A. Mota

Hypertension induced by immunosuppressive drugs: a comparative analysis between sirolimus and cyclosporine

The purpose of this study was to compare the effects of sirolimus (SRL) vs cyclosporine (CsA) concerning the cardiovascular mechanisms hypothetically contributing to hypertension development. Three rat groups were studied: control (vehicle), CsA (5 mg/kg/d), and SRL (1 mg/kg/d). The following parameters were evaluated after 7 weeks of treatment: blood pressured (BP) and heart rate (HR; tail cuff), lipid profile, hematology, plasma and platelet 5-HT and catecholamines (HPLC-ECD), and oxidative equilibrium (serum malondialdehyde [MDA] and total antioxidant status [TAS]). Systolic (SBP) and diastolic blood pressure (DBP) values were higher (P < .001) in both the CsA (146.2 +/- 4.5 and 124.9 +/- 4.5 mm Hg) and SRL (148.9 +/- 4.8 and 126.4 +/- 6.0 mm Hg) groups vs the controls (115.9 +/- 3.3 and 99.1 +/- 2.0 mm Hg). However, HR values were elevated in CsA but not SRL animals. The dyslipidemic pattern of CsA was even more enhanced in the SRL group, with significantly higher low-density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels vs CsA (P < .05); red blood cells, hematocrit, hemoglobin concentration, mean platelet volume, and platelet distribution width were significantly (P < .05) higher in the SRL vs CsA group. The pro-oxidative profile (increased MDA/TAS) in the CsA group was not reproduced in the SRL cohort. While plasma and platelet 5-HT were elevated in SRL rats, catecholamine content was higher in CsA animals. In conclusion, this study demonstrated that CsA and SRL produce identical hypertensive effects. However, while CsA promotes oxidative stress and sympathetic activation, SRL mainly interferes with lipid profile and hematological parameters. Thus, the hypertensive effects of CsA, a calcineurin inhibitor, and of SRL, an mTOR inhibitor, are associated with impairment of distinct cardiovascular pathways.

Surgical complications in 2000 renal transplants

INTRODUCTIONnRenal transplantation is the best treatment for end-stage renal disease. In the last years, we have seen improvements in immunosuppressive treatment, which have allowed patients to experience a better quality of life and graft survival. Nevertheless, surgical complications remain important problems that increase morbidity, mortality, costs, and hospitalization. Our purpose was to evaluate surgical complications among a large series of 2000 renal transplantations.nnnPATIENTS AND METHODSnWe retrospectively analyzed all surgical complications among 2000 renal transplants performed between June 1980 and March 2010 in our department.nnnRESULTSnAmong 318 (15.9%) surgical complications, 4.8% of patients had urologic problems. Ureteral stenosis and fistula, stent obstruction, and ureteral necrosis occurred in 2.7%, 1.8%, 0.1%, and 0.2% of patients, respectively. Vascular complications reported in 2.7% of patients included arterial or venous thrombosis (1.0% or 0.4%), both arterial and venous thrombosis (0.1%), renal infarction (0.1%), renal artery aneurysm (0.1%) as well as arterial stenosis (0.5%), kinking (0.4%), or dissection (0.1%). Other complications, not specifically related with transplantation surgery, occurred in 4.4% of patients.nnnCONCLUSIONnRenal transplantation is a safe surgery by experienced teams. Our rates of surgical complications were within those reported by other series. A meticulous surgical technique is mandatory to prevent them. Prompt diagnosis and management are required to prevent graft damage and patient morbidity.

Impact of hepatitis B and C virus infections on kidney transplantation: a single center experience.

OBJECTIVEnThe impacts of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections on patient and renal graft survivals are controversial. This study sought to evaluate the effects of pretransplantation HCV and HBV infections on renal transplant patients and their grafts at our center.nnnPATIENTS AND METHODSnWe retrospectively examined 1224 renal transplantations performed between 1992 and 2006, including 28 HBsAg positive; 64, anti-HCV; 9, anti-HCV plus HBsAg positive; and 1123, negative for anti-HCV and HBsAg. The mean posttransplantation follow-up was 5.6 +/- 4.1 years.nnnRESULTSnThe prevalences of HBV infection were 6.2% in 1994 and 2.3% in 2006 and those of HCV infection were 6.8% in 1998 and 5.2% in 2006. The rejection rate was higher among HBV+ (46.4%) and HCV+ (40.6%) groups than the negative groups (31.5%), but it was not significant. There were no significant differences in patient and graft survivals among the groups. The major cause of patient death was liver failure among patients with concomitant HBV+ and HCV+ infections and cardiovascular disease among HCV+ and negative patients.nnnCONCLUSIONSnThere has been a decrease in the prevalence of recipients with hepatitis virus infections over the last 15 years. Patient and graft survivals were not affected by HCV or HBV infection.

Early elimination of cyclosporine in kidney transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions.

Cyclosporine elimination in a regimen including sirolimus has been shown to be a safe and effective approach to improve graft function. Nevertheless, it is still unknown whether the functional benefit of CyA withdrawal coincides with a subsequent reduction in histologic lesions of chronic damage or development of chronic allograft nephropathy. This consideration would forecast a reduction in the rate of long-term graft loss. We analyzed 114 graft biopsies from a subgroup of 57 patients that had been included in a randomized study to eliminate CyA at 3 months posttransplant from a regimen including sirolimus either in group A CyA + SRL vs group B of SRL with CyA elimination at 3 months. Every patient had two biopsies, one at transplantation and another at 1 year. The biopsy reading was performed in a blinded manner by a central pathologist using the Banff 1997 and the CADI classifications. A significantly lower rate of progression of tubular and interstitial chronic lesions between basal and 1-year biopsies was observed for group B patients. In addition, the incidence of new cases of chronic allograft nephropathy during the first year was significantly lower in the group in which CyA had been eliminated at 3 months posttransplant. We conclude that early elimination of CyA in the first months posttransplant, when SRL is used as the main immunosuppressant, reduces the appearance or worsening of chronic histologic lesions, probably as a consequence of long-term CyA toxicity prevention.

Invasive Fungal Infections After Kidney Transplantation: A Single-center Experience.

INTRODUCTIONnInvasive fungal infections (IFI) affecting transplant recipients are associated with increased mortality and graft dysfunction.nnnOBJECTIVEnDescribe the frequency, clinical features, and outcomes of IFI (except pneumocystis infection) in kidney transplant recipients.nnnMETHODnSingle-center descriptive study including every kidney transplant recipient with a culture-proven or probable IFI between 2003 and 2013, according to the EORTC-MSG criteria.nnnRESULTSnWe identified 45 IFI. There were 13 cases of invasive candidiasis (C. albicans: 6 and non-C. albicans candidial spp.: 7), 11 cases of pulmonary aspergillosis (A. fumigatus: 9 and A. flavus: 2); 11 cases of subcutaneous mycosis (Alternaria spp.: 9, Paecilomyces spp.: 1, and Pseudallescheria spp.: 1); 7 cases of cryptococcosis; 2 cases of pneumonia by non-Aspergillus molds (Mucor spp.: 1 and Cunninghamella spp.: 1); and 1 case of Geotrichum capitatum pneumonia. All patients were recipients from deceased donors. Six cases occurred in the first 3 months post-transplant, 15 cases between the third and twelfth months, and 21 cases after the twelfth month. Treatment options were fluconazole for Candida infections, voriconazole or caspofungin for aspergillosis, liposomal amphotericin for cryptococcosis, and itraconazole plus excision or cryotherapy for subcutaneous mycosis. Fifteen patients died (33%). Mortality rates were 15% for invasive candidiasis, 45% for aspergillosis, 71% for cryptococcosis, 100% for non-Aspergillus molds and G. capitatum pneumonia, and 0% for subcutaneous mycosis. Six patients who survived (14%) started regular hemodialysis.nnnCONCLUSIONnIFI still have a high mortality and morbidity in kidney transplant recipients, as verified in this report. We reinforce the need for a high index of suspicion and prompt treatment.

Omega-3 Fatty Acids Inhibit Tumor Growth in a Rat Model of Bladder Cancer

Omega-3 (ω-3) fatty acids have been tested on prevention and treatment of several cancer types, but the efficacy on “in vivo” bladder cancer has not been analyzed yet. This study aimed at evaluating the chemopreventive efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) mixture in an animal model of bladder cancer. Forty-four male Wistar rats were divided into 4 groups during a 20-week protocol: control; carcinogen—N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN); ω-3 (DHA + EPA); and ω-3 + BBN. BBN and ω-3 were given during the initial 8 weeks. At week 20 blood and bladder were collected and checked for the presence of urothelium lesions and tumors, markers of inflammation, proliferation, and redox status. Incidence of bladder carcinoma was, control (0%), ω-3 (0%), BBN (65%), and ω-3 + BBN (62.5%). The ω-3 + BBN group had no infiltrative tumors or carcinoma in situ, and tumor volume was significantly reduced compared to the BBN (0.9 ± 0.1u2009mm3 versus 112.5 ± 6.4u2009mm3). Also, it showed a reduced MDA/TAS ratio and BBN-induced serum CRP, TGF-β1, and CD31 were prevented. In conclusion, omega-3 fatty acids inhibit the development of premalignant and malignant lesions in a rat model of bladder cancer, which might be due to anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties.

Chemopreventive Efficacy of Atorvastatin against Nitrosamine-Induced Rat Bladder Cancer: Antioxidant, Anti-Proliferative and Anti-Inflammatory Properties

To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) Control: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: 3 mg/kg bw/day Atorva + BBN. A two phase protocol was used, in which the drug and the carcinogen were given between week 1 and 8 and tumor development or chemoprevention were expressed between week 9 and 20, when the bladders were collected for macroscopic, histological and immunohistochemical (p53, ki67, CD31) evaluation. Serum was assessed for markers of inflammation, proliferation and redox status. The incidence of bladder carcinoma was: control 0/8 (0%); Atorva 0/8 (0%); BBN 13/20 (65%) and Atorva + BBN 1/8 (12.5%). The number and volume of tumors were significantly lower in the Atorva + BBN group, with a marked reduction in hyperplasia, dysplasia and carcinoma in situ lesions. An anti-proliferative, anti-inflammatory and antioxidant profile was also observed in the preventive Atorva group. p53 and ki67 immunostaining were significantly increased in the BBN-treated rats, which was prevented in the Atorva + BBN group. No differences were found for CD31 expression. In conclusion, Atorvastatin had a clear inhibitory effect on bladder cancer development, probably due to its antioxidant, anti-proliferative and anti-inflammatory properties.

Anti-inflammatory, anti-proliferative and antioxidant profiles of selective cyclooxygenase-2 inhibition as chemoprevention for rat bladder carcinogenesis.

Purpose: To evaluate the efficacy of a selective cyclooxygenase-2 (COX-2) inhibitor in rat bladder cancer chemoprevention, as well as to assess the relevance of inflammation, proliferation and oxidative stress in tumour growth and in its prevention. Methods: Drug treatments were performed during the first 8 weeks, followed by 12 weeks for tumour expression/prevention, in the following groups: control – vehicle; carcinogen – 0.05% of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN); celecoxib (CEL) – 10 mg/kg/day and preventive CEL+BBN. The bladders were analysed for number and volume of tumour and nature of urothelium lesions. Serum was assessed for markers of inflammation, proliferation and redox status. Results: The main findings were: a) the incidence of carcinoma was: control: 0% (0/8); BBN: 65% (13/20); CEL: 0% (0/8) and BBN+CEL: 12.5% (1/8); b) the mean tumour volume per rat with tumour and per tumour were significantly lower in the BBN+CEL group (21.2 and 5.3±0.4 mm3) vs BBN (138.5±7.5 and 112.5±6.4 mm3); c) the incidence of pre-neoplasic (hyperplasia and dysplasia) and neoplasic (papillary tumours and carcinoma in situ - CIS) lesions were notoriously reduced in the CEL+BBN treatment; d) CEL significantly reduced serum TGF-β1 and CRP and increase TNF-α and IL-1β (P

Kidney Retransplantation: Removal or Persistence of the Previous Failed Allograft?

A significant percentage of patients with failed renal graft are candidates for retransplantation. The outcomes of retransplantation are poorer than those of primary transplantation and sensitization is documented to be a major reason. The management of a failed allograft that is not immediately symptomatic is still very controversial. The aim of this study was to determine the impact of the failed allograft nephrectomy on a subsequent transplantation and its importance in the sensitization. We performed a retrospective analysis of the local prospective transplantation registry of the outcome of 126 second kidney transplantations among 2438 transplantations performed in our unit between June 1980 and March 2013, comparing those who underwent allograft nephrectomy prior to retransplantation with those who retained the failed graft. Primary endpoints were graft and patient survival. The levels of panel-reactive antibodies (PRA) and rate of acute rejections on retransplantation outcomes were also studied. Among the 126 patients who underwent a second renal transplantation, 76 (60.3%) had a prior graft nephrectomy (Group A), whereas 50 (39.7%) kept their failed graft (Group B). Group A showed significantly more positive PRA levels when compared with the other group (38% vs 10%; Pxa0< .001), as measured before the most recent transplantation, and a higher rate of acute rejection (19% vs 5.6%; Pxa0= .016). There were 28 (36%) renal allograft losses for Group A and 18 (36%) for those who had not had transplantectomy (Pxa0= not significant [NS]). One-, 3-, and 5-year graft survival rates were 96.6%, 90.7%, and 83.4%, respectively, in Group A and 95%, 82%, and 68.4%, respectively, in Group B, with no statistical differences (Pxa0= .19). Five-year actuarial patient survival rates in the 2 groups was 89.3% and 82.8%, respectively (Pxa0= .55). Multivariate analysis showed that PRA level and delayed graft function (DGF) had a statistically significant influence on graft survival (Pxa0= .028; odds ratio [OR]xa0= 1.029; and Pxa0= .024; ORxa0= 8.6), irrespective of whether the patient had graft nephrectomy or not. The allosensitization indicated by PRA increases after transplantectomy and leads to a higher incidence of acute rejection after retransplantation. Nephrectomy of failed allograft does not seem to significantly influence the survival of a subsequent graft. The decision to remove or retain a failed graft in the context of retransplantation should thus be based on known clinical indications for the procedure.

Inhibition of bladder tumour growth by sirolimus in an experimental carcinogenesis model

What’s known on the subject? and What does the study add?