Familial Nephrotic Syndrome Research Articles

Three siblings with steroid-resistant nephrotic syndrome: New NPHS2 mutations in a Turkish family

Steroid-resistant nephrotic syndromes often are resistant to additional immunosuppressive agents and tend to progress to end-stage renal disease. Genetic studies in children with familial nephrotic syndrome have identified mutations in genes that encode important podocyte proteins. NPHS2 mutations are responsible for autosomal recessive familial focal segmental glomerulosclerosis (FSGS), and these mutations were detected in both familial and sporadic forms of FSGS. Interethnic differences were suggested to play a role in the incidence of these mutations. In this report, the cases of 3 siblings with steroid-resistant nephrotic syndrome who carry NPHS2 mutations (R238S and P118L) are presented.

Racial and ethnic differences in the incidence and progression of focal segmental glomerulosclerosis in children

Idiopathic focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome in pediatric and adult patients. Most children with FSGS do not respond to any form of therapy and progress to end-stage renal disease (ESRD). FSGS reoccurs in the transplanted kidney in approximately one third of initial transplants and in a substantially higher percentage of subsequent transplants once FSGS has recurred in an earlier transplant. Thus, FSGS is a disease with substantial morbidity. Over the past several years, the incidence of FSGS in adults and children appears to be increasing, particularly in certain racial groups and ethnic populations. Several recent studies in adult and pediatric patients suggest that the incidence of FSGS is increasing particularly in the black population. In addition, some studies have also demonstrated a more rapid progression of FSGS to ESRD in black patients compared to other ethnic groups. Racial and ethnic background is likely to have a substantial influence on the incidence and progression of FSGS in children and adults. It is likely that specific genes or a combination of genes influence the different clinical manifestations of FSGS in racial and ethnic groups. Genetic mutations in NPHS1 gene, which encodes nephrin, have been found to cause congenital nephrotic syndrome. Genetic mutations in the NPHS2 gene, which encodes podocin, recently have been shown to be strongly associated with a recessive form of steroid-resistant nephrotic syndrome. Mutations in the ACTN4 gene that encodes actinin 4 has also been associated with familial nephrotic syndrome. A role for ACE polymorphisms in the progression of FSGS has been found in some studies. Future investigations to identify polymorphisms that influence the development of FSGS, the progression of FSGS, and the response to therapy will greatly improve understanding of the pathogenesis and management of FSGS.

Podocyte differentiation and hereditary proteinuria/nephrotic syndromes.

The study of familial nephrotic syndromes (NS) and the analysis of murine models of glomerular diseases resulted in major progresses in the knowledge of podocyte physiology and pathology. Numerous proteins participating in the composition of the slit diaphragm region have been identified. The importance of several of them (nephrin, podocin, CD2AP, and Neph1) in the maintenance of the glomerular filtration barrier has been demonstrated by the occurrence of massive proteinuria when they are defective. The role of the cytoskeleton has been revealed by the development of proteinuria/NS in patients with ACTN4 mutation and the occurrence of early and severe NS in alpha-actinin-4-deficient mice. Given the genetic heterogeneity of familial NS and the many other genes to be identified, further insights in the molecular basis of the role of the podocyte in the maintenance of the glomerular filtration barrier may be expected in the near future.

Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome.

Autosomal recessive steroid-resistant nephrotic syndrome (SRINS) belongs to the heterogeneous group of familial nephrotic syndrome and represents a frequent cause of end-stage renal disease in childhood. This kidney disorder is characterized by early onset of proteinuria, progression to end-stage renal disease, and histologic findings of focal segmental glomerulosclerosis, minimal change nephrotic syndrome, or both. A causative gene, NPHS2, has been mapped to chromosome 1q25-q31 and was recently identified by positional cloning. This study reports five novel NPHS2 mutations: A284V, R196P, V290M, IVS4-1G-->T, and 460-467insT in 12 (46%) of 26 multiplex families and in 7 (28%) of 25 single patients with the clinical diagnosis of a SRINS. Because NPHS2 mutations were found in nearly 30% of these patients with "sporadic" SRINS, mutational analysis should also be performed in these patients. Besides better classification of the disease entity, identification of NPHS2 mutations may save some of these patients from unnecessary steroid treatment and also permit the prediction of absence of disease recurrence after kidney transplantation.

Familial nephrotic syndrome: Clinical spectrum and linkage to chromosome 19q13

Familial nephrotic syndrome (NS) has both autosomal dominant and recessive forms of inheritance. Recent studies in families with an autosomal dominant form of focal segmental glomerulosclerosis (FSGS) have been at odds concerning linkage to chromosome 19q13 (Mathis et al, Kidney Int 53:282-286, 1998; Winn et al, Kidney Int 55:1241-1246, 1999), suggesting genetic heterogeneity. This study examines the clinical features and confirms linkage to chromosome 19q13 in a family with autosomal dominant NS. DNA samples were obtained from 16 of 17 family members. Genomic DNA was isolated, and polymerase chain reaction was performed for five markers spanning the area of interest on chromosome 19q13. Data were evaluated using two- and six-point linkage analysis. Clinical features included presentation of NS in childhood, steroid unresponsiveness, and slow progression to renal failure. Renal biopsy in affected family members showed lesions ranging from minimal change to mesangial proliferative glomerulonephritis to FSGS. Linkage was confirmed between the disease state and chromosome 19q13, with a maximum logarithm of odds (LOD) score of 2.41. Linkage was observed for a 7 cM region on chromosome 19q13, defined by markers D19S425 and D19S220. This study confirms the Mathis et al report of linkage to chromosome 19q13 in a family with autosomal dominant NS. However, there were notable differences in the presenting clinical and histopathologic features of our affected family members compared with those of Mathis et al. This suggests that the gene on chromosome 19q13 may be responsible for considerable phenotypic heterogeneity and variable expression in both clinical presentation and renal histopathology.

Clinical and Genetic Features of Familial Nephrotic Syndromes

Clinical and Genetic Features of Familial Nephrotic Syndromes

Corticoresistant Nephrotic Syndrome Associated with T-Cell Deficiency in Two Sisters

The coexistence in two sisters, born to related parents, of a corticoresistant nephrotic syndrome, lymphopenia, an immune deficit, short stature, and photophobia is described. The immune deficit is mainly cellular; studies of lymphocyte markers demonstrate a pronounced deficiency of T lymphocytes and Fc-mu receptor-bearing cells. It is suggested that a thorough examination of number and function of T cells should be performed in patients with a familial corticoresistant nephrotic syndrome and recurrent infectious episodes before considering immunosuppressive treatment.

Familial nephrotic syndrome

Systematic pedigree information was obtained from 70 patients with idiopathic nephrotic syndrome; 16 patients were found to have familial nephrotic syndrome including 1 pair of affected monozygotic twins, 5 affected sibling pairs, 2 affected first cousins from a consanguineous family and 2 patients with sporadic cases from consanguineous families. Patients with familial and sporadic forms of the disease were compared by applying both clinical and histopathologic criteria. No significant differences were found between these groups, but both had a preponderance of males. In contrast to previous reports, the clinical course in the affected monozygotic twins was quite different, providing evidence for the importance of environmental influences on the course of this disease. Furthermore, in affected relatives neither the clinical course nor histopathologic classification was necessarily similar. The recurrence risk for siblings of patients with idiopathic nephrotic syndrome was 0.06. Several possible modes of inheritance were considered. Segregation analysis permitted the exclusion of simple recessive inheritance. The invariable concordance for the occurrence of nephrotic syndrome in both members of monozygotic twinships as well as the sex ratio renders a mixed model, with a small proportion of high risk recessive cases, equally unlikely. The available data are most consistent with a polygenic model which assumes a continuous distribution of disease liability with a discreet threshold effect.

Familial nephrotic syndrome with nephrocalcinosis and tubular dysfunction

Five children in two families, three boys in one family and two girls in another, had the onset of nephrotic syndrome in early infancy. The proteinuria and edema formation were not altered by steroid therapy. Growth retardation, renal osteodystrophy, and tetany appeared at an early age. Glycosuria, aminoaciduria, and renal tubular acidosis developed during the course of illness, and nephrocalcinosis was noted. A renal biopsy specimen from a child in each family showed glomerular proliferative changes, glomerular scarring, interstitial inflammation, and microcalcinosis, together with extensive tubular atrophy. Three of the five children have died so far, all at about 8 years of age. The similarity of the clinical course suggests that the children in each of these families has a distinct inherited disease, a form of familial nephrotic syndrome.