Post-transplant diabetes mellitus in pediatric liver transplantation

Abstract:  To determine the characteristics of pediatric liver transplant recipients who develop GI and/or PTDM, data on children undergoing their first liver transplant from the SPLIT database were analyzed (n = 1611). Recipient and donor characteristics that were evaluated included age at transplant, gender, race, primary disease, hospitalization status at transplant, BMI, recipient and donor CMV status, donor type, donor age, and primary immunosuppression. GI/PTDM was found in 214 individuals (13%) of whom 166 (78%) were diagnosed within 30 days of transplantation (early GI/PTDM). Multivariate analyses suggests that age >5 yr at transplant, hospitalization at transplant, a primary diagnosis other than BA, early steroid use, and tacrolimus use are associated with increased incidence of early GI. Routine monitoring for the development of GI and post-transplant diabetes is indicated in the short- and long-term care of children after liver transplantation.     

Unusual presentation of graft‐versus‐host disease in pediatric liver transplant recipients: Evidence of late and recurrent disease

Graft-versus-host disease (GvHD) is a multi-organ disease caused by mature donor T cells that are activated by alloantigens expressed by the host antigen-presenting cells. GvHD has been reported after solid organ transplantation with two principal presentations: humoral and cellular. In the cellular type of GvHD after liver transplantation the symptoms are identical to the GvHD after bone marrow transplant, except that the liver is spared because it lacks host antigens. We have described three cases of intestinal GvHD after pediatric liver transplant with an unusual recurrent late presentation in two patients. Two patients were female, and their age at the time of transplant was 8 and 9 months, respectively, and one was an 8-month-old male. They all received reduced liver allografts of identical blood type from three different donors. One patient received two doses of donor bone marrow cell infusion. Two patients received double immunosuppressive therapy constituted by tacrolimus at a dose of 0.05 mg/kg p.o. b.i.d. and steroids 10 mg p.o. daily. One patient received a triple drug immunosuppression with tacrolimus (0.05 mg/kg p.o. b.i.d.), steroids (10 mg p.o. daily) and mycophenolate mofetil (125 mg p.o. b.i.d.). Diagnosis of intestinal GvHD was confirmed histologically on intestinal biopsies performed at the time of presentation of the clinical symptoms or at autopsy.     

Ketoacidosis at onset of type 1 diabetes mellitus in children--frequency and clinical presentation

Abstract: Background: Since 1987, patients with newly diagnosed diabetes mellitus type 1 under 15 yr of age have been registered in Baden‐Wuerttemberg (BW), Germany. Aim: Our aim was to describe the frequency and the clinical presentation of diabetic ketoacidosis (DKA) at onset of type 1 diabetes mellitus in children. Methods: All 31 pediatric departments in BW and one diabetes center participated in this study. Hospital records of 2121 children below 15 yr of age were examined retrospectively. DKA was defined as glucose > 250 mg/dL, pH < 7.30 or bicarbonate < 15 mmol/L and ketonuria. Statistical analysis was done after logarithmic transformation. Results: 26.3% (n = 558) of all patients presented with DKA. The mean age of these patients was 7.9 yr. The frequency of DKA is higher in girls than in boys (28.9 vs. 23.8%; p = 0.0079). Those aged 0–4 yr suffered most frequently (p < 0.0001) from ketoacidosis (36.0%). The percentage of DKA in newly diagnosed cases was constant over 10 yr. 23.3% of all patients with DKA presented with an altered level of consciousness; 10.9% of these had clinical signs of coma. No deaths occurred. The proportion of ketoacidosis does not increase concurrently with the number of diabetes manifestations in winter. Conclusion: The proportion of DKA in children with newly diagnosed diabetes mellitus is significant. In particular, children < 5 yr and girls face an increased risk. DKA may be the result of a particularly aggressive subtype of diabetes.     

Rapid steroid discontinuation for pediatric renal transplantation: a single center experience

To determine the outcomes of pediatric renal transplant recipients who received immunosuppression consisting of early withdrawal of corticosteroids at a single Northern California center. Protocols using minimal steroid exposure have been recently reported in adult transplant recipients with successful results. We examined the outcomes of pediatric renal transplant recipients who were managed at our center using a protocol with very early discontinuation of steroids after renal transplantation. We retrospectively studied the medical records of all renal transplant recipients followed at the Children's Hospital at the University of California, Davis Medical Center from 01/2004 to 12/2005. All patients were less than 18 yr of age at the time of transplantation. The immunosuppressive protocol included three tapering daily doses of methylprednisolone, together with five doses of thymoglobulin followed by maintenance therapy with tacrolimus and MMF. Eight patients with equal numbers of males and females were transplanted during this time period. There were equal numbers of Caucasians, African-Americans, Hispanics, and Asians. A total of 37.5% (3/8) of the subjects received preemptive transplantation, 25% (2/8) received peritoneal, and 37.5% (3/8) received hemodialysis before transplantation. The median (range) age at transplantation was 12.3 (3.1-16.0) year with a follow-up of 1.7 (0.9-2.8) year. At one yr post-transplantation, 57% (4/7) of patients still required anti-hypertensives. Three children required erythropoietin supplementation after transplantation. The mean delta height standard deviation score at 12 months was 0.20 +/- 0.56. There were no episodes of clinical acute rejection. One patient switched from tacrolimus to sirolimus due to biopsy-proven CAN. No patient became diabetic or required hypoglycemic agents. Surveillance biopsies showed no subclinical acute rejection in any patient. Steroid-free immunosuppression is safe in children after renal transplantation. Larger number of patients and longer follow-up are required to further confirm the effectiveness and safety of immunosuppression with rapid steroid discontinuation.     

Outcome of bowel perforation after pediatric liver transplantation

Abstract:  Bowel perforation is one of the causes of mortality after pediatric liver transplantation. The aim of this study was to evaluate the incidence, risk factors, clinical presentations, and outcomes of bowel perforation in pediatric liver recipients. This is a retrospective analysis of all pediatric patients who underwent liver transplantation at a single liver transplant center in Iran between 1999 and 2006. During this period 72 liver transplantations were performed in children <18 yr. Twenty-two children underwent 33 re-explorations after liver transplantation. Five bowel perforations occurred in four children (incidence, 6.9%). One patient required two re-explorations. The median time between liver transplantation and the diagnosis of the bowel perforation was seven days. All patients had abdominal distention before re-exploration. The sites of perforation were jejunum (n = 3) and ileum (n = 2), and simple repair was performed in all cases. Three children had a history of prior Kasai operation. One of them received high dose of methylprednisolone before bowel perforation. Two children expired after bowel perforation (mortality rate, 50%). Bowel perforation is relatively frequent after pediatric liver transplantation. Among risk factors, prior Kasai operation may have a role. We observed that abdominal distention is a sign of bowel perforation and a high index of suspicion is required for rapidly diagnosis of this complication. The outcome of bowel perforation is poor and its mortality is high. Further studies are needed to establish real risk factors for this complication.     

Acquired renal cysts after pediatric liver transplantation: association with cyclosporine and renal dysfunction

Abstract:  ACKD has been observed in children on dialysis and with chronic renal insufficiency. In one report, ACKD was observed in 30% of pediatric liver transplant recipients after 10 yr. We retrospectively reviewed all renal imaging and measurements of GFR of 235 childhood liver transplant recipients with no known risk for renal cyst formation, no evidence of renal cyst(s) at the time of transplantation and renal imaging at least one yr post-transplant. Twenty-six patients (11%) developed one or more cyst(s). Mean GFR was significantly lower in patients with renal cyst(s). Two (1.4%) of the 146 patients treated with tacrolimus and 24 (27%) of the 89 patients treated with CsA acquired renal cyst(s) (p < 0.001). CsA-treated patients had significantly lower GFR. Multivariate analysis identified CsA as the only independent variable associated with ACKD. These results confirm that ACKD can be a late complication of pediatric liver transplantation. Those at most risk are at least 10-yr post-liver transplantation, have been treated with CsA and have impaired renal function. We speculate that ACKD in these patients is the result of calcineurin inhibitor nephrotoxicity. Whether patients with ACKD will be prone to develop solid renal tumors is unknown.     

Parenthood in pediatric liver transplant patients

Liver transplantation has become a universally accepted treatment for numerous congenital and acquired hepatic disorders that cause liver failure. Without liver transplantation, patients in their reproductive years are afflicted with oligospermia or azoospermia in men and amenorrhea in women, with infertility being a consequence in both sexes. The aim of this study is to describe our experiences concerning the parenthood of pediatric individuals who are successful recipients of liver transplantations coming into the reproductive years of life. We retrospectively analyzed data of 207 pediatric liver transplanted patients (96 women, 111 men). Among them, three women conceived and delivered four babies, and two men admitted to paternity of two children after they all had been recipients of liver transplants. All female transplant recipients had received tacrolimus-based immunosuppression. Preterm delivery was the most clinically important complication among these patients. Only one of the female patients experienced hypercalcemia during the pregnancy. None had any other complications such as hypertension, preeclampsia, cholestasis, or diabetes. There was no graft insufficiency, rejection, or birth defect. We concluded that maternity and paternity in liver transplant patients show normal outcomes even though this procedure occurs in childhood, and pregnancy did not seem to impair graft function in patients receiving immunosuppressive drugs.     

Tacrolimus in pediatric renal transplantation: a review

Tacrolimus is a T cell-specific immunosuppressive agent that has been used in a relatively small number of pediatric kidney transplant recipients. It has been used as a primary immunosuppressive agent, with patient survival rates of over 95%, and graft survival rates of over 90%. In the largest series reported, some two-thirds of the successfully transplanted recipients have been taken off steroids, with substantial catch-up growth, and over 80% have been taken off antihypertensive medications. Important complications have included EBV-related post-transplant lymphoproliferative disorder and post-transplant diabetes mellitus, both reversible. Tacrolimus has also been used to rescue patients with refractory acute rejection, with a success rate of 70%-75%. This review summarizes the current world experience with tacrolimus in pediatric renal transplantation, and describes the details of tacrolimus dosing and the treatment of tacrolimus-related complications. On balance, tacrolimus is an effective immunosuppressive agent and offers important advantages in the management of pediatric renal transplant recipients.     

Sirolimus in pediatric gastrointestinal transplantation: the use of sirolimus for pediatric transplant patients with tacrolimus-related cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HOCM) associated with the use of tacrolimus is a rare complication of liver and intestinal transplantation seen almost exclusively among pediatric patients. Reduction of tacrolimus dosage or conversion to cyclosporin A (CsA) has been used as an effective treatment in reviewed cases. We present three pediatric transplant recipients who developed hypertrophic obstructive cardiomyopathy while under tacrolimus immunosuppression and were treated with conversion to sirolimus (Rapamycin). The patients (ages 6 yr, 12 yr and 11 months) were transplant recipients (liver, n = 2; liver and intestine, n = 1) who developed significant cardiomyopathy 15 and 96 months post-transplant. One patient died of post-transplant lymphoproliferative disorder 21 days after starting sirolimus. One patient had received two liver transplants and had been on CsA for 12 yr before conversion to tacrolimus at 60 months post-transplant for acute and chronic rejection. The surviving patients were receiving mycophenolate mofetil, tacrolimus and steroids at the time of diagnosis. Dose reduction of tacrolimus and treatment with beta blockers failed to alleviate the hemodynamic changes. The patients were converted to sirolimus 1.6, 37 and 148 months post-transplant and maintained a whole-blood trough level of 15-20 ng/mL 21 days after starting sirolimus. Repeat echocardiograms in the surviving patients showed improvement in cardiomyopathy. One patient had one rejection episode (intestinal biopsy, mild acute cellular rejection) after starting sirolimus that responded to a transient increase in steroids. The early demise of the third patient after sirolimus conversion prevented an adequate assessment of cardiomyopathy. Conversion to sirolimus was associated with a reduction in the cardiomyopathy of the two surviving patients while still providing effective immunosuppression. To our knowledge this observation has not been previously reported.     

Indications and efficacy of conversion from tacrolimus‐ to sirolimus‐based immunosuppression in pediatric patients who underwent liver transplantation for unresectable hepatoblastoma

SRL‐based immunosuppressive strategies in pediatric liver transplantation are not clearly defined, especially within the first year after liver transplant. TAC is the more common, traditional immunosuppressant used. However, SRL may modulate TAC‐associated kidney injury and may also have antiproliferative properties that are valuable in the management of patients following liver transplantation for HB. We sought to determine whether early conversion from TAC to SRL was safe, effective, and beneficial in a subset of liver transplant recipients with unresectable HB exposed to CDDP‐based chemotherapy. Between 2008 and 2013, six patients were transplanted for unresectable HB. All patients received at least one cycle of CDDP‐based chemotherapy prior to transplant. All patients were switched from TAC‐ to SRL‐based immunosuppression within 1 year of transplant. Five patients had improvement in their mGFR, while one patient had a slight decline. The improvement in mGFR was statistically significant. No adverse events were identified. Three patients had BPAR that responded to pulsed steroids. Historical controls showed similar rates of BPAR within the first year after transplant. There were no identified HB recurrences in the follow‐up time period. Conversion from TAC to SRL appears to be safe and effective in this selected group of pediatric liver transplant recipients without adverse reaction or HB recurrences.     

Rapid discontinuation of corticosteroids in pediatric renal transplantation

Abstract:  Corticosteroid immunosuppression has permitted the development of successful allotransplantation; however, corticosteroids are associated significant post-transplant complications. To circumvent these problems, we implemented a protocol of rapid discontinuation of corticosteroids in 19 consecutive pediatric primary kidney transplant recipients. Mean age at time of transplant was 13.4 (±4.5) yr, 52.6% were male, 63.2% underwent living donor transplantation. All patients were administered Thymoglobulin^® [anti-thymocyte globulin (rabbit)] as induction immunosuppression with a rapid tapering dose of corticosteroids (total of five daily doses), and maintained on mycophenolate mofetil and tacrolimus. Two patients had immediate recurrence of primary disease (FSGS), requiring further corticosteroid therapy. Otherwise, remaining 17 patients were maintained off corticosteroids, with excellent graft function; mean baseline eGFR of 112 mL/min/1.73 m² (±19) at 28 months (±14) post-transplantation. There was 100% patient and rejection-free graft survival at 27 months (range 5–58 months) post-transplantation; 47% underwent renal transplant biopsy secondary to acute rise in serum creatinine with or without worsening hypertension. All biopsies had no evidence of acute rejection; 62.5% had findings consistent with tacrolimus toxicity. Renal transplantation utilizing a rapid discontinuation of corticosteroid protocol in pediatric patients appears to be safe and effective, without increasing the risk of acute rejection or graft loss.     

Tacrolimus-associated eosinophilic gastroenterocolitis in pediatric liver transplant recipients: role of potential food allergies in pathogenesis

Tacrolimus is a macrolide agent that is now the primary immunosuppressant used in prevention of graft rejection in transplant recipients. It has been found to be superior to cyclosporine (CSA) for rescue therapy as well as for earlier weaning of steroids. Both tacrolimus and CSA share similar toxicity profiles; however, their gastrointestinal side effects have received little attention. We report three cases of eosinophilic colitis in liver transplant recipients, maintained on tacrolimus as immunosuppressive medication post-liver transplantation. These patients also had high serum immunoglobulin (Ig)E levels, eosinophilia and IgE-positive radioallergosorbent test for milk proteins. The colitis appeared to be mediated by food allergies. Each patient had symptomatic improvement following reduced immunosuppression and an appropriately restricted diet. We conclude that tacrolimus may play a role in the initiation of food allergies, leading to eosinophilic colitis. More studies are needed in a controlled setting to identify the prevalence of similar findings among other pediatric liver transplant recipients.     

Buccal vs. nasogastric tube administration of tacrolimus after pediatric liver transplantation

Tacrolimus is an important drug for immunosuppression after liver transplantation. Bioavailability of enterally administered tacrolimus is poor, and further reduced by gastric residuals or by enteral nutrition. Buccal administration might be an alternative route especially in children. Tacrolimus trough levels (TTLs) obtained after buccal administration of tacrolimus after liver transplantation have not been reported. The aim of this study was to determine whether buccal administration of tacrolimus is feasible and to compare TTLs after nasogastric tube (NGT) administration with buccal administration. TTLs after NGT or buccal administration during the first week after pediatric liver transplantation were analyzed from 28 cadaveric liver transplants in 23 pediatric recipients between June 2002 and March 2004. Each level was scored within, under or above the target range. Buccal administration was well tolerated in all patients. A total of 149 TTLs were obtained of which nine were excluded because of incomplete information on target levels. Overall 27% of TTLs was adequate. The percentage of levels under, within and above the target range were comparable in both groups (chi-square test; p = 0.64). Both groups had a decrease in percentages within the target range on day 3 and 4 after liver transplantation with a subsequent rise. Buccal tacrolimus administration is feasible. Similar TTLs are achieved compared with NGT tacrolimus administration during the first week after pediatric liver transplantation.     

Management of tacrolimus‐associated food allergy after liver transplantation

Increasingly, food allergy associated with tacrolimus after pediatric living‐donor liver transplantation (LT) has been reported. Tacrolimus prevents the activation of T cells by blocking calcineurin, thus producing an immunosuppressive effect, but tacrolimus induces an imbalance in T‐helper type 1 (Th1) and Th2 cells in the food allergy process. This report describes a case of tacrolimus‐associated food allergy after pediatric living‐donor LT. The patient was a 7‐year‐old Japanese girl who had undergone living‐donor LT at 12 months of age, and whom we first saw in the clinic at age 18 months. She received immunosuppressive therapy by tacrolimus after transplantation. Atopic dermatitis developed in post‐transplant month 18. Stridor, facial edema, lip swelling, and skin erythema after consuming tempura udon containing wheat occurred in post‐transplant month 39, and she was subsequently diagnosed with anaphylactic shock. Eosinophilic leukocyte and serum immunoglobulin (Ig)E increased, and specific IgE was positive for some food allergens. Pharmacotherapy was therefore changed from tacrolimus to cyclosporine A, after which eosinophilic leukocyte and serum IgE decreased and atopic dermatitis improved.     

Central pontine myelinolysis: a case report and clinical-pathological review

An 11-yr-old child presented with acute mental status changes and spastic quadriplegia after orthotopic liver transplantation. Magnetic resonance (MR) imaging findings were consistent with central pontine and EPM. Initial immunosuppression included tacrolimus, mycophenolate mofetil, and corticosteroids. Given that neurotoxicity is a well-established side effect of CNI, the patient was converted to rapamycin and subsequently experienced significant neurologic recovery. The temporal resolution of the patient's symptoms suggests that prompt recognition of central pontine and EPM and conversion from tacrolimus to rapamycin during the early post-operative course may have therapeutic benefits for patients undergoing pediatric transplant with CNI-related neurotoxicity.     

Sclerosing cholangitis associated to cryptosporidiosis in liver-transplanted children

Three children of a series of 461 pediatric liver transplant recipients developed diffuse cholangitis associated with intestinal cryptosporidium carriage. All three received immunosuppression consisting of tacrolimus and prednisone. Cryprosporidium carriage was treated with paramomycin, while immunosuppression was decreased according to graft tolerance. No other infectious pathogens were found, and no vascular problems were detected. Bile duct anastomosis was reoperated in all three, but biliary cirrhosis developed in one patient, requiring retransplantation. All three patients are alive and well, and free of intestinal parasites on follow-up. Conclusion Cryptosporidium intestinal infection may play a role in some cases of otherwise unexplained cholangiopathies in pediatric liver transplant recipients. This may lead to significant morbidity, including need for retransplantation. Received: 29 June 1999 and in revised form: 10 September 1999 / Accepted: 21 September 1999     

Early post-transplant vaccination with pandemic influenza A/H1N1 vaccine in pediatric heart transplant recipients

Pandemic influenza A/H1N1 virus has the potential to cause severe disease in pediatric transplant patients. A pandemic vaccine against H1N1 is effective in immunocompetent children. We investigated the immunogenicity of this vaccine when given in the first six months after heart transplantation. Four patients younger than two yr received two doses of vaccine and one patient older than seven yr received one dose. Titers were obtained using the HAI at baseline and after final immunization. Five patients were enrolled, ages 0.5-7 yr. Median age at the time of transplant was five months (range 3 wk-7 yr). All patients received induction with anti-thymoglobulin and maintenance immunosuppression with tacrolimus, MMF, and prednisone. Patients were immunized with the adjuvanted H1N1 vaccine after heart transplant at median time of nine wk (range 5-23 wk) post-transplant. Three of five developed protective titers against H1N1. A proportion of pediatric patients may respond to influenza vaccine even when immunized in the early post-transplant period.     

Prevalence of renal dysfunction in tacrolimus‐treated pediatric transplant recipients: A systematic review

Renal dysfunction after non‐renal transplantation in adult tacrolimus‐treated transplant patients is well documented. Little is known about its prevalence in children. Age‐related changes in both disposition and effect of tacrolimus as well as renal function may preclude extrapolation of adult data to children. To systematically review the literature on renal dysfunction in non‐renal pediatric transplant recipients treated with tacrolimus. PubMed/Medline, Embase, and Google were searched from their inception until April 19, 2012, with the search terms “tacrolimus,” “renal function,” “transplantation,” and “children.” Eighteen of 385 retrieved papers were considered relevant. Twelve dealt with liver, four with heart transplant, one with heart and lung transplant, and one with intestinal recipients. Reported prevalences of mild and severe chronic kidney disease ranged from 0% to 39% and 0% to 71.4%, respectively, for liver, and from 22.7% to 40% and 6.8% to 46%, respectively, for heart and/or lung transplant recipients. Ranges remained wide after adjusting for follow‐up time and disease severity. Possible explanations are inclusion bias and definitions used for renal dysfunction. A considerable proportion of pediatric non‐renal transplant patients who receive tacrolimus‐based immunosuppression, appear to suffer from chronic kidney disease. This conclusion warrants further research into the real risk, its risk factors, and individualization of immunosuppressant therapy.     

Pediatric stroke associated with new onset type 1 diabetes mellitus: case reports and review of the literature

Neurological deterioration in children with diabetic ketoacidosis (DKA) is commonly caused by cerebral edema. However, stroke should also be suspected when focal neurological deficits are apparent, because children with hyperglycemia and DKA are prone to thrombosis. We report three cases of pediatric stroke associated with new onset type 1 diabetes mellitus (T1DM). The first case presented with sinovenous thrombosis, and the other two cases presented in DKA and had a late diagnosis of ischemic stroke following neurological deterioration. Our recent experiences and review of the literature emphasize the importance of early diagnosis, investigation, and treatment for patients that present with new onset T1DM and stroke.     

Preoperative pulmonary assessment of children for liver transplantation

Abstract:  Pulmonary assessment should be part of the preoperative investigation of pediatric patients with chronic liver disease undergoing liver transplantation, as it allows the identification of pulmonary alterations that influence candidacy for transplantation and survival. To describe pulmonary changes found in pediatric patients who were candidates for liver transplantation. Retrospective study of 17 pediatric liver transplant candidates undergoing preoperative pulmonary evaluation assessing pulmonary clinical data, arterial blood gas analysis, CXR, respiratory function test by spirometry, pulmonary scintigraphy, and CEE. Ten patients presented normal chest roentgenograms. The most common radiographic change was interstitial infiltrate in the lung bases. Of the five patients with PaO₂ <70 mmHg, four had cyanosis and dyspnea and two were diagnosed with HPS with intrapulmonary shunt evidenced by contrast echocardiogram. Two patients presented with intrapulmonary shunt but without hypoxemia. Spirometry was normal in six patients, restrictive disturbance was evidenced in one patient, obstructive in three, and combined in two. The most common scintigraphic change was heterogeneous pulmonary perfusion. Pulmonary assessment should be performed routinely in pediatric patients prior to liver transplantation, even in asymptomatic patients. Pulmonary assessment may indicate changes such as HPS that can increase postoperative morbidity/mortality.