Long-term outcome of transplant ureterostomy in children: A National Review.

BACKGROUND: CAKUT are the most common cause of end-stage renal failure in children (Pediatr Nephrol. 24, 2009, 1719). Many children with CAKUT have poor urinary drainage which can compromise post-transplant outcome. Identifying safe ways to manage anatomical abnormalities and provide effective urinary drainage is key to transplant success. Much debate exists regarding optimum urinary diversion techniques. The definitive formation of a continent urinary diversion is always preferable but may not always be possible. We explore the role of ureterostomy formation at transplantation in a complex pediatric group. METHODS: We report six pediatric patients who had ureterostomy formation at the time of transplantation at the National Paediatric Transplant Centre in Dublin, Ireland. We compared renal function and burden of urinary tract infection to a group with alternative urinary diversion procedures and a group with normal bladders over a 5-year period. RESULTS: There was no demonstrable difference in estimated glomerular filtration rate between the groups at 5-year follow-up. The overall burden of UTI was low and similar in frequency between the three groups. CONCLUSIONS: Ureterostomy formation is a safe and effective option for temporary urinary diversion in children with complex abdominal anatomy facilitating transplantation; it is, however, important to consider the implications and risk of ureterostomy for definitive surgery after transplantation.

Vascular endothelial growth factor A is associated with the subsequent development of moderate or severe cardiac allograft vasculopathy in pediatric heart transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the leading cause of chronic allograft loss after pediatric heart transplantation. We hypothesized that biomarkers of endothelial injury and repair would predict CAV development in pediatric heart transplant recipients. METHODS: Blood was collected from pediatric heart transplant recipients at the time of routine annual coronary angiography, and the concentrations of 13 angiogenesis-related molecules were determined. The primary end point was the presence of moderate or severe CAV by angiography during a 5-year follow-up period. RESULTS: The study enrolled 48 recipients (57% male) with a median age of 15.5 years (range, 2-22 years) and median time post-transplant of 5.8 years (range, 2-15 years). Eight recipients developed moderate/severe CAV at a median follow-up of 4.7 years, of whom 3 died, 3 underwent retransplantation, 1 had a myocardial infarction, and 1 was listed for retransplantation. Clinical characteristics associated with the development of moderate/severe CAV included prednisone use at enrollment (p = 0.03) and positive recipient cytomegalovirus immunoglobulin G at the time of transplant (p = < 0.01). Multivariable Cox proportional hazards regression identified plasma vascular endothelial growth factor (VEGF)-A concentration greater than 90 pg/ml at the time of blood draw as a significant predictor of time to moderate or severe CAV (hazard ratio, 14.3; 95% confidence interval, 1.3-163). Receiver operating characteristic curve analysis demonstrated that VEGF-A shows moderate performance for association with the subsequent development of CAV (area under the curve, 0.77; 95% confidence interval, 0.61-0.92). CONCLUSIONS: VEGF-A levels in pediatric heart transplant recipients are associated with clinically important CAV progression within the subsequent 5 years.

Clonal Heterogeneity in the Neuronal and Glial Differentiation of Dental Pulp Stem/Progenitor Cells.

Cellular heterogeneity presents an important challenge to the development of cell-based therapies where there is a fundamental requirement for predictable and reproducible outcomes. Transplanted Dental Pulp Stem/Progenitor Cells (DPSCs) have demonstrated early promise in experimental models of spinal cord injury and stroke, despite limited evidence of neuronal and glial-like differentiation after transplantation. Here, we report, for the first time, on the ability of single cell-derived clonal cultures of murine DPSCs to differentiate in vitro into immature neuronal-like and oligodendrocyte-like cells. Importantly, only DPSC clones with high nestin mRNA expression levels were found to successfully differentiate into Map2 and NF-positive neuronal-like cells. Neuronally differentiated DPSCs possessed a membrane capacitance comparable with primary cultured striatal neurons and small inward voltage-activated K(+) but not outward Na(+) currents were recorded suggesting a functionally immature phenotype. Similarly, only high nestin-expressing clones demonstrated the ability to adopt Olig1, Olig2, and MBP-positive immature oligodendrocyte-like phenotype. Together, these results demonstrate that appropriate markers may be used to provide an early indication of the suitability of a cell population for purposes where differentiation into a specific lineage may be beneficial and highlight that further understanding of heterogeneity within mixed cellular populations is required.

Laparoscopic versus open peritoneal dialysis catheter insertion for the management of pediatric acute kidney injury.

BACKGROUND: Acute pediatric dialysis is provided by a single center in New Zealand. Most acute dialysis in our center is performed in the under 5 age group. The advantage of using peritoneal dialysis (PD) in these children is the ability to perform continuous renal replacement therapy without always requiring an ICU setting, avoiding central venous access and promoting greater cardiovascular stability. The disadvantage of PD in the acute setting includes the requirement for immediate use and the potential for early leaks due to peritoneal disruption with resulting delayed use and restricted volumes. There is a growing trend toward minimally invasive surgery and the laparoscopic method allows this. Surgeons at this center have been using a laparoscopic technique since 2005. METHODS: We performed a 10-year review of acute PD at the Starship Hospital from 2003 to 2013. Data on 102 children who met the criteria were collected. RESULTS: These 102 children had 113 acute PD catheters. The two groups were comparable in terms of age and reason for presentation. The median age of the laparoscopic group was 2 years (interquartile range [IQR] 6) and the open group was 3 years (IQR 3.2). The predominant diagnosis for both groups was hemolytic uremic syndrome (HUS) accounting for 71% of laparoscopic cases, and 72% of open cases. The incidence of infection was 0% versus 7% in the laparoscopic versus open approach. Ten percent of patients required further manipulation of the catheter after initial insertion in the laparoscopic group, compared with 11% in the open approach. Conversion to hemodialysis (HD) due to catheter-related complications was seen in 10% of laparoscopic cases and 9% of the open cases. Dialysate fluid leak was noted in 26% in the laparoscopic group compared with 11% in the open group (p = 0.08). Anesthesia time is longer in the laparoscopic group (p = 0.008). CONCLUSION: We found no significant differences in complication rates between laparoscopic and open surgical approaches regarding acute PD catheter insertion. We saw a trend in increased leakage with laparoscopic procedures and a significantly longer operative time. We concluded that the laparoscopic approach in the acute situation for emergency dialysis is safe and effective.

Adrenal insufficiency in a child following unilateral excision of a dual-hormone secreting phaeochromocytoma.

UNLABELLED: Phaeochromocytomas are a rare clinical entity, with dual hormone-secreting lesions particularly uncommon, seen in <1%. ACTH is the most common hormone co-produced, and is potentially lethal if not diagnosed. We present the case of a previously well 10-year-old boy, who presented acutely with a hypertensive crisis and was found to have a unilateral, non-syndromic phaeochromocytoma. Medical stabilization of his hypertension was challenging, and took 3 weeks to achieve, before proceeding to unilateral adrenalectomy. Post-operatively the child experienced severe fatigue and was subsequently confirmed to have adrenal insufficiency. He improved markedly with hydrocortisone replacement therapy, which is ongoing 6 months post-operatively. In retrospect this likely represents unrecognized, sub-clinical ACTH-dependent Cushing's syndrome secondary to an ACTH/or precursor dual-hormone secreting phaeochromocytoma. At follow-up, his hypertension had resolved, there was no biochemical evidence of recurrence of the phaeochromocytoma, and genetic analysis was indicative of a sporadic lesion. LEARNING POINTS: Dual hormone secreting phaeochromocytomas with ACTH/or a precursor may cause secondary adrenal insufficiency following surgical removal.The concurrent features of Cushing's syndrome can be mild and easily overlooked presenting diagnostic and management pitfalls.As concomitant syndromes of hormone excess are rare in phaeochromocytomas; the diagnosis requires a high index of suspicion.Serial/diurnal cortisol levels, ACTH measurement +/- low dose dexamethasone suppression (when clinically stable, appropriate adrenergic blockade in place, and well supervised), can all be considered as needed.

Effect of vascular endothelial growth factor and its receptor KDR on the transendothelial migration and local trafficking of human T cells in vitro and in vivo.

In these studies, we find that the vascular endothelial growth factor (VEGF) receptor KDR is expressed on subsets of mitogen-activated CD4(+) and CD8(+) T cells in vitro. We also found that KDR colocalizes with CD3 on mitogen-activated T cells in vitro and on infiltrates within rejecting human allografts in vivo. To evaluate whether VEGF and KDR mediate lymphocyte migration across endothelial cells (ECs), we used an in vitro live-time transmigration model and observed that both anti-VEGF and anti-KDR antibodies inhibit the transmigration of both CD4(+) and CD8(+) T cells across tumor necrosis factor α (TNFα)-activated, but not unactivated ECs. In addition, we found that interactions among CD4(+) or CD8(+) T cells and TNFα-activated ECs result in the induction of KDR on each T cell subset, and that KDR-expressing lymphocytes preferentially transmigrate across TNFα-activated ECs. Finally, using a humanized severe combined immunodeficient mouse model of lymphocyte trafficking, we found that KDR-expressing lymphocytes migrate into human skin in vivo, and that migration is reduced in mice treated with a blocking anti-VEGF antibody. These observations demonstrate that induced expression of KDR on subsets of T cells, and locally expressed VEGF, facilitate EC-dependent lymphocyte chemotaxis, and thus, the localization of T cells at sites of inflammation.

Cutting edge: Vascular endothelial growth factor-mediated signaling in human CD45RO+ CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma production.

In this study, we find that CD45RO+ memory populations of CD4+ T lymphocytes express the vascular endothelial growth factor (VEGF) receptors KDR and Flt-1 at both the mRNA and protein levels. Furthermore, by Western blot analysis, we find that VEGF increases the phosphorylation and activation of ERK and Akt within CD4+CD45RO+ T cells. These VEGF-mediated signaling responses were inhibited by a KDR-specific small interfering RNA in a VEGF receptor-expressing Jurkat T cell line and by SU5416, a pharmacological KDR inhibitor, in CD4+CD45RO+ T cells. We also find that VEGF augments mitogen-induced production of IFN-gamma in a dose-dependent manner (p < 0.001) and significantly (p < 0.05) increases directed chemotaxis of this T cell subset. Collectively, our results for the first time define a novel function for VEGF and KDR in CD45RO+ memory T cell responses that are likely of great pathophysiological importance in immunity.

Airways obstruction in survivors of thoracoplasty: reversibility is greater in non-smokers.

OBJECTIVE: Before the advent of antituberculous chemotherapy, thoracoplasty (TPL) was the definitive form of therapy for cavitary pulmonary tuberculosis. This study aimed to characterize the late functional sequelae of TPL, and to establish the degree of reversibility of any consequent airway obstruction. METHODOLOGY: Pulmonary function was studied in 21 long-term (mean 35 years) survivors of TPL between the years 1990-2001. RESULTS: A mixed obstructive/restrictive defect was found in this patient cohort. After inhalation of bronchodilator, marginal increases in FEV(1) and FVC and marginal decreases in FRC, RV and TLC were observed. Maximum mid-expiratory flow rate was severely reduced (28.8% of predicted), but reversibility after inhaled beta(2)-agonist was highest for this parameter of pulmonary function (mean 11%). Smokers had a higher RV (P = 0.04), suggesting hyperinflation, while non-smokers had a larger increase in FEV(1)/FVC ratio postbronchodilator (P = 0.004), suggesting more marked reversibility of airways obstruction in this group. CONCLUSIONS: Long-term survivors of TPL have an obstructive as well as a restrictive ventilatory defect. These patients have partial reversibility of the obstructive defect. The degree of reversibility found suggests that bronchodilator therapy may help these patients.