Download Minoxidil-Related Renal Function Deterioration and Pulmonary

Acta Nephrologica 25(1): 33-36, 2011
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Case Report
Minoxidil-Related Renal Function
Deterioration and Pulmonary Edema:
A Case Report and Literature Review
Chien-Hung Lee, Kuo-Su Chen, and Hao-Hsi Kao
Division of Nephrology, Keelung Branch, Chang Gung Memorial Hospital
Keelung, Taiwan, Republic of China
Abstract
Minoxidil is a highly effective antihypertensive agent for patients with refractory hypertension.
Long-term use of a high dose of minoxidil may cause several side effects. However, the concurrence of
acute pulmonary edema and rapid progression of renal function after short-term and low-dose therapy
is not common. Herein, we report the case of a 70-year-old woman who had diabetes mellitus and mild
impairment of renal function. Low-dose minoxidil (2.5 mg) was prescribed to manage her poorly
controlled blood pressure. The dosage was gradually increased to 5 mg/day. In the nineth week after
the initiation of minoxidil therapy, the patient experienced weight gain (5 kg), orthopnea, and exertional
dyspnea. Physical examination revealed basal crackles in both lung fields. Chest X-ray showed bilateral
pleural effusions and pulmonary congestion. One week after the discontinuation of minoxidil, her body
weight returned to the previous status and the symptoms of pulmonary edema subsided completely. The
pleural effusion resolved gradually two weeks later. However, her renal function deteriorated rapidly
and did not return to normal. This case alerts us that minoxidil should be used with caution in patients
with impaired renal function. Fluid status and renal function should be closely monitored. Whenever
complications develop, minoxidil should be discontinued. (Acta Nephrologica 2011; 25: 33-36)
KEY WORDS: minoxidil, congestive heart failure, renal function deterioration
Introduction
Minoxidil is a potent oral vasodilator that acts
directly on arteriolar smooth muscle cells. It is effective
in controlling blood pressure in patients with refractory
hypertension (1, 2). Its side effects include hirsutism,
fluid retention, weight gain, tachycardia, congestive
heart failure (CHF), pulmonary congestion, electrocardiographic change, alteration in renal function, and
pleural and pericardial effusion. Patients who are
complicated with severe fluid overload or pericardial
effusion had received large doses of minoxidil for a
long time (3-5). The development of severe fluid
overload, congestive heart failure and rapid deterioration
of renal function in patients who received only a small
dose for a very short period is uncommon. In this
report, we describe the clinical course as well as radio-
logic and laboratory findings of a patient who experienced simultaneous weight gain, pleural-pericardial
effusions, pulmonary edema, congestive heart failure
and rapid deterioration of renal function after shortterm low-dose minoxidil therapy.
Case Report
A 70-year-old woman was admitted to our ward
with complaints of exertional dyspnea, orthopnea, and
leg edema for the past week. She had a history of
diabetes mellitus, hypertension, and mild renal function impairment (creatinine around 1.7 mg/dL) for more
than ten years. In two months before this admission,
her blood pressure was not well controlled (around
170/70 mmHg) (Fig. 1) despite receiving treatment
with multiple antihypertensive drugs, including me-
Corresponding author: Dr. Kuo-Su Chen, Division of Nephrology, Keelung Branch, Chang Gung Memorial Hospital, 222, Mai Chin Road,
Keelung, Taiwan, R.O.C. Tel: +886-2-24313131 ext. 3134, Fax: +886-2-27162130, E-mail: [email protected]
Received: February 11, 2010; Accepted: October 21, 2010.
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Lee, Chen and Kao
8
Creatinine (mg/dL)
7
Minoxidil (5 mg/day)
6
Minoxidil (2.5 mg/day)
5
4
3
Minoxidil discontinuation
2
Years
2009/7/17
2009/6/19
2009/6/5
2009/5/15
2009/5/1
2009/4/3
2009/2/3
2008
2007
2006
2005
2004
2003
0
2009/3/7
1
Months
BP
2003
2004
2005
2006
2007
2008
2009/
02/03
2009/
03/07
2009/
04/03
2009/
05/01
2009/
05/15
2009/
06/06
2009/
06/19
2009/
07/17
SBP
135
140
141
144
145
160
170
134
155
137
157
138
135
134
DBP
60
61
62
66
66
70
70
66
68
51
67
66
68
59
BP: Blood pressure
SBP: Systolic blood pressure
DBP: Diastolic blood pressure
Fig. 1. The creatinine level of the patient rose progressively and irreversibly after the administration of minoxidil although it was
discontinued 60 days later. No significant blood pressure drop was noted during the whole course of renal function deterioration.
thyldopa (250 mg, tid), clonidine (75 mcg, tid), bisoprolol
(5 mg qd), amlodipine (5 mg bid), valsartan (160 mg
qd), terazosin (2 mg bid), and furosemide (40 mg qd).
Because the patient refused to take so many antihypertensive drugs, the administration of minoxidil was
started at an initial dose of 2.5 mg once daily with reduction in dosage of the other antihypertensive regimens (methyldopa, 250 mg tid; clonidine, 75 mcg tid;
bisoprolol, 5 mg qd; terazosin, 2 mg bid; and furosemide, 40 mg qd). At this time, chest X-ray showed
borderline cardiomegaly. Retinal examination showed
no papilledema, no retinal hemorrhage or exudates,
and presented grade II hypertensive retinopathy. There
was no evidence of malignant hypertension for this
patient.
One month later, her blood pressure became
normal (around 134/66 mmHg) (Fig. 1), so the other
antihypertensive regimens were further reduced (bisoprolol, 5 mg qd; terazosin, 2 mg bid; and furosemide,
40 mg qd). After tapering other antihypertensive
medications, her blood pressure rose again (around
155/68 mmHg) (Fig. 1). Thus, the dose of minoxidil
was increased to 2.5 mg twice daily for better control
of her blood pressure. Unfortunately, the patient developed leg edema, nocturnal dyspnea, and gained
weight (about 5 kg) one week after changing the dose
to 5 mg per day. On admission, her blood pressure
was 137/51 mmHg and heart rate was 56 beats/min.
Physical examination showed pitting edema (+++,
grade 3) in lower extremities, basal crackles over
bilateral lung fields, decreased breathing sound at
lung bases, and an engorged jugular vein. The hemoglobin level was 10.2 gm/dL. The findings of biochemical analysis were as follows: blood glucose,
156 mg/dL; blood urea nitrogen (BUN), 48 mg/dL;
creatinine (Cr), 4.0 mg/dL; sodium, 139 mEq/L;
potassium, 3.2 mEq/L; total cholesterol, 171 mg/dL;
and albumin, 3.3 g/dL. C3 and C4 complements were
within the normal range. Anti-double-stranded DNA
(dsDNA) and antinuclear antibodies were absent in
the serum. A chest X-ray showed enlargement of the
cardiac silhouette, pulmonary edema and pleural effusions in both sides. Echocardiography revealed a
small pericardial effusion. A diagnostic pleural tapping was performed, and a yellow cloudy fluid was
obtained. The pleural fluid-to-serum protein ratio
Renal Deterioration after Minoxidil Therapy
was 0.54, and pleural fluid-to-serum lactate dehydrogenase (LDH) ratio was 0.65. The pleural fluid
did not contain malignant cells, or acid-fast bacilli,
and both cultures were sterile.
Diabetic nephropathy with severe proteinuria was
initially thought to be the cause of our patient’s severe
edema and fluid overload. However, the analysis of
urine collected over a 24-hour period revealed that
the amount of protein excreted was 1.0 g/day. The
plasma albumin level was only slightly below normal
(3.3 g/dL). Thus, diabetic nephropathy with nephrotic
syndrome is not likely to be the cause of the observed
fluid retention. Furthermore, the liver function test
and liver echo study revealed no evidence of liver cirrhosis. Thyroid function and cortisol levels were also
normal.
Despite treatment with furosemide (160 mg/day),
leg edema and dyspnea did not improve. We suspected
that the fluid overload was related to minoxidil. Thus,
it was discontinued and hydralazine was administered
instead to control the blood pressure. Leg edema,
dyspnea, and weight gain improved rapidly and dramatically within a week. No hypotension episode or
any evidence of volume contraction developed during
the whole course of clinical management. Chest Xray and echocardiogram repeated one month after
discontinuation of minoxidil showed complete disappearance of pulmonary edema, pleural and pericardial
effusions. She was feeling well, and her blood pressure
(Fig. 1) was controlled with clonidine (750 µg three
times daily), amlodipine (10 mg daily), hydralazine
(50 mg four times daily), and furosemide (80 mg daily).
However, her renal function deteriorated rapidly and
irreversibly despite termination of minoxidil therapy
(Fig. 1).
Discussion
Hypertension is frequent among patients with
chronic kidney disease (CKD). Blood pressure may
be difficult to control in some patients with CKD and
the use of other powerful drugs such as minoxidil may
be required (8, 9). The effective dose of minoxidil for
controlling severe hypertension generally ranges from
2 mg to 80 mg per day (6, 8). The usual regimen is 1020 mg twice daily (6, 17, 18).
The most common side effects of minoxidil are
hypertrichosis (60-100%), fluid retention and weight
gain (20-65%) (7, 9-12). In their investigation on
management of intractable hypertension with minoxidil, Mackay et al. reported that hirsutism was a
common side effect of minoxidil therapy (80-100%),
and fluid retention (weight gain > 7 kg) occurred in
around 20% of the patients (10). Occasionally, side
effects such as pericardial effusion (3-10%), tachycardia
and pericarditis (1-9%), congestive heart failure (2%),
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ischemic chest pain (1%), cardiac tamponade (< 1%),
pleural effusion (< 1%) and others would occur (7,
10-13). The symptoms usually disappeared after discontinuation of the drug. Although the development
of fluid overload or pericardial effusion is common,
simultaneous concurrence of severe fluid overload,
congestive heart failure and rapid deterioration of renal
function after low-dose short-term therapy with minoxidil is rare.
There has been no consensus regarding the impact
of minoxidil therapy on renal function (15, 16). Some
authors reported that renal function might improve or
does not change after minoxidil therapy for hypertension
(9, 10, 14). Some groups reported contradictory
findings. Wilburn et al. reported worsened renal
function in three patients with severe hypertension.
These patients had been treated with minoxidil (4060 mg/day) for 11-13 months (17). Mitchell and
Pettinger reported progressive renal failure that required
hemodialysis. It developed in patients with severe
hypertension who received minoxidil treatment (40
mg/day) for periods ranging from six months to five
years (18). In the review from the UpToDate, it is
suggested that adverse effects of this drug on renal
function is usually transient increase in serum BUN
and creatinine, which may return to normal after
discontinuation of minoxidil (19). Our patient, however,
showed rapid and irreversible deterioration of renal
function (from 1.7 mg/dL to 7.4 mg/dL) after the onset
of minoxidil administration (5 mg/day) in weeks.
Several factors including diuretic or congestive
heart failure, induced kidney hypoperfusion, nephrotoxic drugs, and the de novo effect of minoxidil might
have contributed to the development of renal function
deterioration in this patient. However, her creatinine
level had been rising gradually since the initiation of
minoxidil therapy and before the development of
congestive heart failure and acute pulmonary edema.
In addition, no hypotension episode, no volume contraction, and no nephrotoxic agent administration occurred throughout the clinical course. Although the
possibility of diuretics or CHF-related kidney hypoperfusion could be considered, we attributed the irreversible
renal function deterioration in the patient to the application of minoxidil.
Diabetic nephropathy with nephrotic syndrome
may cause fluid retention and congestive heart failure
as seen in our patient. However, her proteinuria was
mild, and her serum albumin level was only slightly
below normal. Furthermore, the fluid overload resolved quickly and completely after discontinuation
of minoxidil treatment. Thus, we believed that the
contributory factor for the observed fluid overload
was minoxidil rather than diabetic nephropathy.
Our findings indicate that physicians should be
careful when prescribing minoxidil to patients with
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Lee, Chen and Kao
CKD. The body weight and renal function of patients
with CKD receiving minoxidil treatment should be
regularly monitored. An apparent weight gain or deterioration of renal function should raise the suspicion
of a minoxidil related complication and in such cases,
the discontinuation of the drug should be considered.
References
1. Limas CJ, Freis ED. Minoxidil in severe hypertension with renal
failure. Am J Cardiol 31: 355-361, 1973.
2. Pettinger WA, Mitchell HC. Minoxidil - an alternative to nephrectomy for refractory hypertension. N Engl J Med 289: 167-171,
1973.
3. Houston MC, McChesney JA, Chatterjee K. Pericardial effusion
associated with minoxidil therapy. Arch Intern Med 41: 69-71, 1981.
4. Shirwany A, D’Cruz IA, Munir A. Very large pericardial effusion
attributable to minoxidil: resolution without drainage of fluid.
Echocardiography 19: 513-516, 2002.
5. Webb DB, Whale RJ. Pleuropericardial effusion associated with
minoxidil administration. Postgrad Med J 58: 319-320, 1982.
6. Canaday B. Minoxidil. South Med J 73: 59-64, 1980.
7. Minoxidil. Drug information. In: Rose BD. Ed. UpToDate.
Wellesley, MA: 2003.
8. Martin WB, Zins GR, Freyburger WA. The use of minoxidil, an
experimental arteriolar dilator, in 510 patients with refractory
hypertension. Clin Sci Mol Med 48: 189s-190s, 1975.
9. Methta PK, Mamdani B, Shansky RM. Severe hypertension treat-
ment with minoxidil. JAMA 233: 249-252, 1975.
10. Mackay A, Isles C, Henderson I, Fife R, Kennedy AC. Minoxidil
in the management of intractable hypertension. Q J Med 50: 175190, 1981.
11. Turcani M, Jacob R. Minoxidil accelerates heart failure development in rats with ascending aortic constriction. Can J Physiol
Pharmacol 76: 613-620, 1988.
12. Javier R, Dumler F, Park JH, Bok DV, Riley RW, Levin NW. Longterm treatment with minoxidil in patients with severe renal failure.
J Cardiovasc Pharmacol Suppl 2: S149-S155, 1980.
13. Palomar R, Morales P, Sanz de Castro S, Tasis A, Rodrigo E, Piñera
C, et al. Pleural effusion secondary to minoxidil in a peritoneal
dialysis patient. Nephrol Dial Transplant 19: 2688, 2004.
14. Luft FC, Bloch R, Szwed JJ, Grim CM, Grim CE. Minoxidil
treatment of malignant hypertension. Recovery of renal function.
JAMA 240: 1985-1987, 1978.
15. Bryan RK, Hoobler SW, Rosenzweig J, Weller JM, Purdy JM.
Effect of minoxidil on blood pressure and hemodynamics in severe
hypertension. Am J Cardiol 39: 796-801, 1977.
16. Bennett WM, Hartnett M, Kuehnel E, McDonald WJ, Porter GA.
Long-term minoxidil therapy in patients with refractory hypertension and renal disease. Proc Clin Dial Transplant Forum 6: 80-84,
1976.
17. Wilburn RL, Blaufuss A, Bennett CM. Long-term treatment of
severe hypertension with minoxidil, propranol and furosemide.
Circulation 55: 706-713, 1975.
18. Mitchell HC, Pettinger WA. Long-term treatment of refractory
hypertensive patients with minoxidil. JAMA 239: 2131-2138,
1978.
19. Drug information of minoxidil. 2010 UpToDate, Inc. Online 18.1
www.uptodate.com