412
The results suggest restriction that will stop
a
need
to assess
the
degree of protein
progression.
Second Department of Internal Medicine, Tokyo Medical and Dental University, 5-45, Yushima 1-chome, Bunhyo-ku, Tokyo 113, Japan
MASAYOSHI SHICHIRI YASUHIDE NISHIO FUMIAKI MARUMO
1. Marom
BJ, Steinmann TI, Mitch WE. A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 1985; 27: 58-65.
FK-506 and haemolytic uraemic syndrome SIR,-Dr McCauley and colleagues (Dec 23/30, p 1516) suggest that FK-506, unlike cyclosporin, may not be a risk factor for the induction of haemolytic uraemic syndrome (HUS). The pathogenesis of HUS involves a final common pathway of endothelial injury and subsequent platelet activation. Remuzzi et al found that in some types of HUS vascular endothelium failed to produce prostacyclin.1 We have argued that both the nephrotoxicity and the propensity of patients receiving cyclosporin to acquire HUS might be related to a direct effect of cyclosporin on vascular endothelium, mediated through the inhibition of prostacyclin production.2 In support of this we found that cyclosporin, in a dose and time dependent manner, could inhibit agonist-stimulated prostacyclin synthesis by human umbilical vein endothelial cells (HUVEC) in culture,3-5 in concentrations that were not cytotoxic (01-5-0 g/ml). In contrast, FK-506 in comparable immunosuppressive doses (0-01-1 g/ml) did not inhibit agoniststimulated prostacyclin synthesis. Confluent HUVEC were treated for 24 h at 37°C with 500 (il FK-506 (0-01-20 JlgJml), solvent only (methanol), or culture medium only (medium 199 plus 20% fetal calf serum). HUVEC monolayers were then stimulated with 2 U/ml of human thrombin for 15 min at 37°C. Experiments were done in duplicate and repeated three to five times. Prostacyclin produced was measured by radioimmunoassay of its stable metabolite 6-keto-prostaglandin Fj(l’ Cytotoxicity, assessed by [3H]-adenine uptake assay, occurred only at very high concentrations of FK-506
(above
10
jig/ml).
Our results support McCauley and colleagues’ view that immunosuppressive doses of FK-506 do not affect the endothelium in the same manner as cyclosporin does. Department of Renal Medicine, Institute of Urology (UCMSM), St Phillip’s Hospital, London WC2A 2EX, UK
Z. BROWN G. H. NEILD
1. Remuzzi G, Misiani
R, Marchesi D, et al. Haemolytic uraemic syndrome: deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 1978; i: 871-72. 2. Neild GH, Rocchi G, Imberti L, et al. Effect of cyclosporin A on prostacyclin synthesis by vascular tissue. Thromb Res 1983; 32: 373-79. 3. Brown Z, Neild GH. Cyclosporin inhibits prostacyclin production by cultured human endothelial cells. Transpl Proc 1987; 19: 1178-80. 4. Brown Z, Neild GH, Levis G. Mechanism of cyclosporine inhibition of prostacyclin synthesis by cultured human umbilical vein endothelial cells. Transpl Proc 1988; 20 (suppl 3): 654-57. 5. Brown Z, Neild GH, Lews GP. Inhibition of prostacyclin formation by cyclosporin is due to reduced availability of arachidonic add in membrane cultured human endothelial cells. Biochem Pharmacol (in press). not
phospholipids of
In the treatment for high blood pressure, even the sceptics accept ithat an excretion rate as high as 90 mmol per 24 h can have a small but measurable effect.4.5 The safety of the RDI is not questioned in Australia and, in a trial of a low-salt diet for mild hypertension, 45 patients with a mean sodium excretion rate as low as 37 mmol per 24 h reported no adverse effects in the full heat of the Canberra surnmer.6 Several of these patients were long-distance runners, who enjoyed having a cleaner (low-salt) sweat. Prevention of hypertension may involve a mechanism different from reversal,’ but the Intersalt data’ are no advertisement for a salt intake above the Australian RDI. Menzies Centre for
Population Health Research,
Hobart, Tasmania 7000, Australia 1. 2. 3.
TREVOR C. BEARD
Muldowney FP, Freaney R, Moloney MF. Importance of dietary sodium m the hypercalcaemic syndrome. Kidney Int 1982; 22: 292-96. Coe FL, Favus MJ. Nephrolithiasis. In: Petersdorf RG, et al, eds. Harrison’s principles of internal medicine, 10th ed. New York: McGraw Hill, 1983: 1672-76. Goulding A, Everitt HE, Cooney JM, Spears GFS. Sodium and osteoporosis. In. Wahlqvist ML, Truswell AS. Recent advances in clinical nutrition. London. John
Libbey, 1986: 99-108. 4. Australian NH and MRC Dietary Salt Sudy Management Committee. Fall in blood pressure with modest reduction in dietary salt intake in mild hypertension. Lancet 1989; i: 399-402. 5. Graudal N, Galløe A. Effect of salt restriction on hypertension. Lancet 1989; ii: 41-42 6. Beard TC, Cooke HM, Gray WR, Barge R. Randomised controlled trial of a no-added-sodium diet for mild hypertension. Lancet 1982; ii: 455-58. 7. Intersalt Cooperative Research Group. Intersalt, an international study of electrolyte excretion and blood pressure: results for 24 hour urinary sodium and potassium excretion. Br Med J 1988; 297: 319-28.
Adrenocortical function in patients on simvastatin Candrina and SiR,-Dr colleagues (Jan 6, p 53) report that the potent cholesterol synthesis inhibitor simvastatin did not affect basal or corticotropin (ACTH) stimulated cortisol concentrations in ten patients with familial hypercholesterolaemia. In a single-blind placebo-controlled study we treated 24 such patients with 40 mg simvastatin per day. During the placebo period and after 8 weeks of treatment, the cortisol response to a short infusion of 0-25 mg ACTH and basal levels of cortisol and ACTH and their response to insulin-induced hypoglycaemia (0-1 U ‘Actrapid’/kg) were measured.1 Serum cholesterol fell significantly by 35%, as did the low-density lipoprotein fraction (40%); high-density lipoprotein cholesterol increased by 9%. After simvastatin treatment, the basal ACTH/cortisol ratio rose significantly (table), suggesting that a higher level of ACTH was needed to maintain the basal cortisol level. The response to the short ACTH test after treatment was reduced (lower peak cortisol [table] and lower plasma cortisol at 30 and 90 min). On the day of the insulin tolerance test, changes in basal ACTH and cortisol were less pronounced but were in the same direction. Cortisol responses during insulin-induced hypoglycaemia were unaffected by treatment.
fmdings suggest some impairment of adrenocortical by simvastatin, this being revealed only after a supraphysiological stimulation of the adrenal cortex. When compared with the effects of drugs such as ketoconazole on steroid These
reserve
Greenhouse effect, renal calculi, and salt SiR,—To prevent
an
increase in urolithiasis in the hotter months
predicted from the greenhouse effect, Dr Curtin and Dr Sampson (Nov 4, p 1110) suggest that the British public should be advised to drink more fluids. This advice would obviously help, but if people also reduced their salt intake to comply with the Australian recommended dietary intake (RDI) of 40-100 mmol per day, they would reduce the obligatory calcium loss that accompanies a salted diet.1 About 75-85 % of stone formers have calcium stones resulting from "idiopathic hypercalciuria"/ but hypercalciuria at a sodium excretion rate of 200 mmol per day is often converted to normocalciuria at 80 mmol per day.1 Healthy subjects also have an obligatory calcium loss at the usual salt intake for western countries, and through the same mechanism Goulding and colleagues3 have predicted that in New Zealand a reduction to 70 mmol per day would help to prevent osteoporosis by reducing urinary calcium losses by 32% in men and 27% in women.
EFFECT OF SIMVASTATIN ON BASAL ACTH LEVELS AND CORTISOL RESPONSE (MEAN AND SD)
The results suggest restriction that will stop
a
need
to assess
the
degree of protein
progression.
Second Department of Internal Medicine, Tokyo Medical and Dental University, 5-45, Yushima 1-chome, Bunhyo-ku, Tokyo 113, Japan
MASAYOSHI SHICHIRI YASUHIDE NISHIO FUMIAKI MARUMO
1. Marom
BJ, Steinmann TI, Mitch WE. A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 1985; 27: 58-65.
FK-506 and haemolytic uraemic syndrome SIR,-Dr McCauley and colleagues (Dec 23/30, p 1516) suggest that FK-506, unlike cyclosporin, may not be a risk factor for the induction of haemolytic uraemic syndrome (HUS). The pathogenesis of HUS involves a final common pathway of endothelial injury and subsequent platelet activation. Remuzzi et al found that in some types of HUS vascular endothelium failed to produce prostacyclin.1 We have argued that both the nephrotoxicity and the propensity of patients receiving cyclosporin to acquire HUS might be related to a direct effect of cyclosporin on vascular endothelium, mediated through the inhibition of prostacyclin production.2 In support of this we found that cyclosporin, in a dose and time dependent manner, could inhibit agonist-stimulated prostacyclin synthesis by human umbilical vein endothelial cells (HUVEC) in culture,3-5 in concentrations that were not cytotoxic (01-5-0 g/ml). In contrast, FK-506 in comparable immunosuppressive doses (0-01-1 g/ml) did not inhibit agoniststimulated prostacyclin synthesis. Confluent HUVEC were treated for 24 h at 37°C with 500 (il FK-506 (0-01-20 JlgJml), solvent only (methanol), or culture medium only (medium 199 plus 20% fetal calf serum). HUVEC monolayers were then stimulated with 2 U/ml of human thrombin for 15 min at 37°C. Experiments were done in duplicate and repeated three to five times. Prostacyclin produced was measured by radioimmunoassay of its stable metabolite 6-keto-prostaglandin Fj(l’ Cytotoxicity, assessed by [3H]-adenine uptake assay, occurred only at very high concentrations of FK-506
(above
10
jig/ml).
Our results support McCauley and colleagues’ view that immunosuppressive doses of FK-506 do not affect the endothelium in the same manner as cyclosporin does. Department of Renal Medicine, Institute of Urology (UCMSM), St Phillip’s Hospital, London WC2A 2EX, UK
Z. BROWN G. H. NEILD
1. Remuzzi G, Misiani
R, Marchesi D, et al. Haemolytic uraemic syndrome: deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 1978; i: 871-72. 2. Neild GH, Rocchi G, Imberti L, et al. Effect of cyclosporin A on prostacyclin synthesis by vascular tissue. Thromb Res 1983; 32: 373-79. 3. Brown Z, Neild GH. Cyclosporin inhibits prostacyclin production by cultured human endothelial cells. Transpl Proc 1987; 19: 1178-80. 4. Brown Z, Neild GH, Levis G. Mechanism of cyclosporine inhibition of prostacyclin synthesis by cultured human umbilical vein endothelial cells. Transpl Proc 1988; 20 (suppl 3): 654-57. 5. Brown Z, Neild GH, Lews GP. Inhibition of prostacyclin formation by cyclosporin is due to reduced availability of arachidonic add in membrane cultured human endothelial cells. Biochem Pharmacol (in press). not
phospholipids of
In the treatment for high blood pressure, even the sceptics accept ithat an excretion rate as high as 90 mmol per 24 h can have a small but measurable effect.4.5 The safety of the RDI is not questioned in Australia and, in a trial of a low-salt diet for mild hypertension, 45 patients with a mean sodium excretion rate as low as 37 mmol per 24 h reported no adverse effects in the full heat of the Canberra surnmer.6 Several of these patients were long-distance runners, who enjoyed having a cleaner (low-salt) sweat. Prevention of hypertension may involve a mechanism different from reversal,’ but the Intersalt data’ are no advertisement for a salt intake above the Australian RDI. Menzies Centre for
Population Health Research,
Hobart, Tasmania 7000, Australia 1. 2. 3.
TREVOR C. BEARD
Muldowney FP, Freaney R, Moloney MF. Importance of dietary sodium m the hypercalcaemic syndrome. Kidney Int 1982; 22: 292-96. Coe FL, Favus MJ. Nephrolithiasis. In: Petersdorf RG, et al, eds. Harrison’s principles of internal medicine, 10th ed. New York: McGraw Hill, 1983: 1672-76. Goulding A, Everitt HE, Cooney JM, Spears GFS. Sodium and osteoporosis. In. Wahlqvist ML, Truswell AS. Recent advances in clinical nutrition. London. John
Libbey, 1986: 99-108. 4. Australian NH and MRC Dietary Salt Sudy Management Committee. Fall in blood pressure with modest reduction in dietary salt intake in mild hypertension. Lancet 1989; i: 399-402. 5. Graudal N, Galløe A. Effect of salt restriction on hypertension. Lancet 1989; ii: 41-42 6. Beard TC, Cooke HM, Gray WR, Barge R. Randomised controlled trial of a no-added-sodium diet for mild hypertension. Lancet 1982; ii: 455-58. 7. Intersalt Cooperative Research Group. Intersalt, an international study of electrolyte excretion and blood pressure: results for 24 hour urinary sodium and potassium excretion. Br Med J 1988; 297: 319-28.
Adrenocortical function in patients on simvastatin Candrina and SiR,-Dr colleagues (Jan 6, p 53) report that the potent cholesterol synthesis inhibitor simvastatin did not affect basal or corticotropin (ACTH) stimulated cortisol concentrations in ten patients with familial hypercholesterolaemia. In a single-blind placebo-controlled study we treated 24 such patients with 40 mg simvastatin per day. During the placebo period and after 8 weeks of treatment, the cortisol response to a short infusion of 0-25 mg ACTH and basal levels of cortisol and ACTH and their response to insulin-induced hypoglycaemia (0-1 U ‘Actrapid’/kg) were measured.1 Serum cholesterol fell significantly by 35%, as did the low-density lipoprotein fraction (40%); high-density lipoprotein cholesterol increased by 9%. After simvastatin treatment, the basal ACTH/cortisol ratio rose significantly (table), suggesting that a higher level of ACTH was needed to maintain the basal cortisol level. The response to the short ACTH test after treatment was reduced (lower peak cortisol [table] and lower plasma cortisol at 30 and 90 min). On the day of the insulin tolerance test, changes in basal ACTH and cortisol were less pronounced but were in the same direction. Cortisol responses during insulin-induced hypoglycaemia were unaffected by treatment.
fmdings suggest some impairment of adrenocortical by simvastatin, this being revealed only after a supraphysiological stimulation of the adrenal cortex. When compared with the effects of drugs such as ketoconazole on steroid These
reserve
Greenhouse effect, renal calculi, and salt SiR,—To prevent
an
increase in urolithiasis in the hotter months
predicted from the greenhouse effect, Dr Curtin and Dr Sampson (Nov 4, p 1110) suggest that the British public should be advised to drink more fluids. This advice would obviously help, but if people also reduced their salt intake to comply with the Australian recommended dietary intake (RDI) of 40-100 mmol per day, they would reduce the obligatory calcium loss that accompanies a salted diet.1 About 75-85 % of stone formers have calcium stones resulting from "idiopathic hypercalciuria"/ but hypercalciuria at a sodium excretion rate of 200 mmol per day is often converted to normocalciuria at 80 mmol per day.1 Healthy subjects also have an obligatory calcium loss at the usual salt intake for western countries, and through the same mechanism Goulding and colleagues3 have predicted that in New Zealand a reduction to 70 mmol per day would help to prevent osteoporosis by reducing urinary calcium losses by 32% in men and 27% in women.
EFFECT OF SIMVASTATIN ON BASAL ACTH LEVELS AND CORTISOL RESPONSE (MEAN AND SD)
