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Intravenous diazoxide in acute poststreptococcal glomerulonephritis
PEDIATRIC PHARMACOLOGY T H E R A P E U T I C S PaulS. Lietman, Editor
AND
Intravenous diazoxide in acute poststreptococcal glomerulonephritis Twenty-six patients with hypertension secondary to acute poststreptococcal glomerulonephritis were treated by the rapid intravenous infusion of diazoxide. The average pretreatment systolic pressure was 159 mm Hg, Five minutes after administration, the average systolic pressure was 122 mm Hg (a 23% reduction). The average initial diastolic pressure was 104 mm Hg, which fell 5 minutes after diazoxide injection to 71 mm Hg (a 32% reduction). No hypotensive episodes were noted. Occasional episodes o f nausea occurred. Concentrations of blood glucose increased after administration of diazoxide; however, no values were above 155 mg/dl. Diazoxide appears to be a safe antihypertensive drug that is effective in the treatment of hypertension secondary to acute poststreptococcal glomerulonephritis.
E. C. Kohaut, M.D.,* C. J. Wilson, M.D., and L. Leighton Hill, M.D., Houston, Texas
DIAZOXIDE was first reported to have antihypertensive effects in 19611 and later shown to lower blood pressure after intravenous administration. 2 The mode of action involves the relaxation of peripheral vascular smooth muscle with a consequent reduction in peripheral resistance? -4 The antihypertensive effect is not altered by sympathectomy, suggesting a direct action on smooth muscle2 Recently, it has been shown that the primary effect of diazoxide is reduction in postcapillary rather than precapillary resistance? The use of diazoxide in the therapy of hypertensive crises in adults is well recognized. In 1971, McLaine and Drummond 7 reported it to be effective and safe in the treatment of severe hypertensive crises in childreru The present study was carried out to assess the efficacy and safety of diazoxide in treating hypertension secondary to From the Renal Section, Department o f Pediatrics, Baylor College o f Medicine. Supported by the United States Public Health Service Training Grant 5-TO1-AM-05432; the Beta Sigma Phi Metabolic Research Fund of the Department o f Pediatrics, Baylor College of Medicine; and RRO0188from the General Clinical Research Center Program of the Division of Research Resources, National Institutes of Health. *Reprint address: 1200 Moursund A re., Houston, Texas 77025.
acute poststreptococcal glomerulonephritis, a common cause of hypertension in children.
METHODS Patients under 14 years of age admitted to Texas Children's Hospital or Ben Taub General Hospital with historic, physical, and laboratory findings compatible with acute glomerulonephritis were considered for the study. The criteria for diagnosis of acute glomerulonephritis generally included an antecedent infection, followed by a latent period ( > 4 days), and then the acute onset of edema, hypertension, hematuria, and proteinuria. However, all of those historic, physical, and laboratory findAbbreviation used GFR: glomerular filtration rate
]
ings were not necessary for diagnosis. If an important component such as proteinuria was absent, then the other major features had to be present. The clinical syndrome included cylindruria, oliguria, anemia, circulatory congestion, and encephalopathy in a varying number of patients. Patients without culture or serologic evidence of recent streptococcal infection were eliminated from the study group. Also excluded were patients with lupus erythematosus, anaphylactoid purpura, hemolytic-uremic syndrome, sickle cell disease, congenital heart disease, or a history to suggest antecedent renal disease. Blood presThe Journal of P E D I A T R I C S Vol. 87, No. 5, pp. 795-798
795
796
Kohaut, Wilson, and Hill
180-
The Journal of Pediatrics November 1975
RESPONSE TO INITIAL DOSE OF
160" w n,.
rr-'r
140-
,aO"
~-E c~E I000 0 ,.J
m
80-
6o40-
6
~
min.
3'0
rain.
hr.
~
hrs,
t~
~4
hrs~ hrs.
Fig. 1. The average blood pressure is plotted against time following the initial dose of diazoxide. Brackets represent 2 SD from the mean.
sures were obtained while the patient was supine and quiet, with a cuff which measured two-thirds the length of the upper arm. Patients less than 5 years of age were admitted to the study group if their diastolic blood pressures were persistently greater than 90 mm Hg. Patients over 5 years of age were included if their diastolic blood pressures were persistently above 100 mm Hg. The total number of patients admitted to the study was 26. The dose of diazoxide was 5 mg/kg by rapid intravenous injection. In most cases, the dose was administered within 15 seconds. Blood pressures were recorded every 5 minutes for 30 minutes, every 15 minutes for 2 hours, hourly for the next day, and then every 4 hours until discharge. Blood glucose values were determined before diazoxide administration and at 1, 6, and 24 hours, respectively, after each injection. Admission and daily body weights were obtained. Patients were given repeat injections of diazoxide if the blood pressure increased to and persisted at levels which met the criteria for admission into the study. No other antihypertensive drugs were used. Furosemide was used at the discretion of the patient's primary physician. Twenty-one of 26 patients received furosemide at some point during the course of their disease. RESULTS
Antihypertensive effect (Fig. 1). A total of 47 doses of diazoxlde was given to the 26 patients. The average preinjection systolic blood pressure was 159 mm Hg with a reduction to 122 mm Hg 5 minutes after administration. Although individual variation occurred, the average systolic blood pressure remained at the same level over the next 24 hours. The average initial diastolic blood pressure was I04 mm Fig with a reduction to 7I mm Hg (average) 5 minutes postinjection. The average diastolic
blood pressure showed a slight tendency to increase over the next 12 hours. Duration of effect (Fig. 2). Eight of the 26 patients required no further antihypertensive therapy. Of the 18 patients who required repeat doses, the average interval between the first and second dose was 41 hours, with a range of 8 to 95 hours. Three patients required a third dose of diazoxide. The average interval between the second and third dose was 36 hours. Blood glucose. The average preinjection concentration of blood glucose was 82 mg/dl, increasing to an average of 100 mg/dl at 1 hour and to 111 mg/dl at 6 hours after injection. Twenty-four hours postinjection, the average blood glucose value was at preinjection levels. The highest blood glucose value recorded was 155 mg/dl. The majority of these patients were anorexic with limited caloric intake. The relationship between meals and glucose determinations was not noted. Weight. After 5 days of hospitalization, patients in the study group lost an average of 8.3% of initial body weight. There was no difference in the weight loss of those receiving a single dose as compared to those receiving multiple doses. Adverse reactions. Occasional episodes of transient nausea occurred immediately after administration of diazoxide. No vomiting occurred and no other adverse reactions such as significant tachycardia or burning at the injection site were recognized. DISCUSSION These data indicate that diazoxide is effective a n d safe in the treatment of hypertension associated with acute poststreptococcal glomerulonephritis. Since 18 of the 26 patients required repeat doses, a total of 47 doses were given9 In every case, a fall in blood pressure to acceptable levels was noted within 5 minutes of injection. Systolic pressure decreased by an average of 23% and diastolic pressure decreased by an average of 32% within 5 minutes. Patients receiving diazoxide alone responded as welt as those who received both diazoxide and furosemide. Although transient hypotensive episodes have been reported in children after the intravenous administration of d i a z o x i d e / n o n e were noted in this study. No symptoms which could be attributed to reduced cerebral blood flow were observed following rapid drop in blood pressure. Thirteen patients had symptoms of hypertensive encephalopathy which rapidly abated following reduction in blood pressure, In 18 patients, a repeat dose of diazoxide was required an average of 41 hours after injection. The duration of action was Ionger than previously noted in children. The half-life of diazoxide given orally to hypoglycemic chip
Volume 87 Number 5
Diazoxide in poststreptococcal glomerulonephritis
797
INTERVAL BETWEEN FIRST AND SECOND DOSE IN EIGHTEEN PATIENTS REQUIRING REPEAT DIAZOXIDE INFUSION 8
Q II
11 J,
1.
It v v
It
w
HOURS Fig. 2. The length of time blood pressure remained controlled following the initial dose of diazoxide is shown in the 18 patients who required repeat doses.
dren who were free of renal disease is said to be 24 hours; 33% is excreted unchanged in the urine. ~ The prolonged effect seen in these patients may have been related to reduced renal excretion secondary to their renal disease. Hyperglycemia is a well-recognized side effect of therapy with diazoxide. Blood glucose determinations were systematically followed in our patients. One-half of the patients had elevations above, normal fasting levels. In only four patients did the level exceed 120 m g / d l and the highest blood glucose value recorded was 155 mg/dl in a patient who received two doses of diazoxide within 18 hours. The effect of diazoxide on glomerular filtration rate is controversial. One study suggested that G F R remained reduced as long as blood pressure remained decreased below preinjection valuesY Recently, it has been demonstrated that an initial fall in G F R after diazoxide was followed by a rapid return to normal? ~ None of the patients we studied had a significant increase in the concentration of blood urea nitrogen following diazoxide therapy. The sodium-retaining effects of diazoxide therapy were reported in 1962,11 and it has been suggested that this effect is on proximal tubular reabsorption of s o d i u m : ~'- ~= Theoretically, diazoxide therapy might enhance edema and circulatory congestion in acute glomerulonephritis, a disease in which abnormal renal salt and water retention is the primary physiologic defect. However, weight loss in our patients was satisfactory (8.3% in 5 days) and prolonged edema was not noted. Weight loss in the patients who required multiple doses was no different from those in the single dose group. Diazoxide did not diminish
the effect of furosemide in those patients receiving both drugs. Powell and associates 13 have demonstrated very low plasma renin activity in ten patients with acute glomerulonephritis and suggested that the degree of hypertension was directly related to the degree of hypervolemia. However, Repetto and associates 14 noted that blood pressure remained elevated despite a significant furosemideinduced diuresis in five patients. This has also been the authors' experience. The effectiveness of diazoxide therapy suggests that at least a relative increase in peripheral vascular resistance may also be present. This could explain why some patients continue to be hypertensive, despite diuresis and loss of edema. These data suggest that diazoxide is a safe and effective agent in the treatment of hypertension associated with acute poststreptococcal glomerulonephritis in childhood. Since it does not produce central nervous system depression and its onset of action is immediate, we feel it is particularly efficacious in patients with symptoms of hypertensive encephalopathy. Blood glucose values must be monitored especially in patients receiving multiple doses of diazoxide. We would like to thank Alvin Jaffee, M.D., for allowing many of his patients to be treated under this protocol. REFERENCES
1. Rubin AA, Roth FE, Winbury MM, Topliss JG, Sherlock MH, Sperber N, and Bloack J: New class of antihypertensive agents, Science 133:2067, 1961. 2. Rubin AA, Roth FE, and' Winbury MM: A non-diuretic benzothiazide with antihypertensive properties, Nature 192:176, 1961.
798
Kohaut, Wilson, and Hill
3. Thomson AE, Nickerson M, Gaskell P, and Grahame GR: Clinical observations on an antihypertensive chlorothiazide analogue devoid of diuretic activity, Can Med Assoc J 87:1306, 1962. 4. Rubin AA, Zitowitz L, and Hausler L: Acute circulatory effects of diazoxide and sodium nitrate, J Pharmacol Exp Ther 140:46, 1963. 5. Ogilvie RI, and Schlieper E: Comparative effects of ethacrynic acid furosemide and diazoxide in the perfused dog hindlimb, Can J Physiol Pharmacol 49:1038, 1971. 6. Larochelle P, Milkulic E, and Ogilvie RI: Effects ofisoproterenol, diazoxide, ethacrynic acid, and furosemide on skeletal muscle vascular resistance, Can J Physiol Pharmacol 51:183, 1973. 7. McLaine PN, and Drummond KN: Intravenous diazoxide for severe hypertension in childhood, J PEDIATR 79:829, 1971. 8. Pruitt AW, Dayton PG, and Patterson JH: Disposition of diazoxide in children, Clin Pharmacol Ther 14:73, 1973.
The Journal of Pediatrics November 1975
9. Johnson BF: Diazoxide and renal function in man, Clin Pharmacol Ther 12:815, 1971. 10. Rado JP, Szende L, Tako J, and Halmos T: Effects of intravenous diazoxide and chlorpropamide on renal function in man, Am Heart J 85:755, 1973. 11. Hutcheon DE, and Barthalmus KS: Antihypertensive action of diazoxide: a new benzothiadiazine with antidiuretic properties, Br Meal J 2:159, 1962. 12. Kohaut EC, Wilson CJ, and Hill LL: Progressive volume expansion and diazoxide infusion under hypotonic saline diuresis in Bartter's syndrome, Clin Res 23:74A, 1975. 13. Powell HR, Rotenberg E, Williams AL, and McCredie DA: Plasma renin activitv in acute post-streptococcal glomerulonephritis and the haemolytic-uraemic syndrome, Arch Dis Child 49:802, 1974. 14. Repetto HA, Lewy JE, Brando JL, and Metcoff J: The renal functional response to Furosemide in children with acute nephritis, J PEDIATR 80:660, 1972,
AND
Intravenous diazoxide in acute poststreptococcal glomerulonephritis Twenty-six patients with hypertension secondary to acute poststreptococcal glomerulonephritis were treated by the rapid intravenous infusion of diazoxide. The average pretreatment systolic pressure was 159 mm Hg, Five minutes after administration, the average systolic pressure was 122 mm Hg (a 23% reduction). The average initial diastolic pressure was 104 mm Hg, which fell 5 minutes after diazoxide injection to 71 mm Hg (a 32% reduction). No hypotensive episodes were noted. Occasional episodes o f nausea occurred. Concentrations of blood glucose increased after administration of diazoxide; however, no values were above 155 mg/dl. Diazoxide appears to be a safe antihypertensive drug that is effective in the treatment of hypertension secondary to acute poststreptococcal glomerulonephritis.
E. C. Kohaut, M.D.,* C. J. Wilson, M.D., and L. Leighton Hill, M.D., Houston, Texas
DIAZOXIDE was first reported to have antihypertensive effects in 19611 and later shown to lower blood pressure after intravenous administration. 2 The mode of action involves the relaxation of peripheral vascular smooth muscle with a consequent reduction in peripheral resistance? -4 The antihypertensive effect is not altered by sympathectomy, suggesting a direct action on smooth muscle2 Recently, it has been shown that the primary effect of diazoxide is reduction in postcapillary rather than precapillary resistance? The use of diazoxide in the therapy of hypertensive crises in adults is well recognized. In 1971, McLaine and Drummond 7 reported it to be effective and safe in the treatment of severe hypertensive crises in childreru The present study was carried out to assess the efficacy and safety of diazoxide in treating hypertension secondary to From the Renal Section, Department o f Pediatrics, Baylor College o f Medicine. Supported by the United States Public Health Service Training Grant 5-TO1-AM-05432; the Beta Sigma Phi Metabolic Research Fund of the Department o f Pediatrics, Baylor College of Medicine; and RRO0188from the General Clinical Research Center Program of the Division of Research Resources, National Institutes of Health. *Reprint address: 1200 Moursund A re., Houston, Texas 77025.
acute poststreptococcal glomerulonephritis, a common cause of hypertension in children.
METHODS Patients under 14 years of age admitted to Texas Children's Hospital or Ben Taub General Hospital with historic, physical, and laboratory findings compatible with acute glomerulonephritis were considered for the study. The criteria for diagnosis of acute glomerulonephritis generally included an antecedent infection, followed by a latent period ( > 4 days), and then the acute onset of edema, hypertension, hematuria, and proteinuria. However, all of those historic, physical, and laboratory findAbbreviation used GFR: glomerular filtration rate
]
ings were not necessary for diagnosis. If an important component such as proteinuria was absent, then the other major features had to be present. The clinical syndrome included cylindruria, oliguria, anemia, circulatory congestion, and encephalopathy in a varying number of patients. Patients without culture or serologic evidence of recent streptococcal infection were eliminated from the study group. Also excluded were patients with lupus erythematosus, anaphylactoid purpura, hemolytic-uremic syndrome, sickle cell disease, congenital heart disease, or a history to suggest antecedent renal disease. Blood presThe Journal of P E D I A T R I C S Vol. 87, No. 5, pp. 795-798
795
796
Kohaut, Wilson, and Hill
180-
The Journal of Pediatrics November 1975
RESPONSE TO INITIAL DOSE OF
160" w n,.
rr-'r
140-
,aO"
~-E c~E I000 0 ,.J
m
80-
6o40-
6
~
min.
3'0
rain.
hr.
~
hrs,
t~
~4
hrs~ hrs.
Fig. 1. The average blood pressure is plotted against time following the initial dose of diazoxide. Brackets represent 2 SD from the mean.
sures were obtained while the patient was supine and quiet, with a cuff which measured two-thirds the length of the upper arm. Patients less than 5 years of age were admitted to the study group if their diastolic blood pressures were persistently greater than 90 mm Hg. Patients over 5 years of age were included if their diastolic blood pressures were persistently above 100 mm Hg. The total number of patients admitted to the study was 26. The dose of diazoxide was 5 mg/kg by rapid intravenous injection. In most cases, the dose was administered within 15 seconds. Blood pressures were recorded every 5 minutes for 30 minutes, every 15 minutes for 2 hours, hourly for the next day, and then every 4 hours until discharge. Blood glucose values were determined before diazoxide administration and at 1, 6, and 24 hours, respectively, after each injection. Admission and daily body weights were obtained. Patients were given repeat injections of diazoxide if the blood pressure increased to and persisted at levels which met the criteria for admission into the study. No other antihypertensive drugs were used. Furosemide was used at the discretion of the patient's primary physician. Twenty-one of 26 patients received furosemide at some point during the course of their disease. RESULTS
Antihypertensive effect (Fig. 1). A total of 47 doses of diazoxlde was given to the 26 patients. The average preinjection systolic blood pressure was 159 mm Hg with a reduction to 122 mm Hg 5 minutes after administration. Although individual variation occurred, the average systolic blood pressure remained at the same level over the next 24 hours. The average initial diastolic blood pressure was I04 mm Fig with a reduction to 7I mm Hg (average) 5 minutes postinjection. The average diastolic
blood pressure showed a slight tendency to increase over the next 12 hours. Duration of effect (Fig. 2). Eight of the 26 patients required no further antihypertensive therapy. Of the 18 patients who required repeat doses, the average interval between the first and second dose was 41 hours, with a range of 8 to 95 hours. Three patients required a third dose of diazoxide. The average interval between the second and third dose was 36 hours. Blood glucose. The average preinjection concentration of blood glucose was 82 mg/dl, increasing to an average of 100 mg/dl at 1 hour and to 111 mg/dl at 6 hours after injection. Twenty-four hours postinjection, the average blood glucose value was at preinjection levels. The highest blood glucose value recorded was 155 mg/dl. The majority of these patients were anorexic with limited caloric intake. The relationship between meals and glucose determinations was not noted. Weight. After 5 days of hospitalization, patients in the study group lost an average of 8.3% of initial body weight. There was no difference in the weight loss of those receiving a single dose as compared to those receiving multiple doses. Adverse reactions. Occasional episodes of transient nausea occurred immediately after administration of diazoxide. No vomiting occurred and no other adverse reactions such as significant tachycardia or burning at the injection site were recognized. DISCUSSION These data indicate that diazoxide is effective a n d safe in the treatment of hypertension associated with acute poststreptococcal glomerulonephritis. Since 18 of the 26 patients required repeat doses, a total of 47 doses were given9 In every case, a fall in blood pressure to acceptable levels was noted within 5 minutes of injection. Systolic pressure decreased by an average of 23% and diastolic pressure decreased by an average of 32% within 5 minutes. Patients receiving diazoxide alone responded as welt as those who received both diazoxide and furosemide. Although transient hypotensive episodes have been reported in children after the intravenous administration of d i a z o x i d e / n o n e were noted in this study. No symptoms which could be attributed to reduced cerebral blood flow were observed following rapid drop in blood pressure. Thirteen patients had symptoms of hypertensive encephalopathy which rapidly abated following reduction in blood pressure, In 18 patients, a repeat dose of diazoxide was required an average of 41 hours after injection. The duration of action was Ionger than previously noted in children. The half-life of diazoxide given orally to hypoglycemic chip
Volume 87 Number 5
Diazoxide in poststreptococcal glomerulonephritis
797
INTERVAL BETWEEN FIRST AND SECOND DOSE IN EIGHTEEN PATIENTS REQUIRING REPEAT DIAZOXIDE INFUSION 8
Q II
11 J,
1.
It v v
It
w
HOURS Fig. 2. The length of time blood pressure remained controlled following the initial dose of diazoxide is shown in the 18 patients who required repeat doses.
dren who were free of renal disease is said to be 24 hours; 33% is excreted unchanged in the urine. ~ The prolonged effect seen in these patients may have been related to reduced renal excretion secondary to their renal disease. Hyperglycemia is a well-recognized side effect of therapy with diazoxide. Blood glucose determinations were systematically followed in our patients. One-half of the patients had elevations above, normal fasting levels. In only four patients did the level exceed 120 m g / d l and the highest blood glucose value recorded was 155 mg/dl in a patient who received two doses of diazoxide within 18 hours. The effect of diazoxide on glomerular filtration rate is controversial. One study suggested that G F R remained reduced as long as blood pressure remained decreased below preinjection valuesY Recently, it has been demonstrated that an initial fall in G F R after diazoxide was followed by a rapid return to normal? ~ None of the patients we studied had a significant increase in the concentration of blood urea nitrogen following diazoxide therapy. The sodium-retaining effects of diazoxide therapy were reported in 1962,11 and it has been suggested that this effect is on proximal tubular reabsorption of s o d i u m : ~'- ~= Theoretically, diazoxide therapy might enhance edema and circulatory congestion in acute glomerulonephritis, a disease in which abnormal renal salt and water retention is the primary physiologic defect. However, weight loss in our patients was satisfactory (8.3% in 5 days) and prolonged edema was not noted. Weight loss in the patients who required multiple doses was no different from those in the single dose group. Diazoxide did not diminish
the effect of furosemide in those patients receiving both drugs. Powell and associates 13 have demonstrated very low plasma renin activity in ten patients with acute glomerulonephritis and suggested that the degree of hypertension was directly related to the degree of hypervolemia. However, Repetto and associates 14 noted that blood pressure remained elevated despite a significant furosemideinduced diuresis in five patients. This has also been the authors' experience. The effectiveness of diazoxide therapy suggests that at least a relative increase in peripheral vascular resistance may also be present. This could explain why some patients continue to be hypertensive, despite diuresis and loss of edema. These data suggest that diazoxide is a safe and effective agent in the treatment of hypertension associated with acute poststreptococcal glomerulonephritis in childhood. Since it does not produce central nervous system depression and its onset of action is immediate, we feel it is particularly efficacious in patients with symptoms of hypertensive encephalopathy. Blood glucose values must be monitored especially in patients receiving multiple doses of diazoxide. We would like to thank Alvin Jaffee, M.D., for allowing many of his patients to be treated under this protocol. REFERENCES
1. Rubin AA, Roth FE, Winbury MM, Topliss JG, Sherlock MH, Sperber N, and Bloack J: New class of antihypertensive agents, Science 133:2067, 1961. 2. Rubin AA, Roth FE, and' Winbury MM: A non-diuretic benzothiazide with antihypertensive properties, Nature 192:176, 1961.
798
Kohaut, Wilson, and Hill
3. Thomson AE, Nickerson M, Gaskell P, and Grahame GR: Clinical observations on an antihypertensive chlorothiazide analogue devoid of diuretic activity, Can Med Assoc J 87:1306, 1962. 4. Rubin AA, Zitowitz L, and Hausler L: Acute circulatory effects of diazoxide and sodium nitrate, J Pharmacol Exp Ther 140:46, 1963. 5. Ogilvie RI, and Schlieper E: Comparative effects of ethacrynic acid furosemide and diazoxide in the perfused dog hindlimb, Can J Physiol Pharmacol 49:1038, 1971. 6. Larochelle P, Milkulic E, and Ogilvie RI: Effects ofisoproterenol, diazoxide, ethacrynic acid, and furosemide on skeletal muscle vascular resistance, Can J Physiol Pharmacol 51:183, 1973. 7. McLaine PN, and Drummond KN: Intravenous diazoxide for severe hypertension in childhood, J PEDIATR 79:829, 1971. 8. Pruitt AW, Dayton PG, and Patterson JH: Disposition of diazoxide in children, Clin Pharmacol Ther 14:73, 1973.
The Journal of Pediatrics November 1975
9. Johnson BF: Diazoxide and renal function in man, Clin Pharmacol Ther 12:815, 1971. 10. Rado JP, Szende L, Tako J, and Halmos T: Effects of intravenous diazoxide and chlorpropamide on renal function in man, Am Heart J 85:755, 1973. 11. Hutcheon DE, and Barthalmus KS: Antihypertensive action of diazoxide: a new benzothiadiazine with antidiuretic properties, Br Meal J 2:159, 1962. 12. Kohaut EC, Wilson CJ, and Hill LL: Progressive volume expansion and diazoxide infusion under hypotonic saline diuresis in Bartter's syndrome, Clin Res 23:74A, 1975. 13. Powell HR, Rotenberg E, Williams AL, and McCredie DA: Plasma renin activitv in acute post-streptococcal glomerulonephritis and the haemolytic-uraemic syndrome, Arch Dis Child 49:802, 1974. 14. Repetto HA, Lewy JE, Brando JL, and Metcoff J: The renal functional response to Furosemide in children with acute nephritis, J PEDIATR 80:660, 1972,