Pediatric Solid Organ Recipients Research Articles

Pathophysiology of De Novo Food Allergies After Solid Organ Transplant in Pediatric Patients.

De novo food allergy is a common phenomenon among pediatric solid organ recipients (8.5%-57%) when compared with the general population (0.45%-10%). Other associated disorders include non-IgE-mediated immune reactions and clinical predisposition to asthma and alterations in the oral mucosa. Originally, passive mechanisms (passive transfer of IgE and immune cells) were thought to be responsible for acute, transient cases of food allergies with a previous history of sensitization for a specific allergen in the donor. Recently proposed pathophysiological mechanisms to explain de novo allergies include TH2/B-cell imbalance, regulatory T-cell (Treg) disruption, gastrointestinal immaturity, and altered gastrointestinal permeability. Recent studies also suggest that immunosuppressive drugs, especially tacrolimus, promote naïve T-cell differentiation into TH2 cells, IgE-promoting cytokine production, decreased IL-5 and IL-10 levels, increased IgA levels, and Treg disruption. Such immunological interactions, in conjunction with altered intestinal permeability, intestinal immaturity in children, history of viral infection, and a personal history of allergies or eczema, are thought to explain most clinical cases of pediatric de novo food allergy after solid organ transplantation reported in the literature. A better understanding of the immunological mechanisms underpinning organ donors and recipients may unveil some of the caveats concerning therapeutic management and improve the quality of life of affected individuals.

Long‐term mortality in pediatric solid organ recipients—A nationwide study

The present study aimed at investigating long-term mortality of patients who underwent solid organ transplantation during childhood and at identifying their causes of death. A cohort of 233 pediatric solid organ transplant recipients who had a kidney, liver, or heart transplantation between 1982 and 2015 in Finland were studied. Year of birth-, sex-, and hometown-matched controls (n=1157) were identified using the Population Register Center registry. The Causes of Death Registry was utilized to identify the causes of death. Among the transplant recipients, there were 60 (25.8%) deaths (median follow-up 18.0 years, interquartile range of 11.0-23.0 years). Transplant recipients' risk of death was nearly 130-fold higher than that of the controls (95% CI 51.9-1784.6). The 20-year survival rates for kidney, liver, and heart recipients were 86.1% (95% CI 79.9%-92.3%), 58.5% (95% CI 46.2%-74.1%), and 61.4% (95% CI 48.1%-78.4%), respectively. The most common causes of death were cardiovascular diseases (23%), infections (22%), and malignancies (17%). There were no significant differences in survival based on sex or transplantation era. The late mortality is still significantly higher among pediatric solid organ recipients in comparison with controls. Cardiovascular complications, infections, and cancers are the main causes of late mortality for all studied transplant groups. These findings emphasize the cruciality of careful monitoring of pediatric transplant recipients in order to reduce long-term mortality.

Pediatric EBV-negative monomorphic post–solid organ transplant lymphoproliferative disorders [EBV(-)M-PTLD]: Characteristics, treatment, and outcome from 11 pediatric academic centers.

10012 Background: Pediatric EBV(-)M-PTLD comprises < 15% of M-PTLD. Two-year-overall survival of pediatric EBV(+) PTLD is 83%. No large multi-institution pediatric-specific reports are available for EBV(-)M-PTLD. Methods: Retrospective study of characteristics, treatment, and outcome of pediatric solid organ recipients diagnosed with EBV(-)M-PTLD at age ≤21 years (y) in 11 pediatric transplant centers in US and UK. Results: Thirty-three patients transplanted with solid organs between 1991-2017 developed EBV(-)M-PTLD. Twenty-two (66%) were male. Median age (range) at organ transplantation was 2.6y(0.1-17), diagnosis of EBV(-)M-PTLD 14y(3-20), interval from transplant to PTLD 8.3y (2.3-18). Transplanted organs were heart (n = 10), kidney (n = 17), liver (n = 4), small bowel (n = 1), liver and small bowel (n = 1). Immunosuppressive therapy at the time of diagnosis of PTLD was available on 31 patients. All were receiving a calcineurin inhibitor except one who was on sirolimus alone. Tacrolimus was given in 27 patients, alone (n = 3), or in various combination with mycophenolate (n = 8), azathioprine (n = 9), prednisone (n = 8), or everolimus (n = 1). Four of these receiving tacrolimus received 3 immunosuppressive drug combinations. Cyclosporine was given in 3 patients, with mycophenolate (n = 1), prednisone (n = 1), or both (n = 2). Murphy stages were I (n = 1), II (n = 7), III (n = 22), and IV (n = 3). Lactate dehydrogenase was elevated in 19/31 (61%) and > 2X upper limit of normal in 10/31 (32%) tested. Pathological diagnoses were diffuse large B-cell lymphoma (n = 30) and B-NHL NOS (n = 3). Treatment included: rituximab alone (n = 1), low-dose cyclophosphamide, prednisone, and rituximab (CPR; n = 9), pediatric mature B-NHL-specific regimen [FAB/LMB with (n = 12) or without (n = 1) rituximab], EPOCH-R (n = 2), R-CHOP (n = 3), modified R-CHOP (n = 2), COP (n = 1), and R-COP (n = 2). At a median 2.9y (0.3-11y) from diagnosis, 26/33 (79%) were alive and in complete remission (CR). Three experienced relapses at 1, 3, and 6.5y after CPR, rituximab alone, and B-NHL therapy, respectively. All achieved a sustained second CR with additional B-NHL therapy. Of the 7 deaths: 6 were from progressive disease despite escalation to intensive B-NHL therapy following initial COP (n = 1), R-COP (n = 1), CPR (n = 2), and B-NHL therapy (n = 2), and one cardiac transplant recipient from presumed cardiotoxicity. There was one graft rejection that was successfully treated. Conclusions: This collaboration represents the first multi-institution series of pediatric EBV(-)M-PTLD. Overall survival was comparable to that reported for pediatric EBV(+) PTLD, but inferior to DLBCL in immunocompetent children. These preliminary data reflect a wide range of therapeutic regimens used over 20 years and strongly support an organized collaborative effort to collect data prospectively.

Diabetes mellitus in pediatric solid organ recipients without and with cystic fibrosis: An analysis from the German-Austrian diabetes database (Diabetes Patienten Verlaufsdokumentation).

Posttransplantation diabetes mellitus (PTDM) increases the risk of cardiovascular disease, graft loss, and decreased survival. Follow-up treatment after solid organ transplantation (SOT) needs to focus on, inter alia, maintaining balanced glucose metabolism. This study aimed to ascertain the prevalence of PTDM and describe patient characteristics in the large DPV (Diabetes Patienten Verlaufsdokumentation) pediatric diabetes database. DPV data of 71 902 patients from the January 01, 1995 to January 04, 2015 period were analyzed for patients with and without cystic fibrosis (CF) after SOT (kidney, liver, heart, and lung). Multivariable analysis served to assess differences between SOT patient groups at risk for developing diabetes. Out of 109 SOT patients, 51 had CF; 72.5% received steroids and 62% were additionally given tacrolimus. PTDM developed in 45% of CF patients and 12% of non-CF patients. SOT patients were older at diabetes onset (mean age, 12.50 ± 3.98 years), shorter (height z-score, -1.67 ± 1.25), and lighter (weight z-score, -1.59 ± 1.57) than non-SOT diabetes patients (P < 0.01). With transplantation, glycated hemoglobin (HbA1c) was significantly lower and treatment for hypertension and dyslipidemia was increased. Among SOT patients, weight and body mass index (BMI) z-scores were significantly lower in patients with CF-related diabetes (P < 0.05). SOT was present in 6.6% of children with diabetes, and this might aggravate the risk of cardiovascular disease in populations with already increased rates of hypertension and dyslipidemia. Dystrophy and short stature were also present, particularly in transplant recipients with CF and diabetes. Comorbidities and long-term consequences call for multidisciplinary collaboration.

The importance of cardiovascular disease in pediatric transplantation and its link to the kidneys.

Cardiovascular disease is a frequent cause of morbidity and mortality in pediatric patients following solid organ transplant. CKD is also common in pediatric patients after a solid organ transplant, and the link between CKD and cardiovascular morbidity is strong. In this review, we examine potential etiologies to explain the risk of cardiovascular morbidity and mortality in pediatric solid organ recipients and identify targets for improving outcomes.

Management of post-transplant Epstein-Barr virus-related lymphoproliferative disease in solid organ and hematopoietic stem cell recipients.

Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) is one of the most serious complications associated with solid organ and hematopoietic stem cell transplantation. PTLD is most frequently seen with primary EBV infection post-transplant, a common scenario for pediatric solid organ recipients. Risk factors for infection or reactivation of EBV following solid organ transplant are stronger immunosuppressive therapy regimens, and being seronegative for receptor. For hematopoietic stem cell transplantation, the risk factors relate to the type of transplant, human leukocyte antigen disparity, the use of stronger immunosuppressants, T-cell depletion, and severe graft-versus-host disease. Mortality is high, and most frequent in patients who develop PTLD in the first six months post-transplant. The primary goal of this article is to provide an overview of the clinical manifestations, diagnosis, accepted therapies, and management of EBV infection in transplant recipients, and to suggest that the adoption of monitoring protocols could contribute to a reduction in related complications.

Cryptosporidiosis in Children Following Solid Organ Transplantation

Cryptosporidium parvum is a common cause of diarrhea. In immunocompetent individuals, spontaneous recovery is the rule. In immunocompromised patients, it may cause a serious disease. Data on cryptosporidiosis in children after solid organ transplantation are few. We report on 6 pediatric solid organ recipients with gastroenteritis caused by Cryptosporidium. All episodes of gastroenteritis in solid organ transplant recipients hospitalized in Schneider Children's Medical Center from January 2008 to August 2011 were identified. Data on the episodes with positive staining for Cryptosporidium antigen in stool were reviewed. Fifty-seven episodes of gastroenteritis were recorded. In 6 (11%) patients (4 kidney recipient, 1 liver and kidney recipient and 1 heart transplant recipient) Cryptosporidium antigen was detected in stool. Mean age at transplantation was 3.7 ± 2 years, mean time between transplantation and cryptosporidial disease was 39 ± 53.9 months. Symptoms included prolonged diarrhea, fever, abdominal pain and weight loss. Mean duration of symptoms before diagnosis was 10.5 ± 8.7 days. In 5 children, kidney function deteriorated, blood concentrations of tacrolimus increased in 5 patients and abnormal values of liver enzymes were detected in 4 patients. All patients were hospitalized and received intravenous fluid replacement and were treated with nitazoxanide for 5-21 days. Two patients had recurrence of symptoms after short course (5 days) therapy. All patients recovered eventually from the disease. Cryptosporidium should be routinely tested in solid organ transplant recipients with diarrhea. Delay in initiation of treatment can result in serious complications including acute renal failure. Long-term therapy with nitazoxanide (at least 14 days) may facilitate recovery.

Vaccination Status of Children Considered for Renal Transplant: Missed Opportunities for Vaccine Preventable Diseases

Infectious diseases, even vaccine preventable ones, might affect transplanting and the life course in pediatric solid-organ recipients. Owing to immunosuppression and decreased antibody production, susceptibility to infections is increased in these patients. The present study was designed to assess the vaccination and antibody status of the pediatric renal transplant patients. Fifty-one patients who were admitted to the regional transplant center for renal transplant were retrospectively evaluated. Patient 's vaccination charts were examined, and their immunization status was determined by antibody titers against hepatitis B, hepatitis A, measles, mumps, rubella, and varicella. The study group was composed of 23 males and 28 females (mean age, 10.8 y; age range, 2-17 y). All patients ' vaccination status was appropriate with their ages according to national vaccination program. Antibodies were positive for hepatitis B in 84.3% patients, 76.5% for hepatitis A, 72.5% for measles, 64.7% for mumps, 64.7% for rubella, and 72.5% for varicella. Seronegativity for common childhood diseases may complicate the posttransplant period owing to increased risk of infections. Especially in developing countries, immunization protocols and vaccination program schedules should be reviewed before transplant to prevent serious complications caused by these diseases.

CXCL13 as a Novel Marker for Diagnosis and Disease Monitoring in Pediatric PTLD

Posttransplant lymphoproliferative disease (PTLD) is a severe complication of immunosuppressive treatment in organ-grafted children. Early diagnosis of PTLD is hampered by both unspecific clinical symptoms and lack of easy accessible markers. The homeostatic chemokine CXCL13, which plays a crucial role in B-cell homing and lymphoid organ development, is expressed in some lymphomatous diseases. This study aims to investigate whether serum CXCL13 (sCXCL13) levels correlate with occurrence and regression of PTLD in pediatric solid-organ graft recipients. Serum samples from PTLD patients (n = 21), patients with Epstein-Barr virus (EBV) reactivation (n = 18), and healthy age-matched controls (n = 19) were tested for CXCL13 using a commercially available ELISA kit. sCXCL13 levels were significantly higher in PTLD patients than in healthy children. PTLD patients had also higher sCXCL13 values than pediatric solid-organ recipients with EBV reactivation. An increase in sCXCL13 levels was observed from EBV reactivation to PTLD diagnosis in most cases. Elevated sCXCL13 levels were detected up to 2 years prior to PTLD diagnosis and correlated well with response to cytoreductive treatment in individual patients. sCXCL13, thus, may be a readily available surrogate marker for the diagnosis of PTLD and for monitoring of response to treatment in patients with initially elevated sCXCL13 levels.

Sirolimus in pediatric renal transplantation

SRL, an mTOR inhibitor that inhibits cell cycle progression, represents an important alternative to CNIs, which are still the cornerstones of pediatric solid organ tx. Because there are still limited data on SRL use among pediatric solid organ recipients, further studies are needed to verify the efficacy and safety of SRL. It has unique pharmacokinetic characteristics concerning dosing intervals and reduction of the dose in combination with other immunosuppressants. SRL also has antineoplastic, antiviral, and antiatherogenic advantages over other immunosuppressive agents. The adverse effects of SRL including thrombocytopenia, hyperlipidemia, proteinuria, impaired wound healing, mouth ulcers, edema, male hypogonadism, TMA, and interstitial pneumonitis must be considered carefully in pediatric population. This article reviews the most recent data on SRL application in the field of pediatric renal tx.

Rotavirus enteritis in solid organ transplant recipients: an underestimated problem?

Diarrhea in solid organ transplantation can be a complication with a high morbidity and mortality. Rotavirus (RV) infection normally occurs in children up to 3 years of age and often presents with severe diarrhea; however, it can also affect adults. We investigated the prevalence and outcome of RV infections in both adult and pediatric patients after solid organ transplantation. Retrospective analysis of RV-related enteritis in solid organ transplant recipients with a minimum of a 1-year follow-up from a single center between 2000 and 2004. Within our cohort of 1303 solid organ transplants, RV infection was observed in 19 patients (1.5%); 14 of these were liver recipients. Infection was most prevalent among pediatric liver recipients, with 52% (11/21) of the children affected. Five adults acquired the infection during their initial hospitalization. Two adult patients had to be readmitted following late-onset RV infection. In all cases, infection was self-limiting, but led to prolonged hospitalization because of significant loss of fluids and electrolytes. RV enteritis is a common infection in pediatric solid organ recipients but may also affect adult patients.

Enterocolitis due to Simultaneous Infection with Rotavirus and Clostridium difficile in Adult and Pediatric Solid Organ Transplantation

Diarrhea is a well-known complication of immunosuppression but is also frequently caused by pathogens such as Clostridium difficile (CD) and rotavirus (RV). Three adult and five pediatric solid organ recipients (SORs) developed diarrhea with simultaneous identification of CD and RV. Rotavirus was identified using an immunochromatografic- or enzyme-linked immunosorbent assay; CD was identified using a rapid immunoassay or enzyme immunoassay. One adult renal, one adult kidney–pancreas, one adult liver, and five pediatric liver recipients were affected. Onset of RV/CD infection ranged from 2 weeks to 4 years posttransplant. All patients presented with enterocolitis causing significant fluid and electrolyte loss. In adults, CD was treated with metronidazole and in children with oral vancomycin. RV infection was treated with fluid/electrolyte replacement. During diarrhea, a significant rise in tacrolimus serum level was noted. All patients cleared CD. One child developed recurrent episodes of RV infection and died from bacterial sepsis; the renal recipient died 6 months posttransplant from myocardial infarction. The remaining six patients are currently alive with well-functioning grafts. Simultaneous infection with CD and RV may lead to severe diarrhea in SORs. Both pathogens should be considered in SOR presenting with diarrhea.

Posttransplant Lymphoproliferative Disorders in Pediatric Solid Organ Recipients: A Multicenter Retrospective Analysis of Patients from 1990 to 2003.

Posttransplant lymphoproliferative disorders (PTLD) have been recognized as severe side effects of immunosuppressive therapy after organ transplantation. However, no standard diagnostic and therapeutic approaches have been defined. Furthermore, few interdisciplinary perspectives comparing patients with heart/liver/kidney transplants are available. Here, we present results of a multicenter, retrospective analysis of pediatric patients treated for PTLD in Germany and Switzerland from 1990 to 2003. Patients were recruited by surveys through the working groups of pediatric renal, liver, and heart/lung transplantation as well as from the registry of pediatric Non-Hodgkin's lymphomas (NHL-BFM). Inclusion criteria consisted of a history of solid organ transplantation, biopsy-proven diagnosis of PTLD, and age at onset of PTLD 18 years of less. Patient charts were analyzed for clinical course from transplant to onset of PTLD, virus serology, treatment regimen, and outcome. A total of 53 patients from 19 centers could be included, among them 25 renal graft recipients, 14 heart-, 11 liver-, and 1 lung transplant recipients as well as 2 patients after combined heart/lung transplantation. PTLD was diagnosed at a median time of 34 months [range 2 – 119 months] post organ transplantation. Histological evaluation based on the WHO classification showed 2 early lesion PTLD, 8 polymorphic PTLD, 26 high-grade B-cell lymphomas, 12 Burkitt-like lymphomas, 3 cases of Hodgkin's disease and 2 T-cell lymphomas. Cytogenetic analysis revealed translocations involving chromosome 8 in five patients with Burkitt-like lymphomas. EBV gene products were detected in 31 tumors by in situ hybridization or immunohistochemistry, while 13 tumors were EBV negative (no data available on 9 tumors). EBV serology was negative in 55% of patients at the time of organ transplantation. However, in 29 patients EBV primary infection/reactivation was documented after organ transplantation (median time to infection/reactivation 5.9 months). In all patients immunosuppressive therapy was reduced. Treatment and follow up data were available in 51 patients: six patients remained in complete remission without additional treatment, in one patient autologous EBV-specific T-cells were infused. 41 patients received monoclonal antibodies (anti-CD20; n=7), chemotherapy (n=28), or a combination thereof (n=5). Fifteen of 51 patients died of progressing PTLD (n=7; among them 3 patients in which treatment was refused), treatment-related mortality (n=7), or fatal graft failure (n=2). Mortality was higher in patients with Burkitt-like lymphomas (7 of 12 patients) compared to all other entities (8 of 39 patients; p=0.026). Patients with stage IV disease had an inferior outcome compared to patients with stage I-III disease (mortality 6 of 7 vs. 9 of 44 patients, p=0.002). Thus, pediatric PTLD is a heterogeneous disease often associated with fatal outcome. The PED-PTLD study group has initiated a prospective multicenter trial of standardized diagnosis and treatment of PTLD after solid organ transplantation in children.

Is ABPM clinically useful after pediatric solid organ transplantation?

When ambulatory blood pressure monitoring (ABPM) is performed in populations with a high risk for secondary hypertension, such as solid organ transplant recipients, hypertension or abnormalities in circadian blood pressure variability are often discovered even in patients with normal office blood pressure (BP). To discuss whether ABPM should be routinely assessed in pediatric solid organ recipients, the available information on pathological findings, association of ABPM abnormalities with outcome parameters, and treatment options is reviewed. ABPM is a useful tool to optimize therapy in the large proportion of transplant recipients with confirmed hypertension. Whether the use of ABPM on a routine basis should be recommended for pediatric transplantation patients without office hypertension remains to be determined.

Tissue HHV6 and 7 determination in pediatric solid organ recipients--a pilot study.

Herpes virus infections remain a major challenge in solid organ transplantation. HHV6 and 7 blood viral load was associated with pathology after renal transplantation. Little is known about the significance of tissue HHV6 and 7 infections. A total of 18 tissue biopsies (13 kidney, three GI and two BAL) from nine pediatric transplant patients (five kidney, two liver, one combined liver and kidney and one bone marrow transplant) were subjected to blood HHV6 IgG and IgM testing. In addition, tissue HHV6 and 7 semi-quantitative PCR analysis with subsequent detection by ELISA and quantitative methods were applied to the same samples. We also studied four native kidney biopsies of children with other kidney disease. The results of the biopsies were correlated with clinical data. Of the transplant patients, 78% were HHV6 IgG positive. Six of nine had a positive IgM on at least one occasion, however, only two of nine transplant patients were symptomatic with a mixed CMV/EBV septic picture of multi-organ failure. Only these two patients had a significant tissue viral load for HHV6. Additionally, a very significant tissue viral load for HHV6 was detected in an immunocompromised patient 3 wk after a roseola-like febrile illness. The HHV6 copies were 31, 88 and 206 per 10 microL of DNA, respectively. In the patient who also had the fourth positive ELISA for HHV6 PCR product, the Multiplex PCR and restriction enzyme assay on its PCR product revealed a significant contribution by HHV7, while the HHV6-B signal was rather weak. Significant tissue HHV6 loads can be found in tissue biopsies from organ recipients with significant illness and also in native kidneys after primary infection. This may explain the high prevalence of HHV6 in transplanted kidneys. Further studies on HHV6 and 7 using molecular techniques should be supported.

Quantitative tissue polymerase chain reaction for Epstein-Barr virus in pediatric solid organ recipients

Background: Infections caused by herpes virus, in particular, Epstein-Barr virus (EBV), remain a major challenge in solid organ transplantation. Little is known about the significance of tissue EBV load. Methods: Twenty-three tissue biopsy specimens (19 kidney, 3 gastrointestinal, and 1 tonsil specimen) and 2 bronchoalveolar lavage specimens from 14 pediatric transplant recipients (10 kidney, 3 liver, 1 combined transplant) were subject to tissue EBV polymerase chain reaction (PCR) semiquantitative analysis and enzyme-linked immunosorbent assay (ELISA) methods. Results of biopsies were correlated with clinical data. Results: Five of 14 patients had clinically diagnosed EBV disease: 2 patients presented with a septic picture with multiorgan failure and pneumonitis; 1 patient had mononucleosis; 1 patient had an increase in serum creatinine level, lymphadenopathy, and chronic fatigue; and 1 patient had EBV nephritis. These 5 patients underwent 12 biopsies at the time of clinically active infection; 8 biopsies had positive results (up to 111 copies/10 μL of extracted DNA). Conversely, 1 of the remaining 13 tissue biopsy specimens from asymptomatic patients had positive results on ELISA, but undetectable viral load, whereas 8 patients had a positive EBV immunoglobulin G titer with historic evidence of EBV replication in the blood. No patient without evidence of EBV had positive EBV tissue PCR results. Conclusion: Increased EBV load was found in more than 50% of patients, pointing to a previously underrecognized importance of EBV detection in tissues from transplant recipients. The presence of EBV in tissue correlated with the presence of viremia, whereas tissue PCR had 100% specificity. EBV load should be included in biopsy evaluation. Am J Kidney Dis 41:212-219. © 2003 by the National Kidney Foundation, Inc.

Cholelithiasis in pediatric organ transplantation: detection and management.

The real incidence and the underlying causes of cholelithiasis in pediatric solid organ recipients is probably not exactly known. In addition to well-established risk factors for cholelithiasis, children after heart, kidney, or liver transplantation may develop gallstones due to drug therapy, sepsis, parenteral nutrition, or surgical complications. For pediatric patients, data are very limited and heterogeneous. However, the incidence in pediatric heart recipients seems to be substantially higher compared with kidney or liver graft recipients. In this review article the present data are discussed focusing on incidence, detection, and management of cholelithiasis in pediatric organ transplantation. In general, surgery is the therapy of choice in symptomatic patients; however, the pharmacological profile of ursodeoxycholic acid and the first results on its clinical impact are promising. The value of prophylactic therapy with ursodeoxycholic acid must be determined in further studies.

Posttransplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression.

Posttransplantation diabetes mellitus (PTDM) is a well-known complication of tacrolimus-based immunosuppression in both adult and pediatric solid organ recipients. The "natural history" of diabetes in the pediatric thoracic transplant population has not yet been described. We identified all pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression who developed PTDM. Medical records were reviewed, with a particular focus on the clinical course of PTDM and its relationship to drug weaning. Diabetes developed in 24 of 143 (17%) 30-day survivors of heart (12/96, 13%) and heart-lung/lung (12/ 47, 26%) transplantation. In 17 (71%) patients, the immunosuppressive regimen at the onset of PTDM also included maintenance corticosteroids. Seventeen patients demonstrated glucose intolerance before the onset of diabetes. Nine patients (38%) developed diabetes during pulsed corticosteroid therapy. Median time of onset after transplantation was 9.0 months. All patients required s.c. insulin for glucose control. The median follow-up from transplant was 49.9 months. There was a significant decrease in mean tacrolimus dosage (P<0.01), tacrolimus level (P<0.04), and steroid dosage (P<0.02) from onset of PTDM to most recent follow-up. Despite this significant reduction in immunosuppression, only 3/24 (13%) patients were successfully weaned off insulin. Diabetes mellitus is a common complication in pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression. Insulin dependence in our population rarely resolved, even after lowering tacrolimus and steroid doses. Discontinuation of steroids did not guarantee resolution of diabetes.

POST-TRANSPLANT DIABETES MELLITUS IN PEDIATRIC THORACIC ORGAN RECIPIENTS RECEIVING TACROLIMUS-BASED IMMUNOSUPPRESSION

894 Background: Post-transplant diabetes mellitus (PTDM) is a well-known complication of tacrolimus-based immunosuppression in both adult and pediatric solid organ recipients. However, the 'natural history' of diabetes in the pediatric thoracic transplant population has not yet been described. Methods: We identified all pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression who developed PTDM. Diabetes was defined as glucose intolerance requiring insulin therapy or oral hypoglycemic agents more than 30 days after transplantation for a minimum duration of 30 days. Medical records were reviewed, with a particular focus on the clinical course of PTDM and its relationship to drug weaning. Results: Diabetes developed in 22 of 139 (16%) thirty day survivors of heart (11/93, 12%) and heart-lung / lung (11/46, 24%) recipients receiving tacrolimus-based immunosuppression since October 1989. Three patients had cystic fibrosis. In 14 (64%) patients, the immunosuppressive regimen at the onset of PTDM also included maintenance corticosteroids. Fifteen (68%) patients had demonstrated glucose intolerance on at least one occasion outside the early postoperative period prior to the onset of diabetes. Eight patients (36%) developed diabetes during pulsed corticosteroid therapy. Median time of onset after transplantation was 9.0 months (range 1 to 62). Two patients were ketotic at presentation. Initial therapy consisted of subcutaneous insulin in 20 (91%) patients. One patient was begun on an oral hypoglycemic agent, and in one patient, dietary intervention was first attempted. Both of these patients required the addition of insulin to their regimen. The median follow-up after development of PTDM was 39.1 months (range 1-76). There was a significant decrease in the mean tacrolimus dosage from onset of PTDM to most recent follow-up (0.26 to 0.16 mg/kg/day, p < 0.01). This was associated with a decrease in mean whole blood tacrolimus level from 16.4 to 12.8 ng/ml. There was also a significant decrease in daily maintenance corticosteroid requirements over the same period (0.21 to 0.13 mg/kg/day, p < 0.04). Despite this significant reduction in immunosuppression, only 3/22 (14%) patients were able to be weaned off insulin, at 5, 14, and 36 months from onset. These 3 patients comprised 2 of 5 weaned off corticosteroids, and one of 9 who required continued maintenance corticosteroids. Two additional patients were changed from tacrolimus to cyclosporine, one for intractable headaches, and one for pancytopenia. Diabetes persisted in both patients after the switch. Conclusions: Diabetes mellitus is a common complication in pediatric thoracic transplant patients receiving tacrolimus-based immunosuppression. Insulin dependence in our population rarely resolved, even after lowering tacrolimus and steroid doses. Discontinuation of steroids does not guarantee resolution of diabetes. The value of switching to cyclosporine has not been fully explored.