Growth hormone treatment improves final height and nutritional status of children with chronic kidney disease and growth deceleration.

PURPOSE: Growth retardation is a common complication of chronic kidney disease (CKD) in children. Treatment with recombinant human growth hormone (rhGH) has been used to help short children with CKD to attain a height more in keeping with their age group, but the scientific evidence regarding the effect of rhGH on final height is scarce. METHODS: Final heights of children with CKD receiving rhGH treatment (cases) were compared with final heights of a matched cohort of children with CKD that did not receive rhGH therapy (controls). RESULTS: Sixty-eight rhGH-treated cases (44 boys) were compared with 92 untreated controls (60 boys). Mean duration of rhGH therapy was 4.2 ± 0.9 years; rhGH dose was 0.3 ± 0.07 mg/kg/week. Height SDS at baseline was lower in rhGH-treated patients than in controls (-2.00 ± 1.02 versus -0.96 ± 1.11, p < 0.001). Baseline height SDS was significantly lower than target height SDS in both groups. Height SDS significantly improved from baseline to final height attainment in rhGH-treated patients, while it slightly decreased in controls (mean SDS variation 0.69 ± 1.05 in rhGH-treated cases versus -0.15 ± 1.2 in controls). Final height SDS was -1.25 ± 1.06 in rhGH-treated cases and -1.06 ± 1.17 in controls (p = 0.29). Target adjusted final height SDS was -0.91 ± 1.03 in rhGH-treated cases and -0.61 ± 1.17 in controls (p = 0.1). CONCLUSIONS: Long-term rhGH therapy is able to reduce the linear growth deceleration of children with CKD, and ultimately to improve their final height, reducing the difference with target height.

Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation.

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low-dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard-dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high-risk (donor+/recipient-) patients (n = 88), the EVR-based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val-)ganciclovir (n = 63), the CMV-free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR-based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard-dose calcineurin inhibitor-based regimen.

Combined kidney and vascularized total bladder transplantation: experience in an animal model.

BACKGROUND: Few reports have described a partial bladder graft with an en bloc kidney transplantation, mainly to facilitate reconstruction of the urinary tract, but also to augment the native bladder. The present study assessed the feasibility to graft vascularized total bladder in association with a renal transplantation. METHODS: The right kidney, in continuity with the ureter and the entire bladder, was retrieved from three female pigs weighing 20 g. The visceral bloc was transplanted to three recipient pigs of the same weight. The entire bladder was transplanted with its vascular connection to ensure a better blood supply. After 3 days of observation, one recipient was humanely killed to examine the bladder graft. Oxygen saturation in the bladder graft monitored for 8 hours was compared with the native bladder in the other two recipients. All three bladder grafts were examined by a pathologist. RESULTS: All bladder grafts seemed to be macroscopically well-perfused upon removal of the vascular clamps. In case 1, the recipient was clinically well with good urinary output over the first 2 days of observation; is contrast, on day 3 the animal displayed an acute reduced urinary output. Laparotomy on day 3 of observation showed recent thrombosis of the bladder and renal graft vessels. In cases 2 and 3, oxygen saturations of the bladder graft were normal during the 8-hour observation period, without any difference between the graft and the native bladder. CONCLUSIONS: According to our results, vascularized total bladder transplantation is feasible. In combination with renal transplantation, it could be applied as an alternative to bladder augmentation or total bladder replacement.

Premature ageing of the immune system relates to increased anti-lymphocyte antibodies (ALA) after an immunization in HIV-1-infected and kidney-transplanted patients.

Low-affinity immunoglobulin (Ig)G with potential autoreactivity to lymphocytes and hypergammaglobulinaemia have been described previously in HIV-1-infected patients. Whether such antibodies increase after challenging the immune system, for example with an immunization, is not known. In the present study, the modulation of antibodies with low affinity and potential autoreactivity was evaluated after 2012-13 seasonal flu vaccination with a simple empirical laboratory test measuring the titres of anti-lymphocyte antibodies (ALA) in two different models of secondary immunodeficiency: HIV-1 vertically infected patients (HIV) and patients treated with immunosuppressive therapies after kidney transplantation (KT) compared to healthy individuals (HC). In parallel, the activation status of B cells and their degree of immune senescence was evaluated by measuring the B cell interleukin (IL)-21R expression/plasma IL-21 levels and the frequencies of mature-activated (MA) and double-negative (DN) B cells. A significant increase of ALA titres was observed after vaccination in HIV and KT but not in HC, and this correlated directly with the frequencies of both MA and DN and inversely with the B cell IL-21R expression. This suggests that the quality of an immune response triggered by flu vaccination in HIV and KT may depend upon the activation status of B cells and on their degree of immune senescence. Further investigations are needed to verify whether high frequencies of MA and DN may also relate to increase autoimmunity after immunization in high-risk populations.

Renal transplantation in patients with "valve bladder": is bladder augmentation necessary?

INTRODUCTION: Posterior urethral valve is a common cause of renal failure in children. This disorder often results in small bladder and low compliance, which frequently requires bladder augmentation. Herein, we report our experience in 5 children with "valve bladder" who underwent renal transplantation without preliminary bladder enlargement. MATERIALS AND METHODS: Thirteen children with valve bladder undergoing renal transplantation were considered candidates for bladder augmentation. All had oligoanuria at transplantation. In 8 children, bladder augmentation was performed before renal transplantation; in the remaining 5, the decision was postponed until after transplantation. These children underwent transplantation with a ureteral reimplant, and a suprapubic catheter was in place for 2 months. Periodically, renal function, bladder capacity, and compliance were assessed, and renal ultrasonography was performed. RESULTS: At 1-, 2-, 4-, and 6-month follow-up, the 5 children who did not undergo bladder augmentation demonstrated normal renal function, with improved bladder capacity and absence of hydronephrosis. No significant difference was evident between the 2 groups (augmented vs nonaugmented) insofar as renal function, bladder capacity, or hydronephrosis. After transplantation, bladder augmentation was not deemed necessary in any of the 5 children because of complete restoration of clinical and urodynamic parameters. CONCLUSION: Renal transplantation can be performed safely without preemptive bladder augmentation. Ureteral reimplantation is recommended, even in patients with small valve bladders. The decision about the need for bladder augmentation should be made only after normal diuresis is restored.

[Controversies about the use of calcineurin inhibitors in pediatric patients]. / Controversie nell'uso degli inibitori della calcineurina in pediatria.

The availability of new drugs has prompted transplant physicians to devise new immunosuppressive protocols without the calcineurin inhibitors cyclosporine and tacrolimus in order to reduce the incidence of their side effects, particularly nephrotoxicity. However, recent data suggest that these drugs still procure the longest organ survival after transplant. In addition, although they have been used for a long time, it is not clear which calcineurin inhibitor is to be preferred: tacrolimus seems most effective in reducing the acute rejection rate, possibly associated with a better glomerular filtration rate in the following years, but its benefit in the long run is not definitely established. It may allow a dose reduction of steroids, which is of particular interest in pediatric age, but it is associated with a higher incidence of severe side effects, in particular post-transplant lymphoproliferative disorders and diabetes. In recent protocols, the reduction of the dose of this drug has led to a reduction of these side effects, even though they are still more frequent than side effects observed during cyclosporine treatment.

Renal-coloboma syndrome: a single nucleotide deletion in the PAX2 gene at Exon 8 is associated with a highly variable phenotype.

BACKGROUND: Renal-coloboma syndrome (RCS) is an autosomal dominant disorder characterized by renal abnormalities and optic nerve defects, caused by heterozygous mutations of the PAX2 gene. This gene encodes for the PAX2 developmental nuclear transcription factor, which is primarily expressed during embryogenesis in kidneys, eyes, ears and in the central nervous system. The aim of the present study was to characterize PAX2 mutations in a renal coloboma syndrome family with a highly variable phenotype. METHODS: DNA screening was performed by direct sequencing. RESULTS: Five subjects over three generations presented with renal hypodysplasia or horseshoe kidneys in association with bilateral optic nerve colobomas in four cases, one patient with early-onset renal failure had no detectable eye defects. All five subjects carried a novel PAX2 mutation consisting in a frameshift mutation located in Exon 8 (G91 I del), which causes premature termination of translation and loss of the PAX2 transactivation domain. CONCLUSION: This is the first report of a PAX2 mutation located in Exon 8. The variability of clinical symptoms may be explained by the limited disruption of the protein sequence at the transactivation domain.

Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients.

This open-label, longitudinal, long-term study of de novo pediatric renal transplant recipients was designed to investigate the pharmacokinetics (PK) of mycophenolic acid (MPA) and its possible interaction with cyclosporine (CsA). Thirty-four children on an immunosuppressive regimen of CsA, prednisone, and mycophenolate mofetil (MMF, 300-400 mg/m2 twice daily) were investigated at 6, 30, 180, and 360 days after transplantation. Considerable interindividual variability in the areas under the concentration curve (AUC(0-12)) of MPA was observed during the follow-up, although the dose of MMF remained the same over the same time. Predose levels (C0) increased significantly during the first 6 months after transplantation: C0 at 6 and 180 days after transplantation was 0.8 +/- 0.6 and 1.9 +/- 1.1 microg/mL (P < .0001). A significant time-dependent increase in the AUC of MPA was also observed during the first 6 posttransplant months: AUC(0-12) at 6 and 180 days after transplantation was 23.3 +/- 10.8 and 40 +/- 11.6 mg*h/L (P = .003). MPA concentrations 3 and 4 hours after MMF intake were the individual time points that best correlated with the full MPA AUC (r = 0.8 and 0.79; P < .001). The abbreviated MPA AUC (0-4 hours) correlated reasonably with the full AUC (r = 0.87; P < .001). Finally, a significant reduction in CsA dose during the first 6 posttransplant months (P < .001) matched the significant increases in both MPA C0 and full MPA AUC, thus demonstrating the interaction of the 2 immunosuppressive drugs. These observations suggest the need for therapeutic drug monitoring when adjusting the dose of MMF in children.

Renal hemodynamic effect of tacrolimus in renal transplanted children.

Like cyclosporine (CsA), tacrolimus acts through the inhibition of renal phosphatase calcineurin. CsA induces reversible vasoconstriction, causing a transient reduction of renal plasma flow in patients with renal transplantation. The aim of this study was to determine the effect of tacrolimus on renal plasma flow in renal transplanted children. Eight children were studied with a median age of 10.6 years, a mean glomerular filtration rate (inulin clearance) of 55 ml/min per 1.73 m2 (range 29-95), and a mean follow-up after transplantation of 5.6 months. Effective renal plasma flow (ERPF) was studied in each patient for 12 h after tacrolimus administration. Clearances were obtained every 2 h for 12 h after drug administration. Tacrolimus pharmacokinetics was also studied. Average ERPF at the start of the test was 289 ml/min per 1.73 m2 (range 177-404, SD +/- 106). Variation in each of the 2-h periods was not significant, although a mild reduction of plasma flow was observed in three of the eight children. No correlation was found between tacrolimus AUC, peak, or trough levels and renal blood flow variations. Despite the relatively small number of patients studied, these data suggest that, in vivo, a therapeutic oral dose of tacrolimus is not necessarily followed by a significant reduction of ERPF in renal transplanted children.

Simultaneous determination of inulin and p-aminohippuric acid in plasma and urine by reversed-phase high-performance liquid chromatography.

A simple, accurate and sensitive high-performance liquid chromatographic method with UV detection was carried out to measure simultaneously plasma and urine concentrations of both p-aminohippuric acid and inulin. Following a simplified acid hydrolysis of the sample, the separation was carried out in 4 min using a C18 reversed-phase column with a flow-rate of 1 ml/min, and monitoring the absorbance at 280 nm. Within the investigated concentration ranges of inulin (0.1-3.2 mg/ml) and p-aminohippuric acid (0.0097-0.3 mg/ml), good linearity (r>0.99) was obtained. Within-run RSD ranged from 2.9 to 6.1% and between-run RSD ranged from 6.4 to 10%. Analytical recoveries were 101-112%, with little differences between plasma and urine samples. The detection limit was 1 microg/ml for all the analytes studied. This method might be ideal for renal function studies where a rapid and reproducible assessment of both renal glomerular filtration rate and blood flow-rate is required.

Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes have been described. The gene responsible for type I, SLC3A1, encodes the amino acid transporter rBAT. This gene is not responsible for types II or III. Recently the type III locus (CSNU3) was mapped by two groups to overlapping 6-Mb regions on chromosome 19q. In the present study, we restrict the critical region for non-type I cystinuria to 2.4 Mb by recombination analysis in Italian, German, and Spanish families. For this purpose, we have used the microsatellite markers described in the region plus new microsatellites that we have developed. Our results locate the non-type I cystinuria gene in an interval flanked by the markers C13 and D19S587, which are about 2.8 cM apart.

Cyclosporine A monitoring in children: abbreviated area under curve formulas and C2 level.

Cyclosporine A (CsA) is the most commonly used drug in organ transplantation. To evaluate exposure the gold standard is area under curve (AUC), but this is expensive and requires many blood samples. For this reason, abbreviated formulae have been developed in adults. Data in children are scanty. Formulae cannot be applied in patients taking CsA every 8 h. We tested the abbreviated AUC formula published for adults in renal transplant children on twice daily therapy and we propose a method, requiring three blood samples, for those taking CsA every 8 h. A very good correlation was obtained for both groups. Furthermore, we studied the correlation between CsA concentration 2 h after administration and AUC. A good correlation was found supporting the possible use of this parameter for monitoring CsA therapy.

Combined heart and kidney transplantation in a child: will we need it more in the future?

A 12-year-old girl affected by idiopathic dilated cardiomyopathy and renal failure was referred to our institution for cardiac transplantation. A simultaneous heart-kidney transplantation from the same donor was decided. The immunosuppression schedule consisted of azathioprine, antithymocyte globulin, steroids, and cyclosporine. At a follow-up visit at 24 months after transplantation, no episodes of heart or kidney rejection had occurred and cardiac and renal function were good. Concomitant failure of heart and kidney is well known in the literature, but it appears to be more frequent in adult as compared with the pediatric population. This is the first case of combined heart and kidney transplantation in a child. Because of the successful outcome and good follow-up, the number of combined organ transplantations will most likely increase in the future.

Feeding dysfunction in infants with severe chronic renal failure after long-term nasogastric tube feeding.

Nasogastric tube feeding (NGTF) is frequently necessary to overcome the inadequate caloric intake of children with severe chronic renal failure (CRF). In a multicenter retrospective study, we evaluated feeding dysfunction after tube feeding withdrawal in children with severe CRF who started long-term enteral nutrition early in childhood. We considered, almost exclusively, infants who had started NGTF very early and continued to be tube fed for at least 9 months. Twelve patients were included in the study: 8 showed significant and persistent eating difficulties, with difficulties in chewing and swallowing in 7 and food refusal in 6. For 2 patients "panic attacks" from swallowing were repeatedly reported. These problems persisted for more than year in 5 patients and between 1 and 6 months in 4. The possible feeding difficulties that may follow NTGF must be carefully evaluated. A possible means of overcoming these difficulties might include: encouraging the use of a pacifier, proposing water for spontaneous assumption, leaving the child the possibility of eating food spontaneously during the daytime, and increased support for the parents during weaning. These need prospective study.

Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism.

A cystinuria disease gene (rBAT) has recently been identified, but evidence strongly suggests that only Type-I cystinuria is due to mutations in this gene. Sixteen point mutations and a large deletion causing the disease have so far been described in the rBAT gene sequence. To identify new mutated alleles, genomic DNA was analyzed, after the determination of the entire genomic structure of the rBAT gene, by RNA-single strand conformation polymorphism analysis, an accurate and sensitive method able to detect nucleotide changes. Four new point mutations, a large deletion, and a common intragenic polymorphism were detected. These new mutations increase to 22 the number of mutated alleles so far characterized in rBAT. In addition, the frequency of 21 mutations was assessed in a sample of accurately defined Type-I cystinuria chromosomes. They account for about 58% of all Type-I chromosomes, mutation M467T being the most common (0.26).

[Combined heart-kidney transplantation in pediatric age]. / Trapianto combinato cuore-rene in età pediatrica.

A case of simultaneous heart and kidney transplantation is presented in a 12 years old girl. The patient suffered from dilated cardiomyopathy and end-stage kidney disease. Bilateral vesico-renal refluxes were corrected at the same time of the duplex transplantation. A multiorgan harvesting from a pediatric 8 years old donor was utilized. Follow-up is 40 months. Cytomegalovirus (CMV) infection and acute tubular necrosis from haemoglobinuria were transient complications. Hemolysis from bypass and extracorporeal circulation was involved as pathogenetic factor of the acute tubular necrosis. Cardiac and renal function remain excellent and the child is fully recovered and resumed a normal and active life. Combined heart and kidney transplantation may be of benefit in selected patients, also in pediatric age.

Sensorineural hearing loss in patients reaching chronic renal failure in childhood.

The incidence of sensorineural hearing loss (SNHL) was investigated in 68 patients who reached chronic renal failure (CRF) in childhood with the aim of identifying possible risk factors. Tests were carried out by means of pure-tone and impedance audiometry. SNHL was found in 29% of patients on conservative treatment, 28% of patients on hemodialysis, and 47% after renal transplantation. Differences among groups were not significant. A significant correlation was found with the administration of ototoxic drugs (aminoglycosides and furosemide). We hypothesize that SNHL may be reduced in patients with CRF or on renal replacement therapy by strictly monitoring ototoxic therapy.

Cyclosporine-induced transient renal hypoperfusion in adolescent transplant recipients.

We investigated the acute hemodynamic effect of a single oral dose of cyclosporine A (CsA) given as part of the immunosuppressive schedule in six adolescents with renal transplants. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by continuous infusion of inulin and amino-hippuric acid for 12 h. A fall in both GFR and RPF was observed 4-6 h after peak plasma CsA levels. No significant correlation was found with CsA dosage or any pharmacokinetic parameters. This study demonstrates that CsA also has a vasoconstrictory effect in adolescent recipients; this could be one of the causes of its nephrotoxicity.

Relapsing gross haematuria in Münchausen syndrome.

A 10-year-old female with relapsing gross haematuria and Münchausen syndrome is reported, emphasizing the rarity of this situation in children and the difficult diagnostic pathway. A careful personality study of the patient and family members is absolutely necessary in order to proceed with diagnosis and successful treatment.