Congenital and infantile nephrotic syndrome

Congenital and infantile nephrotic syndrome

Apr 5, 2001

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Patrick Niaudet, MD

The term congenital nephrotic syndrome refers to disease which is present at birth or within the three first months of life. Later onset, between three months and one year of age, is called infantile nephrotic syndrome. Most of these children have a genetic basis for the renal disease and a poor outcome. The precise diagnosis of the glomerular lesion is based on clinical, laboratory and histological criteria. The congenital nephrotic syndrome of Finnish type (CNF) and diffuse mesangial sclerosis are the two main causes. There are, however, rare secondary and possibly curable disorders, such as congenital nephrotic syndrome induced by syphilis or toxoplasmosis (show table).

CONGENITAL NEPHROTIC SYNDROME OF FINNISH TYPE – CNF is most frequent in Finland, with initial studies suggesting an incidence of 1.2 per 10,000 births [1,2]. With prenatal screening, the incidence has fallen to 0.9 per 10,000 births [3]. CNF has also been described in various ethnic groups throughout the world [4-6].

CNF is inherited as an autosomal recessive trait, with both sexes being involved equally. There are no manifestations of the disease in heterozygous individuals.

Pathology – Light microscopic studies of renal biopsy specimens obtained early in the course of the disease show mild mesangial hypercellularity and increased mesangial matrix in the glomeruli [4,7]. No immune deposits are detected by immunofluorescence studies. Over time, there is an increase in mesangial matrix accompanied by progressive glomerulosclerosis.

Tubulointerstitial changes are also prominent in CNF. Irregular microcystic dilatation of proximal tubules is the most striking feature; however, this change is not specific and is not seen in all patients [8]. Later in the course, interstitial fibrosis, lymphocytic and plasma cell infiltration, tubular atrophy, and periglomerular fibrosis develop in parallel with sclerosis of the glomeruli.

Pathogenesis – It has been proposed that proteinuria in CNF results from an inherited error in the structure of the glomerular capillary filter. The abnormal gene was localized to the long arm of chromosome 19 in both Finnish and non-Finnish families [9-11].

The defective gene in CNF has been cloned [12]. The gene encodes for a transmembrane protein, named nephrin, which is a member of the immunoglobulin family of cell adhesion molecules. Nephrin is specifically located at the slit diaphragm of the glomerular podocytes; this could explain the absence of slit diaphragms and foot processes in patients with CNF who have a mutant nephrin protein [13,14].

In the original report, four different mutations in this gene were found to segregate with the disorder in affected Finnish families [12]; however, the two most common mutations, Fin-major and Fin-minor, account for nearly 90 percent of all affected Finnish patients [12,15]. In another study, 32 novel mutations in the nephrin gene were discovered in patients elsewhere in Europe and North America, but no abnormalities were found in seven affected individuals (including the 5' flanking region) [16]. These patients may have mutations elsewhere in the promoter, in intron areas, or in a gene encoding another protein that interacts with nephrin [17]. These results may indicate genetic heterogeneity in the disease.

Clinical features – Most infants with the CNF are born prematurely (35 to 38 weeks), with a low birth weight for gestational age. The placenta is enlarged, being more than 25 percent of the total birth weight. Fetal distress is common and the cranial sutures are widely separated due to delayed ossification. Infants often have a small nose and low ears. Flexion deformities of the hips, knees, and elbows are thought to be secondary to the large placenta.

Edema is present at birth or appears during the first week of life in one-half of cases. Severe nephrotic syndrome with marked ascites is always present by three months. The proteinuria is highly selective early in the course of the disease and hematuria is uncommon, reflecting the lack of inflammation in the glomeruli. The urinary protein losses are accompanied by profound hypoalbuminemia and severe hypogammaglobulinemia due in part to loss of selectivity as the disease progresses. As a result of these changes, nutritional status and statural growth are poor, and affected infants are highly susceptible to bacterial infections (peritonitis, respiratory infections) and to thromboembolic complications due to the severity of the nephrotic syndrome. (See "Renal vein thrombosis and other thromboemboli in nephrotic syndrome"). Hypothyroidism due to urinary losses of thyroxine-binding proteins is also common.

The blood urea nitrogen and creatinine concentrations are initially normal. Renal ultrasonography shows enlarged, hyperechogenic kidneys without normal corticomedullary differentiation.

End-stage renal failure invariably occurs between three and eight years of age. Prolonged survival is possible with aggressive supportive treatment, including dialysis and renal transplantation.

Treatment – The nephrotic syndrome in CNF is always resistant to corticosteroids and immunosuppressive drugs, since this is not an immunologic disease. Furthermore these drugs may be harmful due to the already high susceptibility to infection. A retrospective study of 21 infants with CNF, for example, found that 63 verified and 62 suspected septic episodes occurred over a mean followup period of one year [18].

Standard conservative treatment includes daily or every other day albumin infusion, gamma globulin replacement, nutrition with a high-protein, low-salt diet, vitamin and thyroxine substitution, and prevention of infections and thrombotic complications. The diet is provided by tube feeding or by parenteral alimentation.

However, the rate of intercurrent complications remains high and growth and development are usually retarded. As a result, some patients may require bilateral nephrectomy to prevent continued massive protein losses before the development of renal failure. Dialysis is then performed until the patient reaches a weight of 8 to 9 kg. At this stage, renal transplantation can be considered [19,20]. No recurrence of the nephrotic syndrome has been observed after transplantation.

A possible medical alternative to nephrectomy has been described in two children. The combination of an angiotensin converting enzyme inhibitor and indomethacin therapy, both of which should lower intraglomerular pressure, led to a marked fall in protein excretion and striking improvement in nutritional status and growth [21].

Antenatal diagnosis – The CNF becomes manifest during early fetal life, beginning at the gestation age of 15 to 16 weeks. The initial symptom is fetal proteinuria, which leads to a more than 10-fold increase in the amniotic fluid alpha-fetoprotein (AFP) concentration. A parallel, but less important increase in the maternal plasma AFP level is observed. These changes are not specific, but they permit the antenatal diagnosis of CNF in high risk families in which termination of the pregnancy might be considered [22]. Measurement of maternal plasma AFP levels is currently the only method available for general screening. However, false positive results do occur, often leading to abortion of healthy fetuses. Preliminary studies suggest that genetic linkage and haplotype analyses may diminish the risk of false positive results in informative families [23]. The four major haplotypes, which cover 90 percent of the CNF alleles in Finland, have been identified, resulting in a test with up to 95 percent accuracy. The recent identification of the gene responsible for the congenital nephrotic syndrome will soon permit antenatal diagnosis of the disease.

DIFFUSE MESANGIAL SCLEROSIS – Diffuse mesangial sclerosis is a second hereditary cause of infantile nephrotic syndrome associated with glomerular injury and rapid progression to end-stage renal failure. The same glomerular lesions are observed in the Drash syndrome which is characterized by the combination of nephropathy, male pseudohermaphroditism, and Wilms' tumor.

Diffuse mesangial sclerosis is seen exclusively in infancy [4,24-28] and appears to be transmitted in some families as an autosomal recessive trait [29]. The defective gene has not been identified.

Pathology – The glomerular lesions are characterized in the early stages by a fibrillar increase in mesangial matrix without mesangial cell proliferation [27-29]. The capillary walls are lined by hypertrophied podocytes. The fully developed lesion consists of the combination of thickening of the glomerular basement membranes and massive enlargement of mesangial areas, leading to reduction of the capillary lumens. The mesangial sclerosis eventually contracts the glomerular tuft into a sclerotic mass within a dilated urinary space. There is usually a corticomedullary gradient of involvement, with the deepest glomeruli being less affected. Tubules are severely damaged, especially in the deeper cortex where they are markedly dilated and often contain hyaline casts.

Electron microscopy reveals hypertrophic mesangial cells surrounded by an abundant mesangial matrix which often contains collagen fibrils. The podocytes are hypertrophied and contain many vacuoles. There is also irregular effacement of foot processes with focal detachment of the epithelial cell from the glomerular basement membrane.

Immunofluorescence shows mesangial deposits of IgM, C3, and C1q in the least affected glomeruli, while deposits of IgM and C3 outline the periphery of the sclerosed glomeruli. These immune deposits are probably nonspecific, occurring in areas of previous injury.

The same glomerular lesion is observed in the Drash syndrome (see below). As a result, all patients with diffuse mesangial sclerosis should be screened for the Drash syndrome. This consists of karyotyping in phenotypic females, looking for male pseudohermaphroditism with a 46 XY genotype, and ultrasonography should be performed in all patients, looking for Wilms' tumor and abnormal gonadal development. Some investigators also suggest that an assessment for mutations in the Wilms' tumor predisposing gene, WT1, should be performed to help identify individuals at risk for the tumor (see below) [30,31]. As an example, among 10 patients presenting with isolated diffuse mesangial sclerosis, four had mutations in the WT1 gene [31].

Pathogenesis – The pathogenesis of the isolated form of diffuse mesangial sclerosis is unknown. A primary defect involving the epithelial cell or one of the components of the glomerular extracellular matrix has been proposed.

Clinical and laboratory features – As opposed to the CNF, children with diffuse mesangial sclerosis appear normal at birth, with a normal birth weight and without placental enlargement. The nephrotic syndrome may be present at birth or even suspected in utero by the finding of an elevated plasma alpha-fetoprotein level in the mother or the discovery of large hyperechogenic kidneys [32]. More commonly, however, proteinuria with a bland urine sediment develops postnatally, increasing progressively during the first or the second year of life. Various types of extrarenal signs have been reported in isolated patients including nystagmus, cataract, mental retardation, microcephaly, severe myopia, muscular dystrophy.

All children progress to end-stage renal failure, frequently in association with hypertension. This usually occurs before age three, within a few months after the discovery of renal symptoms [28].

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Treatment – Diffuse mesangial sclerosis is resistant to corticosteroids and immunosuppressive drugs. The degree of proteinuria it typically less severe than in the CNF and specific supplemental therapy is usually not required.

Treatment is supportive and consists of maintenance of electrolyte and water balance and adequate nutrition, prevention and treatment of infectious complications, and management of renal failure. Bilateral nephrectomy has been considered at the time of transplantation because of the theoretical risk of developing a Wilms' tumor. This issue remains unresolved, although Habib found no Wilms' tumor in the kidneys from 14 children with renal failure [28]. Recurrent disease does not develop in the transplant.

DIFFUSE MESANGIAL SCLEROSIS WITH DRASH SYNDROME – Denys and Drash first reported the triad of progressive renal disease, male pseudohermaphroditism, and Wilms' tumor [33,34]. All of the patients were infants with heavy proteinuria progressing rapidly to renal failure. Incomplete forms of the syndrome were described and the glomerulopathy was identified as diffuse mesangial sclerosis [35].
Epidemiology and genetics – More than 60 cases of Drash syndrome have currently been reported [33-37]. The Drash syndrome is usually sporadic, although occurrence in two kindreds has been reported. However, constitutional mutations occur in the Wilms' tumor predisposing gene, WT1 [38].
Wilms' tumor is an embryonic kidney tumor thought to arise from aberrant mesenchymal stem cell differentiation secondary to the loss of a tumor suppressor gene or genes [39,40]. The WT1 gene lies at chromosomal position 11p13; it appears to encode a zinc finger protein which is probably a transcription factor [41-44]. WT1 is also expressed in the gonads, suggesting that the genital abnormalities in the Drash syndrome may result from pleiotropic effects of mutations in the WT1 gene itself. This hypothesis was first confirmed in a report which identified constitutional heterozygous mutations within the WT1 gene in some individuals with the Drash syndrome [45].

Subsequently, mutations of WT1 have been found in most patients with this syndrome. Most abnormalities are missense changes either in exon 9, which encodes for zinc finger 3 (with a mutational hot spot at an arginine residue thought to interact with the consensus DNA sequence), or in exon 8 which encodes for zinc finger 2 [46].

Clinical presentation – Diffuse mesangial sclerosis is a constant feature of the Drash syndrome. It is associated with the two other components of the triad in the complete form, but with only one of the two in the incomplete forms.
The clinical course of the nephropathy is not different from that described above in isolated diffuse mesangial sclerosis. However, Wilms' tumor may be the first clinical manifestation of the syndrome. Thus, careful renal ultrasonography should be performed, looking for nephroblastoma, in any patient found to have diffuse mesangial sclerosis. The tumor may be unilateral or bilateral and is associated in a few cases with nodules of nephroblastomatosis [29,38].

Male pseudohermaphroditism, characterized by ambiguous genitalia or female phenotype with dysgenetic testis or streak gonads, is observed in all 46 XY patients. In contrast, all 46 XX children appear to have a normal female phenotype, with normal ovaries, when the information was available. The finding of a normal male phenotype seems to exclude the diagnosis of Drash syndrome.

IDIOPATHIC NEPHROTIC SYNDROME – Idiopathic nephrosis rarely occurs at birth, more commonly presenting during the first year of life. All the morphological variants of idiopathic nephrotic syndrome seen in older children can occur at this time including minimal change disease, diffuse mesangial proliferation, and focal and segmental glomerular sclerosis.
Establishing the diagnosis of one of these disorders may be important clinically, since steroid-responsiveness with a favorable course can be seen [6,47]. However, most affected infants are resistant to therapy and many progress to end-stage renal disease.

Such cases are often familial and an autosomal recessive mode of inheritance has been observed. The causative gene for the autosomal recessive form of this disorder has been identified using a positional cloning technique directed at the chromosomal area 1q25-31 [48]. It encodes a newly described integral membrane protein, podocin, which is found exclusively in glomerular podocytes. (See "Causes of focal glomerulosclerosis", section on Familial disease).

OTHER – A number of other disorders are infrequent causes of infantile nephrotic syndrome:
• Congenital syphilis can cause membranous nephropathy [49,50]. Histological examination often shows a mixed pattern with membranous nephropathy and mesangial proliferation. Penicillin treatment leads to the resolution of the syphilis and the renal abnormalities.

• The nephrotic syndrome may be induced by congenital toxoplasmosis [51]. Proteinuria may be present at birth or may develop during the first three months, in association with ocular or neurological symptoms. Histological examination often shows mesangial proliferation with or without focal glomerulosclerosis. Treatment of toxoplasmosis or steroid therapy usually leads to remission of the proteinuria.

• Congenital or infantile nephrotic syndrome has been reported in association with cytomegalovirus, rubeola virus, human immunodeficiency virus, and mercury intoxication.

• The Galloway syndrome is characterized by microcephaly, mental retardation, hiatus hernia, and the nephrotic syndrome [52]. It appears to be transmitted as an autosomal recessive trait. The nephrotic syndrome is usually severe, resistant to steroid therapy and present from the first days of life. Renal biopsy reveals focal and segmental glomerulosclerosis. The underlying defect is not known.

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عدد الرسائل : 14 تاريخ التسجيل : 27/09/2008

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