Diuretic effect of furosemide in acute glomerulonephritis

306

August 1976 The Journal o f P E D I A T R I C S

Diuretic effect of furosemide in acute glo meru lo nep hri tis Twenty-five children with the diagnosis of acute glomerulonephritis were treated with oral or intravenous doses o f furosemide. The intravenous administration of I mg/kg or greater resulted in an increase in urine volume in all patients. Oral doses of less than 2 m g / k g were not as effective, but there was wide variation in diuretic response to the drug. In 13 patients, plasma concentrations o f furosemide were measured. The plasma half-life varied from 2.3 to 4.4 hours after intravenous administration of the drug. The plasma concentration of furosemide did not correlate with diuretic response.

Albert W. Pruitt, M.D.,* and Ann Boles, M.T., A tlanta, Ga.

IN THE TREATMENT of symptoms accompanying poststreptococcal acute glomerulonephritis, drug therapy has primarily included antihypertensive agents and occasionally cardiac glycosides. Management of the edematous state has been limited to restriction of water and salt intake. Diuretic agents have not been used frequently because of unreliable response and because spontaneous diuresis is expected as the renal lesion resolves. With the development of the potent diuretic drugs, furosemide and ethacrynic acid, many previously unresponsive renal diseases 1, ~ may now be affected by these agents. One evaluationof furosemide in acute glomerulonephritis 3 suggested that hospital stay was shortened and less antihypertensive medication was needed. Another showed that a single intravenous dose of the drug increased urine volume and sodium excretion. ~ It was the purpose of the present study to evaluate dosage, route of administration, and effectiveness of furosemide in the symptomatic treatment of a group of children hospitalized because of acute giomerulonephritis. In addition, plasma concentration of furosemide was

From the Clinical Pharmacology Program Departments o f Pediatrics and Pharmacology, Emory University School o f Medicine. Supported by United States Public Health Service Grants GM 14270 and 04-D-001031; and HoechstRoussel Pharmaceuticals, Inc. *Reprint address: Woodruff Memorial Building, Emory University School of Medicine, Atlanta, Gal 30322.

Vol. 89, No. 2, pp. 306-309

measured in several patients with the disease, and compared with the dosage of the drug.

METHODS Twenty-five patients between the ages of three and 15 years were admitted to Grady Memorial Hospital with peripheral edema and the diagnosis of acute glomerulonephritis. Laboratory data, which included serum concentrations of electrolytes, creatinine, beta-l-C globulin, blood urea nitrogen, and urinalysis, were consistent with the diagnosis of acute glomerulonephritis. In most cases the antecedent streptococcal infection was believed Abbreviations used T~A: half life BUN: blood urea nitrogen to have been skin lesions. After examination, each child' was placed at bed rest with restriction of salt and water intake. The daily salt intake was 500 to 1,000 m g / d a y and the maximum fluid allowed was 400 m l / m ~ plus the volume of firine output. In the presence of a diastolic blood pressure greater than 100 mm Hg, parenteral reserpine (0.02 to 0.07 mg/kg) and hydralazine (0.15 to 0.4 mg/kg) wer e administered. Subsequent examinations after discharge confirmed resolution of an acute process. Before furosemide therapy in 20 of the patients, a timed urine collection of at least one hour was obtained by spontaneous voiding and represented the control urine

Volume 89 Number 2

Furosemide in glomerulonephritis

Table I. Half-life of furosemide in plasma o f children with acute glomerulonephritis

9 76.9 9 58.5 AI9.2

Age (YO

BUN (mg/dl)

8 6/12

93 94 11 20 11 32

Patient

tat lbt 2 3 4 5

15 11 13 4

3/12 11/12 4/12 8/12

Dose* (mg/ kg)

1 1 I l 1.5 2

13.8

t,

T 1/2 (hO

3.5 4.4 2.3 2.7 4.3 2.8

307

9 a 9 o 9 =

7 6 I

5 8'"'

I mg/kg I mg/kg 2rng/kcJ 2mg/kg 3rncj/kg 5mg/kg

p.o. I.M p.O. I.V. po. p.o.

9

4

=

3 *Administered intravenously. At least three bloo d samples were obtained from each patient between 2 and 10 hours after receiving the drug. ~'Patient la and lb are the same individual but studied on two different days.

output (ml/hour) for the patient. Furosemide was administered either orally or intravenously in dosages ranging from 1 to 5 mg/kg. When more than one dose of furosemide was given to a patient, a timed urine collection of at least one hour was obtained before subsequent doses of the drug. The rate of urine output in that sample served as the pretreatment control value for the subsequent dose. During the course of the study, each spontaneously voided urine was collected and its volume recorded. Repeat measurements of renal function were obtained as often as clinically indicated. In 13 of the 25 patients, heparinized blood samples were obtained for assay of plasma concentrations of furosemide. These patients were not fasting at the time of drug administration. The drug was assayed according to a modification of the method of Forrey and associates? Plasma (1-2 ml) was added to 50/A of concentrated HC1 and 5 ml ethylhexanol (Eastman). After shaking 15 minutes, the liquid phases were separated by centrifugation. An aliquot of the organic phase was added to 1 ml of 0.1M potassium phosphate buffer (pH 7.0), and after shaking, the organic phase was discarded. The aqueous phase was acidified with HCI (1 ml of 0.5M), and fluorescence measured on an Aminco Bowman instrument with excitation at 345 nm and emission at 417 nm. This method, however, is not specific for parent drug alone, since a portion (less than to%) of the major metabolite of furosemide, 4-chloro-5-sulfamoyl-anthranilic acid, will also be extracted with the drug. RESULTS In 20 of the 25 patients there were 50 treatment periods during which time urine output was obtained. Pharmacologic effect of furosemide was evaluated in terms of increase in urine volume only. This response was examined after oral and intravenous doses of 1 to 5 mg/kg given one time or as multiple doses.

2

..-

0

o

,6

".."i::. , : . " - - io

,;b

5'0

vb

BASELINE V O L U M E ( m l / h r : )

Fig l. Relationship of change in urine volume following furosemide dose (volume response) to urine volume prior to treatment (volume baseline). Each point represents the peak response to a single dose of the drug. Note that the ordinate is the ratio minus 1, so as to achieve a negative number for a response that was less than the control urine output. As shown in Fig. 1 there was an increase in urine flow in response to administration of the drug in all but three treatment periods; and in six other periods, the response was minimal. The increase in urine volume was greater in those patients with low pretreatment urine output than in those with a higher urine flow just prior to the dose. Fig. 1 also shows the difference in response to the various oral or intravenous doses of furosemide. The greatest number of treatment periods were with oral doses of 2 mg/kg. Data from a typical patient who was treated multiple times with this dose are shown in Fig. 2. In this patient an increase in urine volume was observed soon after receiving the drug. Several hours after dose, however, the rate of urine flow declined to near pre-furosemide level. Although several doses of drug were administered, baseline urine flow did not improve during the study period and the increase in urine output was directly associated with administration of the diuretic. A patient treated by the intravenous and oral route (Fig. 3) responded to both regimens with an increase in urine output. The responses to the intravenous doses (1 and 2 mg/kg) were similar with regard to total urine volume excreted. Following ora:l administration (2 rag/ kg) of the drug to this patient, the duration of effect was longer and the urine output was greater than after the

308

Pruitt and Boles

The Journal of Pediatrics August 1976

300

z::

. . . . . Urine output prior to furosemiOe dose _ _ Urine output in response to furosernide dose

250

E (3I-D

furosemide

200

15C

0

.....

. . . . . . . . .

5C t2mg/kg 0

I0

20

50

40

,50

60

70

80

t2mcj/kg 90

I00

I10

HOURS

Fig. 2. Change in urine volume in a patient with acute glomerulonephritis treated with oral doses of furosemide (2 rag/ kg). The broken line shown throughout a treatment period represents the urine output measured just before furosemide dose. After response to each dose, the urine volume was allowed to return to near baseline level before administering the next dose. variation in the plasma levels measured (Table I1). Especially in Patients 6, 8, and 9, the intrasubject dissimilarities might have been due to differences in food intake, since absorption of this drug is affected by feeding# For the group as a whole, the peak concentration of furosemide in plasma could not be correlated with the urine flow response. Such a lack of correlation between plasma concentration of the drug and response has also been noted in patients with advanced renal failure#

55C

30C . . . . Urine o u t p u t prior to furosernide dose _ _ Urine o u t p u t in response tO f u r o s e m i d e dose 41~ furosemide

.~ 25C F(3_ ~D

2OC

2rng/kg p.o.

I rag/k9 2rng/kg ,~- p.o.

UJ

_z ~5c 12.m~q v. LOC

DISCUSSION

5C O 0

I0

20

30

40

50

60

70

80

90

HOURS

Fig. 3, Response to furosemide in a child with acute glomerulonephritis treated both intravenously and orally. intravenous doses. The difference in output may, however, reflect improvement in renal function. Patients treated with a single oral dose of 1 mg/kg showed minimal or no response. When this low oral dose was given repeatedly, urine output increased but in some patients there was concomitant improvement in the baseline urine volume. The range of values of blood urea nitrogen for the patients included in this study was 5 to 94 mg/dl. The diuretic response to furosemide administration could not be correlated with this measurement of renal function. The plasma half-life of the diuretic after intravenous administration to five children with acute glomerulonephritis could not be correlated with BUN (Table I). The T1/2 in these patients was 2.3 to 4.4 hours. After oral administration of furosemide, there was wide individual

The management of acute glomerulonephritis is directed toward supportive care and avoidance of complications. Hypertension causes great concern, but several pharmacologic agents are available for control of this problem. 8~ Reduction in extracellular fluid volume in these patients is likely to have a beneficial effect on the cardiovascular and neurologic complications of the disease. In order to evaluate the potent diuretic agent, furosemide, in acute glomerulonephritis: we have treated a group of children with ,this disease and observed the diuretic response and the drug concentration achieved in plasma. Clearly diuresis can be produced by intravenous or oral doses of furosemide in these patients. The intravenous dose of 1 mg/kg or greater results in an increase in urine output, but single oral doses of less than 2 mg/kg are often minimally effective. If the response to the initial dose is poor, stepwise increases may be made. It appears that with frequent administration .of furosemide a steady diuresis can be achieved. We have chosen to administer the drug less frequently, however, unless there .is an urgent need for diuresis. If furosemide is used more than once dailyl particular attention should be paid to the

Volume 89 Number 2

Furosemide in glomerulonephritis

Table II. P l a s m a c o n c e n t r a t i o n o f f u r o s e m i d e after oral a d m i n i s t r a t i o n in children with acute g l o m e r u l o n e phritis

Plasma

I

Age I (yr)

Patient* 6a 6b 6c 7 8a 8b 9a 9b 9c 10 11 12 13

6

7/12

5 11/12 12 4/12 6

6/12

8 10 8 7

7/12 8/12 5/12 0/12

I

BUN I Dose I 2 hrt l 4hr'~ (mg/dl)

(mg/kg)

(t~g/ml)

(l~g/ml)

20 18 17 19 34 33 34 40 33 29 15 5 25

1 1 1 1 1 1 1 1 1 1 2 2 3

0.17 0.42 0.38 0.60 0.53 0.74 0.27 1.11 0.33 1.17 0.59 1.41 --

0.15 0.12 0.23 0.85 0.36 0.35 0.42 0.92 0.42 1.03 0.33 2.21

*Patients 6, 8, and 9 were studied on more than one day (i.e., a,b,c). tHours after oral dose of furosernide.

serum c o n c e n t r a t i o n s of electrolytes in the patient. In n o n e o f our patients did excessive diuresis or electrolyte disturbance develop. T h e r e is clinical evidence that h i g h e r doses o f furosemide are r e q u i r e d in patients with chronic a b n o r m a l renal f u n c t i o n t h a n in patients with n o r m a l r e n a l function. TM In a d d i t i o n there are e x p e r i m e n t a l d a t a suggesting that less s o d i u m a n d water are excreted in response to a given dose o f the diuretic in azotemic animals. I~ However, in o u r patients with transient renal failure and a wide range o f values of B U N , n o correlation b e t w e e n the c o n c e n t r a t i o n o f b l o o d urea n i t r o g e n a n d diuresis in response to f u r o s e m i d e was seen. This study was not designed to evahlate tl-fb a n t i h y p e r tensive effect o f furosemide in acute g l o m e r u l o n e p h r i t i s . R e t a n a n d Dillon a r e p o r t e d that less a n t i h y p e r t e n s i v e m e d i c a t i o n was required to control ~blood pressure in patients treated with f u r o s e m i d e t h a n in a control g r o u p with acute nephritis. T h e haft-life o f the drug in p l a s m a o f five p e d i a t r i c patients varied from 2.3 to 4.4 hours, b u t d i d n o t correlate directly with r e n a l function. In adult patients with advanced r e n a l failure, a m u c h longer e l i m i n a t i o n T 1 / 2 was noted. 7 T h e plasma half-life o f the d r u g in h e a l t h y

309

adults as d e t e r m i n e d over six h o u r s after the dose was 22.6 to 40.3 minutes. W h e n the p e r i o d o f s a m p l i n g was longer, however, a slower p h a s e of drug e l i m i n a t i o n was n o t e d and the T 1 / 2 was a p p r o x i m a t e l y two hours. 1~ F r o m these investigations we c o n c l u d e that f u r o s e m i d e is a safe agent in children with acute glomerulonephritis. Effective diuresis m a y be a c h i e v e d after i n t r a v e n o u s or oral doses of the drug. REFERENCES

1. Hagedorn CW, Kaplan AA, and Hulet WH: Prolonged administration of ethacrynic acid in patients with chronic renal disease, N Engl J Med 272:1152, 1965. 2. Levin NW: Furosemide and ethacrynic acid in renal insufficiency, Med Clin North Am 55:107, 1971. 3. Retan JW, and Dillon HC: Furosemide in the treatment of acute post-streptoc0ccal glomerulonephfitis, South Med J 62:157, 1969. 4. Repetto HA, Lewy JE, Braudo JL, and Metcoff J: The renal functional response to furosemide in children with acute glomerulonephritis, J P~DIATR 80:660, 1972. 5. Forrey AW, Kimpel B, Blair AD, and Curler RE: Furosemide concentrations in serum and urine, and its binding by serum proteins as measured fluorometrically, Clin Chem 20:152, 1974. 6. Kelley MR, Cutler RE, Forrey AW, and Kimpel BM: Pharmacokinetics of orally administered furosemide, Clin Pharmacol Therap 15:178, 1974. 7. Huang CM, Atkinson AJ Jr, Levin M, Levin NW, and Quintanella A: Pharmacokinetics of furosemide in advanced renal failure, Clin Pharmacol Therap 16:659, 1974. 8. Etteldorf JN, Smith JD, and Johnson C: The effect of reserpine and its combination with hydralazine on blood pressure and renal hemodynamics during the hypertensive phase of acute nephritis in children, J PEDIATR 48:129, 1956. 9. Kohaut EC, Wilson C J, and Hill LL: Intravenous diazoxide in acute post streptococcal glomerulonephritis, J PEDIATR 87:795, 1975. 10. Muth RG: Diuretics in chronic renal insufficiency, in Lant AF, and Wilson GM, editors: Modern diuretic therapy in the treatment of cardiovascular and renal disease, Amsterdam, 1973, Excerpta Medica, pp 294-305. 11. Rose HJ, Pruitt AW, and McNay JL: Relationship of urinary furosemide excretion rate to natriuretic effect: A mechanism of decreased responsiveness in azotemi a, Abst Am Soc Nephrol, p 65, 1975. 12. Cutler RE, Forrey AW, Christopher TF, and Kimpel BM: Pharmacokinetics of furosemide in normal subjects and functionally anephric patients, Ctin Pharmacol Therap 15:588, 1974. 13. Beermann B, Dalen E, Lindstrom B, and Rosen A: On the fate of furosemide in man, Eur J Clin Pharmacol 9:57, 1975.