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Hydralazine, Hydrochlorothiazide and Ampicillin Associated with Retroperitoneal Fibrosis: Case Report
0022-534 7/89/1414-0936$02.00/0
Vol. 141, April Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1989 by The Williams & Wilkins Co.
HYDRALAZINE, HYDROCHLOROTHIAZIDE AND AMPICILLIN ASSOCIATED WITH RETROPERITONEAL FIBROSIS: CASE REPORT VICTOR V. WATERS* From the Department of Internal Medicine, St. Luke's Hospital, Temple University Affiliate, Bethlehem, Pennsylvania
ABSTRACT
A case of retroperitoneal fibrosis possibly associated with hydralazine, hydrochlorothiazide and ampicillin therapy is reported. (J. Ural., 141: 936-937, 1989) A patient presented with biopsy proved retroperitoneal fibrosis after 8 years of therapy with hydralazine, hydrochlorothiazide and ampicillin. Hydralazine is a widely used and effective antihypertensive agent. A review of the literature revealed no reports of retroperitoneal fibrosis induced by hydralazine, hydrochlorothiazide or ampicillin. The pathogenesis of retroperitoneal fibrosis may be related to an autoimmune or hypersensitivity reaction. CASE REPORT
A 44-year-old white woman was hospitalized with severe azotemia. For the last 8 years she had been on 2.5 mg. hydralazine and 25 mg. hydrochlorothiazide orally once daily for control of essential hypertension (160/80 mm. Hg). A week before hospitalization the patient presented to a local physician with a viral-like symptomatology associated with mild facial swelling, for which she received ampicillin (500 mg. orally 4 times a day). Presumptive diagnosis was acute sinusitis. The ampicillin was discontinued after 6 days because of a red, blotchy, nonpruritic rash. Also, the patient began to complain of increased urinary urgency and frequency (voiding only in small amounts) that progressed to anuria 8 hours later. She had occasional episodes of nausea and vomiting without abdominal or flank pain but she denied fever, chills, anorexia, oral intake of ergot alkaloids, or prior surgery or radiation exposure. There was no known connective tissue disease and no family history of renal disease. Physical examination revealed a well nourished, slightly overweight white woman in no apparent distress. Blood pressure was 170/100 mm. Hg, pulse 95 beats per minute, respirations 15 per minute and temperature 38.8C. The skin revealed a generalized erythematous maculopapular rash and the head showed no evidence of facial or periorbital edema. Frontal and maxillary sinuses were nontender to light percussion. There was no palpable lymphadenopathic condition. The lungs were clear to ausculation. The heart was regular without evidence of a rub or summation gallop. The abdomen was soft, nondistended and nontender. No masses were palpable. Musculoskeletal examination showed trace pretibial edema and no costovertebral angle tenderness. Neurological examination was normal. Laboratory data. Blood urea nitrogen (BUN) was 84 (normal 5 to 25 mg./dl.), creatinine 12 (normal 0.5 to 1.4 mg.jdl.), serum sodium 124 (normal135 to 153 mEq.jl.), potassium 3.7 (normal 3.5 to 5.3 mEq./l.), chloride 87 (normal 95 to 110 mEq./l.) and bicarbonate 22. Urinalysis showed 1 red and 2 white blood cells per high power field, and trace protein with no cast cells. Urine for eosinophils was negative. Urine sodium was 82, urine potassium 27 and urine chloride 81. Arterial blood gases on 0.21 mm. Hg revealed an oxygen pressure of 84, carbon dioxide pressure 35 and pH 7.38. Sedimentation rate was 61 mm. per Accepted for publication September 19, 1988. * Requests for reprints: Department of Physiology, University of Pennsylvania, School of Medicine, A201 Richards Building, Philadelphia, Pennsylvania 19104.
hour (normal 0 to 20). White blood count was 19,000 (normal 5,000 to 10,000/mm. 3) with a normal differential. Fluorescent antinuclear antigen and smooth muscle antibody studies were negative. Complement studies (C3, C4 and CH50) were normal except for a slight decrease of C3 levels. Serum protein electrophoresis showed an acute inflammatory pattern and a normal urine electrophoresis. Chest radiography showed small bilateral pleural effusion. A plain film of the kidneys, ureters and bladder was normal. Ultrasound of the kidneys showed bilateral hydronephrosis (right kidney measuring 12 em. and left kidney 13 em.). A computerized tomography scan ofthe abdomen showed both kidneys to be diffusely enlarged with marked bilateral hydronephrosis and hydrometers at the level of the aortic bifurcation. A localized density was noted within the paraaortic and para-vena caval region. Bilateral retrograde pyelography showed a high grade bilateral ureteral stenosis at the L5 level. The patient was treated with steroids (60 mg. oral prednisone once daily). After 24 hours of observation she began to excrete a net total (output minus input) of 4 l. urine during a 16-hour period. BUN and creatinine returned to normal by hospital day 7. Blood pressure remained normal without antihypertensive agents. On day 9 of hospitalization the patient underwent bilateral ureterolysis. Both ureters were encased in fibrofatty tissue at the area of the bifurcation of the aorta and common iliac vein. Biopsy specimens showed fibrous connective tissue. Light microscopy revealed acute and chronic organizing inflammation. Light microscopy of a right renal biopsy specimen showed no significant interstitial or glomerular inflammation. Electron microscopy revealed only minimal histological changes involving fusion of local foot processes. No deposits were noted. DISCUSSION
Retroperitoneal fibrosis was described first as a clinical entity by Ormond in 1948. 1 Some of the causes of retroperitoneal fibrosis include malignancy (for example lymphoma), infection, radiation, connective tissue diseases and drugs. 2 The most well known drug associated with retroperitoneal fibrosis is methysergide.3 Other isolated cases have been reported with lysergic acid diethylamide, phenacetin, methyldopa and ergotamine. 4 • 5 The pathogenesis of retroperitoneal fibrosis remains unclear. It is believed that methysergide acts as a hapten, inducing an autoimmune reaction. However, evidence for this effect is lacking. Presently, there are no reports of hydralazine-induced retroperitoneal fibrosis. Hydralazine is well known to cause a lupus-like syndrome within 2 years of treatment and usually with dosages greater than 100 mg. per day. 6 ' 7 There are reports of patients with systemic lupus in whom eosinophilic fasciitis and retroperitoneal fibrosis develop. 8 However, our patient had negative studies for lupus as well as normal complements, suggesting that an autoimmune reaction probably was not occurring. Ampicillin can be excluded as a causative factor, since the facial swelling was due to the renal failure rather than
936
RETROPERITONEAL FIBROSIS
the presumptive and incorrect diagnosis of sinusitis. However, it is possible that ampicillin may have accelerated the obstructive uropathic condition via a hypersensitivity reaction as evidenced by the atypical features on biopsy of an acute inflammatory reaction with eosinophils. The dramatic response to high dose steroids suggests that the obstruction was predominantly that of acute inflammation even though typical chronic changes were noted. 9 In a review of 60 patients with idiopathic retroperitoneal fibrosis steroids sometimes improved the obstruction and renal function. 10 Hydrochlorothiazide also may be a contributing or causative factor but the mechanism of this remains unclear. In conclusion, it is unclear whether hydralazine, hydrochlorothiazide or ampicillin was associated with or caused the retroperitoneal fibrosis, or whether the condition was idiopathic. It is possible that 1 or more of these drugs may have been involved but there currently is no evidence in the literature. However, since retroperitoneal fibrosis remains a mystery as to its true incidence, natural course and pathogenesis, these drugs should be considered as possible etiological agents. REFERENCES
1. Ormond, J. K.: Bilateral ureteral obstruction due to envelopment and compression by an inflammatory retroperitoneal process. J.
937
Urol., 59: 1072, 1948. 2. Lepor, H. and Walsh, P. C.: Idiopathic retroperitoneal fibrosis. J. Urol., 122: 1, 1979. 3. Koep, L. and Zuidema, G. D.: The clinical significance of retroperitoneal fibrosis. Surgery, 81: 250, 1977. 4. Graham, J. R., Suby, H. I., Le Compte, P. R. and Sadowsky, N. L.: Fibrotic disorders associated with methysergide therapy for headache. New Engl. J. Med., 274: 360, 1966. 5. Damstrup, L. and Jensen, T. T.: Retroperitoneal fibrosis after long-term daily use of ergotamine. Int. Urol. Nephrol., 18: 299, 1986. 6. Perry, H. M., Jr.: Possible mechanisms of the hydralazine-related lupus-like syndrome. Arth. Rheum., 24: 1093, 1981. 7. Cameron, H. A. and Ramsey, L. E.: The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Brit. Med. J., 289: 410, 1984. 8. Garcia-Morteo, 0., Nitsche, A., Maldonado, J. A. and Barcelo, H. A.: Eosinophilic fasciitis and retroperitoneal fibrosis in a patient with systemic lupus erythematosus. Letter to the Editor. Arth. Rheum., 30: 1314, 1987. 9. Osborne, H. M., Butler, J. J., Bloustein, P. and Sumner, G.: Idiopathic retroperitoneal fibrosis (sclerosing retroperitonitis). Hum. Path., 18: 735, 1987. 10. Baker, L. R.I., Mallinson, W. J. W., Gregory, M. C., Menzies, E. A. D., Cattell, W. R., Whitfield, H. N., Hendry, W. F., Wickham, J. E. A. and Joekes, A.M.: Idiopathic retroperitoneal fibrosis. A retrospective analysis of 60 cases. Brit. J. Urol., 60: 497, 1987.
Vol. 141, April Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1989 by The Williams & Wilkins Co.
HYDRALAZINE, HYDROCHLOROTHIAZIDE AND AMPICILLIN ASSOCIATED WITH RETROPERITONEAL FIBROSIS: CASE REPORT VICTOR V. WATERS* From the Department of Internal Medicine, St. Luke's Hospital, Temple University Affiliate, Bethlehem, Pennsylvania
ABSTRACT
A case of retroperitoneal fibrosis possibly associated with hydralazine, hydrochlorothiazide and ampicillin therapy is reported. (J. Ural., 141: 936-937, 1989) A patient presented with biopsy proved retroperitoneal fibrosis after 8 years of therapy with hydralazine, hydrochlorothiazide and ampicillin. Hydralazine is a widely used and effective antihypertensive agent. A review of the literature revealed no reports of retroperitoneal fibrosis induced by hydralazine, hydrochlorothiazide or ampicillin. The pathogenesis of retroperitoneal fibrosis may be related to an autoimmune or hypersensitivity reaction. CASE REPORT
A 44-year-old white woman was hospitalized with severe azotemia. For the last 8 years she had been on 2.5 mg. hydralazine and 25 mg. hydrochlorothiazide orally once daily for control of essential hypertension (160/80 mm. Hg). A week before hospitalization the patient presented to a local physician with a viral-like symptomatology associated with mild facial swelling, for which she received ampicillin (500 mg. orally 4 times a day). Presumptive diagnosis was acute sinusitis. The ampicillin was discontinued after 6 days because of a red, blotchy, nonpruritic rash. Also, the patient began to complain of increased urinary urgency and frequency (voiding only in small amounts) that progressed to anuria 8 hours later. She had occasional episodes of nausea and vomiting without abdominal or flank pain but she denied fever, chills, anorexia, oral intake of ergot alkaloids, or prior surgery or radiation exposure. There was no known connective tissue disease and no family history of renal disease. Physical examination revealed a well nourished, slightly overweight white woman in no apparent distress. Blood pressure was 170/100 mm. Hg, pulse 95 beats per minute, respirations 15 per minute and temperature 38.8C. The skin revealed a generalized erythematous maculopapular rash and the head showed no evidence of facial or periorbital edema. Frontal and maxillary sinuses were nontender to light percussion. There was no palpable lymphadenopathic condition. The lungs were clear to ausculation. The heart was regular without evidence of a rub or summation gallop. The abdomen was soft, nondistended and nontender. No masses were palpable. Musculoskeletal examination showed trace pretibial edema and no costovertebral angle tenderness. Neurological examination was normal. Laboratory data. Blood urea nitrogen (BUN) was 84 (normal 5 to 25 mg./dl.), creatinine 12 (normal 0.5 to 1.4 mg.jdl.), serum sodium 124 (normal135 to 153 mEq.jl.), potassium 3.7 (normal 3.5 to 5.3 mEq./l.), chloride 87 (normal 95 to 110 mEq./l.) and bicarbonate 22. Urinalysis showed 1 red and 2 white blood cells per high power field, and trace protein with no cast cells. Urine for eosinophils was negative. Urine sodium was 82, urine potassium 27 and urine chloride 81. Arterial blood gases on 0.21 mm. Hg revealed an oxygen pressure of 84, carbon dioxide pressure 35 and pH 7.38. Sedimentation rate was 61 mm. per Accepted for publication September 19, 1988. * Requests for reprints: Department of Physiology, University of Pennsylvania, School of Medicine, A201 Richards Building, Philadelphia, Pennsylvania 19104.
hour (normal 0 to 20). White blood count was 19,000 (normal 5,000 to 10,000/mm. 3) with a normal differential. Fluorescent antinuclear antigen and smooth muscle antibody studies were negative. Complement studies (C3, C4 and CH50) were normal except for a slight decrease of C3 levels. Serum protein electrophoresis showed an acute inflammatory pattern and a normal urine electrophoresis. Chest radiography showed small bilateral pleural effusion. A plain film of the kidneys, ureters and bladder was normal. Ultrasound of the kidneys showed bilateral hydronephrosis (right kidney measuring 12 em. and left kidney 13 em.). A computerized tomography scan ofthe abdomen showed both kidneys to be diffusely enlarged with marked bilateral hydronephrosis and hydrometers at the level of the aortic bifurcation. A localized density was noted within the paraaortic and para-vena caval region. Bilateral retrograde pyelography showed a high grade bilateral ureteral stenosis at the L5 level. The patient was treated with steroids (60 mg. oral prednisone once daily). After 24 hours of observation she began to excrete a net total (output minus input) of 4 l. urine during a 16-hour period. BUN and creatinine returned to normal by hospital day 7. Blood pressure remained normal without antihypertensive agents. On day 9 of hospitalization the patient underwent bilateral ureterolysis. Both ureters were encased in fibrofatty tissue at the area of the bifurcation of the aorta and common iliac vein. Biopsy specimens showed fibrous connective tissue. Light microscopy revealed acute and chronic organizing inflammation. Light microscopy of a right renal biopsy specimen showed no significant interstitial or glomerular inflammation. Electron microscopy revealed only minimal histological changes involving fusion of local foot processes. No deposits were noted. DISCUSSION
Retroperitoneal fibrosis was described first as a clinical entity by Ormond in 1948. 1 Some of the causes of retroperitoneal fibrosis include malignancy (for example lymphoma), infection, radiation, connective tissue diseases and drugs. 2 The most well known drug associated with retroperitoneal fibrosis is methysergide.3 Other isolated cases have been reported with lysergic acid diethylamide, phenacetin, methyldopa and ergotamine. 4 • 5 The pathogenesis of retroperitoneal fibrosis remains unclear. It is believed that methysergide acts as a hapten, inducing an autoimmune reaction. However, evidence for this effect is lacking. Presently, there are no reports of hydralazine-induced retroperitoneal fibrosis. Hydralazine is well known to cause a lupus-like syndrome within 2 years of treatment and usually with dosages greater than 100 mg. per day. 6 ' 7 There are reports of patients with systemic lupus in whom eosinophilic fasciitis and retroperitoneal fibrosis develop. 8 However, our patient had negative studies for lupus as well as normal complements, suggesting that an autoimmune reaction probably was not occurring. Ampicillin can be excluded as a causative factor, since the facial swelling was due to the renal failure rather than
936
RETROPERITONEAL FIBROSIS
the presumptive and incorrect diagnosis of sinusitis. However, it is possible that ampicillin may have accelerated the obstructive uropathic condition via a hypersensitivity reaction as evidenced by the atypical features on biopsy of an acute inflammatory reaction with eosinophils. The dramatic response to high dose steroids suggests that the obstruction was predominantly that of acute inflammation even though typical chronic changes were noted. 9 In a review of 60 patients with idiopathic retroperitoneal fibrosis steroids sometimes improved the obstruction and renal function. 10 Hydrochlorothiazide also may be a contributing or causative factor but the mechanism of this remains unclear. In conclusion, it is unclear whether hydralazine, hydrochlorothiazide or ampicillin was associated with or caused the retroperitoneal fibrosis, or whether the condition was idiopathic. It is possible that 1 or more of these drugs may have been involved but there currently is no evidence in the literature. However, since retroperitoneal fibrosis remains a mystery as to its true incidence, natural course and pathogenesis, these drugs should be considered as possible etiological agents. REFERENCES
1. Ormond, J. K.: Bilateral ureteral obstruction due to envelopment and compression by an inflammatory retroperitoneal process. J.
937
Urol., 59: 1072, 1948. 2. Lepor, H. and Walsh, P. C.: Idiopathic retroperitoneal fibrosis. J. Urol., 122: 1, 1979. 3. Koep, L. and Zuidema, G. D.: The clinical significance of retroperitoneal fibrosis. Surgery, 81: 250, 1977. 4. Graham, J. R., Suby, H. I., Le Compte, P. R. and Sadowsky, N. L.: Fibrotic disorders associated with methysergide therapy for headache. New Engl. J. Med., 274: 360, 1966. 5. Damstrup, L. and Jensen, T. T.: Retroperitoneal fibrosis after long-term daily use of ergotamine. Int. Urol. Nephrol., 18: 299, 1986. 6. Perry, H. M., Jr.: Possible mechanisms of the hydralazine-related lupus-like syndrome. Arth. Rheum., 24: 1093, 1981. 7. Cameron, H. A. and Ramsey, L. E.: The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Brit. Med. J., 289: 410, 1984. 8. Garcia-Morteo, 0., Nitsche, A., Maldonado, J. A. and Barcelo, H. A.: Eosinophilic fasciitis and retroperitoneal fibrosis in a patient with systemic lupus erythematosus. Letter to the Editor. Arth. Rheum., 30: 1314, 1987. 9. Osborne, H. M., Butler, J. J., Bloustein, P. and Sumner, G.: Idiopathic retroperitoneal fibrosis (sclerosing retroperitonitis). Hum. Path., 18: 735, 1987. 10. Baker, L. R.I., Mallinson, W. J. W., Gregory, M. C., Menzies, E. A. D., Cattell, W. R., Whitfield, H. N., Hendry, W. F., Wickham, J. E. A. and Joekes, A.M.: Idiopathic retroperitoneal fibrosis. A retrospective analysis of 60 cases. Brit. J. Urol., 60: 497, 1987.