title: Renal sodium transporters are increased in urinary exosomes of cyclosporine-treated kidney transplant patients.
abstract: OBJECTIVE
  Cyclosporine (CsA) is a calcineurin inhibitor widely used as an immunosuppressant in organ transplantation. Previous studies demonstrated the relationship between CsA and renal sodium transporters such as the Na-K-2Cl cotransporter in the loop of Henle (NKCC2). Experimental models of CsA-induced hypertension have shown an increase in renal NKCC2.
  
  
  METHODS
  Using immunoblotting of urinary exosomes, we investigated in CsA-treated kidney transplant patients (n = 39) the excretion of NKCC2 and Na-Cl cotransporter (NCC) and its association with blood pressure (BP) level. We included 8 non-CsA-treated kidney transplant patients as a control group. Clinical data, immunosuppression and hypertension treatments, blood and 24-hour urine tests, and 24-hour ambulatory BP monitoring were recorded.
  
  
  RESULTS
  CsA-treated patients tended to excrete a higher amount of NKCC2 than non-CsA-treated patients (mean ± SD, 175 ± 98 DU and 90 ± 70.3 DU, respectively; p = 0.05) and showed higher BP values (24-hour systolic BP 138 ± 17 mm Hg and 112 ± 12 mm Hg, p = 0.003; 24-hour diastolic BP, 83.8 ± 9.8 mm Hg and 72.4 ± 5.2 mm Hg, p = 0.015, respectively). Within the CsA-treated group, there was no correlation between either NKCC2 or NCC excretion and BP levels. This was confirmed by a further analysis including potential confounding factors. On the other hand, a significant positive correlation was observed between CsA blood levels and the excretion of NKCC2 and NCC.
  
  
  CONCLUSIONS
  Overall, these results support the hypothesis that CsA induces an increase in NKCC2 and NCC in urinary exosomes of renal transplant patients. The fact that the increase in sodium transporters in urine did not correlate with the BP level suggests that in kidney transplant patients, other mechanisms could be implicated in CsA-induced hypertension.
authors.affiliation: Molecular Biology Laboratory, Fundació Puigvert, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteva-Font
authors.forename: Elena
authors.initials: E
authors.lastname: Guillén-Gómez
authors.forename: Joan Manuel
authors.initials: JM
authors.lastname: Diaz
authors.forename: Luís
authors.initials: L
authors.lastname: Guirado
authors.forename: Carmen
authors.initials: C
authors.lastname: Facundo
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
authors.forename: Jose A
authors.initials: JA
authors.lastname: Ballarin
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández-Llama
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure; D016022:Case-Control Studies; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012964:Sodium / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1 / Q000187:drug effects / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3 / Q000187:drug effects / Q000378:metabolism; D014556:Urine; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C578714:SLC12A1 protein, human; C578874:SLC12A3 protein, human; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D016572:Cyclosporine; D012964:Sodium