Volume 75, Issue 4, Pages 389-398 (February 2009) Hepatocellular transport and gastrointestinal absorption of lanthanum in chronic renal failure  An R.J. Bervoets, Geert J. Behets, Dominick Schryvers, Frank Roels, Zhang Yang, Steven C. Verberckmoes, Stephen J.P. Damment, Simonne Dauwe, Valentine K. Mubiana, Ronny Blust, Marc E. De Broe, Patrick C. D'Haese  Kidney International  Volume 75, Issue 4, Pages 389-398 (February 2009) DOI: 10.1038/ki.2008.571 Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 1 Subcellular localization of La in the liver. (a) XRF mapping of La (1) and Fe (2) in liver samples of La-loaded rats showing co-localization of both elements. (b) TEM image of liver tissue of rat with normal renal function not exposed to La showing smoothly contoured electron-dense particles within the lysosomes. (c) TEM image of liver tissue of La-loaded rat (dose: 0.3 mg/kg per day i.v., 4 weeks) showing electron-dense precipitates displaying a crystalline granular structure within the lysosomes. (d) EELS spectrum of electron-dense particles within lysosomes of liver tissue of La-loaded rat (dose: 0.3 mg/kg per day i.v., 4 weeks) evidencing the presence of La. (e) TEM image of liver tissue of La-loaded rats (dose: 0.3 mg/kg per day i.v., 4 weeks) with La being present in the bile canaliculus (artificially colored in brown for educational purposes). White arrows show mitochondria whereas black arrows indicate lysosomes. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 2 La concentration in rat hepatocytes after incubation with serum-free cell culture medium containing 0, 2.5, 5.0, and 25.0 μg/l La as the La-Tf complex. Results show a time- and dose-dependent intracellular uptake of La by the hepatocytes. Data represent the mean±s.d. La concentration of 4 wells per condition and per time point. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 3 Liver enzymes and liver weight in study no. 2. Liver enzymes at killing: (a) ALAT, (b) ASAT, (c) liver ALP, and (d) liver weight versus body weight (%). *P<0.05 versus normal renal function and #P<0.05 versus previous time point. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 4 Organ La content in study no. 2. Organ La content: (a) brain, (b) heart, (c) spleen, (d) bone. *P<0.05 versus normal renal function; #P<0.05 versus previous time points. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 5 Liver La concentration during 20 weeks of oral La loading, data indicate liver La levels reached a already after 6 weeks of La loading in both NRF and CRF animals. *P<0.05 versus normal renal function; #P<0.05 versus previous time point. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 6 Liver La concentration in intravenously versus oral-loaded groups with CRF and NRF indicating an increased gastrointestinal absorption of La in the uremic animals. *P<0.05 versus NRF. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 7 Proposed transhepatocellular transport mechanism of La. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 8 Study setup of study no. 2. Animals received 1000 mg/kg per day La carbonate 6 days a week by oral gavage. At each time point at least six animals per group of CRF or NRF were killed. Biochemical blood analysis was performed before induction of CRF, at the start of the oral loading and at killing. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 9 Study setup of study no. 3. Animals received either 1000 mg/kg per day La carbonate 6 days a week by gavage or 0.05 mg/kg per day 3 days a week by intravenous injection. Kidney International 2009 75, 389-398DOI: (10.1038/ki.2008.571) Copyright © 2009 International Society of Nephrology Terms and Conditions