Analysis of genitourinary anomalies in patients with VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association

The goal of this study was to describe a novel pattern of genitourinary (GU) anomalies in VACTERL association,which involves congenital anomalies affecting the vertebrae,anus, heart, trachea and esophagus, kidneys, and limbs.We collected clinical data on 105 patients diagnosed with VACTERL association and analyzed a subset of 89 patients who met more stringent inclusion criteria. Twenty-one percent of patients have GU anomalies, which are more severe (but not more frequent) in females. Anomalies were noted in patients without malformations affecting the renal, lower vertebral, or lower gastrointestinal systems. There should be a high index of suspicion for the presence of GU anomalies even in patients who do not have spatially similar malformations.     

VACTERL anomalies in patients with esophageal atresia: an updated delineation of the spectrum and review of the literature

The VACTERL complex refers to anomalies of the bony spinal column (V), atresias in the gastrointestinal tract (A), congenital heart lesions (C), tracheoesophageal defects (TE), renal and distal urinary tract anomalies (R) and limb lesions (L). The incidence of each of these components has not been precisely quantified in the recent literature and the full array of anomalies within each systemic class of the VACTERL complex has not been well described. Therefore, we reviewed our most recent 20-year experience of patients born with esophageal atresia to comprehensively delineate and accurately describe the type and incidence of associated lesions. A retrospective review was then conducted on all patients diagnosed with esophageal atresia between 1985 and 2005. Patient demographics recorded included gestational age, weight and gender. The specific types of lesions were carefully cataloged. The outcome measure recorded was survival. One hundred and twelve patients were diagnosed with esophageal atresia were identified during the study period. The gestational age range was 28-41 weeks with an average of 36.5 weeks. Average birth weight was 2,557 g (range 1,107-3,890). A male predominance was seen with 62 males and 50 females. The overall survival was 92.9%. The categorical breakdown of anomalies were vertebral (24.1%), atresia (14.3%), cardiac (32.1%), tracheoesophageal fistula (95.5%), urinary (17.0%), skeletal (16.1%) and other (10.8%). VACTERL anomalies are common in patients with esophageal atresia, however, they appear to have little impact on overall survival.     

Outcomes and predictive factors of pediatric kidney transplants: An analysis of the Thai Transplant Registry

As universal coverage for pediatric kidney transplantation (KT) was introduced in Thailand in 2008, the number of recipients has been increasing. We evaluated predictive factors for graft failure to understand how to improve clinical outcomes in these children. Using data obtained from the National Transplant registry, we assessed the risk of graft failure using the Kaplan–Meier method and Cox proportional hazards regression. Altogether, 201 recipients aged <21 yr at the time of KT were studied. Living donors (LD) were significantly older than deceased donor (DD). Mean cold ischemia time of DD was 17 h. The mean donor glomerular filtration rate (GFR) was 84.0 mL/min/1.73 m². Induction immunosuppressive therapy was administered more frequently in DD than in LDKT. Delayed graft function (DGF) occurred in 36 transplants. Over 719 person years of follow‐up, 42 graft failures occurred. Graft survival at one, three, and five yr post‐transplant were 95%, 88% and 76%, respectively. Two factors independently predicted graft failure in multivariate analysis. The hazard ratios for graft failure in patients with DGF and in patients with donor GFR of ≤30 mL/min/1.73 m² were 2.5 and 9.7, respectively. Pediatric recipients should receive the first priority for allografts from young DD with a good GFR, and DGF should be meticulously prevented.     

Changing concepts in urological management of the congenital anomalies of kidney and urinary tract, CAKUT

Recent advancement in ultrasonographic evaluation has prompted early detection and diagnosis of congenital anomalies in the kidney and urinary tract (CAKUT) in the asymptomatic phase. Consequently, early surgical intervention has become possible in the asymptomatic phase for the purpose of controlling manifestations early, thereby avoiding renal functional deterioration. However, some lesions detected by ultrasonography have been shown to often resolve or disappear without intervention. Thus, it has become more important to identify and understand the natural history of CAKUT. For the precise evaluation of the results of surgical intervention, one must understand the maturational process of renal function during infancy. Without considering this process, we cannot differentiate the renal significance of the surgical management from the natural course of CAKUT. Recent advancement in the field of radioisotopic studies has also made a major contribution to the more precise assessment of renal function. Recent progress in the understanding of the pathophysiology and the natural history of CAKUT has helped rationalize its treatment and management. Improvement in the surgical techniques and tools, together with improvements in pediatric anesthesiology, have made an appreciably positive impact on the outcome. Herein, we present the emerging concepts in the urological management of CAKUT, specifically, multicystic dysplastic kidney, vesicoureteral reflux, congenital hydronephrosis, ectopic ureters and ureteroceles.     

Preoperative intubation of the distal tracheoesophageal fistula for gastric decompression in patients with esophageal atresia

In patients with esophageal atresia (EA) and distal tracheoesophageal fistula (TEF) Gross type C and D, escape of ventilatory gases through the TEF exposes the stomach to gaseous distension with the risk of respiratory distress and gastric perforation. In seven patients with EA, Gross type C, primary esophagoesophagostomy was planned within the first 2 days of life. After induction of anesthesia by mask, a rigid ventilation bronchoscope was inserted into the trachea and the TEF was cannulated with a catheter that was pushed down to the stomach. After removal of the endoscope, the patient was intubated beside or over the inserted catheter. Until division and closure of the TEF, continuous suction over the catheter prevented gaseous gastric distention. Intubation of a distal TEF in patients with Gross type C and D EA can easily be combined with routine preoperative bronchoscopy, and is a safe and effective method to decompress a distended stomach and prevent respiratory distress and gastric perforation during controlled ventilation.     

Retrospective study of the renal function using estimated glomerular filtration rate and congenital anomalies of the kidney-urinary tract in pediatric Turner syndrome

Although Turner syndrome (TS) is frequently associated with congenital anomalies of the kidney-urinary tract (CAKUT), which is a major cause of pediatric chronic kidney disease, renal function in TS is usually considered normal. The present study aimed to analyze the frequency of renal dysfunction and CAKUT in pediatric patients with TS. Our study included 122 patients with TS between the ages of 2 and 18 years from 30 hospitals across Japan. Clinical data related to renal function and CAKUT were retrospectively collected. The estimated glomerular filtration rate (eGFR) was calculated using the serum creatinine-based formula recommended by the Japanese Society for Pediatric Nephrology. An eGFR <90 mL/min/1.73 m² for two consecutive years was defined as renal dysfunction. Fifteen (13.5%) of 122 patients had CAKUT, and four patients had renal dysfunction (3.2%, 95% confidence interval: 0%-6.7%). Three of the four did not have CAKUT. Of the CAKUT manifestations, horseshoe kidney, renal hypodysplasia, and multicystic dysplastic kidney were seen in nine, two, and one patient, respectively. Eight of the nine patients with horseshoe kidney had a normal renal function; however, the remaining patient with renal hypodysplasia had renal dysfunction. A small percentage of patients with pediatric TS may had an eGFR below 90 mL/min/1.73 m² which was not necessarily associated with CAKUT.     

先天性食管闭锁食管肌层超微结构及神经递质表达的研究

目的对先天性食管闭锁患儿食管肌层进行电镜观察和免疫组化检测,研究其超微结构变化及神经递质表达的特点。方法食管闭锁组:2003年6月~2004年6月间新生儿先天性食管闭锁伴食管气管瘘远端食管肌层组织10例;对照组:非食管疾病死亡新生儿食管中段组织10例。分别进行HE染色光镜观察、透射电镜观察和NSE、SP、VIP和NOS的免疫组化检测。结果光镜下,食管闭锁组肌间神经丛分布稀疏,4.2±0.6/10×视野,神经节细胞减少,细胞核偏位,深染。电镜下,食管闭锁组平滑肌纤维线粒体肿胀,内质网扩张。线粒体细胞膜边缘现象明显。在肌间神经丛突触末梢中,核心小泡/清亮小泡较对照组明显增高(0.511±0.139vs0.192±0.020,P<0.05)。免疫组化染色食管闭锁肌间神经丛及神经节细胞的NSE,SP表达阳性率分别为20%和10%,明显低于对照组(90%和80%,P<0.05);VIP和NOS表达阳性率分别为90%和90%,明显高于对照组(30%和10%,P<0.05)。结论食管闭锁患儿食管肌层存在内源性神经结构缺陷和神经递质表达异常。     

先天性肾脏和尿路畸形超声筛查三级转诊体系的高危儿肾盂扩张筛查和随访研究

目的 对0~3月龄高危儿肾盂扩张（RPD）筛查和随访,探讨先天性肾脏和尿路畸形泌尿系统超声筛查三级（社区卫生服务中心-妇幼保健院-儿童专科医院）转诊体系（简称三级转诊体系）实施的可行性。方法 在三级转诊体系中,社区卫生服务中心甄别高危儿并转诊至妇幼保健院,妇幼保健院泌尿系统超声筛查RPD、随访和转诊,儿童专科医院对转诊RPD患儿确诊和制定干预措施。 结果①筛查结果：2010年6月至2012年5月,3 743名0~3月龄高危儿泌尿系统超声筛查RPD阳性率9.0%（338例）,男婴在总的RPD以及轻、中和重度RPD的筛查阳性率均明显高于女婴,但男女婴轻、中、重度RPD构成比差异无统计学意义;②随访结果：285例在1岁时统计随访结果,诊断肾盂输尿管连接处梗阻 3例,巨输管症2例,重复肾、重复上肾积水伴输尿管异位开口1例,其中手术3例;余279例RPD患儿经(5.4±4.5)个月随访,241例RPD恢复正常,其中轻、中和重度比例分别为91.9%、76.3%和22.2%;RPD好转16例,持续17例,加重5例。③三级转诊体系：第2年度较第1年度自愿接受泌尿系统超声筛查高危儿的比例增加（83.0% vs 64.1%）,RPD筛查阳性率未见明显差异（9.5% vs 7.8%）;第1年度较第2年度转诊率及随访率差异均无统计学意义。结论 基于三级转诊体系的高危儿RPD筛查、随访和转诊运行实施效果良好,儿童专科医院需进一步完善培训和转诊机制,妇幼保健院在三级转诊体系中的作用关键,特别是随访和转诊是三级转诊体系的最重要环节。     

Elective, postoperative ventilation in the management of esophageal atresia and tracheoesophageal fistula

The management of esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) has undergone many changes. As a result of recent advances in neonatal intensive care and pediatric anesthesia, the survival of infants with EA and TEF has improved markedly, but the occurrence of anastomosic complications has remained constant. To overcome this problem, various techniques and suture materials have been used. This review of 20 consecutive cases of EA/TEF stresses the importance and influence of non-reversal of anesthesia, paralysis, and elective ventilation for protection of the esophageal anastomosis following repair of EA and TEF.     

Prospective analysis of carotid arterial wall structure in pediatric renal transplants with ambulatory normotension and in treated hypertensive recipients

Increased carotid IMT was found to be associated with cardiovascular risk factors. As pediatric renal transplants are at high risk for cardiovascular disease, we examined whether there is a relationship between BP and IMT in normotensive and in treated hypertensive recipients after transplantation. Thirty-one recipients aged 10 +/- 3.5 yr (16 M, 15 F) underwent repeated carotid ultrasound examinations 5.4 +/- 3.2 yr after transplantation with a 4.1 +/- 1 yr interval and were followed with annual ambulatory BP monitoring. Baseline IMT was significantly higher in transplants compared with controls. When recipients were again investigated, follow-up IMT measurements were similar compared with measurements obtained at baseline. The analysis of variance showed that baseline IMT both in recipients with strict normotension, i.e., ambulatory normotension without antihypertensive therapy at baseline and throughout the study period (n = 9), and in recipients with treated hypertension or newly diagnosed hypertension (n = 22) was significantly higher than in healthy controls (n = 21). Baseline IMT did not differ between these subgroups of recipients. Similarly, pairwise comparisons showed that baseline and follow-up IMT within each subgroup of recipients were not significantly different. Overall and regardless of time-point, no significant associations were found between systolic and diastolic 24-h BP, daytime BP, night-time BP, ambulatory BP standard deviation scores, BP loads and IMT. Our results suggest that increased IMT in pediatric renal transplants does not seem to be related to BP but more likely to other factor(s) not investigated in this study.     

The role of prophylactic chest drainage in the operative management of esophageal atresia with tracheoesophageal fistula

Introduction  Anastomotic leakage and respiratory complications are among the most common and potentially life-threatening complications following the surgical repair of esophageal atresia. Controversies exist regarding the efficacy of prophylactic extrapleural chest tube (EPCT) drainage in patients who have undergone repair of esophageal atresia. Materials and methods  In this prospective study, 50 newborns with esophageal atresia and distal tracheoesophageal fistula (EA-DTEF) were randomized into two groups, with no significant differences regarding gender ratio, birth body weight and delivery status. Group 1 (n = 29) underwent a right thoracotomy and a single-stage extrapleural esophageal anastomosis. Group 2 (n = 21) received additionally an intraoperative EPCT next to the anastomosis. These groups were then compared with regard to postoperative respiratory complications (such as respiratory distress, pneumonia, pneumothorax, lung collapse, and apnea), anastomotic leakage, need for mechanical ventilation, time on mechanical ventilation, and outcome. Statistical analyses were performed with Mann–Whitney U test, Fisher’s exact test, and binary logistic regression analysis. Results  The rates of respiratory complications and anastomotic leakage, need for mechanical ventilation, time on mechanical ventilation, and mortality rate were comparable between the two groups (P > 0.05). Mortality was associated with respiratory complications (P = 0.003) and anastomotic leakage (P = 0.007). Conclusion  It seems that prophylactic EPCT drainage does not decrease the early postoperative respiratory complications and mortality rates in newborns with EA-DTEF.     

Evolution of renal function and urinary biomarker indicators of inflammation on serial kidney biopsies in pediatric kidney transplant recipients with and without rejection

Urinary CXCL10 and metabolites are biomarkers independently associated with TCMR. We sought to test whether these biomarkers fluctuate in association with histological severity of TCMR over short time frames. Forty‐nine pairs of renal biopsies obtained 1‐3 months apart from 40 pediatric renal transplant recipients were each scored for TCMR acuity score (i + t; Banff criteria). Urinary CXCL10:Cr and TCMR MDS were obtained at each biopsy and were tested for association with changes between biopsies in acuity, estimated GFR (ΔeGFR), and 12‐month ΔeGFR. Sequential biopsies were obtained 1.8 ± 0.8 months apart. Biopsy 1 was usually obtained under protocol (75%), and 62% percent had evidence of TCMR. Using each biopsy pair for comparison, ΔeGFR did not predict change in acuity. By contrast, change in acuity was significantly correlated with change in urinary CXCL10:Cr (ρ 0.45, P  = .003) and MDS (ρ 0.29, P  = .04) between biopsies. The 12‐month ΔeGFR was not predicted by TCMR acuity or CXCL10:Cr at Biopsy 2; however, an inverse correlation was seen with urinary MDS (ρ ?0.35; P  = .02). Changes in eGFR correlate poorly with evolving TCMR acuity on histology. Urinary biomarkers may be superior for non‐invasive monitoring of rejection, including histological response to therapy, and may be prognostic for medium‐term function.     

Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose fingolimod (FTY720) in adolescents with stable renal transplants

Oral fingolimod signals the sphingosine 1-phosphate receptor and this in turn mediates immunomodulatory activity. No data of fingolimod in any pediatric population existed before this study. We put our study results in perspective against data from adult renal transplant patients. We investigated pharmacokinetics and pharmacodynamics of single-dose fingolimod (0.07 mg/kg) and its effects on lymphocytes and heart rate in seven adolescents (14.1 ± 1.6 yr) with stable renal transplants. Blood samples for pharmacokinetics and lymphocytes were collected at screening, baseline, and up to 28 days post-dosing. Cardiac monitoring included 12-lead ECG, 24-h Holter monitoring, and echocardiography. A fingolimod dose of 0.07 mg/kg resulted in mean AUC of 731 ± 240 ng·h/mL and C(max) of 3.6 ± 0.6 ng/mL. Drug exposure was nearly identical to adults receiving the same dose. Absolute lymphocyte count decreased 85% from baseline; average nadir occurred by six h post-dose. Heart rate decreased from 74 bpm (predose mean) to 53 bpm (nadir) three h post-dose. Mean heart rates recovered by Day 14 (75 bpm). Weight-adjusted doses of fingolimod in adolescents resulted in drug exposure similar to adults. Adolescents and adults shared comparable negative chronotropic effects and decreased lymphocyte count. Recovery trajectories of these parameters back to baseline were similar between age groups.     

Aspergillus "fungus ball" of the bladder after hematopoietic transplantation in a pediatric patient: successful treatment with intravesical voriconazole and surgery

Abstract:  Aspergillosis is an important cause of mortality in allogeneic HSCT. A "fungus ball" formation of Aspergillus in the bladder has seldom been reported. We report a child that underwent HSCT and developed possible disseminated aspergillosis with an intravesical "fungus ball," diagnosed by genitourinary MRI and PCR of the mass that was removed from the bladder. It is important to consider this complication in a patient with HC after HSCT. The treatment included a combination of systemic antifungal therapy along with intravesical voriconazole and surgical removal.     

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis

Sirolimus (Rapamune, rapamycin) has been shown to be an effective and safe immunosuppressive drug in adult kidney transplant patients when administered concomitantly with cyclosporine (CsA) and steroids. This study reports on a phase 1 assessment of the drug's tolerance, safety, and pharmacokinetic parameters in pediatric patients. The safety and pharmacokinetic profiles of ascending single doses of sirolimus oral solution were investigated in 32 clinically stable pediatric patients on chronic hemodialysis (n = 26) or peritoneal dialysis (n = 6). Patients were divided into two age groups (5-11 and 12-18 yr), and each patient received either a single dose of sirolimus (1, 3, 9, or 15 mg/m(2)) or placebo. Whole blood and plasma samples were collected from each patient for the determination of sirolimus pharmacokinetic parameters. Safety assessments were based on reports of adverse events and results of scheduled physical examinations, vital sign measurements and clinical laboratory tests. The younger patients (5-11 yr) showed statistically significant increases in whole blood sirolimus t(max) (p < or = 0.05) and weight-normalized CL/F (p<0.05) when compared with older patients (12-18 yr). There were no differences in terminal t(1/2), V(ss)/F, dose-normalized peak concentration (C(max)) and AUC, or the B/P. The whole blood sirolimus mean t(max) and weight-normalized CL/F in younger patients were increased by approximately 41.5% and 30%, respectively. Whole blood sirolimus concentrations exhibited less than proportional increases with ascending doses, which may have been caused by the large inter-subject variability in CL/F, small number of subjects, and a potentially inherent decrease in sirolimus bioavailability in younger pediatric patients. Adverse events occurred in all dose and age groups, with headache and stomach pain being the most frequently observed events. No deaths or serious adverse events were reported, and no patient withdrew from the study because of an adverse event. Based on an inter-study analysis, weight-normalized CL/F in the current population of younger pediatric dialysis patients (5-11 yr, 544 +/- 463 mL/h/kg, n = 7) was increased by 90% (p < or = 0.05) compared with healthy adults (19-36 yr, 287 +/- 111 mL/h/kg, n = 25). These results suggest that younger pediatric patients might require an increased maintenance dose of sirolimus to achieve whole blood exposures similar to those in healthy adults. Sirolimus is well tolerated as a single dose of 1, 3, 9, or 15 mg/m(2).