RESUMO
BACKGROUND: IgA deficiency associated with glomerulonephritis is rare. In particular, there is no prior report regarding the association between IgA deficiency and membranoproliferative glomerulonephritis (MPGN) in children. Herein, we describe the case of a 5-year-old girl with selective IgA deficiency and MPGN. CASE PRESENTATION: The patient presented with persisting urinary abnormality and hypocomplementemia following a group A treptococcal infection. Renal biopsy revealed the presence of diffuse mesangial hypercellularity, endocapillary proliferation, and focal thickening of the walls of the glomerular capillaries using light microscopy, with IgG and moderate C3 deposits observed using immunofluorescence. Electron microscopy images revealed nodular deposits in the subendothelial areas, with hump-shaped subepithelial deposits. The pathological diagnosis was confirmed as MPGN. Treatment using oral prednisolone (PSL), mizoribine (MZR), and angiotensin-converting enzyme inhibitors reduced the proteinuria. The PSL dose was gradually tapered, with the low dose of PSL and MZR continued for 4 years. Histological findings were improved on repeated renal biopsy, and PSL and MZR administration was discontinued. CONCLUSIONS: We report a rare case of MPGN related to a streptococcal infection in a child. The clinical presentation included selective IgAD, with several pathological findings and a clinical course typical of glomerulopathy. The patient was successfully treated using multidrug therapy.
Assuntos
Glomerulonefrite Membranoproliferativa/etiologia , Deficiência de IgA/complicações , Glomérulos Renais/patologia , Infecções Estreptocócicas/complicações , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pré-Escolar , Quimioterapia Combinada , Feminino , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Glomérulos Renais/ultraestrutura , Prednisolona/uso terapêutico , Proteinúria/tratamento farmacológico , Ribonucleosídeos/uso terapêuticoRESUMO
BACKGROUND: Early multiple-drug therapy for severe childhood immunoglobulin A (IgA) nephropathy prevents the progression of nephritis and improves the long-term prognosis. Recent studies have focused on the relationship between the pathophysiology of IgA nephropathy and tonsillar focal infection, and the efficacy of tonsillectomy with methylprednisolone pulse therapy in children has been demonstrated. However, no study has reported on the relationship between the period from diagnosis to tonsillectomy and the long-term prognosis of IgA nephropathy. METHODS: To clarify the long-term effects of an early tonsillectomy, 40 patients who were diagnosed with severe IgA nephropathy in childhood and underwent a tonsillectomy were divided into two groups based on the period from diagnosis to undergoing tonsillectomy: Group A, less than 3 years; and Group B, more than 3 years. The primary endpoint of this study was the change in the amount of proteinuria. Renal prognosis was evaluated 10 years after the diagnosis. RESULTS: This study enrolled 40 patients diagnosed with severe IgA nephropathy in childhood who underwent tonsillectomy after multiple-drug therapy with/without methylprednisolone pulse therapy at Kindai University Hospital; eight patients were excluded based on the exclusion criteria. Group A consisted of 18 patients and Group B, 14 patients. Proteinuria and hematuria levels were significantly reduced in the early surgery group (P < 0.01). No significant differences were found in serum creatinine, uric acid, and IgA/C3 ratio. CONCLUSIONS: High proteinuria levels worsen the renal prognosis in IgA nephropathy. Tonsillectomy in less than 3 years combined with multiple-drug therapy after the initial diagnosis could improve long-term prognosis.
Assuntos
Glomerulonefrite por IGA/cirurgia , Proteinúria/diagnóstico , Tonsilectomia/métodos , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Creatinina/sangue , Feminino , Glomerulonefrite por IGA/tratamento farmacológico , Glucocorticoides/uso terapêutico , Hematúria/diagnóstico , Hematúria/epidemiologia , Humanos , Rim/patologia , Masculino , Metilprednisolona/uso terapêutico , Prognóstico , Proteinúria/epidemiologia , Pulsoterapia/métodos , Fatores de Tempo , Resultado do Tratamento , Ácido Úrico/análiseRESUMO
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurologic complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor. Although the prognosis for CNSL is generally dismal, reconstitution of the immune system from a normal donor contributed to the patient remaining in remission for 30 months.
Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas , Linfoma/terapia , Transtornos Linfoproliferativos/terapia , Adolescente , Aloenxertos , Neoplasias do Sistema Nervoso Central/etiologia , Infecções por Vírus Epstein-Barr/complicações , Humanos , Linfoma/etiologia , Transtornos Linfoproliferativos/complicações , MasculinoRESUMO
BACKGROUND: The pathological findings of tonsils in IgA nephropathy include the expansion of T-cell nodules around lymphoid follicles and abnormal reticulation of the crypt epithelium in contrast to chronic tonsillitis. Recently, several studies have reported that regulatory T cells play an important role in the maintenance of self-tolerance, an abnormality that is involved in the onset of nephrotic syndrome (NS). We encountered a patient of 28-year-old male with frequently relapsing nephrotic syndrome (FRNS) and chronic tonsillitis whose tonsils demonstrated pathological findings similar to those of IgA nephropathy. CASE PRESENTATION: A patient had developed NS at the age of 5 years, and was pathologically diagnosed with minimal change disease (MCD), for which he received various immunosuppressive agents as treatment for recurrence. Because tonsillitis often triggers the recurrence of NS, a tonsillectomy was performed for chronic tonsillitis at the age of 25 years. Immunohistochemical staining of his tonsils showed the expansion of CD4 positive lymphocytes around the lymphoid follicles and abnormal reticulation of the crypt epithelium. The number of peripheral blood CD4+CD25+ regulatory T cells increased, and the frequency of relapses decreased after tonsillectomy. CONCLUSION: A similar self-tolerance abnormality exists in NS and IgA nephropathy; therefore, tonsillectomy might become a novel therapeutic approach for FRNS to redress the unbalanced self-tolerance and to remove the tonsillar focal infection. Further studies are necessary to verify the clinical efficiency of tonsillectomy for FRNS with recurrent episodes triggered by tonsillitis.
Assuntos
Síndrome Nefrótica/cirurgia , Tonsilite/patologia , Tonsilite/cirurgia , Adulto , Linfócitos T CD4-Positivos/patologia , Doença Crônica , Glomerulonefrite por IGA/patologia , Humanos , Masculino , Síndrome Nefrótica/complicações , Tonsila Palatina/patologia , Recidiva , Tonsilectomia , Tonsilite/complicaçõesRESUMO
MAGEL2 is the paternally expressed gene within Prader-Willi syndrome critical region at 15q11.2. We encountered three individuals in whom truncating mutations of MAGEL2 were identified. Patients 1 and 2, siblings born to healthy, non-consanguineous Japanese parents, showed generalized hypotonia, lethargy, severe respiratory difficulty, poor feeding, and multiple anomalies including arthrogryposis soon after birth. We carried out whole-exome sequencing, which detected a MAGEL2 mutation (c.1912C>T, p.Gln638*, heterozygous). The patients' father was heterozygous for the mutation. Patient 3 was a female infant, showed respiratory difficulty reflecting pulmonary hypoplasia, generalized hypotonia, feeding difficulty and multiple anomalies soon after birth. Targeted next-generation sequencing detected a novel heterozygous mutation in MAGEL2 (c.3131C>A, p.Ser1044*). This mutation was not found in the parents. MAGEL2 mutations, first reported to be the cause of the Prader-Willi like syndrome with autism by Schaaf et al. (2013) Nature Genetics, 45: 1405-1408 show the wide range of phenotypic spectrum from lethal arthrogryposis multiplex congenital to autism spectrum disorder (ASD) and mild intellectual disability (ID). Our results indicate that MAGEL2 mutations cause multiple congenital anomalies and intellectual disability accompanied by arthrogryposis multiplex congenita and various endocrinologic abnormalities, supporting that the view that clinical phenotypes of MAGEL2 mutations are variable.
Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Sistema Endócrino/anormalidades , Adolescente , Alelos , Biomarcadores , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Imageamento por Ressonância Magnética , Mutação , Linhagem , Fenótipo , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Proteínas/genética , Síndrome , Sequenciamento do ExomaRESUMO
BACKGROUND: Cyclosporine A (CsA) is used globally as an immunosuppressant for the treatment of immune-mediated nephrotic syndrome (NS). However, its long-term use causes nephrotoxicity characterized by tubulointerstitial injury and glomerulosclerosis. The present study aimed to investigate the associations between histomorphological findings and immunohistological expression of Cathepsin L (CatL) and CD2-associated protein (CD2AP) in patients with NS mediated with CsA. METHODS: A total of 18 patients with child-onset NS were divided into two groups after treatment with CsA for 2 years (group A; n = 10) and more than 4 years (group B; n = 8), respectively. Analyses of relationships between tubulointerstitial disorders and expression of CatL and CD2AP proteins were performed using immunohistochemistry of paired renal specimens. RESULTS: Glomeruli with arteriole hyalinization were significantly increased in both groups depending on dosage periods, although degrees of tubule and interstitial injury did not differ between groups. CD2AP expression was significantly greater in podocytes (P = 0.046) and was significantly less in proximal tubule cells (P = 0.014) in patients of group B compared with those of group A. Moreover, CD2AP expression was significantly increased in lateral tubule cells in both groups (group A, P = 0.02; group B, P = 0.001), and CatL expression in glomeruli and tubule cells did not change with the duration of CsA treatment in either patient group. CONCLUSIONS: CD2AP expression in renal tubules may histologically associate with tissue hypoxia and reflected recovery from CsA-mediated renal injury in patients, even with mild histological features of tubulointerstitial disorder.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/análise , Catepsina L/análise , Ciclosporina/efeitos adversos , Proteínas do Citoesqueleto/análise , Glomerulonefrite/induzido quimicamente , Imunossupressores/efeitos adversos , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Síndrome Nefrótica/tratamento farmacológico , Adolescente , Adulto , Criança , Feminino , Glomerulonefrite/enzimologia , Glomerulonefrite/patologia , Humanos , Imuno-Histoquímica , Glomérulos Renais/enzimologia , Glomérulos Renais/patologia , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Masculino , Síndrome Nefrótica/diagnóstico , Podócitos/enzimologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Patients with minimal change nephrotic syndrome (MCNS) often also have allergic diseases. Abnormalities of Th2-derived cytokines and T-cell functions contribute to development of these diseases. On the other hand, imbalances between reactive oxygen species (ROS) and antioxidants have been implicated in MCNS and progression of atopic dermatitis. ROS, produced mainly within mitochondria, subject cells to oxidative stress, while prohibitin 2 protects mitochondria by increasing tolerance to ROS. Additionally, podocin, a member of the slit diaphragm protein complex, contains PHB-like domain that serves as a signaling platform regulating podocyte function through associated transmembrane proteins. PATIENTS AND METHOD: Then, we performed exome sequencing analysis in five patients with frequently relapsing their MCNS associated with allergic disease and serum IgE concentrations of 2000 IU/L or higher. RESULTS: We detected a heterozygous prohibitin 2 polymorphism, c.873-3_873-2 delCA (rs111523336), in 1 patient. This mutation in exon 9 caused frameshifts in regions connected to splicing sites, where they could disrupt transcription of prohibitin 2. Frequency of this polymorphism in exon 9 is 7.3% among Japanese. Increase in peripheral blood ROS even MCNS remission state suggests the heterozygous prohibitin 2 variant may contribute to give more susceptibility towards the recurrence of MCNS as well as atopic skin disease. This increase may have progression of atopic dermatitis, which sometimes heralded. CONCLUSION: The prohibitin-2 polymorphism may reduce ROS tolerance in glomerular epithelium and led to high local exposure to ROS, increasing permeability of the glomerular basement membrane to result in proteinuria. Imbalance between ROS and antioxidants together with failure of signal transduction in the glomerular slit membrane caused by prohibitin 2 abnormality could have contributed to nephrotic syndrome in our patients. Prohibitin 2 analysis is needed in additional MCNS patients with concomitant allergic disease.
Assuntos
Dermatite Atópica/genética , Nefrose Lipoide/genética , Polimorfismo Genético , Proteínas Repressoras/genética , Adolescente , Biomarcadores/sangue , Biópsia , Citocinas/sangue , Análise Mutacional de DNA , Dermatite Atópica/sangue , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Exoma , Mutação da Fase de Leitura , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Heterozigoto , Humanos , Imunoglobulina E/sangue , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/ultraestrutura , Masculino , Microscopia Eletrônica , Nefrose Lipoide/sangue , Nefrose Lipoide/diagnóstico , Nefrose Lipoide/imunologia , Estresse Oxidativo , Fenótipo , Proibitinas , Proteinúria/genética , Proteinúria/imunologia , Espécies Reativas de Oxigênio/sangue , Recidiva , Fatores de Risco , Sequenciamento do ExomaRESUMO
BACKGROUND: Nephronophthisis (NPH) accounts for 4-5 % of end-stage renal disease occurring in childhood. METHOD: We investigated the clinical context and characteristics of renal and extrarenal symptoms, as well as the NPHP genes, in 35 Japanese patients with clinical and histologic features suggesting NPH. RESULTS: NPH occurred fairly uniformly throughout Japan irrespective of region or gender. In three families, NPH affected siblings. The median age of patients was 12.5 years. Renal abnormalities attributable to NPH discovered through mass screening, such as urine tests in school. However, NPH accounted for less than 50 % of children with abnormal findings, including incidentally discovered renal dysfunction during evaluation of extrarenal symptoms or during routine check-ups. Typical extrarenal manifestations leaded to discovery including anemia and delayed physical development. The urine often showed low gravity specific density and low molecular weight proteinuria. Frequent renal histologic findings included cystic dilation of tubules, mainly in the medulla, and irregularity of tubular basement membranes. Genetically abnormalities of NPHP1 were not common, with large deletions frequently noted. Compound heterozygotes showing single abnormalities in each of NPHP1, NPHP3, and NPHP4 were observed. CONCLUSIONS: Our findings resemble those reported in Western populations.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doenças Renais Císticas/congênito , Cinesinas/genética , Proteínas de Membrana/genética , Proteínas/genética , Adolescente , Adulto , Criança , Proteínas do Citoesqueleto , Feminino , Humanos , Japão/epidemiologia , Rim/patologia , Doenças Renais Císticas/epidemiologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Adulto JovemRESUMO
BACKGROUND: Several shared common gene networks participate in development of interstinal ganglia and also nephron formation; the glial cell line-derived neurotrophic factor/Ret/glial cell line-derived neurotrophic factor receptor gene network is particularly important. CASE PRESENTATION: We encountered a patient with total colonic aganglionosis as well as right renal agenesis and oligomeganephronia. Gene analysis in this patient disclosed a heterozygous p.S811F mutation was in Ret gene exon 14, resulting in a substitution of phenylalanine for serine. The large side chain of phenylalanine obstructed the opening of the hydrophobic pocket of the Ret molecule causing interference with its interaction with adenosine triphosphate and consequent marked reduction in its enzyme activity. This could account for our patient's severe intestinal disease and renal dysplasia. We know of no previous reports of concomitant Hirschsprung's disease and oligomeganephronia. CONCLUSIONS: The patient's overall illness could be considered a novel Ret gene mutation syndrome.
Assuntos
Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/genética , Doença de Hirschsprung/diagnóstico por imagem , Doença de Hirschsprung/genética , Nefropatias/congênito , Rim/anormalidades , Proteínas Proto-Oncogênicas c-ret/genética , Criança , Feminino , Heterozigoto , Humanos , Rim/diagnóstico por imagem , Nefropatias/diagnóstico por imagem , Nefropatias/genética , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-ret/químicaRESUMO
Transient abnormal myelopoesis is mostly self-resolving and has a good prognosis, but some patients subsequently die of liver fibrosis. We report the case of an infant with Down syndrome who developed life-threatening liver fibrosis at the same time as the blasts were about to disappear. This patient also had a marked increase in eosinophils, which were possibly harboring a GATA1 mutation and were expressing a high level of platelet-derived growth factor-B mRNA; these may have been involved in the development of liver fibrosis. Low-dose cytosine arabinoside therapy effectively treated both hypereosinophilia and liver fibrosis.
Assuntos
Síndrome de Down/etiologia , Eosinofilia/complicações , Reação Leucemoide/etiologia , Cirrose Hepática/complicações , Mielopoese , Biópsia , DNA/genética , Análise Mutacional de DNA , Síndrome de Down/complicações , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Eosinofilia/diagnóstico , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Humanos , Recém-Nascido , Reação Leucemoide/diagnóstico , Reação Leucemoide/genética , Cirrose Hepática/diagnóstico , MasculinoRESUMO
BACKGROUND: Abnormal cellular and humoral immunity underlie both immunoglobulin A (IgA) nephropathy and tubulointerstitial nephritis and uveitis (TINU) syndrome. We encountered a teenage boy who developed TINU syndrome during the course of IgA nephropathy. CASE REPORT: 1 year after onset of IgA nephropathy following acute enteritis, a 14-year-old boy again experienced acute enteritis caused by Campylobacter jejuni, which was followed by TINU syndrome with prominent low-molecular-weight proteinuria. Renal histologic examination showed T-cell-dominant tubulointerstitial infiltration of marked immune cells including CD54-positive cells. Steroid therapy improved renal function, reversing aggravation of IgA nephropathy by TINU syndrome. CONCLUSIONS: The boy's human leukocyte antigen profile suggested predisposition to these two diseases, triggered by which were intestinal infections. The enteritis probably induced abnormalities in cellular and humoral immunity. Low-molecular-weight proteinuria, which reflected our patient's tubulointerstitial lesions, should call for consideration of TINU syndrome, including ophthalmologic assessment for possible uveitis.
Assuntos
Glomerulonefrite por IGA/complicações , Nefrite Intersticial/complicações , Uveíte/complicações , Adolescente , Humanos , MasculinoRESUMO
BACKGROUND: Hyperlipidemia is not merely a complication but a major exacerbating factor in longstanding nephrotic syndrome (NS). Low-density lipoprotein apheresis (LDL-A) has been reported to ameliorate dyslipidemia and induce rapid remission of NS. Several clinical studies have suggested the therapeutic efficacy of LDL-A, but the level of clinical evidence is insufficient. Therefore, a multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was initiated in Japan. METHOD: Patients with drug-resistant NS were prospectively recruited into the study and treated with LDL-A in facilities that were registered in advance. In the POLARIS study design, the clinical data are to be followed up for 2 years. In the current study, we aimed at evaluating the short-term efficacy based on the treatment outcome of LDL-A immediately after completion of treatment. RESULTS: Along with rapid improvement of hyperlipidemia, LDL-A significantly improved proteinuria and hypoproteinemia after treatment. More than half of the patients showed remission of NS based on the urinary protein level at the completion of LDL-A. The duration of NS before the start of treatment was significantly shorter in patients who responded to LDL-A. CONCLUSIONS: An analysis of patients registered in the POLARIS study indicated that LDL-A has short-term efficacy for drug-resistant NS. Rapid relief of dyslipidemia by LDL-A may provide early remission in about half of the NS patients who are resistant to conventional medication. Completion of the POLARIS study may reveal additional long-term effects of LDL-A in these patients.
Assuntos
Remoção de Componentes Sanguíneos , Hiperlipidemias/terapia , Lipoproteínas LDL , Síndrome Nefrótica/terapia , Adulto , Idoso , Resistência a Medicamentos , Feminino , Humanos , Hiperlipidemias/etiologia , Hipoproteinemia/etiologia , Hipoproteinemia/terapia , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/complicações , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/urina , Estudos Prospectivos , Proteinúria/etiologia , Proteinúria/terapia , Albumina Sérica/metabolismo , Fatores de TempoRESUMO
For accurate diagnosis of childhood hypertension, selection of appropriate manchette size according to the child age and the circumstantial size of upper limb is essentially important. In addition, except for the emergency case of hypertension, repeated measurement of blood pressure would be desirable in several weeks interval. Recently, childhood hypertension might be closely related to the abnormality of maternal gestational period caused by the strict diet and the maternal smoking. Developmental Origins of Health and Disease(DOHaD) theory is now highlighted in the pathogenesis of adulthood hypertension. To prevent hypertension of small-for-date baby in later phase of life, maternal education for child nursing should be conducted. In children, secondary hypertension caused by renal, endocrinologic, or malignant disease is predominant rather than idiopathic hypertension.
Assuntos
Hipertensão , Monitorização Ambulatorial da Pressão Arterial , Criança , Feminino , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Hipertensão/terapia , Masculino , Obesidade/complicações , Nascimento Prematuro , Fatores de Risco , Caracteres SexuaisRESUMO
Malignant peripheral nerve sheath tumor (MPNST), very rare in childhood, is a highly aggressive soft-tissue tumor. We experienced a case of a 7-year-old boy with MPNST who was treated with imatinib mesylate (imatinib) after the identification of platelet-derived growth factor receptor expression in his tumor. We were unable to observe clinical benefits of imatinib in this patient. Therefore, cellular reactions of imatinib were investigated in vitro using 3 MPNST cell lines. Imatinib induced cytotoxicity in vitro with variable IC50 values (11.7 to >30 µM). Induction of apoptosis was not a pivotal mechanism in the inhibitory effects. We found that the treatment of MPNST cell lines with imatinib induced autophagy. Suppression of the initiation of autophagy by 3-methyladenine or small interfering RNA (siRNA) against beclin-1 attenuated the imatinib-mediated cytotoxicity. In contrast, blocking the formation of autophagosomes or the development of autolysosomes using siRNA against microtubule-associated protein light chain 3B, bafilomycin A1, chloroquine, or an MEK1/2 inhibitor (U0126) enhanced the imatinib-induced cytotoxicity in MPNST cells. Our data showed that the imatinib-mediated autophagy can function as a cytotoxic mechanism and that appropriate modulation of autophagy may sensitize MPNST cells to imatinib, which in turn may be a novel therapeutic strategy for MPNST.
Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzamidas/uso terapêutico , Neurilemoma/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Mesilato de Imatinib , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neurilemoma/metabolismo , Neurilemoma/patologia , Fagossomos/efeitos dos fármacos , RNA Interferente Pequeno/genética , Transdução de Sinais , Células Tumorais CultivadasRESUMO
BACKGROUND/AIMS: Alport syndrome (AS) is a renal disorder caused by a genetic abnormality of type IV collagen α3 and α4, or α5 genes and shows a poor prognosis. Since the defect of type IV collagen synthesis disturbs the maturation process of the glomerular capillary loop, residual immature glomeruli persist after birth. The therapeutic efficacy of cyclosporin A (CyA) for AS patients seems to be controversial. We recently noted that renal specimens obtained from a child with AS who was treated with CyA and then developed CyA nephropathy included an increased number of undifferentiated embryonic-type glomeruli. METHODS: We analyzed renal histologic and immunohistologic findings in children with AS who did (n = 3) or did not (n = 2) develop CyA-induced nephropathy despite appropriately low serum CyA concentrations (<100 ng/mL) being maintained over a period of 2 years. To discriminate embryonic-type from mature glomeruli, staining for type IV collagen α1, laminin ß1, and laminin ß2 accompanied by light microscopic observation were employed. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII). RESULTS: In initial biopsy specimens, residual embryonic-type glomeruli were observed in each patient. Patients with early-onset CyA nephropathy had a high GII (median value 2.91 vs 1.23 ± 0.62 normal kidney tissues). In the follow-up biopsy after CyA treatment, surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli that had failed to differentiate were observed. Taken together, the number of these glomeruli essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment. CONCLUSIONS: Our findings indicate a need for caution in CyA therapy for patients with AS, even for a relatively short course of administration, because some patients may have an unexpected number of embryonic-type glomeruli that predispose to CyA nephropathy.
Assuntos
Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Nefropatias/induzido quimicamente , Glomérulos Renais/patologia , Nefrite Hereditária/tratamento farmacológico , Adolescente , Biópsia , Diferenciação Celular , Criança , Colágeno Tipo IV/metabolismo , Feminino , Seguimentos , Humanos , Nefropatias/epidemiologia , Nefropatias/patologia , Glomérulos Renais/metabolismo , Laminina/metabolismo , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Patients with X-linked agammaglobulinemia (XLA) develop immune-complex induced diseases such as nephropathy only rarely, presumably because their immunoglobulin (Ig) G concentration is low. We encountered a patient with XLA who developed tubulointerstitial nephritis during treatment with intravenous immunoglobulin (IVIG). CASE PRESENTATION: A 20-year-old man was diagnosed with XLA 3 months after birth and subsequently received periodic γ-globulin replacement therapy. Renal dysfunction developed at 19 years of age in association with high urinary ß2-microglobulin (MG) concentrations. A renal biopsy specimen showed dense CD3-positive lymphocytic infiltration in the tubulointerstitium and tubular atrophy, while no IgG4-bearing cell infiltration was found. Fibrosclerosis and crescent formation were evident in some glomeruli. Fluorescent antibody staining demonstrated deposition of IgG and complement component C3 in tubular basement membranes. After pulse steroid therapy was initiated, urinary ß2-MG and serum creatinine concentrations improved. CONCLUSION: Neither drug reactions nor collagen disease were likely causes of tubular interstitial disorder in this patient. Although BK virus was ruled out, IgG in the γ-globulin preparation might have reacted with a pathogen present in the patient to form low-molecular-weight immune complexes that were deposited in the tubular basement membrane.
Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Imunoglobulinas Intravenosas/efeitos adversos , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/diagnóstico , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Nefrite Intersticial/complicações , Adulto JovemRESUMO
Renovascular hypertension caused by renal dysplasia often is resistant to drug therapy. For a 14-year-old girl with such refractory hypertension, a non-invasive right renal ablation by embolization with anhydrous ethanol using a shepherd 's-crook' balloon catheter, was done. Blood pressure then rapidly normalized. Apart from mild fever after the procedure, no adverse effects occurred. In patients with mild renal artery stenosis and hypertension resistant to anti-hypertensive drug therapy, renal artery embolization may be a useful option.
Assuntos
Embolização Terapêutica/métodos , Etanol/administração & dosagem , Hipertensão Renovascular/etiologia , Nefropatias/congênito , Adolescente , Feminino , Seguimentos , Humanos , Hipertensão Renovascular/terapia , Injeções Intra-Arteriais , Nefropatias/complicações , Artéria RenalRESUMO
Oculocerebrorenal syndrome of Lowe (OCRL, OMIM 309000), also known as Lowe syndrome, is a rare X-linked multisystem disorder characterized by congenital cataracts, mental retardation, and Fanconi syndrome of the kidney proximal tubules. Lowe syndrome is caused by mutations in the gene encoding a member of the inositol polyphosphate-5-phosphatase protein family (OCRL1) on chromosome Xq26.1. OCRL1 contains 24 exons and encodes a 105-kDa phosphatidylinositol (4,5) bisphosphate 5-phosphatase. An OCRL1 isoform generated by alternative splicing is predominantly expressed in brain, and localizes to the trans-Golgi network, lysosomes, and endosomes. Impaired inositol polyphosphate-5-phosphatase activity elevates phosphatidylinositol (4,5) bisphosphate levels that are required for vesicle trafficking within the Golgi apparatus, actin cytoskeleton remodeling closely associated with Golgi, and endosomal membrane trafficking. Accordingly, abnormalities in the actin cytoskeleton may influence the function of renal epithelial cells in patients with Lowe syndrome. OCRL1 mutations exist in about 95% of patients with Lowe syndrome, and new mutations occur in 32% affected males. We here describe a Japanese male with the mild phenotype of Lowe syndrome. Physical examination revealed mild congenital bilateral cataracts, mild mental disability, and short stature. Proteinuria was also mild with a high ß2-microglobulinuria level. Nucleotide sequence analysis identified a hemizygous mutation (T-to-C transition) at nucleotide 2039 in exon 18 that substitutes Ser (TCT) for Phe (TTT) at amino acid position 680. This missense mutation is located outside the known catalytic domain that is encoded by exons 4 through 15. The present patient carries a novel OCRL1 mutation that is helpful for genetic counseling.