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Losartan and renal sodium handling
  1. R JALAN
  1. Institute of Hepatology
  2. Royal Free and University College London
  3. Medical School
  4. 69–75 Chenies Mews, London WC1E 6HX, UK
  5. Cardiovascular Research Unit
  6. Department of Cardiology, Royal Infirmary
  7. Lauriston Place
  8. Edinburgh EH3 9YW, UK
  1. Dr R Jalan. Emailr.jalan{at}ucl.ac.uk
  1. D E NEWBY
  1. Institute of Hepatology
  2. Royal Free and University College London
  3. Medical School
  4. 69–75 Chenies Mews, London WC1E 6HX, UK
  5. Cardiovascular Research Unit
  6. Department of Cardiology, Royal Infirmary
  7. Lauriston Place
  8. Edinburgh EH3 9YW, UK
  1. Dr R Jalan. Emailr.jalan{at}ucl.ac.uk
  1. F WONG
  1. 9EN/220, Toronto General Hospital
  2. 200 Elizabeth Street, Toronto M5G 2C4
  3. Ontario, Canada
  4. florence.wong{at}utoronto.ca
  5. 9EN/220, Toronto General Hospital
  6. 200 Elizabeth Street, Toronto M5G 2C4
  7. Ontario, Canada and
  8. Gastroenterology Institute, Ichilov Hospital
  9. Tel Aviv, Israel
    1. L BLENDIS
    1. 9EN/220, Toronto General Hospital
    2. 200 Elizabeth Street, Toronto M5G 2C4
    3. Ontario, Canada
    4. florence.wong{at}utoronto.ca
    5. 9EN/220, Toronto General Hospital
    6. 200 Elizabeth Street, Toronto M5G 2C4
    7. Ontario, Canada and
    8. Gastroenterology Institute, Ichilov Hospital
    9. Tel Aviv, Israel

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      Editor,—We read with great interest the paper by Girgrah et al (

      ) . Their report suggests that the subtle sodium retention that is characteristic of preascitic cirrhosis is improved by administration of low dose losartan. This is despite the paradoxical observation of an angiotensin concentration that is significantly lower in patients compared with healthy volunteers (mean (SEM) patients 6 (2); controls 40 (10) pmol/l). Our results of angiotensin II measurements are at variance with those published by Girgrah et al and are summarised in fig 1.1 2 Our studies suggest that there is a progressive increase in angiotensin II concentrations with increasing severity of sodium retention. In fact, this increase in angiotensin II is evident before any measurable derangement in systemic haemodynamic characteristics.3 The values measured in healthy volunteers are also significantly higher than those reported in the literature.4 We are not sure if these differences in measured values are the result of different patient populations, differences in the method of collection of the sample (Girgrahet al—EDTA and aprotinin; Newbyet al and Helmy et al—0.5 ml of 0.45% O-phenanthroline and 1% disodium EDTA), or different assay techniques (were the samples extracted prior to the radioimmunoassay?).

      The authors hypothesise that the increase in renal sodium excretion observed after administration of losartan was possibly due to its effect on intrarenal angiotensin II secretion. If this were true then, why was there a significant increase in plasma angiotensin II concentrations after administration of losartan? Values of angiotensin II observed in this study are contradictory to expected values. Indeed, in patients with severe heart failure, mean values of 60–70 pg/ml are reported and a value >10 pg/ml in patients given angiotensin converting enzyme inhibitors is considered high.4 5 These findings question the pathophysiological interpretation of the main results of the study by Girgrah et al. It is more likely that improvement in sodium excretion after administration of losartan was due to its effect on reducing portal pressure6 which in turn alters renal function through the hepatorenal axis.7-9

      References

      Figure 1

      Measured angiotensin II concentrations in healthy volunteers (HV) and in patients with cirrhosis and varying degrees of severity of sodium retention (preascitic (PA) cirrhosis, diuretic responsive (DR) ascites, and refractory ascites). Our results are in pg/ml and the values reported by Girgrah et al are in pmol/l; 1 pg/ml is approximately equal to 1 pmol/l, taking the molecular weight of angiotensin II as 1046.2.**p<0.01 v controls; †p<0.05 v preascitic cirrhosis and controls; ‡p<0.05 v controls, preascitic cirrhosis, and refractory ascites.

      Reply

      Editor,—We thank Drs Jalan and Newby for their comments on our recent study (Gut2000;46:114–120). We understand that our findings of decreased angiotensin II levels in preascitic cirrhotic patients compared with normals are at variance with their findings of elevated levels in such patients.1-1 1-2 Before we comment on this, we will first address their second point that our results in healthy volunteers are higher than those previously reported.1-3 On reviewing the literature, we noted that our values were within the same “ballpark” as the reported reference values of 20 (7) pg/ml,1-3 whereas those from the Edinburgh group (3.2 (0.3) pg/ml1-1) are on the low side. Furthermore, their angiotensin II levels in cirrhotic patients with ascites (238 (30) pg/ml1-1) are several times higher than those reported in patients with severe heart failure.1-3 We believe the explanation for these disparate results in normals and patients is laboratory variation, which is why each investigation needs its own reference values.

      Concerning the differences between our findings and those of Helmyet al of increases in angiotensin II levels in preascitic patients, the Edinburgh group not surprisingly found an increase in plasma renin activity also. They acknowledge in their publications that this is at variance with much of the literature on the subject in which several studies found suppression of the renin-angiotensin-aldosterone system in preascitic patients in the supine position,1-4-1-8 the position the Edinburgh group used in their studies.1-1 1-2 In addition, their preascitic patients had normal levels of atrial natriuretic peptide, which is also at variance with much of the literature, as summarised in the review by Bernardi and colleagues.1-9 1-10 Hence how do we explain these differences? We cannot explain them in terms of decreased sodium intake as their patients were on a diet of 150 mmol of sodium per day. However, we noted that a significant percentage of their preascitic patients had primary biliary cirrhosis. These patients were cholestatic, giving rise to an unusually high mean serum bilirubin level (35 (12) μmol/l) for a group of preascitic cirrhotics.1-1 This in turn may have contributed to some of their preascitic patients being classified as Child B whereas such patients are generally in the Child A category.1-1 1-2 These cholestatic patients, with or without jaundice, also have elevated levels of serum bile acids which are vasodilators1-11 and could be partly responsible for the decreased effective blood volume in the jaundiced patients, even in the absence of cirrhosis.1-12 Relatively mild jaundice may also explain the reduced vascular responsiveness to angiotensin II found by the Edinburgh group.1-13

      In general, we largely agree with much of the Edinburgh group's findings. In particular, we agree with the increase in serum angiotensin II levels with deterioration of liver disease; with their findings after the TIPS procedure; and with the importance of liver function and portal hypertension in the pathogenesis of sodium retention in chronic liver disease. Therefore, we concur with their concluding remark that improvement in renal sodium handling found in preascitic cirrhotic patients after low dose losartan may well be due in part to the lowering effect of losartan on portal pressure.1-14

      References

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