Multinational case-control study of risk factors for the development of late invasive pulmonary aspergillosis following kidney transplantation.

OBJECTIVES: To assess the risk factors for development of late-onset invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT). METHODS: We performed a multinational case-control study that retrospectively recruited 112 KT recipients diagnosed with IPA between 2000 and 2013. Controls were matched (1:1 ratio) by centre and date of transplantation. Immunosuppression-related events (IREs) included the occurrence of non-ventilator-associated pneumonia, tuberculosis, cytomegalovirus disease, and/or de novo malignancy. RESULTS: We identified 61 cases of late (>180 days after transplantation) IPA from 24 participating centres (accounting for 54.5% (61/112) of all cases included in the overall study). Most diagnoses (54.1% (33/61)) were established within the first 36 post-transplant months, although five cases occurred more than 10 years after transplantation. Overall mortality among cases was 47.5% (29/61). Compared with controls, cases were significantly older (p 0.010) and more likely to have pre-transplant chronic obstructive pulmonary disease (p 0.001) and a diagnosis of bloodstream infection (p 0.016) and IRE (p <0.001) within the 6 months prior to the onset of late IPA. After multivariate adjustment, previous occurrence of IRE (OR 19.26; 95% CI 2.07-179.46; p 0.009) was identified as an independent risk factor for late IPA. CONCLUSION: More than half of IPA cases after KT occur beyond the sixth month, with some of them presenting very late. Late IPA entails a poor prognosis. We identified some risk factors that could help the clinician to delimit the subgroup of KT recipients at the highest risk for late IPA.

Surveillance Registry of Sirolimus Use in Recipients of Kidney Allografts From Expanded Criteria Donors.

BACKGROUND: The use of expanded criteria donor (ECD) kidneys has increased the overall availability of renal transplants. This study assessed the use of sirolimus in patients receiving Argentina-ECD kidneys. METHODS: This observational, open-label, 1-arm, prospective, longitudinal pilot study was conducted at 8 transplant centers in Argentina. Adults receiving kidney transplants (without pancreas) from ECDs were eligible if they were converted to sirolimus 1 to 36 months' posttransplantation, with sirolimus becoming base therapy within 1 month after conversion. Patients were followed up for 1 year. Outcomes included reasons for conversion, acute rejection, patient and graft survival, graft status, and safety. RESULTS: The intention-to-treat population included 52 patients (mean age, 48.7 years). Calcineurin inhibitor nephropathy (40%) and chronic allograft nephropathy (25%) were the most frequent reasons for conversion. Two acute rejections occurred during follow-up, but no patients experienced graft loss. One patient died during follow-up, and 3 patients died within 1 month of the last sirolimus dose. Levels of serum creatinine and creatinine clearance remained stable from baseline to week 52/53. Mean proteinuria measured in a subset of patients was 0.2 ± 0.2 g/24 hours before conversion and increased to 0.6 ± 1.2 g/24 hours at week 24/25 and 0.5 ± 0.6 g/24 hours at week 52/53. Adverse events were consistent with those in previous conversion trials; the most common were infections and infestations (54%). CONCLUSIONS: This pilot study illustrates the potential benefits of sirolimus in recipients of ECD kidneys in Argentina. Larger, randomized controlled trials are needed to confirm these findings and to clarify the long-term benefits of sirolimus in this patient population.

Clinical Presentation and Determinants of Mortality of Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: A Multinational Cohort Study.

The prognostic factors and optimal therapy for invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT) remain poorly studied. We included in this multinational retrospective study 112 recipients diagnosed with probable (75.0% of cases) or proven (25.0%) IPA between 2000 and 2013. The median interval from transplantation to diagnosis was 230 days. Cough, fever, and expectoration were the most common symptoms at presentation. Bilateral pulmonary involvement was observed in 63.6% of cases. Positivity rates for the galactomannan assay in serum and bronchoalveolar lavage samples were 61.3% and 57.1%, respectively. Aspergillus fumigatus was the most commonly identified species. Six- and 12-week survival rates were 68.8% and 60.7%, respectively, and 22.1% of survivors experienced graft loss. Occurrence of IPA within the first 6 months (hazard ratio [HR]: 2.29; p-value = 0.027) and bilateral involvement at diagnosis (HR: 3.00; p-value = 0.017) were independent predictors for 6-week all-cause mortality, whereas the initial use of a voriconazole-based regimen showed a protective effect (HR: 0.34; p-value = 0.007). The administration of antifungal combination therapy had no apparent impact on outcome. In conclusion, IPA entails a dismal prognosis among KT recipients. Maintaining a low clinical suspicion threshold is key to achieve a prompt diagnosis and to initiate voriconazole therapy.

Risk Factors Associated With Early Invasive Pulmonary Aspergillosis in Kidney Transplant Recipients: Results From a Multinational Matched Case-Control Study.

Risk factors for invasive pulmonary aspergillosis (IPA) after kidney transplantation have been poorly explored. We performed a multinational case-control study that included 51 kidney transplant (KT) recipients diagnosed with early (first 180 posttransplant days) IPA at 19 institutions between 2000 and 2013. Control recipients were matched (1:1 ratio) by center and date of transplantation. Overall mortality among cases was 60.8%, and 25.0% of living recipients experienced graft loss. Pretransplant diagnosis of chronic pulmonary obstructive disease (COPD; odds ratio [OR]: 9.96; 95% confidence interval [CI]: 1.09-90.58; p = 0.041) and delayed graft function (OR: 3.40; 95% CI: 1.08-10.73; p = 0.037) were identified as independent risk factors for IPA among those variables already available in the immediate peritransplant period. The development of bloodstream infection (OR: 18.76; 95% CI: 1.04-339.37; p = 0.047) and acute graft rejection (OR: 40.73, 95% CI: 3.63-456.98; p = 0.003) within the 3 mo prior to the diagnosis of IPA acted as risk factors during the subsequent period. In conclusion, pretransplant COPD, impaired graft function and the occurrence of serious posttransplant infections may be useful to identify KT recipients at the highest risk of early IPA. Future studies should explore the potential benefit of antimold prophylaxis in this group.

Variances in the Use of Everolimus in Kidney Transplantation: A 2-Year Registry of Everyday Practice.

BACKGROUND: Everolimus (EVL)-based immunosuppressive strategies may permit the reduction of calcineurin inhibitors (CNI) and their side effects, while offering a safe and efficient treatment. Our aim was to describe our experience with EVL in everyday practice and provide information for its optimal utilization. METHODS: Prospective, multicenter study of 181 kidney transplant recipients treated with EVL as part of their immunosuppressive regimen, with a follow-up of 24 months. We studied demographic data, transplant characteristics, clinical information, drugs used, serum creatinine, estimated glomerular filtration rate (eGFR), rejection episodes, and adverse events. RESULTS: In total, 181 renal transplant recipients were included. Of these, 30 (16.6%) received EVL de novo and 151 (83.4%) were converted; median time from transplantation to conversion was 10 (range, 1-312) months. Main reasons for conversion were prevention of interstitial fibrosis and tubular atrophy (23.9%), intolerance to immunosuppressants (11.1%), neoplasia (13.9%), nephrotoxicity (8.9%), and cytomegalovirus infections (8.3%). The eGFR values at baseline, months 12, and 24 were 46.4 ± 27.4 mL/min, 54.8 ± 22.9 mL/min, and 55.9 ± 26.5 ml/min, respectively. Two of 181 (1.1%) patients died, 5 of 181 (2.8%) lost their grafts, 12 of 181 (6.6%) had an episode of acute rejection, 13 of 181 (7.2%) had ≥1 serious event and infection, and 85 of 181 (49.9%) had ≥1 nonserious adverse event or infection. Multivariate analysis showed that increased eGFR at month 24 was associated with lower donor age, shorter time from transplant to EVL introduction, and a baseline eGFR ≥40 mL/min. CONCLUSION: Through different strategies among centers, the inclusion of EVL improved renal function during the first 12 months.

Short- and long-term outcomes of every graft recovered during a multi-organ procurement procedure including the intestine.

BACKGROUND: The development of intestinal transplant (Tx) programs introduces thymoglobulin donor treatment as well as an almost complete warm dissection of the abdominal organs to allocate them to different recipients. Our aim is to assess the reproducibility and feasibility of the surgical technique of multi-organ procurement with the use of thymoglobulin donor pre-treatment and report the short- and long-term outcomes of every graft harvested as part of multi-organ procurement (MTOp), including the intestine. METHODS: Data were collected of all organs harvested from MTOp, including the intestines allocated to our center from March 2006 to July 2011. Data from 92 recipients and 116 organs procured from 29 MTOp were analyzed. Twelve hearts, 2 lungs, and 1 cardio-pulmonary block were transplanted; primary graft dysfunction developed in 4 of the 12 hearts and in the cardio-pulmonary block. RESULTS: The survival rate was 75% and 100% for hearts and lungs, respectively. Nineteen livers, 9 kidney-pancreas, 19 kidneys, and 29 intestines were transplanted. Delayed graft function (DGF) of the pancreas developed in 3 of 9 kidney-pancreas, and the other 3 exhibited DGF of the kidney; 4 of 19 Tx kidneys had DGF. The survival was 84%, 78%, 95%, and 65.5% for livers, kidney-pancreas, kidneys, and intestines, respectively. CONCLUSIONS: Organs procured during MTOp including the intestine can be safely used, increasing organ availability and transplant applicability without compromising allocation, quality, and long-term results of the non-intestinal-procured organs.

[Idiophatic inflammatory myophaties: its asociation with liver disorders]. / Miopatías inflamatorias idiopática: su asociación a hepatopatías.

UNLABELLED: The aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) are sensitive indicators of liver damage. While the TSGOT is also found in other organs, the SGPT is considered an enzyme specific liver. However, some authors state that the TGP can rise also in cases of muscle injury. Furthermore, there are reports in the literature suggesting the association of idiopathic inflammatory myopathies (IIM) with viral hepatitis. OBJECTIVE: To determine the frequency of abnormal liver function tests in patients with idiopathic inflammatory myopathies, evaluate possible associationsto liver diseases, determine its relationship with elevation of muscle enzymes and whether these patients have particular clinical and / or serological characteristics. MATERIAL AND METHODS: Consecutive patients older than 16 years diagnosed with DM / PM according to Bohan and Peter criteria during 1999-2000 were included. Patients with other connective tissue disease (CTD) were excluded. Demographic data were recorded, characteristics of the disease, laboratory data and elevated liver enzymes and muscle during the course of the disease. Serologic tests were performed for viral hepatitis B and C and confirmatory tests (HBV-DNA and HCV-RNA by PCR). Autoantibodies were determined: ANA (antinuclear antibody) by Hep II, ASMA (anti smooth muscle antibody), AMA (anti-mitochondrial antibodies) and LKM (Liver Kidney Microsomal) by mouse wound, MSA (myositis-specific antibodies) by ELISA. Patients who had abnormal liver tests underwent hepatic ultrasonography. For statistical analysis, descriptive statistics, categorical variables were compared by Fisher's exact test. RESULTS: We included 27 patients, of whom 22 had sufficient data for analysis. Mean age 47.95 years ± 16, 18 female (81.8%) and mean disease duration 8.09 ± 5.6 years. With regard to liver enzymes, 14/22 patients (63.3%) had elevated SGPT and 11/22 (50%) elevated SGOT, 10 of these patients also had elevated SGPT concomitantly. In the 10/15 (66.7%) abdominal ultrasonography showed abnormalities, 8 patients had liver hyperechogenicity, 4 cholelithiasis and 1 patient hepatomegaly. No patient bearing of HBV or HCV. The 8 patients with liver hyperechogenicity matched the 8 patients with isolated elevation of SGPT/SGOT. As for the 10 patients who had both elevated liver enzymes (SGPT and SGOT), only one case could be explained by liver disease (patient ASMA +). However in the 15 cases studied, elevations of SGPT and / or SGOT coincided with outbreaks of myositis,findingconcomitant apparent liver disease in only 9 of them. CONCLUSIONS: In this study, elevated transaminases, including the TGP, was observed concomitantly with the activity of myositis. Approximately half of these cases could not be associated with coexisting liver disease, which could be attributed to injury to muscle secondary to inflammatory myopathy.

Results of the conversion to everolimus in renal transplant recipients with posttransplantation malignancies.

Management of posttransplantation malignancies should include control of the neoplasia and preservation of renal function. Conversion to everolimus (EVL) would potentially have both effects. Twenty-one patients were converted to EVL due to posttransplantation neoplasms. We have presented herein descriptive data and postconversion (PC) outcomes among subjects of mean age 53.6 +/- 10.1 years (range, 36-69), 57.1% were males, undergoing conversion at 108.2 +/- 74.7 (range, 5-316) months after transplantation. All patients received standard immunosuppressive therapy and 9.5% had been induced with thymoglobulin. Malignant neoplasms were as follows: skin (n = 7), gynecological (n = 3), gastrointestinal (n = 3), PTLD (n = 2), renal (n = 2), CNS (n = 1), seminoma (n = 1), Kaposi's sarcoma (n = 1), and prostate cancer (n = 1). PC to EVL, calcineurin inhibitors (CNIs) were discontinued in 18 of 19 patients, mycophenolate in 9/12, and azathioprine in 5/7; all patients continued to receive steroids. In 16 patients (79%) tumors were removed. Chemotherapy was performed in 2 patients with PTLD and radiotherapy was performed in 1 patient with prostate cancer. Mean follow-up was 505 days (range, 59-1151); baseline glomerular filtration rate (GFR) was 53.5 +/- 21.6 mL/min versus 48.5 +/- 25.7 mL/min (P = not significant [NS]) at the last control. One patient experienced graft loss at day 744 after conversion due to chronic rejection. Adverse events were observed in 57% of patients and 28% displayed infections; no patient discontinued EVL. There were 2 deaths: 1 due to an infection and the other due to postsurgical complication. No deaths due to cancer progression were observed. The results observed in this series suggested that conversion to EVL for a posttransplantation neoplasm is a valid therapeutic alternative to preserve graft function and control disease progression.

National survey of anemia prevalence after kidney transplantation in Argentina.

Anemia is prevalent in kidney transplant recipients and likely contributes to morbidity and mortality. The definition of anemia as established by the World Health Organization and subsequently adopted by the American Society of Transplantation is a hemoglobin concentration of 12 g/dL or less in women and 13 g/dL or less in men. Using this definition, the prevalence of anemia is nearly 30%. The National Survey of Post Transplant Anemia (PTA) in kidney transplant recipients in Argentina was conducted to evaluate the incidence of PTA at 1 year and its relationship to variables that influence transplantation outcome. At 1 year posttransplantation, mean (SD) hemoglobin concentration was 12.43 (1.77) g/dL (n = 379), hematocrit concentration was 38.26% (5.59%) (n = 379), serum creatinine concentration was 1.51 (0.72) mg/dL (n = 380), and creatinine clearance was 60.8 (22.47) mL/min (n = 334). The prevalence of PTA in Argentina at 1 year posttransplantation was 42.25%. At univariate analysis, female sex, immunosuppression regimen (mycophenolate mofetil plus mammalian target of rapamycin), and pediatric age group were associated with anemia. At multivariate analysis, only renal function and pediatric age group were associated with anemia. The mean hemoglobin level at year of transplant was 12.43 g/dL +/-1.77 and the prevalence of PTA in Argentina at year of transplant is 42.25%. Results of our survey show a correlation between Hb levels and graft function and pediatric recipient.

Stent-graft deployment for aortic rupture after stenting for aortic recoarctation.

We present the case of a 62-year-old woman who presented with recoarctation and then experienced rupture of the aorta and severe clinical deterioration after a stent was deployed. She was treated immediately by intrastent deployment of a stent-graft, which resolved the extremely serious situation.

Rapamycin at six years can exhibit normal renal function without proteinuria or neoplasia after renal transplantation. A single-center experience.

Currently, long-term experience with Rapamune (RAPA) after renal transplantation is scarce. We present our experience with RAPA in patients who were included in clinical trials. Between 1996 and 1999, 27 renal transplant patients received RAPA alone or in combination with cyclosporine (CyA). We study 15 of them (9 males, 6 females; mean age 36 years) who are currently functioning with a mean follow-up of 6 years (range, 5.2-8 years). The presence of delayed graft function was 40% and acute rejection 26.6%, all of them controlled with steroids. Notably, no patients experienced an acute rejection episode after the first year. Among 15 patients, 12 received steroids, RAPA and CyA; and 3 received steroids, RAPA, azathioprine (AZA) or mycophenolate mofetil (MMF) for immunosuppression. At the end of follow-up, the situation was the opposite: 12 patients received steroids (2.5-5 mg/d) and RAPA associated with or without AZA/MMF, and 3 were maintained with steroids, RAPA and CyA. Renal function was excellent in the entire group: mean SCr 1.1 mg/dL (range, 0.7-1.8) with mean RAPA blood levels (HPLC) of 11 ng/dL (range 8-16). Hyperlipidemia was universal with all patients (100%) receiving statins maintaining acceptable levels of cholesterol (mean 209 +/- 28 mg/dL) and tryglycerides (mean 154 +/- 76 mg/dL). Arterial hypertension present in 12 of 15 (80%) patients was controlled with a mean of 1.5 drugs. Notably, no patient presented with proteinuria, neoplasia, posttransplant diabetes, or cardiovascular events. In conclusion, these single-center results suggest that Rapamune may be useful in the long-run after renal transplantation. The presence of normal renal function and the absence of proteinuria and neoplasia in these renal transplant patients may have important clinical implications.

Ten years of treatment with tacrolimus is related to an excellent renal function, allowing monotherapy in a large proportion of cases: unicentric results of the tacrolimus versus cyclosporine A European Multicentric Study in kidney transplant patients.

Tacrolimus (Tac) is the most frequently used base inmunosuppressant for transplantation in Spain and the United States. However, long-term data on its use in renal transplant patients are lacking. The aim of this study was to analyze the 10-year outcome of patients from our institution treated with Tac or cyclosporine (CsA) who were included in the European Multicenter Study of kidney transplantation (1993 to 1994). This trial compared the efficacy and safety of steroids + Tac + azathioprine versus steroids + CsA + azathioprine at 1 year, showing a significantly lower acute rejection rate in Tac patients, with no differences in graft or patient survival. In our long-term analysis, we included patients with a functioning graft after the first year: 15 patients on Tac and 11 on CsA. In the "intent-to-treat" (ITT) analysis, patient survival was 14/15 (93%) versus 9/11 (82%) and death noncensored graft survival was 10/15 (67%) versus 8/11 (73%) in Tac and CsA, respectively. Analyzing patients "into treatment" (TT), death/noncensored graft survival was 11/16 (69%) versus 6/9 (67%), respectively. Serum creatinine tended to be lower in Tac group (ITT 1.26 +/- 0.42 vs 1.63 +/- 1.16 mg/dL, P = NS; TT 1.23 +/- 0.4 vs 1.86 +/- 1.28 mg/dL, P = NS). However, in the TT analysis, Tac patients exhibited a significantly better creatinine clearance (89.3 +/- 40 vs 46.8 +/- 21 mL/min, P = .037) and lower systolic blood pressure (125 +/- 5 vs 140 +/- 12 mm Hg, P = .007) at 10 years. No other significant differences were observed in blood pressure, lipid profile, or glucose metabolism. Outstandingly, Tac monotherapy was the most frequently used regimen after 10 years: ITT 6/9 (67%) versus 1/8 (12.5%), P = .05, TT 7/10 (70%) versus 0/6 (0%), P = .011. Patients under Tac monotherapy exhibited an excellent graft function (serum creatinine 1.08 +/- 0.14 mg/dL) and negative proteinuria, with Tac trough levels of 7.9 +/- 1.3 ng/mL. In summary, our results suggest that Tac-based immunosuppression provides an excellent kidney function 10 years after transplantation and allows monotherapy in a high percentage of kidney transplant patients.

Systemic lupus erythematosus: mortality and survival in Argentina. A multicenter study.

OBJECTIVE: To analyze the factors associated with mortality, survival and causes of death in patients with systemic lupus erythematosus (SLE) in Argentina. PATIENTS AND METHOD: A series of 366 patients with SLE (45 men and 321 women), mean age 29 y (range 11-70 y) and mean disease duration 6 y, was evaluated from 1990 to 1998. A total of 57 clinical, serological and therapeutic variables were studied. RESULTS: Five- and 10-year survival was 91% and 85% respectively. Forty four patients died (12%): 54% due to sepsis and 32% due to active SLE. Mortality risk factors included heart involvement CRR 3.82), hyperlipidemia (RR 2.72), renal damage (RR 2. 62), infections (RR 2.44), lung disease (RR 2.20) and myositis (RR 2. 07). High-dose prednisone (RR 3.4) or cyclophosphamide (RR 9.19) treatments increased the risk of sepsis (P=0.003) as a cause of death. However, corticosteroids, antimalarial agents and accumulated cyclophosphamide doses proved to be protective factors in overall mortality figures (RR <1). CONCLUSIONS: The main risk factors of death in SLE were heart involvement, hyperlipidemia and renal damage. Treatment with steroids, antimalarial agents and cyclophosphamide improved survival. High-dose corticosteroids and cyclophosphamide were associated with sepsis as a cause of death.

Effect of oral L-carnitine on serum myoglobin in hemodialysis patients.

Oral L-carnitine has been reported to lower the elevated serum myoglobin of renal failure in chronic peritoneal dialysis patients, and intravenous L-carnitine can improve muscle fatigue and cramps in chronic hemodialysis patients. In this study oral L-carnitine, 1.98 g/day, was administered to 6 chronic hemodialysis patients for 8 weeks. Serum levels of myoglobin, creatine kinase, and aldolase, as well as skeletal muscle symptoms (cramps during dialysis, fatigue, and weakness) were monitored biweekly for 12 weeks. Mean baseline serum myoglobin level was 337 +/- 34 ng/mL. By 6 and 8 weeks mean serum myoglobin was 234 +/- 39 and 233 +/- 40 ng/mL, significantly lower by the Friedman test (p < 0.05). Four weeks after carnitine was discontinued, mean serum myoglobin had risen to 320 +/- 118 ng/mL. Serum creatine kinase and aldolase levels were normal throughout the study. All 6 patients noted improvement in muscular symptoms, with maximal effect at 8 weeks, although 2 patients did not improve until 2 to 4 weeks after carnitine was stopped. We conclude that oral L-carnitine may lower serum myoglobin and improve muscle cramps and weakness in hemodialysis patients. The maximal effect of carnitine on myoglobin occurs 2 weeks before the maximal improvement in muscular symptoms.

[Neonatal herpetic encephalitis. Current concepts concerning a case]. / Encefalitis herpética neonatal. Conceptos actuales a propósito de un caso.

We describe a newborn patient with herpes simplex infection localized to the central nervous system. The diagnosis was suspected on clinical grounds and it was corroborated by tissue culture isolation of the virus and by herpes simplex glycoprotein B DNA detection by PCR in cerebrospinal fluid. We describe the clinical manifestations of this patient and we present some considerations regarding pathogenesis, diagnosis, prognosis and treatment of this viral infection in the newborn period.