RESUMEN
Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.
Asunto(s)
Túbulos Renales/embriología , Riñón Poliquístico Autosómico Dominante/genética , Insuficiencia Renal/genética , Canales Catiónicos TRPP/genética , Conductos Mesonéfricos/patología , Alelos , Animales , Modelos Animales de Enfermedad , Epitelio/embriología , Epitelio/patología , Femenino , Mutación de Línea Germinal , Humanos , Túbulos Renales/patología , Ratones , Ratones Noqueados , Riñón Poliquístico Autosómico Dominante/sangre , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/patología , Insuficiencia Renal/sangre , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/patología , Transducción de Señal/genética , Conductos Mesonéfricos/embriologíaRESUMEN
Cyclosporin A (CsA) is known to possess antiviral activity against several viruses in vitro, but the effect of CsA on BK polyoma virus (BKV) replication has not been examined. We investigated the impact of CsA on primary, chronic, and high-level BKV infection using a cell system of kidney cell origin (Vero E6 cells). During the first 2 h post infection, cells treated with CsA up to 3200 microg/L showed a near-identical BK viral load to untreated cells, with only a very minor reduction in the CsA-treated cells observed at 4 h. In chronic culture, CsA completely suppressed the primary BKV infection peak in a non-dose-dependent manner within the dose range of 200-12,800 microg/L (P<0.05). BKV reactivation was also inhibited in the presence of CsA at doses of 200-3200 microg/L: the mean number of BKV DNA copies/mL remained stable or even decreased slightly compared with a 7-log increase in the non-CsA group (P<0.01). CsA did not influence BKV DNA copies/mL in Vero E6 cells with high-level infection (>10(9) copies/mL). Cellular protein measurements indicated that the antiviral effect of CsA was not a result of cytotoxicity. These findings from a relevant in vitro kidney cell system indicate that CsA suppresses the primary BKV infection peak and inhibits escape to BKV reactivation; these effects are dose independent and not related to cytotoxicity. The intracellular antiviral mode of action of CsA against BKV does not appear to be via inhibition of viral cell entry pathways.
Asunto(s)
Antivirales/farmacología , Virus BK/efectos de los fármacos , Ciclosporina/farmacología , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Activación Viral/efectos de los fármacos , Animales , Virus BK/fisiología , Chlorocebus aethiops , Factores de Tiempo , Células VeroRESUMEN
Tandem mass spectrometry (MS/MS) was used to analyze multiple serum metabolites for the first time in a surfactant/virus mouse model of acute hepatic encephalopathy (AHE). AHE is characterized by acute liver failure that can lead to potentially lethal increases in intracranial pressure. We have reproduced AHE in young CD-1 mice exposed from postnatal day (P) 2-13 to the industrial surfactant, Toximul 3409F (Tox), and then infected intranasally on P14 with sublethal doses (LD(10-30)) of mouse-adapted human influenza B (Lee) virus (FluB). The sera analyzed by MS/MS were from mice exhibiting typical markers of Tox-mediated potentiation of viral illness, including reduced weights and blood glucose levels. Most metabolite abnormalities were not evident until five days after viral infection (P19), the time corresponding to the onset of weight loss and mortality. Values for fatty acylcarnitines and amino acids in the Tox+FluB-treated mice were either additive or supra-additive relative to the effects of either treatment alone. Amino acid profiles were consistent with those reported for human AHE. None of the treated mice exhibited signs of carnitine deficiency, and propionylcarnitine levels were normal. On P19, mice given combined Tox+FluB treatment had significant increases in levels of both medium- and long-chain acylcarnitines (C6:0-C12:0 and C14:0-C20:0, respectively), including their monounsaturated metabolites. Levels of medium-chain dicarboxylic and long-chain hydroxy-acylcarnitines were also elevated in the combined treatment group. The results of this study indicate a diffuse mitochondrial dysfunction in Tox+FluB-treated mice that results in a serum metabolite profile unique from those observed in classic inherited metabolic disorders.
Asunto(s)
Aminoácidos/sangre , Carnitina/análogos & derivados , Carnitina/sangre , Modelos Animales de Enfermedad , Encefalopatía Hepática/sangre , Virus de la Influenza B/fisiología , Tensoactivos/toxicidad , Aminoácidos/química , Animales , Carnitina/química , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/virología , Ratones , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
BK virus (BKV) nephropathy has a poor prognosis for renal allograft survival with 30% to 60% risk of allograft loss over 1 year. In the past decade, BKV nephropathy has occurred in 1% to 10% of renal transplant patients, with higher rates observed in patients with increased immunosuppression exposure and renal allograft injury. Vero cells (Green monkey kidney cell origin) were optimized for BKV primary and chronic infection inclusive of culture requirements for 60-day growth and monolayer confluence. Quantification of BKV replication in the culture supernatant (SN) and cells was by real-time polymerase-chain reaction (PCR) using the Roche Lightcycler 2.0. Primary BKV infection of Vero cells is achieved by 2 hour incubation with 6.5 x 10(5) BKV copies with subsequent washing of cells leading to steady-state cellular infection of 10(2) to 10(3) BKV copies. Primary infection is demonstrated within 7 to 10 days by a >10-fold increase of BKV copies in SN. Thereafter, a BKV viral load reduction in SN to a chronic/latent level (<10(2) BKV copies in SN) is observed by 14 days. Vero cells with chronic low-level BKV infection (10(2)-10(3) BKV copies in cells) exhibited reactivation (>10(5) BKV copies in SN) in >72% of late culture wells after 40 days. Vero cells can accommodate primary and chronic BKV infection followed by viral reactivation in late culture. The performance characteristics of 3 different pathogenic BKV strains obtained from patients with BKV nephropathy had infectivity profiles that correlated well the relative clinical profile in this Vero cell culture system.
Asunto(s)
Virus BK , Infecciones por Polyomavirus/fisiopatología , Infecciones Tumorales por Virus/fisiopatología , Animales , Antivirales/uso terapéutico , Niño , Chlorocebus aethiops , Cidofovir , Citosina/análogos & derivados , Citosina/uso terapéutico , Humanos , Modelos Biológicos , Organofosfonatos/uso terapéutico , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológico , Células VeroRESUMEN
Success of renal transplantation in children is largely due to improvements in immunosuppressant therapy since the introduction of calcineurin inhibitors. The aim of this study was to identify possible factors that result in formulation differences in the exposure of pediatric patients to cyclosporine (CsA). We examined the handling of the two major formulations of CsA in a group of pediatric renal transplant recipients. The pharmacokinetic profiles of both formulations were assessed, and the data stratified to assess the effects of age, gender, time posttransplant, and other concomitant drug therapy on the two CsA formulations. The microemulsified formulation (MEC) enhanced bioavailability compared to the older oil-based formulation (CYA), especially at C2, with more predictable and consistent absorption in children. This higher bioavailability allowed a 15% reduction of dosing to achieve equal drug exposure. The concentration achieved by MEC at C2 demonstrated a much higher correlation with area under the concentration curve (AUC) than the concentration at C0. In the case of CYA a strong correlation was obtained between AUC and the concentrations obtained at both C0 and C2. Calcium channel blockers increased AUC(0-8) for both CsA formulations. Norfloxacin and pravastatin cotreatment had no effect on either of the CsA formulations. In contrast, the bioavailability of CsA was increased in boys using MEC formulation but this gender-based difference was absent during the use of CYA. This suggests that caution is required for introduction of new formulations of drugs to pediatric patients to evaluate differential effects of age, gender, and concomitant drug therapy.
Asunto(s)
Ciclosporina/uso terapéutico , Trasplante de Riñón/inmunología , Adolescente , Área Bajo la Curva , Química Farmacéutica , Niño , Ciclosporina/farmacocinética , Femenino , Humanos , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Masculino , Tasa de Depuración MetabólicaRESUMEN
The human polyomavirus BK virus (BKV) remains latent in the urinary tract and may be reactivated in immunocompromised states. BKV is noted to be the etiologic agent of polyomavirus-associated nephropathy (PVAN), which is a significant cause of allograft failure in renal transplant patients. Renal dysfunction following non-renal solid organ transplantation is common and is typically attributed to drug toxicity or patient comorbidities. In this article we describe a case of PVAN in the native kidneys of a heart transplant recipient and review the literature. Although this is only the fourth case reported, BKV nephropathy should be considered in the differential diagnosis of new renal failure following non-kidney solid organ transplantation, as early diagnosis of PVAN is necessary to prevent irreversible renal damage.
Asunto(s)
Virus BK/crecimiento & desarrollo , Trasplante de Corazón/inmunología , Enfermedades Renales/virología , Adulto , Humanos , Enfermedades Renales/inmunología , MasculinoRESUMEN
Previous studies demonstrated that young mice exposed chronically to industrial surfactant (IS) do not exhibit obvious adverse health effects, but do have persistently reduced body weights and compromised hepatic energy metabolism. The present study examined the time course of effects of two formulations of the Toximul (Tox) class of anionic/nonionic IS on body weights and liver glycogen (+/-virus) during early development. Results showed that effects differed in two commonly used strains of mice. In CFW mice, 12 days' exposure to Tox resulted in retardation of weight gain that was most obvious several days after exposure ceased. In this strain effects were greater with Tox 3409F than with Tox MP-A and appeared to be reversible except when the mice were treated with both Tox 3409F and FluB. Weights of the CD-1 mice were not affected by either Tox treatment alone, but were significantly reduced on postnatal day 20 when Tox exposure had been combined with FluB infection. Postnatal replenishment of hepatic glycogen stores during the first three weeks also occurred at different rates in CFW and CD-1 mice. The effects of Tox (+/-FluB) on glycogen also varied with mouse strain and Tox formulation. In CFW mice, exposure to either formulation resulted in significant (55-59%) reductions in glycogen, although reductions were not evident until nine days after Tox exposure stopped. By contrast, hepatic glycogen in CD-1 mice was reduced both during and after dermal exposure to Tox 3409F, whereas no effect was observed with Tox MP-A. Notably, the 3409F effect was reversible in the CD-1 mice, but reversal did not occur in mice also infected with FluB. Tox MP-A+FluB-treated mice exhibited only a transient glycogen reduction. These results illustrate the importance of mouse strain and formulation specificities in assessing biological effects of xenobiotic surfactants. As well, they emphasize that chronic IS exposure can induce changes in growth and energy substrate availability in young mice that may not be evident unless there is a precipitating cofactor such as a viral infection.
Asunto(s)
Glucógeno/metabolismo , Virus de la Influenza B , Hígado/efectos de los fármacos , Ratones/metabolismo , Ratones/virología , Tensoactivos/toxicidad , Aumento de Peso/efectos de los fármacos , Animales , Femenino , Hígado/metabolismo , MasculinoRESUMEN
Antibody induction therapy is frequently used in pediatric renal transplantation to reduce risk of early rejection. We previously reported lower rates of human herpes virus type 6 (HHV-6) reactivation in patients receiving monoclonal antibody induction with basiliximab, compared to patients receiving antithymocyte globulin/antilymphocyte globulin treatment. Subclinical rejection events were still present in many patients in the first 6 months after transplantation. This prompted a third dose of basiliximab to be administered at day 21 in addition to the standard two doses given immediately prior to transplantation and on day 4. No significant reduction of subclinical rejections was noted in the 11 patients receiving triple dosing of basiliximab. Two patients developed an allergic reaction responsive to intravenous fluids, steroids, and antihistamines with full resolution within 30 minutes of administration. There was no increase in de novo infection or reactivation of HHV-6 or Epstein-Barr virus in this group compared to patients receiving two doses of basiliximab. The goal of reduction of early subclinical rejection events was not achieved with the third dosing of basiliximab in this initial group of pediatric renal transplant patients. However, 63.6% of patients receiving triple basiliximab remained free of clinical and/or subclinical rejection for the first 6 months posttransplant compared to only 36.4% remaining rejection-free for the same interval in the group who received the conventional two doses of basiliximab.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunosupresores/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/uso terapéutico , Basiliximab , Niño , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Inmunosupresores/administración & dosificación , Periodo Intraoperatorio , Masculino , Periodo Posoperatorio , Proteínas Recombinantes de Fusión/administración & dosificación , Estudios RetrospectivosRESUMEN
Herpes virus reactivation is of increasing interest as we aim to decrease morbidity and mortality in the pediatric renal transplant population. We previously reported increased reactivation of HHV-6 and Epstein Barr virus (EBV) with anti-thymocyte globulin/ALG induction therapy. HHV-6 reactivation and de novo infection has been monitored in 31 consecutive pediatric renal transplant patients receiving antibody induction with Simulect. Human Herpes virus-6 (HHV-6) was correlated with EBV reactivation and de novo infection rates, allograft function at 1 year, donor source and number, and patient age and gender. One HHV-6 de novo infection was associated with an early grade II rejection that was steroid resistant but ATG/ALG responsive. Sixteen of 31 (54.8%) patients had HHV-6 reactivation during the first year and eight patients had a prior reactivation profile before transplant. Thirteen patients (41.9%) were naïve to EBV infection prior to transplant with evidence of primary infection in 11 of 13 patients between 6 weeks and 1 year posttransplant. EBV reactivation was noted in four patients with past immunity to EBV. IgM Ab to EBV or HHV-6 during the first year posttransplant did not correlate with risk of rejection during the first year or graft function one year posttransplant. The only patient with positive HHV-6 IgM Ab in the first posttransplant month was a de novo infection in a 2-year-old boy who was naïve for HHV-6 at the time of transplant. Simulect appears safe in pediatric renal transplant with low risk of HHV-6 or EBV infection in the first 1 to 2 months posttransplant.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Herpesvirus Humano 6 , Trasplante de Riñón/inmunología , Proteínas Recombinantes de Fusión/uso terapéutico , Infecciones por Roseolovirus/epidemiología , Corticoesteroides/uso terapéutico , Anticuerpos Antivirales/sangre , Basiliximab , Niño , Preescolar , Monitoreo de Drogas , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Inmunoglobulina M/sangre , Inmunosupresores , Masculino , Metilprednisolona/uso terapéutico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/virología , Periodo Posoperatorio , Prednisona/uso terapéuticoRESUMEN
OBJECTIVE: To determine the bone mineral density (BMD) status of our juvenile dermatomyositis (DM) population and to compare the frequency of osteopenia in patients with active disease requiring corticosteroids with that in patients with inactive disease who are not receiving corticosteroids. METHODS: Medical charts of all children diagnosed as having juvenile DM at our institution between 1989 and 1999 were reviewed for demographic and clinical data, including disease activity and duration of corticosteroid therapy. BMD measurements of the lumbar spine (L1-L4) were performed using dual x-ray absorptiometry (DXA). Z scores were calculated from the BMD data for comparison with published normative data. RESULTS: A total of 15 patients were assessed: 10 with active disease, and 5 with inactive disease who had not taken corticosteroids for an average of 6.0 years (range 3.4-8.1 years). Baseline BMD measurements demonstrated osteopenia or frank osteoporosis in the majority of patients, including 6 of the 10 patients with active disease and 4 of the 5 patients whose disease was in remission. Fourteen patients had serial BMD measurements. Persistent or worsening osteopenia was documented in all patients who had ongoing active disease, except for 3 patients who had been treated with bisphosphonates because of vertebral compression fractures. CONCLUSION: Osteopenia is common in patients with juvenile DM, and it usually worsens with ongoing disease. It can persist for many years after the disease enters remission. Bisphosphonates appeared to beneficially affect bone mineralization in our patients. Treatment to prevent the long-term complications of osteoporosis in patients with juvenile DM should be considered and requires further study.
Asunto(s)
Densidad Ósea , Enfermedades Óseas Metabólicas/diagnóstico por imagen , Dermatomiositis/diagnóstico por imagen , Absorciometría de Fotón , Adolescente , Corticoesteroides/uso terapéutico , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas Metabólicas/epidemiología , Enfermedades Óseas Metabólicas/prevención & control , Niño , Preescolar , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/epidemiología , Difosfonatos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Vértebras Lumbares , Masculino , Factores de Riesgo , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/prevención & controlRESUMEN
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.
Asunto(s)
Densidad Ósea , Trasplante de Riñón/efectos adversos , Proteínas Recombinantes de Fusión , Adolescente , Anticuerpos Monoclonales/uso terapéutico , Basiliximab , Densidad Ósea/efectos de los fármacos , Niño , Preescolar , Ciclosporina/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Lactante , Estudios Longitudinales , Masculino , Hemisuccinato de Metilprednisolona/uso terapéutico , Prednisolona/uso terapéutico , Estudios Prospectivos , Tacrolimus/uso terapéuticoAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Rechazo de Injerto/epidemiología , Infecciones por Herpesviridae/epidemiología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Complicaciones Posoperatorias/epidemiología , Proteínas Recombinantes de Fusión , Anticuerpos Monoclonales/efectos adversos , Suero Antilinfocítico/efectos adversos , Basiliximab , Niño , Infecciones por Citomegalovirus/epidemiología , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 6 , Humanos , Inmunosupresores/efectos adversos , Trasplante de Riñón/patología , Trasplante de Riñón/fisiología , Necrosis Tubular Aguda/prevención & control , Complicaciones Posoperatorias/clasificaciónRESUMEN
The use of ureteric double-J stents and the Lich-Gregoir (extravesical) technique of ureteroneocystotomy have both been shown to decrease the rate of urologic complications in adult kidney transplantation (Tx). There are, however, few studies of the systematic use of stents in pediatric renal Tx. Between 1991 and 1997, 32 consecutive pediatric renal transplant recipients routinely received a 6F-12 cm indwelling double-J stent and were studied prospectively. These patients were compared with 32 consecutive pediatric recipients in whom a stent was not used. The latter were transplanted between 1987 and 1991 and formed the control group. All patients had a Lich-Gregoir ureteroneocystotomy. Stents were removed under general-anesthetic cystoscopy 2 3 weeks after Tx. Immunosuppression for stented patients was polyclonal antibody induction, delayed (7-10 days) cyclosporin A, azathioprine, and prednisone. The control group received the same triple drug regimen but with no induction in 29 of the 32 patients. All patients were followed-up with at least one ultrasound evaluation in the first month, and a renal scan and repeat ultrasound were performed if there was any rise in serum creatinine. In the stented group there were two patients with urinary leak and no obstructions. In the non-stented group there were no leaks and one obstruction. There was no graft loss owing to urologic complications in either group. There were three cases of stent expulsion (all in girls) and one case of stent migration in the posterior urethra (a boy). The 1-yr graft survival rate was 90.6% in the stented group and 65.6% in the non-stented group. The prophylactic use of an indwelling ureteral stent in pediatric renal Tx did not reduce the risk of urinary leakage or obstruction. Stent migration is a common phenomenon and, while not a serious complication, is traumatic to children. Furthermore, removal of an internalized double-J stent requires a general anesthetic. We recommend using a stent for selected patients only.
Asunto(s)
Cistostomía/métodos , Trasplante de Riñón/métodos , Stents/efectos adversos , Uréter/cirugía , Adolescente , Anastomosis Quirúrgica/métodos , Niño , Preescolar , Femenino , Supervivencia de Injerto , Humanos , Lactante , Masculino , Estudios Prospectivos , Reflujo Vesicoureteral/prevención & controlRESUMEN
BACKGROUND: Graft survival in children who undergo kidney transplantation is lower than that in adults. The objective of the study was to review the experience of the first 22 years of operation of the regional pediatric kidney transplantation unit for Atlantic Canada, based at the IWK-Grace Health Centre, Halifax, and to use the results to improve graft survival. METHODS: All cases of kidney transplantation performed at the centre from 1971 to 1992 were reviewed and the data compiled with the use of a predetermined database outline. Data for first transplants were analysed and compared with those in North American databases. Of the 40 graft failures, 19 (48%) occurred within the first 3 months after transplantation, a rate similar to that at other centres. The overall survival rates tended to be slightly lower than those of international databases. The introduction of cyclosporine A as an immunosuppressant, in 1985, did not provide the expected marked improvement in survival. Infection frequently accompanied acute rejection, and there was a delay in treatment of infections and rejection after discharge home. On the basis of these preliminary findings, several program changes were made: 1) a sequential immunosuppression protocol was implemented, 2) the intensity of the medical surveillance was increased for the first 3 months after transplantation, with aggressive treatment of infections and rejections, 3) a dedicated pediatric transplantation team was established as a subset of the adult team and 4) pediatric-specific selection criteria for cadaver donors were formulated. After these changes were implemented, data were collected and analysed up to June 30, 1997. RESULTS: Graft survival rates at 1, 2 and 5 years improved dramatically. After the beginning of 1993, there were only 2 graft losses among 22 transplants. Only one of these occurred in the first 3 months, and it was due to recurrent disease. Twenty-four rejection episodes occurred (10 in the first 3 months after transplantation), but all were reversed easily with high-dose steroid therapy. INTERPRETATION: Sequential immunosuppression with close medical surveillance and early aggressive treatment of infection and rejection contribute to a marked improvement in kidney graft survival in children.
Asunto(s)
Rechazo de Injerto/mortalidad , Supervivencia de Injerto , Trasplante de Riñón/mortalidad , Complicaciones Posoperatorias/mortalidad , Adolescente , Adulto , Causas de Muerte , Niño , Preescolar , Estudios Transversales , Bases de Datos Factuales , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/administración & dosificación , Incidencia , Lactante , Masculino , Nueva Escocia/epidemiología , Evaluación de Procesos y Resultados en Atención de Salud , Complicaciones Posoperatorias/prevención & control , Reoperación , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Enfermedades Renales/cirugía , Fallo Renal Crónico/cirugía , Trasplante de Riñón/fisiología , Enfermedades de la Retina/cirugía , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Renales/genética , Trasplante de Riñón/mortalidad , Masculino , Enfermedades de la Retina/genética , Tasa de Supervivencia , SíndromeAsunto(s)
Rechazo de Injerto/epidemiología , Infecciones por Herpesviridae/epidemiología , Herpesvirus Humano 4 , Herpesvirus Humano 6 , Trasplante de Riñón , Complicaciones Posoperatorias/epidemiología , Enfermedad Aguda , Anticuerpos Antivirales/sangre , Cadáver , Niño , Estudios de Seguimiento , Infecciones por Herpesviridae/diagnóstico , Humanos , Inmunoglobulina M/sangre , Terapia de Inmunosupresión , Trasplante de Riñón/inmunología , Donadores Vivos , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Donantes de TejidosRESUMEN
Renal allograft rejection episodes are frequent in children and often lead to allograft failure. Frequent association of fever with rejection in our transplant program provoked a prospective evaluation of concurrent infection during rejection episodes. Because cytomegalovirus has an established role in rejection and allograft survival, evaluation of cytomegalovirus and other herpes viruses (human simplex virus type 1, varicella, Epstein-Barr virus, and human herpes virus type 6 [HHV-6]) was undertaken in addition to standard bacterial investigation. A total of 37 patients were followed over a 30-month period. Six of eight rejection episodes were associated with herpes viruses (HHV-6, n = 6, and Epstein-Barr virus, n = 1). Three of the herpes-group-associated rejection episodes were treated with antiviral therapy in addition to pulse steroid treatment, with full recovery. The three patients with HHV-6-associated rejection episodes who were treated with pulse steroids, but no antiviral therapy, developed chronic allograft rejection. The recipient's response to allograft antigens may be influenced by concomitant herpes infection, and specific antiviral therapy appears to be indicated when infection is confirmed in association with rejection. An antiviral treatment program coupled with modulation of standard antirejection immunotherapy has the potential to improve morbidity and mortality in the pediatric renal transplant population.
Asunto(s)
Infecciones Bacterianas/complicaciones , Rechazo de Injerto/inducido químicamente , Trasplante de Riñón/inmunología , Virosis/complicaciones , Adolescente , Infecciones Bacterianas/inmunología , Niño , Preescolar , Fiebre/complicaciones , Fiebre/etiología , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Humanos , Estudios Prospectivos , Virosis/inmunologíaAsunto(s)
Glucocorticoides/toxicidad , Metilprednisolona/análogos & derivados , Enfermedades Renales Poliquísticas/inducido químicamente , Triyodotironina/farmacología , Animales , Animales Recién Nacidos , Antitiroideos/farmacología , Hipotiroidismo/sangre , Hipotiroidismo/inducido químicamente , Metilprednisolona/toxicidad , Acetato de Metilprednisolona , Ratones , Ratones Endogámicos C57BL , Enfermedades Renales Poliquísticas/patología , Enfermedades Renales Poliquísticas/prevención & control , Propiltiouracilo/farmacología , Tirotropina/sangreRESUMEN
Prophylactic treatment with norfloxacin was initiated in a group of pediatric patients undergoing renal transplantation who were receiving cyclosporine and were susceptible to recurrent urinary tract infections. At discharge from the hospital, the mean daily dose of cyclosporine needed to maintain trough cyclosporine blood levels of 150 to 400 ng/ml was 4.5 mg/kg/day for the patients who received norfloxacin compared with 7.4 mg/kg/day for patients who did not receive the antibiotic. This observation suggested that the clearance of cyclosporine was decreased by the concomitant use of norfloxacin. The effect of norfloxacin on specific drug-metabolizing cytochrome P450 isozymes in vitro was examined to determine if the metabolism and subsequent clearance of cyclosporine and possibly other drugs are altered through a metabolic interaction with norfloxacin. In human liver microsomes, the activity of cytochrome P4503A4, the isozyme that metabolizes cyclosporine in humans, was inhibited by norfloxacin. In rat liver microsomes, norfloxacin inhibited the activity of cytochrome P4503A2, the isozyme responsible for cyclosporine metabolism in this species, but did not alter the activity of the rat cytochrome P450 isozymes 1A, 2E1, and 4A1. The in vitro studies suggest that the lower cyclosporine dose required by pediatric patients who were given norfloxacin was caused by inhibition of the metabolism of cyclosporine.