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Abstract: TH-PO906

Hepatic Alkaline Phosphatase Activity Is Increased in CKD and Is Regulated by the Intestinal Microbiota

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Johnson, Cassandra R., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Omede, Ogorchukwu Faith, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Stubbs, Jason R., University of Kansas Medical Center, Kansas City, Kansas, United States
Background

Patients with chronic kidney disease (CKD) exhibit a pro-inflammatory phenotype that may partially result from intestinal dysbiosis and gut barrier dysfunction. A major function of liver alkaline phosphatase (ALP) is the neutralization of microbial toxins that enter the portal circulation from the intestine. The purpose of this study was to characterize expression and activity levels of liver ALP in both mice and humans with CKD, and explore the role of the intestinal microbiota in regulating ALP activity.

Methods

We first assessed liver ALP expression (Western blot) and function (ALP activity assay) in two CKD mouse models (Col4a3-/- and adenine diet) and non-CKD controls. Next, we confirmed the generalizability of our findings to humans by assessing ALP expression and function in liver samples from deceased tissue donors with advanced CKD or normal kidney function (n=10/group). Lastly, we performed fecal transplant studies to examine how repopulating the intestine of wild-type mice with microbiota from either CKD or control mice impacted liver ALP expression and function.

Results

CKD mice (Col4a3-/- model) exhibited a 50% higher liver ALP protein expression (P<0.05), that was accompanied by a 10-fold greater liver ALP activity (CKD 3,140 vs. non-CKD 294 mU/mg protein; P<0.001). Similar findings were observed in mice with CKD induced by chronic adenine ingestion. Despite markedly higher liver ALP activity in CKD mice, serum ALP activity was equal between CKD and non-CKD mice. Next, we observed 3-fold higher liver ALP activity in human CKD livers (CKD 6,624,488 vs. non-CKD 2,459,531 mU/mg protein; P=0.09), but no obvious difference in total protein expression. Lastly, transplantation of CKD stool into wild-type mice resulted in substantially higher liver ALP protein expression and ALP activity compared to wild-type mice transplanted with non-CKD stool (ALP activity: CKD stool 5,104 vs. non-CKD stool 863.4 mU/mg protein; P<0.05).

Conclusion

Both mice and humans with CKD exhibit higher liver ALP activity that may be partially stimulated by factors derived from the CKD microbiome. We speculate that enhanced liver ALP activity is important for neutralizing microbial toxins that enter the portal circulation as a result of gut dysbiosis and barrier dysfunction in CKD.

Funding

  • NIDDK Support