Tolerability of up to 200 days of prophylaxis with valganciclovir oral solution and/or film-coated tablets in pediatric kidney transplant recipients at risk of cytomegalovirus disease.

This multicenter, open-label study evaluated the tolerability of extended prophylaxis with valganciclovir in pediatric kidney transplant recipients at risk of CMV disease. Fifty-six patients aged 4 months to 16 years received once-daily valganciclovir oral solution and/or tablets, dosed by BSA and renal function, for up to 200 days. The most common AEs on treatment were upper respiratory tract infection (33.9%), urinary tract infection (33.9%), diarrhea (32.1%), leukopenia (25.0%), neutropenia (23.2%), and headache (21.4%). There were fewer AEs during days 101-228 vs days 1-100. Twenty-seven patients (48.2%) had treatment-related AEs during valganciclovir treatment, most commonly leukopenia (21.4%), neutropenia (19.6%), anemia (7.1%), and tremor (5.4%). Treatment-related serious AEs were reported for nine patients (16.1%) and six withdrew due to AEs. Viremia was centrally confirmed in 10 patients; there was no confirmed CMV disease. One patient tested positive for a resistance mutation (UL97 L595F). Biopsy-proven acute rejection occurred in six patients (10.7%), but no graft loss or deaths occurred. In conclusion, up to 200 days of valganciclovir prophylaxis in pediatric kidney allograft recipients showed a safety profile consistent with that established in adult transplant patients.

CYP3A5 Genotype and Time to Reach Tacrolimus Therapeutic Levels in Renal Transplant Children.

BACKGROUND: CYP3A5 gene polymorphism rs776746 has been associated with lower tacrolimus dose requirements and bioavailability in both adults and children. This variant causes a loss of CYP3A5 activity owing to a splice site variant leading to a truncated inactive enzyme. The aim of this study was to determine if the rs776746 gene polymorphism is related to the time to reach tacrolimus therapeutic levels in renal transplant children. METHODS: A prospective study was performed in renal transplant children receiving tacrolimus as part of their immunosuppressive regime. CYP3A5 genotype was determined by direct sequencing. Tacrolimus trough levels and serum creatinine at 1 week and 1 month after renal transplantation was obtained from clinical chart. RESULTS: A total of 42 patients were included; 19 (45.2%) were female, 23 (54.8%) received living-donor transplants, and 21 patients expressed CYP3A5*1/*1 or CYP3A5*1/*3. Tacrolimus dose was higher in expressers at week 1 (0.13 vs 0.10 mg/kg/d; P = .011), and week 4 after transplantation (0.17 vs 0.09 mg/kg/d; P < .0001). At 4 weeks after renal transplantation, only 9 patients from the expressers group (42.8%) had levels ≥7 ng/mL, in contrast to 18 in the nonexpressers group (85.7%; Fisher exact P = .008). CONCLUSIONS: Tacrolimus dose was significant higher in functional CYP3A5 expressers. Only 42.8% of such expressers had tacrolimus trough levels ≥7 ng/mL at 1 month after transplantation despite dose adjustments. Long-term follow up is needed to address the consequences of early post-transplantation bioavailability differences due to CYP3A5 genotype.

A Scheduled Program of Molecular Screening for Epstein-Barr Virus Decreases the Incidence of Post-transplantation Lymphoproliferative Disease in Pediatric Liver Transplantation.

This is a cohort, retrospective, comparative study of all liver transplant recipients from a single center, from May 1998 to July 2015. Patients were divided into two groups according to the type of Epstein-Barr viral load monitoring. For group I (1998-2007), polymerase chain reaction (PCR) was not available or it was only qualitative with limited access. For group II (2008-2015), we used periodically scheduled quantitative PCR in plasma and leukocytes, with aggressive tapering of immunosuppression as soon as viral replication was detected. Ninety-eight recipients were included, 41 (41.8%) were Epstein-Barr virus (EBV) - seronegative before liver transplantation (LT). EBV replication was confirmed in 74 patients (75.5%), being more frequent in seronegative (87.8%) than seropositive patients (66.6%). Eight recipients (8.1%) developed post-transplantation lymphoproliferative disorder (PTLD) on average at 14.3 months post-LT, seven of eight were <3 years at LT, four of eight were D+/R- for EBV, and all had post-LT EBV replication confirmed by PCR. PTLD was classified as lymphoma (n = 4), polymorphic polyclonal (n = 3), and lymphoid hyperplasia (n = 1). Five patients died, and three cleared PTLD after immunosuppression tapering or interruption. There were no significant differences in the etiology, age at LT (5.6 vs. 7.3 years, P = .069), patients <4 years (53.2% vs. 35.3%, P = .103), or EBV seronegative recipients (44.7% vs. 37.3%, P = .54); however, the incidence of PTLD decreased from 14.9% to 1.9% (P = .026), and graft rejection from 51.1% to 29.4% (P = .039). One- and 5-year patient survival rates were 94.7% and 85%, respectively, with no differences between groups. This strategy dramatically decreased the incidence of PTLD (14.9% vs. 1.9%), without increasing the incidence of rejection; therefore, we recommend that it should be used in the follow-up of all pediatric LT recipients.

Anesthetic risk factors associated with early mortality in pediatric liver transplantation.

INTRODUCTION: Early mortality in pediatric patients after liver transplantation (30 days) may be due to surgical and anesthetic perioperative factors. OBJECTIVE: To identify anesthetic risk factors associated with early mortality in pediatric patients who undergo liver transplantation (OLT). MATERIALS AND METHODS: This retrospective study of all patients who underwent a deceased or living donor liver transplantation evaluated demographic variables of age, weight, gender, degree of malnutrition, and etiology, as well as qualitative variables of anesthesia time, bleeding, massive transfusion, acid-base balance, electrolyte and metabolic disorders, as well as graft prereperfusion postreperfusion characteristics. Chi-square tests with corresponding odds ratio (OR) and 95% confidence intervals as well as Interactions were tested among significant variables using multivariate logistic regression models. P < or =.05 was considered significant. RESULTS: We performed 64 OLT among whom early death occurred in 20.3% (n = 13). There were deaths associated with malnutrition (84.6% vs 43.6%) in the control group (P < .01); massive bleeding, 76.9% (n = 10) versus 25.8% in the control group (P < .05) including transfusions in 84.6% (n = 11) versus 43.6% in the control group (P < .03); preperfusion metabolic acidosis in 84.6% (n = 11) versus 72.5% (n = 37; P < .05); posttransplant hyperglycemia in 69.2% (n = 9) versus 23.5% (n = 12; P < .01); and postreperfusion hyperlactatemia in 92.3% (n = 12) versus 68.6% (n = 35; P < .045). CONCLUSION: Prereperfusion metabolic acidosis, postreperfusion hyperlactatemia, and hyperglycemia were significantly more prevalent among patients who died early. However, these factors were exacerbated by malnutrition, bleeding, and massive transfusions. Postreperfusion hypokalemia and hypernatremia showed high but not significant frequencies in both groups.

Should a complex uropathy be a contraindication for renal transplantation in children?

BACKGROUND: Anatomic and functional disorders of the lower urinary tract represent up to 40% of the causes of renal failure in children. Several centers avoid renal transplantation in these patients because of the high risk of complications and lower graft survival. The aim of this work was to determine the frequency of urinary tract abnormalities (UTAs) among our pediatric series, and to compare the frequency of complications, function, and long-term graft survival among patients without versus with UTA. METHODS: This single-center, retrospective study compared outcomes between pediatric recipients with versus without UTA. We analyzed demographic features, etiology, pretransplant protocol, urinary tract rehabilitation, incidence of complications, rejection events, as well as graft function and survival. RESULTS: Among 328 pediatric cases performed between 1998 and 2008, we excluded nine patients due to incomplete medical records, analyzing 319 procedures in 312 patients. Sixty-seven patients (21%) had UTA. The average age, weight, and height at the time of grafting were significantly lower in the urologic group: 11.1 versus 12.6 years, 28.8 versus 34.4 kg; 125.4 versus 138.4 cm, respectively. There were significantly higher frequencies of a transperitoneal approach and vena cavae and aortic anastomoses among patients with UTA (P < .001), posing a greater technical challenge in this population. No differences in creatinine levels were observed at 0.5, 1, 2, 5, and 10 years: 1.3 versus 1.6 at 5 years, and 1.4 versus 1.5 at 8 years. Urologic complications, including urinary tract infections (UTIs), occurred among 80.6% of patients with UTA versus 42.1% in the non-UTA group (P < .001). UTIs appeared predominantly in patients with UTA (62.7% vs 35.3%, P < .001), representing a 2.7-fold risk compared with those children transplanted for other reasons. Rejection incidence was similar in both groups (49.8%). There was no significant difference in 5-y (89.8% vs 85%) or 10-year (83% vs 67%) graft survivals between the groups (P = .162). CONCLUSION: Our results demonstrated that with proper interdisciplinary care, graft and patient survivals of pediatric recipients with UTAs were not affected; therefore, these patients should not be rejected for transplantation.

Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients.

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients < or =2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 x body surface area x creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 +/- 11.9 microg * h/mL; liver 61.7 +/- 29.5 microg * h/mL; heart 58.0 +/- 21.8 microg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults.

Experience of a successful pediatric liver transplant program in Mexico.

Orthotopic liver transplantation (OLT) has been very difficult to develop in Mexico and for many years its occurrence was anecdotal. This report presents the results of a pediatric liver transplant program, analyzing the variables that affect outcomes. Between June 1998 and March 2004, 35 OLT were performed in 34 recipients including 80% cadaveric whole-organ grafts and 20% segmental grafts, with 11% from cadaveric and 9% from living donors. Most of the recipients were infants or toddlers weighing less than 15 kg. There was only 1 case of arterial thrombosis (2.8%); the graft was saved with a Kasai procedure. Biliary complications were present in 22% of cases, all resolved with reoperations. Posttransplant cytomegalovirus infection or reactivation (28%), acute rejection (25%), or posttransplant lymphoproliferative disorders (5.7%) were not a cause of graft or patient loss. Overall, 1- and 5-year patient survival rates are 77.1% and 74.2%, respectively; however, when the 1998-2000 cohort was compared with the 2001-2004 cohort, there was a significant difference in survival (P = .004). The 1-year patient survival for the later group is 91.6%. We performed the first successful living donor liver transplantation and the first simultaneous liver-kidney transplantation in a child in our country. Our results demonstrate that pediatric liver transplantation is a feasible undertaking in Mexico, with survival rates comparable to those of foreign centers.

Infantile hypertrophic pyloric stenosis: a comparative study of pyloric traumamyoplasty and Fredet-Ramstedt pyloromyotomy.

PURPOSE: The aim of this study was to compare the incidence of surgical complications (duodenal perforation, postoperative vomiting, wound infection or dehiscence, incisional hernia) between 2 different surgical techniques for the resolution of hypertrophic pyloric stenosis in children. METHODS: A clinically controlled, randomized study with follow-up from 24 to 36 months was conducted. One hundred children between 15 days and 2 months old, who underwent surgical resolution of hypertrophic pyloric stenosis, were put randomly into 2 groups: I, pyloric traumamyoplasty (n = 43); II, Fredet-Ramstedt pyloromyotomy (n = 57). Both groups were controlled for the main demographic variables. Postoperative follow-up was blind for the surgical team. Statistical analysis was done with simple frequencies, percentages, Student's t test, and chi(2). RESULTS: There was not a single case of duodenal perforation, incomplete pyloromyotomy, wound infection, dehiscence, or incisional hernia in any group (P value, not significant). Postoperative emesis was present in 8 patients, uniformly distributed between groups. The operating room time for traumamyoplasty was 39.3 +/- 16.4 minutes versus 54 +/- 16.4 minutes for pyloromyotomy (P =.0003). CONCLUSIONS: This controlled study proves that traumamyoplasty is a simple procedure, quicker to perform, and as safe as pyloromyotomy for the treatment of infantile hypertrophic pyloric stenosis in children. For these reasons, the authors believe it should be considered as an alternative.

Intestinal anastomosis in children: a comparative study between two different techniques.

PURPOSE: The aim of this study was to compare the incidence of surgical complications between two different surgical techniques for intestinal anastomosis in children. METHODS: This was a clinically controlled, randomized study with blind follow-up from 18 to 36 months performed at the Reference Government Hospital in Mexico City. Eighty-six children required intestinal anastomosis, ages ranged between 1 month and 16 years, with emergency or elective surgery. Anastomoses of duodenum, rectum, with enteroplasty or protected with a proximal stoma were excluded. Two randomized groups were formed: (1) anastomosis with one layer of suture (Gambee stitches) and (2) with two layers of suture (first with Connel-Mayo stitches then with Lembert). Both groups were controlled in the principal variables without differences, and the follow-up concerning postoperative recovery was blind for the surgical team. RESULTS: Forty-two cases in group 1 and 44 in group 2 were compared. Intestinal dehiscence was found in 5 of 86 (5.8%), two from group I and three from group II (P value, not significant). Surgical time for anastomosis with one layer was an average of 26 minutes versus 43 minutes with two layers (P<.001). There were no stenoses within the follow-up period. CONCLUSIONS: This study proves that intestinal anastomosis with one layer of suture is as safe as anastomosis with two layers in children, and the time spent for completion of the procedure is significantly less with one plane of suture. For those reasons, it is the method of choice for intestinal anastomosis in children.

Selective portal blood flow diversion in auxiliary partial orthotopic liver transplantation to induce regeneration of the graft.

Experience with auxiliary partial orthotopic liver transplantation (APOLT) is still very limited and many questions remain to be solved. In this article, we present the case of a 5-year-old girl with ornithine transcarbamylase deficiency who initially did well after APOLT. During a severe rejection episode 16 months after transplantation, she developed encephalopathy and hyperammonemia. Despite a good clinical and histopathological response to antirejection therapy, the graft had become smaller and the native liver had undergone compensatory hypertrophy. After we surgically ligated the right portal branch, the graft recovered and the patient was able to stop her medication 1 month after surgery. We have estimated that the minimum volume of normal liver required to correct the metabolic defect in ornithine transcarbamylase deficiency is 8 cm3/kg. The ligation of the right portal branch was a safe and effective method of inducing a gradual and progressive involution of the hypertrophic native liver and regeneration of the atrophic graft.

Biliary atresia-polysplenia syndrome: surgical and clinical relevance in liver transplantation.

OBJECTIVE: To review a single center's 10-year experience with liver transplantation (LTx) for the biliary atresia-polysplenia syndrome (BA-PS) and to define surgical and clinical guidelines for its management. SUMMARY BACKGROUND DATA: BA is the most common indication for pediatric liver transplantation (LTx) and is associated with PS in 12% of cases. Only a few studies of LTx for BA-PS have been reported, and the optimal management of BA-PS patients undergoing LTx has yet to be determined. METHODS: From July 1985 to September 1995, 166 liver transplants were performed in 130 patients with BA and were included in the study. The malformations most commonly associated with BA-PS, surgical techniques used to overcome these anomalies, and surgical pitfalls that could have contributed to the outcome were characterized. Actuarial 10-year patient and graft survival for patients undergoing LTx for BA-PS were calculated and compared to those with isolated BA. RESULTS: Ten patients (7.8%) with BA had associated PS. An additional patient with PS without BA was included in the study. The diagnosis of PS was unknown before the transplantation in 72% of cases. Thirteen liver transplants were performed in these 11 patients. Modifications of the usual surgical technique were used to overcome the complex anatomy encountered. There was no association between the type of anomaly and the outcome, nor were there any significant differences in patient survival (72% vs. 73.5%, p = 0.79) or graft survival (56.4% vs. 54.6%, p = 0.54). CONCLUSIONS: The association of BA with various anomalies should be considered a spectrum that may vary widely from patient to patient. The finding of two or more of these malformations in a patient awaiting transplantation should lead the surgeon to look systematically for other associated anomalies. With some special surgical considerations, the outcome in BA-PS patients should not differ from those with isolated BA.

Short bowel syndrome in patients studied at the National Institute of Pediatrics in Mexico. Care, cost and perspectives.

BACKGROUND: Short bowel syndrome (SBS) continues to be one of the most challenging problems in pediatric surgery. Intestinal transplantation (IT) seems to be the best form of treatment for this pathology. However, it is thought that the development of an IT program may be more expensive than the present manner of treatment. METHODS: To assess this item, and to identify potential candidates for IT, we reviewed the charts of all the patients with SBS treated at our Institute from 1989 to 1994. RESULT: Nine patients were identified as carriers of SBS; six with intestinal atresia, two with midgut volvulus and one with post-traumatic mesenteric thrombosis. The small bowel remnants varied from 1 to 80 cm, seven patients had remnants shorter than 30 cm, and the ileocecal valve was resected in three. RESULTS: The overall morbidity and mortality was extremely high; four patients died within the first 3 months postresection and those still alive have had several complications: sepsis; hydroelectrolyte imbalances secondary to loose stools; thrombosis or infection of the catheter; TPN-related cholestasis, and malabsorption syndromes, etc. No patient survived with an intestinal remnant shorter than 15 cm. Of the five survivors, four have a weight/age deficit greater than 40%, two have rickets, one still depends on TPN and all, except one, require special enteral diets. Multiple central venous accesses had to be performed in every patient (mean 4.8). They all required multiple readmissions and have spent a considerable part of their lives as inpatients. The mean of the calculated cost per patient was $50,000 USD, while the minimal wage in Mexico is $1,616 USD/year (1). CONCLUSIONS: The shorter the segment of the retained bowel and the longer the survival, the higher the cost. These results may be further improved with the development of IT and, probably, with the same economic burden.

[Comparison of 2 types of experimental transplant in the treatment of lethal short bowel syndrome]. / Comparación de dos tipos de trasplante experimental en el tratamiento del intestino corto letal.

OBJECTIVE: To evaluate the functional response, morbidity and histostructural changes in rats enterectomized and without cecum using two types of syngenic enteral transplants. MATERIAL AND METHODS: Controlled randomized surgical-therapeutic trial. Four groups of male Lewis rats 8-10 weeks old underwent the following procedures: 1. Lethal enteral resection (n = 10). 2. Lethal enteral resection + total yeyuno-ileal transplant (n = 28). 3. Lethal enteral resection + distal segmentary of 40% and cecum transplant (n = 32). 4. Control group (n = 10). RESULTS: 11% of the transplanted animals died due to technical failures; both transplanted groups had a similar proportion of late complications, mostly enteral obstruction. A persistent diarrhea was observed in 20% of the yeyuno-ileal transplanted group, but no significant differences were found between the two groups concerning survival, weight gain, protein and triglycerides serum levels, and a maltose absorption test; villus and crypt hypertrophy was observed in both grafts. The enteral graft integration was followed by structural changes similar to those found in intestinal remnants on deficit conditions after enteral resection. CONCLUSION: The bowel distal segmentary transplant with ileocecal valve and cecum may be a good option in cases of irreversible enteral failure, as the functional response and morbidity are similar to those found with the standard total transplant.

Testosterone biotransformation by the isolated perfused canine pancreas.

There is strong evidence indicating that the pancreas is under the influence of sex steroid hormones, and that it may even participate in their biosynthesis and metabolism. In the present study, [3H]testosterone was perfused into the isolated canine pancreas, and measured in the effluent with several of its metabolites (5 alpha-dihydrotestosterone, androstenedione, and estradiol). Results show that testosterone is readily transformed by the canine pancreas. The main product found in the effluent is androstenedione. The testis and spleen were also perfused with [3H]testosterone and used as controls. In both cases, this hormone appeared mostly unchanged in the effluent as compared to the pancreatic perfusion (p less than 0.0001). From our data, we conclude that the canine pancreas has the capacity to transform sex steroid hormones, and could be considered an extragonadal site of sex steroid biosynthesis.