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Aims: To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients., Materials and Methods: The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.5 months post-transplant, with annual follow-up visits to 5 years post-transplant., Results: Of the 80 LDKT patients who were randomized, 75 completed the 1-year core study and 60 attended the 5-year follow-up visit. At year 5, 15/31 (48.4%) everolimus patients and 20/29 (69.0%) cyclosporine patients remained on the study drug. Mean adjusted estimated glomerular filtration rate (GFR) at year 5 in LDKT recipients was 67.2 vs. 60.8 mL/min/1.73m2 for everolimus vs. cyclosporine (mean difference 6.4 mL/min/1.73m2; p = 0.031). For patients who remained on study drug, the mean difference was 13.2 mL/min/1.73m2 (p = 0.003), but no significant difference was seen in patients who switched from study drug (mean -2.6 mL/min/1.73m2, p = 0.701). Patient and graft survival rates were similar with everolimus and cyclosporine. Biopsy-proven acute rejection occurred in 22.0% vs. 7.5% of LDKT patients randomized to everolimus vs. cyclosporine (p = 0.116). Only 1 LDKT patient discontinued everolimus due to adverse events during years 1 - 5., Conclusions: Early initiation of everolimus with calcineurin-inhibitor (CNI) withdrawal after LDKT improved graft function to 5 years post-transplant compared to standard CNI-based therapy. The renal benefit was concentrated in patients who remained on everolimus. An increase in mild acute rejection was not associated with long-term graft loss.

Conversion of living-donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265 μmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5 months post-transplant. In a post hoc analysis of 80 living-donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73 m(2) with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73 m(2) ) with cyclosporine, a difference of 10.5 ml/min/1.73 m(2) in favour of everolimus (P < 0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73 m(2) with everolimus versus -0.7 (95% CI [-4.6, 3.1]) ml/min/1.73 m(2) ) (P < 0.001) with cyclosporine. There were six biopsy-proven acute rejection episodes in everolimus-treated patients (five Banff grade I) and one episode in cyclosporine-treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12 months post-transplant that is observed in both living and deceased-donor recipients. (clinicaltrials.gov NCT00154310)., (© 2014 Steunstichting ESOT.)

We report on the case of an unexpected blind-ending ureter in a kidney transplant. To our knowledge, this is the first report of a blind-ending ureter in kidney transplantation. The recipient was a 60-year-old woman, with a 6-year history of chronic haemodialysis. During the performance of ureterocystostomy, the ureteric stent could not be placed in the renal pelvis as the ureter, surprisingly, was found as blind-ending in the ureteral sheath. Dissecting the ureteral sheath a second shorter ureter was found and used for ureterocystostomy. The histology reported a normal ureter, which led to a thread of connective tissue. The patient had an uneventful recovery; the creatinine was 1.07 mg/dl at discharge from the hospital. It is mandatory for the transplanting surgeon to be aware of the ureteral variations and the surgeon should be trained in the surgical management of these variations. Accuracy should be ensured when exploring the exact anatomy of the donor organ.

Recently, we showed that serum beta-trace protein (BTP) is an alternative marker of glomerular filtration rate (GFR) in renal transplant recipients (RTR). We have now developed three BTP-based GFR formulae derived by multiple regression analyses from the patients who had participated in that study. Currently, we validated the diagnostic performance of these BTP-formulae in 102 consecutive RTR who underwent a technetium diethylenetriamine pentaacetic acid (DTPA) clearance for GFR measurement in comparison to the re-expressed Modification of Diet in Renal Disease (MDRD) equation and a recently proposed BTP-based equation (referred to as 'White equation'). The best-performing BTP formula was found to be: GFR = 89.85 x BTP(-0.5541)x urea(-0.3018). This equation estimated true GFR virtually without bias (+0.43 mL/min/1.73 m(2), not significant [NS]), while a small, but significant, overestimation was seen for the MDRD formula (+3.43 mL/min/1.73 m(2), p = 0.003). Precision and accuracies within 50% of true GFR (93.1% and 88.2%, respectively) tended to be higher for the BTP formula, but the differences did not reach significance. The White equation overestimated the true GFR by 9.43 mL/min/1.73 m(2)(p = 0.001), and was inferior with respect to precision and 50% accuracy (79.4%). BTP-based GFR calculations are reliable, and may serve as an alternative to the re-expressed MDRD equation.

Objective: Surgical complications in kidney transplantation often demand reoperation and therefore may severely affect graft survival. Major complications can be divided into ureteral and vascular related. Reoperation for ureteral complications is supposed to worsen graft survival, but vascular complications or anastomosis technique has not been evaluated for this issue., Patients and Methods: Between 1994 and 2004 260 patients underwent kidney transplantation. All ureterovesical junctions were performed in extravesical technique with ureteral stenting in 132/260 (50.7%) patients. Arterial end-to-side anastomosis was performed routinely except for 13/260 (5%) with end-to-end anastomosis. Mean follow-up was 43 months (0-121) including serum creatinine and ultrasound inter alia., Results: Graft failure rate was 8.1% 12 months and 12.7% 60 months postoperatively. Of the patients, 29/260 (11.5%) underwent reoperation within 30 days after transplantation (stenosis or leakage of the ureterovesical junction: n = 8; vascular complications: n = 10; thrombectomy for graft vein thrombosis: n = 1; evacuation of hematoma: n = 6; nephrectomy for complete graft ischemia: n = 4). Reoperation for vascular-related complications significantly enhances the risk of graft failure (P < 0.05, Cox proportional hazard) compared to urological complications. Arterial end-to-end anastomosis was also found to have a negative impact on graft survival. No correlation between routine ureteral stenting and ureteral stenosis or leakage was found., Conclusion: Our data emphasize the importance of vascular complications compared to ureteral ones in kidney transplantation. Resolving 'non-urological' problems successfully, kidney transplantation is a safe procedure in urological hands.

Background: Two modifications of the MDRD equation [the Mayo Clinic (MC) equation and Rule's refitted (RR) MDRD formula] were proposed to overcome disadvantages of the original MDRD formula to calculate glomerular filtration rate (GFR). Additionally, a correction factor for the original MDRD formula has been introduced to adapt this formula to creatinine values measured by the isotope-dilution mass spectrometry (IDMS) method. Although precise determination of GFR is of central importance in renal transplant recipients, these equations have not been tested in these patients so far., Methods: Considering the impact of different creatinine calibrations, we analysed the MC equation and the RR-MDRD formula in comparison with the old as well as the re-expressed (IDMS traceable) MDRD equation and the Cockcroft-Gault (C-G) formula in 126 consecutive patients after kidney transplantation with respect to correlation, bias, precision, accuracy and ROC analysis. GFR was determined as technetium-diethylenetriamine pentaacetic acid ((99m)Tc-DTPA-clearance)., Results: After adjustment to IDMS creatinine determination, the performance of the re-expressed MDRD formula improved considerably in comparison to the original MDRD equation. In comparison with the re-expressed MDRD formula bias of the MC formula and the RR-MDRD formula were significantly smaller (2.31 and -0.35 vs 3.82 ml/min/1.73 m(2)). However, precision and correlation of these formulae did not differ significantly from one another, but all equations showed a higher precision than the C-G formula (P < or = 0.006 each). The accuracies within 30% of true GFR of the MC (79.4%) and the RR-MDRD equation (84.9%) were significantly higher than those of the re-expressed MDRD formula (72.2%; P < 0.03)., Conclusion: In comparison to the original and the re-expressed MDRD formula, calculation of GFR by the MC equation and the RR-MDRD formula led to improved diagnostic performance in renal transplant recipients after adjustment of creatinine. In quotidian work both formulae can be applied to these patients. Nonetheless, to determine GFR exactly, gold standard techniques are mandatory.

Cystatin C (Cys C) has been shown to be an alternative marker of renal function. However, estimation of the glomerular filtration rate (GFR) based on Cys C has received little attention. Recently, several Cys C-based equations were developed in different patient cohorts. To date, the benefit of a Cys C-based GFR calculation in patients after renal transplantation (RTx) remains to be elucidated. We compared the diagnostic accuracy of three Cys C-based formulae (Larsson, Hoek, Filler which used an immunonephelometric method) with the results of the Modification of Diet in Renal Disease (MDRD) formula. GFR was measured by means of technetium-diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) clearance in 108 consecutive patients after RTx. Correlation coefficients of all calculated GFR estimates with the true GFR were high but did not differ significantly from one another (0.83-0.87). The MDRD and Filler equations overestimated GFR significantly, whereas the Larsson equation significantly underestimated GFR. Bias of the Hoek formula was negligible. Precision of the Hoek (8.9 ml/min/1.73 m(2)) and Larsson equations (9.6 ml/min/1.73 m(2)) were significantly better than MDRD equations (11.4 ml/min/1.73 m(2); P< or =0.035 each). Accuracy within 30% of real GFR was 67.0 and 65.1% for the MDRD and Filler formulae, and 77.1% for the Larsson and Hoek formulae, respectively. Accuracy within 50% of true GFR for the Hoek formula (97.2%) was better than for the MDRD equations (85.3%). Cys C-based formulae may provide a better diagnostic performance than creatinine-based equations in GFR calculation after RTx.

Background: To overcome disadvantages of serum creatinine two strategies have been suggested to identify patients with reduced glomerular filtration rate (GFR). On the one hand, the Modification of Diet in Renal Disease (MDRD) equation is now recommended to classify the stage of chronic kidney disease. On the other hand, cystatin C (Cys C) has been investigated in numerous studies, finding a higher sensitivity than creatinine in detecting diminished GFR. To date, no comparison of both strategies in patients after renal transplantation has been performed., Methods: One hundred and five consecutive renal transplant recipients underwent (99m)Tc-DTPA-- clearance measurement. Simultaneously, MDRD estimates were calculated and Cys C serum levels were determined. ROC analyses were performed at different decision points from 20 to 70 mL/min/1.73 m(2)., Results: Although the area under the curve did not differ significantly between MDRD and Cys C within the tested GFR range, the AUC for Cys C tended to be higher when GFR exceeded 55 mL/min/1.73 m(2). A significantly higher diagnostic accuracy for Cys C compared with MDRD (p = 0.045 at 65 mL/min/1.73 m(2)) was found when investigating the subgroup of patients with well-functioning grafts (GFR>40 mL/min/1.73 m(2))., Conclusion: MDRD equation is equivalent to Cys C measurement in renal transplant recipients. As availability of MDRD is superior to Cys C, we recommend GFR estimation using the MDRD equation. Nevertheless, Cys C may serve as a confirmation test of high MDRD estimates in patients with well-functioning grafts because of superior accuracy in these patients.

Due to viral replication in erythroid precursor cells, severe anemia represents a major complication of B19 infection. However, cytomegalovirus (CMV) is the leading cause of virus-induced complications with a significant impact on graft outcome of renal transplant patients. Herein, we present a long-term B19 infection in a 45-year-old female renal transplant patient, which aggravated the renal anemia associated with a concomitant CMV infection. Since no data were available on the seroprevalence of this virus in pretransplant patients, we determined the B19 serostatus of 90 dialyzed pretransplant adult subjects.

After renal transplantation monitoring and detection of slight-to-moderate changes in GFR is a prerequisite for an optimal patient management. Recently, several equations to estimate GFR were developed and verified in the MDRD study cohort. However, little is known about the application of the MDRD formulas in the setting of renal transplantation. We prospectively conducted a study of the GFR estimates of the Cockcroft and Gault (C&G), MDRD6-, MDRD7 and the abbreviated MDRD (aMDRD) with the true GFR as measured by (99m)Tc-DTPA clearance in 95 consecutive patients 6.5, 5.3-7.7 years (mean, 95% CI) after renal transplantation. On average the DTPA clearance was 37.4, 34.4-40.4 mL/min/1.73 m(2), which differed significantly from estimates of GFR by C&G (52.6, 48.3-56.9 mL/min/1.73 m(2)), MDRD7 (44.8, 40.7-49.0 mL/min/1.73 m(2)), MDRD6 (43.8, 39.9-47.7 mL/min/1.73 m(2)) and aMDRD (46.6, 42.4-50.9 mL/min/1.73 m(2)). Bias was lowest for MDRD6 (6.4 mL/min/1.73 m(2)) and highest for C&G (15.2 mL/min/1.73 m(2)). Precision was similar for MDRD7 and aMDRD (10.6 and 11.1 mL/min/1.73 m(2)) but significantly better for MDRD6 (8.6 mL/min/1.73 m(2); p < 0.035). Accuracy within 50% of real GFR was 55.8% for C&G, 83.2% for aMDRD, 87.4% for MDRD7 and 90.5% for MDRD6. MDRD equations perform significantly better than the commonly used C&G formula. Moreover, the MDRD6 equation provides the best diagnostic performance, and should therefore be preferred in renal transplant recipients.

Background: Cystatin C (Cys C) is an established new marker of renal function in patients with various renal diseases and in kidney transplantation. However, few data are available for the early post-transplantation period., Methods: Twenty-two patients who underwent renal transplantation (RTx) were evaluated for the kinetics of Cys C from day 0 to 14 in relation to creatinine and beta-2 microglobulin (B2MG). Blood samples were obtained immediately before and after transplantation and on a daily basis thereafter. Serum levels before transplantation (100%) were used to calculate reduction ratios., Results: The decrease of the analytes differed considerably: immediately after RTx Cys C declined by 27.3% (P < 0.01). However, after 3 days, on average, all patients showed a significant increase in Cys C levels (15+/-2.5%; P < 0.01). B2MG levels fell quickly by 55.4 and 73.8% after days 1 and 7, respectively, and remained stable thereafter. In contrast, creatinine did not decrease immediately after RTx but fell slowly by 67.5% at the end of the study. Prior to rejection, all analytes showed a similar behaviour. Rejection treatment with high-dose methylprednisolone induced a significant increase in Cys C (+22.8+/-7.9%, P < 0.05), while in parallel, creatinine and B2MG decreased (-12.9+/-3.4 and -8.4+/-6.89%)., Conclusions: Corticosteroid treatment for induction of immunosuppression or rejection therapy significantly induces Cys C, but decreases B2MG. Cys C and B2MG are not helpful in establishing the diagnosis of rejection earlier. Thus, our data indicate that Cys C and B2MG testing does not accurately reflect changes in the glomerular filtration rate early after transplantation.

Background: Serum creatinine is the most common endogenous marker used to estimate the glomerular filtration rate (GFR). However, creatinine depends considerably on muscle mass, and its tubular secretion increases, especially in chronic renal failure. Cystatin C is a 13-kD protease inhibitor which is produced by all nucleated cells and is independent of muscle mass and sex. Cystatin C is eliminated by glomerular filtration and metabolized by proximal tubular cells. Its measurement has been proposed as an alternative and more sensitive marker of GFR than creatinine in patients with slight to moderately decreased GFR., Methods: We investigated serum cystatin C levels in comparison with creatinine as a single measurement for estimation of GFR in 173 patients after renal transplantation. GFR was calculated as creatinine clearance according to standard equations., Results: Serum creatinine correlated well with cystatin C (r = 0.84; p < 0.0001). No significant differences were obtained for the comparison of the linear correlation of 1/creatinine with creatinine clearance (r = 0.77; p < 0.0001) and for the linear correlation of 1/cystatin C with creatinine clearance (r = 0.73; p < 0.0001). However, we found a significant advantage of cystatin C in detecting a clinical relevant reduction of kidney function (GFR <70 ml/min; p = 0.0047, McNemar test)., Conclusion: Cystatin C is an alternative marker for the assessment of GFR in renal allograft recipients that may be superior to creatinine., (Copyright 2003 S. Karger AG, Basel)

Background: The advantages of organ allocation based on human leukocyte antigen (HLA) typing are controversial. This evaluation compares the results of HLA-dependent and non-HLA-dependent allocation in the transplantation of donor kidneys., Methods: Seventy-seven donor kidney pairs explanted locally between 1984 and 1994 were examined. One half of each pair was transplanted locally in Bonn on the basis of criteria including blood group, waiting time and currently negative cross-match. The other half of these pairs was allocated in accordance with the Eurotransplant (ET) criteria., Results: Cold ischaemia time was an average of 14.02 h in Bonn vs. 24.18 h in the ET group (P<0.0001). The number of HLA mismatches was calculated and, for example, for locus A it was 1.13 in Bonn vs. 0.73 in the ET group (P=0.0003). One-year graft survival for the locally transplanted kidneys was 92.2% and, for the ET kidneys, 90.9%. Five-year survival was 79.5% vs. 81.7%, respectively. Patient survival after 1 year was 100% vs. 97.4%, and after 5 years, 93.4% vs. 93.1%., Conclusion: The results show that it is possible to provide patients with a locally allocated kidney graft that enables good function after a short waiting period. This procedure avoids long cold ischaemia time and long waiting periods.

Immunosuppressed organ transplant recipients have a markedly increased risk of neoplasia. Among these malignancies acute myeloid leukaemia (AML) is rare. However, until now no case of successful chemotherapy has been reported. We present a 39-year-old male patient who developed AML (FAB M4 Eo) 4 years after renal transplantation and achieved a stable complete remission after induction therapy with standard dose cytarabine and daunorubicin. Remission duration is now 11 months. At present the transplant is functioning well after two additional courses of consolidation chemotherapy with high-dose cytarabine combined with mitoxantrone and idarubicine respectively. Cyclosporin A was given during all cycles of chemotherapy. We conclude that intensive chemotherapy in patients with AML following renal transplantation in good performance status is feasible.

Immunosuppressed recipients of organ transplants have a higher incidence of carcinoma than the general population. A retrospective analysis was made at the Department of Urology of Bonn University, investigating 236 renal allograft recipients as to the incidence of neoplasms before and after transplantation. Eleven patients developed malignant tumours after transplantation. In 4 out of these 11 patients, case history showed pre-existing malignancies. Two of the 4 patients developed a second tumour, while the other two had tumour progression (latency period 21-77 months). Three of the 4 patients died of their tumours 21, 42 and 77 months after transplantation, whereas one female patient is still alive and free of neoplasms 32 months after transplantation. In 7 out of these 11 patients de novo tumours were diagnosed (latency period 3-88 months). All of them are still alive (NED between 15 and 85 months), six of them with good transplant function. There was no difference to be seen in the incidence of malignancies between kidneys supplied by Eurotransplant (n = 40) and ABO compatible kidneys from our own donors (n = 196). The higher incidence rate of neoplasms in transplant recipients requires high standards in preventive measures. Any suspicious change that may occur in the course of a thorough follow-up of transplant recipients must be removed and examined histologically. Patients with previous malignant diseases must be payed special attention, since they frequently tend to develop another malignant tumour and progression of existing tumours, respectively. As far as immunosuppression is concerned, therapeutic guidelines for the treatment of transplant recipients do not differ from those set up for patients on haemodialysis. Since immunosuppression with increased rates of tumour incidence can also be observed in dialysis patients, the mere fact of increased incidence of neoplasms cannot be taken as an argument against transplantation. With a more or less equal risk of tumour incidence the crucial factor should be the higher quality of life for transplant recipients.

Objective: To compare the functional results after transplantation of locally obtained and assigned kidneys (without taking into account HLA typing) with those after transplantation of kidneys obtained via Eurotransplant (with HLA typing as principal criterion for assignment)., Patients and Methods: Between December 1983 and December 1993 a total of 236 kidneys were transplanted into 234 patients, 40 kidneys having been obtained via Eurotransplant and 196 removed locally and transplanted directly into patients on the local waiting list according to strict criteria: same blood group; waiting time since decision on transplantation; negative current crossmatch between recipient's serum and donor lymphocytes. Transplantation results were analysed retrospectively according to: ischaemia time, HLA mismatch, postoperative renal failure, postoperative renal function, rejection rate and transplant survival. Mean observation period was 55 months for the local and 50 months for the Eurotransplant kidneys., Results: The number of HLA matches was higher in Eurotransplant group (P < 0.001). However, the cold ischaemia time was greater for this group (20.2 vs 15.7 hours; P < 0.01). Acute renal failure was less common with locally assigned kidneys (33 vs 53%: P < 0.02). There were no significant differences with regard to one-year and five-year renal function (serum creatinine; percentage of normal): 90.2% local vs 88.3% Eurotransplant and 81.8% vs 62.3%, respectively). Survival rates were also similar (96.9% local vs 95% Eurotransplant after one year, 94.4% vs 90% after 5 years)., Conclusion: Local assignment by waiting time and blood group gave results that were similar to those via Eurotransplant based on HLA typing criteria.

A group of 113 patients were investigated after allogenic cadaver renal transplantation to analyse whether the small number of patients presenting acute rejection relapses could be defined by risk factors and whether there is an efficacious regimen for the safe therapy of recurrent rejection episodes. According to these results we are aware of a group of "highly reactive rejectors" especially within the younger recipients and there are further characteristics which can be identified as being associated with an elevated risk of recurrent acute rejection. By adequate antirejection therapy we can achieve a favourable transplant survival rate of 97% in the critical first year. An additional benefit may result from ALG consolidation related to suppression of the remaining CD8-positive human natural killer cells.

Objective: To evaluate the transplant-preserving management of renal allograft rupture., Patients and Methods: From April 1982 to January 1994 a total of 238 renal transplantations were performed on 227 patients. Eight cases (3.5%) of renal allograft rupture occurred. Transplant nephrectomy was necessary in one patient. Seven patients were surgically treated with collagen foam, fibrin glue and vicryl mesh., Results: In all seven cases treated conservatively, renal salvage and satisfactory graft function was achieved. After a mean follow-up of 52.9 months (range 2-94) the mean creatinine level was 15.6 mg/L (range 11-21). Of these seven patients with renal allograft rupture one returned to haemodialysis 22 months after transplantation and had several episodes of rejection. Almost 4.5 years after renal allograft rupture, the creatinine value in six of the seven patients was only slightly higher than the mean creatinine values of all donor kidney recipients (14.4 +/- 5.5 mg/L)., Conclusion: There should be an attempt to salvage the transplant after allograft rupture in all cases. Using these transplant-preserving techniques, renal function could be achieved for all patients with allograft rupture.

4.5 months after successful kidney transplantation a Non-Hodgkin-lymphoma with polymorph centroblastic appearance of the tonsillar gland developed in a 21 years old male patient during immunosuppressive therapy with cyclosporine A and prednisone parallel to infection with Epstein Barr virus. Focal epileptic seizures occurred and were due to cerebral posttransplantation lymphomas as proven by brain biopsy. Reduction of immunosuppressive therapy led to complete remission as shown by CCT and MRI.

The results obtained by MR tomography in 30 patients after renal grafting are compared with the clinical and histological data in respect of corticomedullary contrast (CMC). In 22 patients with regular functioning of the transplant the CMC was normal at 19.4%. Eight MR examinations yielded a clearly reduced CMC below 14%. In 7 of these 8 patients it was possible to prove histologically the existence of an acute tubular necrosis or of a transplant rejection. Noninvasive MR tomography yielded an early indication for treating the acute renal transplant rejection without being able to differentiate between such a rejection and acute renal failure.