Kidney nontumor / medical renal

• Exact prevalence of Alport syndrome is unknown, although it is frequently reported as ranging from 1 in 5,000 in the United States to 1 in 50,000 in Europe; predicted pathogenic COL4A3 - COL4A5 variants show a much higher frequency, suggesting that other genetic and environmental factors mitigate the clinical manifestation of the disease (Kidney Med 2023;5:100631, J Am Soc Nephrol 2021;32:2273)
• X linked Alport syndrome accounts for up to 80% of Alport syndrome cases
• Autosomal recessive Alport syndrome is estimated at 15% of cases
• Autosomal dominant Alport syndrome accounts for 20% of cases (Clin Kidney J 2020;13:1025)
• Digenic inheritance is rare
• Thin basement membrane disease is the most common cause of persistent hematuria in children and affects at least 1% of the population

• Glomerular basement membrane contains 5 isoforms of collagen IV (α1, α2, α3, α4, α5) encoded by genes COL4A1, COL4A2, COL4A3, COL4A4 and COL4A5, providing tensile strength to the glomerular basement membrane and serving as scaffold for assembly of other proteins
• Immature glomerular basement membrane contains isoforms α1 and α2 only, produced by both podocytes and endothelial cells
• At the capillary loop stage of development, the α1α1α2 network is replaced by the α3α4α5 network
  • The latter provides greater strength to resist the intracapillary hemodynamic pressure increasing with age
  • Collagen IV α3, α4 and α5 isoforms are produced by the podocytes only and form the thicker subepithelial network, whereas collagen IV α1 and α2 forms the subendothelial network (Elife 2013;2:e01149)
• Absence or functional compromise of one of the components of the α3α4α5 network results in reduced ability of the glomerular basement membrane to counter the hemodynamic intracapillary pressure, stressing the filtration barrier and leading to an adaptive reaction of the podocytes, endothelium and mesangial cells; compensatory expansion of the subendothelial α1α2 network provides temporary support (Matrix Biol 2017;57:45)
• An early pathogenetic event in Alport syndrome glomeruli is elevated expression of endothelin 1 by the endothelial cells, leading to subsequent activation of the mesangial cells, deposition of the mesangial matrix proteins in the GBM causing a podocyte reaction with production of proinflammatory cytokines and matrix metalloproteinases (Front Med (Lausanne) 2022;9:846152)
• Slowly progressing structural and biochemical changes in the glomerular basement membrane lead to deterioration of the podocyte architecture and eventually focal and segmental glomerulosclerosis (FSGS)
• Collagen IV is also a major component of the cochlea, cornea, lens capsule and retinal basement membranes, accounting for the sensorineural hearing loss and ocular abnormalities

• Early in the course of Alport syndrome
  • Glomeruli appear normal (Glomerular Dis 2021;1:135)
    • In young children, features of glomerular immaturity may be seen (small glomeruli with indistinct capillaries, circumference of the capillary segments lined with cuboidal epithelial cells); such features have no association with Alport syndrome
  • Tubulointerstitial compartment appears normal (Glomerular Dis 2021;1:135)
• With progression of the disease
  • Segmental thickening of the glomerular capillary walls (more appreciable on the silver stain) and mesangial expansion become visible
  • Red blood cell casts may be seen in the tubules
  • Foci of interstitial fibrosis and tubular atrophy develop (Glomerular Dis 2021;1:135)
• Lipid laden interstitial foam cells are considered a marker of Alport syndrome; they appear as rows or clusters in the cortex or at the corticomedullary junction (Glomerular Dis 2021;1:135)
• Eventually, with marked thickening of the glomerular basement membranes and expansion of the mesangium, segmental tuft scarring develops in an increasing number of glomeruli; the end point is global glomerulosclerosis
• In patients with thin basement membrane disease, the renal tissue is usually normal by light microscopy (Kidney Int 2003;64:1169)
  • Mesangial expansion and mild mesangial proliferation may occur
  • Red blood cells may be seen within tubules

Contributed by Alexei Mikhailov, M.D., Ph.D.

• Immunofluorescence for the antibodies and complement is usually negative, although with progression of Alport syndrome, faint deposits of IgM, C3 or C1q may be seen
• Biopsies from most male patients with X linked Alport syndrome are completely negative for collagen IV α5 isoform in the glomerular capillary walls and the Bowman capsule (Glomerular Dis 2021;1:135)
• Female patients with X linked Alport syndrome show a mosaic pattern of collagen IV α5 expression in the glomerular capillary segments (Glomerular Dis 2021;1:135)
• In autosomal recessive Alport syndrome, the glomerular capillary walls are negative for α3, α4 and α5 staining, whereas the Bowman capsule is positive for α5 (Glomerular Dis 2021;1:135)
• Biopsies from patients with thin basement membrane disease show normal distribution of the collagen IV isoforms in the glomeruli (Arch Pathol Lab Med 2001;125:631)

Contributed by Alexei Mikhailov, M.D., Ph.D., Volker Nickeleit, M.D. and Sharan Singh, M.D.

Contributed by Alexei Mikhailov, M.D., Ph.D.

• COL4A3, COL4A4 and COL5A5 are the most frequent causative genes of monogenic chronic kidney disease after the polycystic kidney disease genes PKD1 and PKD2 (N Engl J Med 2019;380:142)
• COL4A3 and COL4A4 genes reside on chromosome 2, while COL4A5 gene I is located on the X chromosome
• There are 4 modes of inheritance of Alport syndrome
  • X linked Alport syndrome: pathogenic variants in the COL4A5 gene on the X chromosome, genetic state - hemizygous (male subjects) and heterozygous (female subjects)
  • Autosomal recessive: pathogenic variants in COL4A3 / COL4A4 genes
  • Autosomal dominant: pathogenic variants in COL4A3 / COL4A4 genes due to heterozygous COL4A3 and COL4A4 mutations
  • Digenic: combination of 2 mutations in different genes, typically a pathogenic variant in COL4A3 and COL4A4 (Clin Genet 2017;92:34)
• ClinVar database currently documents 680 pathogenic variants of COL4A5, 239 pathogenic variants of COL4A4 and 236 pathogenic variants of COL4A3 (NIH: ClinVar - COL4A5[gene] [Accessed 25 August 2023], NIH: ClinVar - COL4A4[gene] [Accessed 25 August 2023], NIH: ClinVar - COl4A3[gene] [Accessed 25 August 2023])
• Thin basement membrane disease shows autosomal dominant inheritance in 50% of cases with heterozygous COL4A3 or COL4A3 mutations (carrier state for autosomal recessive Alport syndrome) (Pediatr Nephrol 2009;24:877)
  • Other genetic causes such as COL4A1 variants have also been proposed (Nephrol Dial Transplant 2016;31:1758)
  • Mutations are usually different in each family and there is no hotspot; some sources report that the mutation detection rate in thin basement membrane disease is low (Kidney Int 2003;64:1169)

• Alport syndrome associated conditions
  • AMME syndrome (Alport syndrome, midface hypoplasia, intellectual deficit and elliptocytosis) (J Med Genet 2017;54:269)
    • Associated with contiguous gene deletions in the chromosomal region Xq22.3-Xq23 including the entire COL4A5 gene and its adjacent genes
    • Abovementioned dysmorphic, developmental and hematologic abnormalities form the basis for the differential diagnosis
  • Diffuse and global Alport-like changes are seen in
    • Focal and segmental glomerulosclerosis (FSGS) associated with variants in nonmuscle myosin myosin1e (Pediatr Nephrol 2023;38:439):
      • These patients may become proteinuric early in life, with early onset of FSGS and early progression to renal failure
    • Fechtner and Epstein syndrome associated with mutations in myosin heavy chain 9 gene (MYH9) (Hum Genet 2002;110:182):
      • Platelet macrocytosis, thrombocytopenia, sensorineural hearing loss, cataracts, nephritis and characteristic MYH9 aggregates in the granulocyte cytoplasm (Pediatr Nephrol 2023;38:439)
    • Steroid resistant nephrotic syndrome:
      • Caused by activation of a Rac1 GTPase as a result of mutation in a regulatory protein ARHGAP24 manifesting ultrastructurally as subepithelial extensions of the glomerular basement membrane and localized areas of glomerular basement membrane lamellation (The Open Urology & Nephrology Journal 2016;9:88)
    • Renal coloboma syndrome due to mutated podocyte PAX2 (Pediatr Nephrol 2012;27(:1189)
      • Presents as optic disk coloboma and renal insufficiency
      • Collagen IV α5 immunostaining is normal
    • Frasier syndrome with male pseudohermaphroditism and slowly progressing nephropathy associated with mutation in Wilms tumor suppressor gene WT1 (Am J Kidney Dis 2003;41:1110)
  • Conditions that may resemble Alport syndrome
    • Nail patella syndrome (hereditary osteo-onychodysplasia) associated with mutations in LIM homeodomain transcription factor LMX1B and showing collagen fibrils in the GBM (Pflugers Arch 2017;469:927)
    • Collagen type III glomerulopathy (collagenofibrotic glomerulopathy):
      • Seen mostly in Asian patients and manifested by accumulation of collagen type III in the glomerular extracellular matrix (Pflugers Arch 2017;469:927)
    • Pierson syndrome:
      • Congenital nephrotic syndrome with massive proteinuria, ocular abnormalities and rapid progression to end stage renal disease due to variants in the β2 laminin chain (LAMB2 gene) (Matrix Biol 2018;71:250)
    • HANAC syndrome:
      • COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms and muscle cramps
      • Renal manifestations include hematuria and bilateral large cysts (N Engl J Med 2007;357:2687)
    • Renal perfusion mismatched transplants (Am J Surg Pathol 1999;23:437, Clin Nephrol 2017;88:364):
      • Alport-like GBM changes may be seen
    • Membranous glomerulopathy and sometimes glomerulonephritis of various etiologies:
      • GBM rearrangements resembling Alport syndrome may be seen
  • Thin basement membrane disease:
    • Alport syndrome
    • IgA nephropathy
      • Segments of thin glomerular basement membrane may be seen

A 7 year old girl presents with hematuria and very mild proteinuria; she has not undergone laboratory testing previously. Her mother states that the men in the family develop renal failure. A biopsy is done and a representative glomerulus is displayed in the image shown above. Immunofluorescence shows segmental loss of Collagen IV α5 isoform in the glomerular capillary walls. What is the most likely diagnosis?

1. Alport syndrome, autosomal recessive
2. Alport syndrome, X linked heterozygous
3. Minimal change disease
4. Normal kidney
5. Thin basement membrane disease

B. Alport syndrome, X linked heterozygous. Family history suggests an X linked disease. Segmental loss of Collagen IV α5 or mosaic pattern of expression is due to differential X inactivation. Answer C is incorrect because minimal change disease does not show a family history of renal failure and loss of Collagen IV α5 expression. Answer E is incorrect because thin basement membrane disease does not show loss of Collagen IV α5 expression. Answer A is incorrect because autosomal recessive Alport syndrome affects male and female family members equally and shows complete loss of the Collagen IV α345 glomerular expression. Answer D is incorrect because the patient presents with nephrological symptoms and family history and displays an abnormal distribution of glomerular Collagen IV α5.

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Reference: Alport syndrome and thin basement membrane lesion

A man with end stage renal disease due to X linked Alport syndrome and associated focal and segmental glomerulosclerosis (FSGS) receives a renal transplant at the age of 16 years. 6 months after the procedure, his serum creatinine increases from 0.9 g/dL to 4 mg/dL in a matter of days. The allograft kidney biopsy shows 90% global cellular crescents and segmental fibrinoid glomerular tuft necrosis with no evidence of mesangial expansion or endocapillary hypercellularity. What is the most likely diagnosis?

1. Acute cell mediated rejection
2. Antiglomerular basement membrane disease
3. De novo immune complex glomerulonephritis
4. FSGS relapse

B. Antiglomerular basement membrane disease. The patient is a man with X linked Alport syndrome who developed end stage renal disease early; this strongly suggests that the mutation completely prevented the synthesis of collagen IV α5 isoform. Thus, the patient's glomerular basement membranes do not contain the collagen IV α345 network. The transplanted kidney glomeruli contain the normal collagen IV α345 network, which may induce the generation of antibodies. This usually occurs during the first year after transplantation. De novo anti-glomerular basement membrane nephritis develops in approximately 3% of transplanted men (UpToDate: Clinical Manifestations, Diagnosis and Treatment of Alport Syndrome (Hereditary Nephritis) [Accessed 25 August 2023]). Answer A is incorrect because glomerular crescents are not seen in rejection. Answer D is incorrect because the patient's FSGS was secondary to the Alport syndrome and thus cannot relapse after transplantation, as primary FSGS may. Answer C is incorrect because the histological presentation (lack of capillary tuft hypercellularity and mesangial reaction) is not consistent with immune complex glomerulonephritis.

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Reference: Alport syndrome and thin basement membrane lesion