Comparison of Segmental Versus Longitudinal Intravascular Ultrasound Analysis for Pediatric Cardiac Allograft Vasculopathy.

Intravascular ultrasound (IVUS) has been routinely used in some centers to investigate cardiac allograft vasculopathy in pediatric heart transplant recipients. We present an alternative method using more sophisticated imaging software. This study presents a comparison of this method with an established standard method. All patients who had IVUS performed in 2014 were retrospectively evaluated. The standard technique consisted of analysis of 10 operator-selected segments along the vessel. Each study was re-evaluated using a longitudinal technique, taken at every third cardiac cycle, along the entire vessel. Semiautomatic edge detection software was used to detect vessel imaging planes. Measurements included outer and inner diameter, total and luminal area, maximal intimal thickness (MIT), and intimal index. Each IVUS was graded for severity using the Stanford classification. All results were given as mean ± standard deviation (SD). Groups were compared using Student t test. A P value <.05 was considered significant. There were 59 IVUS studies performed on 58 patients. There was no statistically significant difference between outer diameter, inner diameter, or total area. In the longitudinal group, there was a significantly smaller luminal area, higher MIT, and higher intimal index. Using the longitudinal technique, there was an increase in Stanford classification in 20 patients. The longitudinal technique appeared more sensitive in assessing the degree of cardiac allograft vasculopathy and may play a role in the increase in the degree of thickening seen. It may offer an alternative way of grading severity of cardiac allograft vasculopathy in pediatric heart transplant recipients.

The Influence of Race and Common Genetic Variations on Outcomes After Pediatric Heart Transplantation.

Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow-up was 6.25 years. Unadjusted 5-year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8-19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes.

ABH-Glycan Microarray Characterizes ABO Subtype Antibodies: Fine Specificity of Immune Tolerance After ABO-Incompatible Transplantation.

Organ transplantation from ABO blood group-incompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century-old assay used clinically, does not discriminate subtype-specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO-glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor-specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO-compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens-the only ABH antigen subtypes expressed in heart tissue-were absent, demonstrating the fine specificity of B cell tolerance to donor/graft blood group antigens. In contrast to the hemagglutination assay, the ABO-glycan microarray allows detailed characterization of donor-specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection.

A 16-year multi-institutional study of the role of age and EBV status on PTLD incidence among pediatric heart transplant recipients.

The objective was to determine the incidence and hazard for posttransplant lymphoproliferative disease (PTLD) in a study of 3170 pediatric primary heart transplants between 1993 and 2009 at 35 institutions in the Pediatric Heart Transplant Study. 147 of 151 reported malignancy events were classified as PTLD. Overall freedom from PTLD was 98.5% at 1 year, 94% at 5 years and 90% at 10 years. Freedom from PTLD was lowest in children (ages 1 to < 10 years) versus infants (<1 year) and adolescents (10 to < 18 years) with children at highest risk for PTLD with a relative risk of 2.4 compared to infants and 1.7 compared to adolescents. Positive donor EBV status was a strong risk factor for PTLD in the seronegative recipient, but risk magnitude was dependent on recipient age at the time of transplantation. Nearly 25% of EBV seronegative recipients of EBV+ donors at ages 4-7 at transplantation developed some form of PTLD. The overall risk for PTLD declined in the most recent transplant era (2001-2009, p = 0.003). These findings indicate that EBV status and the age of the recipient at the time of transplantation are important variables in the development of PTLD in the pediatric heart transplant recipient.

A pathway to insulin independence in newborns and infants with diabetes.

Permanent neonatal diabetes was previously assumed to require insulin injection or infusion for life. Recently, permanent neonatal diabetes resulting from mutations in the two protein subunits of the adenosine triphosphate-sensitive potassium channel (Kir6.2 and SUR1) has proven to be successfully treatable with high doses of sulfonylureas rather than insulin. Many patients with these mutations first develop hyperglycemia in the nursery or intensive care unit. The awareness of the neonatolgist of this entity can have dramatic effects on the long-term care and quality of life of these patients and their families. In this study, we present the experience of our center, highlighting aspects relevant to neonatal diagnosis and treatment.

Association of race and socioeconomic position with outcomes in pediatric heart transplant recipients.

We assessed the association of socioeconomic (SE) position with graft loss in a multicenter cohort of pediatric heart transplant (HT) recipients. We extracted six SE variables from the US Census 2000 database for the neighborhood of residence of 490 children who underwent their primary HT at participating transplant centers. A composite SE score was derived for each child and four groups (quartiles) compared for graft loss (death or retransplant). Graft loss occurred in 152 children (122 deaths, 30 retransplant). In adjusted analysis, graft loss during the first posttransplant year had a borderline association with the highest SE quartile (HR 1.94, p = 0.05) but not with race. Among 1-year survivors, both black race (HR 1.81, p = 0.02) and the lowest SE quartile (HR 1.77, p = 0.01) predicted subsequent graft loss in adjusted analysis. Among subgroups, the lowest SE quartile was associated with graft loss in white but not in black children. Thus, we found a complex relationship between SE position and graft loss in pediatric HT recipients. The finding of increased risk in the highest SE quartile children during the first year requires further confirmation. Black children and low SE position white children are at increased risk of graft loss after the first year.

BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient.

BK virus is a human polyoma virus that may cause nephropathy in immunosuppressed patients. It is a well-recognized cause of renal allograft dysfunction and allograft loss in renal transplant recipients, but it is an infrequent cause of nephropathy outside this setting. There are a few case reports of BK virus nephropathy in the native kidneys of immunosuppressed adult patients with non-renal transplants, but so far it has not been reported in pediatric non-renal solid organ transplant recipients. We report a case of a seven-yr-old heart transplant patient who was diagnosed with BK virus nephropathy, eight months after his second heart transplant. Despite intervention, his renal dysfunction progressed to renal failure. He is currently receiving maintenance hemodialysis and awaiting renal transplantation. It is important to recognize BK virus infection as a possible cause of renal dysfunction in immunosuppressed children who are non-renal transplant recipients.

Efficacy comparison between intraportal and subcapsular islet transplants in a murine diabetic model.

BACKGROUND: It is important to determine the efficacy of intraportal (IP) islet transplantation in comparison with other transplant sites. In this study, we sought to determine the optimal number of islets to achieve normoglycemia following transplantation into the liver versus the kidney using a mouse model. METHODS: Streptozotocin-induced diabetic mice (Balb/C) were transplanted with syngeneic islets via the IP versus renal subcapsular (SC) routes. The transplanted islet numbers were 0 to 800 (n = 3-5). We assessed the correlation between parameters and islet numbers, comparing IP versus SC groups. The parameters were: (1) percentage of normoglycemia; (2) postoperative days to normoglycemia; (3) mean blood glucose levels at various points from pretransplantation to the end of the study (postoperative day 28); (4) mean serum insulin; and (5) area under the curve of blood glucose levels after glucose injection. RESULTS: Two hundred islets yielded normoglycemia in renal subcapsular grafts, while 800 islets were the minimum required for normoglycemia with IP transplantation. The transplant efficacy in SC transplantation was 2 to 5 times greater than that of IP transplantation. The days to normoglycemia were significantly different between IP versus renal SC islets (13.25 +/- 4.38 days vs 4.50 +/- 0.81 days; P = .007). CONCLUSION: The efficacy of islet transplantation in murine diabetic models was significantly greater under the kidney capsule. Clinical islet transplantation could benefit from trials of alternative transplant sites.

Dynamic production of hypoxia-inducible factor-1alpha in early transplanted islets.

More than half of transplanted beta-cells undergo apoptotic cell death triggered by nonimmunological factors within a few days after transplantation. To investigate the dynamic hypoxic responses in early transplanted islets, syngeneic islets were transplanted under the kidney capsule of balb/c mice. Hypoxia-inducible factor-1alpha (HIF-1alpha) was strongly expressed at post-transplant day (POD) 1, increased on POD 3, and gradually diminished on POD 14. Insulin secretion decreased on POD 3 in association with a significant increase of HIF-1alpha-related beta-cell death, which can be suppressed by short-term hyperbaric oxygen therapy. On POD 7, apoptosis was not further activated by continually produced HIF-1alpha. In contrast, improvement of nerve growth factor and duodenal homeobox factor-1 (PDx-1) production resulted in islet graft recovery and remodeling. In addition, significant activation of vascular endothelial growth factor in islet grafts on POD 7 correlated with development of massive newly formed microvessels, whose maturation is advanced on POD 14 with gradual diminution of HIF-1alpha. We conclude that (1) transplanted islets strongly express HIF-1alpha in association with beta-cell death and decreased insulin production until adequate revascularization is established and (2) early suppression of HIF-1alpha results in less beta-cell death thereby minimizing early graft failure.

Beneficial effects of nerve growth factor on islet transplantation.

OBJECTIVE: Development of the Edmonton protocol was a pivotal contribution to clinical islet transplantation (ITx). Persistent limitations to ITx include insufficient supply and posttransplant functional failure of islets. In this study, nerve growth factor (NGF) was used to enhance both cultured and transplanted beta-cell function, thus achieving prolonged graft survival. METHODS: Fluorescence microscopy with ethidium bromide and SYTO green staining was used to evaluate balb/c mouse islet viability. Islets were syngeneically transplanted under the kidney capsule of recipients with streptozotocin-induced diabetes. Intraperitoneal glucose tolerance was used to test posttransplant function. RESULTS: Improved viability was found in murine islets cultured for 48 hours in 500 ng/mL NGF (P < .05). A submarginal islet mass (260 islet equivalents/recipient) was used for ITx. The NGF-culture resulted in prolonged islet survival (24.7 days vs 5.5 days without NFG culture, n = 6). Intravenous injection of NGF (6 mug) on the day of transplant and postoperative days (POD) 1 + 2 prolonged islet survival from 4.1 days (no treatment) to 13.2 days (n = 6). Glucose tolerance testing performed at posttransplant day 4 showed improvement at 60 and 120 minutes in recipients treated intravenously with NGF (blood glucose of 95 +/- 15 vs 210 +/- 78 and 57 +/- 6 vs 176 +/- 70 mg/dL, respectively). CONCLUSION: NGF may improve beta-cell function and result in prolonged survival of both cultured and transplanted islets.

Fate of infants with hypoplastic left heart syndrome listed for cardiac transplantation: a multicenter study.

BACKGROUND: Infants with hypoplastic left heart syndrome (HLHS) commonly undergo cardiac transplantation as primary management. METHODS: We examined outcomes of primary transplantation for unpalliated HLHS. We analyzed data from the 20 institutions of the Pediatric Heart Transplant Study Group, from January 1, 1993, through December 31, 1998, using actuarial and parametric survival analysis and competing outcomes analysis. RESULTS: During the 6 years studied, 1,234 patients were listed for cardiac transplantation; 262 patients (21.2%) had unpalliated HLHS. The number (and percentage) of patients with HLHS decreased from 58 (27% of patients listed) in 1993 to 30 (14%) in 1998. Overall, 25% of infants with HLHS died while waiting; primary cause of death was cardiac failure (50%). Of the remaining patients awaiting transplantation, 23 (9%) underwent Norwood/Fontan-type surgeries as interim palliation: 52% died. Ultimately, 175 patients underwent cardiac transplantation (67%); 50% received organs by 2 months after listing. Post-transplant actuarial survival was 72% at 5 years, with 76% of deaths (35/46) occurring within 3 months; early mortality was caused primarily by graft failure within the first 30 days after transplantation (in 54%). Among 1-month survivors, survival at 1 and at 5 years was 92% and 85%, respectively. Of the 262 patients listed with unpalliated HLHS, overall survival, taking into account mortality after listing and after transplantation, was 68% at 3 months and 54% at 5 years. CONCLUSIONS: Cardiac transplantation offers good intermediate survival for infants with unpalliated HLHS.

Morbidities in patients with hypoplastic left heart syndrome.

We sought to document morbidities and growth for patients with hypoplastic left heart syndrome (HLHS) to inform the initial surgical decision and understand healthcare needs. Data were obtained on 137 patients with HLHS, born between 1989 and 1994, who survived staged surgery ( n = 62) or transplantation ( n = 75) and had follow-up information available from four pediatric cardiac surgical centers. In patients with HLHS older than 1 year of age at follow-up, 93% experienced at least one major postsurgical morbidity. Morbidities depended on the surgery received. Hypertension, renal compromise, and abnormal infections were more common in transplanted patients than staged surgery patients. Staged surgery patients used more anticongestive medications and experienced more morbidities requiring interventional catheterization than did transplanted patients. Rejection was common for transplanted patients. On average these children spent 23 days per year in the hospital. Patients with HLHS were small for their age; 43% of staged surgery patients weighed below the third percentile at last information, compared to 19% of transplanted patients ( p = 0.003). The median height percentile was the 10th in both groups. Normal activity level was reported in more transplanted patients (90%) than staged surgery patients (49%; p < 0.001). Trade-offs between mortality and morbidity outcomes can help inform the initial surgical decision.

A comparison of treatment strategies for hypoplastic left heart syndrome using decision analysis.

OBJECTIVES: We sought to identify the optimal treatment strategy for hypoplastic left heart syndrome (HLHS). BACKGROUND: Surgical treatment of HLHS involves either transplantation (Tx) or staged palliation of the native heart. Identifying the best treatment for HLHS requires integrating individual patient risk factors and center-specific data. METHODS: Decision analysis is a modeling technique used to compare six strategies: staged surgery; Tx; stage 1 surgery as an interim to Tx; and listing for transplant for one, two, or three months before performing staged surgery if a donor is unavailable. Probabilities were derived from current literature and a dataset of 231 patients with HLHS born between 1989 and 1994. The goal was to maximize first-year survival. RESULTS: If a donor is available within one month, Tx is the optimal choice, given baseline probabilities; if no donor is found by the end of one month, stage 1 surgery should be performed. When survival and organ donation probabilities were varied, staged surgery was the optimal choice for centers with organ donation rates < 10% in three months and with stage 1 mortality <20%. Waiting one month on the transplant list optimized survival when the three-month organ donation rate was > or =30%. Performing stage 1 surgery before listing, or performing stage 1 surgery after an unsuccessful two- or three-month wait for transplant, were almost never optimal choices. CONCLUSIONS: The best strategy for centers that treat patients with HLHS should be guided by local organ availability, stage 1 surgical mortality and patient risk factors.

Association of viral genome with graft loss in children after cardiac transplantation.

BACKGROUND: The survival of recipients of cardiac allografts is limited by rejection, lymphoproliferative disease, and coronary vasculopathy. The purpose of this study in children who had received heart transplants was to evaluate the cardiac allografts for myocardial viral infections and to determine whether the presence of viral genome in the myocardium correlates with rejection, coronary vasculopathy, or graft loss. METHODS: We enrolled heart-transplant recipients 1 day to 18 years old who were undergoing evaluation for possible rejection and coronary vasculopathy. Endomyocardial-biopsy specimens were evaluated for evidence of rejection with the use of standard criteria and were analyzed for the presence of virus by the polymerase chain reaction (PCR). RESULTS: PCR analyses were performed on 553 consecutive biopsy samples from 149 transplant recipients. Viral genome was amplified from 48 samples (8.7 percent) from 34 patients (23 percent); adenovirus was found in 30 samples, enterovirus in 9 samples, parvovirus in 5 samples, cytomegalovirus in 2 samples, herpes simplex virus in 1 sample, and Epstein-Barr virus in 1 sample. In 29 of the 34 patients with positive results on PCR (85 percent), an adverse cardiac event occurred within three months after the positive biopsy, and 9 of the 34 patients had graft loss due to coronary vasculopathy, chronic graft failure, or acute rejection. In 39 of the 115 patients with negative results on PCR (34 percent), an adverse cardiac event occurred within three months of the negative PCR finding; graft loss did not occur in any of the patients in this group. The odds of graft loss were 6.5 times as great among those with positive results on PCR (P=0.006). The detection of adenovirus was associated with considerably reduced graft survival (P=0.002). CONCLUSIONS: Identification of viral genome, particularly adenovirus, in the myocardium of pediatric transplant recipients is predictive of adverse clinical events, including coronary vasculopathy and graft loss.

Pediatric cardiac retransplantation: intermediate-term results.

BACKGROUND: Cardiac retransplantation (re-CTx) in children is a controversial therapy, yet it remains the best treatment option to recipients with failing grafts. Our objective was to determine the incidence of re-CTx in a large pediatric population of recipients and evaluate the outcome of such therapy. METHODS: Between November 1985 and November 1999, 347 children underwent cardiac transplantation at the Loma Linda University Medical Center. Of these, 32 children were listed for re-CTx. Ten patients died while waiting, and 22 recipients underwent re-CTx. Median age at re-CTx was 7.1 years (range, 52 days to 20.1 years). RESULTS: Indications for re-CTx were allograft vasculopathy (n = 16), primary graft failure (n = 5), and acute rejection (n = 1). Two patients with primary graft failure underwent retransplantation within 24 hours of the first transplantation procedure while on extracorporeal membrane oxygenation support. Median time interval to re-CTx for the others was 7.2 years (range, 32 days to 9.4 years). Operative mortality for all cardiac re-CTx procedures was 13.6%. Causes of hospital mortality were pulmonary hypertension with graft failure (n = 2) and multiorgan failure (n = 1). Median hospital stay after re-CTx was 14.1 days (range, 6 to 45 days). There was one late death from severe rejection. Actuarial survival at 3 years for re-CTx was 81.9% +/- 8.9% compared with 77.3% +/- 2.6% for primary cardiac transplantation recipients (p = 0.70). CONCLUSIONS: Elective re-CTx can be performed with acceptable mortality. Although the number of patients undergoing retransplantation in this report is small and their long-term outcome is unknown, the intermediate-term survival after re-CTx is similar to that of children undergoing primary cardiac transplantation.

Late rejection is a predictor of transplant coronary artery disease in children.

OBJECTIVE: The study objectives were to determine posttransplant coronary artery disease (TxCAD) incidence, predisposing factors and optimal timing for retransplantation (re-Tx) in pediatric heart transplantation (Tx) recipients. BACKGROUND: The TxCAD limits long-term survival following heart Tx, with re-Tx being the primary therapy. Information on risk factors and timing of listing for re-Tx is limited in children. METHODS: The records of children who survived >1 year post-Tx at Loma Linda University were reviewed. Nonimmune and immune risk factors were analyzed. RESULTS: TxCAD was documented in 24 of 210 children. Freedom from TxCAD was 92 +/- 2% and 75 +/- 5% at 5 and 10 years' post-Tx, respectively. The TxCAD diagnosis was established at autopsy in 10 asymptomatic patients who died suddenly within nine months following the most recent negative angiograms. The remaining 14 children had angiographic diagnoses of TxCAD and had symptoms and/or graft dysfunction (n = 10) or positive stress studies (n = 4). Three of 14 died within three months after the diagnosis was made. Eleven patients underwent re-Tx within seven months of diagnosis; nine survived. Univariate and multivariate analyses showed that only late rejection (>1 year posttransplant) frequency (p = 0.025) and severity (hemodynamically compromising) (p < 0.01) were independent predictors of TxCAD development. Freedom from TxCAD after severe late rejection was 78 +/- 8% one year postevent and 55 +/- 10% by two years. CONCLUSIONS: Late rejection is an independent predictor of TxCAD. Patients suffering severe late rejection develop angiographically apparent TxCAD rapidly and must be monitored aggressively. Both TxCAD mortality and morbidity occur early; therefore, we recommend immediate listing for re-Tx upon diagnosis.

Outcome of infants with hypoplastic left heart syndrome who undergo atrial septostomy before heart transplantation.

This study evaluated the procedural and long-term outcome of infants who underwent atrial septostomy while awaiting transplant. The results suggest that septostomy improved outcome in these patients although infants needing a transseptal perforation were at higher risk.