Not all in the family: mutations of podocin in sporadic steroid-resistant nephrotic syndrome.

The causes of familial nephrotic syndromes are varied and diverse. Although phenotypic differences are seen with distinct congenital and adult forms, renal pathology tends to be less well defined, with blurring and overlap of diagnoses. Clinically, symptoms of the familial nephrotic syndromes may appear from birth to late in life, which demonstrates the heterogeneity of these diseases. The disease may be mild or severe, such that there is variable progression to end-stage renal disease (ESRD) (1–3). Pathologic diagnoses associated with familial nephrotic syndromes include minimal changetype lesions, mesangial sclerosis, and focal segmental glomerulosclerosis (FSGS) (4,5). Treatment depends on the specific disease state, ranging from bilateral nephrectomy and transplantation directly after birth in Finnish nephropathy (6) to attempts at more traditional treatment with steroid therapy. Of particular interest is whether the disease recurs after transplantation, which would direct one to systemic pathogenetic mechanisms. The genetic bases for several forms of congenital nephrotic syndrome have been recently solved. The commonality among known causes of familial nephrotic syndromes is the underlying pathophysiology that is associated with increased glomerular permeability due to defects of some feature of podocyte biology (7–10). Although the implications of these genetic discoveries in these rare inherited disorders to more common forms of nephrotic syndrome have been questioned, the article by Karle et al. in this issue suggests common genetic mechanisms and pathophysiology between inherited and sporadic forms of steroid-resistant nephritic syndrome. The classical syndrome of steroid-resistant congenital nephrotic syndrome (chromosome 1q) is inherited in an autosomal recessive fashion with an age of onset between 3 mo and 5 yr (11). Progression to ESRD is usually rapid, and pathology is characterized initially by minimal glomerular changes early and FSGS later in the course of disease. The disease does not recur after transplantation. The causative gene was recently identified by Boute et al (9). The gene, named podocin or NPHS2, is solely expressed in podocytes and is an integral membrane protein that belongs to the stomatin protein family. Members of this family are known to interact with ion channels and may be involved with protein trafficking (12). Recently an adult form of autosomal recessive FSGS has been linked to this region (13). The article by Karle et al. (14) describes novel mutations of NPHS2 in steroid-resistant congenital nephrotic syndrome and provides first-time evidence for mutations in NPHS2 in sporadic disease. These findings bear out a frequently held assumption that genetic studies of rare familial diseases will provide insight into the pathogenesis of that disease and the mechanism of the more common sporadic forms of that same disease. The patients described by Karle et al. appear to differ phenotypically from the original description of families with steroid-resistant idiopathic nephrotic syndrome. For example, these individuals present much later in life (1 to 24 yr of age). They also exhibit a recurring theme that has emerged from studies of congenital nephropathies: phenotypic heterogeneity but genetic similarity. Although the original steroid-resistant idiopathic nephrotic syndrome was described as an autosomal recessive disease, mutations found in eight of the families were heterozygous, implying an autosomal dominant mode of inheritance. Nonetheless, three of the families appear to have an autosomal recessive pattern of inheritance even though they have heterozygous mutations. This might be explained if these patients were compound heterozygotes, as such, inheriting a different mutation from each parent. This study also supports the hypothesis that minimal change disease and FSGS are different points on the same disease spectrum. In the study, patients with the same genetic defect exhibited a range of pathologies from minimal change to FSGS. This also highlights the issue of whether FSGS is just the generic result of a cascade of events or the primary event. For example, some have suggested that long-standing proteinuria may contribute to the transformation of minimal change disease to FSGS (15). In support of this view are studies showing that the administration of large amounts of albumin to rats causes glomerulosclerosis, tubular injury, and interstitial fibrosis (16). Similarly, in a study by Ahmad and Tejani (17) of 49 patients who over a 10-yr period had repeat renal biopsies, over 50% of the renal disease in these patients evolved into FSGS. These findings raise additional issues that are related to the diagnosis and therapy of idiopathic nephrotic syndrome (INS). If genetic studies of patients with INS reveal NPHS2 mutations, should these patients be treated with corticosteroids or immunosuppressive therapy? To decide this issue, it must be shown that people with INS who are steroid-responsive do not have NPHS2 mutations. It is also reasonable to question Correspondence to: Dr. Michelle P. Winn, Duke University Medical Center, Division of Nephrology, Box 2903, Durham, NC 27710. Phone: 919-6600038; Fax: 919-970-5813; E-mail: [email protected]