Tom Florian Fuller

Steroid- and calcineurin inhibitor free immunosuppression in kidney transplantation: state of the art and future developments

Owing to the increasing disparity of organ demand and organ supply the search for optimal immunosuppressive strategies has become a central issue in kidney transplantation (KTX). In the focus today are modifications of the use of calcineurin-inhibitors (CNIs, Cyclosporine A/Tacrolimus) and steroids, as they are nephrotoxic and promote cardiovascular risk factors like arterial hypertension, hyperlipidemia and diabetes mellitus. These modifications can either be withdrawal or avoidance of these substances in combination with new and/or established immunosuppressants. Because about half of all KTXs are performed by or with the help of urologists’ knowledge of modern immunosuppressive regimens is crucial also for urologists. We performed a literature research (PubMed, DIMDI, medline) for CNI- and steroid-sparing protocols and studies to elucidate their influence on graft-function and graft- and patient-survival. New substances and actual studies were also evaluated. Several published reports on CNI- and steroid-sparing protocols after KTX exist, including withdrawal, reduction or avoidance. The time of reduction seems to be crucial: an initially increased immune response should be counterbalanced by an initially intensified immunosuppression. Therefore, late steroid withdrawal seems to be safer than early withdrawal especially in Cyclosporine-based immunosuppression. Steroid avoidance also seems feasible on a CNI based regimen, especially in context with induction therapy. Withdrawal or avoidance of CNIs seems feasible with mycophenolate acid and/or induction therapy with IL 2-receptor antibodies as co-immunosuppressants. This is of interest in grafts with deteriorating function or from donors with extended criteria. Also, CNI- and steroid-free immunosuppression can be successfully performed with new immunosuppressants but results are yet premature. CNI- and/or steroid reduction, withdrawal or even avoidance is feasible. As long-term graft function is the goal of KTX and as more kidneys from donors with extended criteria are transplanted “tailored immunosuppression” will replace standards in the future.

Erratum to: No need for systemic heparinization during laparoscopic donor nephrectomy with short warm ischemia time

Purpose Systemic heparin administration during laparoscopic donor nephrectomy (LDN) may prevent microvascular thrombus formation following warm ischemia. We herein present our experience with and without systemic heparinization during LDN.

An Epigenetic Screen Unmasks Metallothioneins as Putative Contributors to Renal Cell Carcinogenesis

Objective: Functional epigenetic studies aimed to re-express transcriptionally silenced genes in renal cell carcinoma (RCC) may facilitate the ongoing search for appropriate markers supporting clinical decision-making. Methods: The RCC cell line A-498 was treated with the DNA methyltransferase inhibitor zebularine under low-cytotoxicity conditions. RNA chip analyses revealed several upregulated transcripts that were further validated by qPCR on 49 matched pairs of human kidney tissues to identify suitable marker candidates. Results: Members of the metallothionein (MT) group were remarkably downregulated in tumor tissues. MT1G and MT1H expression was decreased in 98% of cases, whereas MT2A expression was downregulated in 73% of all cases. Comparison of 308 reactivated transcripts upregulated more than 1.5-fold to published data revealed a high number of shared candidates, which supports the consistency of this experimental approach. Conclusion: MTs were found to be transcriptionally inactivated in human RCC. Our observations support the hypothesis of a possible involvement of these metalloproteins in renal cell carcinogenesis. Additional functional studies of these genes may provide clues for understanding renal cancers as essentially metabolic diseases.

Fate of finally transplanted deceased donor kidneys initially rejected at other kidney transplantation centers.

Objective: We conducted this study to determine whether it is justifiable for transplant centers to reject cadaveric donor organs based on marginal organ quality. There is a growing discrepancy between the demand for renal transplants and the number of transplants conducted. For the many patients on the renal transplant waiting list, this translates into increased dialysis-associated morbidity, mortality and a reduced quality of life. Patients and Methods: In our retrospective analysis, we focused on deceased donor kidneys that had been rejected in other transplant centers because of poor organ quality (111 patients) and then accepted for transplantation at our center, compared with a control group consisting of 343 patients. Results: Cold ischemia time was statistically significantly shorter in the control group (11 vs. 12.5 h, p = 0.005). Also, delayed graft function occurred significantly (p = 0.004) more often in the study group (45.9-30.3%). Parameters regarding perioperative data and recipient outcome did not show significant differences and except for 2 time points at 1 week and 3 months, graft function did not differ either. Conclusions: We propose that acceptance criteria for marginal donor kidneys should be expanded. Centers should reconsider their acceptance criteria in the light of these findings as the results of these transplantations may even be much better if the delay due to reallocation and retransport can be spared.

Extracorporeal Shock Wave Lithotripsy (ESWL) of a Renal Calculus in a Liver Transplant Recipient: Report of a Severe Complication—A Case Report

INTRODUCTION Extracorporeal shock wave lithotripsy (ESWL) has evolved as a standard treatment modality for calculi of the upper urinary tract. Noninvasive ESWL shows rare life-threatening complications. Herein we have reported the case of a liver transplant recipient who developed severe renal hemorrhage after ESWL of a renal calculus. Transfusion of erythrocytes and platelets led to anaphylactic shock with acute renal failure requiring intensive care. The patient fully recovered shortly thereafter and was discharged home with a residual left kidney stone measuring 8 mm. CASE PRESENTATION A 55-year-old man with a single left kidney underwent ESWL due to symptomatic left nephrolithiasis. He had undergone successful liver transplantation 11 years earlier. At the time of ESWL his liver functions were normal and his serum creatinine level was 1.3 mg/dL. Two weeks before the treatment a double pigtail ureteral stent was inserted because of a symptomatic left hydronephrosis. Several hours after ESWL treatment the patient complained of left-sided flank pain. An ultrasound revealed a large subcapsular hematoma of the left kidney, which was confirmed using abdominal computed tomography (CT). With the patient being hemodynamically stable, we opted for conservative management. Despite postinterventional complications, the patient made a fast recovery. CONCLUSION ESWL is a noninvasive, safe, and efficient method to treat renal calculi. Patients who are at risk for hemorrhage should undergo close postinterventional monitoring, including red blood cell count and renal ultrasound.

Long-Term Donor Outcomes after Pure Laparoscopic versus Open Living Donor Nephrectomy: Focus on Pregnancy Rates, Hypertension and Quality of Life

Introduction: The aim of the present study was to compare long-term donor outcomes after open and laparoscopic living donor nephrectomy. The focus was on pregnancy rates, hypertension and quality of life parameters. Materials and Methods: Data were retrospectively collected using our institutions electronic database and a structured questionnaire. The study included 30 donors after open donor nephrectomy (ODN) and 131 donors after laparoscopic donor nephrectomy (LDN). Results: Demographic data did not differ between groups. When asked for their preference, significantly more donors in the LDN group would choose the same surgical approach again. The overall frequency of postoperative complications was significantly lower in the LDN group. The incidence of grade III complications was 2% after LDN and 10% after ODN (p = 0.79). Only 2 out of 15 female donors aged between 18 and 45 years delivered a healthy child after DN. On interview, only 4 out of 15 female donors declared the desire to have children after DN. Conclusions: From the donor perspective, long-term outcomes after LDN are more favorable than after ODN. To ensure favorable functional outcomes, strict preoperative donor selection and diligent long-term donor follow-up are required.

Outcome of Patients after Third and Fourth Kidney Transplantation

Introduction: A debate exists whether patients after second graft loss should be considered for a third and subsequent graft. Hence, a retrospective analysis was undertaken to assess outcomes of patients who underwent third and fourth transplantation. Materials and Methods: A total number of 16 kidney transplantations, were included in the present study. Thirteen patients out of them underwent a third kidney transplantation and 3 were fourth graft recipients. Data and variables on patient and graft survival were retrieved and analyzed using Kaplan-Meier statistics. Postoperative complications were assessed and graded based on Clavien-Dindo classification. Results: Patient survival was 92.3% after 1 year and 76.9% after 5 years (third graft). One year censored graft survival was 100% and a 5-year graft survival was 74.1% (third graft), respectively. In the cases of fourth transplantation, graft survivals of 33.3% at 1 and 2 years were noted among 3 patients. All fourth graft recipients have survived during our observation time. The overall rate of postoperative surgical complications among third graft recipients was 46.2 and 66.7% among patients after fourth transplantation. Conclusions: Results on third kidney transplantation showed satisfactory patient and graft survival with acceptable outcome.

Long-Term Follow-Up after Paediatric Kidney Transplantation and Influence Factors on Graft Survival: A Single-Centre Experience of 16 years

Introduction: To evaluate graft- and patient survival after paediatric kidney transplantation and detecting influence factors, which affect the post-transplant time. Materials and Methods: We analysed long-term survival rates and complications after paediatric kidney transplantation and searched for predictive parameters for graft function. Results: In 132 patients, 143 kidney transplantations were performed. Graft failure occurred in 25%. Chronic rejections were the leading cause of graft loss (42.9%). Graft survival rates were 92.2% after 1 year, 85.5% after 5 years, 71.1% after 10 years and 62.1% after 15 years. The following parameters strongly influenced graft survival: number of transplants (p = 0.014), year of transplant (p < 0.0001 for 1997–2005), Epo-therapy post-transplant (p = 0.001), hypotension donor (p = 0.027), cold ischemia time (p = 0.023), anastomosis time >50 min (p = 0.008), delayed graft function (p = 0.003) and deceased donation (p = 0.039). The percentage of patients who died was 5.6%. Overall patient survival rates were 99.3% after 1 year, 95.2% after 5 years, 94.2% after 10 years and 90.7% after 15 years. Various types of infections (42.9%) were the main causes of death. Conclusions: The main causes of death after kidney transplantations in paediatric recipients are malignancy and infections. To avoid vascular complications especially in young recipients (<9 years), the cold ischemia time should be as short as possible.

PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient’s overall survival

OBJECTIVE To identify the clinicopathological association of PBRM1 (Polybromo-1 gene) and VHL (von Hippel-Lindau gene) expression at mRNA and protein levels in clear cell renal cell carcinoma (ccRCC) and its role in tumor progression. PATIENTS AND METHODS Immunohistochemical analysis, Western blotting and qPCR analysis of PBRM1 and VHL were performed on fresh-frozen ccRCC and adjacent normal tissue obtained from 70 patients who underwent radical nephrectomy. In addition, a tissue microarray (TMA) from specimens of 326 ccRCC patients was used to evaluate the effect of loss of PBRM1 and VHL immunohistological expression on clinicopathological features as well as patient survival. RESULTS In frozen tissue, PBRM1 and VHL mRNA were significantly down-regulated in most ccRCC tumors (77.6%/80.6%). Simultaneous weak PBRM1 and VHL protein expression was observed in 21.4% of frozen tumors. In the TMA samples, weak PBRM1 and VHL immunohistochemical staining was observed in 60.4% of the cases and was correlated (P<0.001). The association of PBRM1 and VHL immunohistochemical expression with clinicopathological parameters depicts a variable picture: predominantly weak PBRM1 and VHL expression were significantly associated with higher Fuhrman grade (P = 0.012 and 0.024, respectively) but only weak VHL expression was associated with a higher pT stage (P = 0.023). PBRM1 expression did not affect the overall survival, whereas weak VHL expression was associated with decreased patient overall survival (P = 0.013). CONCLUSIONS Our data suggest that reduced expression of PBRM1 and VHL is correlated with an increased tumor aggressiveness. Low VHL expression was identified as a risk factor for worse patient overall survival, independently from PBRM1 expression pattern.

Development of Graft-Site Candidiasis in 3 Solid Organ Transplant Recipients from the Same Donor

Case series Patient: Female, 61 • Female, 33 • Female, 58 Final Diagnosis: Candida arteritis Symptoms: Severe bleeding Medication: — Clinical Procedure: — Specialty: Infectious Diseases Objective: Unusual clinical course Background: Graft-site candidiasis rarely develops in solid organ transplant recipients; however, severe life-threatening complications can occur. We report the course of 3 solid organ transplant recipients developing graft-site candidiasis. Case report: All grafts, consisting of 2 kidneys and 1 liver, were procured from a single donor. Patient data were collected from our database. Candida albicans was isolated from a swab taken during multiple-organ recovery. Complications associated with candidiasis occurred in all 3 recipients with preservation of the liver transplant. Both renal transplant recipients had vascular complications, eventually resulting in graft nephrectomy and subsequent return to dialysis. The patients recovered completely without residual effects of their prior fungal infection. Conclusions: Fungal infections in solid organ transplant recipients are rare. Since the sequelae of these infections are serious and usually pertain to more than 1 recipient at a time, antifungal prophylaxis may be warranted in select donors.