- Email: [email protected]
Primary systemic arterial vasodilation in cirrhotic patients
letter to the editor
http://www.kidney-international.org & 2010 International Society of Nephrology
Primary systemic arterial vasodilation in cirrhotic patients To the Editor: The increased plasma volume in cirrhotic patients with ascites made untenable the ‘underfill hypothesis’ secondary to ascites-mediated diminished plasma volume. Thus, the ‘overflow hypothesis’ was proposed in which a hepatic–renal reflex caused renal sodium retention with resultant plasma and extracellular fluid (ECF) expansion. The ECF expansion then increases cardiac output and causes secondary systemic arterial vasodilation. In a recent review in Kidney International,1 a figure from an experimental study supports secondary arterial vasodilation in cirrhosis.1 However, another experimental study demonstrated that prehepatic portal hypertension caused primary systemic vasodilation followed by increased total body sodium.2 Primary systemic arterial vasodilation, as occurs early in the splanchnic circulation in cirrhosis, must be distinguished from ECF volume expansion causing increased cardiac output and secondary systemic arterial vasodilation (overflow hypothesis). With secondary arterial vasodilation due to ECF volume expansion blood pressure should be increased or remain normal because of suppression of the neurohumoral axis including plasma norepinephine (NE), renin-angiotensin-aldosterone system (RAAS), and arginine vasopressin (AVP). However, as cirrhotic patients progress from compensated to decompensated to hepatorenal syndrome (HRS), there is a progressive decline in systemic vascular resistance and decreased blood pressure. Moreover, there is a progressive rise in plasma NE, plasma renin activity, and AVP with resultant hyponatremia during progression of cirrhosis to HRS, all known risk factors for increased mortality in cirrhosis.3 Thus, the ‘primary systemic arterial vasodilation hypothesis’ causing arterial underfilling (Figure 1) has been proposed to explain the pathogenesis of renal sodium and water retention in cirrhotic patients.4 1. Oliver JA, Verna EC. Afferent mechanisms of sodium retention in cirrhosis and hepatorenal syndrome. Kidney Int 2010; 77: 669–680. 2. Albillos A, Colombato LA, Groszmann R. Vasodilation and sodium retention in prehepatic portal hypertension. Gastroenterology 1992; 102: 102–105.
Primary systemic arterial vasodilation Compensated cirrhosis (no ascites)
Decompensated cirrhosis (ascites)
Hepatorenal syndrome
Primary systemic arterial vasodilation Plasma hormones (AVP, renin, aldosterone, NE)
Normal*
3. 4.
Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med 2009; 361: 1279–1290. Schrier RW, Arroyo V, Bernardi M et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988; 8: 1151–1157.
Robert W. Schrier1 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA Correspondence: Robert W. Schrier, Department of Medicine, University of Colorado Denver, 12700 East 19th Avenue C281, Aurora, Colorado 80045, USA. E-mail: [email protected]
Kidney International (2010) 78, 619; doi:10.1038/ki.2010.241
The Authors Reply: We thank Dr Schrier for his comments1 on our review in which we proposed2 that the stimulus initiating and maintaining salt retention in cirrhosis is located in the liver (that is, in a hepatic ‘volume’ sensor). Dr Schrier suggests that the syndrome of worsening extracellular fluid volume (ECFV) expansion plus low blood pressure and activation of the neuro-humoral axis of ECFV control in advanced cirrhosis and hepatorenal syndrome is best attributed to primary systemic vasodilation because secondary vasodilation due to ECFV expansion would not lower blood pressure plus would suppress the neuro-humoral axis, and Albillos et al.3 found systemic vasodilation before sodium retention in portal hypertension. Although the hemodynamic and neuro-humoral response to ECFV expansion in normal conditions would be as he stated, there is no a priori reason why it should be the same in diseases where homeostatic responses to abnormal stimuli frequently cause unpredictable changes. Indeed, patients with congestive heart failure due to obstructive pulmonary disease4 and patients with edema due to severe chronic anemia,5 have ECFV expansion, low blood pressure, systemic vasodilation and activated neuro-humoral axis of ECFV control. A similar phenotype is also found in pregnancy wherein the reason for it also remains unexplained.6–8 Concerning the study of Albillos et al.,3 leaving aside the experimental difficulties in accurately measuring systemic hemodynamics in anesthetized rodents, these workers constricted the portal vein and thus created a model quite different from cirrhosis. In sum, we believe that the available evidence best supports the presence of a hepatic ‘volume’ sensor that is pathologically activated during cirrhosis and that systemic vasodilation is a secondary phenomena. Nonetheless, we agree with Dr Schrier’s underlying point that the current understanding of the stimulus that drives salt retention in cirrhosis is still in the hypothesis stage.1 Clearly, experimental work to resolve this issue is urgently needed.
Plasma volume
Figure 1 | Primary systemic arterial vasodilation. *Not suppressed in spite of plasma volume expansion. (Schrier RW et al.4) Kidney International (2010) 78, 619–623
1. 2.
Schrier RW. Primary systemic arterial vasodilation in cirrhotic patients. Kidney Int 2010; 78: 619. Oliver JA, Verna EC. Afferent mechanisms of sodium retention in cirrhosis and hepatorenal syndrome. Kidney Int 2010; 77: 669–680.
619
letter to the editor
3. Albillos A, Colombato LA, Groszmann RJ. Vasodilatation and sodium retention in prehepatic portal hypertension. Gastroenterology. 1992; 102: 931–935. 4. Anand IS, Chandrashekhar Y, Ferrari R et al. Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery. Circulation. 1992; 86: 12–21. 5. Anand IS, Chandrashekhar Y, Ferrari R et al. Pathogenesis of oedema in chronic severe anaemia: studies of body water and sodium, renal function, haemodynamic variables, and plasma hormones. Br Heart J. 1993; 70: 357–362. 6. Ganzevoort W, Rep A, Bonsel GJ et al. Plasma volume and blood pressure regulation in hypertensive pregnancy. J Hypertens 2004; 22: 1235–1242. 7. Zhang J, Klebanoff MA. Low blood pressure during pregnancy and poor perinatal outcomes: an obstetric paradox. Am J Epidemiol 2001; 153: 642–646. 8. Irani RA, Xia Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008; 29: 763–771.
a
c
Juan A. Oliver1 and Elizabeth C. Verna1 1
Department of Medicine, Physicians and Surgeons, Columbia University, New York, USA Correspondence: Juan A. Oliver, Department of Medicine, Columbia University, Physicians and Surgeons Room 10–445, 630 West 168th St, New York, NY 10032, USA. E-mail: [email protected] Kidney International (2010) 78, 619–620; doi:10.1038/ki.2010.242
Only anti-CD133 antibodies recognizing the CD133/1 or the CD133/2 epitopes can identify human renal progenitors To the Editor: Ivanova et al.1 describe the expression of CD24 and CD133 in developing human kidneys. Their study is based on our previous reports, showing the existence of a CD24 þ CD133 þ renal progenitor population in human kidney.2,3 In agreement with our results, they show that CD24 is a reliable marker to detect and purify human renal progenitors, whereas they are unable to obtain a further enrichment of human renal progenitors using CD133 as an additional marker, as we previously reported.2,3 However, Ivanova et al. used antiCD133 polyclonal antibodies, which stained diffusely differentiated epithelial structures in embryonic, as well as adult kidneys.1 By contrast, we used anti-CD133 monoclonal antibodies recognizing CD133/1 (clone AC133) or CD133/2 (clone 293C3) epitopes, which selectively recognized renal progenitors.2,3 It is common knowledge in the stem-cell field that only anti-CD133/1 or anti-CD133/2 antibodies can be used to detect and purify stem cells in several human tissues, whereas other anti-CD133 antibodies show expression in differentiated cells.4 Recent studies have clarified this apparent discrepancy.5 Indeed, different tertiary structures of the CD133 molecule justify the diverse accessibility of the CD133/1 or CD133/2 epitopes in undifferentiated versus differentiated cells.5 Differential recognition of CD133 mRNA variants has also been suggested.4 Consistently, double-label immunofluorescence performed with anti-CD133 antibodies used by Ivanova et al. and anti-CD133/1 or anti-CD133/2 antibodies, confirmed that only the latter recognized human renal progenitors (Figure 1). Thus, 620
b
b’
Figure 1 | Only antibodies recognizing the CD133/1 or CD133/2 epitopes can identify human renal progenitors. (a, b) Double-label immunofluorescence performed with the anti-CD133 polyclonal antibody used by Ivanova et al. (pCD133, red) and the anti-CD133/2 monoclonal antibody (green) in embryonic human kidneys. The anti-CD133 antibody used by Ivanova et al. poorly stains primary vesicles, comma-shaped bodies and Sshaped bodies, while it extensively stains differentiated tubular cells as well as the differentiating ureteric bud (red). By contrast, the anti-CD133/2 antibody (green) selectively stains condensed mesenchyme-derived primordial structures, primary vesicles, comma-shaped bodies, S-shaped bodies and, in maturing glomeruli, the urinary pole of the Bowman’s capsule (arrows). In (b), asterisk indicates a maturing glomerulus. Merged areas appear in yellow. Topro-3 counterstains nuclei (blue). Bar 100 mm. (b0 ) Split image of the maturing glomerulus identified by the asterisk in (b). The arrow indicates the urinary pole of the Bowman’s capsule. Bar 50 mm (c) Double label immunofluorescence performed with the anti-CD133 polyclonal antibody used by Ivanova et al. (pCD133, red) and the anti-CD133/1 monoclonal antibody (green) in embryonic human kidneys. Only CD133/1 antibody selectively stains human progenitors of the Bowman’s capsule (arrow). Merged areas appear in yellow. Topro-3 counterstains nuclei (blue). Bar 100 mm.
we recommend the usage anti-CD133/1 or CD133/2 antibodies to detect or purify human renal progenitors. 1. 2.
3.
4. 5.
Ivanova L, Hiatt MJ, Yoder MC et al. Ontogeny of CD24 in the human kidney. Kidney Int 2010; 77: 1123–1131. Sagrinati C, Netti GS, Mazzinghi B et al. Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys. J Am Soc Nephrol 2006; 17: 2443–2456. Lazzeri E, Crescioli C, Ronconi E et al. Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. J Am Soc Nephrol 2007; 18: 3128–3138. Mizrak D, Brittan M, Alison MR. CD133: molecule of the moment. J Pathol 2008; 214: 3–9. Kemper K, Sprick MR, de Bree M et al. The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res 2010; 70: 719–729.
Maria L. Angelotti1,2, Elena Lazzeri1,2, Laura Lasagni1,2 and Paola Romagnani1 1 Department of Clinical Pathophysiology, Nephrology Section, University of Florence, Florence, Italy and 2Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
Kidney International (2010) 78, 619–623
http://www.kidney-international.org & 2010 International Society of Nephrology
Primary systemic arterial vasodilation in cirrhotic patients To the Editor: The increased plasma volume in cirrhotic patients with ascites made untenable the ‘underfill hypothesis’ secondary to ascites-mediated diminished plasma volume. Thus, the ‘overflow hypothesis’ was proposed in which a hepatic–renal reflex caused renal sodium retention with resultant plasma and extracellular fluid (ECF) expansion. The ECF expansion then increases cardiac output and causes secondary systemic arterial vasodilation. In a recent review in Kidney International,1 a figure from an experimental study supports secondary arterial vasodilation in cirrhosis.1 However, another experimental study demonstrated that prehepatic portal hypertension caused primary systemic vasodilation followed by increased total body sodium.2 Primary systemic arterial vasodilation, as occurs early in the splanchnic circulation in cirrhosis, must be distinguished from ECF volume expansion causing increased cardiac output and secondary systemic arterial vasodilation (overflow hypothesis). With secondary arterial vasodilation due to ECF volume expansion blood pressure should be increased or remain normal because of suppression of the neurohumoral axis including plasma norepinephine (NE), renin-angiotensin-aldosterone system (RAAS), and arginine vasopressin (AVP). However, as cirrhotic patients progress from compensated to decompensated to hepatorenal syndrome (HRS), there is a progressive decline in systemic vascular resistance and decreased blood pressure. Moreover, there is a progressive rise in plasma NE, plasma renin activity, and AVP with resultant hyponatremia during progression of cirrhosis to HRS, all known risk factors for increased mortality in cirrhosis.3 Thus, the ‘primary systemic arterial vasodilation hypothesis’ causing arterial underfilling (Figure 1) has been proposed to explain the pathogenesis of renal sodium and water retention in cirrhotic patients.4 1. Oliver JA, Verna EC. Afferent mechanisms of sodium retention in cirrhosis and hepatorenal syndrome. Kidney Int 2010; 77: 669–680. 2. Albillos A, Colombato LA, Groszmann R. Vasodilation and sodium retention in prehepatic portal hypertension. Gastroenterology 1992; 102: 102–105.
Primary systemic arterial vasodilation Compensated cirrhosis (no ascites)
Decompensated cirrhosis (ascites)
Hepatorenal syndrome
Primary systemic arterial vasodilation Plasma hormones (AVP, renin, aldosterone, NE)
Normal*
3. 4.
Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med 2009; 361: 1279–1290. Schrier RW, Arroyo V, Bernardi M et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988; 8: 1151–1157.
Robert W. Schrier1 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA Correspondence: Robert W. Schrier, Department of Medicine, University of Colorado Denver, 12700 East 19th Avenue C281, Aurora, Colorado 80045, USA. E-mail: [email protected]
Kidney International (2010) 78, 619; doi:10.1038/ki.2010.241
The Authors Reply: We thank Dr Schrier for his comments1 on our review in which we proposed2 that the stimulus initiating and maintaining salt retention in cirrhosis is located in the liver (that is, in a hepatic ‘volume’ sensor). Dr Schrier suggests that the syndrome of worsening extracellular fluid volume (ECFV) expansion plus low blood pressure and activation of the neuro-humoral axis of ECFV control in advanced cirrhosis and hepatorenal syndrome is best attributed to primary systemic vasodilation because secondary vasodilation due to ECFV expansion would not lower blood pressure plus would suppress the neuro-humoral axis, and Albillos et al.3 found systemic vasodilation before sodium retention in portal hypertension. Although the hemodynamic and neuro-humoral response to ECFV expansion in normal conditions would be as he stated, there is no a priori reason why it should be the same in diseases where homeostatic responses to abnormal stimuli frequently cause unpredictable changes. Indeed, patients with congestive heart failure due to obstructive pulmonary disease4 and patients with edema due to severe chronic anemia,5 have ECFV expansion, low blood pressure, systemic vasodilation and activated neuro-humoral axis of ECFV control. A similar phenotype is also found in pregnancy wherein the reason for it also remains unexplained.6–8 Concerning the study of Albillos et al.,3 leaving aside the experimental difficulties in accurately measuring systemic hemodynamics in anesthetized rodents, these workers constricted the portal vein and thus created a model quite different from cirrhosis. In sum, we believe that the available evidence best supports the presence of a hepatic ‘volume’ sensor that is pathologically activated during cirrhosis and that systemic vasodilation is a secondary phenomena. Nonetheless, we agree with Dr Schrier’s underlying point that the current understanding of the stimulus that drives salt retention in cirrhosis is still in the hypothesis stage.1 Clearly, experimental work to resolve this issue is urgently needed.
Plasma volume
Figure 1 | Primary systemic arterial vasodilation. *Not suppressed in spite of plasma volume expansion. (Schrier RW et al.4) Kidney International (2010) 78, 619–623
1. 2.
Schrier RW. Primary systemic arterial vasodilation in cirrhotic patients. Kidney Int 2010; 78: 619. Oliver JA, Verna EC. Afferent mechanisms of sodium retention in cirrhosis and hepatorenal syndrome. Kidney Int 2010; 77: 669–680.
619
letter to the editor
3. Albillos A, Colombato LA, Groszmann RJ. Vasodilatation and sodium retention in prehepatic portal hypertension. Gastroenterology. 1992; 102: 931–935. 4. Anand IS, Chandrashekhar Y, Ferrari R et al. Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery. Circulation. 1992; 86: 12–21. 5. Anand IS, Chandrashekhar Y, Ferrari R et al. Pathogenesis of oedema in chronic severe anaemia: studies of body water and sodium, renal function, haemodynamic variables, and plasma hormones. Br Heart J. 1993; 70: 357–362. 6. Ganzevoort W, Rep A, Bonsel GJ et al. Plasma volume and blood pressure regulation in hypertensive pregnancy. J Hypertens 2004; 22: 1235–1242. 7. Zhang J, Klebanoff MA. Low blood pressure during pregnancy and poor perinatal outcomes: an obstetric paradox. Am J Epidemiol 2001; 153: 642–646. 8. Irani RA, Xia Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008; 29: 763–771.
a
c
Juan A. Oliver1 and Elizabeth C. Verna1 1
Department of Medicine, Physicians and Surgeons, Columbia University, New York, USA Correspondence: Juan A. Oliver, Department of Medicine, Columbia University, Physicians and Surgeons Room 10–445, 630 West 168th St, New York, NY 10032, USA. E-mail: [email protected] Kidney International (2010) 78, 619–620; doi:10.1038/ki.2010.242
Only anti-CD133 antibodies recognizing the CD133/1 or the CD133/2 epitopes can identify human renal progenitors To the Editor: Ivanova et al.1 describe the expression of CD24 and CD133 in developing human kidneys. Their study is based on our previous reports, showing the existence of a CD24 þ CD133 þ renal progenitor population in human kidney.2,3 In agreement with our results, they show that CD24 is a reliable marker to detect and purify human renal progenitors, whereas they are unable to obtain a further enrichment of human renal progenitors using CD133 as an additional marker, as we previously reported.2,3 However, Ivanova et al. used antiCD133 polyclonal antibodies, which stained diffusely differentiated epithelial structures in embryonic, as well as adult kidneys.1 By contrast, we used anti-CD133 monoclonal antibodies recognizing CD133/1 (clone AC133) or CD133/2 (clone 293C3) epitopes, which selectively recognized renal progenitors.2,3 It is common knowledge in the stem-cell field that only anti-CD133/1 or anti-CD133/2 antibodies can be used to detect and purify stem cells in several human tissues, whereas other anti-CD133 antibodies show expression in differentiated cells.4 Recent studies have clarified this apparent discrepancy.5 Indeed, different tertiary structures of the CD133 molecule justify the diverse accessibility of the CD133/1 or CD133/2 epitopes in undifferentiated versus differentiated cells.5 Differential recognition of CD133 mRNA variants has also been suggested.4 Consistently, double-label immunofluorescence performed with anti-CD133 antibodies used by Ivanova et al. and anti-CD133/1 or anti-CD133/2 antibodies, confirmed that only the latter recognized human renal progenitors (Figure 1). Thus, 620
b
b’
Figure 1 | Only antibodies recognizing the CD133/1 or CD133/2 epitopes can identify human renal progenitors. (a, b) Double-label immunofluorescence performed with the anti-CD133 polyclonal antibody used by Ivanova et al. (pCD133, red) and the anti-CD133/2 monoclonal antibody (green) in embryonic human kidneys. The anti-CD133 antibody used by Ivanova et al. poorly stains primary vesicles, comma-shaped bodies and Sshaped bodies, while it extensively stains differentiated tubular cells as well as the differentiating ureteric bud (red). By contrast, the anti-CD133/2 antibody (green) selectively stains condensed mesenchyme-derived primordial structures, primary vesicles, comma-shaped bodies, S-shaped bodies and, in maturing glomeruli, the urinary pole of the Bowman’s capsule (arrows). In (b), asterisk indicates a maturing glomerulus. Merged areas appear in yellow. Topro-3 counterstains nuclei (blue). Bar 100 mm. (b0 ) Split image of the maturing glomerulus identified by the asterisk in (b). The arrow indicates the urinary pole of the Bowman’s capsule. Bar 50 mm (c) Double label immunofluorescence performed with the anti-CD133 polyclonal antibody used by Ivanova et al. (pCD133, red) and the anti-CD133/1 monoclonal antibody (green) in embryonic human kidneys. Only CD133/1 antibody selectively stains human progenitors of the Bowman’s capsule (arrow). Merged areas appear in yellow. Topro-3 counterstains nuclei (blue). Bar 100 mm.
we recommend the usage anti-CD133/1 or CD133/2 antibodies to detect or purify human renal progenitors. 1. 2.
3.
4. 5.
Ivanova L, Hiatt MJ, Yoder MC et al. Ontogeny of CD24 in the human kidney. Kidney Int 2010; 77: 1123–1131. Sagrinati C, Netti GS, Mazzinghi B et al. Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys. J Am Soc Nephrol 2006; 17: 2443–2456. Lazzeri E, Crescioli C, Ronconi E et al. Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. J Am Soc Nephrol 2007; 18: 3128–3138. Mizrak D, Brittan M, Alison MR. CD133: molecule of the moment. J Pathol 2008; 214: 3–9. Kemper K, Sprick MR, de Bree M et al. The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res 2010; 70: 719–729.
Maria L. Angelotti1,2, Elena Lazzeri1,2, Laura Lasagni1,2 and Paola Romagnani1 1 Department of Clinical Pathophysiology, Nephrology Section, University of Florence, Florence, Italy and 2Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
Kidney International (2010) 78, 619–623