poorly reflected the administered CsA dose. On the other hand, there was a good correlation between drug dose and both impaired cell-mediated lympholysis and reduced frequency of alloantigen-specific T cytotoxic cell precursors f(CTL)p. Animals treated with therapeutic doses of CsA showed different patterns of T cell-mediated lympholysis: 3 mg/kg did not prevent anti-BUF Tc cell sensitization; 5 mg/kg maintained f(CTL)p levels similar to the normal controls; and 10 mg/kg significantly reduced Tc clones against donor but not third-party targets. These data demonstrate that the fate of alloantigen-specific Tc clones activated in vivo depends upon the local drug concentration. Furthermore, the present studies suggest that CML and f(CTL)p afford useful in vitro indices of in vivo immunosuppression with CsA in rat cardiac allograft recipients.