BACKGROUND:Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). METHODS:In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). RESULTS:Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. CONCLUSIONS:The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.

OBJECTIVEUnder immunosupression with sirolimus (rapamycin) procoagulant effects and platelet activation have been controversially discussed.METHODSWe evaluated patients of a prospectly designed substudy as part of a randomized trial investigating the effect of a switch from non-mTOR-based immunosuppression to sirolimus in renal transplant recipients. Our substudy consisted of 7 patients who switched therapy from azathioprine to sirolimus (conversion group) and 8 patients who remained on azathioprine (controls) before (V1) and after (V2) 3 months of treatment. In all patients we assessed flowcytometric markers of platelet activation (PAC-1), platelet degranulation (CD62P), formation of platelet leukocyte-aggregates (PLA), monocyte activation (CD11b), endogenous thrombin potential (ETP) and platelet aggregation.RESULTSBoth groups were similar in terms of baseline demographics and had stable transplant function for at least 6 months. CD62P increased significantly in the control group (p < 0.03). PLA were significantly reduced in the sirolimus conversion group at V2 (p < 0.02), whereas no effect was seen in the controls. Expression of PAC-1, CD11b, ETP-peak, ETP-time to peak, ETP-AUC and platelet aggregation showed no significant changes in both groups compared to V2.CONCLUSIONFrom clinical data, performing in depth platelet function testing, we found no evidence for increased platelet activation parameters in RTR who switched therapy from azathioprine to sirolimus.

INTRODUCTION:The aim of the current study was to explore the clinico-oncological characteristics, and the therapeutic and survival parameters, of renal transplant recipients who developed de novo transitional cell carcinoma (TCC) over a 30-year period at the authors' center.METHODS:Retrospective analysis of records from all registered patients who underwent kidney transplantation at the center between November 1979 and January 2010 who developed de novo TCC of the urinary tract.RESULTS:From all 2001 patients analyzed during the study period, 21 recipients developed 19 TCCs of the bladder and 6 TCCs of the upper urinary tract. Among bladder TCCs, 13 (68.4%) cases were confined to mucosa (pTa or carcinoma in situ, n = 7) or submucosa (pT1, n = 6) and 6 others (31.6%) infiltrated the detrusor muscle (≥p T2); the grading distribution was 5 cases of G1, 6 of G2 and 8 of G3. All recurrent cases (n = 8) revealed local or systemic progression. The overall and tumor-specific patient survival rates were 80.2%, 54.0% and 30.0% and 84.9%, 67.4% and 58.9% for 1, 5 and 10 years, respectively.CONCLUSIONS:In the light of the observed increased aggressiveness of TCC in renal transplant recipients, more frequent examinations and possibly more invasive follow-up protocols should be considered for patients with 1 or more risk factors for development of TCC. Urine cytology (including ureteral wash cytology) may be used as a reliable diagnostic tool in these patients. Prophylactic contralateral nephroureterectomy might be an option in patients at high risk.

Gossmann, J.; Graff, J.; Dragutinovic, I.; Brandhorst, G.; Scheuermann, E.; Oellerich, M. Author Information

Richter, R.; Köhler, S.; Schulz, M.; Scheuermann, E.; Kachel, H.; Gossmann, J.; Gauer, S.; Seifried, E.; Geiger, H.; Seidl, C.; Hauser, I. A. Author Information

Fatal post‐transplant malignancies with a high proportion of genitourinary neoplasms represent a serious long‐term challenge. With continuous improvement of the allograft and patient survival, cancer development after renal transplantation may soon turn to the leading morbidity cause. In a retrospective single‐center study of 1990 renal transplant recipients between November 1979 and November 2009, records of patients with urological neoplasms including epidemiological, clinical and survival parameters were accessed. Sixty‐six de novo urological malignancies in 58 recipients were recorded in the study period, being most common after skin cancers (15.6% of enregistered tumors). From these, 29 were renal cell cancers, including five neoplasms of transplanted kidney, 24 transitional cell carcinomas, 11 prostate carcinomas, and two germ cell carcinomas with incidence rates of 1.5%, 1.2%, 0.9% and 0.2%, respectively. The patient follow up was virtually complete. Tumor‐related death was found in 44% of cases. By multivariate analysis, no influence of either duration of dialysis, mode or duration of immunosuppression, gender or age at transplantation on overall patient survival could be demonstrated. This study, documenting a 30‐year single center experience, emphasizes the increased risk for urological neoplasms occuring after renal transplantation. Screening strategies for urological cancers should be optimized. (Cancer Sci 2010; 101: 2430–2435)

Hutchinson, J. A.1; Riquelme, P.2; Brown, D. P.1; Sawitzki, B.3; Rehli, M.4; Tomiuk, S.5; Schröder, J.4; Sotnikova, A.6; Miqueu, P.7; Zuhayra, M.6; Oberg, H. H.6; Pascher, A.8; Lützen, U.6; Janen, U.5ß; Thaiss, F.9; Scheuermann, E.10; Henze, E.6; Chatenoud, L.11; Volk, H.12; Lechler, R. I.13; Wood, K. J.14; Kabelitz, D.6; Schlitt, H. J.15; Fändrich, F.6; Geissler, E. K.2 Author Information

Study Type – Therapy (case series)

Background. Ischemia-reperfusion injury (IRI) is common after pancreas transplantation, leading to pancreatitis or thrombosis with the need for relaparotomy or even graft loss. Optimal donor selection may reduce the postoperative morbidity of IRI. The Eurotransplant preprocurement pancreas suitability score (P-PASS) seeks to identify ideal donors with a value <17. Owing to the organ shortage the waiting time for pancreas transplantation is increasing, a problem that may be addressed with the use of extended-criteria donors. We analyzed our pancreas transplantations regarding postoperative complications according to the P-PASS. To reflect IRI we used the peak C-reactive protein (CRP) levels during the first 3 postoperative days.Methods. From January 2009 to July 2010, we transplanted 52 pancreas grafts, including, 50 simultaneous pancreas-kidney transplantations (SPK), 1 after a kidney graft, and 1 alone. For 3 SPK donors the P-PASS was not available. All transplantations were performed using systemic venous and enteric drainage. The immunosuppression protocol included antibody induction with antithymocyte globulin and maintenance therapy with steroids, tacrolimus, and mycophenolate mofetil. The peak CRP in the first 3 postoperative days was used as a marker for IRI.Results. The mean P-PASS of our donors was 16.4 +/- 2.6 (range, 12-22). We compared 24 patients receiving organs from "ideal" donors (P-PASS <17; ID) with 25 receiving grafts from extended-criteria donors (P-PASS >= 17; ED). There was no significant difference in the incidence of graft loss among ID versus ED grafts (20.8% vs 20.0%; P = 1.0). Comparing the rates of postoperative complications of patients, we did not observe a significant difference in graft thrombosis (4.2% vs 16.0%; P = .349), relaparotomy (29.2% vs 40.0%; P = .551), a pancreatic fistula (37.5% vs 28.0%; P = .543), or the length of hospital stay (36.5 +/- 19.2 vs 37.4 +/- 20.8 days; P = .875), respectively. Regarding IRI, there was no significant difference in peak CRP values (14.1 +/- 5.5 vs 16.2 +/- 6.0 mg/dL; P = .211).Conclusion. This single center analysis failed to show that P-PASS significantly predicted pancreas graft survival, postoperative morbidity, or IRI severity. These findings suggested a chance to increase the donor pool using extended-criteria donors.

Hirsch, H. H.; Vincenti, F.; Friman, S.; Wiecek, A.; Pescovitz, M. D.; Jenssen, T.; Rostaing, L.; Citterio, F.; Scheuermann, E.; Prestele, H. Author Information

Woeste, G.1; Moench, C.2; Hauser, I. A.3; Geiger, H.4; Scheuermann, E.2; Bechstein, W. O.5 Author Information

Background. Simultaneous pancreas and kidney transplantation (SPK) is associated with great postoperative morbidity, including the need for relaparotomy in up to 40% of cases. Because the pancreatic graft is known to be the major cause of the high morbidity, we examined the incidence and treatment of pancreatic fistula (PF) in this retrospective analysis.Methods. From January 2004 to July 2010, we transplanted 52 pancreas grafts, including 50 SPK, 1 pancreas after kidney, and 1 pancreas transplantation alone. There were 22 female and 30 male patients with an overall mean age of 42.4 +/- 7.4 years. The mean duration of diabetes was 27.3 + 8.1 years, mean duration of dialysis was 24.2 +/- 28.6 months, and 14 cases were pre-emptive transplantations. All procedures were performed using systemic venous and enteric drainage.Results. The incidence of clinically relevant PF was 16/52 (30.8%), including 11(68.8%) that were treated conservatively with a drain. Five patients (31.2%) needed relaparotomy: 2 due to enteric leakage, 2 due to acute abdominal pain with graft pancreatitis observed at laparotomy, and 1 due to acute hemorrhage. In 3 cases, graft pancreatectomy was necessary. Comparing the patients with (PF+) versus without (PF-) fistulas, there was no significant difference in cold ischemia time (10.9 +/- 2.6 hours vs 10.4 +/- 4.4 hours; P = .633), donor age. We found a significantly higher peak C-reactive protein (CRP) level in the patients with pancreatic fistula (3661.4 +/- 3474.8 U/L vs 821.8 +/- 1293.7 U/L, P = .022). The lipase concentration measured in the drainage fluid postoperatively showed a significant difference between the 2 groups (3661.4 +/- 3474.8 U/L vs 821.8 +/- 1293.7 U/L; P = 0.006). Also, the amylase concentration was higher in the PF+ group (1747.3 +/- 3346.7 U/L vs 265.3 +/- 254.9 U/L; P = .097). Graft loss occurred in 4/16 cases (25.0%) of PF+ and 7/36 (19.4%) of PF (P = .719).Conclusion. The incidence of PF after pancreas transplantation is high and seems to be associated with ischemia-reperfusion injury reflected by peak-CRP. In most cases a conservative treatment is successful. The occurrence of a PF does not significantly impair graft survival.

We report on the reactivation of hepatitis B in a renal transplant patient who had been treated with rituximab for recurrent focal segmental glomerulosclerosis two and a half yr previously. He lost his anti-hepatitis B surface antigens and anti-hepatitis B core antigen antibodies and developed hepatitis B virus (HBV)-DNA positive hepatitis. Hepatitis C, which had been successfully treated by alpha interferon 10 yr before, remained quiescent. We suggest regular controls of HBV-DNA, anti-HBV antibodies and transaminases for prolonged periods in patients with status post-hepatitis B treated with rituximab. Prophylactic therapy with lamivudine and/or hepatitis B hyperimmune globulin may be considered in patients with a decrease in anti-HBV antibodies.