RESUMO
BACKGROUND: Growth retardation in paediatric end-stage renal disease (ESRD) has a serious impact on adult life. It is potentially treatable with recombinant growth hormone (rGH). In this study, we aimed to quantify the variation in rGH policies and actual provided care in these patients across Europe. METHODS: Renal registry representatives of 38 European countries received a structured questionnaire on rGH policy. Cross-sectional data on height and actual use of rGH on children with ESRD aged <18 years were retrieved from the ESPN/ERA-EDTA Registry. RESULTS: In 21 (75%) of 28 responding countries, rGH is reimbursed for children with ESRD. The specific conditions for reimbursement (minimum age, maximum age and chronic kidney disease stage) vary considerably. Mean height standard deviation scores (SDS) at renal replacement therapy (RRT) [95% confidence interval (CI)] were significantly higher in countries where rGH was reimbursed -1.80 (-2.06; -1.53) compared with countries in which it was not reimbursed [-2.34 (-2.49;-2.18), P < 0.001]. Comparison of the mean height SDS at onset of RRT and final height SDS yielded similar results. Among the 13 countries for which both data on actual rGH use between 2007 and 2011 and data from the questionnaire were available, 30.1% of dialysis and 42.3% of transplanted patients had a short stature, while only 24.1 and 7.6% of those short children used rGH, respectively. CONCLUSION: Reimbursement of rGH associates with a less compromised final stature of ESRD children. In many countries with full rGH reimbursement, the actual rGH prescription in growth-retarded ESRD children is low and obviously more determined by the doctor's and patients' attitude towards rGH therapy than by financial hurdles.
Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Falência Renal Crônica/terapia , Padrões de Prática Médica/legislação & jurisprudência , Medicamentos sob Prescrição/administração & dosagem , Adolescente , Adulto , Estatura , Criança , Pré-Escolar , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Sistema de Registros , Terapia de Substituição Renal/estatística & dados numéricos , Inquéritos e Questionários , Adulto JovemRESUMO
Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard-dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 +/- 0.32 with TAC/MMF/DAC and 0.03 +/- 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04-0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05-0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy-proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Crescimento , Imunoglobulina G/administração & dosagem , Imunossupressores/administração & dosagem , Falência Renal Crônica/cirurgia , Transplante de Rim , Esteroides/administração & dosagem , Tacrolimo/administração & dosagem , Adolescente , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Daclizumabe , HumanosRESUMO
Mutations in nucleoporin 93 (NUP93) gene have been shown recently to be one of the very rare causes of genetic steroid-resistant nephrotic syndrome (SRNS). Until now, none of the 7 published cases with NUP93-SRNS, experienced recurrence of nephrotic syndrome (NS) after transplantation. Here, we present the first case of recurrent NS in a patient with NUP93-SRNS ever reported. A 3-year-old boy with infantile SRNS was started on chronic peritoneal dialysis because of end-stage renal failure owing to biopsy-proven focal segmental glomerulosclerosis (FSGS). At the age of 6 years, the boy received a renal allograft. The posttransplant period was uncomplicated until 1.7 years after transplantation, when the patient developed nephrotic proteinuria during a respiratory tract infection. Renal graft biopsy showed subtotal fusion of podocytes, which was compatible with an early histopathologic sign of recurrence of FSGS. Immediate treatment with daily plasma exchange (PE) was started at the second day. The proteinuria disappeared completely after the second PE. However, it reappeared after stopping daily PE. It disappeared again after reintroduction of daily PE, therefore PE-dependent recurrent NS was diagnosed and treatment with rituximab was given. After the first dose, proteinuria never reappeared despite stopping PE therapy. Surprisingly, next-generation sequencing revealed compound heterozygous mutations in exons 16 and 18 of the NUP93 gene (c.1772G>T - European founder allele and 1916T>C) and his parents confirmed heterozygous asymptomatic carriers. This is the first case of recurrent NS in a patient with NUP93 gene mutations, suggesting a new pathomechanism possibly involving the nucleoporins.
Assuntos
Transplante de Rim , Síndrome Nefrótica/genética , Síndrome Nefrótica/cirurgia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Pré-Escolar , Heterozigoto , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Mutação , Síndrome Nefrótica/complicações , Plasmaferese , Recidiva , Rituximab/uso terapêuticoRESUMO
Atypical hemolytic-uremic syndrome (aHUS) is an extremely rare disease, and up to 70% of the patients have a genetic mutation in the encoding components of complement activation or anti-complement factor H autoantibodies. The risk of recurrence after kidney transplantation is 10% to 80%. Eculizumab, a monoclonal antibody that binds complement protein C5, has shown to be highly effective in patients with aHUS; however, there are only few reports on the efficacy and safety of long-term eculizumab treatment in children with recurrent aHUS. Only 3 case reports regard treatment in patients with complement factor H (CFH/CFHR1/CFHR3) hybrid gene. This report presents the efficacy and safety of long-term eculizumab treatment in a child with recurrent aHUS who has been successfully treated with eculizumab for more than 7 years. The patient presented as a 9-year-old with aHUS due to CFH/CFHR1/CFHR3 hybrid gene and received deceased donor kidney transplantation. After the transplantation, he experienced recurrence of aHUS 2 months later. Daily plasma exchanges were ineffective in the transplanted kidney; the patient became anuric and hemodialysis was needed. Eculizumab was started as therapy and led to complete remission of aHUS including restoration of diuresis. Eculizumab has been given as therapy for 7 years. The young patient is in a sustained remission without any adverse events. This patient is only the sixth patient reported with recurrent aHUS due to CFH/CFHR1/CFHR3 hybrid gene and is the patient with the longest remission of recurrent aHUS ever published.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/cirurgia , Criança , Ativação do Complemento/genética , Fator H do Complemento/genética , Humanos , Transplante de Rim/efeitos adversos , Masculino , Mutação , Complicações Pós-Operatórias/genética , Recidiva , Fatores de TempoRESUMO
BACKGROUND: Proteinuria together with hypertension are known risk factors for poor allograft as well as patient survivals after renal transplantation. In adults, proteinuria can be reduced by lowering blood pressure and by using angiotensin-converting enzyme inhibitors. In children, no study has investigated the antiproteinuric effects of antihypertensive therapy. Herein we investigated changes in proteinuria among a subgroup of children with proteinuria>or=200 mg/m2d in an interventional study primary aimed to improve the efficacy of antihypertensive therapy. PATIENTS AND METHODS: Twelve children with proteinuria>or=200 mg/m2d were included in the study. Proteinuria was investigated at baseline and at 1 year after changes in antihypertensive therapy. Blood pressure (BP) was measured using ambulatory BP monitoring. RESULTS: The median protein excretion of 226 mg/m2/d (range, 41-1478 mg/m2/d) at 1 year before the study did not change significantly at study baseline (278 mg/m2/d; range, 205-1264 mg/m2/d), but decreased significantly to 199 mg/m2/d (range, 65-749 mg/m2/d) after 1 year (P<.05 vs baseline). The number of antihypertensive drugs was increased from 1.6+/-1.0 to 2.2+/-0.9 drugs/patient after 1 year (P<.05). The use of different classes of antihypertensive drugs did not change significantly. Mean ambulatory systolic and diastolic BP at daytime and diastolic BP at nighttime did not change significantly after 1 year; mean ambulatory systolic BP at night decreased from 1.60+/-1.54 to 1.04+/-0.97 standard deviation score (P<.05). Graft function did not change significantly. CONCLUSION: We demonstrated that proteinuria among children after renal transplantation was reduced by intensified antihypertensive therapy using all classes of antihypertensive drugs.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Transplante de Rim/efeitos adversos , Proteinúria/prevenção & controle , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Criança , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Proteinúria/etiologia , Transplante HomólogoRESUMO
Idiopathic focal segmental glomerulosclerosis (FSGS) is believed to be caused by a circulating permeability factor. FSGS recurrence is common after transplantation. The treatment is still a matter of debate; plasmapheresis (PE) and immunoadsorption (IA) are often used. We report on PE and IA in the treatment of two children with recurrent nephrotic proteinuria. Patient 1 was a 16-year-old girl who had recurrence of nephrotic proteinuria on the first day after transplantation (proteinuria-19 g/d). Primary immunosuppressive therapy was changed to high-dose cyclosporine and cyclophosphamide; plasmapheresis was started on day 4. Altogether we performed 53 PE and 38 IA procedures. During the first month, PE procedures were performed with no more than a 2-day interval between sessions, and the girl achieved partial remission (proteinuria 3 g/d). PE was then stopped. After 2 months, a relapse of heavy proteinuria occurred. This relapse was successfully treated again with intensified PE treatment. After achieving remission, a chronic PE regimen was started (PE once a week), similar to the previous series. The child remained in partial remission. Seven months after renal transplantation, she was switched from PE to IA, because of severe hypoproteinemia. Graft biopsy performed at 4 months showed effacement of the foot processes. At the present time she has a good graft function and 3 g/d proteinuria. Patient 2 was a 13-year-old girl with FSGS since 9 years. On the second day after renal transplantation she developed nephrotic proteinuria (proteinuria-14 g/d), which was treated with 39 PE and 16 IA treatments. She went into complete remission on the intensified PE regimen, had one relapse, and was switched to chronic IA. Graft biopsy performed at 2 weeks after transplantation showed effacement of the foot processes. At the present time she has good graft function and low proteinuria (0.3 g/d). In conclusion, intensified PE or IA treatments induced remission of recurrent nephrotic range proteinuria. Chronic PE or IA can maintain patients with frequent relapses in long-term remission.
Assuntos
Glomerulosclerose Segmentar e Focal/cirurgia , Técnicas de Imunoadsorção , Transplante de Rim , Plasmaferese , Complicações Pós-Operatórias/terapia , Proteinúria/terapia , Adolescente , Feminino , Humanos , Imunossupressores/uso terapêutico , Recidiva , Resultado do TratamentoRESUMO
Glucocorticoid (GC) therapy is one of the methods of choices for treatment of autoimmune diseases (ADs). In addition, adrenal androgens are known as immunoprotective GC-antagonists. Adrenal steroids preferentially influence the Th1-components over the Th2 ones. We investigated steroid metabolome (using gas chromatography-mass spectrometry) in healthy controls (H), GC-untreated patients with ADs different from IgA nephropathy (U), GC-treated patients with ADs different from IgA nephropathy (T) and in patients with IgA nephropathy (IgAN), which were monitored on the beginning (N0), after one week (N1) and after one month (N2) of prednisolone therapy (60 mg of prednisolone/day/m(2) of body surface). Between-group differences were assessed by one-way ANOVA, while the changes during the therapy were evaluated by repeated measures ANOVA. The ANOVA testing was followed by Duncan's multiple comparisons. IgAN patients and patients with other ADs exhibited lack of adrenal androgens due to attenuated activity of adrenal zona reticularis (ZR). Androgen levels including their 7alpha-, 7beta-, and 16alpha-hydroxy-metabolites were further restrained by GC-therapy. Based on these results and data from the literature, we addressed the question, whether a combination of GCs with delta(5)-steroids or their more stable synthetic derivatives may be optimal for the treatment of antibodies-mediated ADs.
Assuntos
Glândulas Suprarrenais/metabolismo , Androgênios/sangue , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/tratamento farmacológico , Glucocorticoides/uso terapêutico , Fatores Imunológicos/sangue , Peptídeos/sangue , Glândulas Suprarrenais/efeitos dos fármacos , Adulto , Androgênios/farmacologia , Androgênios/uso terapêutico , Feminino , Glucocorticoides/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/farmacologia , Prednisolona/uso terapêuticoRESUMO
BACKGROUND: Hypertension in patients after renal transplantation (RTx) is associated with impaired graft functions and graft survival. Control of hypertension in children after RTx is low--only 20-50 % of children have well controlled hypertension. The aim of this interventional study is to improve blood pressure control and to investigate whether the improved control will improve the graft survival. METHODS AND RESULTS: 36 children after RTx (mean age 13.9 +/- 4.4 years, time after RTx 2.7 +/- 2.4) fulfilled the inclusion criteria. Ambulatory blood pressure monitoring (ABPM) and graft function were examined. In children with uncontrolled hypertension, the dose and number of antihypertensive drugs were increased to reach BP <95th centile. ABPM was repeated after 12 months. After 12 months day-time and night-time BP dropped non-significantly, however prevalence of uncontrolled hypertension improved significantly from 42 % to 34 % (p<0.05). Number of antihypertensive drugs increased from 2.1 +/- 0.9 to 2.4 +/- 0.8 drugs per patient (p<0.05), namely that of ACE-inhibitors (from 19% to 27%, p<0.05). Graft function decreased by 3.6 ml/min/1.73m2/year (p<0.05). CONCLUSIONS: This 12 months interventional trial demonstrated that control of hypertension in children after RTx can be improved by increasing number of prescribed antihypertensive drugs. The decline of graft function was lower comparing with previous trials.
Assuntos
Hipertensão/tratamento farmacológico , Transplante de Rim , Rim/fisiopatologia , Adolescente , Criança , Humanos , Hipertensão/etiologia , Rim/efeitos dos fármacos , Transplante de Rim/fisiologiaRESUMO
Proteinuria is associated with poor long-term allograft as well as patient survival among adults after renal transplantation. In children, there are no studies focusing primarily on posttransplant proteinuria. The aim of this cross-sectional study was to investigate the prevalence of and possible risk factors associated with proteinuria. Thirty-three children (mean age of 13.7 +/- 4.3 years; mean time after renal transplantation = 2.3 +/- 2.2 years) were eligible for the study. There was an 82% prevalence of proteinuria (> or =96 mg/m2/d) with nephrotic range proteinuria (> or =960 mg/m2/d) in 12% of children. The mean urinary protein excretion was 256 +/- 299 mg/m2/d (range = 47 to 1264). Children with hypertension, as defined by ambulatory blood pressure monitoring, showed significantly higher proteinuria than normotensive children (382 +/- 435 vs 163 +/- 79 mg/m2/d, P < .05). Children with a history of a previous acute rejection episode showed significantly higher proteinuria than children who never had an episode (416 +/- 445 vs 165 +/- 91 mg/m2/d, P < .05). Children with proteinuria did not show statistically different graft function than children without proteinuria. No statistically significant correlation was observed between proteinuria and ambulatory blood pressure values or graft function. In conclusion, proteinuria is a frequent finding also in children after renal transplantation; it is associated with hypertension and a history of rejection episodes.
Assuntos
Transplante de Rim/efeitos adversos , Proteinúria/epidemiologia , Adolescente , Monitorização Ambulatorial da Pressão Arterial , Criança , Pré-Escolar , Feminino , Humanos , Transplante de Rim/fisiologia , Masculino , PrevalênciaRESUMO
Impaired glomerular filtration rate (GFR) is a risk factor for the development of hypertension in patients with autosomal dominant polycystic kidney disease (ADPKD). However, markers of tubular function were not tested whether they are linked to hypertension or blood pressure (BP) level. The aim of our study was to investigate the relationship between renal concentrating capacity and BP in children with ADPKD. Fifty-three children (mean age 11.8+/-4.4 years) were investigated. Standardized renal concentrating capacity test was performed after nasal drop application of desmopressin, BP was measured by ambulatory BP monitoring (ABPM). Renal concentrating capacity was decreased in 58 % of children. The prevalence of hypertension was significantly higher in children with decreased renal concentrating capacity (35 %) than in children with normal renal concentrating capacity (5 %) (p<0.05). Significant negative correlations were found between renal concentrating capacity, ambulatory BP and number of renal cysts (r = -0.29 to -0.39, p<0.05 to p<0.01). In conclusion, the concentrating capacity is decreased in about half of the patients and is linked to BP. Decreased renal concentrating capacity should be considered.
Assuntos
Pressão Sanguínea , Hipertensão Renal/diagnóstico , Hipertensão Renal/fisiopatologia , Capacidade de Concentração Renal , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/fisiopatologia , Medição de Risco/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão Renal/etiologia , Testes de Função Renal/métodos , Masculino , Rim Policístico Autossômico Dominante/complicações , Fatores de Risco , Estatística como AssuntoRESUMO
Arterial hypertension is a common complication in children after renal transplantation and the control of hypertension is often difficult. This retrospective investigates the prevalence and rate of control of hypertension using ambulatory blood pressure monitoring (ABPM) in 45 children (mean age 14.1 +/- 4.3 years, mean time after renal transplantation 2.2 +/- 2.7 years), all on cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil plus daily steroids. The overall prevalence of hypertension was 82%. None of the transplanted children had normal blood pressure without antihypertensive therapy (ie, spontaneous normotension). Twenty percent of children had untreated hypertension, 18% had controlled hypertension, and 62% had uncontrolled hypertension. Prevalence of the nondipping phenomenon was 53%. The mean number of antihypertensive drugs (without diuretic monotherapy) in treated patients was 1.9 drugs per patient. The prevalence of arterial hypertension in children after renal transplantation is high and the control of hypertension is often unsatisfactorily low.
Assuntos
Monitorização Ambulatorial da Pressão Arterial/métodos , Hipertensão/fisiopatologia , Transplante de Rim/fisiologia , Complicações Pós-Operatórias/fisiopatologia , Adolescente , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Criança , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etiologiaRESUMO
The authors present their own observation of five child patients with Münchhausen's syndrome and Münchausen's syndrome by proxy resp. Both these units are included in the wider framework of the syndrome of the battered child. Four boys and one girl are involved, aged 12-16 years. In all instances the reason for admission to hospital was macroscopic haematuria. The children were prior to hospitalization subjected to a series of various invasive examinations, incl. repeated examinations under anaesthesia to elucodate the cause of macroscopic haematuria. The uncommon course of the "disease" and results of the examinations led in four of the five children to suspicion of Münchhausen's syndrome. Based on this suspicion after immobilization of the patients associated with prevention of manipulation with the hands, macroscopic haematuria disappeared as well as haematuria in general. In the fifth patient Münchhausen's syndrome by proxy was involved. The patient was referred because of repeated attacks of macroscopic haematuria a renal biopsy. The authors analyze in more details the individual case-histories and in the conclusion to they raise their objections to the opinion that these two syndromes are extremely rare.
Assuntos
Síndrome de Munchausen , Adulto , Criança , Feminino , Hematúria/etiologia , Humanos , Síndrome de Munchausen/diagnóstico , Síndrome de Munchausen Causada por Terceiro/diagnósticoRESUMO
The aim of the study is to review results of pediatric renal transplantation in center in Prague, Czech Republic. Results are compared with the registry data from Europe and United States. Patients, who underwent RTx at the University Hospital Motol, Prague (Czech Republic) between 1977 and the end of 1999, were analyzed. Since 1977 128 Rtx from cadaveric donors were performed in children in mean age 12.8 +/- 4.1 years. In 1977-1987, patients were treated with prednisone and azathioprine, and since 1988, cyclosporine A, added to prednisone and azathioprine. Sequential quadruple immunosuppression was used only in few highly sensitized patients. Acute graft rejections were treated with methylprednisolone pulses, antithymocyte globulin and monoclonal antibodies OKT3, in selected cases. In 1988 and 1999 cyclosporine A was replaced by tacrolimus as initial immunosuppression in some patients. The number of Tx ranged between 5 and 13 per year. Patients and graft survival were significantly lower in the first time period 1977-1987 with a median patients 5-year survival rate of only 50% and graft survival 30%. In the last period (1988-1999) 5-year patients survival is 90% and 5-year graft survival is 68% (p = 0.01). Two cases of posttransplant lymphoproliferative disease were diagnosed so far. One of them died several months after RTx, the other received cytostatic therapy for Hodgkin tumor and graft function was maintained. Main causes of graft failure were chronic rejection followed by acute steroid resistant rejections, severe cytomegalovirus infections, noncompliance, vascular thrombosis, and recurrence of original disease.
Assuntos
Rejeição de Enxerto/epidemiologia , Transplante de Rim/estatística & dados numéricos , Sistema de Registros , Adolescente , Adulto , Área Programática de Saúde , Criança , República Tcheca/epidemiologia , Europa (Continente) , Humanos , LactenteRESUMO
In a 6-month, multicenter, randomized, controlled, open-label, parallel-group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric renal transplant recipients. Patients < 18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10-20 ng/mL between days 0-21 and 5-15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients < 40 kg) or 20 mg (patients > or = 40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy-proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid-resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 micromol/L in the TAS and 91 micromol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus-based regimen is safe in pediatric patients, but does not improve clinical efficacy.
Assuntos
Anticorpos Monoclonais/farmacologia , Transplante de Rim , Proteínas Recombinantes de Fusão/farmacologia , Tacrolimo/farmacologia , Adolescente , Anticorpos Monoclonais/efeitos adversos , Basiliximab , Biópsia , Criança , Pré-Escolar , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Masculino , Proteínas Recombinantes de Fusão/efeitos adversos , Tacrolimo/efeitos adversos , Tacrolimo/sangueRESUMO
We describe a Czech patient with combined adenine phosphoribosyltransferase (APRT) deficiency (2,8-dihydroxyadenine urolithiasis) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency (mucopolysaccharidosis Type IVA, Morquio disease A). Adenine and its extremely insoluble derivative, 2,8-dihydroxyadenine, were identified in the urine, and APRT deficiency was confirmed in erythrocytes. There was excessive excretion of keratan sulfate in the urine, and GALNS deficiency was confirmed in leukocytes. GALNS and APRT are both located on chromosome 16q24.3, suggesting that the patient had a deletion involving both genes. PCR amplification of genomic DNA indicated that a novel junction was created by the fusion of sequences distal to GALNS exon 2 and proximal to APRT exon 3, and that the size of the deleted region was approximately 100 kb. The deletion breakpoints were localized within GALNS intron 2 and APRT intron 2. Several other genes, including the alpha subunit of cytochrome B (CYBA), which is deleted or mutated in the autosomal form of chronic granulomatous disease, are located in the 16q24.3 region, but PCR amplification showed that this gene was present in the proband. A patient with hemizygosity for GALNS deficiency and APRT deficiency has been reported from Japan recently. These findings indicate that: (i) APRT is located telomeric to GALNS; (ii) GALNS and APRT are transcribed in the same orientation (centromeric to telomeric); and (iii) combined APRT/GALNS deficiency may be more common than hitherto realized.