F. Oppenheimer

Normothermic recirculation reduces primary graft dysfunction of kidneys obtained from non-heart-beating donors.

Abstract Our aim was to analyze the short‐ and long‐term function of kidneys procured from non‐ heart‐beating donors (NHBD) by means of three techniques: in situ perfusion (ISP), total body cooling (TBC) and normothermic recirculation (NR). Fifty‐seven potential NHBD were included. Mean warm ischemia time was 68.9 ± 35.6 min. Forty‐four kidneys were obtained from donors perfused with ISP, 8 with TBC, and 8 with NR. Eighteen kidneys (32%) started functioning immediately, 29 (52 %) showed delayed graft function (DGF) and 9 (16%) showed primary non function (PNF). The actuarial graft survival rate was 76.4 % at 1 year and 56 % at 5 years. The patient survival rate was 89.3 % at 5 years. Incidence of DGF and PNF was significantly lower in kidneys perfused with NR than those with ISP or TBC (P < 0.01). Duration of DGF was shorter in kidneys obtained through TBC than in kidneys obtained with ISP (P < 0.05). In conclusion, NR reduces the incidence of DGF and may be considered the method of choice for kidney procurement from NHBD.

Randomized double-blind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation.

BACKGROUND Acute rejection remains a major problem in renal transplantation. Immunoprophylaxis with basiliximab (Simulect) has achieved significant reductions in acute rejection episodes in renal allograft recipients receiving dual immunosuppression. This study explored the tolerability and cumulative benefit of combining basiliximab with triple-drug therapy-cyclosporine (USP Modified, Neoral), mycophenolate mofetil, and steroids. METHODS In a randomized, double-blind, placebo-controlled, multicenter study, 123 kidney transplant recipients received either basiliximab at 20 mg before transplantation (day 0) and 20 mg on day 4 (n=59), or placebo (n=64). All received triple-drug immunosuppression and were followed for 6 months. RESULTS Tolerability of basiliximab was equivalent to placebo, with no increase in serious adverse events, infection, malignancy, or posttransplant lymphoproliferative disorder. At 6 months, there were trends in favor of basiliximab over placebo in the incidences of first biopsy-confirmed acute rejection (15.3% vs. 26.6%, P=NS) and of acute rejection treated with antibody (5.1% vs. 15.6%, P=NS). Kaplan-Meier estimates at 4 weeks and 6 months were significantly in favor of basiliximab treatment for first acute rejection, biopsy-confirmed rejection, rejection episodes treated with antibody therapy, and treatment failure. Renal function improved more rapidly in the basiliximab group, with mean creatinine clearance at week 2 being 54.7 mL/min versus 43.2 mL/min for placebo (P=0.034). At 12 months, patient survival was 100% in both groups; graft survival was 94.9% with basiliximab and 92.2% with placebo. CONCLUSIONS Basiliximab immunoprophylaxis is safe, well tolerated, and shows a trend toward reduction in number of acute rejection episodes in renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.

The influence of innate immunity gene receptors polymorphisms in renal transplant infections.

Background. Genetically defined deficiencies in key components of the innate immune system have been associated with a greater risk of infection. The aim of this study was to assess the influence of genetic variability of innate immune receptors (mannose-binding lectin [MBL], mannose-associated serine-protease-2 [MASP-2], and Toll-like receptors [TLR4]) in the risk of infections after a kidney transplantation. Methods. All patients undergoing a kidney or kidney–pancreas transplantation during a 3-year period were included. Functionally relevant mutations in MBL2, MASP2, and TLR4 genes were determined by DNA sequencing. The incidence of major bacterial infections, asymptomatic cytomegalovirus (CMV) infection, and CMV disease were compared among groups. Results. There were no differences regarding major transplant characteristics among groups. Older age, requirements for posttransplant hemodialysis, and pretransplant diabetes, but not gene polymorphisms, were associated with a greater number of bacterial infections. In univariate analysis, low-MBL genotypes were associated with CMV disease in pretransplant CMV seropositive patients (P=0.015), whereas the TLR4 mutation was associated with higher risk of CMV primary infection (P=0.024). TLR4 mutation was an independent factor associated with CMV disease (odds ratio 5.84, 95% confidence interval 1.35−25.20, P=0.018). Conclusion. Polymorphisms of innate immunity receptors, especially TLR4 mutation, were associated with higher risk of CMV disease, while susceptibility to other infectious disorders was not observed.

Long-term experience with kidney transplantation from hepatitis C-positive donors into hepatitis C-positive recipients.

Kidney transplantation from hepatitis C virus (HCV) antibody positive donors (HCVD+) into HCV antibody positive recipients (HCVR+) is controversial. We implemented this policy in our units in 1990. Herein, we report the long‐term safety of this strategy. From March 1990 to March 2007, 162 HCVR+ received a kidney from HCVD+ (group 1) and 306 from HCVD− (group 2) in our units. Mean follow‐up was 74.5 months. Five‐and 10‐year patient survival was 84.8% and 72.7% in group 1 vs. 86.6% and 76.5% in group 2 (p = 0.250). Three deaths in group 1 and two in group 2 were liver‐disease related. Five‐ and 10‐year graft survival was 58.9% and 34.4% versus 65.5% and 47.6% respectively (p = 0.006) while death‐censored graft survival was 69% and 47% versus 72.7% and 58.5% (p = 0.055). Decompensated chronic liver disease was similar: 10.3% versus 6.2%. Cox‐regression analysis could not identify the donors HCV serology as a significant risk factor for death, graft failure and severe liver disease in HCVR+. In conclusion, long‐term outcome of HCVR+ transplanted with kidneys from HCVD+ seems good in terms of patient survival, graft survival and liver disease. HCVD+ was not a significant risk factor for mortality, graft failure and liver disease among HCVR+. These data strongly suggest that the use of kidneys from HCVD+ in HCVR+ is a safe long‐term strategy that helps to prevent kidney loss.

Risk Factors for Infection with Extended‐Spectrum and AmpC β‐Lactamase‐Producing Gram‐Negative Rods in Renal Transplantation

Increasing prevalence of infections caused by multi‐resistant gram‐negative enteric bacilli due to synthesis of extended‐spectrum β‐lactamase (ESBL) or to desrepressed chromosomic AmpC β‐lactamase (AmpC) is a major concern in the hospitalized patient population. Renal transplant recipients are especially susceptible to these infections. A cohort observational study in a 3‐year period was performed. ESBL‐production was determined by phenotypic analysis based on the CLSI recommendations. A multi‐variate logistic regression analysis was performed to identify independent variables associated with multi‐resistant gram‐negative bacilli infection. The study included 417 patients (61 double kidney‐pancreas recipients). The incidence of ESBL‐producing and desrepressed chromosomic AmpC β‐lactamase resistance was 11.8% (49 patients). The most frequent bacteria isolated was E. coli (35/60 isolations), followed by Klebsiella spp (12/60 isolations). Double kidney‐pancreas transplantation (OR 3.5, CI95% 1.6–7.8), previous use of antibiotics (OR 2.1,CI95% 1.1–4.1), posttransplant dialysis requirement (OR 3.1, CI95% 1.5–6.4) and posttransplant urinary obstruction (OR 5.8, CI95% 2.2–14.9) were independent variables associated with these multi‐resistant gram‐negative enteric bacilli infections. The incidence of ESBL‐producing and desrepressed AmpC β‐lactamase gram‐negative enteric bacilli infection in our population was high. These infections are associated with significant morbidity after renal transplantation.

Alendronate for treatment of renal transplant patients with osteoporosis.

UNLABELLED Osteoporosis is a frequent complication after renal transplantation. Some workers have shown that bisphosphonates may be effective to prevent and treat corticosteroid-induced osteoporosis in these patients. In this study we report our experience with administration of the biphosphonate alendronate to treat renal transplanted patients with established osteoporosis. MATERIALS AND METHODS Twelve to 24 months after transplantation (9 women, 5 men) 14 renal transplant patient were treated with alendronate and 12 patients (7 women, 5 men) were untreated. All patients displayed an iPTH <240 pg/mL and a bone mineral density (BMD) t-score <-2.5. All patients received cyclosporine and prednisone therapy. Biochemical measurements, BMD, and X-rays of the lumbar spine were measured during study. Patients in the treatment group received alendronate 10 mg/d (po) and vitamin D plus calcium (800 UI cholecalciferol and 2.5 g of CaCO(3)) per day while those in the control group only received vitamin D plus calcium, at the same dose. RESULTS There was no difference in mean age, weight, time after transplantation, or immunosuppression between the treatment and control groups. There were no significant differences in the biochemical parameters during the study period. Over the 1-year study period, patients receiving alendronate displayed a greater increase in BMD. Lumbar spine BMD increased 4.3 +/- 6.1% in the treatment group versus 0.55 +/- 5.30% in controls. Femoral neck BMD increased 10.3 +/- 11.9% and 2.2 +/- 5.7%, respectively, in the treatment and control groups. Patients receiving alendronate frequently experienced intestinal disconfort. CONCLUSIONS The bisphosphonate alendronate is effective to treat renal transplant patients suffering from established osteporosis.

Impact of Antibiotic Resistance on the Development of Recurrent and Relapsing Symptomatic Urinary Tract Infection in Kidney Recipients

We sought to determine the frequency, risk factors, and clinical impact of recurrent urinary tract infections (UTI) in kidney transplant recipients. Of 867 patients who received a kidney transplant between 2003 and 2010, 174 (20%) presented at least one episode of UTI. Fifty‐five patients presented a recurrent UTI (32%) and 78% of them could be also considered relapsing episodes. Recurrent UTI was caused by extended‐spectrum betalactamase (ESBL)–producing Klebsiella pneumoniae (31%), followed by non‐ESBL producing Escherichia coli (15%), multidrug‐resistant (MDR) Pseudomonas aeruginosa (14%), and ESBL‐producing E. coli (13%). The variables associated with a higher risk of recurrent UTI were a first or second episode of infection by MDR bacteria (OR 12; 95%CI 528), age >60 years (OR 2.2; 95%CI 1.15.1), and reoperation (OR 3; 95%CI 1.37.1). In addition, more relapses were recorded in patients with UTI caused by MDR organisms than in those with susceptible microorganisms. There were no differences in acute rejection, graft function, graft loss or 1 year mortality between groups. In conclusion, recurrent UTI is frequent among kidney recipients and associated with MDR organism. Classic risk factors for UTI (female gender and diabetes) are absent in kidney recipients, thus highlighting the relevance of uropathogens in this population.

Pharmacokinetic and pharmacodynamic correlations of cyclosporine therapy in stable renal transplant patients: evaluation of long-term target C2

We investigated the relationship between the pharmacokinetics and pharmacodynamics of cyclosporine in 15 stable renal transplant patients in order to define an effective and safe therapeutic range. The area under the curve of the first 4 h (AUC0−4), trough (C0) and 2 h (C2) levels showed median values of 1655 ng×h/ml, 114 ng/ml and 384 ng/ml, respectively. C2 showed a strong correlation with AUC0–4 (r=0.942, p=0.0005). C0 correlated poorly with C2 and AUC0–4 (r=0.596, p=0.019 and r=0.538, p=0.031, respectively). Calcineurine activity (CNa) was 6.74% at 0 h and 3.90% at 2 h, representing significant reductions (82% and 89.6%, respectively; p<0.0005) compared with normal healthy controls (median basal value 37.4%). IL-2 production was 349 pg/ml at 0 h and 276.35 pg/ml at 2 h; both results were significantly lower (reductions of 44.5% and 56.1%, respectively; p=0.04 and 0.005) than the controls of 629.1 pg/ml. IFN-γ at 2 h post-dose (8.16 UI/ml) was significantly lower (72.1% reduction, p=0.005) than in controls (29.2 UI/ml). There was a good correlation between CNa and IFN-γ production, particularly at 2 h post-dose (r=0.537, p=0.007), and a fair correlation between CNa and IL-2 concentration (p=0.030, r=0.426). C2 showed an inverse significant correlation with CNa (Spearmans p=0.000, r=−0.753), IL-2 (p=0.000, r=−0.725) and IFN-γ (p=0.000, r=−0.701) production. In treated patients, the Emax inhibitory sigmoidal model showed that a C2 of 279 ng/ml was needed to achieve a 50% inhibition (EC50) of IL-2 and INF-γ production. The results demonstrated a significant inhibition of calcineurin activity and IL-2 and IFN-γ production in patients receiving cyclosporine monotherapy compared to healthy controls. A median C2 value of 384 ng/ml was associated with a good degree of inhibition of CNa and IL-2 and IFN-γ synthesis, and the lack of rejection episodes and relevant toxicity.

Simultaneous Pancreas-Kidney Transplantation in HIV-infected Patients: A Case Report and Literature Review

Since the introduction of combined antiretroviral therapy (cART), solid organ transplantation (SOT) has become a therapeutic option for the HIV-positive population. In contrast with liver and kidney transplantation, only three simultaneous pancreas-kidney transplants (SPKT) have been reported among HIV-infected patients. Herein we have reported the first SPKT in an HIV-infected patient in Spain. The pancreas graft failed at 2 weeks and the patient died at 9 months because of a Pseudomonas aeruginosa infection. The three recipients reported in the literature lived, despite the failure of both the pancreas and kidney grafts in one subject. Despite the poor outcome of our case, HIV-1 infection was controlled after transplantation (stable CD4(+) cells and no AIDS-related events), and the kidney graft functioned with no episodes of rejection. The cART regimen used in the pretransplant period was switched at the time of transplantation to raltegravir and two nucleoside reverse transcriptase inhibitors (NRTI). Raltegravir has no interactions with immunosuppressive drugs. Target plasma levels of tacrolimus were achieved at a dose similar to that used in HIV-negative transplant recipients. The most adequate antiretroviral regimen for HIV-infected SOT recipients has not yet been established; however, one may consider switching protease inhibitors or non-NRTI-based regimens for a raltegravir-based regimen at the time of transplantation.

Outcome of simultaneous liver-kidney transplantation in highly sensitized, crossmatch-positive patients

BACKGROUND In simultaneous liver-kidney transplantation (SLKT), the liver has been described to protect the kidney from rejection, and acceptable results are possible despite a pretransplant positive crossmatch. At our center, 21 SLKT have been performed since 1993, 2 of them against a positive crossmatch. OBJECTIVES In this study we retrospectively analyzed two cases of SLKT after positive pretransplant crossmatch. METHODS Two highly sensitized women (30 and 52 years) with hepatic cirrhosis VHC on hemodialysis after a first KT failure were assessed. Pretransplant panel reactive antibodies (PRA) by complement dependent cytotoxicity NIH (CDC) were 81% and 99% respectively. Both patients received a SLKT. CM was performed at pretransplant and 24 and 48 hours posttransplant by CDC and by flow cytometry with double labeling with CD3-PE and antihuman IgG-FITC. Patients received ATG, cyclosporine, and prednisone therapy. RESULTS CM was positive pretransplant by CDC and flow cytometry. At 48 hours, CDC became almost negative (10%-20% mortality) and flow cytometry became negative. One of the patients experienced an episode of acute rejection at 10 days posttransplant that resolved with steroid pulses. Both patients presently have working grafts 26 and 24 months posttransplant (Cr, 1.1 and 1.5 mg/dL; GOT, 34 and 14 IU/L; GTP, 29 and 12 IU/L; GGT, 9 and 66 IU/L). CONCLUSIONS Our experience suggests that a positive crossmatch is not an absolute contraindication for SLKT. Good graft and patient survival rates are possible even among highly sensitized patients.