In severe forms of CNS, generalized edema, urinary protein > 20 g/L, and serum albumin level <10 g/L can be detected in the newborn period. The amount of proteinuria, however, varies in different entities, and the clinical signs may not be evident during the first weeks of life. Also, the true magnitude of proteinuria may be detectable only after partial correction of hypoproteinemia by albumin infusions. Small amounts of red blood cells and leucocytes are often present in urine. Serum creatinine and urea levels are variable. Renal function remains quite normal for the first months in NPHS1, but in other forms, kidney failure may develop faster. Blood pressure values can be low due to hypoproteinemia or elevated if renal failure is already present.
In newborns, the placental weight >25% of birth weight is present in NPHS1 but may be seen in other forms of CNS [14
]. The kidneys may be of normal size or larger than normal in ultrasound scanning, and the renal cortex is often hyperechogenic. Search for possible nonrenal malformations is important, especially since they may give clues to the etiologic diagnosis. These include genital abnormalities (WT1), eye defects (LAMB2), and neurological disorders (Mowat–Galloway). Cardiac evaluation often reveals ventricular hypertrophy but no structural defects.
Renal biopsy does not reveal the etiology of CNS. As pointed out, the genetic defects may cause several types of glomerular lesions, such as mesangial expansion, FSGS, MCNS, and DMS, and the findings overlap in different entities. Also, the nonglomerular findings, such as tubular dilatations and interstitial fibrosis and inflammation, can be seen in all forms of proteinuric diseases. Thus, the indications for renal biopsy are not quite clear. The knowledge of severity of glomerular sclerosis and interstitial fibrosis may help in the assessment of treatment strategies. On the other hand, the lesions are focal, and the biopsy findings may be misleading. If immunohistochemistry for nephrin and podocin is available, analysis of their expression in a biopsy sample is useful. Total lack of either protein speaks for a severe disorder not responding to antiproteinuric therapy.
Genetic analysis is the method of choice for precise CNS diagnosis. The knowledge of etiology helps in assessing management and prognosis, in follow-up for possible associated symptoms, and in genetic counseling of the family. Analysis of NPHS1
mutations is warranted in all CNS patients. These analyses are commercially available in Athena Diagnostics (www.athenadiagnostics.com
). If no mutations are detected in these genes or if clinical findings speak for mutations in WT1
gene, analysis of these genes can be obtained at research laboratories.
Prenatal diagnosis in families with a known risk for CNS should be based on genetic testing whenever possible. The results can be obtained fast if the mutations are known in advance. In case of no family history or if the mutations in the affected child were not identified, prenatal genetic testing is a challenge, since sequencing the NPHS1
(29 exons) and NPHS2
(eight exons) genes is time consuming and usually not possible within the short time frame available. NPHS1 especially can still be suspected prenatally based on elevated alpha-fetoprotein (AFP) levels in maternal serum and amniotic fluid. If the AFP concentration in amniotic fluid is very high and the ultrasound examination does not reveal fetal anencephaly or other malformations, NPHS1 is a probable diagnosis. However, heterozygous fetal carriers of NPHS1
gene mutations may have temporarily elevated AFP levels in amniotic fluid and maternal serum, and repeated measurement of amniotic fluid AFP before the 20th week of pregnancy is recommended in cases with high AFP levels [35