Authors

Lyubov Chaykovska, Karoline von Websky, Jan Rahnenführer, Markus Alter, Susi Heiden, Holger Fuchs, Frank Runge, Thomas Klein, Berthold Hocher

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Background

Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).

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Methodology/Principal Findings

In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.

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Results

This study showed that 5/6N caused a significant decrease in GFR as measured by creatinine clearance and increased plasma cystatin C levels. Tubular function was significantly impaired after 5/6N as evidenced by increased plasma β2-microglobulin, NGAL and osteopontin levels. There was no significant difference in DPP-4 activity in 5/6N rats compared with sham-operated rats before treatment, but DPP-4 activity decreased significantly in all groups following drug administration with no significant differences between control or 5/6N groups. The strongest DPP-4 inhibition was achieved after administration of 7 µmol/kg linagliptin, whereas the other groups were comparable. The GLP-1 receptor mRNA expression was reduced about 40% in uremic rats as compared to healthy control rats.

We tested plasma glucose concentrations on alternate days while the rats were being treated with DPP-4 inhibitors. There was no change in plasma glucose in rats treated with DPP-4 inhibitors compared with nontreated animals (data not shown).

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Conclusions/Significance

DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.​