RESUMEN
BACKGROUND: The immunosuppressant mizoribine (Miz) can reduce progression of childhood IgA nephropathy (IgAN). This study examined whether Miz affects CD163+ M2-type macrophages which are associated with kidney fibrosis in childhood IgAN. METHODS: A retrospective cohort of 90 children with IgAN were divided into groups treated with prednisolone (PSL) alone (P group; n = 42) or PSL plus Miz (PM group; n = 48) for a 2-year period. Normal human monocyte-derived macrophages were stimulated with dexamethasone (Dex), or Dex plus Miz, and analyzed by DNA microarray. RESULTS: Clinical and histological findings at first biopsy were equivalent between patients entering the P and PM groups. Both treatments improved proteinuria and haematuria, and maintained normal kidney function over the 2-year course. The P group exhibited increased mesangial matrix expansion, increased glomerular segmental or global sclerosis, and increased interstitial fibrosis at 2-year biopsy; however, the PM group showed no progression of kidney fibrosis. These protective effects were associated with reduced numbers of glomerular and interstitial CD163+ macrophages in the PM versus P group. In cultured human macrophages, Dex induced upregulation of cytokines and growth factors, which was prevented by Miz. Miz also inhibited Dex-induced expression of CD300E, an activating receptor which can prevent monocyte apoptosis. CD300e expression by CD163+ macrophages was evident in the P group, which was reduced by Miz treatment. CONCLUSION: Miz halted the progression of kidney fibrosis in PSL-treated pediatric IgAN. This was associated with reduced CD163+ and CD163+CD300e+ macrophage populations, plus in vitro findings that Miz can suppress steroid-induced macrophage expression of pro-fibrotic molecules. A higher resolution version of the Graphical abstract is available as Supplementary information.
Asunto(s)
Glomerulonefritis por IGA , Humanos , Niño , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Inmunoglobulina A , Estudios Retrospectivos , Glomérulos Renales/patología , Macrófagos/metabolismo , Prednisolona/farmacología , Prednisolona/uso terapéutico , FibrosisRESUMEN
BACKGROUND: Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient). RESULTS: TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. CONCLUSIONS: Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.
Asunto(s)
Inmunosupresores/administración & dosificación , Ácido Micofenólico/administración & dosificación , Síndrome Nefrótico/tratamiento farmacológico , Rituximab/administración & dosificación , Adolescente , Niño , Preescolar , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Síndrome Nefrótico/inmunología , Recurrencia , Esteroides/administración & dosificación , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Type 3 renal tubular acidosis is a pathological condition characterized by the simultaneous occurrence of distal renal tubular acidosis, which causes urinary acidification disorders, and proximal renal tubular acidosis, which causes impaired reabsorption of bicarbonate ions. Type 3 renal tubular acidosis is considered rare. A 5-year-old boy was admitted to our hospital because of frequent vomiting, poor vitality, and fever. He was diagnosed with cyclic vomiting syndrome. Type 3 renal tubular acidosis was also diagnosed because of severe mixed metabolic acidosis with impaired urinary acidification, a low tubular phosphorus reabsorption rate with hypophosphatemia, low-molecular-weight proteinuria, pan-aminoaciduria, and glucosuria. Fluid infusion was performed. On the second day of hospitalization, the vomiting disappeared and the patient was able to eat and drink. He was discharged on the eighth day of hospitalization. The laboratory test abnormalities associated with the renal tubular acidosis gradually improved, and testing at discharge on the eighth day of admission showed no metabolic acidosis, hypophosphatemia, low-molecular-weight proteinuria, or glucosuria. These findings suggested that the type 3 renal tubular acidosis was transient. Severe metabolic acidosis was observed in this patient because of both normal anion gap metabolic acidosis due to type 3 renal tubular acidosis and anion gap metabolic acidosis due to cyclic vomiting syndrome. Although type 3 tubular acidosis is rare, the resultant metabolic acidosis worsens when combined with a disease that causes metabolic acidosis. Type 3 tubular acidosis should be ruled out when severe metabolic acidosis is present.
Asunto(s)
Acidosis Tubular Renal , Acidosis , Hipofosfatemia , Acidosis/complicaciones , Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/diagnóstico , Acidosis Tubular Renal/metabolismo , Preescolar , Humanos , Hipofosfatemia/complicaciones , Masculino , Proteinuria/complicaciones , Vómitos/complicacionesRESUMEN
Thrombotic microangiopathy (TMA) is a disease that causes organ damage due to microvascular hemolytic anemia, thrombocytopenia, and microvascular platelet thrombosis. Streptococcus pneumoniae-associated TMA (spTMA) is a rare complication of invasive pneumococcal infection. In addition, atypical hemolytic uremic syndrome (aHUS) is TMA associated with congenital or acquired dysregulation of complement activation. We report the case of a nine-month-old boy with refractory nephrotic syndrome complicated by spTMA in the setting of heterozygous complement factor-I (CFI) gene mutation and CFHR3-CFHR1 deletion. He repeatedly developed thrombocytopenia, anemia with schistocytes, hypocomplementemia, and abnormal coagulation triggered by infection, which manifested clinically with convulsions and an intraperitoneal hematoma. Eculizumab (a monoclonal humanized anti-C5 antibody) provided transient symptomatic benefit including improvement in thrombocytopenia; however, he developed unexplained cardiac arrest and was declared brain dead a few days later. In this report, we highlight the diagnostic challenges of this case and the causal relationship between spTMA and complement abnormalities and consider the contribution of heterozygous mutation of CFI and CFHR3-CFHR1 deletion.
Asunto(s)
Síndrome Hemolítico Urémico Atípico , Microangiopatías Trombóticas , Humanos , Lactante , Masculino , Anticuerpos Monoclonales , Síndrome Hemolítico Urémico Atípico/complicaciones , Síndrome Hemolítico Urémico Atípico/genética , Proteínas Sanguíneas/genética , Proteínas Inactivadoras del Complemento C3b/genética , Factor I de Complemento/genética , Mutación/genética , Streptococcus pneumoniae , Microangiopatías Trombóticas/genéticaRESUMEN
BACKGROUND: M1-type proinflammatory macrophages (MΦ) promote glomerular injury in lupus nephritis (LN). However, whether this phenotype is altered by steroid therapy is unclear. Therefore, we investigated the effect of steroid treatment on MΦ phenotype in LN. METHODS: Patients with LN (7-18 years old) were divided into 2 groups: those with no treatment (N) before biopsy (n = 17) and those who underwent steroid (S) treatment (3-73 days) before biopsy (n = 15). MΦ number and phenotype were assessed by immunofluorescence. In vitro studies used monocyte-derived MΦ from healthy volunteers. RESULTS: Age at biopsy, urine findings, and kidney function (eGFR) were comparable between the two groups. Biopsies in N group had higher levels of active lesions such as endocapillary hypercellularity, necrosis, and cellular crescent formation (p < 0.05). The total CD68+ MΦ infiltrate was comparable between N and S groups. However, N group had more M1 MΦ (CD68+ CD86+ cells) (p < 0.05) and fewer M2 MΦ (CD68+ CD163+ cells) (p < 0.05), giving a 6-fold increase in the M2/M1 ratio in S vs. N groups. Dexamethasone treatment of cultured MΦ induced upregulation of CD163 expression, increased production of anti-inflammatory (IL-10, IL-19) and profibrotic factors (FGF-22, PDGF), and upregulated the scavenger receptor, stabilin-1. Upregulation of stabilin-1 in CD163+ M2 MΦ was confirmed in biopsies from S group. CONCLUSIONS: Initial steroid treatment induces MΦ phenotypic change from proinflammatory M1 to anti-inflammatory or profibrotic M2 in LN with acute/active lesions. Although steroid treatment is effective for resolution of M1-medated injury, promotion of fibrotic lesions via M2 MΦ is a potential downside of steroid single therapy in LN.
Asunto(s)
Nefritis Lúpica , Macrófagos/fisiología , Adolescente , Antiinflamatorios , Diferenciación Celular , Niño , Humanos , Nefritis Lúpica/tratamiento farmacológico , FenotipoRESUMEN
Renal tubular dysgenesis (RTD) is the absence or poor development of the renal proximal tubules caused by gene mutations in the renin-angiotensin system. Although RTD has been considered fatal, improving neonatal intensive care management has enhanced survival outcomes. However, little has been reported on the survival of extremely preterm infants. This study reports the survival of an extremely preterm infant with RTD and discusses the appropriate management of RTD by reviewing the literature. A female infant weighing 953 g was delivered at 27 weeks' gestation by Cesarean section because of oligohydramnios. She exhibited severe persistent pulmonary hypertension, severe systemic hypotension, and renal dysfunction shortly after birth. Respiratory management was successfully undertaken using nitric oxide inhalation and high-frequency oscillatory ventilation. Desmopressin was effective in maintaining her blood pressure and urinary output. She was diagnosed with RTD based on genetic testing, which revealed a compound heterozygous mutation in the angiotensin-converting enzyme gene in exon 18 (c.2689delC; p.Pro897fs) and exon 20 (c.3095dupT; p.Leu1032fs). At 2 years, she started receiving oral fludrocortisone for treating persistently high serum creatinine levels, which was attributed to nephrogenic diabetes insipidus caused by RTD. Subsequently, her urine output decreased, and renal function was successfully maintained. Currently, there is no established treatment for RTD. Considering cases reported to date, treatment with vasopressin and fludrocortisone appears to be most effective for survival and maintenance of renal function in patients with RTD. This study presents the successful management of RTD using this strategy in an extremely preterm infant.
Asunto(s)
Recien Nacido Prematuro/fisiología , Túbulos Renales Proximales/anomalías , Anomalías Urogenitales/terapia , Secuencia de Bases , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Túbulos Renales Proximales/enzimología , Peptidil-Dipeptidasa A/genética , Análisis de Supervivencia , Anomalías Urogenitales/enzimología , Anomalías Urogenitales/genéticaRESUMEN
BACKGROUND: Several immunosuppressants have been used to treat children with steroid-dependent nephrotic syndrome (SDNS). Mizoribine (MZR) is an immunosuppressant used to maintain remission in children with SDNS, although its effectiveness for treating SDNS remains controversial. Therefore, in this study, we assessed the clinical factors associated with children having SDNS who were successfully treated with MZR. METHODS: A total of 47 children with SDNS who underwent MZR treatment were retrospectively evaluated. Clinical features including pharmacokinetics after MZR administration were compared between MZR responders and non-responders. RESULTS: The comparison of the two groups revealed no significant differences in age, body weight (BW), daily dose of MZR per BW, serum concentration 2 h after administration (C2), peak serum concentration (Cmax), and area under the concentration curve 0-4 h after administration (AUC0-4). C2/(single dose/BW), Cmax/(single dose/BW), and AUC0-4/(single dose/BW) were significantly higher in the MZR responders than in the non-responders (all p < 0.01). Receiver operating characteristic analysis revealed that the cutoff values of C2 (single dose/kg), Cmax/(single dose/BW), and AUC0-4/(single dose/BW) were 0.55, 0.58, and 1.37, respectively. CONCLUSIONS: MZR is a useful immunosuppressant for treating frequent-relapse NS in children who are susceptible to the drug. The efficacy of MZR may be associated with not only serum concentrations defined by the dosage or absorption efficiency through MZR transporters, but also the susceptibility defined by the expression level and performance of MZR transporters on the target cells.
Asunto(s)
Inmunosupresores/uso terapéutico , Síndrome Nefrótico/tratamiento farmacológico , Ribonucleósidos/uso terapéutico , Esteroides/uso terapéutico , Factores de Edad , Femenino , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Masculino , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/inmunología , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Ribonucleósidos/efectos adversos , Ribonucleósidos/farmacocinética , Esteroides/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM: This study was aimed at examining the effects of treatment with rituximab, a chimeric monoclonal antibody against the protein CD20, in a B-lymphocyte independent adriamycin-induced rat model of nephrotic syndrome. Rituximab is an emerging rescue therapy used in patients with complicated nephrotic syndrome and, therefore, we sought to elucidate the apparent B-lymphocyte independent mechanism underlying its anti-proteinuric effect. METHODS: Adriamycin-induced nephropathy was established in Wistar rats by intravenously injecting 10 mg/kg of adriamycin, which were then treated with rituximab or purified human IgG weekly and euthanized on day 28. Proteinuria, glomerular expression of sphingomyelin phosphodiesterase acid-like 3b protein, and podocyte-related proteins were examined using immunofluorescence staining and a reverse transcription-polymerase chain reaction. RESULTS: Rituximab treatment of rats with adriamycin-induced nephropathy significantly reduced urinary protein excretion 14 to 28 days after induction of disease, compared with those treated with purified normal human IgG. Furthermore, rituximab treatment also prevented the reduction of glomerular nephrin and podocin expression on day 28. Double-immunofluorescence staining revealed that after in vivo administration, rituximab was bound to the glomeruli, which also expressed synaptopodin or sphingomyelin phosphodiesterase, acid-like 3b. Moreover, sphingomyelin phosphodiesterase, acid-like 3b expression was significantly decreased on day 28 of adriamycin-induced nephropathy, which was also prevented by rituximab. CONCLUSIONS: This study demonstrated that rituximab directly affected glomerular podocytes and ameliorated proteinuria in adriamycin-induced nephropathy in rats. Furthermore, protection of podocyte function by rituximab may be mediated by direct modulation of a sphingomyelin phosphodiesterase, acid-like 3b-dependent mechanism.
Asunto(s)
Linfocitos B/efectos de los fármacos , Doxorrubicina , Enfermedades Renales/prevención & control , Podocitos/efectos de los fármacos , Sustancias Protectoras/farmacología , Proteinuria/prevención & control , Rituximab/farmacología , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Citoprotección , Modelos Animales de Enfermedad , Femenino , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Proteínas de Microfilamentos/metabolismo , Podocitos/metabolismo , Podocitos/patología , Proteinuria/inducido químicamente , Proteinuria/metabolismo , Proteinuria/patología , Ratas Wistar , Esfingomielina Fosfodiesterasa/genética , Esfingomielina Fosfodiesterasa/metabolismo , Factores de TiempoRESUMEN
Henoch-Schönlein purpura nephritis (HSPN) is one of the most common types of chronic glomerulonephritis in children; however, there have been few reports on the pathogenesis and management of grade VI HSPN. We present the case of a 6-year-old boy with grade VI HSPN accompanied by severe nephrotic syndrome and hypocomplementaemia. Immunohistological studies revealed profound glomerular accumulation of CD45- and CD68-positive inflammatory cells. Moreover, some cells expressed the proliferating marker proliferating cell nuclear antigen. His proteinuria and general oedema persisted despite repeated high-dose steroid therapy; however, these clinical symptoms immediately improved after beginning treatment with cyclophosphamide (CyP). Grade VI HSPN was successfully treated with steroids and immunosuppressants. Among immunosuppressive drugs, CyP was considered the most effective.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Ciclofosfamida/uso terapéutico , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Vasculitis por IgA/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Riñón/efectos de los fármacos , Leucocitos/efectos de los fármacos , Biopsia , Niño , Quimioterapia Combinada , Técnica del Anticuerpo Fluorescente , Glomerulonefritis Membranoproliferativa/diagnóstico , Glomerulonefritis Membranoproliferativa/inmunología , Glucocorticoides/uso terapéutico , Humanos , Vasculitis por IgA/diagnóstico , Vasculitis por IgA/inmunología , Riñón/inmunología , Riñón/patología , Leucocitos/inmunología , Leucocitos/patología , Masculino , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/inmunología , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Prevention of chronic kidney allograft injury (CAI) is a major goal in improving kidney allograft survival; however, the mechanisms of CAI are not clearly understood. The current study investigated whether alternatively activated M2-type macrophages are involved in the development of CAI. METHODS: A retrospective study examined kidney allograft protocol biopsies (at 1 h and at years 1, 5, and 10--a total of 41 biopsies) obtained from 13 children undergoing transplantation between 1991 and 2008 who were diagnosed with CAI: interstitial fibrosis and tubular atrophy (IF/TA) not otherwise specified (IF/TA-NOS). RESULTS: Immunostaining identified a significant increase in interstitial fibrosis with accumulation of CD68 + CD163+ M2-type macrophages. CD163+ cells were frequently localized to areas of interstitial fibrosis exhibiting collagen I deposition and accumulation of α-smooth muscle actin (SMA) + myofibroblasts. There was a significant correlation between interstitial CD163+ cells and the parameters of interstitial fibrosis (p < 0.0001), and kidney function (r =-0.82, p < 0.0001). The number of interstitial CD163+ cells at years 1 and 5 also correlated with parameters of interstitial fibrosis at years 5 and 10 respectively. Notably, urine CD163 levels correlated with interstitial CD163+ cells (r = 0.79, p < 0.01) and parameters of interstitial fibrosis (p < 0.0001). However, CD3+ T lymphocytic infiltration did not correlate with macrophage accumulation or fibrosis. In vitro, dexamethasone up-regulated expression of CD163 and cytokines (TGF-ß1, FGF-2, CTGF) in human monocyte-derived macrophages, indicating a pro-fibrotic phenotype. CONCLUSIONS: Our findings identify a major population of M2-type macrophages in patients with CAI, and suggest that these M2-type macrophages might promote the development of interstitial fibrosis in IF/TA-NOS.
Asunto(s)
Trasplante de Riñón/efectos adversos , Riñón/inmunología , Activación de Macrófagos , Macrófagos/inmunología , Insuficiencia Renal Crónica/inmunología , Adolescente , Adulto , Aloinjertos , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Atrofia , Biomarcadores/metabolismo , Biopsia , Células Cultivadas , Niño , Dexametasona/farmacología , Femenino , Fibrosis , Humanos , Inmunohistoquímica , Inmunosupresores/uso terapéutico , Riñón/metabolismo , Riñón/patología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Fenotipo , Receptores de Superficie Celular/metabolismo , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/metabolismo , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Although the creatinine (Cr)-based equation is widely used for estimating glomerular filtration rate (GFR), this equation is not ideally suited for children with low body weight or aged <2 years. Therefore, we established a new equation using serum beta-2 microglobulin (ß2MG) levels for Japanese children with chronic kidney disease (CKD). METHODS: Inulin clearance and standardized serum ß2MG and Cr levels were measured in 137 CKD patients aged 1 month-18 years. Using the previously established normal ß2MG levels, Cr reference values, and Cr-based equation of estimated GFR (eGFR) in Japanese children, receiver operating characteristics (ROC) analyses were performed to compare the diagnostic accuracy between ß2MG- and Cr-based estimations of GFR. RESULTS: Serum ß2MG concentrations progressively increased as GFRs reduced. The correlation coefficients between GFR and ß2MG, and between GFR and 1/ß2MG were -0.74 (p < 0.001) and 0.86 (p < 0.001), respectively. The inulin clearance, as based on 1/serum ß2MG expression, in pediatric CKD patients resulted in the equation: inulin GFR (mL/min/1.73 m(2)) = 149.0 × 1/serum ß2MG (mg/L) +9.15. ROC analyses indicated that the ability of serum ß2MG-based GFR <95 mL/min/1.73 m(2) in children >2 years was better than the Cr-based estimated GFR (areas under the ROC curve 0.960 vs. 0.948, respectively). CONCLUSION: The new ß2MG-based eGFR formula is useful for clinical screening of renal function in Japanese children and adolescents, and measurement of serum ß2MG and Cr levels as markers for predicting glomerular function may aid the early detection of mildly reduced GFR in this population.
Asunto(s)
Tasa de Filtración Glomerular , Inulina/metabolismo , Insuficiencia Renal Crónica/sangre , Microglobulina beta-2/sangre , Adolescente , Área Bajo la Curva , Niño , Preescolar , Creatinina/sangre , Femenino , Humanos , Lactante , Recién Nacido , Japón , Pruebas de Función Renal , Masculino , Conceptos Matemáticos , Curva ROC , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
BACKGROUND: Recent reports suggest that low birthweight (LBW) is a risk factor for kidney diseases, including focal segmental glomerulosclerosis (FSGS), although the underlying pathological mechanism remains unknown. Podocyte loss triggers glomerulosclerosis; however, whether FSGS in LBW children is associated with podocytopenia is unclear. METHODS: We reviewed the birthweights and gestational age of all patients who underwent renal biopsies from 1995 to 2011 at our Institute. Sixteen patients had FSGS, of which 6 (37.5%) had LBW; this LBW rate was significantly higher than the overall LBW rate in Japan (9.7%). The incidence of LBW was also high in patients with minimal change nephrotic syndrome (MCNS; 12.5%). The glomerular cell numbers in biopsy sections were calculated using computer image analysis and compared with FSGS of normal birthweight (NBW-FSGS). Biopsy specimens from age-matched patients with MCNS were also compared. Wilms' tumor-1 (WT1) immunohistochemistry was performed to enumerate the podocytes. RESULTS: All patients in the LBW-FSGS group were also preterm, with an average gestational age of 25.8 weeks. The number of podocytes per glomerulus in the LBW-FSGS patients was 34 and 24% lower as compared to that in the MCNS patients (p < 0.01) and the NBW-FSGS patients (p < 0.05), respectively. Similar results were observed for the WT1-positive glomerular cell number. CONCLUSION: LBW and premature birth were associated with FSGS development. The possibility that LBW and premature birth may be predisposing factors for severe podocytopenia in children with FSGS warrants further investigation.
Asunto(s)
Peso al Nacer , Edad Gestacional , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Podocitos/patología , Adolescente , Biopsia , Niño , Femenino , Humanos , Inmunohistoquímica , Incidencia , Recién Nacido de Bajo Peso , Recién Nacido , Recien Nacido Prematuro , Japón , Riñón/patología , Enfermedades Renales/epidemiología , Masculino , Nefrosis Lipoidea/diagnóstico , Estudios Retrospectivos , Factores de Riesgo , Proteínas WT1/metabolismoRESUMEN
OBJECTIVE: Serum ß2 microglobulin (ß2MG) is considered to be a marker of renal function, which is independently associated with age. However, only a few studies have reported the reference values for ß2MG in children thus far, particularly in young children. In this study, we evaluated the distribution of serum ß2MG values in healthy Japanese children and assessed its clinical usefulness. METHOD: The normal reference value of serum ß2MG was assessed in serum samples from 1131 normal Japanese children (504 boys and 627 girls; age 0-17 years). To test the validity of the reference value, serum samples from children with various kidney diseases were also examined retrospectively. RESULTS: The mean values for ß2MG were significantly negatively correlated with age (r = -0.47, P < 0.001). No significant difference was observed between the values of boys and girls in any age group. The established ß2MG reference range covered 99.7 % of patients with decreased kidney function below 75 % based on their serum creatinine (Cr) value and body length. CONCLUSION: The newly established ß2MG reference value in children can be used to detect kidney impairment in children. Serum ß2MG in combination with serum Cr used as markers for predicting glomerular function can provide an accurate detection of kidney dysfunction in children.
Asunto(s)
Pruebas de Función Renal , Riñón/fisiopatología , Insuficiencia Renal Crónica/diagnóstico , Microglobulina beta-2/sangre , Adolescente , Distribución por Edad , Factores de Edad , Análisis de Varianza , Biomarcadores/sangre , Estatura , Distribución de Chi-Cuadrado , Niño , Preescolar , Creatinina/sangre , Femenino , Humanos , Lactante , Recién Nacido , Japón , Modelos Lineales , Masculino , Valor Predictivo de las Pruebas , Valores de Referencia , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatología , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
OBJECTIVE: The data available on reference ranges for cystatin C in children are limited, and there are discrepancies among the available data. The aim of this study was to describe the reference ranges for cystatin C in Japanese children by using 4 automated assays. METHODS: Serum cystatin C levels were measured in 1128 Japanese children aged 3 month to 16 years without kidney disease. We calculated age-, gender-, race- and assay-specific cystatin C ranges. RESULTS: For all 4 assays, the median serum cystatin C levels were raised in term infants compared with older children and decreased by the first 2 years. The median serum cystatin C levels remained constant throughout up to the age of 14 years and decreased in children aged 15-16 years. The median serum cystatin C levels in children aged 12-16 years were slightly higher in males than in females. Assay-specific differences were also observed in the levels of serum cystatin C measured. CONCLUSION: Age-, gender-, race- and assay-specific ranges for serum cystatin C should be used as another tool to assess kidney function in children.
Asunto(s)
Pueblo Asiatico , Cistatina C/sangre , Adolescente , Autoanálisis/normas , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Valores de ReferenciaRESUMEN
UNLABELLED: The present study was performed to determine whether the new Schwartz "bedside" equation can be used to estimate the glomerular filtration rate (GFR) in Japanese children as there are differences in renal function and muscle mass between Japanese and American individuals. It is also important to determine whether one common equation can be used in children from 1 to 16 years old, including the period of adolescence. Blood samples were collected from a total of 1,074 healthy children (466 males and 608 females) between 1 and 16 years old. The estimated GFR (eGFR) derived by the new Schwartz bedside formula [eGFR (in milliliters per minute per 1.73 m(2)) = 0.413 × body length (in centimeters)/serum Cr value (in milligrams per deciliter)] was calculated in all subjects, and the relationship between age and eGFR was analyzed. The eGFR decreased gradually with age, and the decrease was more marked in males than females, mainly in adolescence. Weak negative but significant correlations were observed in 466 males and 608 females. The median of the eGFR value showed a gradual significant decrease with age. CONCLUSION: A common coefficient cannot be used in children between 1 and 16 years old, including the period of adolescence, with the Schwartz type formula, and the new Schwartz bedside formula cannot be used when we estimated GFR in Japanese children. It is necessary to establish an eGFR equation specifically for Japanese children.
Asunto(s)
Estatura , Creatinina/sangre , Tasa de Filtración Glomerular , Adolescente , Distribución por Edad , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Japón , Masculino , Valores de Referencia , Distribución por SexoRESUMEN
Alport syndrome is a hereditary disorder characterized by renal impairment, hearing loss, and ocular symptoms and is caused by COL4A3, COL4A4, and COL4A5 mutations. Here, we report the case of 3-year-old boy with isolated hematuria detected in routine preventative urinary screening conducted in 3-year-old children. He carried a novel variant, NM_033380.3:c. 1032 + 1 G > A, which caused a splicing abnormality in COL4A5. He was diagnosed with X-linked Alport syndrome.
RESUMEN
The slit diaphragm connecting the adjacent foot processes of glomerular epithelial cells (podocytes) is the final barrier of the glomerular capillary wall and serves to prevent proteinuria. Podocytes are understood to be terminally differentiated cells and share some common features with neurons. Neurexin is a presynaptic adhesion molecule that plays a role in synaptic differentiation. Although neurexin has been understood to be specifically expressed in neuronal tissues, we found that neurexin was expressed in several organs. Several forms of splice variants of neurexin-1α were detected in the cerebrum, but only one form of neurexin-1α was detected in glomeruli. Immunohistochemical study showed that neurexin restrictedly expressed in the podocytes in kidneys. Dual-labeling analyses showed that neurexin was colocalized with CD2AP, an intracellular component of the slit diaphragm. Immunoprecipitation assay using glomerular lysate showed that neurexin interacted with CD2AP and CASK. These observations indicated that neurexin localized at the slit diaphragm area. The staining intensity of neurexin in podocytes was clearly lowered, and their staining pattern shifted to a more discontinuous patchy pattern in the disease models showing severe proteinuria. The expression and localization of neurexin in these models altered more clearly and rapidly than that of other slit diaphragm components. We propose that neurexin is available as an early diagnostic marker to detect podocyte injury. Neurexin coincided with nephrin, a key molecule of the slit diaphragm detected in a presumptive podocyte of the developing glomeruli and in the glomeruli for which the slit diaphragm is repairing injury. These observations suggest that neurexin is involved in the formation of the slit diaphragm and the maintenance of its function.
Asunto(s)
Glomérulos Renales/citología , Podocitos/metabolismo , Receptores de Superficie Celular/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Secuencia de Aminoácidos , Estructuras Animales/metabolismo , Animales , Cerebro/metabolismo , Proteínas del Citoesqueleto/metabolismo , Embrión de Mamíferos/metabolismo , Femenino , Expresión Génica/genética , Glicoproteínas/genética , Guanilato-Quinasas/metabolismo , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Proteínas de la Membrana/metabolismo , Datos de Secuencia Molecular , Síndrome Nefrótico/inducido químicamente , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Proteínas del Tejido Nervioso/genética , Neuropéptidos/genética , Podocitos/patología , Unión Proteica/fisiología , Isoformas de Proteínas/genética , Proteinuria/orina , Ratas , Ratas Wistar , Receptores de Superficie Celular/genética , Organismos Libres de Patógenos EspecíficosRESUMEN
AIMS: New onset of the clinical symptoms of immunoglobulin A (IgA) nephropathy (IgAN) manifests with proliferative glomerular lesions in children, whereas adults exhibit mesangial matrix expansion and interstitial fibrosis. Alternatively, activated (M2) macrophages have been implicated in promoting tissue fibrosis in some settings. Therefore, the aim of this study was to investigate whether M2 macrophages are present in new-onset IgAN and if they are related to pathological differences between paediatric and adult disease. METHODS AND RESULTS: Biopsy specimens from paediatric (<10 years, n=14; >12 years, n=15) and adult (n=27) IgAN showed a significant infiltrate of CD68(+) macrophages. M2 macrophages, identified by CD163 or CD204 expression, were detected in glomeruli and the interstitium, being more prominent in adults versus young children. CD163(+) and CD204(+) macrophages were present in areas of fibrosis containing myofibroblasts, and double staining showed that CD163(+) cells produced the profibrotic molecule, connective tissue growth factor. In young children, total CD68(+) macrophages, but not M2 macrophages, correlated with glomerular hypercellularity. In contrast, in adults and older children, mesangial matrix expansion correlated with M2 macrophages but not with the total CD68(+) macrophage infiltrate. CONCLUSIONS: Alternatively activated M2 macrophages are present in new-onset paediatric and adult IgAN, and this population may promote the development of fibrotic lesions.
Asunto(s)
Mesangio Glomerular/patología , Glomerulonefritis por IGA/patología , Macrófagos/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Fibrosis/patología , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Activación de Macrófagos , Masculino , Adulto JovenRESUMEN
BACKGROUND: Enzymatic methods have recently been used to measure creatinine (Cr) instead of the Jaffe method. Therefore, it is necessary to determine the reference serum Cr value for these enzymatic methods to evaluate renal function in Japanese children. METHODS: To determine reference values of serum Cr in Japanese children, 1151 children (517 male, 634 female) aged between 1 month and 18 years had their serum Cr values measured by an enzymatic method. To be included in the study the children had to be without kidney disease, urogenital disease, infectious disease, inflammatory disease, dehydration, muscular disease, anomaly syndrome, cardiovascular disease, malignant disease, hypertension, liver or pancreas disease, or pregnancy. RESULTS: The medians of reference values increased gradually with age, i.e., 0.30 mg/dl at 4 years old and 0.41 mg/dl at 10 years old. In adolescence, they increased significantly more rapidly in males than in females. We found a linear regression equation capable of estimating the reference value of serum Cr in children aged 2-11 years, and quintic regression equations capable of estimating the reference values of serum Cr in male and female children of all ages. CONCLUSION: The reference serum Cr levels determined by an enzymatic method related to age, gender, and body length, and our linear and polynomial equations showing the relationship between body length and serum Cr level will be applicable for screening of renal function in Asian as well as Japanese children.
Asunto(s)
Estatura , Creatinina/sangre , Adolescente , Factores de Edad , Pueblo Asiatico , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Valores de Referencia , Factores SexualesRESUMEN
BACKGROUND: Macrophages with a pro-inflammatory (M1) phenotype mediate renal injury in proliferative forms of glomerulonephritis, while alternatively activated (M2) macrophages are thought to be anti-inflammatory and promote repair. Glucocorticoids, the mainstay therapy for proliferative glomerulonephritis, can induce alternative macrophage activation in vitro, but it is unknown whether this occurs in vivo and if this is required for glucocorticoid responsiveness. In addition, clinical studies have suggested that the ability of mizoribine (MZR) to suppress steroid-resistant proliferative glomerulonephritis may operate via inhibiting pro-inflammatory macrophage activation. METHODS: This study examined prednisolone (PSL) and/or MZR treatment of rat Thy-1 disease - a model in which macrophages promote mesangial proliferative glomerulonephritis. RESULTS: PSL treatment of Thy-1 nephritis induced an M2-like macrophage phenotype, but failed to modify mesangial hypercellularity and actually exacerbated global glomerulosclerosis. In contrast, MZR treatment reduced hypercellularity and glomerulosclerosis and suppressing both M1 and M2 markers of macrophage activation, with a selective reduction in CD169+ macrophages. Combined PSL/MZR treatment suppressed glomerular lesions and prevented steroid induction of an M2-like macrophage phenotype. In vitro, MZR prevented steroid induction of an M2 macrophage phenotype. CONCLUSIONS: Glucocorticoid induced alternative macrophage activation failed to ameliorate rat mesangial proliferative glomerulonephritis, whereas MZR suppression of this disease model was attributed, in part, to inhibition of M1-like pro-inflammatory macrophage activation.