923 SARALASIN BOLUS TEST
SIR,—We very interested to read the account by Dr Marks and his colleagues of their saralasin bolus test (Oct. 25, p. 784). Whilst their test has many advantages in simplicity and time, we have several reservations which we believe need to be considered before a bolus test is widely used as a screenwere
ing procedure. Saralasin has agonist as well as antagonist activity, on angiotensin-n vascular receptors, on release of renin from the juxtaglomerular apparatus, and on mechanisms controlling unne How and sodium excretion.’ 2 We believe that this agonist activity is dependent, firstly, on the endogenous level of angiotensin i) which in itself will be partly dependent on the state of sodium balance and, secondly, on the amount of saralisin infused. It is not surprising, using a bolus dose which is around 70 µg/kg/min for a 75 kg person, that initially, whatever the eventual response, a large rise in blood-pressure was seen by Dr Marks and his colleagues. It is possible that transiently the rise in blood-pressure may have been much higher, for the arteriosonde takes at least one minute to record one bloodpressure measurement. We would submit that such sudden large rises in blood-pressure subject the patient to the risk of a stroke. We ourselves have also noted that when saralasin is infused at an initial rate of 10 ug/kg/min all patients have a rise in blood-pressure. We now use an incremental rate of infusion starting at 0.25 ilg/kg/min; the rise in blood-pressure is much less, and under conditions of sodium depletion the rise only occurs in low-renin hypertensive patients. If large amounts of saralasin are given it is possible to miss patients who are on the borderline of angiotensin-n dependency. This may partly explain why Dr Marks and his colleagues had difficulty in obtaining a hypotensive response in
angiotensin-n dependent hypertensives on a normal diet. It would also explain why there was a further fall of blood-pressure below that achieved with a bolus injection when they were subsequently infused at 10 µg/kg/min. In sodium-depleted norfound that saralasin infused at 5 to 10 µg/kg/min caused no change in lying or standing blood-pressure. When they were infused using an incremental rate of infusion starting at 0.25 µg/kg/min there was a fall in standing blood-pressure which was maximal at an infusion-rate of 1 11g/kg/min. This fall in standing blood-pressure was largely abolished as the infusion-rate was increased to 10 ug/kg/min.2 Subsequently, we have infused all patients using an incremental rate of infusion and, in those patients that have responded, blood-pressure has always fallen at an infusion-rate below 2.5ug/kg/min. Recently saralasin even at small doses has been reported to cause hypotension ;3 and we have now seen this in patients with malignant hypertension, and in hypertensive patients on dialysis who have not been on any drug therapy. The fall in blood-pressure can be controlled by adjusting the rate of infusion.4 When screening large numbers of hypertensives using a 10 µg/kg/min infusion-rate we feel that there is a risk of severe hypotension occasionally occurring. This might also occur with a bolus injection although the agonist effect of this very large dose may prevent hypotension developing. For the above reasons, we feel at the present time that an incremental rate of infusion starting at 0.25 lkg/kg/min is preferable to a bolus injection. We did not intend to claim in our abstract of 5 patients with essential hypertension infused with saralasin5 that high-renin mals
high salt intake, do not show a fall in blood-pressure lying or standing when infused with saralasin on a low salt intake. This demonstrates that, in these patients with normal-renin hypertension, angiotensin-it is playing no direct role in maintaining their blood-pressure. Department of Medicine, Charing Cross Hospital Medical School, London W6.
GRAHAM A. MACGREGOR
Department of Pharmacology, I.C.I.,
Alderley Park,
P. M. DAWES
Cheshire.
COMBINED IMMUNOSUPPRESSION AND ANTICOAGULATION IN RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
SIR,-A tients with
year ago we’
presented data
on
16 consecutive pa-
rapid decline in renal function and extensive extracapillary proliferation around the glomerular tuft who had been treated with a combination of immunosuppressive drugs and anticoagulants. Although further informationhas emphasised the poor prognosis of patients with extracapillary proliferation, the role of multiple therapy directed against mediators of glomerular injury remains controversial, and controlled data are lacking. We review here a further year’s experience with this form of treatment. Criteria were as set out in our paper.’ Patients were included only if a renal biopsy showed at least 10 (and usually many more) glomeruli surrounded by extracapillary proliferation at least two cell-layers thick in more than 60% of glomeruli, and covering at least 60% of the glomerular circumference. Thus, patients with segmental crescents and those with a single layer of epithelial-cell "capsular reaction" were a
excluded.
we
1. Brown, C. B., Wilson, D., Turner, D., Cameron, J. C., Gill, D. Lancet, 1974, ii, 1174.
S., Ogg, C. S., Chantler,
essential
hypertensives are not angiotensin-n dependent, and apologise for this misunderstanding. What we intended to say, and have found, is that patients with essential hypertension who have values of angiotensin-n and plasma-renin acti-
we
vity within 1
our
normal range
on
their normal diet, and
on a
Mimran, A., Hinrichs, K. J., Hollenberg, N. K., Am J Physiol 1974, 226, 185
2 MacGregor, G. A., Dawes, P. M. J. clin. Pharmac. (in the press). 3. Pettinger, W. A., Keeton, K. Lancet, 1975, i, 1387. 4 MacGregor, G. A. ibid. July 26, 1975, p.181. 5 MacGregor, G. A., Markandu, N. D., Dawes, P M. Proceedings of the International Congress of Nephrology, Florence, Italy, 1975, p 519.
Sixth
Fig. 1—G.F.R. in 5 patients with dramatic improvement anticoagulation and immunosuppression.
coincident with
SIR,—We very interested to read the account by Dr Marks and his colleagues of their saralasin bolus test (Oct. 25, p. 784). Whilst their test has many advantages in simplicity and time, we have several reservations which we believe need to be considered before a bolus test is widely used as a screenwere
ing procedure. Saralasin has agonist as well as antagonist activity, on angiotensin-n vascular receptors, on release of renin from the juxtaglomerular apparatus, and on mechanisms controlling unne How and sodium excretion.’ 2 We believe that this agonist activity is dependent, firstly, on the endogenous level of angiotensin i) which in itself will be partly dependent on the state of sodium balance and, secondly, on the amount of saralisin infused. It is not surprising, using a bolus dose which is around 70 µg/kg/min for a 75 kg person, that initially, whatever the eventual response, a large rise in blood-pressure was seen by Dr Marks and his colleagues. It is possible that transiently the rise in blood-pressure may have been much higher, for the arteriosonde takes at least one minute to record one bloodpressure measurement. We would submit that such sudden large rises in blood-pressure subject the patient to the risk of a stroke. We ourselves have also noted that when saralasin is infused at an initial rate of 10 ug/kg/min all patients have a rise in blood-pressure. We now use an incremental rate of infusion starting at 0.25 ilg/kg/min; the rise in blood-pressure is much less, and under conditions of sodium depletion the rise only occurs in low-renin hypertensive patients. If large amounts of saralasin are given it is possible to miss patients who are on the borderline of angiotensin-n dependency. This may partly explain why Dr Marks and his colleagues had difficulty in obtaining a hypotensive response in
angiotensin-n dependent hypertensives on a normal diet. It would also explain why there was a further fall of blood-pressure below that achieved with a bolus injection when they were subsequently infused at 10 µg/kg/min. In sodium-depleted norfound that saralasin infused at 5 to 10 µg/kg/min caused no change in lying or standing blood-pressure. When they were infused using an incremental rate of infusion starting at 0.25 µg/kg/min there was a fall in standing blood-pressure which was maximal at an infusion-rate of 1 11g/kg/min. This fall in standing blood-pressure was largely abolished as the infusion-rate was increased to 10 ug/kg/min.2 Subsequently, we have infused all patients using an incremental rate of infusion and, in those patients that have responded, blood-pressure has always fallen at an infusion-rate below 2.5ug/kg/min. Recently saralasin even at small doses has been reported to cause hypotension ;3 and we have now seen this in patients with malignant hypertension, and in hypertensive patients on dialysis who have not been on any drug therapy. The fall in blood-pressure can be controlled by adjusting the rate of infusion.4 When screening large numbers of hypertensives using a 10 µg/kg/min infusion-rate we feel that there is a risk of severe hypotension occasionally occurring. This might also occur with a bolus injection although the agonist effect of this very large dose may prevent hypotension developing. For the above reasons, we feel at the present time that an incremental rate of infusion starting at 0.25 lkg/kg/min is preferable to a bolus injection. We did not intend to claim in our abstract of 5 patients with essential hypertension infused with saralasin5 that high-renin mals
high salt intake, do not show a fall in blood-pressure lying or standing when infused with saralasin on a low salt intake. This demonstrates that, in these patients with normal-renin hypertension, angiotensin-it is playing no direct role in maintaining their blood-pressure. Department of Medicine, Charing Cross Hospital Medical School, London W6.
GRAHAM A. MACGREGOR
Department of Pharmacology, I.C.I.,
Alderley Park,
P. M. DAWES
Cheshire.
COMBINED IMMUNOSUPPRESSION AND ANTICOAGULATION IN RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
SIR,-A tients with
year ago we’
presented data
on
16 consecutive pa-
rapid decline in renal function and extensive extracapillary proliferation around the glomerular tuft who had been treated with a combination of immunosuppressive drugs and anticoagulants. Although further informationhas emphasised the poor prognosis of patients with extracapillary proliferation, the role of multiple therapy directed against mediators of glomerular injury remains controversial, and controlled data are lacking. We review here a further year’s experience with this form of treatment. Criteria were as set out in our paper.’ Patients were included only if a renal biopsy showed at least 10 (and usually many more) glomeruli surrounded by extracapillary proliferation at least two cell-layers thick in more than 60% of glomeruli, and covering at least 60% of the glomerular circumference. Thus, patients with segmental crescents and those with a single layer of epithelial-cell "capsular reaction" were a
excluded.
we
1. Brown, C. B., Wilson, D., Turner, D., Cameron, J. C., Gill, D. Lancet, 1974, ii, 1174.
S., Ogg, C. S., Chantler,
essential
hypertensives are not angiotensin-n dependent, and apologise for this misunderstanding. What we intended to say, and have found, is that patients with essential hypertension who have values of angiotensin-n and plasma-renin acti-
we
vity within 1
our
normal range
on
their normal diet, and
on a
Mimran, A., Hinrichs, K. J., Hollenberg, N. K., Am J Physiol 1974, 226, 185
2 MacGregor, G. A., Dawes, P. M. J. clin. Pharmac. (in the press). 3. Pettinger, W. A., Keeton, K. Lancet, 1975, i, 1387. 4 MacGregor, G. A. ibid. July 26, 1975, p.181. 5 MacGregor, G. A., Markandu, N. D., Dawes, P M. Proceedings of the International Congress of Nephrology, Florence, Italy, 1975, p 519.
Sixth
Fig. 1—G.F.R. in 5 patients with dramatic improvement anticoagulation and immunosuppression.
coincident with
