Soluble Klotho levels in adult renal transplant recipients are modulated by recombinant human erythropoietin.
BACKGROUND
Data on serum soluble Klotho levels in chronic kidney disease are contradictory and even less is known after renal transplantation. Experimental studies demonstrated that recombinant human erythropoietin (rhEPO) treatment mitigates Klotho reduction caused by renal damage. Therefore, this study aimed to determine serum Klotho levels in a cohort of kidney transplant recipients (KTR) and to evaluate whether rhEPO treatment can modulate, in vivo and in vitro, soluble Klotho.


METHODS
117 KTR and 22 healthy subjects (HS) were enrolled. In 17 KTR, rhEPO was discontinued for 5 weeks and Klotho levels were compared to 34 propensity score-matched controls. Moreover, we evaluated Klotho mRNA expression and protein secretion in HK-2 tubular cells treated with cyclosporin A (CyA) and rhEPO, alone or in combination.


RESULTS
Serum Klotho levels in KTR were significantly higher than in HS (0.68 vs. 0.37, p = 0.002) and significantly associated with estimated glomerular filtration rate (r = -0.378, p = 0.003) and fibroblast growth factor 23 (r = -0.307, p < 0.0001). After 5 weeks of rhEPO discontinuation, treated KTR showed a sharper reduction of Klotho levels than controls (-0.56 vs. -0.11 ng/ml, p < 0.0001). In HK-2 cells CyA treatment induced a Klotho down-regulation that was mitigated by rhEPO pre-treatment. In the same experimental conditions, our results revealed that cells treated with CyA + rhEPO secreted higher soluble Klotho levels than those exposed to CyA or rhEPO alone.


CONCLUSIONS
Our results demonstrate that KTR have higher serum Klotho levels than HS and that rhEPO treatment modulates these concentrations, suggesting a link between rhEPO and soluble Klotho in KTR.
Kidney and Transplantation Research Center, "Annunziata" Hospital, via F. Migliori, 87100, Cosenza, Italy.
Francesca
F
Leone
Danilo
D
Lofaro
Paolo
P
Gigliotti
Anna
A
Perri
Donatella
D
Vizza
Giuseppina
G
Toteda
Simona
S
Lupinacci
Filomena
F
Armentano
Teresa
T
Papalia
Renzo
R
Bonofiglio
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002460:Cell Line; D003430:Cross-Sectional Studies; D016572:Cyclosporine / Q000494:pharmacology; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005966:Glucuronidase / Q000097:blood* / Q000235:genetics; D006397:Hematinics / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D008875:Middle Aged; D057216:Propensity Score; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D015415:Biomarkers; C554270:EPO protein, human; D006397:Hematinics; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D004921:Erythropoietin; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D016572:Cyclosporine; D005966:Glucuronidase; D000090265:Klotho Proteins