Failure of Fenoldopam to Control Severe Hypertension Secondary to Renal Graft Rejection in a Pediatric Patient
We report the first case of the failure of fenoldopam for a pediatric patient with severe hypertension and renal failure. Our patient was a 3-year-old child with severe hypertension secondary to renal graft rejection and high-dose steroid treatment. The patient’s hypertension was controlled with nitroprusside but not with fenoldopam.
Introduction
Fenoldopam is a new agent for control of severe hypertension. It has been studied among adults with hypertensive emergencies, including allograft rejection, and is as potent as nitroprusside.1 Studies show that this dopamine-1 (DA1) receptor agonist works in controlling severe hypertension among adults with very few side effects.1’2 It may be the drug of choice for hypertensive emergencies among adult patients with decreased renal function.2 Fenoldopam has been used successfully for pediatrie patients, particularly patients requiring controlled hypotension during spinal fusion.3 Furthermore, fenoldopam has controlled hypertension in isolated cases among pediatrie patients.4 However, fenoldopam use in the pediatric population with renal failure and hypertension has not been documented. We report the use of fenoldopam in the treatment of a 3-year-old male patient with a history of renal transplantation who developed severe hypertension during an episode of acute rejection.
Case Report
A 3-year-old Hispanic male patient, with a history of membranoproliferative glomerulonephritis and subsequent cadaveric renal transplantation 18 months before admission, presented to the pediatric renal team with severe hypertension after incision and drainage with hypospadias repair. As an outpatient, he had a 1-year history of hypertension. His medication regimen, including clonidine (0.1 mg b.i.d.), atenolol (10 mg q.d.), and nifedipine (7.5 mg t.i.d.), adequately controlled his hypertension in the range of 90 to 105/40 to 50 mm Hg on an outpatient basis. After the surgery, however, the patient developed pneumonia, acute rejection of his transplanted kidney, and severe hypertension.
The patient tolerated the procedure well but returned to the pediatric intensive care unit with fever to 103F and significant respiratory distress. His chest X-ray results were consistent with alveolar infiltrates in both lungs. With the patient receiving cyclosporin A (CsA; 6 mg/kg per day), mycophenolate mofetil (250 mg b.i.d.), and prednisone (5 mg four times per week) for immunosuppression, treatment of pneumonia with vancomycin, piperacillin/tazobactam, and trimethoprim was initiated.
One day after admission to the pediatric intensive care unit, the patient developed tenderness over his renal graft site in the right iliac fossa. An evaluation for acute rejection was started. Blood results were obtained; the serum creatinine level had increased to 1.8 mg/dL from the baseline level of 1.1 mg/dL. The hemoglobin level was 7.4 mg/dL, decreased from the baseline value of 9.9 mg/dL. The patient had a CsA level of 30.7 ng/mL. His CsA levels were monitored throughout the hospitalization and never exceeded 40 ng/mL. A urinalysis showed hematuria, with more than 50 red blood cells per high-power field, and 3+ protein levels. The baseline urinalysis sample was free of blood and protein. Radiological studies included a renal ultrasound scan and an echocardiogram. The renal ultrasound scan revealed normal blood flow and appearance of the transplanted kidney, with no lymphocele. The echocardiogram showed concentric left ventricular hypertrophy consistent with chronic hypertension.
The patient experienced an episode of acute renal graft rejection 2 weeks before admission, which was treated with 3 days of intravenous, high-dose steroid therapy at another hospital. His renal function returned to baseline after the steroid bolus, with the creatinine level decreasing from 1.9 mg/dL to 1.1 mg/dL. Another renal biopsy was performed. The renal biopsy showed several foci of intratubular inflammation (tubulitis), indicating acute rejection. In addition, extensive interstitial infiltration, predominantly mononuclear, was noted in the biopsy. Given this clinical picture of graft tenderness with biopsy results consistent with acute rejection, a decision to administer a 5-day course of intravenous, high-dose methylprednisone (10 mg/kg per day) therapy was made. The patient continued to receive CsA (6 mg/kg per day), mycophenolate mofetil (250 mg b.i.d.), and his outpatient antihypertensive medications.
The patient developed severe hypertension on day 3 of his hospitalization, shortly after starting the high-dose steroid therapy. He had systolic blood pressures ranging from 158 to 212 mm Hg and diastolic blood pressures ranging from 74 to 118 mm Hg, with mean arterial pressures ranging from 84 to 150 mm Hg. His creatinine level peaked on day 2, at 2.1 mg/dL. Orally administered nifedipine in doses of 10 mg only partially and transiently controlled his severe hypertension. The patient maintained good urine output of ~2 mL/kg per hour for his entire stay in the hospital. Although the patient’s weight remained stable and no edema was present, he was placed on intravenous furosemide therapy (3 mg/kg per day) on day 2 of hospitalization. He did not respond significantly with either lower blood pressure or increased urine output. Given the severe hypertension and lack of response to nifedipine and furosemide, the patient began to receive intravenous nitroprusside therapy at a dose of 1 g/kg per minute, which was gradually increased to 5 g/kg per minute to achieve blood pressure control (Fig. 1). The high doses of nitroprusside in conjunction with renal failure led to concern that this patient was at risk of thiocyanate toxicity. Therefore, treatment was changed to intravenous fenoldopam therapy starting at a dose of 0.03 g/kg per minute, which was increased to a maximal dose of 1.5 g/kg per minute. Even at the maximal recommended dose, fenoldopam failed to control the patient’s blood pressure (Fig. 1). The patient was then switched to intravenous labetalol therapy, increased to a dose of 3 mg/kg per hour, with continued inadequate control of his blood pressure (Fig. 1). On day 4, intravenous nicardipine therapy was started at a dose of 0.5 g/kg per minute and increased to a dose of 5 g/kg per minute, with adequate control of the patient’s blood pressure (mean arterial pressures in the range of 90-110 mm Hg) (Fig. 1). By day 4, the patient responded to the high-dose steroid therapy, with creatinine levels returning to baseline values (1.0 mg/dL). The high-dose steroid therapy was stopped on day 5 and the oral prednisone therapy was resumed. The patient’s blood pressure was well controlled with orally administered nifedipine (10 mg t.i.d.) and renal function remained stable, with creatinine levels at baseline values (1.0-1.1 mg/dL).
Discussion
The use of fenoldopam among adult patients with severe hypertension has been very encouraging.5 Fenoldopam mesylate is a short-acting, DA^sub 1^ receptor agonist that lowers systemic vascular resistance by binding to DA^sub 1^ receptors.6 These DA^sub 1^ receptors are present in the mesenteric, coronary, cerebral, and renal afferent arterioles.7 Fenoldopam dilates renal afferent arterioles, decreases renal vascular resistance, and increases renal blood flow.8 It has been shown in some studies to preserve renal function better than nitroprusside and to cause saline diuresis among patients with severe hypertension and renal failure.9 Studies among adults have suggested that fenoldopam is as potent as nitroprusside in controlling severe hypertension and has similar advantages.10 Because of these characteristics, some consider fenoldopam to be a drug of choice for severe hypertension among patients with renal failure.11 Therefore, for our patient with renal failure and severe hypertension, fenoldopam appeared to be a medication of choice for lowering blood pressure.
Fig. 1, Line graph of systolic blood pressure (SBP) and diastolic blood pressure (DBP) throughout the course of the patient’s hospitalization. The times and dates, along with the antihypertensive medication used during those time periods, are shown on the x-axis of the graph. The blood pressures (mm Hg) are shown on the y-axis.
Our patient had multiple factors leading to his hypertension. The first reason for his hypertension centered on high-dose steroid therapy inducing mineralocorticoid excess, which causes retention of sodium and water. The second reason was that CsA itself causes hypertension through vasoconstricting effects and enhanced proximal tubular reabsorption of sodium and water.12 Finally, transplant rejection leads to a reduction in the glomerular filtration rate, as evidenced by increased serum creatinine levels; this reduction leads to salt and water retention.
Nitroprusside, a potent vasodilator, controlled the patient’s blood pressure. Although nitroprusside was effective, the patient was at high risk for nitroprusside toxicity because of his renal failure and the high doses of nitroprusside required. This prompted the use of fenoldopam despite the lack of any reports of its use among pediatric patients with renal failure. With fenoldopam increasing the glomerular filtration rate and producing saline excretion, our patient’s hypertension might have been expected to re\spond. Studies showed that oral fenoldopam therapy reduced blood pressure in cases of hypertension caused by CsA.13
However, for our patient with severe hypertension and acute renal failure, fenoldopam failed to adequately control his blood pressure even at the maximal recommended adult dose. The reasons for this failure are not clear, but several possibilities exist. Perhaps fenoldopam is not as potent an antihypertensive drug as nitroprusside, despite contrary evidence among adults. Our patient’s hypertension was very severe, as manifested by the fact that it could not be controlled with intravenously administered labetalol and required high-dose nitroprusside therapy for control. A second possible explanation for the failure of fenoldopam for our patient is that it may not be as effective among children as it is among adults. It is possible that the DA^sub 1^ receptor system is not as well developed in children as in adults. There are data showing the maturity of the central DA^sub 1^ receptor system in children but no age-related data on the DA^sub 1^ receptor system in the renal vascular system.14,15 A third possible explanation is that the fenoldopam doses established for adults are inadequate for children. Children may metabolize the drug differently than adults and require higher doses to be effective. Further study will determine whether fenoldopam is a useful drug for the treatment of severe hypertension among children. However, the use of fenoldopam to control hypertension for a pediatric patient with renal failure, such as our patient, is not recommended at this time.
The reason why intravenous nicardipine therapy worked in controlling the hypertension for our patient, when the fenoldopam and labetalol infusions failed, is not known. We suspect it is because this drug was used at a time when rejection was reversed and high-dose steroid therapy was being stopped, i.e., the patient’s blood pressure was returning to baseline levels. However, we cannot exclude the possibility that intravenously administered nicardipine is a more effective antihypertensive agent than fenoldopam among children. This also will require further study among pediatric patients with severe hypertension.
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Guarantor; MAJ Brent Lee Lechner, MC USA
Contributors: MAJ Brent Lee Lechner, MC USA; COL Jose F. Pascual, MC USAF; COL John D. Roscelli, MC USA
San Antonio Military Pediatric Center, Brooke Army Medical Center/ Wilford Hall Air Force Medical Center, 2200 Bergquist Drive, Suite 1, San Antonio, TX 78236.
This manuscript was received for review in December 2003. The revised manuscript was accepted for publication in March 2004.
Reprint & Copyright by Association of Military Surgeons of U.S., 2005.
Copyright Association of Military Surgeons of the United States Feb 2005