Endoscopic treatment of symptomatic refluxing renal transplant ureteroneocystostomies in children

Vemulakonda VM, Koyle MA, Lendvay TS, Risk MC, Kirsch AJ, Cheng EY, Cisek LJ, Campbell JB. Endoscopic treatment of symptomatic refluxing renal transplant ureteroneocystostomies in children. Pediatr Transplantation 2010:14:212–215. © 2009 John Wiley & Sons A/S. Abstract: To present a multi‐center experience with the use of Dx/HA copolymer for treatment of symptomatic refluxing renal transplant UNC in children. A multi‐center, retrospective chart review was performed. Eleven patients with a mean age of eight yr underwent renal transplantation with an anti‐refluxing UNC. Data were collected to determine the safety and effectiveness of the procedure and to identify possible predictors of success. Endoscopic treatment was successful in one of five males and five of six females, for an overall success rate of 54.5%. The etiology of renal failure was associated with success of treatment, with 4/6 (67%) patients with upper tract pathology demonstrating resolution of the VUR, as compared with one of three (33%) patients with lower tract pathology. Male patients had a higher incidence of lower tract pathology. No complications were associated with the endoscopic procedure. Endoscopic injection of Dx/HA remains a safe option for the treatment of symptomatic refluxing transplant UNC in children. Although the success rate is lower than that seen in the treatment of primary VUR, the minimally invasive nature and safety of this technique may offer advantages over open reconstruction of the refluxing transplant ureter.     

Predictors for abnormal voiding cystourethrography in pediatric patients undergoing renal transplant evaluation

The role of pretransplant voiding cystourethrography (VCUG) in adults has been questioned owing to the low prevalence of abnormal findings. As there are no studies evaluating the relevance of VCUG in children and because vesicoureteral reflux (VUR) occurs with higher prevalence in children, we performed a retrospective cohort study to identify any predictors for abnormal VCUG. We reviewed 271 consecutive renal transplants performed between 1980 and 1997. By logistic regression, the etiology of end-stage renal disease (ESRD) and age at transplantation (Tx) were strong predictors of abnormal pretransplant VCUG findings in children. On multi-variate analysis, children with urologic etiologies of renal disease had an odds ratio (OR) of 16.5 (p < 0.0001) for abnormal VCUG as compared to children with non-urologic or acquired causes of ESRD. Similarly, children transplanted when younger than 8 yr of age had an OR of 3.0 (p = 0.0043) for having an abnormal VCUG when compared with older children. Finally, our analysis suggests that children with abnormal pretransplant VCUG findings, whether or not pretransplant surgical correction was performed, were over three-fold more likely to require post-transplant urologic surgery when compared to children with normal pretransplant VCUG. We conclude that urologic causes of ESRD and age under 8 yr are strong independent predictors of abnormal pretransplant VCUG findings, and that these findings are of clinical relevance both in deciding whether to pursue pretransplant VCUG and in the post-transplant course of the patient.     

Five years' experience with thymoglobulin induction in a pediatric renal transplant population

Antibody induction therapy is used in the majority of pediatric patients undergoing renal transplantation. Our center has previously reported short-term outcomes with TMG as induction therapy. We now present our experience over the last five yr. Patients received TMG intra- and post-operatively at a dose of 1.5 mg/kg/day. The dose was decreased to 0.75 mg/kg/day or held dependent on the patient's WBC and platelet counts. Post-transplant immunosuppression also included corticosteroids, MMF, and either TAC or CSA. Patient and graft survival, number of acute rejection episodes, creatinine clearance, incidence and type of infections, and trough levels of calcineurin inhibitor drugs were monitored during the follow-up period. Thirty-four renal transplants were performed in 33 pediatric patients ranging in age from 1.7 to 17.8 yr. Seventeen rejection episodes occurred during the time of follow-up with three patients having more than one episode, but only three episodes occurred within the first year after transplantation. Three patients had graft loss in the first week after transplantation from primary non-function (1) or technical failure/thrombosis (2). Graft losses occurred in seven additional patients during the time of follow-up with the first loss occurring at 17.7 months. Among patients with functional grafts at one wk after transplant, graft survival at one and three yr was 100% and 73% respectively. There were no patient deaths. There were no cases of post-transplant lymphoproliferative disease or other malignancy. One patient had symptomatic CMV disease. TMG is safe and effective as induction therapy in pediatric renal transplant patients. Late graft loss remains a challenge in the pediatric patient population, particularly in adolescents.     

Cryptosporidiosis: a rare and severe infection in a pediatric renal transplant recipient

Cryptosporidium is an intracellular protozoan parasite that causes gastroenteritis in human. In immunocompromised individuals, cryptosporidium causes far more serious disease. There is no effective specific therapy for cryptosporidiosis, and spontaneous recovery is the rule in healthy individuals. However, immunocompromised patients need effective and prolonged therapy. Here, we present our clinical experience in a six-yr-old boy who underwent living-related donor renal transplantation and who was infected with Cryptosporidium spp. Our patient was successfully treated with antimicrobial agents consisting of spiramycin, nitazoxanide, and paromomycin. At the end of second week of therapy, his stool became negative for Cryptosporidium spp. antigen and spiramycin was discontinued. Nitazoxanide and paromomycin treatment was extended to four wk. With this case, we want to emphasize that cryptosporidiosis should be considered in the differential diagnosis of severe or persistent diarrhea in solid organ transplant recipients where rigorous antimicrobial therapy is needed.     

Bone mineral density in pediatric and adolescent renal transplant patients: how to evaluate

Reduced bone mass is a common complication of renal transplantation in adults but only few data are present for pediatric transplant patients. Bone mineral status of pediatric renal transplant patients ages ranging from 7.5 to 17.6 years (mean age 14.9 +/- 2.3) who were at least 6 months postrenal transplantation was examined. Bone mineral density (BMD) of lumbar vertebrea and femoral neck was determined by dual energy X-ray absorptiometry (DEXA) and z-scores according to age, puberty, height and bone age were compared to sex and ethnic specific reference data. z-scores were calculated for both areal and volumetric bone density. BMD L1-4 z-scores were more than 2 SD below the mean according to chronological age in 12 patients (63%), pubertal status in six patients (31.5%), bone age in five patients (26.3%) and height in five patients (26.3%). The BMD femoral neck z-scores were more than 2 SD below the mean according to age in 10 patients (55.5%), puberty in five patients (27.7%), bone age in three (16.6%) patients and height in five (26.3%) patients. Correction of the vertebrae and femoral neck for bone size yielded osteoporotic values for seven patients (36.8%) for lumbar BMD and for four patients (22%) for femoral neck BMD. The use of aBMD in growth-retarded children has some restrictions in determining z-scores. Deficits in spinal bone density still persisted after correcting for height, puberty, bone age and volume. In renal transplant patients who have short stature it is reasonable to give values corrected for height, puberty, bone age and bone size and interpret each of these values for each patient.     

Immune response to rabies vaccination in pediatric transplant patients

Children have become engaged in a wider variety of activities as the success of solid organ transplantation has improved. These activities can result in exposure to infectious agents for which there are no data documenting the efficacy of standard treatment in children on immunosuppressive therapy. This is a retrospective review of five OLT patients and three RT patients who were potentially exposed to rabies during camp. They completed the immunoprophylaxis treatment for rabies exposure outlined by the CDC in the 2003 Red Book. Rabies titers were followed for six to 12 months post-immunization. All five OLT patients were on tacrolimus. All three RT patients were on tacrolimus, mycophenolate mofetil, and prednisone. At the time of exposure median age was 10.0 yr (8.4-17.3). None of the subjects developed rabies. A positive rabies titer, indicative of successful immunization, was present by one month in seven subjects and all subjects by six months. Rabies vaccination in pediatric transplant patients is safe and associated with the successful production of antirabies titers.     

Results of one-year follow-up of steroid-free immunosuppression in pediatric renal transplant patients

Renal transplantation in children has traditionally required immunosuppression with multiple medications including glucocorticoids. Data collected over almost 30 yr suggest that although glucocorticoids are efficacious as part of a regimen to minimize the incidence of acute rejection episodes, their use is associated with increased risk for post-transplant hypertension, hyperlipidemia, and reduced growth rates. We desired to reduce these complications and thus used an immunosuppressive protocol including daclizumab, tacrolimus, and mycophenolate mofetil and study the efficacy of this protocol in a population with a high percentage of African-American recipients. No patient received glucocorticoids at any time post-transplant. Our results show that at 1 yr post-transplant, glomerular filtration rate, serum glucose, calcium and phosphorous metabolism, serum magnesium, and serum lipids were similar in patients receiving steroid-free and those receiving steroid-based immunosuppression. The incidence of acute rejection was similar in the two groups. Hematocrit and white blood count levels were lower 1 month after transplant in the steroid-free patients but these levels increased within several months. Systolic blood pressure was similar in the two groups, although this was achieved, in part, in the patients who received steroids by the administration of medications to lower blood pressure. Finally, tacrolimus levels were similar in the two groups, but patients receiving steroids required higher doses of tacrolimus at several time points studied during the first post-transplant year. Taken together, our data suggests that at one-year follow-up, steroid-free immunosuppression is safe, and efficacious in pediatric renal transplant recipients.     

Assessment of risk factors for cardiovasuclar disease in pediatric renal transplant patients

Pediatric renal TP recipients are at risk for CVD. We performed a cross-sectional study of the prevalence of RF for CVD in 45 long-term pediatric renal TP patients. The time since TP was 42 months. The GFR was 87.8 +/- 3.4 mL/min/1.73 m(2); 25/45 (56%) had Stage 2-4 CKD. A total of 33% had elevated SBP and 24% had high DBP; 57% had elevated SBP or DBP. A total of 20% had elevated serum CHOL levels, while 45% had high serum TG levels. A total of 42% had high HCY levels and 50% had low HCT levels. The vast majority (66.7%) had at least two RF for CVD. A total of 18.2% had abnormal post-TP echocardiography results. There was a negative correlation between GFR and SBP, DBP, serum CHOL, HCY, and BMI. There was a positive correlation between GFR and HCT. Serum CHOL was significantly lower and SBP and DBP trended lower in patients on a SF immunosuppression regimen. Similarly, SBP and DBP trended higher and CHOL was significantly higher in patients receiving SRL vs. mycophenolate mofetil. We conclude that the majority of pediatric renal TP patients exhibit multiple CVD RF.     

Adenovirus-associated hemorrhagic cystitis in a pediatric renal transplant recipient

Adenovirus infection has been associated with the development of hemorrhagic cystitis in bone marrow transplant recipients. However, limited information exists regarding adenovirus-associated hemorrhagic cystitis in solid organ transplantation, especially in renal transplant recipients. In most cases, the disease is self-limited. However, some patients may have a protracted course. Although no particular antiviral agent has been identified as the gold standard of therapy, cidofovir has been found to be effective in a number of bone marrow transplant recipients. In this study, we report a five-yr-old boy who presented with adenovirus-associated hemorrhagic cystitis 68 days after renal transplant and was successfully treated with reduction of immunosuppression and an intermediate dose of intravenous cidofovir.     

Lipid profile during rhGH therapy in pediatric renal transplant patients

To evaluate the effect of recombinant human growth hormone (rhGH) treatment on the lipid profile of pediatric renal transplant patients, we studied nine children treated with rhGH for 1 yr and a control group of 12 untreated patients matched in terms of age, renal transplant function and post-transplant follow-up. The levels of lipoprotein (a [Lp(a)], cholesterol, triglycerides, apolipoprotein A (APO A) and apolipoprotein B (APO B), and the APO B/APO A ratio, were determined at baseline and after 6 and 12 months of follow-up. RhGH therapy had no effect on cholesterol, triglycerides or apolipoproteins. Mean serum Lp(a) levels increased from 6.7 +/- 5.7 mg/dL at baseline to 11.8 +/- 10.7 after 6 months (p = 0.018) and 13.6 +/- 15.1 after 12 months of rhGH treatment (p = 0.04), but did not change in the control group. Lp(a) is a risk factor for cardiovascular morbidity, and increased Lp(a) levels may be a side-effect of rhGH treatment in renal transplant patients. Although long-term follow-up of a large number of patients is needed to establish the duration and extent of the effects of rhGH treatment on Lp(a) levels in transplanted children, serum Lp(a) levels should be carefully monitored in those receiving rhGH therapy.     

Growth hormone therapy before and after pediatric renal transplant

Children undergoing successful renal transplantation anticipate optimal growth and development. The use of rhGH pre- and post-Tx has been evaluated and supported by randomized control trials. Several strategies are required to maximize the potential benefit of this treatment in the renal population including provision of adequate nutrition intake, following bone parameters with appropriate interventions, and strategies to reduce steroid therapy including utilization of alternate day steroid treatment. Studies are required to further assess the impact of rhGH on renal allograft function, rejection risk, and allograft ultrastructural changes.     

Decreased bone mineral density in the pediatric renal transplant population

All renal transplant recipients at our centre have had bone mineral density assessment (BMD) by DEXA scans of their lumbar spine while on the transplant waitlist and at 6-month intervals post-transplant over the past 7 yr. Risk factors for osteopenia and osteoporosis including donor source, dialysis status prior to transplantation, prior renal disease, and biopsy confirmed rejection events and their relationship to BMD of the lumbar spine were assessed. Thirty-nine children transplanted over the past 7 yr were included in this study. In total, 127 BMD longitudinal assessments were performed. From 1990 to 1997, ATG/ALG was used as antibody induction therapy. From 1997 to 2002, Basiliximab was utilized. Cyclosporin A (CyA) was the primary immunosuppressant for most children with tacrolimus as primary (n = 2) and switch for CyA failure or toxicity (n = 16). Prednisone was administered at a dose of 1 mg/kg/day for the first week and tapered to 10 mg/m2/alternate day by 1 month post-transplant. Azathioprine 1.5 mg/kg/day was continued for 1 yr and discontinued in children who were rejection free. All rejections were biopsy confirmed and treated with a prednisone pulse. Using a repeated measures regression analysis, we have found that L1-L4 BMD z score is affected by height and transplant number. It is also related to time relative to transplant in a quadratic fashion. There was an inverse relationship between advancing patient age and L1-L4 BMD z score. L1-L4 BMD z score was not related to weight, pre-existing renal disease, gender, donor source, type of renal replacement therapy prior to transplantation, or rejection events.     

Risk factors for cardiovascular disease in pediatric renal transplant recipients

About 1,000 children develop end-stage renal disease (ESRD) each year in the United States and about 5,000 children are currently receiving dialysis. Children who develop ESRD are eligible to receive renal replacement therapy, including renal transplantation. There are inherent risks associated with transplantation, including renal insufficiency, infections, post-transplant lymphoproliferative disorder, and cardiovascular disease (CVD). Potential risk factors for CVD in pediatric renal transplant recipients include renal insufficiency, hyperlipidemia, hyperhomocysteinemia, inflammation, malnutrition, anemia, and hyperglycemia/insulin resistance. Despite evidence that many children may possess various risk factors for CVD post-renal transplantation, there are very few studies that have attempted to assess the link between these risk factors and CVD in pediatric renal transplant recipients.     

Risk factors for bone mineral density loss in pediatric renal transplant patients

Bone mineral density (BMD) is decreased in both adult and pediatric renal transplant recipients. To investigate the risk factors associated with this decrease in BMD post-renal transplant, we studied 33 children, aged 7-22 yr, who had received a renal transplant from 0.3 to 10 yr prior to this study. BMD analysis of the total body, spine, and femur was carried out by using dual-energy X-ray absorptiometry (DEXA). Age, weight, Tanner stage, time on dialysis prior to transplantation, cumulative corticosteroid dosage, and cyclosporin A (CsA) dosage since transplantation, and use of corticosteroid therapy prior to transplantation, were recorded. Spine, femur, and total body BMD Z-scores were greater than two standard deviations (2 SD) below the mean in 45%, 42%, and 17% of patients, respectively. Age correlated inversely with total body and spine BMD Z-scores (p = 0.001 and p = 0.008); no child under 14 yr of age had a total body or spine BMD Z-score greater than 2 SD below the mean for age. Patients at a Tanner stage of 4 or 5 had lower total body and spine BMD Z-scores than did patients at Tanner stages 1-3 (p = 0.043). Time post-transplant correlated inversely with both spine and total body BMD Z-score (p = 0.013 and p = 0.023). Only total body BMD Z-score correlated inversely with cumulative corticosteroid dose (in g, p = 0.045). BMD did not correlate with cumulative CsA dose. Black patients tended to have decreased total body BMD compared with Caucasian patients. In pediatric renal transplant patients, decreases in BMD start in adolescence. Risk factors for BMD loss in these patients include increasing age, time post-transplant, increasing Tanner stage, and ethnicity. Longitudinal studies in these patients and strategies to improve BMD are needed.     

Atorvastatin treatment for hyperlipidemia in pediatric renal transplant recipients

The objective of this prospective study was to determine the prevalence of hyperlipidemia in our pediatric renal transplant patients and to treat those with persistently elevated cholesterol and/or low-density lipoprotein (LDL) levels. All patients with a functioning renal allograft for greater than 6 months were studied (n = 18). Patients with cholesterol and/or LDL levels greater than the 95th percentile (n = 9) were commenced on an HMG-CoA reductase inhibitor, Atorvastatin and monitoring was performed for efficacy and adverse effects. Total serum cholesterol was elevated in 11 of 18 (61%) and triglyceride (TG) was elevated in 12 of 18 (67%) patients. Atorvastatin treatment was effective with a mean percentage reduction of total cholesterol of 41 +/- 10% (p < 0.01 vs. before treatment), LDL 57 +/- 7% (p < 0.01 vs. before treatment) and TG 44 +/-25% (p = 0.05 vs. before treatment). No adverse effects on allograft function or cyclosporin levels were experienced. Hyperlipidemia is a common problem and Atorvastatin is a safe and effective treatment in pediatric renal transplant recipients.     

Demographic and medical predictors of medication compliance among ethnically different pediatric renal transplant patients

Medication adherence in African-American and European-American pediatric renal transplant recipients was evaluated by four separate measures. Demographic and medical factors were analyzed. Based on pill count/refill history, European-American females were more compliant than their male counterparts. Based on self-ratings of compliance, African-American recipients were more compliant if they had vs. had not had dialysis experience prior to their transplant. These recipients also had higher self-ratings of compliance if their donors were cadaveric rather than living related.     

Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric heart transplant recipients

The introduction of cyclosporine revolutionized the practice of immunosuppression for solid organ transplant recipients, and has resulted in a significant increase in survival. While CNI use has been the mainstay of immunosuppressive therapy in pediatric heart transplantation, CNIs have been associated with an increased risk of nephropathy leading to significant morbidity and mortality. We evaluated the effect on renal function of a CNI minimization protocol using SRL in pediatric heart transplant patients with CNI induced renal insufficiency. An IRB approved retrospective chart review and case control study was performed. There were 20 patients identified with renal insufficiency who had been converted to SRL (target 5-8 ng/mL) and cyclosporine (target 50-75 vs. 125-150 ng/mL). Renal insufficiency was defined as isotopic (Indium 111 DTPA) GFR <60 mL/min per 1.73 m(2) or sCr >1 mg/dL. Outcome variables evaluated were GFR and sCr at time of conversion and at two yr post conversion. Comparison was made with case control subjects matched for age at Tx, time from Tx to conversion, and initial GFR. The median age at Tx = 81 days (S.D. ±26), median time of conversion after Tx = 10 yrs (s.d. ±0.65). Self-limited/treatable side effects included hypercholesterolemia (10), neutropenia (6), aphthous ulcer (3), edema (2), anemia (2), and tremor (1). One patient rejected in the two yr prior to conversion, and one patient had two rejection episodes following conversion. GFR at conversion for study group was 51 ± 14 vs. 60 ± 2 at two yr, p = 0.018. GFR at inclusion for control group was 56 ± 20 vs. 53 ± 21, p = 0.253. This report demonstrates that minimizing CNI exposure by addition of SRL to the immunosuppressant regimen in pediatric heart transplant recipients result in improved renal function in comparison to historically managed patients. Furthermore, immunotherapy with SRL and lower-dose CNI can effectively prevent rejection with an acceptable side-effect profile.     

Tracking of blood pressure and its impact on graft function in pediatric renal transplant patients

We studied tracking of BP and its impact on GFR in 44 PRTP followed for 56 months. Three months PT 77% had elevated SBP percentile. First year SBP and DBP correlated positively with final values (p < 0.0001, 0.0002, respectively). Pretransplant and three month PT SBP correlated positively (p = 0.02). At one yr, SBP and DBP were inversely associated with GFR (p = 0.002, p < 0.0001, respectively). SBP and BMI were positively associated at all time points. DBP was significantly higher in deceased recipients throughout the study period. Final DBP was higher (p = 0.03) and GFR lower (p = 0.04) in African-American patients. Patients with end-stage renal disease caused by glomerular disease had higher SBP (p = 0.03) and DBP (p = 0.04) than those with congenital malformations. GFR at one-yr PT (p = 0.02) and end of study (p = 0.003) was significantly lower in patients with high BP. Moreover, patients who maintained a normal systolic BP throughout the study had a significantly higher final GFR than those who were hypertensive at both time points [84 (normal BP throughout) vs. 52 mL/min/1.73 m(2) (high BP throughout), p = 0.02]. We conclude that PT hypertension is common in PRTP and predicts lower GFR.