Triple Regimen with Rituximab, Plasmapheresis and Intravenous Immunoglobulin in the Treatment of Dialysis Dependent Acute Humoral-Mediated Rejection in Kidney Grafts

Introduction: The clinical importance of humoral-mediated acute rejection has been progressively recognised. Early recognition and treatment with plasmapheresis and intravenous immunoglobulin have recently improved short term prognosis. Case report: In this report we describe the clinical features of three 2nd transplant patients developing severe acute humoral rejection during the first week post-transplant while on anti-thymocyte globulin therapy. Treatment with plasmapheresis/ intravenous immunoglobulin/rituximab resulted in rapid reversal of oliguria,and recovery of renal function within the 1st week of treatment in 2/3 patients. Diagnosis was confirmed by graft biopsies revealing peritubular neutrophiles and C4d deposits. Sequential graft biopsies in all three patients revealed complete histological recovery within two weeks. One patient never recovered renal function, and one patient lost his graft at three months following hemorrhagic shock. After 2 years follow up, the remaining patient maintains a serum creatinine of 1.1mg/dl. Conclusion: The regimen using plasmapheresis plus intravenous immunoglobulin and rituximab was effective in rapidly reversing severe acute humoral rejection.

Peritubular Capillaries C4d Deposits in Renal Allograft Biopsies and Anti HLA I/II Alloantibodies Screening. Incidence and Clinical Importance

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<0.0001), a previous renal transplant (p=0.007), and with a panel reactivity antibody (PRA) ≥ 50%(p=0.0098). The anti-HCV+ patients had longer time on dialysis (p=0.0019) and higher PRA(p=0.005). Circulating anti-HLA I/II alloantibodies were screened in 46 serum samples. They were positive in 10.9% of samples, all obtained after six months post transplant. Circulating alloantibodies were absent in 92.5% of the C4d negative biopsies. Conclusion: We found an association between the presence of C4dPTCD and 2nd transplant recipients,higher PRA and the presence of anti-HCV antibodies. The presence of HCV antibodies is not a risk factor for C4dPTCD per se, but appears to reflect longer time on dialysis and presensitisation. In renal dysfunction a negative alloantibody screening is associated with a reduced risk of C4dPTCD (<10%).

Sirolimus-Induced Drug Fever in a Renal Transplant Patient: a Case Report

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.

Renal Transplantation in HIV-Infected Patients: The First Portuguese Review

INTRODUCTION: With the introduction of combination antiretroviral therapy (cART), prognosis of human immunodeficiency virus (HIV) infection has been improved and kidney transplantation (KT) in HIV-positive patients became possible. METHODS: We reviewed the demographic, clinical, laboratory, and therapeutic data of all the HIV-infected patients who underwent KT between 2009 (first KT in Portugal in a HIV-infected patient) and May 2014. Case accrual was through all Portuguese KT centers where a KT in an HIV-infected patient was performed. Patients were transplanted following the American and Spanish guideline recommendations that included maintenance on cART, undetectable plasma HIV RNA copies, and absolute CD4 counts of ≥ 200 cells/μL in the last 6 months. RESULTS: Fourteen KT were performed on men and 3 on women. The mean age of patients at the time of transplantation was 49.9 ± 11.7 years. HIV status was known for 12 ± 5 years. Eight patients had AIDS in the past and all patients received grafts from deceased donors. Twelve patients (64.7%) underwent induction therapy with basiliximab and 2 patients experienced early graft loss. In 2 patients, humoral rejection was diagnosed and in 3 patients, cellular rejection. Two patients died and an additional patient had early graft loss. CONCLUSION: KT is a possible, but challenging, renal replacement therapy in selected HIV-positive patients. Even in those with AIDS criteria in the past, when the disease is controlled, and after the reconstitution of the immune system with cART, KT can be performed. Nevertheless, the risk-benefit ratio for each patient needs to be taken in consideration.

ABO-Incompatible Liver Transplantation in Acute Liver Failure: A Single Portuguese Center Study

INTRODUCTION: ABO-incompatible liver transplantation (ABOi LT) is considered to be a rescue option in emergency transplantation. Herein, we have reported our experience with ABOi LT including long-term survival and major complications in these situations. PATIENT AND METHODS: ABOi LT was performed in cases of severe hepatic failure with imminent death. The standard immunosuppression consisted of basiliximab, corticosteroids, tacrolimus, and mycophenolate mofetil. Pretransplantation patients with anti-ABO titers above 16 underwent plasmapheresis. If the titer was above 128, intravenous immunoglobulin (IVIG) was added at the end of plasmapheresis. The therapeutic approach was based on the clinical situation, hepatic function, and titer evolution. A rapid increase in titer required five consecutive plasmapheresis sessions followed by administration of IVIG, and at the end of the fifth session, rituximab. RESULTS: From January 2009 to July 2012, 10 patients, including 4 men and 6 women of mean age 47.8 years (range, 29 to 64 years), underwent ABOi LT. At a mean follow-up of 19.6 months (range, 2 days to 39 months), 5 patients are alive including 4 with their original grafts. One patient was retransplanted at 9 months. Major complications were infections, which were responsible for 3 deaths due to multiorgan septic failure (2 during the first month); rejection episodes (4 biopsy-proven of humoral rejections in 3 patients and 1 cellular rejection) and biliary. CONCLUSION: The use of ABOi LT as a life-saving procedure is justifiable in emergencies when no other donor is available. With careful recipient selection close monitoring of hemagglutinins and specific immunosuppression we have obtained acceptable outcomes.

Acute Otitis Media a Reliable Warning Sign for Primary Immunodeficiencies?- A Critical Appraisal

Acute otitis media (AOM) is the most common infection in childhood, resulting from both anatomic and immunologic specificities of this age group. Recurrent AOM has been defined as one of the warning signs for primary immunodeficiencies (PID), In this study we evaluated the strength of recurrent AOM as clinical predictor of PID. Methods: Retrospective study (August 2010 - December 2013) which included all patients referred to PID appointment because of recurrent AOM (= 8 AOM episodes/year). Syndromic patients or those presenting with another warning sign for PID were excluded. Clinical, demographic and laboratory results were analized and statistical analysis was made using SPSS 20. Results: Seventy-five patients were included (median age 37,8 months; 62,7% male gender), corresponding to 15% of all first appointments. Other comorbidities were present in 20% of the patients and 17% had ORL surgery prior to PID referral. In most patients, the immunologic screening consisted on the evaluation of humoral function, but in selected cases other studies were performed (namely complement and lymphocyte immunophenotyping). A PID was identified in 12 children (16,0%) and the majority of these patients had other distinctive feature (personal or familiar antecedent of infection or auto-immunity, 66,7%, p<0,05). Nine children (12,0%) underwent prophylactic cotrimoxazole. The average length of follow-up was 11,2 months. Conclusion: Despite being a very frequent cause of immunologic screening, in this study recurrent AOM was not found to be a good predictor of underlying PID, unless the patients presents other significant personal or family history.

The Prognostic Impact of Renal Failure in Patients with ST-Segment Elevation Acute Myocardial Infarction

INTRODUCTION: Renal insufficiency (RI) is associated with higher morbidity and mortality in patients (P) with coronary artery disease and in P submitted to angioplasty. In ST-segment elevation acute myocardial infarction (STEAMI), this impact has not been well demonstrated. AIM: To evaluate the impact of RI in P with STEAMI. METHODS: We evaluated 160 P admitted with STEAMI, mean age of 62+/-14 years, 76% male. We determined creatinine levels on admission. RI was defined as a level >1.5 mg/dl. Analysis of clinical, electrocardiographic and laboratory variables was performed, in relation to the endpoint defined as the occurrence of death at 30-day follow-up. RESULTS: There were 16 deaths (10%) at 30-day follow-up. P with RI (n=21) were older (68+/-11 vs 61+/-14 years, p<0.001), more often had diabetes (57 vs 24 %, p=0.004) and presented more often with Killip class > or =2 (57 vs 12%, p<0.001). The use of statins (62 vs 83%, p=0.05) and beta-blockers (24 vs 65%, p<0.001) was lower in P with RI. Mortality was higher in RI P (62 vs 2%, p<0.001). The univariate predictors of death were age > or =75 years, diabetes, Killip class > or =2 on admission, RI, non-use of statins and beta-blockers and use of diuretics. In multivariate analysis, independent predictors of death at 30 days were RI (HR 29.6, 95% CI 6.3-139.9, p<0.001) and non-use of beta-blockers (HR 0.13, 95% CI 0.02-1.01, p=0.01). CONCLUSION: In P admitted for STEAMI, the presence of RI was an independent predictor of death at 30 days whereas the usage of beta-blockers was protective.

Candidemia in Acute Leukemia Patients

Fungal infections are an important cause of morbidity and mortality in patients with acute leukemia (AL). Candidemia, once rare, is now a common nosocomial infection because of the intensity of chemotherapy, prolonged neutropenia, administration of broad-spectrum antibiotics and use of central venous catheters (CVC). We retrospectively identified patients treated for AL from 6/86 to 6/95 who also had candidemia. We describe 28 patients (incidence 6.3%) with a median age of 39 years, 24 of whom were on remission induction and 4 on postremission chemotherapy. All patients had CVC and empiric antimicrobial therapy, 4 had been given prophylactic antifungal drugs, and 2 had parenteral nutrition. Neutropenia was profound (median leukocyte nadir 200/microliters, median duration 19 days). Candida was isolated in blood cultures 10 days (median) after the start of neutropenia. The clinical presentation included fever (100%), respiratory symptoms (71.4%), skin lesions (39.2%) and septic shock (17.8%). Amphotericin B was given to 17 patients and liposomal amphotericin to 5 patients. Infection resolved in 18 patients (64.2%). 10 of whom were in complete remission. Mortality from candidemia was 17.8% (5/28). In conclusion, fungal infections are responsible for death in a significant number of patients. In our series treatment success was related to its rapid onset and to the recovery of neutropenia.

Effects of Acute Autonomic Modulation on Atrial Conduction Delay and Local Electrograms Duration in Paroxysmal Atrial Fibrillation

Slowed atrial conduction may contribute to reentry circuits and vulnerability for atrial fibrillation (AF). The autonomic nervous system (ANS) has modulating effects on electrophysiological properties. However, complex interactions of the ANS with the arrhythmogenic substrate make it difficult to understand the mechanisms underlying induction and maintenance of AF. AIM: To determine the effect of acute ANS modulation in atrial activation times in patients (P) with paroxysmal AF (PAF). METHODS AND RESULTS: 16P (9 men; 59±14years) with PAF, who underwent electrophysiological study before AF ablation, and 15P (7 men; 58±11years) with atrioventricular nodal reentry tachycardia, without documentation or induction of AF (control group). Each group included 7P with arterial hypertension but without underlying structural heart disease. The study was performed while off drugs. Multipolar catheters were placed at the high right atrium (HRA), right atrial appendage (RAA), coronary sinus (CS) and His bundle area (His). At baseline and with HRA pacing (600ms, shortest propagated S2) we measured: i) intra-atrial conduction time (IACT, between RAA and atrial deflection in the distal His), ii) inter-atrial conduction time (interACT, between RAA and distal CS), iii) left atrial activation time (LAAT, between atrial deflection in the distal His and distal CS), iv) bipolar electrogram duration at four atrial sites (RAA, His, proximal and distal CS). In the PAF group, measurements were also determined during handgrip and carotid sinus massage (CSM), and after pharmacological blockade of the ANS (ANSB). AF was induced by HRA programmed stimulation in 56% (self-limited - 6; sustained - 3), 68.8% (self-limited - 6; sustained - 5), and 50% (self-limited - 5; sustained - 3) of the P, in basal, during ANS maneuvers, and after ANSB, respectively (p=NS). IACT, interACT and LAAT significantly lengthened during HRA pacing in both groups (600ms, S2). P with PAF have longer IACT (p<0.05), a higher increase in both IACT, interACT (p<0.01) and electrograms duration (p<0.05) with S2, and more fragmented activity, compared with the control group. Atrial conduction times and electrograms duration were not significantly changed during ANS stimulation. Nevertheless, ANS maneuvers increased heterogeneity of the local electrograms duration. Also, P with sustained AF showed longer interACT and LAAT during CSM. CONCLUSION: Atrial conduction times, electrograms duration and fractionated activity are increased in PAF, suggesting a role for conduction delays in the arrhythmogenic substrate. Acute vagal stimulation is associated with prolonged interACT and LAAT in P with inducible sustained AF and ANS modulation may influence the heterogeneity of atrial electrograms duration.

Acute Bivalvular Left-Sided Methicillin-Resistant Staphylococcus Aureus Endocarditis with Cardiac, Cerebral, Renal and Septic Complications

Infective endocarditis (IE) is now rare in developed countries, but its prevalence is higher in elderly patients with prosthetic valves, diabetes, renal impairment, or heart failure. An increase in health-care associated IE (HCAIE) has been observed due to invasive maneuvers (30% of cases). Methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus are the most common agents in HCAIE, causing high mortality and morbidity. We review complications of IE and its therapy, based on a patient with acute bivalvular left-sided MRSA IE and a prosthetic aortic valve, aggravated by congestive heart failure, stroke, acute immune complex glomerulonephritis, Candida parapsilosis fungémia and death probably due to Serratia marcescens sepsis. The HCAIE was assumed to be related to three temporally associated in-hospital interventions considered as possible initial etiological mechanisms: overcrowding in the hospital environment,iv quinolone therapy and red blood cell transfusion. Later in the clinical course,C. parapsilosis and S. marcescens septicemia were considered to be possible secondary etiological mechanisms of HCAIE.

Specificity and Sensitivity of Screening for Anti-HLA Antibodies in Kidney Allograft Dysfunction

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.

Impact of Donor and Recipient Cytokine Genotypes on Renal Allograft Outcome

Allelic differences in gene promoter or codifying regions have been described to affect regulation of gene expression, consequently increasing or decreasing cytokine production and signal transduction responses to a given stimulus. This observation has been reported for interleukin (IL)-10 (-1082 A/G; -819/-592 CT/CA), transforming growth factor (TGF)-beta (codon 10 C/T, codon 25 G/C), tumor necrosis factor (TNF)-alpha (-308 G/A), TNF-beta (+252 A/G), interferon (IFN)-gamma (+874 T/A), IL-6 (-174 G/C), and IL-4R alpha (+1902 G/A). To evaluate the influence of these cytokine genotypes on the development of acute or chronic rejection, we correlated the genotypes of both kidney graft recipients and cadaver donors with the clinical outcome. Kidney recipients had 5 years follow-up, at least 2 HLA-DRB compatibilities, and a maximum of 25% anti-HLA pretransplantation sensitization. The clinical outcomes were grouped as follows: stable functioning graft (NR, n = 35); acute rejection episodes (AR, n = 31); and chronic rejection (CR, n = 31). The cytokine genotype polymorphisms were defined using PCR-SSP typing. A statistical analysis showed a significant prevalence of recipient IL-10 -819/-592 genotype among CR individuals; whereas among donors, the TGF-beta codon 10 CT genotype was significantly associated with the AR cohort and the IL-6 -174 CC genotype with CR. Other albeit not significant observations included a strong predisposition of recipient TGF-beta codon 10 CT genotype with CR, and TNF-beta 252 AA with AR. A low frequency of TNF-alpha -308 AA genotype also was observed among recipients and donors who showed poor allograft outcomes.

Terapêutica Endovascular de Pseudoaneurisma e Fístula Arteriovenosa em Enxerto Renal

A 31 year old male Caucasian received a renal cadaveric allograft. Reconstruction of an inferior polar artery was corrected pre-implantation. Delayed graft function occurred leading to dialysis support for one month. Graft biopsies(days 7, 15) showed acute tubular necrosis(ATN) and no rejection. Serial ultrasound (US), performed on average weekly, were compatible with ATN. On day 31, Doppler US and a CAT scan suggested for the first time a pseudoaneurysm adjacent to the implantation of the graft artery on the external iliac artery. For clinical and technical reasons, arteriography was only performed on day 67, when serum creatinine was 3.3 mg/dl. It showed a large pseudoaneurysm with an arteriovenous fistula to the right common iliac vein. Compression of the right external iliac artery was clear. In an attempt to close the arteriovenous fistula, the communication with the pseudoaneurysm was embolised with gelfoam and metallic coils with partial success. One week later, by right femoral approach a covered wallstent was placed immediately below the origin of the graft artery.Subsequent Doppler US and arteriography con-firmed closure of the communication with thepseudoaneurysm and of the arteriovenous fistula. The calibre of the right external iliac artery was then normal. By month 18, serum creatinine is stable at 2.1 mg/dl. We can only speculate on the origin of thepseudoaneurysm and of the AV fistula, whichwere not evident until one month post-transplantation. Backtable surgery was performed on thepolar not the main graft artery. Invasive angiography was irreplaceable in this unusual clinical situation.

Safety and Effectiveness of the Genous™ Endothelial Progenitor Cell-Capture Stent in the First Year Following ST-Elevation Acute Myocardial Infarction: A Single Center Experience and Review of the Literature

PURPOSE: The Genous™ stent (GS) is designed to accelerate endothelization, which is potentially useful in the pro-thrombotic environment of ST-elevation acute myocardial infarction (STEMI). We aimed to evaluate the safety and effectiveness of the GS in the first year following primary percutaneous coronary intervention (PCI) and to compare our results with the few previously published studies. METHODS AND MATERIALS: All patients admitted to a single center due to STEMI that underwent primary PCI using exclusively GS, between May 2006 and January 2012, were enrolled. The primary study endpoints were major adverse cardiac events (MACEs), defined as the composite of cardiac death, acute myocardial infarction and target vessel revascularization, at one and 12months. RESULTS: In the cohort of 109 patients (73.4% male, 59 ±12years), 24.8% were diabetic. PCI was performed in 116 lesions with angiographic success in 99.1%, using 148 GS with median diameter of 3.00mm (2.50-4.00) and median length of 15mm (9-33). Cumulative MACEs were 2.8% at one month and 6.4% at 12months. Three stent thromboses (2.8%), all subacute, and one stent restenosis (0.9%) occurred. These accounted for the four target vessel revascularizations (3.7%). At 12months, 33.9% of patients were not on dual antiplatelet therapy. CONCLUSIONS: GS was safe and effective in the first year following primary PCI in STEMI, with an apparently safer profile comparing with the previously published data. SUMMARY: We report the safety and effectiveness of the Genous™ stent (GS) in the first year following primary percutaneous coronary intervention in ST-elevation acute myocardial infarction. A comprehensive review of the few studies that have been published on this subject was included and some suggest a less safe profile of the GS. Our results and the critical review included may add information and reinforce the safety and effectiveness of the GS in ST-elevation in acute myocardial infarction.