Gitelman Syndrome and Glomerular Proteinuria: A Link Between Loss of Sodium-Chloride Cotransporter and Podocyte Dysfunction?

Nephrol Dial Transplant. 2014 Sep;29 Suppl 4:iv117-20. doi: 10.1093/ndt/gfu075.

Abstract

We report on a 27-year-old patient presenting with chronic hypokalaemia, inappropriate kaliuresis, hypomagnesaemia and alkalosis, associated with moderate proteinuria. Genetic analysis evidenced a homozygous mutation (p.Arg399Cys) in the SLC12A3 gene coding for the sodium-chloride cotransporter (NCC), confirming the diagnosis of Gitelman syndrome. Further genetic testing did not show any mutation in NPHS2. A renal biopsy was performed in view of the unusual association with proteinuria. Light microscopy showed hypertrophy of the juxtaglomerular apparatus and discrete mesangial thickening. In addition to possible focal segmental glomerular sclerosis lesions, electron microscopy showed extensive segments of variably thickened glomerular basement membrane (GBM), contrasting with segments of regular GBM of low range thickness, and effacement of podocyte foot processes. Of interest, alterations of the GBM were also observed in a Slc12a3 knock-out mouse model for Gitelman syndrome. These data suggest that the association between Gitelman syndrome and secondary changes of the GBM is probably not coincidental. Possible mechanisms include angiotensin II- or renin-induced podocyte lesions, as well as chronic hypokalaemia.

Keywords: glomerular basement membrane; hypokalaemia; secondary aldosteronism; tubulopathy.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Gitelman Syndrome / genetics
  • Gitelman Syndrome / metabolism
  • Gitelman Syndrome / pathology*
  • Glomerular Basement Membrane / metabolism
  • Glomerular Basement Membrane / pathology*
  • Humans
  • Hypokalemia / complications
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Mutation / genetics
  • Podocytes / metabolism
  • Podocytes / pathology*
  • Proteinuria / metabolism
  • Proteinuria / pathology*
  • Solute Carrier Family 12, Member 3 / physiology*

Substances

  • Solute Carrier Family 12, Member 3