Bile Acids as Potential Biomarkers to Assess Liver Impairment in Polycystic Kidney Disease

Abstract

Polycystic kidney disease is characterized by the progressive development of kidney cysts and declining renal function with frequent development of cysts in other organs including the liver. The polycystic kidney (PCK) rat is a rodent model of polycystic liver disease that has been used to study hepatorenal disease progression and evaluate pharmacotherapeutic interventions. Biomarkers that describe the cyst progression, liver impairment, and/or hepatic cyst burden could provide clinical utility for this disease. In the present study, hepatic cyst volume was measured by magnetic resonance imaging in PCK rats at 12, 16, and 20 weeks. After 20 weeks, Sprague Dawley (n = 4) and PCK (n = 4) rats were sacrificed and 42 bile acids were analyzed in the liver, bile, serum, and urine by liquid chromatography coupled to tandem mass spectrometry. Bile acid profiling revealed significant increases in total bile acids (molar sum of all measured bile acids) in the liver (13-fold), serum (6-fold), and urine (3-fold) in PCK rats, including those speciated bile acids usually associated with hepatotoxicity. Total serum bile acids correlated with markers of liver impairment (liver weight, total liver bile acids, total hepatotoxic liver bile acids, and cyst volume [ r > 0.75; P < 0.05]). Based on these data, serum bile acids may be useful biomarkers of liver impairment in polycystic hepatorenal disease.

Keywords: bile acids; biomarkers; hepatotoxicity; polycystic kidney disease.

Conflict of interest statement

Conflict of Interest

The authors declare that there are no conflicts of interest with respect to the research, authorship or the publication of this article.

Figures

Figure 1

Representative magnetic resonance images of the hepatic parenchyma and cysts (white) in (A) Sprague-Dawley and (B-D) three different polycystic kidney (PCK) rats at 20 weeks of age.

Figure 2

Total bile acid concentrations in the (A) liver, (B) bile, (C) serum, and (D) urine in Sprague-Dawley (white) and polycystic kidney (PCK) (grey) rats. Data represent the mean, first and third quartiles, and the maximum and minimum values (n=4/cohort except n=3 in bile of Sprague-Dawley). Individual values are shown (black circles); * p

Figure 3

Unconjugated and conjugated bile acids in the (A) liver, (B) bile, (C) serum, and (D) urine of Sprague-Dawley (white) and polycystic kidney (PCK) (grey) rats. Data represent the mean, first and third quartiles, and the maximum and minimum values (n=4/cohort except n=3 in bile of Sprague-Dawley). Individual values are shown (black circles); * p

Figure 4

Bile acids associated with hepatotoxicity [i.e., deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), chenodeoxycholic acid (CDCA), glycochenodeoxycholic (GCDCA), lithocholic acid (LCA)] in the (A) liver, (B) bile, (C) serum, and (D) urine of Sprague-Dawley (white) and polycystic kidney (PCK) (grey) rats. Data represent the mean, first and third quartiles, and the maximum and minimum values (n=4/cohort except n=3 in bile of Sprague-Dawley). Individual values are shown (black circles); * p

Figure 5

Score plots of the Principal Component Analysis models of bile acid profiles in the (A) liver, (B) bile, (C) serum, and (D) urine of Sprague-Dawley (black circles) and polycystic kidney (PCK) (open circles) rats.

Figure 6

Correlation between (A) liver weight, (B) total liver bile acids, (C) total liver bile acids associated with hepatotoxicity, (D) cyst volume and total serum bile acids; and between (E) liver weight, (F) cyst volume and total serum bile acids associated with hepatotoxicity in Sprague-Dawley (black circles) and polycystic kidney (PCK) (open circles) rats (n=4/cohort). The best-fit line is represented by the solid black line. Cyst volume was assumed to be zero in Sprague-Dawley rats.