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Fibrogenesis markers, such as alpha-actin (AA), CD163 (macrophages), and E-cadherin, have been studied as chronic kidney allograft injury (CAI) predictors, a major cause of allograft failure. OBJECTIVE: Investigate the value of these markers in predicting CAI and initiation of dialysis. MATERIALS AND METHODS: Retrospective analysis of 26 kidney allograft biopsies (from 22 patients with CAI) during 2 years, evaluating intensity and percentage of marked cells on glomeruli and tubulointerstitial compartment. At the time of the biopsy, patients were 45.5 ± 15.8 years and 4.2 years after transplant, and they had a mean glomerular filtration rate (GFR) of 25.8 ± 9.9 mL/min. From an average of 8.5 glomeruli per biopsy, there was ≤25% sclerosis in 17 cases, 26% to 50% in 5, and >50% in 4. Interstitial fibrosis or tubular atrophy affected ≤25% of cortical area in 14 cases, 26% to 50% in 8, and >50% in 2. Twelve patients started dialysis 5.8 ± 4.7 years after transplant, with an average GFR 20.9 mL/min at the time of the biopsy. RESULTS: There was a higher intensity and percentage of CD163-marked cells in the tubulointerstitial compartment in advanced interstitial fibrosis. We found an association between intensity of AA in the tubulointerstitial compartment and initiation of dialysis (P = .003) and a negative correlation between intensity of E-cadherin loss and GFR (r = -0.56, P = .012). CONCLUSIONS: In our study, intensity of tubulointerstitial AA was shown to be a predictor of initiation of dialysis, and E-cadherin loss intensity was associated to CAI progression. However, prospective and larger studies are needed to evaluate the predictive value of these markers. info:eu-repo/semantics/publishedVersion

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BACKGROUND: The purpose of this study was to determine the incidence of early surgical complications of kidney transplantation in our institution and its association with donor and recipient factors, as well as patient and transplant outcome. METHODS: A retrospective cohort study of all kidney transplants performed during 2015 was made. We evaluated the incidence of surgical complications and the outcome of patients and grafts at a 3-month follow-up interval. RESULTS: During the study period, 141 kidney transplants occurred. Seventeen patients had surgical complications (6 urologic, 6 vascular, and 5 other complications). Five patients lost the graft during the follow-up. Older age was associated with other surgical complications (P = .023), and graft loss was associated with the existence of surgical complications, namely, vascular complications (P

BACKGROUND: Polyomavirus nephropathy (BKVN) is an important cause of chronic allograft dysfunction (CAD). Recipient determinants (male sex, white race, and older age), deceased donation, high-dose immunosuppression, diabetes, delayed graft function (DGF), cytomegalovirus infection, and acute rejection (AR) are risk factors. Reducing immunosuppression is the best strategy in BKVN. The objective of our study was to evaluate CAD progression after therapeutic strategies in BKVN and risk factors for graft loss (GL). METHODS: Retrospective analysis of 23 biopsies, from patients with CAD and histological evidence of BKVN, conducted over a period of 10 years. Glomerular filtration rate was 60 years), and 22 had a deceased donor. Diabetes affected 4 patients, DGF occurred in 3, cytomegalovirus infection in 2, and AR in 15. All patients were medicated with calcineurin inhibitors (CNI) (95.7% tacrolimus) and corticoids, and 16 also received an antimetabolite. One year after antimetabolite reduction/discontinuation and/or CNI reduction/switching and/or antiviral agents, graft function was decreased in 11 patients, increased/stabilized in 10, and unknown in 2. GL occurred in 9 patients. Older age (hazard ratio, 1.76; 95% confidence interval, 0.94-3.28) and DGF (hazard ratio, 2.60; 95% confidence interval, 0.54-12.64) were the main risk factors for GL. The lower GFR at the time of the BKVN diagnosis was associated with an increased risk of initiation of dialysis. CONCLUSIONS: GL occurred in 39.1% of patients with BKVN and DGF; older age and lower GFR at the time of diagnosis were important risk factors. Early diagnosis of BKVN is essential to prevent GL. info:eu-repo/semantics/publishedVersion

INTRODUCTION: There is a high incidence of nephrotic proteinuria in renal transplant recipients, which is an accurate predictor of graft loss. Despite this, its histologic correlates and prognostic implications are still not well characterized. We assessed the clinical and histological correlates of kidney transplantation patients with nephrotic range proteinuria. METHODS: We have retrospectively analyzed clinical and histological data from 50 kidney transplantation biopsy specimens from 44 renal transplant recipients with nephrotic range proteinuria between 2006 and 2015. The median follow-up time was 93 months (range, 14 months to 190 months). RESULTS: The mean age of the patients was 45.2 ± 13.7 years and our cohort included 86% recipients of deceased-donor grafts. The maintenance immunosuppressive regimen included calcineurin inhibitors in 68% and mammalian target of rapamycin inhibitors in 32% of patients. The average proteinuria was 6.9 ± 3.8 g/d and 52% of patients presented with nephrotic syndrome. The main histological findings were transplant glomerulopathy (22%), de novo glomerular disease (22%), and recurrence of primary disease (22%). Tubular atrophy and interstitial fibrosis was present in 78% of the biopsy specimens. Thirty-one patients (62%) lost the graft at follow-up. There was no statistically significant difference between the histologic diagnosis nor the proteinuria levels and the outcome of the graft. CONCLUSIONS: The main causes of nephrotic range proteinuria in patients undergoing biopsy were transplant glomerulopathy, recurrence of the underlying disease, and de novo glomerulonephritis. Nephrotic range proteinuria was related to a high rate of graft loss. info:eu-repo/semantics/publishedVersion

INTRODUCTION: Rehospitalization early post-kidney transplant is common and has a negative impact in morbidity, graft survival, and health costs. Infection is one the most common causes, and identifying the risk factors for early readmission due to infectious complications may guide a preventive program and improve outcome. The aim of this study was to evaluate the incidence, characterize the population, and identify the risk factors associated with early readmission for infectious complications post-kidney transplantation. METHODS: We performed a retrospective cohort study of all the kidney transplants performed during 2015. The primary outcome was readmission in the first 3 months post-transplant due to infectious causes defined by clinical and laboratory parameters. RESULTS: We evaluated 141 kidney transplants; 71% of subjects were men, with an overall mean age of 50.8 ± 15.4 years. Prior to transplant, 98% of the patients were dialysis dependent and 2% underwent pre-emptive living donor kidney transplant. The global readmission rate was 49%, of which 65% were for infectious complications. The most frequent infection was urinary tract infection (n = 28, 62%) and the most common agent detected by blood and urine cultures was Klebsiella pneumonia (n = 18, 40%). The risk factors significantly associated with readmission were higher body mass index (P = .03), diabetes mellitus (P = .02), older donor (P = .007), and longer cold ischemia time (P = .04). There were 3 graft losses, but none due to infectious complications. CONCLUSION: There was a high incidence of early rehospitalization due to infectious complications, especially urinary tract infections to nosocomial agents. The risk factors identified were similar to other series. info:eu-repo/semantics/publishedVersion

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Copyright © Ordem dos Médicos 2016, Introduction: Peritoneal dialysis is the dialytic method of choice in chronic end-stage renal disease in children. This study main purpose was to characterize the long-term survival of a pediatric population who began peritoneal dialysis within the first two years of life. Material and Methods: A descriptive and retrospective study was performed in a portuguese nephrology and renal transplantation pediatric unit, between January 1991 and August 2014. End-stage renal disease etiology, mortality, comorbidities and complications of peritoneal dialysis and end-stage renal disease, growth and psychomotor development were evaluated. Results: Twenty children started peritoneal dialysis within the first two years of life. There were six deaths, but no deaths of children with primary chronic kidney disease were registered over the past decade. The 14 living children were characterized; 13 were males. Congenital abnormalities of the kidney and urinary tract were the leading etiology of chronic kidney disease (45%). The average age start of peritoneal dialysis was 6.1 months; six children started before 30 days of life. Peritonitis was the most frequent cause of hospitalization. Ten children were transplanted at an average age of 5.3 years. All of the children who are still in peritoneal dialysis have short stature, but nine of the transplanted have final height within the expected for their mid-parental height target range. Nine (64%) had some type of neurodevelopmental delay. Discussion: Peritoneal dialysis is a technique possible and feasible since birth, as evidenced in the study, as more than half of children successfully started it before 6 months of life. It allows long-term survival until the possibility of renal transplantation despite the associated morbidity, including peritonitis and complications of chronic renal disease. The ten transplanted children improved their growth, recovered from chronic anemia and improved dyslipidemia, compared with the period of dialysis. However, the average waiting time until the renal transplant was 5.3 years higher than other international centers. Conclusion: These data support the use of peritoneal dialysis from birth, but complications and the worst growth reflect the need to develop strategies to optimize care relating to nutrition, growth and development and to reduce pre-transplant time.

The genus Alternaria is one of the most common black moulds and appears to be increasing as a causative agent of subcutaneous phaeohyphomycosis, particularly among immunosuppressed patients. A 53-year-old patient who had received a kidney transplant presented with multiple verrucous lesions on the distal extremities. Positive histopathology and cultures, in addition to rDNA ITS region sequencing, identified the fungal isolate as Alternaria infectoria. Oral itraconazole was administered for 10 months. A follow-up at 15 months demonstrated no signs of infection. Clinical manifestations of cutaneous alternariosis vary significantly and only a few cases have been described in the literature. Although optimal treatment options remain controversial, this case of phaeohyphomycosis was successfully treated with itraconazole monotherapy.

Hepatitis E virus (HEV) infection can be responsible for chronic hepatitis in immunocompromised patients, and can rapidly evolve into fibrosis and/or hepatic cirrhosis. We present two cases of chronic hepatitis E, emphasizing the need to be aware of this entity as a growing etiology of hepatitis in transplant and immunocompromised patients.

INTRODUCTION: Renal transplantation is the best treatment for end-stage renal disease, including when using expanded criteria donors (ECD) kidneys. However, these suboptimal kidneys should be evaluated rigorously to meet their usefulness. Opinions differ about the best way to evaluate them. MATERIALS AND METHODS: We retrospectively reviewed kidneys from ECD harvested by a single academic institution between January 2008 and September 2013. Needle biopsies were performed at the time of the harvest when considered relevant by the transplant team. Two pathologists where responsible for their analysis; the Remuzzi classification has been used in all cases. RESULTS: We evaluated 560 ECD kidneys. Biopsies were made in 197 (35.2%) organs, 20 of which were considered not usable and 36 good only for double transplantation. Sixty-three kidneys (11.3%) were discarded by the transplant team based on the biopsy result and clinical criteria. Donors who underwent a biopsy were older (P < .001) and had a worse glomerular filtration rate (GFR; P = .001). Comparing donors approved and rejected by the biopsy, the rejected donors were heavier (P = .003) and had a lower GFR (P = .002). Cold ischemia time was longer for the biopsy group (P < .001). Regarding graft function, the biopsy overall score correlated with the transplant outcome in the short and long term. Separately, glomeruli and interstitium scores were correlated with recipient's GFR in the earlier periods (3 months; P = .025 and .037), and the arteries and tubules correlated with GFR in the longer term (at 3 years P = .004 and .010). CONCLUSION: The decision on the usability of ECD grafts is complex. At our center, we chose a mixed approach based on donor risk. Low-risk ECD do not require biopsy. In more complex situations, especially older donors or those with a lower GFR, prompted a pretransplant biopsy. The biopsy results proved to be useful as they relate to subsequent transplant outcomes, thereby allowing us to exclude grafts whose function would most probably be less than optimal.

BACKGROUND: The shortage of kidneys available for transplantation has led to enlarged criteria donors (ECD): namely, donors older than 60 years or aged between 50 and 59 years with 2 of the following characteristics-hypertension, predonation serum creatinine level higher than 1.5 mg/dL or cerebrovascular disease as the cause of death. The aim of this study was to analyze renal transplants using ECD compared with standard criteria donors (SCD) concerning the incidences of delayed graft function (DGF), acute rejection episodes (ARE), and patient and graft survivals. MATERIALS AND METHODS: This retrospective study of 409 cadaveric renal transplants over the last 4 years identified ECD in contrast with SCD. RESULTS: Of the transplants, 24.4% used ECD. The baseline characteristics of recipients of ECD versus SCD kidneys were similar, except for age and cold ischemia time. Comparing ECD and SCD, we observed an higher incidence of DGF (35% vs 18%), occurrence of ARE (34.4% vs 16.6%), average serum creatinine levels at 6 (1.87 vs 1.4 mg/dL), and 12 months (1.88 vs 1.43 mg/dL) as well as lower graft survival at 1 (82% vs 91%) and 3 years (75% vs 84%) after transplantation. Recipient survival at 1 year was not different. Multivariate analysis identified recipient age, cold ischemia time, ARE, and DGF as risk factors for graft failure. CONCLUSIONS: Renal transplantation with grafts from ECD shows significantly worse outcomes with higher rates of DGF and ARE, worse graft function, and lower graft survival.

Immunosuppressive drugs, such as tacrolimus (FK506) and cyclosporine (CsA), play an essential role in graft survival, preventing rejection. Large interindividual differences in drug-metabolizing enzymes as well as in drug transporters make the task of reaching the optimal concentrations difficult. The bioavailability of CsA and FK506 seems to be associated with the cytocrhome P450 IIIA (CYP3A) gene. It has also been described that the Multi Drug Resistance 1 (MDR1) gene that encodes for polyglycoprotein-P (P-gp) may influence the metabolizing action of FK506 and CsA. Therefore, we sought, to correlate single nucleotide polymorphisms (SNPs) in the CYP3A and MDR1 genes with the concentrations of FK506 and CsA. For this purpose we analyzed 2 groups of renal transplant recipients by sequencing: one receiving a CsA immunosuppressive regime, and other, an FK506-immunosuppression. This study showed that subjects in the FK506 group who had encoded the 1236C>T substitution in the MDR1 gene displayed 44.4% higher drug concentrations compared with ("wild-type") individuals. Individuals carrying the 2677G>T,A mutation showed FK506 concentrations that were 44.7% higher than the wild-type individuals. Concerning the CsA group, individuals carrying the 22915A>C substitution displayed CsA concentrations 52.1% higher than wild-type individuals.

A 50-year-old post-menopausal recipient of a kidney allograft with bone pain, osteoporosis, persistent hypercalcaemia and elevated parathormone (PTH) levels, despite a satisfactory graft function, was treated with bisphosphonates and cinacalcet starting, respectively, 5 and 6 months after renal transplantation (RT). Sixteen months after treatment, there was improvement of bone mineral density (BMD) measured by dualenergy X-ray absorptiometry (DEXA). A bone biopsy was taken, unveiling a surprising and worrisome result. Post-RT bone disease is different from classic CKD-MBD and should be managed distinctly, including, in some difficult cases, an invasive evaluation through the performance of a bone biopsy, as suggested in the KDIGO guidelines.

Submitted by Ana Quininha (ana.quininha@chlc.min-saude.pt) on 2014-05-06T15:04:13Z No. of bitstreams: 1 RPNH 2014 69.pdf: 1054021 bytes, checksum: cc970d084b8d61c17049b9329b2493bd (MD5) Made available in DSpace on 2014-05-06T15:04:13Z (GMT). No. of bitstreams: 1 RPNH 2014 69.pdf: 1054021 bytes, checksum: cc970d084b8d61c17049b9329b2493bd (MD5) Previous issue date: 2014

INTRODUCTION: There are no studies on the phenomena that occur on the ureter during organ preservation and immediately after transplantation. MATERIAL AND METHODS: We studied ureteral fragments obtained during organ harvesting in the cadaver (n = 9), after cold preservation period (n = 18), and immediately after kidney graft reperfusion (n = 126). In addition to the histological analysis, we evaluated the risk factors for the development of lesions and their relation to the evolution of the transplant. RESULTS: Alterations were detected in 120 of the 126 fragments studied after graft reperfusion. Global cellular infiltration was considered to be normal, mild, and moderate to severe in 34.9%, 41.3%, and 23.8%, respectively, consisting mainly of CD8(+) T lymphocytes. Urothelial exfoliation and cell vacuolization were detected in 42% and 52.4% of the cases, respectively. There was an inverse relationship between donor ventilation time and the intensity of the cellular infiltration. Seven and three of the nine fragments obtained during organ harvesting showed mild cellular infiltration of the chorion and urothelium, respectively. Cold storage promoted minor histological changes. After reperfusion, there was increased urothelial infiltration in 11 of the 18 cases. There was no relation between the lesions encountered and human leukocyte antigen compatibilities, renal rejections episodes, or the evolution of the graft itself. CONCLUSIONS: Consequences of brain death mechanical ventilation were detected at the ureteral level, with abnormal lymphocytic infiltration in most cases. Cold storage did not produce any major histological changes. The lesions detected after graft reperfusion do not seem to involve immunological phenomena.

Submitted by Ana Quininha (ana.quininha@chlc.min-saude.pt) on 2013-10-16T11:57:22Z No. of bitstreams: 1 RPNH 2013 209.pdf: 512308 bytes, checksum: 35f0152a1d38e36d45e1002ba48daea9 (MD5) Made available in DSpace on 2013-10-16T11:57:22Z (GMT). No. of bitstreams: 1 RPNH 2013 209.pdf: 512308 bytes, checksum: 35f0152a1d38e36d45e1002ba48daea9 (MD5) Previous issue date: 2013

Transplant glomerulopathy is a sign of chronic kidney allograft damage. It has a distinct morphology and is associated with poor allograft survival. We aimed to assess the prevalence and clinic-pathologic features of transplant glomerulopathy, as well as determine the functional and histological implications of its severity. We performed a single-centre retrospective observational study during an eight-year period. Kidney allograft biopsies were diagnosed and scored according to the Banff classification, coupled with immunofluorescence studies. The epidemiology, clinical presentation, outcomes (patient and graft survival) and anti-HLA alloantibodies were evaluated. Transplant glomerulopathy was diagnosed in 60 kidney transplant biopsies performed for clinical reasons in 49 patients with ABO compatible renal transplant and a negative T-cell complement dependent cytotoxicity crossmatch at transplantation. The estimated prevalence of transplant glomerulopathy was 7.4% and its cumulative prevalence increased over time. C4d staining in peritubular capillaries (27.6%) was lower than the frequency of anti-HLA antibodies (72.5%), the majority against both classes I and II. Transplant glomerulopathy was associated with both acute (mainly glomerulitis and peritubular capillaritis) and chronic histologic abnormalities. At diagnosis, 30% had mild, 23.3% moderate and 46.7% severe transplant glomerulopathy. The severity of transplant glomerulopathy was associated with the severity of interstitial fibrosis. Other histological features, as well as clinical manifestations and graft survival, were unrelated to transplant glomerulopathy severity A glomerulopatia do transplante e um sinal de lesão cronica do enxerto renal. Apresenta uma morfologia distinta e esta associada a uma pior sobrevida do enxerto. O objectivo do estudo foi avaliar a prevalência e características clinico-patológicas da glomerulopatia do transplante, bem como determinar as implicações funcionais e histológicas da sua gravidade. Estudo retrospectivo e observacional realizado num único centro durante um período de oito anos. As biopsias de enxerto renal foram diagnosticadas e avaliadas segundo a classificação Banff, complementadas com estudos de imunofluorescência. Analise da epidemiologia, apresentação clinica, outcomes (sobrevida do paciente e enxerto) e aloanticorpos anti-HLA. A glomerulopatia de transplante foi diagnosticada em 60 biopsias realizadas por motivos clinicos, em 49 receptores de transplante renal ABO compatível e com crossmatch antilinfocitario negativo por citotoxicidade dependente do complemento aquando transplante. A prevalência estimada da glomerulopatia do transplante foi 7.4%, a prevalência cumulativa aumentou ao longo do tempo. A deteção de C4d nos capilares peritubulares (27.6%) foi inferior a dos anticorpos anti-HLA (72.5%), a maioria contra as classes I e II. A glomerulopatia do transplante associou-se tanto as lesões histologicas agudas (principalmente glomerulite e capilarite peritubular), como cronicas. Aquando diagnostico, 30%, 23.3% e 46.7% apresentavam glomerulopatia do transplante leve, moderada e severa, respectivamente. Verificou-se uma associação entre a gravidade da glomerulopatia do transplante e a severidade da fibrose intersticial. Os outros indicadores histológicos, as manifestações Clinicas e a sobrevida do enxerto, foram independentes da gravidade da glomerulopatia do transplante

The genus Alternaria is one of the most common black moulds and appears to be increasing as a causative agent of subcutaneous phaeohyphomycosis, particularly among immunosuppressed patients. A 53-year-old patient who had received a kidney transplant presented with multiple verrucous lesions on the distal extremities. Positive histopathology and cultures, in addition to rDNA ITS region sequencing, identified the fungal isolate as Alternaria infectoria. Oral itraconazole was administered for 10 months. A follow-up at 15 months demonstrated no signs of infection. Clinical manifestations of cutaneous alternariosis vary significantly and only a few cases have been described in the literature. Although optimal treatment options remain controversial, this case of phaeohyphomycosis was successfully treated with itraconazole monotherapy.

Objectivos: A transplantação renal é a forma de tratamento de eleição da doença renal crónica terminal. Este tratamento cirúrgico tem vindo a sofrer alterações ao longo dos anos, com vista a melhorar os resultados do mesmo, e diminuir as co-morbilidades associadas, sendo a técnica do procedimento o alvo deste estudo de revisão. Materiais e Métodos: Realizou-se uma revisão da literatura nesta área, recorrendo-se a livros e artigos publicados, bem como, à observação de procedimentos no Serviço de Urologia e Transplantação Renal dos Hospitais da Universidade de Coimbra, com início em Maio de 2010 e término em Março de 2011. Resultados: Da análise realizada, são apresentados dois grandes procedimentos: a nefrectomia do dador (vivo ou cadáver) e a implantação no receptor, composta pela incisão, colocação do enxerto, anastomose vascular e anastomose urinária. Cada um possui opções técnicas que são empregues por diferentes centros, e serão alvo de análise. Conclusões: Dentro destes passos, existem diferentes técnicas, todas elas possuindo vantagens e desvantagens, que não trazem um total consenso sobre o procedimento de eleição, pelo que, a escolha deve ser adequada ao doente e à experiência do centro. Purpose: Kidney transplantation is the treatment of choice for patients with end-stage renal disease. This surgical procedure has suffered some changes over the past decades to achieve better outcomes and less co-morbidity, being the goal of this study its technical aspects. Materials and Methods: From May 2010 to March 2011, a revision on the literature about this theme has been made, investigating books and articles published in this area. To enrich the study, renal transplants made by the Department of Urology and Renal Transplantation of Hospitais da Universidade de Coimbra have been carefully observed, and its procedure carefully analised. Results: From the investigation made, two main procedures will be presented: donor nephrectomy (living-donor and deceased-donor) and kidney implantation in the receptor, composed by the incision, kidney positioning, vascular and urinary anastomoses. Each one of these steps has different technical options, which will be object of analysis.Conclusions: In the steps mentioned before, there are different techniques to conceive them, each one with advantages and disadvantages, which do not achieve total consensus between transplantation centers. Thus, the procedure should be chosen according to the surgeons’ experience.

Chronic hepatitis C virus (HCV) infection exists in a large proportion of patients undergoing renal transplantation. Nowadays it is not considered to be an absolute contraindication to transplantation; however, it is associated with an increased risk for the patient and accounts for a shorter half-life of the renal allograft. We present three transplant recipients who displayed serious hepatic dysfunction after renal transplantation due to an HCV infection. In two of these cases, the liver biopsies established the diagnosis of FCH. In the third case, the liver biopsy was compatible with the early stages of FCH. All patients were started on peg-interferon alfa 2-b and ribavirin with subsequent normalization of hepatic function and early complete viral responses.

Introduction. The chronic use of immunosuppressive drugs in renal transplant recipients increases the risk of developing de novo malignancies. Herein we analyze the incidence of de novo tumors and the potential role of sirolimus to improve cancer-specific survival among a cohort at a single center. Methods. This retrospective analysis of our 1,816 patients allografted between January 1983 and December 2009 sought subjects who developed de novo tumors. Epidemiological and clinical data were examined using Mann-Whitney and Pearson’s chi-square or Fisher exact tests for statistical comparisons of continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to determine cancer-specific survival according to type of neoplasia and immunosuppressive regimen, namely, conversion to sirolimus. Results. One hundred patients (5.5%) were diagnosed with a de novo malignancy. The 110 different cancers were diagnosed at a median interval of 73 months after kidney transplantation. The overall cancer-specific survivals at 1 and 5 years after cancer diagnosis were 87.0% and 76.9%, respectively. The 15 patients converted to sirolimus showed no difference in survival. Conclusion. The observed frequencies of cancer in our center are consistent with the literature. Among our cohort, sirolimus did not significantly impact survival among subjects who had de novo malignancies.

Herein we have described the case of a male renal transplant recipient who developed drug fever apparently related to sirolimus. He had been stable under an immunosuppressive regimen of tacrolimus and mycophenolate mofetil, but developed acute cellular rejection at 5 years after transplantation due to noncompliance. Renal biopsy showed marked interstitial fibrosis, and immunosuppression was switched from mycophenolate to sirolimus, maintaining low tacrolimus levels. One month later he was admitted to our hospital for investigation of intermittently high fever, fatigue, myalgias, and diarrhea. Physical examination was unremarkable and drug levels were not increased. Lactic dehydrogenase and C-reactive protein were increased. The blood cell count and chest radiographic findings were normal. After extensive cultures, he was started on broad-spectrum antibiotics. Inflammatory markers and fever worsened, but diarrhea resolved. All serologic and imaging tests excluded infection, immune-mediated diseases, and malignancy. After 12 days antibiotics were stopped as no clinical improvement was achieved. Drug fever was suspected; sirolimus was replaced by mycophenolate mofetil. Fever and other symptoms disappeared after 24 hours; inflammatory markers normalized in a few days. After 1 month the patient was in good health with stable renal function. Although infrequent, the recognition of drug fever as a potential side effect of sirolimus may avoid unnecessary invasive diagnostic procedures. Nevertheless, exclusion of other common causes of fever is essential.

The purpose of this study was to assess the impact of a corticosteroid-free maintenance immunosuppression on graft survival in kidney transplantation. We analyzed 79 patients who were transplanted between June 1, 2006 and May 31, 2007. We excluded hyperimmunized patients, second transplantations, living donors, and black recipients. Patients underwent induction with thymoglobulin or basiliximab, followed by treatment with mycophenolate mofetil (MMF), tacrolimus, and methylprednisolone. On the 5th day, the patients were divided into 2 groups: group A (n = 45) discontinued steroid therapy; group B (n = 34) continued prednisone therapy. We performed a comparative analysis of incidence of delayed graft function (DGF), acute rejection episodes (ARE), renal function at 6 and 12 months, graft and patient survivals, causes of graft loss, and mortality. The 2 groups were similar for donor, recipient, and graft characteristics. The incidences of DGF were 8.9% in group A and 14.7% in group B; those for ARE were 2.3% in group A and 13.8% in group B (P = .077). The mean serum creatinine levels at 6 and 12 months were similar. There were 8 graft losses: 3 in group A (3 deaths with functioning grafts) and 5 in group B (1 death, 3 vascular causes, 1 kidney nonfunction). The 4 deaths were due to infection (n = 3) or neoplasia (n = 1). Graft survivals at 1 year were 98% in group A and 85% in group B, and patient survivals were 98% and 97%, respectively. An immunosuppressive regimen using antibody induction and steroid-free treatment proved to be effective in low-risk patients.

We describe the case of a 59-year-old male renal transplant recipient who presented with a 1 month history of nodular, erythematous, and crusted lesions on the anterior surface of the left leg. There was no history of trauma. The patient had no systemic signs or symptoms. A skin biopsy revealed evidence of a deep fungal infection, with septate and branching hyphae amongst the dermal inflammatory infiltrate, but the culture was negative. Initial treatment with itraconazole proved ineffective and new lesions appeared. New tissue samples were obtained for culture, allowing the isolation of Pseudallescheria boydii. The patient underwent surgical excision of the lesions combined with voriconazole 400 mg/day for 2 months. After this period no new lesions appeared and the patient has remained without recurrence after 2 years of follow-up. Pseudallescheria boydii is an opportunistic fungus that can cause systemic infection mainly in immunocompromised patients that manifests as pulmonary, osteoarticular, ocular, vascular, cutaneous or central nervous system disease. Resistance to therapy can occur with infection progression and high mortality. Treatment with the combination of an antifungal agent, mainly voriconazole, and surgery, when feasible, probably provide the best results in cutaneous infections.

Polyomavirus nephropathy is a major complication in renal transplantation, associated with renal allograft loss in 14 to 80% of cases. There is no established treatment, although improvement has been reported with a variety of approaches. The authors report two cases of polyomavirus infection in renal allograft recipients. In the first case, a stable patient presented with deterioration of renal function, worsening hypertension and weight gain following removal of ureteral stent placed routinely at the time of surgery. Ultrasound examination and radiology studies revealed hydronephrosis due to ureteral stenosis. A new ureteral stent was placed, but renal function did not improve. Urinary cytology revealed the presence of decoy cells and polyomavirus was detected in blood and urine by qualitative polymerase chain reaction. Renal biopsy findings were consistent with polyomavirus -associated nephropathy. In the second case, leucopaenia was detected in an asymptomatic patient 6 months after transplantation. Mycophenolate mophetil dosage was reduced but renal allograft function deteriorated, and a kidney biopsy revealed polyomavirus -associated nephropathy, also with SV40 positive cells. In both patients immunosuppression with tacrolimus was reduced, mycophenolate mophetil stopped and intravenous immune globulin plus ciprofloxacin started. As renal function continued to deteriorate, therapy with leflunomide (40 mg/day) was associated and maintained during 5 and 3 months respectively. In the first patient, renal function stabilised within one month of starting leflunomide and polymerase chain reaction was negative for polyomavirus after 5 months. A repeated allograft biopsy 6 months later showed no evidence of polyomavirus nephropathy. In the second patient, polyomavirus was undetectable in blood and urine by polymerase chain reaction after 3 months of leflunomide treatment, with no evidence of polyomavirus infection in a repeated biopsy 6 months after beginning treatment.

BACKGROUND: The major causes of renal transplant loss are death and chronic allograft dysfunction (CAD). The aims of this study were to determine the incidence of CAD in our population and the relation between allograft survival and immunosuppressive regimens. METHODS: We studied retrospectively 473 patients who received deceased donor kidney transplants with at least 1 allograft biopsy between January 1990 and May 2007. Clinical data included age, gender, biopsy data, and immunosuppression before and after kidney biopsy. Mean age was 45.4 +/- 12.7 years including 65% males with a mean follow-up of 6.7 +/- 4.5 years. CAD was observed in 177 of 473 biopsies: 48 patients showed interstitial fibrosis (IF); 101 chronic rejection (CR); 16 transplant glomerulopathy (TG); and 12, CR and TG. Mean follow-up since the discovery of the histologic feature was 60.5 +/- 50.5 months for IF; 38.3 +/- 40.8 for CR, and 18.2 +/- 19.2 for TG. RESULTS: CAD, which was more common in younger patients (P = .03), correlated upon univariate and multivariate analysis with CKD stage 5d development (P < .001). Deposition of C4d in peritubular capillaries was more frequent among CAD patients (P = .004), an association with particular relevance to recipients with CR (P = .02) and TG (P < .001). When we analyzed CAD subpopulation, we observed a positive correlation between allograft survival and immunosuppression modification after biopsy. Substitution of sirolimus (40/177) was shown in univariate, multivariate and Cox regression analyses to be a renal protector (P < .002). Allograft survival was also correlated with initial mycophenolate mofetil versus azathioprine, (62/177) immunosuppression (P < .001). CONCLUSION: CAD, a frequent histologic feature, may benefit from sirolimus conversion.

Background Prospective testing for posttransplant circulating anti-HLA antibodies seems to be a critical noninvasive tool, but confirmatory data are lacking. Materials and Methods Over the last 3 years, peritubular capillary (PTC) C4d deposition was prospectively sought by an immunofluorescence technique applied to frozen tissue in biopsies obtained for allograft dysfunction. Screening for circulating anti-HLA class I/II alloantibodies (AlloAb) by the flow cytometric test was performed simultaneously. Results We evaluated 132 sets of biopsies and simultaneous serum samples. PTC C4d deposition was demonstrated in 15.9% (21/132) of biopsies. Circulating anti-HLA I/II AlloAb were detected in 25% (33/132) of serum samples. Employing receiver-operator characteristic (ROC) curves for all C4d-positive biopsies, screening for AlloAb showed a global specificity of 82% and sensitivity of 61.9%. When this analysis was restricted to biopsies obtained in the first month posttransplantation, the sensitivity increased to 81.8%, but the specificity decreased to 76.9%. After the first month posttransplantation, we observed sensitivity of 40.0% and a specificity of 86.4%. In the first month posttransplantation, all patients with a diagnosis of acute antibody-mediated rejection displayed circulating anti-HLA class I/II, but not always at the same time as the C4d-positive biopsy. Conclusions In the first month posttransplantation, prospective monitoring of anti-HLA antibodies may be useful. The high sensitivity allows the identification of patients at risk, affording an earlier diagnosis of antibody-mediated rejection. After the first month, the test can be used to evaluate allograft dysfunction episodes, since positivity is highly suggestive of an antibody-mediated process.

Cytomegalovirus (CMV) is the most common viral infection after transplantation. Valganciclovir (VGC) is established for prophylaxis and treatment of CMV infections, but leukopenia which appears in 10% to 13% (severe in 4.9%) is the principal side effect. We have recently noted an increased incidence of leukopenia and severe neutropenia among our renal transplant patients and thought to identify the associated factors. We conducted a retrospective analysis of all kidney transplantations performed between January 2005 and December 2006. All patients received mycophenolate mofetil (MMF), tacrolimus, and steroids. VGC was used for targeted prophylaxis and preemptive therapy of CMV infection, with doses adjusted to renal function. Of the 64 patients undergoing renal transplantation 13 (20.3%) developed leukopenia within 3 +/- 2 months after transplantation with severe neutropenia in 5 (7.8%). All patients were on MMF and VGC (VGC 605 +/- 296 mg/d). Leukopenia was significantly associated with simultaneous liver-kidney transplantation and with second kidney transplantations (P < .01). The incidence of leukopenia was higher among patients under VGC since day 1 of transplantation (P = .008) with maximal incidence observed among patients prescribed 900 mg/d as opposed to those on lower doses (P < .01). There was no increase in CMV infection among patients with a low dose of VGC. No patient developed clinical CMV disease. In conclusion, VGC prophylaxis was associated with an increased frequency of leukopenia on MMF-tacrolimus treated patients or regimens. Low-dose VGC for CMV prophylaxis appeared to be as effective as high-dose treatment, and associated less frequently with leukopenia and neutropenia.

Aim: To characterise clinically the patients with C4d in peritubular capillaries deposits (C4dPTCD) and/or circulating anti-HLA class I/II alloantibodies. To determine the correlation between positive C4dPTCD and circulating anti-HLA class I/II alloantibodies during episodes of graft dysfunction. Subjects and Methods: C4d staining was performed in biopsies with available frozen tissue obtained between January 2004 and December 2006. The study was prospective from March 2005, when a serum sample was obtained at the time of biopsy to detect circulating anti-HLA class I/II alloantibodies. Results: We studied 109 biopsies in 86 cadaver renal transplant patients. Sixteen of these (14.7%) presented diffuse positive C4dPTCD. There was a 13.5% rate of +C4dPTCD incidence within the first six months of transplantation and 16% after six months (p>0.05). Half of the +C4dPTCD in the first six months was associated with acute humoral rejection. After six months, the majority of +C4dPTCD (n=7/8) was present in biopsies with evidence of interstitial fibrosis/tubular atrophy and/or transplant glomerulopathy. The C4dPTCD was more frequent in patients with positive anti-HCV antibodies(p

Objective. The objective of this study was to evaluate the risk factors for delayed graft function (DGF) and their influence on renal graft outcome. Patients and Methods. We reviewed 1462 consecutive renal transplantation and identified 245 patients (17.1%) with delayed graft function and 1120 patients with immediate graft function. Forty-one cases were excluded because of a nonfunctioning graft as well as 26 other cases because of insufficient data. We compared the incidence, donor and recipient risk factors, and impact on graft outcomes, as well as patient and graft survival of delayed graft function. Results. Donor weight and age, recipient weight, age, length of dialysis, and cold ischemia time were significantly higher in the delayed graft function group. Higher rates of acute rejection and chronic graft dysfunction were observed in this group of patients; we also observed worse graft function and survival. Conclusions. Multiple risk factors are associated with delayed graft function, which contribute decisively to a worse outcome.

Proteinuria has been reported in several papers after conversion from calcineurin inhibitors to Sirolimus (SRL), but this complication has not been analyzed in randomized clinical trials using de novo SRL. It is not known whether de novo use of SRL is a risk factor for proteinuria. We analyzed a series of patients included in a big multicenter randomized trial (RMR trial) corresponding to all patients in Spain and Portugal with respect to this issue. We retrospectively evaluated 24-hour proteinuria in all the patients during the study period (5 years postransplant) for comparison between treatment arms group A, continuous cyclosporine (CyA) + SRL and group B SRL with CyA elimination at 3 months postransplant. The elimination of CyA after the third month was not followed by significant changes in proteinuria. Nevertheless, during the last year of follow-up (between 48 and 60 months postransplant) an impressive increase in proteinuria was observed in group A. This surprising finding seemed to be a consequence of a protocol amendment that recommended CyA elimination in patients of group A, due to poorer results in the intermediate analysis of the trial. This fact suggests that the hemodynamic changes induced by elimination of the vasoconstrictor CyA might be responsible for the proteinuria but only in the long term probably when significant pathological lesions are already present. This finding argues for earlier conversion.

Our purpose was to evaluate changes in cadaveric donor factors between 1993 and 2004 and their impact on the short- and long-term outcomes of renal transplants in a single center. PATIENTS AND METHODS: Cadaveric renal transplants performed in our unit between 1993 and 2004 were divided in two groups of identical length: A (n = 455; 1993-1998) and B (n = 465; 1999-2004). Major differences related to donor, graft, and recipient factors were analyzed between groups and correlated with main outcome parameters. Recipient age, gender, weight, etiology of end-stage renal disease, average length of dialysis, and cold ischemia were not different in the two periods. RESULTS: Grafts harvested in our hospital were more frequent in group A (92.3 vs 78.2%; P < .005). Traumatic causes of death were more frequent before 1999: 90.9 vs 70.9% (P < .001). Mean donor age was higher after 1999: 31.37 vs 35.94 years (P < .005). Female donors were more frequent in the second period: 20.5 vs 26.6% (P < .05). Mean donor weight was also higher: 52.36 vs 67.86 kg (P < .05). All of these differences were unfavourable characteristics regarding graft outcomes. Delayed graft function (A = 13%, B = 24.2%), acute rejection episodes (A = 41.2%, B = 28%), and chronic allograft dysfunction (A = 23.5%, B = 14.4%) were also significantly different between the two cohorts (P < .005). Graft function (serum creatinine at 1 and 2 years), patient and graft survivals, causes of graft loss, and of patient death were similar across time. CONCLUSION: The unfavorable tendency in the quality of cadaveric donors during the last 12 years had no negative impact on graft function and patient outcome.

INTRODUCTION: We characterized the alterations in ureteral biopsies from normally functioning kidney allografts to study risk factors. MATERIALS AND METHODS: We studied 55 ureteral fragments from kidney grafts obtained during cystoscopy for routine double-J stent extraction. We evaluated the type and severity of the lesions, the risk factors for their occurrence, and their relation to the evolution of the transplant, including the occurrence of renal rejection episodes or ureteral complications. RESULTS: Borderline or rejection lesions were detected in 21 of the 55 fragments. Rejection lesions were more common among biopsies performed in the first 80 days (54.6%) than during the 120 days afterward (15.4%, P = .043). Similarly, urothelium reactivity was detected in 71.4% and 30.7% of the biopsies performed up to and after 4 months, respectively (P = .008). Urothelial atrophy was detected in 20% of the fragments, the age of the donors being higher in these cases (P = .026). There was a trend to the association of borderline or rejection lesions in the ureteral biopsies and a history of an acute renal rejection episode (P = .053). There were no detectable relations between those findings and the evolution of the transplant. CONCLUSIONS: Thirty-eight percent of the biopsed ureters showed rejection or borderline lesions, these lesions were more common among biopsies done in the first months after transplantation. These findings are similar to the ones found in routine renal biopsies. We did not find any significant relation between the nature of the lesions encountered on the ureteral biopsies and the evolution of the transplant.

PURPOSE: To retrospectively review our experience with pediatric renal transplantation and to compare the results with the adult population. PATIENTS AND METHODS: Between January 1981 and August 2003, 74 renal transplants were performed in patients < or =18 years at the time of the transplant--the pediatric group versus 1153 patients in the adult group. We analyzed various risk factors for actuarial kidney graft and patient survivals using the Kaplan-Meier method. RESULTS: Median ages were 13.8 +/- 3.5 and 42.6 +/- 2.4 years, respectively. There was no statistically significant difference in the human leukocyte antigen matching or immunosuppression. There was, however, a younger donor age and shorter ischemia time in the pediatric group. Overall, kidney transplant survival rates for patients < or =18 years at 1, 2, 5, and 10 years were 94.4%, 91.3%, 70.6%, and 58.2%, respectively, with no significant difference for patients older than 18 (91.2%, 89.3%, 78.8%, 60.5%, P = .4325). There was a significantly decreased graft survival in the adult group at 10 years when the donor age was over 60 years and when the ischemia time was > or =20 hours. The incidence of delayed graft function and the creatinine levels of functioning grafts did not differ between the two groups. During the follow-up, acute rejections were more frequent in the younger group. Patient survival in the pediatric group at 1, 2, 5, and 10 years was 98.6%, 98.8%, 98.6%, and 90.3%, respectively, significantly lower in the adult group (95.3%, 94.0%, 87.9%, 76.8%, P < .02). CONCLUSIONS: Renal transplantation may be successfully performed in the pediatric patients with end-stage renal disease. Overall graft survival at 10 years did not differ significantly between the two groups. There is a higher incidence of acute rejections but longer patient survival in the pediatric population

PURPOSE: To describe our initial results using a calcineurin inhibitor-free immunosuppression protocol in renal transplants. PATIENTS AND METHODS: Between October 2001 and June 2003, 56 recipients of a renal allografts were started on an immunosuppression protocol without calcineurin inhibitors, consisting of basiliximab, sirolimus, mycophenolate mofetil, and steroids. We analyzed patient and graft survival, acute rejection episodes, and renal function. RESULTS: The mean follow-up was 19.6 months. Actuarial patient survival at 1 and 2 years was 98.1% and 95.3%, respectively. Actuarial graft survival at 1 and 2 years was 92.9% and 87.6%, respectively. Acute rejection occurred in 27.8% of the patients, usually Banff 1 (73.3%). There was stable renal function with mean serum creatinine of 1.3, 1.4, 1.3, and 1.3 mg/dL at 1, 6, 12, and 24 months after transplant. CONCLUSIONS: The use of immunosuppression free of calcineurin inhibitors is effective and safe. Further follow-up is needed to evaluate the impact on long-term results.

A clinic case of simultaneous pancreas/kidney transplantation on a type 1 diabetic patient is described. A six years follow-up was made with both organs functionating and a good quality of live.Then the authors make a review of the available surgical techniques, indications and complications of this form of treatment. A comparison between the Portuguese and the International experience was discussed.

BACKGROUND: Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. METHODS: We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. RESULTS: The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P

Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen improved renal function and blood pressure. We report the protocol-mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL-CsA-ST were randomized at 3 months after transplantation to remain on SRL-CsA-ST, or to have CsA withdrawn (SRL-ST group). Protocol-mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL-ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL-ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL-ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA-withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL-CsA-ST regimen resulted in improved renal histology and function.

OBJECTIVES: The aim of this study was to study the incidence and causes of acute rejection (AR) on cadaveric renal transplants under cyclosporine A-based immunosuppression, and to investigate the AR effect on the ocurrence of chronic dysfunction (CD) and on the outcome of transplantation. METHODS: We analyzed 794 renal transplants from cadaver donor between December, 1985 and December, 1999. We examined the major donor, recipient and graft-related factors and their influence in graft outcome. The diagnosis of AR was in 65% based in clinical and laboratorial findings: fever, decrease of diuresis, graft pain and/or strained and a serum creatinine increase of at least 0,4 mg/dl, and in 35% the diagnosis of AR was biopsy-proven. Statistics included univariate and multivariate analysis. Graft and patient survival rates were calculated by Kaplan-Meier method (with log-rank test). RESULTS: In the 794 renal transplants included in the study, 498 (63%) didn't have AR and 296 (37%) had at least one episode of AR. This overall incidence of AR of 37% is decreasing and in the last two years, 1998 and 1999 remained in 24% and 25%, respectively. The AR was associated with cadaver donor-related factors [ non traumatic cause of death (p=0,018), perfusion with Eurocollins solution (p=0,008) and cold ischemia time > 24 hours (p= 0,032)] and with recipient-related factors [age < 45 years (p=0,000) and immunosuppression with antithymocyte globulin (ATG) + azathioprine (Aza) + prednisone (Pred) + cyclosporine A (CsA) (p=0,006)]. Concerning graft-related factors acute tubular necrosis (ATN) was related with higher incidence of AR (35% of AR without ATN versus 48% of AR with ATN, p= 0,008) and this, was responsible by a significative increase of chronic dysfunction (CD) (p= 0,000) and by the worst graft function at the end of the first year (p= 0,000). Our results also showed that CD as a cause of graft loss increased substantially (23% vs 49%) in the presence of AR. The 1, 3, 5, 10 and 15-year graft survival in the patients with AR were, 94%, 85%, 74%, 50% and 38%, respectively, and in the patients without AR, 97%, 91%, 87%, 77% and 67%, respectively. These results were statistically significant ( p= 0,000). The AR didn't influence patient survival (p= 0,814). CONCLUSIONS: Our overall incidence of AR (37%) is decreasing reaching in the last year 25%. The AR incidence increased significantly with grafts from cadaver donors with non-traumatic cause of death, preserved with Eurocollins solution, with cold ischemia times > 24 hours and in recipients with age < 45 years and with ATG+Aza+Pred+CsA immunosuppression regimen. ATN increased the AR incidence and this was associated with a higher ocurrence of CD and a worst graft function at 1 year. The graft lost by CD duplicate in the patients with AR. Graft survival was significantly worse in the patients with AR. The AR did not adversely affect patient survival.