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Kidney Week

Abstract: SA-PO346

Potential Impact of Adenine (P0) Receptors on Urinary Albumin/Creatinine Ratio in CKD

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Zhang, Yue, Univ. of Utah & VA Medical Center, Salt Lake City, Utah, United States
  • Müller, Christa E., University of Bonn, Bonn, Germany
  • Liu, Tao, Univ. of Utah & VA Medical Center, Salt Lake City, Utah, United States
  • Brandes, Anna U., Univ. of Utah & VA Medical Center, Salt Lake City, Utah, United States
  • Kishore, Bellamkonda K., Univ. of Utah and VA Medical Center, Salt Lake City, Utah, United States
Background

P0 is a G protein-coupled receptor (R), which binds adenine with high affinity, but not adenosine, AMP/ADP/ATP. Blood levels of adenine are markedly elevated in chronic kidney disease (CKD), and positively correlate with the duration or severity of CKD. We observed that P0-R is expressed in all regions of the mouse kidney, and hypothesized that blocking it in CKD will have significant effects.

Methods

5/6th nephrectomized (Nx) CD-1 mice were divided into 2 groups. One group was infused with PSB-08162, a selective antagonist of P0-R, through osmotic minipumps to attain steady state plasma concentration ~30 µM. Controls were sham-operated. After 4 weeks of infusion, urine and blood samples were collected, and the mice were euthanized.

Results

The results of analysis (mean ± se) of terminal urine and serum samples are shown in the Table. Despite no significant differences in serum creatinine (CR) between Nx and Nx+PSB groups, the latter showed marked increase in urinary albumin/CR ratio (UACR), apparently due to low urinary CR excretion. In parallel the serum levels of 3-hydroxybutyrate, a ketone body, were significantly elevated.

Conclusion

Our results suggest that blocking the P0-R in CKD may elevate UACR by reducing urinary excretion of CR, probably by decreasing its secretion by the kidney. The elevated keto acid may also contribute to reduction in CR secretion in the kidney. Conversely, the elevated adenine levels in CKD may increase CR secretion in the kidney, and thus may decrease UACR values.

Terminal Urine and Serum Parameters
 ShamNxNx + PSB
 N = 4N 5 or 6N = 5 or 6
Urine Output (ml/24 h)1.07 ± 0.163.54 ± 0.14*3.15 ± 0.29*
Urine Osmolality (mOsm/Kg H2O)1817 ± 341855 ± 33*765 ± 101*
Urine Albumin (μg/24 h)20.0 ± 4.1304.5 ± 109*326.0 ± 99.0
Urine CR (mg/24 h)0.98 ± 0.2310.8 ± 3.5*3.36 ± 1.3**
Urine CR (mg/dl)101.1 ± 27.1303.8 ± 102.466.2 ± 23.2**
UACR (Urine Alb/CR Ratio)‡24.8 ± 8.247.3 ± 27.5*158.7 ± 43.0**
Serum CR (mg/dl)#0.163 ± 0.0220.222 ± 0.0110.244 ± 0.065
Serum CR (AUC)†0.483 ± 0.1650.690 ± 0.0830.960 ± 0.417
Serum Urea (AUC)†3993 ± 7218233 ± 352*8743 ± 318*
Serum 3-hydroxybutyrate (AUC)†25.79 ± 3.6133.40 ± 4.0356.96 ± 8.07**

All statistics by ANOVA; #determined by enzymatic method; †determined by HPLC-MS (Area Under Curve); ‡calculated as albumin µg/L / creatinine mg/L; *significantly different from Sham; **significantly different from Nx group.

Funding

  • Veterans Affairs Support