Kidney nontumor
Glomerular disease
Inherited glomerular disease
Congenital nephrotic syndrome


Topic Completed: 8 June 2021

Minor changes: 8 June 2021

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PubMed Search: Congenital nephrotic syndrome [title] "loattrfree full text"[sb]

See also: Diffuse mesangial sclerosis, Finnish type

Chunlai Zuo, M.D., M.S.
Jonathan E. Zuckerman, M.D., Ph.D.
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Cite this page: Zuo C, Zuckerman JE. Congenital nephrotic syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneycongenitalnephroticsyndrome.html. Accessed June 20th, 2021.
Definition / general
  • Congenital nephrotic syndrome caused by nephrin (NPHS1) mutations
Essential features
  • Excessive proteinuria starting within the first 3 months of life; patients typically develop end stage renal disease by early childhood
  • Dysfunction of glomerular filtration barrier due to absent or mutant nephrin
  • No response to immunosuppressive medication
Terminology
  • Finnish nephropathy
  • Congenital nephrotic syndrome of the Finnish type (CNF)
  • Congenital nephrotic syndrome (CNS) type I
ICD coding
  • ICD-10: N04.9 - nephrotic syndrome with unspecified morphologic changes
Epidemiology
Sites
  • Glomerular filtration barrier: podocyte layer and slit diaphragms
Etiology
  • Nephrin is coded by NPHS1, which is located at the long arm of chromosome 19 (19q13.1) (Mol Cell 1998;1:575)
  • Nephrin is a transmembrane protein of the podocyte foot processes and is a main structural protein of the glomerular slit diaphragm
  • Absence or dysfunction of nephrin results in nonfunction or dysfunction of the glomerular slit diaphragm; proteins pass the glomerular filtration barrier easily, massive proteinuria results
Diagrams / tables

Images hosted on other servers:
Normal glomerular capillary and capillary wall

Normal glomerular capillary and capillary wall

Clinical features
  • Heavy proteinuria, hypoproteinemia and edema starting soon after birth (Pediatr Nephrol 1995;9:87)
  • Increased maternal serum and amniotic fluid alpha fetoprotein in some cases
Diagnosis
  • Massive fluid retention and generalized swelling, hypertension and signs of malnutrition and failure to thrive
  • Large amounts of protein and the presence of fat in the urine
  • Kidney biopsy
  • Genetic tests to confirm the diagnosis (Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019;36:1022)
Laboratory
  • Elevated plasma alpha fetoprotein (AFP) level in the mother
  • Proteinuria, hypoalbuminemia or hypogammaglobulinemia
Radiology description
  • Enlarged, hyperechogenic kidneys without normal corticomedullary differentiation
  • Microcystic changes
Radiology images

Images hosted on other servers:
Enlarged and hyperechogenic kidneys by ultrasound Enlarged and hyperechogenic kidneys by ultrasound

Enlarged and hyperechogenic kidneys by ultrasound

Prognostic factors
  • Unfavorable
  • Typically develop end stage renal disease between ages 2 and 8
Case reports
Treatment
  • Supportive therapy: albumin infusion, gamma globulin replacement, high protein low salt diet, vitamin and thyroxine substitution and infections and thrombotic complications prevention
  • Diuretic medications
  • Angiotensin converting enzyme (ACE) inhibitor medications and nonsteroidal anti-inflammatory drugs
  • Dialysis
  • Kidney transplant (patient weight should be > 8 kg):
    • About 20% of patients develop recurrent nephrotic syndrome in the transplanted kidney due to antinephrin antibodies (Transplantation 2007;83:1316)
    • Circulating antinephrin antibodies can be detected
    • Plasmapheresis combined with anti-CD20 antibodies and cyclophosphamide may be used to treat recurrent nephrotic syndrome (Pediatr Nephrol 2014;29:2309)
Gross description
  • Enlarged kidneys
Gross images

Contributed by Chunlai Zuo, M.D., M.S.
Enlarged pale kidney

Enlarged pale kidney

Microscopic (histologic) description
  • Cystically dilated proximal and distal tubes with an attenuated tubular epithelium, microcytic changes (Int J Pediatr Nephrol 1980;1:10)
  • May be minimal glomerular changes in early disease
  • With disease progression may see mesangial hypercellularity, increased mesangial matrix
  • Rare immature glomeruli often present
  • Focal segmental glomerulosclerosis (FSGS) or global glomerulosclerosis (Int J Pediatr Nephrol 1980;1:10)
  • Interstitial fibrosis and tubular atrophy with progressive disease
Microscopic (histologic) images

Contributed by Chunlai Zuo, M.D., M.S. and Jonathan E. Zuckerman, M.D., Ph.D.
Mesangial hypercellularity

Mesangial hypercellularity

Segmental glomerulosclerosis

Segmental glomerulosclerosis

Dilated proximal and distal tubes Dilated proximal and distal tubes

Dilated proximal and distal tubes

Cystic change and interstitial fibrosis

Cystic change and interstitial fibrosis

Immunofluorescence description
  • Generally negative
  • Segmental glomerulosclerosis lesions may exhibit segmental smudgy staining for IgM, C1q and C3 due to nonspecific trapping
  • Other findings may include increased tubular protein reabsorption droplet staining with albumin
Positive stains
  • Podocin
Negative stains
  • Nephrin stain negative with frame shift or truncating mutations
  • Sometimes detected with point mutations of nephrin
Electron microscopy description
  • Complete podocyte foot process effacement (Kidney Int 2000;58:972)
  • Microvillus transformation of podocytes
  • No slit diaphragms
  • Various sized filtration slits
  • Increased mesangial cellularity
  • Swelling of endothelial cells and endothelial blebs
  • Normal fenestrations and normal glomerular basement membrane
Electron microscopy images

Contributed by Jonathan E. Zuckerman, M.D., Ph.D.
Diffuse foot processes effacement Diffuse foot processes effacement

Diffuse foot processes effacement

Loss of slit diaphrams Loss of slit diaphrams

Loss of slit diaphrams


Mesangial hypercellularity

Mesangial hypercellularity

Endothelial cell blebs Endothelial cell blebs

Endothelial cell blebs

Molecular / cytogenetics description
  • Autosomal recessive disease
  • Homozygous mutation in NPHS1
    • Located at chromosome 19q13.1 (Am J Hum Genet 1994;54:757, Am J Hum Genet 1995;57:1377)
    • 29 exon gene, encodes protein nephrin
      • Transmembrane protein, immunoglobulin superfamily containing 1241 amino acids with 8 extracellular C2 type Ig-like domains and 1 fibronectin type III-like module (Mol Cell 1998;1:575)
      • Essential component of interpodocyte spanning slit diaphragm (Proc Natl Acad Sci U S A 1999;96:7962)
    • 2 most common mutations (Fin-major and Fin-minor) found in the affected Finnsh population:
      • Fin-major (nt-121delCT, L41fsX91) (Mol Cell 1998;1:575)
        • Frameshift mutation causing a stop codon in exon 2 results in a 90 amino acid truncated nephrin
        • Complete loss of nephrin
      • Fin-minor (c.3325 C>T, R1109X) (Mol Cell 1998;1:575)
        • Nonsense mutations in exon 26
        • Leading to a truncated 1109 residual nephrin
  • > 250 mutations of NPHS1 in non Finnish populations
    • Involving entire NPHS1
    • Including insertions, deletions, nonsense mutations and missense mutations
  • Heterozygous NPHS1 mutations uncommon
    • May present as adult onset focal segmental glomerulosclerosis
  • Heterozygotes with 1 normal NPHS1 allele
    • Transient deficiency of nephrin in utero
    • False positive alpha fetoprotein test in amniotic fluid and maternal serum may happen
    • Normal after birth
Sample pathology report
  • Kidney, right, total nephrectomy:
    • End stage kidney consistent with history of congenital nephrotic syndrome, type 1 (NPHS1 mutation) (see comment)
    • Comment: Histologic sections of the renal parenchyma are examined with H&E, periodic acid-Schiff, stained sections. Sections consist of renal cortex, medulla common and collecting system. Cortical structures exhibit normal developmental orientation and generation of glomeruli. Glomeruli are mildly enlarged and display variable mild mesangial hypercellularity. Focal segmental glomerulosclerosis is present. A few glomeruli exhibit embryonal hyperplasia / metaplasia of Bowman capsule epithelium. Prominent cystically dilated proximal and distal tubules with an attenuated epithelium are present. There is extensive interstitial fibrosis associated with patchy and focally heavy interstitial inflammation (mainly lymphocytes) as well as scattered lymphoid follicles.
Differential diagnosis
  • Minimal change disease:
    • Primary (idiopathic) disease frequently in children, secondary to drugs, allergic reactions, immunologic diseases and neoplasia at all ages
    • Minimal or no light microscopic or immunofluorescence abnormalities
    • Diffuse podocyte foot process effacement by electron microscopy (J Exp Med 1957;106:649)
    • Decreased nephrin staining along glomerular basement membrane due to loss of slit diaphragms; loss of nephrin is seen in advanced stages
    • Decreased podocyte α dystroglycan
    • Genetic studies negative
    • Usually steroid responsive
  • Primary focal and segmental glomerulosclerosis:
    • Common cause of nephrotic syndrome in children and adults (15 - 20% of biopsies) (Nephrol Dial Transplant 1999;14:68)
    • Affects juxtamedullary glomeruli early
    • Segmental scars in some glomeruli and adhesion of tuft to Bowman capsule
    • Extensive podocyte foot process effacement by electron microscopy
    • IgM and C3 in segmental scars by immunofluorescence
    • May be steroid responsive
    • Genetic studies negative
  • NPHS2 related nephrotic syndrome:
    • No distinctive feature described by light microscopy: focal segmental glomerulosclerosis (50%) and minimal changes (50%) (Pediatr Nephrol 2009;24:2121)
    • Loss of podocin immunoreactivity (podocin deficiency)
    • Effacement of podocyte foot processes and segmental adhesion by electron microscopy
    • Genetic studies required to differentiation from NPHS1 mutations
  • Secondary congenital nephrotic syndrome:
    • Infectious causes, such as in utero infection (rubella, pertussis, syphilis, malaria toxoplasmosis and others) (Clin Pediatr (Phila) 2005;44:169)
    • Others: drug reaction, toxins and systemic lupus erythematosus
Board review style question #1


Which of the following is the most commonly mutated gene associated with congenital nephrotic syndrome?

  1. LAMB2
  2. Nephrin (NPHS1)
  3. PLCE1
  4. Podocin (NPHS2)
  5. WT1
Board review style answer #1
Board review style question #2
A 2 month old baby presents with renal abnormality and NPSH1 mutation. Which of the following is the most common clinical presentation?

  1. Allergic reaction
  2. Heart failure
  3. Nephritic syndrome
  4. Nephrotic syndrome
  5. Weight loss
Board review style answer #2
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