A cross-sectional nationwide survey of congenital and infantile nephrotic syndrome in Japan.

BACKGROUND: Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) cause substantial morbidity and mortality. In Japan, there is a lack of knowledge regarding the characteristics of CNS and INS. This study aimed to clarify the characteristics of CNS and INS in Japan. METHODS: This cross-sectional nationwide survey obtained data from 44 institutions in Japan managing 92 patients with CNS or INS, by means of two survey questionnaires sent by postal mail. Patients aged < 16 years by 1 April 2015, with a diagnosis of CNS or INS, were included in this study. The primary outcome was end-stage kidney disease. RESULTS: A total of 83 patients with CNS or INS were analyzed. The most frequent disease type was non-Finnish (60.2%); 33 patients (39.8%) had Finnish type. Among those with non-Finnish-type disease, 26 had no syndrome and 24 had a syndrome, of which the most frequent was Denys-Drash syndrome (70.8%). Patients with non-Finnish-type disease with syndrome showed the earliest progression to end-stage kidney disease compared with the other two groups, whereas patients with non-Finnish-type disease without syndrome progressed more slowly compared with the other two groups. In the Finnish-type group, the disease was diagnosed the earliest; a large placenta was reported more frequently; genetic testing was more frequently performed (93.8%); mental retardation was the most frequent extra-renal symptom (21.2%); and thrombosis and infection were more frequent compared with the other groups. Patients with non-Finnish-type disease with syndrome had a higher frequency of positive extra-renal symptoms (79.2%), the most common being urogenital symptoms (54.2%). Treatment with steroids and immunosuppressants was more frequent among patients with non-Finnish-type disease without syndrome. Two patients with non-Finnish-type disease without syndrome achieved complete remission. In all groups, unilateral nephrectomy was performed more often than bilateral nephrectomy and peritoneal dialysis was the most common renal replacement therapy. CONCLUSIONS: The present epidemiological survey sheds light on the characteristics of children with CNS and INS in Japan. A high proportion of patients underwent genetic examination, and patient management was in accord with current treatment recommendations and practices. TRIAL REGISTRATION: Not applicable.

WT1 Haploinsufficiency Supports Milder Renal Manifestation in Two Patients with Denys-Drash Syndrome.

Denys-Drash syndrome (DDS) is characterized by nephropathy, genital abnormalities, and predisposition to Wilms' tumor. DDS patients usually present heterozygous de novo germline WT1 mutations. The WT1 gene comprises 10 exons encoding the N-terminal transactivation and the C-terminal DNA-binding regions. Two unrelated patients with genital ambiguity and Wilms' tumor were analyzed by sequencing of the WT1 gene, and 3 mutations in exon 1 were identified of which 2 are novel. Patient 1 carried a c.555delC mutation that causes a frameshift and a premature stop codon. Patient 2 carried both c.421A>C and c.424C>T aberrations that lead to the missense p.Lys141Gln and the nonsense p.Lys142* mutation, respectively. As both patients were heterozygous for the mutations, we tested their parents who did not carry any mutation. Therefore, the 3 WT1 mutations occurred de novo in both patients. Heterozygous mutations result in WT1 haploinsufficiency as they impair protein production. They are associated with a milder DDS phenotype as observed in the patients studied here.

Glomerular epithelial cell phenotype in diffuse mesangial sclerosis: a report of 2 cases with markedly increased urinary podocyte excretion.

We report 2 cases of diffuse mesangial sclerosis (DMS) accompanied by severe podocyte excretion in urine. Patient 1 was a 9-day-old girl with a WT1 mutation who developed Wilms tumor at 6 months of age and was subsequently diagnosed with Denys-Drash syndrome. Patient 2 was a 1-year-old boy without a WT1 abnormality but presenting with heavy proteinuria. In both patients, histological examination showed findings of DMS. Immunohistochemical staining for synaptopodin (a podocyte marker) revealed a reduced number of podocytes in the glomeruli with severe sclerosis; however, podocytes persisted in the relatively intact glomeruli. Some glomeruli were accompanied by sclerotic lesions surrounded by proliferating cells; immunofluorescence staining revealed a majority of these proliferating cells to be positive for claudin-1 (a parietal cell marker) but negative for synaptopodin. These findings suggest that podocyte loss and the consequent proliferation of parietal cells are common processes in the pathogenesis of DMS.

Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy.

Mutation of the Wilms tumor gene (WT1) is associated with two well-described syndromes called Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features. The known risk of Wilms tumor in DDS and gonadoblastoma (GB) in FS patients requires tumor surveillance. The literature reports the occurrence of GB in DDS as lower than FS. This case highlights a very early presentation of bilateral GB in DDS and the consideration of early prophylactic gonadectomy at the time of diagnosis with DDS.

The role of VEGF 165b in pathophysiology.

Anti-angiogenic vascular endothelial growth factor A (VEGF) 165b and pro-angiogenic VEGF 165 are generated from the same transcript, and their relative amounts are dependent on alternative splicing. The role of VEGF 165b has not been investigated in as much detail as VEGF 165, although it appears to be highly expressed in non-angiogenic tissues and, in contrast with VEGF 165, is downregulated in tumors and other pathologies associated with abnormal neovascularization such as diabetic retinopathy or Denys Drash syndrome. VEGF 165b inhibits VEGFR2 signaling by inducing differential phosphorylation, and it can be used to block angiogenesis in in vivo models of tumorigenesis and angiogenesis-related eye disease. Recent reports have identified three serine/arginine-rich proteins, SRSF1, SRSF2 and SRSF6, and studied their role in regulating terminal splice-site selection. Since the balance of VEGF isoforms is lost in cancer and angiogenesis-related conditions, control of VEGF splicing could also be used as a basis for therapy in these diseases.

Denys-Drash syndrome with neonatal renal failure in monozygotic twins due to c.1097G>A mutation in the WT1 gene.

Denys-Drash syndrome, characterized by nephrosis, dysgenetic gonads and a predisposition to Wilms tumor, is due to germline mutations in the WT1 gene. We report the pathologic findings on monozygotic twins, both of whom presented with male pseudohermaphroditism, nephrotic syndrome, and progressed to renal failure and death within the first month of life. Sequence analysis of WT1 demonstrated a G-to-A substitution in exon 8 of the gene (c.1097G > A), resulting in an arginine-to-histidine (R366H) substitution in the second zinc finger domain. To the best of our knowledge, this is only the second set of monozygotic twins with Denys-Drash syndrome reported to date.

Pathogenic role of TGF-ß in the progression of podocyte diseases.

In patients with progressive podocyte diseases, such as focal segmental glomerulosclerosis and membranous nephropathy, there is enhanced expression of transforming growth factor (TGF-ß) in podocytes. Biomechanical strain in these diseases may cause overexpression of TGF-ß and angiotensin II (Ang II) by podocytes. Oxidative stress induced by Ang II may activate the latent TGF-ß. Increased TGF-ß activity by podocytes may induce not only the thickening of the glomerular basement membrane (GBM), but also podocyte apoptosis and/or detachment from the GBM, initiating the development of glomerulosclerosis. Furthermore, mesangial matrix expansion frequently occurs in podocyte diseases in association with the development of glomerulosclerosis. This review examines open questions on the pathogenic role of TGF-ß that links podocyte injury to GBM thickening, podocyte loss, mesangial matrix expansion and glomerulosclerosis in podocyte diseases. It also describes paracrine regulatory mechanisms of podocyte TGF-ß on mesangial cells leading to increased matrix synthesis.

New insights into the function of the Wilms tumor suppressor gene WT1 in podocytes.

The Wilms tumor suppressor gene WT1 is essential for early urogenital development: homozygous mutations in WT1 result in embryonic lethality due to a failure in the development of kidneys and gonads. In the adult kidney, WT1 expression is limited to the glomerular podocytes. Several human nephrotic diseases arise from mutations of the WT1 gene, including mutations that affect its zinc-fingers and alternative splicing of +/- KTS isoforms. These include WAGR (for Wilms tumor, aniridia, genitourinary anomalies, and mental retardation), and Frasier and Denys-Drash syndromes. Recent advances including the development of transgenic mouse models and conditionally immortalized podocyte cell lines are beginning to shed light on WT1's crucial role in podocyte function.

Síndrome nefrótico idiopático en el niño / Primary nephrotic syndrome in children

El síndrome nefrótico idiopático (SNI) es responsable de más del 80% de los síndromes nefróticos en la infancia y de un 20-25% en los adultos. Aun cuando puede presentarse a cualquier edad es una enfermedad típicamente pediátrica cuya mayor frecuencia de aparición se sitúa entre los 2-6 años y con mayor incidencia en el genero masculino. Dentro del síndrome nefrótico infantil debemos considerar de forma diferencial el que aparece en el primer año de vida. Igualmente, en el momento actual, los conocimientos genéticos identifican otras formas (que excluiríamos de la denominación SNI) las formas genéticas, ligadas a daños estructurales de los podocitos. En pediatría se define síndrome nefrótico una proteinuria superior a 40 mg/m2/hora con albúmina plasmática inferior a 2,5 g/dl. La histología subyacente en el SNI es mayoritariamente las lesiones mínimas, 76,6% en el Estudio Internacional de Enfermedades Renales en el niño (ISKDC). Otras variantes histológicas menos frecuentes, son la glomerulonefritis segmentaria y focal y la glomerulonefritis mesangial difusa, sin depósitos o con depósitos focales o difusos de IgM, no reconocida universalmente como entidad diferenciada por ser considerada por algunas escuelas como una variante de las lesiones mínimas. En niños, el SNI se caracteriza por su buena respuesta al tratamiento, alta tendencia a las recidivas y buen pronóstico final sin deterioro de la función renal. Siendo el curso de la enfermedad habitualmente prolongado, con mayor o menor número de recaídas, la elección del esquema terapéutico con corticoides y/o inmunosupresores deben plantearse con unos objetivos básicos: 1) Inducción lo más rápidamente posible de la remisión. 2) Prevención de las recaídas y 3) Evitar la iatrogenia farmacológica inducida por la inmunosupresión. Los corticoides siguen siendo el tratamiento de elección sin que se haya esclarecido su mecanismo de acción. Los protocolos empleados son múltiples y los únicos con alta evidencia son: la respuesta a los corticoides y la respuesta a la ciclofosfamida o clorambucil para modificar la corticodependencia en los casos que evolucionan de esta forma. El tratamiento inicial del SNI será: Prednisona 60 mg/m2/día 4-6 semanas, seguido de prednisona 40 mg/m2/48 h durante 4-6 semanas con supresión progresiva en 6 semanas (tabla I). El tratamiento de la recaída: 60 mg/m2/día hasta la desaparición de la proteinuria (Albustix negativo o indicios) durante 5 días consecutivos, seguido de prednisona 40 mg/m2/48 h durante 4-6 semanas y supresión en 6 semanas (tabla II). El tratamiento del SNI corticodependiente o corticorresistente (definición en texto) se recoge en las figuras 1 y 2. 33 Ante la falta de niveles altos de evidencia en el tratamiento de estas formas evolutivas, el esquema propuesto es solo recomendado, pudiendo ser aceptables otras alternativas terapéuticas. Junto al tratamiento de base: corticoides y/o inmunosupresores, debemos considerar el tratamiento general: dieta normocalórica y normoproteica, adecuada a la edad. No profilaxis antibiótica. Administración de vacunas cumpliendo el calendario vacunal completo y vacunación de varicela, neumococo y gripe. Aporte de calcio y vit. D. El tratamiento del edema será la restricción de sodio, no de agua, administrando seroalbúmina solo en situaciones especiales como hipovolemia sintomática o edema incapacitante. Consideración específica debe tenerse a las formas genéticas: NPHS1, NPHS2 y WT1 y a los síndromes nefróticos de comienzo durante el primer año de vida, por ser distinto el planteamiento dado su resistencia al tratamiento. En el SNI del niño dado el predominio de lesiones mínimas y corticosensibilidad, no está indicado proceder a una biopsia renal al inicio de la enfermedad sino instaurar un tratamiento esteroideo, realizándose la biopsia con criterios distintos según grupos, aun cuando existe unanimidad en realizarla en el síndrome nefrótico corticorresistente, en los de comienzo dentro del primer año de vida y en los casos con datos clínicos y/o analíticos que sugieran ser formas secundarias a una enfermedad sistémica. Dentro del primer año de vida tienen su manifestación la mayor parte de las formas genéticas; destacando el síndrome nefrótico finlandés (SNF), la esclerosis mesangial difusa aislada o asociada a otras anomalías y las infrecuentes causas infecciosas, aunque también puede observarse histología de lesiones mínimas, mesangial o membranosa más raramente. Por último es de señalar la posibilidad de recidiva postrasplante en las formas corticorresistentes, específicamente la esclerosis segmentaria y focal, con alto índice de recidivas, oscilando en las distintas series entre 10-80%, de tratamiento difícil, sin nivel de evidencia, y repercusión negativa en la evolución del injerto. Algunas formas genéticas, síndrome nefrótico finlandés o esclerosis segmentaria y focal en su forma genética también puede mostrar recidiva postrasplante aunque con menor frecuencia

No disponible

Hydrothorax in a patient with Denys-Drash syndrome associated with a diaphragmatic defect.

The Wilms tumor suppressor gene, WT1, plays an important role in the development of the urogenital system and the gonads, and clinical syndromes associated with WT1 mutations, such as WAGR syndrome, Denys-Drash syndrome and Frasier syndrome, typically manifest as renal and genitourinary abnormalities. WT1 may also play an important role in the development of the diaphragm, and recently several papers have reported an association between WT1 mutations and diaphragmatic hernias. In addition, WT1 mutations were also detected in some patients with Meacham syndrome, a rare malformation syndrome comprising congenital diaphragmatic hernia, double vagina, sex reversal, and cardiac malformations. Here, we report a case of an infant with typical clinical features of Deny-Drash syndrome and a heterozygous missense mutation, Arg366His, in the WT1 gene, in whom a diaphragm defect was detected after starting peritoneal dialysis. Diaphragmatic defects are rare but may be considered as clinical manifestations of WT1 mutation syndromes. In addition, we suggest that WT1 abnormalities should be suspected in patients with chronic renal failure who develop hydrothorax after peritoneal dialysis, especially in those with genitourinary abnormalities.

Slow progressive FSGS associated with an F392L WT1 mutation.

Constitutional missense mutations in the WT1 gene are usually associated with the Denys-Drash syndrome, characterized by a rapid progressive nephropathy, male pseudohermaphroditism, and an increased risk for Wilms tumor. We report here a patient with scrotal hypospadias and a slow progressive nephropathy due to focal and segmental glomerulosclerosis. WT1 mutation analysis revealed a constitutional missense mutation in exon 9 resulting in an exchange F392L. This mutation has previously been reported by others in a patient with a similar mild course of nephropathy. In contrast, a mutation in the corresponding codon of exon 8 (F364L) was previously found by us in a patient with a very rapid progression to end-stage renal disease. Whether the position of a mutation may influence the course of the nephropathy must be evaluated in a larger patient cohort. The individual tumor risk for this alteration cannot be given at present because neither of the two patients has shown evidence of a Wilms tumor or a gonadoblastoma to date.

Embryonal hyperplasia of Bowman's capsular epithelium in patients with WT1 mutations.

Embryonal hyperplasia of Bowman's capsular epithelium (EHBCE) is a rare condition, observed in patients with end-stage renal disease when treated with long-term dialysis. Immunohistochemical studies have suggested that EHBCE originates from the visceral epithelium of the Bowman's capsule. Here we report two patients with WT1 missense mutations in exon 7, who received continuous ambulatory peritoneal dialysis and developed EHBCE without Wilms tumor. One patient showed manifestations of Denys-Drash syndrome (DDS), while the other patient exhibited rapid progress into end-stage renal disease, but no genitourinary anomaly. Recently, abnormal expression of WT1 and PAX2 was shown in the podocytes in diffuse mesangial sclerosis (DMS) associated with DDS and isolated DMS. We hypothesize that EHBCE is a reversion of Bowman's capsular epithelial cells to an earlier cell differentiation state, which has the characteristics of a progenitor cell of both Bowman's capsular epithelia and podocytes. Immunohistochemical analysis of WT1, PAX2, vimentin, cytokeratin, and epithelial membrane antigen was performed in the kidney specimens obtained at autopsy or surgery. Abnormal expression of WT1 and PAX2 in the EHBCE was observed in both patients, supporting our hypothesis. The nephropathy associated with constitutional WT1 mutations might therefore be associated with EHBCE.

A mutant form of the Wilms' tumor suppressor gene WT1 observed in Denys-Drash syndrome interferes with glomerular capillary development.

The Wilms' tumor suppressor gene WT1 encodes a zinc finger protein that is required for urogenital development. In the kidney, WT1 is most highly expressed in glomerular epithelial cells or podocytes, which are an essential component of the filtering system. Human subjects heterozygous for point mutations in the WT1 gene develop renal failure because of the formation of scar tissue within glomeruli. The relationship between WT1 expression in podocytes during development and glomerular scarring is not well understood. In this study, transgenic mice that expressed a mutant form of WT1 in podocytes were derived. The capillaries within transgenic glomeruli were dilated, indicating that WT1 might regulate the expression of growth factors that affect capillary development. Platelet endothelial cell adhesion molecule-1 expression was greatly reduced on glomerular endothelial cells of transgenic kidneys. These results suggest that WT1 controls the expression of growth factors that regulate glomerular capillary development and that abnormal capillary development might lead to glomerular disease.

A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X.

The gene WT1 is required for the normal development and function of the urogenital tract. Constitutional mutations are associated with familial Wilms tumor and syndromes such as Denys-Drash syndrome (DDS) characterized by nephropathy, genital anomalies and often a predisposition to Wilms tumor. We report a case of constitutional WT1 mutation in an XX female with multifocal Wilms tumor but no genital anomalies or renal dysfunction and, for the first time, review patients previously reported with this germline mutation. The mutation (1084C>T) changes the amino acid arginine at position 362 to the translation stop codon TGA (R362X) resulting in a predicted truncated protein lacking three of the four zinc finger domains necessary for correct functioning of the gene. This constitutional mutation has been reported to cause a variety of phenotypes in eleven different patients, including the classical Denys-Drash phenotype of diffuse mesangial sclerosis which leads to early renal failure, genital anomalies in XY individuals and Wilms tumors. The absence of mesangial sclerosis and renal failure in our patient excludes DDS. Our case differs from those previously described as the normal kidney tissue shows some small subcapsular glomeruli indicating that the WT1 mutation has impaired nephron development. This patient extends the range and variation of phenotypes that may arise from a specific germline mutation in WT1.