Loss of pediatric kidney grafts during the "high-risk age window": insights from pediatric liver and simultaneous liver-kidney recipients.

Pediatric kidney transplant recipients experience a high-risk age window of increased graft loss during late adolescence and early adulthood that has been attributed primarily to sociobehavioral mechanisms such as nonadherence. An examination of how this age window affects recipients of other organs may inform the extent to which sociobehavioral mechanisms are to blame or whether kidney-specific biologic mechanisms may also exist. Graft loss risk across current recipient age was compared between pediatric kidney (n = 17,446), liver (n = 12,161) and simultaneous liver-kidney (n = 224) transplants using piecewise-constant hazard rate models. Kidney graft loss during late adolescence and early adulthood (ages 17-24 years) was significantly greater than during ages <17 (aHR = 1.79, 95%CI = 1.69-1.90, p < 0.001) and ages >24 (aHR = 1.11, 95%CI = 1.03-1.20, p = 0.005). In contrast, liver graft loss during ages 17-24 was no different than during ages <17 (aHR = 1.03, 95%CI = 0.92-1.16, p = 0.6) or ages >24 (aHR = 1.18, 95%CI = 0.98-1.42, p = 0.1). In simultaneous liver-kidney recipients, a trend towards increased kidney compared to liver graft loss was observed during ages 17-24 years. Late adolescence and early adulthood are less detrimental to pediatric liver grafts compared to kidney grafts, suggesting that sociobehavioral mechanisms alone may be insufficient to create the high-risk age window and that additional biologic mechanisms may also be required.

Living donor liver transplantation in children: a single North American center experience over two decades.

Little data concerning hospital charges and long-term outcomes of LDLT in North American children according to transplant indications have been published. To compare outcomes of patient and graft survival and healthcare charges for LDLT for those with BA vs. other diagnoses (non-BA). A retrospective review of 52 children receiving 53 LDLT (38 BA and 14 non-BA) from 1992 to 2010 at our institution was performed. One-, five-, and 10-yr patient and graft survival data were comparable to national figures reported to UNOS. Average one-yr charges for recipients and donors were $242 849 for BA patients and $183 614 for non-BA (p = 0.074). BA patients were 1.23 ± 1.20 yr of age vs. 4.25 ± 5.02 for non-BA, p = 0.045. Examination of the total population of patients who were alive in 2010 in five chronological groupings showed that the crude five-yr survival rates were 1992-1995: 9/11 (82%); 1995-1997: 6/10 (60%); 1997-1999: 8/10 (80%); 1999-2001: 9/10 (90%); and 2001-2003: 7/7 (100%). Thus, examination of the clinical and financial data together over the entire period of the transplant program suggests that the dramatic improvement in patient survival was accomplished without a dramatic increase in indexed charges. All 53 donors survived, and only 10% had complications requiring hospitalization. LDLT in children results in excellent outcomes for patients and donors. Ways to lower costs and maximize graft outcome should be investigated.

Cyclosporine A, an in vitro calmodulin antagonist, induces nuclear lobulations in human T cell lymphocytes and monocytes.

Cyclosporine A is a noncytotoxic, natural, 11 amino acid cyclic peptide used clinically as an immunosuppressant to prevent organ rejection after transplantation. Cyclosporine A is an in vitro calmodulin antagonist. At the low concentrations required to inhibit calmodulin-dependent phosphodiesterase in vitro, cyclosporine A causes a dramatic alteration in the nuclear morphology of 23% of human peripheral blood mononuclear leukocytes in vitro without loss of viability. The shape of the nucleus changes from ovoid to a distinctive, radially splayed lobulated structure. The changes occur in a dose-dependent manner in 60 min at 37 degrees C. Specific monoclonal antibodies to human leukocytes identify the cells susceptible to nuclear lobulation by cyclosporine A as OKT4 antigen-positive T cell lymphocytes and monocytes. The lobulated nuclei are 2N as determined by flow cytometric measurement of ethidium bromide fluorescence of DNA. The cyclosporine A-induced lobulation of T cell nuclei requires both physiologic temperature and metabolic energy. Although structurally different than cyclosporine A, the calmodulin antagonists R24571 and W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide] also produce T cell nuclear lobulations that are indistinguishable from the nuclear lobulations caused by cyclosporine A. These data indicate that nonmitotic structural elements that govern normal nuclear morphology in a subset of mononuclear leukocytes appear to require a calmodulin-mediated process. Cyclosporine A may be a useful noncytotoxic inhibitor of calmodulin-dependent systems that influence nuclear structure and function.

Cyclosporin A binding to calmodulin: a possible site of action on T lymphocytes.

Cyclosporin A, a potent immunosuppressive agent, has been widely used to treat patients with solid organ transplants. Although its precise mechanism of action is unknown, it appears to inhibit subsets of T lymphocytes at an early stage in cell activation. Fluorescent, fully active derivatives of cyclosporin A and calmodulin, a protein that binds calcium and is therefore essential to normal cell function, were utilized to demonstrate that cyclosporin A binds to calmodulin. Flow cytometry showed that the calmodulin inhibitors R24571 and W-7 competitively inhibited binding of cyclosporin A to cloned T lymphocytes. Cyclosporin A inhibited the calmodulin-dependent activation of phosphodiesterase in a dose-dependent manner. Binding of cyclosporin A to calmodulin may prevent the latter's role in the activation of the second messengers and enzymes required for effective cell proliferation and function in the immune response.

Gastroschisis in the United States 1988-2003: analysis and risk categorization of 4344 patients.

OBJECTIVE: Gastroschisis is a rare congenital abdominal wall defect through which intraabdominal organs herniate and it requires surgical management soon after birth. The objectives of this study were to profile patient characteristics of this anomaly utilizing data from two large national databases and to validate previous risk stratification categories of infants born with this condition. METHODS: An analysis was performed using 13 years of the National Inpatient Sample database (1988-1996, 1998, 1999, 2001, 2002) and 3 years of the Kids' Inpatient Database (1997, 2000, 2003). These combined databases contain information from nearly 93 million discharges in the United States. Infants with gastroschisis were identified by International Classification of Disease-9 procedure code 54.71 (repair of gastroschisis) and an age at admission of <8 days. Variables of gender, race, geographic region, co-existing diagnoses, length of stay, hospital charges adjusted to 2005 dollars, complications and inpatient mortality were collected from the databases. Infants were divided into simple and complex categories based on the absence or presence of intestinal atresia, stenosis, perforation, necrosis or volvulus. Comparisons between groups were performed using Pearson's chi (2) for categorical outcomes and the Kruskal-Wallis test for non-normally distributed continuous variables. RESULTS: A total of 4344 infants with gastroschisis were identified. These were comprised of 44.0% female infants (n=1910), 46.4% male infants (n=2017) whereas 9.6% were not reported (n=415). Racial analysis showed the largest subset being white in 40.9% of infants (n=1775) with Hispanic infants being the next highest group reported at 17.2% (n=745). Co-existing intestinal anomalies were the most common, affecting 9.9% (n=429) infants, whereas certain cardiac (6.8%, n=294) and pulmonary (1.7%, n=72) conditions were also identified. Simple gastroschisis represented 89.1% (n=3870) of the group whereas 10.9% (n=474) were complex in nature. Simple and complex patients differed in median length of stay (28 vs 67 days, P<0.01), inpatient mortality (2.9 vs 8.7%, P<0.01) and median inflation-adjusted hospital charges (90,788 dollars vs 197,871 dollars, P<0.01). CONCLUSIONS: These data represent a national analysis of the largest group of infants with gastroschisis to date which further aids the characterization and understanding of this serious congenital condition.

Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.

PURPOSE: The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. PATIENTS AND METHODS: We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. RESULTS: Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. CONCLUSION: Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.

Cyclosporine and the immune response: basic aspects.

Cyclosporine (CsA) is a novel immunosuppressive agent currently used clinically, to prevent rejection of solid organ allografts and to prevent graft-vs.-host disease. Early studies in a variety of animal models exhibited transplantation tolerance after limited treatment with this unique agent. The apparent specific immunological unresponsiveness induced by CsA is thought to be maintained by antigen-specific suppressor T lymphocytes. Studies attempting to dissect the mechanism of action of this unique agent suggested that CsA selectively affected different T lymphocyte populations. Cyclosporine was very effective at inhibiting the production of interleukin-2 (IL-2), a soluble lymphokine known to amplify cytotoxic T cell responses and was also capable of preventing IL-2 receptor expression on the precursor cytotoxic T lymphocyte. In contrast, to the effect on T helper cells and on the precursor cytotoxic T lymphocyte, studies in vitro and in vivo demonstrated that CsA had a sparing effect on suppressor T cell induction. More recent studies have indicated that CsA allows for the amplification of suppressor T lymphocytes independent of interleukin-2 indicating that other cellular and/or soluble factors are important for potentiation of suppressor T lymphocyte activity. However, the molecular action of CsA at the cellular level still remains unresolved. Thus, CsA is not only a useful drug in clinical transplantation but it has become increasingly important as an immunologic probe allowing the dissection of complex cellular interactions involved in the immune response.

Inverse correlation of cyclosporine binding with sensitivity and resistance.

The primary effects of CsA on human lymphocyte responses in vitro appear to be the inhibition of IL-2 production and the inhibition of cytotoxic T cell activation. Induction of suppressor T cell activity is resistant to the effects of CsA. These data imply two distinct subsets of lymphocytes: CsA-resistant and CsA-sensitive. The current studies used a bioactive, dansylated derivative of CsA (dans-CsA), which is fluorescent, to assess binding of CsA at the single-cell level by flow cytometry. The results demonstrate that two populations of cells can be distinguished based on differential staining with dans CsA--a weakly staining subset and a population that binds intensely. Both subsets consist of CD4 (helper) and CD8 (cytotoxic/suppressor) T lymphocytes. Functional analysis revealed that the weakly staining subset consists of IL-2-producing T cells and precursor cytotoxic T lymphocytes. On the other hand, the intensely staining subset includes T cells that suppress in an antigen-specific manner after activation with alloantigen. Further studies showed that the weakly staining subset is markedly sensitive to the immunosuppressive effects of CsA in a PHA stimulation assay, while the intensely binding population is markedly resistant, requiring 10- to 100-fold more CsA to inhibit the PHA response. These studies suggest that sensitivity and resistance to CsA is inversely correlated with binding.

Eosinophilic infiltrates in a pulmonary allograft: a case and review of the literature.

An unusual case of peribronchial eosinophilic infiltrates associated with peripheral blood eosinophilia in a lung transplant patient is described. The role that eosinophils play in lung allograft rejection is reviewed. Tissue eosinophils have been associated with acute pulmonary allograft rejection. Although, eosinophils in bronchoalveolar lavage fluid (BAL) have been observed in allograft rejection, this relationship is less well defined. The role of eosinophils in the pathophysiology of allograft rejection is unclear.

Superior mesenteric vein inflow for liver transplantation when the portal vein is occluded.

An alternative solution to the problem of liver transplantation in the patient with an occluded portal vein is described. It uses a bridge graft of donor iliac vein from the superior mesenteric vein at the base of the colonic mesentery. The graft is tunnelled over the pancreas and under the stomach to the region of the liver hilum to provide portal inflow. This procedure was employed successfully in four patients, with patency for more than 2 years in the patient with the longest follow-up. By this approach it is routinely possible to perform a transplant procedure in a recipient with an occluded portal vein.

Diagnosis and management of congenital vascular rings: a 22-year experience.

Between 1968 and 1990, we operatively treated 39 patients (19 boys, 20 girls) with congenital aortic arch anomalies. Median age was 7 months (range, 1.5 months to 23 years). Thirty-seven patients (95%) had respiratory symptoms. Barium swallow was diagnostic in 95%. Right arch with aberrant left subclavian artery and double aortic arch were the most common types (11 each). Treatment of an aortic diverticulum was documented in 19 patients; the aortic diverticulum was excised (9), managed by aortopexy (7), or left in situ (3). Postoperative recovery was rapid, with a median intensive care unit stay of 2 days, time to oral feeding of 1 day, and postoperative time to discharge of 7 days. Two deaths occurred: 1 infant had undergone emergent operation for control of hemorrhage from an aortotracheal fistula due to tracheostomy tube erosion, and the other had multiple associated congenital heart defects. Postoperative complications included bleeding (1), pneumonia (5), and chylothorax (4). One boy had persistent severe symptoms due to an untreated aortic diverticulum and underwent subsequent excision of the aortic diverticulum with complete relief of symptoms. Median length of follow-up was 12.5 months, with at least 97% of survivors completely or nearly completely free of symptoms from the vascular ring. These results suggest that early repair of congenital aortic vascular rings, including fixating or excising an associated serious aortic diverticulum, is safe and effective and allows for normal tracheal growth.

Chest wall constriction after too extensive and too early operations for pectus excavatum.

BACKGROUND AND METHODS: Since 1990 we have evaluated 12 children and teenagers in whom severe cardiorespiratory symptoms have developed due to failure of chest wall growth after very extensive pectus excavatum operations (removal of five or more ribs) at very early ages (< 4 years). RESULTS: Apparently these extensive procedures have removed or prevented growth center activity, which resulted in restriction of chest wall growth with marked limitation of ventilatory function. The forced vital capacity ranged from 30% to 50% of predicted and the forced expiratory volume in 1 second from 30% to 60%. All patients are symptomatic with mild exercise and cannot compete in running games. Our protocol for critical evaluation includes exercise pulmonary function studies and axial computed tomographic reconstruction. CONCLUSIONS: This report is an alert to recognize such patients and also to recommend delay in operative repair in small children until at least 6 to 8 years of age. The younger the patient the more limited the chest wall resection for pectus excavatum should be. Five of these patients have had a chest cavity expansion operation with encouraging early results.

Atypical thrombotic and septic complications of totally implantable venous access devices in patients with cystic fibrosis.

The use of vascular access systems in patients with cystic fibrosis (CF) is well accepted, with lower overall complications and maintenance costs than percutaneous silastic catheters. We report our 6 year experience with 22 infusaports in 15 CF patients. Our patients had indwelling catheters for an average of 539 days per catheter (range, 14-2,224 days). These infusaports were used for home antibiotic therapy, blood sampling, and total parenteral nutrition. The overall complication rate was relatively low, 1 in every 1,483 catheter days. Infectious complications were extremely infrequent at a rate of 1 in 5,929 catheter days. The rate of mechanical complications was 1 in 1,976 catheter days. However, superior vena caval syndrome or deep venous thrombosis was associated with 3 of 22 catheters (13.6%). Due to this high incidence of major thrombotic events with the attendant risk of pulmonary embolism, all patients with CF using infusaports and without evidence of liver disease or bleeding problems receive aspirin prophylaxis.

Multipurpose central venous access in the immunocompromised pediatric patient.

During a 21-month period, 50 consecutive pediatric oncology patients undergoing bone marrow transplantation and/or cytoreductive chemotherapy had 61 silastic central venous catheters placed to facilitate their therapy. All catheters were used for medications, routine blood sampling, and transfusions, with 45% also used for hyperalimentation and 57% used for bone marrow transplantation. Catheters were utilized during both inpatient and outpatient therapy periods. Total catheter days numbered 8455, an average of 139 days per catheter. Forty-seven catheters (77%) were removed electively or were in place at time of patient death. Seven were removed for mechanical complications (1/1409 catheter days). Four additional episodes of presumed catheter sepsis were managed with antibiotics and did not require catheter removal (40% of septic episodes). One catheter is still in place after 585 days. Complication rates were not influenced by this multiple use protocol. With standardized catheter care and surveillance, multipurpose, long-term central venous access can be safely utilized in the immunosuppressed pediatric patient.

P-glycoprotein status of favorable-histology Wilms' tumor predicts treatment outcome.

Patients with advanced-stage favorable-histology (FH) Wilms' tumor have a 4-year relapse-free survival rate of 70% to 90% after resection and chemotherapy of actinomycin D, vincristine, and doxorubicin. These three agents are actively pumped out of cells by P-glycoprotein (Pgp). The authors studied whether Wilms' tumor expresses Pgp and if the degree of Pgp expression correlates with treatment outcome. At the time of diagnosis, eight blinded paraffin-embedded FH and four anaplastic (ANA) Wilms' tumor sections were immunogold-labeled with a Pgp monoclonal antibody (17F9). Four of the FH-tumor patients had had relapse (FH+) according to the National Wilms' Tumor Study-3 protocol. Negative-relapse FH-tumor patients (FH-) had at least 6 years of follow-up. All 12 Wilms' tumors stained positive for Pgp. Both differentiated tubular structures and blastemal elements expressed Pgp. By the pathologist's score and the computerized cell image analysis, the degree of Pgp staining was greater at the time of diagnosis in FH+ tumors than in FH- tumors (P < .03; Mann-Whitney test). There was no statistically significant difference between ANA and FH+ or FH- tumors. These results show that both FH and ANA Wilms' tumors express Pgp, with higher levels of Pgp expression found in FH patients who had relapse. Current chemotherapeutic protocols, using Pgp-sensitive agents, may not be optimal for all FH Wilms' tumor patients.

Early reconstruction of Poland's syndrome using autologous rib grafts combined with a latissimus muscle flap.

The complex chest wall deformity of Poland's Syndrome may require intervention in early childhood for missing ribs and paradoxical movement of the involved anterior chest with lung herniation. To stabilize the chest wall, we have used autologous rib grafts and prosthetic fabric to replace absent endothoracic fascia. While physiologically sound, this method does nothing for the cosmetic defect which consists of absence of the pectoralis minor and one half to two thirds of the pectoralis major muscles. Silastic implants are not satisfactory in childhood and have complications from recurrent trauma and mobility in young adults. We have had recent experience in three patients (ages 10, 14, and 16 years) with an original technique which results in chest wall stabilization and immediate cosmetic reconstruction without prostheses. The operation utilizes simultaneous rib grafts and a rotational latissimus muscle flap. The muscle not only produces a near-normal contour, but also maintains sensation and contractile function. We propose this technique as a method of choice for the correction of Poland's Syndrome and suggest that it may have wider application in children and teenagers who need soft tissue and muscle replacement of the chest wall for other reasons.

One-year experience in a regional pediatric trauma center.

During 1982, 267 children with life-threatening injuries were admitted to the Maryland Regional Pediatric Trauma Center at the Johns Hopkins Hospital. Seventy-three percent of patients arrived directly from the injury scene by helicopter (46%), ambulance (50%), or other (4%). Mechanisms of injury included motor vehicle accidents (MVA; 55%), falls (27%), assaults (8%), and sports and other injuries (10%). In 75% of MVA the child was a pedestrian. Fifty-one percent of injuries were single organ system, 29% involved two systems, and 20% involved three or more systems. Remarkably, the mortality of 6.7% was not affected by the number of organ systems involved, but was directly related to the presence or absence of head injury. Fourteen of seventeen deaths resulted from head injury. Eighty percent of documented liver and spleen injuries were managed nonoperatively. This nonoperative plan of management simplified the optimal treatment of head injury. The high frequency of head injury has mandated a more aggressive approach to the management of brain trauma including intracranial monitoring to facilitate control of cerebral edema. Our data demonstrate that an excellent quality of life may be anticipated even in children with severe head injury.

Management of a floating sternum after repair of pectus excavatum.

PURPOSE: The aim of this study was to examine the authors' experience with patients who have floating sternum after correction of pectus excavatum via the classical Ravitch procedure. A floating sternum is defined as a sternum in which the only attachment to the chest wall is its superior (cranial) border, and in which the body is secured only by the manubrium and whatever lateral and inferior fibrous bands are present. Typically, a floating sternum is caused by either extensive resection of the costal cartilages and perichondrium during correction of pectus excavatum or failure of proper regrowth of these cartilages. METHODS: The authors retrospectively assessed the charts of all patients diagnosed with a floating sternum noting age at original correction of pectus excavatum, time from original correction of pectus excavatum to diagnosis of floating sternum, age at correction of floating sternum, complaints before stabilization of the sternum, methods of repair, and postoperative complications. RESULTS: Between July 1993 and June 1999, floating sternum was diagnosed in 7 patients. The mean age of patients who underwent operative correction of a floating sternum was 28.9 years (range, 16 to 42 years). The mean time interval between original correction of pectus excavatum, or "redo," and diagnosis of a floating sternum was 9.9 years (range, 2 to 20 years). Complaints before correction of the floating sternum included sternal pain and instability, exercise intolerance, and difficulty breathing. Operative repair consisted of mobilizing the lateral and inferior edges of the sternum, detaching the fibrous perichondrium, performing anterior sternal osteotomies, and finally supporting the sternum with substernal Adkins struts. All 7 patients had successful stabilization of the sternum. Two of 7 patients underwent 2 procedures to successfully stabilize the sternum. One patient has Adkins struts still in place because of hematopoetic malignancy. Six of 7 patients are now without symptoms. CONCLUSIONS: A floating sternum is a morbid phenomenon that may manifest many years after the original procedure. It can cause significant sternal pain, chest wall instability, and respiratory dysfunction, which are the hallmark indications for correction. Repair of a floating sternum can be accomplished successfully.

Cumulative experience with pediatric living related liver transplantation.

PURPOSE: This study reports the authors' cumulative experience with pediatric living related orthotopic liver transplantation. METHODS: The charts of all patients who received living-related liver transplantation to study complications of transplant surgery, immunosuppression, rejection, and overall survival rate were reviewed retrospectively. RESULTS: Between November 1992 and October 1998, 30 children underwent living-related liver transplantation. Patients were between the ages of 3 months and 7 years of age (mean, 28 months). All received left lateral segmental living-related transplants. At the time of transplant, 14 of 30 patients were listed as United Network of Organ Sharing (UNOS) status 3, 11 were listed as UNOS status 2B, and 5 were listed as UNOS status 1. Indications for transplant included biliary atresia (n = 21), alpha-1-antitrypsin deficiency (n = 2), hepatitis C (n = 2), giant cell hepatitis (n = 2), hepatoblastoma (n = 1), valproic acid toxicity (n = 1), and hemangioendothelioma (n = 1). All donors were parents except for one uncle. There were no major donor complications. Minor complications included wound infection (n = 4), ventral hernia (n = 2), postoperative gastric dysmotility (n = 2), and 1 case of central line-related pneumothorax (n = 1). All but 4 recipients received primary tacrolimus immunosuppressive regimens, and the other 4 underwent conversion from cyclosporine. Initial tacrolimus therapy was begun at 0.15 mg/kg/dose PO/NG every 12 hours. Concomitant immunosuppression included methylprednisolone and mycophenolate mofetil. Fifty-three percent of patients experienced at least 1 episode of rejection, and 27% experienced multiple episodes. Immediate postoperative complications included primary nonfunction (n = 2), vascular thrombosis (n = 3), biliary leaks (n = 3), and infections (n = 17). Two patients (n = 2) required retransplantation. Complications of immunosuppressive therapy included persistent systemic hypertension (n = 6), renal tubular acidosis (n = 3), short-term hyperglycemia (n = 2), neurotoxicity (n = 2), nephrotoxicity (n = 2), food allergies (n = 8), and posttransplant lymphoproliferative disease (n = 4). All patients with PTLD were treated with immunosuppression reduction or withdrawal. Two of 4 had disease progression requiring chemotherapy. The majority of complications were treated with dose adjustments. There were 4 early deaths (13%): 1 of primary nonfunction, 2 of sepsis, and 1 of arrhythmia and renal failure. There was 1 late death of recurrent disease. Twenty-five patients (83%) are alive at 3 months to 6 years post-transplant. CONCLUSION: Living-related orthotopic liver transplantation is an effective intervention for pediatric patients with end-stage disease.