The Impact of Tacrolimus as Rescue Therapy in Children Using a Double Immunosuppressive Regimen After Heart Transplantation

Background. Organ transplant recipients with refractory rejection or intolerance to the prescribed immunosuppressant may respond to rescue therapy with tacrolimus. We sought to evaluate the clinical outcomes of children undergoing heart transplantation who required conversion from a cyclosporine-based, steroid-free therapy to a tacrolimus-based regimen. Methods. We performed a prospective, observational, cohort study of 28 children who underwent conversion from cyclosporine-based, steroid-free therapy to a tacrolimus-based therapy for refractory or late rejection or intolerance to cyclosporine. Results. There was complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (X100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (P <= .0001). There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. Conclusion. Tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option for pediatric patients.

Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: Implications for Diagnosis and Therapy

BACKGROUND & AIMS: Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. METHODS: We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. RESULTS: Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant. CONCLUSIONS: We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.

Histologic and functional evaluation of lungs reconditioned by ex vivo lung perfusion

BACKGROUND: Only about 15% of donor lungs are considered suitable for transplantation (LTx). Ex vivo lung perfusion (EVLP) has been developed as a method to reassess and repair damaged lungs. We report our experience with EVLP in non-acceptable donor lungs and evaluate its ability to recondition these lungs. METHODS: We studied lungs from 16 brain-dead donors rejected for LTx. After harvesting, the lungs were stored at 4 degrees C for 10 hours and subjected to normothermic EVLP with Steen Solution (Vitro life, Goteborg, Sweden) for 60 minutes. For functional evaluation, the following variables were assessed: partial pressure of arterial oxygen (Pao(2)), pulmonary vascular resistance (PVR), and lung compliance (LC). For histologic assessment, lung biopsy was done before harvest and after EVLP. Tissue samples were examined under light microscopy. To detect and quantify apoptosis, terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling assay was used. RESULTS: Thirteen lima donors were refused for having impaired lung function. The mean Pao(2) obtained in the organ donor at the referring hospital was 193.7 mm Hg and rose to 489 mm Hg after EVLP. During EVLP, the mean PVR was 652.5 dynes/sec/cm(5) and the mean LC was 48 ml/cm H2O. There was no significant difference between the mean Lung Injury Score before harvest and after EVLP. There was a trend toward a reduction in the median number of apoptotic cells after EVLP. CONCLUSIONS: EVLP improved lung function (oxygenation capacity) of organs considered unsuitable for transplantation. Lung tissue structure did not deteriorate even after 1 hour of normothermic perfusion. J Heart Lung Transplant 2012;31:305-9 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.

Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report

Neoplasms in children after organ transplantation are related to the type and intensity of immunosuppression and the donorrecipient serostatus, especially in relation to the EpsteinBarr virus. The patient was a two-yr-old female child with biliary atresia who underwent a liver transplantation from a female cadaver donor. Two adults received kidney transplants from the same donor. Nine months after transplantation, one of the adult recipients developed an urothelial tumor in the kidney graft. Imaging tests were repeated monthly in the liver-transplanted child and revealed no abnormalities. However, one yr and two months after the transplantation, the patient developed episodes of fever. At that time, imaging and liver biopsy showed a clear cell tumor of urothelial origin in the graft and the disease was limited to the liver. The patient underwent liver retransplantation, and she is currently free of tumor recurrence. Although rare, the occurrence of tumors in the post-transplant period from cadaver donors, without previously diagnosed tumors, is one of the many problems encountered in the complex world of organ transplantation.

Electrocardiographic manifestation of the middle fibers/septal fascicle block: a consensus report

There are fibers in the left ventricle (LV) (LV middle network) that in around one third of cases may be considered a true septal fascicle that arises from the common left bundle. Its presence and the evidence that there are 3 points of activation onset in the LV favor the quadrifascicular theory of the intravantricular activation of both ventricles. Since the 70s, different authors have suggested that the block of the left middle fibers (MS)/left septal fascicle may explain different electrocardiographic (ECG) patterns. The 2 hypothetically based criteria that are in some sense contradictory include: a) the lack of septal "q" wave due to first left and later posteriorly shifting of the horizontal plane loop and b) the presence of RS in lead V-2 (V-1-V-2) due to some anterior shifting of the horizontal plane vectorcardiogram loop. However, there are many evidence that the lack of septal q waves can be also explained by predivisional first-degree left bundle-branch block and that the RS pattern in the right precordial leads may be also explained by first-degree right bundle-branch block. The transient nature of these patterns favor the concept that some type of intraventricular conduction disturbance exists but a doubt remains about its location. Furthermore, the RS pattern could be explained by many different normal variants. To improve our understanding whether these patterns are due to MF/left septal fascicle block or other ventricular conduction disturbances (or both), it would be advisable: 1) To perform more histologic studies (heart transplant and necropsy) of the ventricular conduction system; 2) To repeat prior experimental studies using new methodology/technology to isolate the MF; and 3) To change the paradigm: do not try to demonstrate if the block of the fibers produces an ECG change but to study with new electroanatomical imaging techniques, if these ECG criteria previously described correlate or not with a delay of activation in the zone of the LV that receives the activation through these fibers or in other zones. (C) 2012 Elsevier Inc. All rights reserved.

Comparative experimental study of myocardial protection with crystalloid solutions for heart transplantation

Background: There is a growing need to improve myocardial protection, which will lead to better performance of cardiac operations and reduce morbidity and mortality. Therefore, the objective of this study was to compare the efficacy of myocardial protection solution using both intracellular and extracellular crystalloid type regarding the performance of the electrical conduction system, left ventricular contractility and edema, after being subjected to ischemic arrest and reperfusion. Methods: Hearts isolated from male Wistar (n=32) rats were prepared using Langendorff method and randomly divided equally into four groups according the cardioprotective solutions used Krebs-Henseleit-Buffer (KHB), Bretschneider-HTK (HTK), St. Thomas-1 (STH-1) and Celsior (CEL). After stabilization with KHB at 37 degrees C, baseline values (control) were collected for heart rate (HR), left ventricle systolic pressure (LVSP), maximum first derivate of rise left ventricular pressure (+dP/dt), maximum first derivate of fall left ventricular pressure (-dP/dt) and coronary flow (CF). The hearts were then perfused at 10 degrees C for 5 min and kept for 2 h in static ischemia at 20 degrees C in each cardioprotective solution. Data evaluation was done using analysis of variance in completely randomized One-Way ANOVA and Tukey's test for multiple comparisons. The level of statistical significance chosen was P<0.05. Results: HR was restored with all the solutions used. The evaluation of left ventricular contractility (LVSP, +dP/dt and -dP/dt) showed that treatment with CEL solution was better compared to other solutions. When analyzing the CF, the HTK solution showed better protection against edema. Conclusion: Despite the cardioprotective crystalloid solutions studied are not fully able to suppress the deleterious effects of ischemia and reperfusion in the rat heart, the CEL solution had significantly higher results followed by HTK>KHB>STH-1.

Lithiasis in 1,313 Kidney Transplants: Incidence, Diagnosis, and Management

Background. Renal transplantation remains the optimal treatment of patients with end-stage renal disease. Urinary lithiasis represents an unusual urologic complication in renal transplantation, with an incidence of <1%. Today, recipients of kidneys from deceased donors are more likely to receive grafts with undiagnosed lithiasis, which does not occur in patients from living donors, owing to screening with computerized tomography. Objective. The aim of this study was to evaluate the incidence, diagnosis, and therapeutic management of renal lithiasis in transplanted kidneys at a single institution. Methods. We reviewed the medical records for 1,313 patients who underwent kidney transplantation from February 1968 to February 2011. Results. Among the grafts, 17 patients (1.29%) had nephrolithiasis: 9 women and 8 men. Ages ranged from 32 to 63 years (mean = 45.6 years). Fifteen patients received kidneys from cadaveric and only 2 from living related donors. Two stones, both located inside the ureter, were identified during transplant surgery (11.7%). Three instances of lithiasis were incidentally diagnosed by ultrasound during graft evaluation, within 7 days after surgery (17.6%); all 3 were in the calyces. The 12 remaining patients had the stones diagnosed later (70.58%): 6 in the calyces, 3 in the renal pelvis, and 3 inside the ureter. Conclusions. Urinary lithiasis is a rare complication in renal transplantation. In most patients the condition occurs without pain. The diagnosis and treatment options for graft urolithiasis are similar to those patients with nephrofithiasis in the general population. Extracorporeal shock wave lithotripsy (ESWL) was the most common treatment method.

Malakoplakia after renal transplantation in the current era of immunosuppressive therapy: case report and literature review

Malakoplakia is a rare chronic granulomatous disease of unknown cause. It is thought to be caused by an acquired bactericidal defect of macrophages. Malakoplakia is associated with chronic infections and immunosuppression. Although it occurs mainly in the urinary tract, it has already been reported in almost every organ system. The isolation of bacteria, especially Escherichia coli, is common in malakoplakia patients. Here, we present a case of primary cutaneous malakoplakia in a kidney transplant recipient who had been taking prednisone, tacrolimus, and mycophenolate. Culture of a lesion grew Burkholderia cepacia complex. Treatment with high doses of trimethoprim-sulfamethoxazole was successful. We also present a systematic review of the literature, identifying 4 previously reported cases of malakoplakia after renal transplantation under similar immunosuppressive therapy, most occurring in the urinary tract or perineum and following benign courses to cure. Data in the literature suggest that malakoplakia has become even rarer since changes were made in the immunosuppressive therapy employed after kidney transplantation.

Responses of transplanted native tree species to invasive alien grass removals in an abandoned cattle pasture in the Lacandon region, Mexico

We tested the early performance of 16 native early-, mid-, and late-successional tree species in response to four intensities of grass removal in an abandoned cattle pasture dominated by the introduced, invasive African grass, Cynodon plectostachyus, within the Lacandon rainforest region, southeast Mexico. The increase in grass removals significantly improved the performance of many species, especially of early-and mid-successional species, while performance of late-successional species was relatively poor and did not differ significantly among treatments. Good site preparation and at least one additional grass removal four months after seedling transplant were found to be essential; additional grass removals led to improved significantly performance of saplings in most cases. In order to evaluate the potential of transplanting tree seedlings successfully in abandoned tropical pastures, we developed a "planting risk index", combining field performance measurements and plantation cost estimations. Our results showed a great potential for establishing restoration plantings with many early-and mid-successional species. Although planting risk of late-successional species was considered high, certain species showed some possibilities of acclimation after 18 months and should be considered in future plantation arrangements in view of their long-term contributions to biodiversity maintenance and also to human welfare through delivery of ecosystem services. Conducting a planting risk analysis can help avoid failure of restoration strategies involving simultaneous planting of early-, mid-, and late-successional tree species. This in turn will improve cost-effectiveness of initial interventions in large-scale, long-term restoration programs.

The Seville Expert Workshop for Progress in Posttransplant Lymphoproliferative Disorders

Posttransplant lymphoproliferative disorders (PTLDs) are associated with significant morbidity and mortality among solid-organ transplant patients, but approaches to diagnosis and management vary considerably. An international multidisciplinary panel evaluated current understanding of risk factors and classification systems and developed recommendations to aid in PTLD prevention. We considered evidence on PTLD risk factors including Epstein- Barr virus serostatus and immunosuppression and identified knowledge gaps for future research. Recommendations address prophylactic and preemptive strategies to minimize PTLD development, including modulation of immunosuppression and antiviral drug regimens. Finally, new classification criteria were outlined that may help facilitate standardized reporting and improve our understanding of PTLD.

Wilson's disease: an analysis of 28 Brazilian children

OBJECTIVES: Clinical-laboratory and evolutionary analysis of twenty-eight patients with Wilson's disease. METHODS: Twenty-eight children (twelve females and sixteen males) with Wilson's disease were evaluated retrospectively between 1987 and 2009, with a follow-up of 72 months (1 -240 months). The clinical, laboratory, and histologic features at diagnosis were recorded at the end of the study. RESULTS: The median age at diagnosis was 11 years (2 -18 years). Twelve patients were asymptomatic, seven had hepatitis symptoms, five had raised aminotransferase levels, three had hepatomegaly associated with neurological disorders, one had fulminant hepatitis with hemolytic anemia, and six patients presented with a Kayser-Fleischer ring. A histological analysis revealed that six children had chronic hepatitis, seven had cirrhosis, two had steatosis, one had portal fibrosis, and one had massive necrosis. The treatment consisted of D-penicillamine associated with pyridoxine for 26 patients. Adverse effects were observed in the other two patients: one presented with uncontrollable vomiting and the other demonstrated elastosis perforans serpiginosa. At the end of the study, all 26 treated patients were asymptomatic. Twenty-four of the patients were treated with D-penicillamine and pyridoxine, and two were treated with trientine and zinc sulfate. A liver transplant was performed in one patient with fulminant hepatitis, but the final patient died 48 hours after admission to the intensive care unit. CONCLUSIONS: Family screenings associated with early treatment are important in preventing Wilson's disease symptoms and potentially fatal disease progression. The study suggests that Wilson's disease must be ruled out in children older than two years presenting with abnormal levels of hepatic enzymes because of the heterogeneity of symptoms and the encouraging treatment results obtained so far.

Cellular Infiltrates and NF kappa B Subunit c-Rel Signaling in Kidney Allografts of Patients With Clinical Operational Tolerance

Background. Nuclear factor kappa B (NF kappa B) plays a potential role in tolerance by orchestrating onset and resolution of inflammation and regulatory T cell differentiation through subunit c-Rel. We characterized cellular infiltrates and expression of NF kappa B1, c-Rel and its upstream regulators phosphatidylinositol 3-kinase/RAC-alpha serine/threonine kinase, in allograft biopsies from patients with spontaneous clinical operational tolerance (COT). Methods. Paraffin-fixed kidney allograft biopsies from 40 patients with COT (n=4), interstitial rejection (IR; n=12), borderline changes (BC; n=12), and long-term allograft function without rejection (NR; n=12) were used in the study. Cellular infiltrates and immunohistochemical expression of key proteins of the NF kappa B pathway were evaluated in the cortical tubulointerstitium and in cellular infiltrates using digital image analysis software. Results were given as mean +/- SEM. Results. Biopsies from patients with COT exhibited a comparable amount of cellular infiltrate to IR, BC, and NR (COT, 191 +/- 81; IR, 291 +/- 62; BC, 178 +/- 45; and NR, 210 +/- 42 cells/mm(2)) but a significantly higher proportion of forkhead box P3-positive cells (COT, 11%+/- 1.7%; IR, 3.5%+/- 0.70%; BC, 3.4%+/- 0.57%; and NR, 3.7%+/- 0.78% of infiltrating cells; P=0.02). c-Rel expression in cellular infiltrates was significantly elevated in IR, BC, and NR when analyzing the number of positive cells per mm(2) (P=0.02) and positive cells per infiltrating cells (P=0.04). In contrast, tubular PI3K and c-Rel expression were significantly higher in IR and BC but not in NR compared with COT (P=0.03 and P=0.006, respectively). With RAC-alpha serine-threonine kinase, similar tendencies were observed (P=0.2). Conclusions. Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NF kappa B pathway and a higher proportion of forkhead box P3-positive cells.

Which patients are more likely to benefit from renal transplantation?

Background: We evaluated whether the advantages conferred by renal transplantation encompass all individuals or whether they favor more specific groups of patients. Methods: One thousand and fifty-eight patients on the transplant waiting list and 270 receiving renal transplant were studied. End points were the composite incidence of CV events and death. Patients were followed up from date of placement on the list until transplantation, CV event, or death (dialysis patients), or from the date of transplantation, CV event, return to dialysis, or death (transplant patients). Results: Younger patients with no comorbidities had a lower incidence of CV events and death independently of the treatment modality (log-rank = 0.0001). Renal transplantation was associated with better prognosis only in high-risk patients (p = 0.003). Conclusions: Age and comorbidities influenced the prevalence of CV complications and death independently of the treatment modality. A positive effect of renal transplantation was documented only in high-risk patients. These findings suggest that age and comorbidities should be considered indication for early transplantation even considering that, as a group, such patients have a shorter survival compared with low-risk individuals.

De Novo Thrombotic Microangiopathy After Kidney Transplantation: Clinical Features, Treatment, and Long-Term Patient and Graft Survival

Introduction. Posttransplant thrombotic microangiopathy (TMA)/hemolytic uremic syndrome (HUS) can occur as a recurrent or de novo disease. Methods. A retrospective single-center observational study was applied in order to examine the incidence and outcomes of de novo TMA/HUS among transplantations performed between 2000 and 2010. Recurrent HUS or antibody-mediated rejections were excluded. Results. Seventeen (1.1%) among 1549 kidney transplant recipients fulfilled criteria for de novo TMA. The mean follow-up was 572 days (range, 69-1769). Maintenance immunosuppression was prednisone, tacrolimus (TAC), and mycophenolic acid in 14 (82%) patients. Mean age at onset was 40 +/- 15 years, and serum creatinine was 6.1 +/- 4.1 mg/dL. TMA occurred at a median of 25 days (range, 1-1755) after transplantation. Nine (53%) patients developed TMA within 1 month of transplantation and only 12% after 1 year. Clinical features were anemia (hemoglobin < 10 g/dL) in 9 (53%) patients, thrombocytopenia in 7 (41%), and increased lactate dehydrogenase in 12 (70%). Decreased haptoglobin was observed in 64% and schistocytes in 35%. Calcineurin inhibitor (CM) withdrawal or reduction was the first step in the management of 10/15 (66%) patients, and 6 (35%) received fresh frozen plasma (FFP) and/or plasmapheresis. TAC was successfully reintroduced in six patients after a median of 17 days. Eight (47%) patients needed dialytic support after TMA diagnosis and 75% remained on dialysis. At 4 years of follow-up, death-censored graft survival was worse for TMA group (43.0% versus 85.6%, log-rank = 0.001; hazard ratio = 3.74) and there was no difference in patient survival (53.1% versus 82.2%, log-rank = 0.24). Conclusion. De novo TMA after kidney transplantation is a rare but severe condition with poor graft outcomes. This syndrome may not be fully manifested, and clinical suspicion is essential for early diagnosis and treatment, based mainly in CM withdrawal and FFP infusions and/or plasmapheresis.

Preserving the B-Cell Compartment Favors Operational Tolerance in Human Renal Transplantation

Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-c ell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00281