COMPLICATIONS DURING CLOFIBRATE TREATMENT OF NEPHROTIC-SYNDROME HYPERLIPOPROTEINÆMIA

506

(B) lymphocyte populations, this would suggest that eosinophil response was unrelated to immunologically specific induction or that there was a sparing of those lymphocytes which mediate the differentiation of granulocytic precursors to eosinophils. We cannot exclude the possibility that the unusual either the

disease which we and Omenn have described represents either a variant of the Letterer-Siwe syndrome or a G.v.H.R. in infants with severe, combined immunological deficiency, but we feel that the features which we have observed suggest that this is a distinct disease. Primary immunological deficiency has not been recognised a3 a characteristic of the LettererSiwe syndrome, a recent report notwithstanding. G.V.H.R. have only rarely been described in infants with combined immunological deficiency disorders who have not been reconstituted, and have never been reported to have an autosomal recessive mode of inheritance. The bone-marrow of infants undergoing G.V.H.R. has only rarely shown histiocytosis. In contrast, we have found pathological evidence of a severe combined immunological deficiency together with a diffuse, abnormal proliferation of bizaire histiocytes in the bone-marrow, lymph-nodes, and dermis of both cases. The cytological abnormality and invasive of pattern growth of these histiocytes suggests that they may be malignant cells. If this were true, the disease might aptly be called familial malignant histiocytosis with eosinophilia. This work was supported in part by Public Health General Research Grant 1 SO 4 RRO 06147, Grant DRG-1075 from the Damon Runyon Memorial Fund for Cancer Research, and a grant from the Kansas Division, American Cancer Society. We thank Dr. G. Vawter, Department of Patholcgy, Children’s Hospital Medical Center, Boston, for allowing one of us (R. F. B.) to review slides from case 3; Dr. G. Omenn for follow-up information; and Mrs. Karen Phipps for expez-t secretarial assistance.

REFERENCES

Omenn, G. S. New Engl. J. Med. 1965, 273, 427. Stalsberg, H. Acta path. microbiol. scand. A, 1971, 79, 37. Fudenberg, H., et al. Pediatrics, Springfield, 1971, 47, 927. Siwe, S. Adv. Pediat. 1949, 4, 117. Lichtenstein, L. J. Bone Jt Surg. 1964, 46, 76. Otani, S. J. Mt Sinai Hosp. 1957, 24, 1079. 7. Lieberman, P. H., Jones, C. R., Dargeon, H. W. K., Begg, C. F. Medicine, 1969, 48, 375. 8. Dargeon, H. W. K. Reticuloendotheliosis in Childhood. A Clinical Survey. Springfield, Illinois, 1966. 9. Farquhar, J. W., Claireaux, A. E. Archs Dis. Childh. 1952, 26, 519. 10. Nelson, P., Santamaria, A., Olson, R. L., Nayak, N. C. Pediatrics, Springfield, 1961, 27, 931. 11. Marrian, V. J., Sanerkin, N. G. J. clin. Path. 1963, 16, 65. 12. Miller, D. R. Pediatrics, Springfield, 1966, 38, 986. 13. Buist, N. R. M., Jones, R. N., Cavens, T. R. Archs Dis. Childh. 1971, 46, 728. 14. McMahon, H. E., Bedizel, M., Ellis, C. A. Pediatrics, Springfield, 1. 2. 3. 4. 5. 6.

1963, 32,

COMPLICATIONS DURING CLOFIBRATE TREATMENT OF NEPHROTIC-SYNDROME HYPERLIPOPROTEINÆMIA S. M. ROSEN J. F. BRIDGMAN J. M. THORP

Department of Renal Medicine, Leeds (St. James’s) University Hospital, and Research Department, Pharmaceuticals Division, I.C.I. Ltd., Macclesfield, Cheshire with hyperlipoproteinæmia the nephrotic syndrome were treated with clofibrate. They were also receiving maintenance diuretic therapy. Muscular pain, stiffness, general malaise, and a pronounced diuresis developed in five of the six patients given clofibrate. Although clofibrate is normally firmly bound to serum-albumin, this investigation revealed that a higher proportion of the clofibrate in the sera of these patients was unbound, and this was responsible for its toxic effects. It is postulated that low serum-albumin reduces the number of binding sites for the drug. Similarly, the diuresis induced in these patients was due to the displacement offrusemide from its albumin-binding site by clofibrate. An increased proportion of unconjugated clofibrate was excreted in the urine of these patients. This may be due to a higher percentage of non-protein-bound clofibrate being excreted or a defect in the glucuronide conjugating mechanism in the kidney. It is recommended that the daily dose of clofibrate used in patients with a low serum-albumin should not exceed 0·5 g. for each 1 g. per 100 ml. of the serumalbumin concentration.

Summary

patients

to

Introduction

HYPERLIPOPROTEINÆMIA is

a common

feature of the

nephrotic syndrome.1-4 In our own series (unpublished) of thirty cases, twenty had an abnormal lipid profile. Since hyperlipoproteinæmia is associated with the development of ischæmic heart-disease,5-7 and since the prevalence of ischæmic heart-disease is increased in patients with the nephrotic syndrome,8 it has been suggested that all available means should be used to normalise the high lipid levels associated with this condition.4, 8

22.

23. 24.

25.

868.

15. Falk, W., Gellei, B. Acta pœdiat. Stockh. 1957, 46, 471. 16. Schoeck, V. W., Peterson, R. D. A., Good, R. A. Pediatrics, Springfield, 1963, 32, 1055. 17. Freundlich, E., Amit, S., Montan, Y., Suprun, H., Nevo, S. Archs Dis. Childh. 1972, 47, 122. 18. Juberg, R. C., Kloepfer, H. W., Oberman, H. A. Pediatrics, Springfield, 1970, 45, 753. 19. Cederbaum, S. D., Niwayama, G., Stiehm, E. R., Neerhout, R. C., Ammann, A. J., Berman, W. J. Pediat. Res. 1972, 6, 379. 20. Batson, R., Shapiro, J., Christie, A., Riley, H. D. Am. J. Dis. Child. 1955, 90, 323. 21. Hathaway, W. E., Githens, J. H., Blackburn, W. R., Fulginiti, V., Kempe, C. H. New Engl. J. Med. 1965, 273, 953.

Six

secondary

26. 27. 28. 29. 30.

Rosen, F. S., Gotoff, S. P., Craig, J. M., Ritchie, J., Janeway, C. A. ibid. 1966, 274, 18. Miller, M. E. J. Pediat. 1967, 70, 730. Hathaway, W. E., Fulginiti, V. A., Pierce, C. W., Githens, J. H., Pearlman, D. S., Muschenheim, F., Kempe, C. H.J. Am. med. Ass. 1967, 201, 1015. Dooren, L. J., de Vries, M. J., van Bekkum, D. W., Cleton, F. J., de Koning, J. J. Pediat. 1968, 72, 51. Kersey, J. H., Meuwissen, H. J., Good, R. A. Human Path. 1971, 2, 389. Kadowaki, J. I., Thompson, R. I., Zuelzer, W. W., Woolley, P. V., Jr., Brough, A. J., Gruber, D. Lancet, 1965, ii, 1152. Shapiro, M. Transfusion, 1967, 7, 281. Githens, J. H., Muschenheim, F., Fulginiti, V. A., Robinson, A., Kay, H. E. M. J. Pediat. 1969, 75, 87. Tung, K. S., Hoffman, G. C., Lonsdale, D. Am. J. clin. Path. 1969,

52, 726. Rappaport, H. in Atlas of Tumor Pathology; section 3, fasc. 8. Washington, D.C., 1966. 32. Imamura, M., Sakamoto, S., Hanazono, H. Cancer, 1971, 28, 467. 33. Jose, D. G., Gatti, R. A., Good, R. A.J. Pediat. 1971, 79, 748. 34. Basten, A., Beeson, P. B.J. exp. Med. 1970, 131, 1288. 35. McGarry, M. P., Speirs, R. S., Jenkins, V. K., Trentin, J. J. ibid. 1971, 134, 801. 31.

507 Clofibrate (’Atromid S’) is a branched-chain fatty-acid phenolester and is an effective hypolipxmic drug which is usually well tolerated. The mechanism of its action is not fully understood and probably involves multiple factors. These include inhibition of cholesterol biosynthesis at a stage between acetate and mevalonate, an increase in fsecal sterol excretion, and interference by the free acid (clofibrate) with the binding to albumin of serum free fatty acids and thyroxine.9 Although remarkably few side-effects of clofibrate therapy have been found, Langer and Levy 10 reported an acute muscular syndrome associated with the administration of the drug. In five out of sixty patients with idiopathic hyperlipoproteinaemia treated with clofibrate, serum transaminases and creatine phosphokinase (C.P.K.) levels rose. In two patients severe myalgia, stiffness, weakness, and malaise developed coincident with the drug therapy.

In a preliminary trial of the efficacy of clofibrate in the treatment of hyperlipoproteinæmia secondary to the nephrotic syndrome, severe and disabling muscular complications developed in five out of six patients given the drug. These complications were investigated further, and the results are presented here.

Case-reports Case1 A woman of 22, who had had the nephrotic syndrome for a year, was being treated with frusemide (120 mg. daily) and spironolactone (25 mg. four times a day) when she was started on a divided daily dose of 2 g. clofibrate. Within 36 hours severe cramp-like pains in the proximal muscles of all her limbs and low lumbar backache developed. She also noticed an increasing thirst and polyuria during this time. Her leg muscles were tender, but no other abnormal physical signs were present. The symptoms resolved within 1 week of stopping the drug. Although the

TABLE I-DETAILS BEFORE TREATMENT WITH CLOFIBRATE

*

Normal range 130-300 mg. per 100 ml.

Normal range 74-172 mg. per 100 ml.

TABLE II-RESULTS AFTER ADMINISTRATION OF

Numbers in parentheses

are

CLOFIBRATE*

percentages.

TO NEPHROTIC PATIENTS

508 serum

transaminases

were

normal, the

c.P.K. was

raised

(800 i.u.). Case 2 A 20-year-old man was taking 80 mg. frusemide daily to control his oedema when he was started on 2 g. of clofibrate daily. On the 3rd day of treatment he had severe muscular pain in all his limbs, which prevented any moveHe also had pain and tenderness over the left ment. kidney and pronounced thirst and polyuria. He was admitted to a local hospital. c.p.K.levels were not measured. the serum-glutamic-oxaloacetic-transaminase 588 units and the serum-glutamic-pyruvictransaminase (s.G.P.T.) was 598 units (upper limit of normal in the laboratory where these tests were performed was 110 units). The patient recovered completely within 4 days.

However,

(S.G.O.T.)

was

Case 3 A man

aged 52 with gross oedema was being treated as inpatient and was taking 500 mg. frusemide daily. However, even the high dose of frusemide had little effect on the oedema until he was started on clofibrate (2 g. daily); on this drug combination he had an enormous diuresis, and lost 10 kg. over 4 days. At the same time he also had severe low back pain and cramps in both thighs. The clofibrate was stopped and the symptoms resolved in 2 days. an

Case 4 A man of 40 had minimal oedema which was controlled with bendrofluazide (10 mg.) and spironolactone (75 mg.) daily. He was started on 2 g. clofibrate daily. After 3 days his muscles, especially the proximal muscles of both legs, TABLE III-RESULTS AFTER ADMINISTRATION OF

became painful and tender. Apart from the tenderness of the muscles there was no weakness nor any neurological abnormality. The liver was not palpable. Electromyography was within normal limits. Serial serum levels of clofibrate, C.P.K., S.G.O.T., and

raised. The normal half-life for clofibrate is 12 hours. However, in this case serum levels took 24 hours to fall to 80 !1-g. per ml. from 210 µg. per ml., and 48 hours to fall to 45 !1-g. per ml. S.G.P.T. were

Case 5 man was taking 160 mg. of frusemide control his oedema. The pre-treatment level of cholesterol was 600 mg. per 100 ml. and triglyceride 440 mg. per 100 ml. After 2 months of treatment with clofibrate (2 g. daily) the levels were reduced to 225 mg. per 100 ml. and 110 mg. per 100 ml., respectively. Although he was symptom-free, C.P.K. rose to 140 units per litre and aldolase to 16-6 units per litre on one occasion. This coincided with a raised serum-clofibrate level of 175 µg. per ml. Because of these readings the dose of clofibrate At this dosage was subsequently reduced to 1 g. daily. the serial C.P.K. and aldolase levels were normal.

A

UNCONJUGATED CLOFIBRATE LEVELS

to

Case 6 A man aged 45 had been a severe nephrotic for 2 years and was being treated as an outpatient with 120 mg. of frusemide and 100 mg. of spironolactone daily. He started clofibrate (1 g. daily) on July 21, 1971, and had mild muscular cramps on one occasion. However, the drug was stopped on Sept. 9, 1971, because of high serum-enzyme 1 g. OF CLOFIBRATE TO NORMAL CONTROLS

Numbers in parentheses TABLE IV—UNBOUND AND

62-year-old

daily

are

percentages.

IN THE SERUM AND URINE AFTER ORAL ADMINISTRATION OF

CLOFIBRATE*

509

levels. During this time the serum-clofibrate levels reachedl the upper limit of the normal therapeutic range. Further details of each patient before treatment with are given in table I. The similarity of the side-effects seems to be peculiar to patients with the nephrotic syndrome, and these were; further investigated.

clofibrate

.

Methods and Patients Four patients and four normal controls consented to be! studied after the procedure was explained to them. The patients were admitted to hospital for 3 days and continued their usual treatment. Blood was taken daily for estimations of S.G.O.T., s.G.P.T., C.P.K., aldolase, plasma proteins, urea, and electrolytes. On the morning of the 2nd day they were given 1 g. of clofibrate orally. Blood was taken to determine serum-clofibrate levels at 0, 2, 4, 8, and 24 hours after the drug was taken, and urine was collected at 0-4 hours, 4-8 hours, and 8-24 hours with 2 ml. of concentrated acetic acid and 2 ml. of chloroform, .

as

preservative.

The total and unconjugated concentrations of clofibrate were measured by using the method of Thorp.ll The protein-bound and unbound serum-clofibrate levels were determined by using a 14C-labelled tracer and ultra-

centrifugation. Results

The results are shown in tables II, III, and IV. Compared with the controls (3’1-8’2%) there is a significantly higher percentage (21-25%) of free clofibrate in the serum of three of the four nephrotics studied. This is correlated with the serum-albumin concentration. The percentage of the urinary unconjugated clofibrate is markedly raised in the

nephrotic group (mean 31-1%, range 11-92%) compared with the controls (mean 7°2%, range 3-24%). Because there was some renal impairment in the nephrotic group the total urinary excretion of the clofibrate was reduced. In three of the patients, 30% of the clofibrate was recovered in the urine during 24 hours, compared with over 70% for the controls. Discussion

Five of the six patients who received clofibrate had muscular symptoms, and all cases had raised levels of serum transaminases, C.P.K., and aldolase at some time during the course of treatment. There was a striking similarity in the pattern of the clinical presentation, the acute onset of symptoms within 3 days of starting treatment, the general malaise with tenderness, the pains predominating in the proximal muscles of the legs, and low lumbar backache. There was also a diuresis which was often associated with significant weight-loss. These features resolved rapidly when the drug was stopped. Clofibrate can bind firmly to albumin. In those patients who have a low serum-albumin there is a reduction in the number of available binding sites and the quantity of unbound clofibrate in the serum is increased. This was confirmed by the studies which showed that the unbound clofibrate in the serum ranged from 21 % to 28% of the total level, whereas the normal percentage of unbound clofibrate is about 4%. We cannot explain the muscular side-effects in case

especially

6, who had normal serum albumin and clofibrate levels. Frusemide, like clofibrate, is bound to albumin. Both drugs could therefore be competing for similar binding sites. Preliminary in-vitro studies have shown that when diuretics such as frusemide and bendrofluazide are added to sera previously treated with clofibrate the percentage of the unbound clofibrate increases. In most of the cases, especially case 3, there was a pronounced diuresis whilst on this drug combination. This is therefore probably due to the clofibrate displacing some of the bound frusemide and thus potentiating its diuretic effect. The sudden diuresis could contribute to the muscular cramps by causing increased urinary losses of sodium and

potassium. Clofibrate is excreted in the urine. 92 to 98% of the compound present in the urine is conjugated in the kidney with glucuronic acid.12 However, in these nephrotic patients a high percentage of the clofibrate present in the urine was in the unconjugated form. Whether this is an effect of the diuretics interfering with the conjugating processes, or an underlying structural abnormality of the kidney, is still under investigation. There was a significant delay of excretion of the drug in our patients because of some impairment of renal function. Normally, the half-life of the drug is about 12 hours, whereas it was well over 36 hours in most of these cases. This, in itself, would cause an excessive accumulation of the drug and thus potentiate its toxic effects. In view of these potential hazards of clofibrate therapy it would be prudent to measure the serumproteins and evaluate renal function before starting any patient on treatment with this drug. If there is a significant reduction in the serum-albumin then the total daily dosage of clofibrate should not exceed 0-5 g. for each 1 g. per 100 ml. of the albumin concentration, and regular estimations of serum transaminases and C.P.K. should be made during the course of treatment. Why muscular symptoms predominate is not clear. Perhaps there is a chronic protein-depletion state in the nephrotic syndrome and therefore possibly some muscle-wasting which increases the sensitivity to the toxic levels of clofibrate. We thank Dr. Ray Brosnan, of I.C.I. Pharmaceuticals, for his kind assistance with this project.

Requests for reprints should be addressed James’s Hospital, Leeds LS9 7TF.

to

S. M. R., St.

REFERENCES 1. 2.

3. 4. 5.

6. 7. 8.

9. 10. 11. 12.

Epstein, A. A. J. Am. med. Ass. 1917, 69, 444. Baxter, J. H., Goodman, H. C., Havel, J. J. clin. Invest. 1960, 39, 455. Jensen, H. Acta med. scand. 1967, 182, 465. Chopra, J. S., Mallick, N. P., Stone, M. C. Lancet, 1971, i, 317. Gofman, J. W., De Lalle, O., Glazier, F., Freeman, N., Lindgren, F. T., Nicholls, A., Strisower, B., Tamplin, A. Plasma, 1954, 2, 413. Gofman, J. W., Young, W., Tandy, R. Circulation, 1966, 34, 679. Kannel, W. B., Dawber, T. R., Friedman, G. D., Glennan, W. E., McNamara, P. M. Ann. intern. Med. 1964, 61, 888. Berlyne, G. M., Mallick, N. P. Lancet, 1969, ii, 399. New Engl. J. Med. 1968, 279, 885. Langer, T., Levy, R. I. ibid. p. 856. Thorp, J. M. Determination of ’Atromid S’ in urine and serum. I.C.I. Pharmaceuticals, 1963. Thorp, J. M. Lancet, 1962, i, 1323.