Fenoldopam Reverses Cyclosporine-Induced Renal Vasoconstriction in Kidney Transplant Recipients Diane K. Jorkasky, MD, Patricia Audet, PharmD, Neil Shusterman, MD, Bernard IIson, MD, Donald Dafoe, MD, Diane Hedrich, BS, and Robert M. Stote, MD • Cyclosporine causes renal vasoconstriction and reduced renal blood flow that may contribute to chronic nephrotoxicity. This effect has not been consistently reversed by available pharmacologic agents. The efficacy of orally administered fenoldopam, a dopamine-1 (DA-1) agonist with renal vasodilator properties, was evaluated in six patients whose condition was stable 3 to 6 months following renal transplantation. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate (PAH) clearances, respectively, at baseline, after the acute oral administration of 100 mg of fenoldopam, and following 3 weeks of chronic oral fenoldopam therapy (100 mg thrice daily). Mean ERPF increased from 3.15 ± 0.17 mL/s/1.73 m2 (189 ± 10 mL/min/1.73 m2) at baseline to 3.48 ± 0.17 mL/s/1.73 m2 (209 ± 10 mL/min/1.73 m2 ) 4 hours after acute administration of fenoldopam (P = 0.04). Urine flow rate and fractional excretion of sodium also increased after acute administration, but not significantly. Mean systolic (SBP) and diastolic blood pressure (DBP) decreased maximally by 18 and 6 mm Hg, respectively, and mean pulse rate increased maximally by 8 bpm between 75 and 90 minutes after both acute and chronic administration. GFR was unchanged following both acute and chronic administration. The increase in ERPF was not maintained to the end of the dosing interval during chronic administration, probably due to the short half-life of fenoldopam, However, the renal vasodilatory response was still observed 3 to 4 hours after readministration of the drug following 3 weeks of oral dosing. Thus, fenoldopam significantly reverses the renal vasoconstriction caused by cyclosporine in renal transplant recipients. Further evaluation of fenoldopam in preventing cyclosporine-induced nephrotoxicity appears warranted. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Fenoldopam; cyclosporine; nephrotoxicity; kidney transplantation.
A
LTHOUGH THE VALUE of cyclosporine in improving both graft and patient survival in all areas of organ transplantation is widely recognized, the renal toxicity associated with its use is equally well known. 1,2 Chronic administration of cyclosporine to heart transplant recipients significantly reduces renal blood flow and glomerular filtration rate (GFR),3 effects that may be secondary to renal vasoconstriction. Consequently, a drug that could prevent or reverse renal vasoconstriction may substantially improve the renal function of patients who need long-term cyclosporine therapy following organ transplantation. The purpose of this study was to assess the acute and chronic effects of orally administered fenoldopam, a selective dopamine (DA-l) agonist known to be a renal vasodilator,4 on renal blood flow and GFR in patients receiving cyclosporine therapy following renal transplantation. METHODS
Patient Selection Six patients, 18 to 60 years old, who had received a renal transplant approximately 3 to 6 months before entry into the study were selected. These patients had to have stable serum creatinine levels of no greater than 265.20 mol/L (3.0 mg/ dL) for at least I month before entry, with no fluctuation greater than 44.20 mol/L (0.5 mg/dL) during that time. In addition, patients had to have hypertension defined as a di-
astolic blood pressure (DBP) of 90 to 105 mm Hg, and were receiving stable doses of cyclosporine (trough blood levels by whole blood high-performance liquid chromatography [HPLC) during chronic dosing between 50 and 150 ng/mL). Not more than 30 mg/d of prednisone was permitted. Excluded from the study were pregnant or lactating women or women of childbearing potential using contraceptives other than an intrauterine device (IUD); patients using other investigational drugs within 30 days of entry into the study; patients with unstable angina or evidence of myocardial infarction within 3 months of study entry; and patients with significant congestive heart failure, severe cardiac arrhythmias, or clinical or laboratory evidence of significant hepatic disease. Nonsteroidal antiinflammatory drugs, phenothiazines, and dopamine antagonists, eg, metoclopramide, had to be discontinued at least 2 weeks before the start of the study. 5 Antihypertensive medications were withheld at least 12 hours before the visit on each study day. All other concomitant medications were permissible.
From the Presbyterian Medical Center of Philadelphia and the Hospital of the University of Pennsylvania, Philadelphia, PA. This study was conducted at the Hospital of the University of Pennsylvania and Presbyterian Medical Center, Philadelphia, PA. Supported by a grant from SmithKline Beecham Pharmaceuticals, Philadelphia, PA. Address reprint requests to Diane K. Jorkasky, MD, Presbyterian Medical Center of Philadelphia, 51 N 39th St, Philadelphia, PA 19104. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/1906-0010$3.00/0
American Journal of Kidney Diseases, Vol XIX, No 6 (June), 1992: pp 567-572
567
JORKASKY ET AL
568
Table 1. Mean ± SEM Values of Major Renal Function Parameters at Baseline and at 4 Hours After the Dose of Fenoldopam on Study Days A and B Study Day A (n = 6)
Study Day B (n = 5)
Parameter
Baseline
4 Hours
Inulin clearance mL/s/1 .73 m2 (mL/min/1.73 m2 ) PAH clearance mL/s/1.73 m2 (mL/min/1 .73 m2 ) Urine flow rate (mL/min) Fractional excretion of sodium (%) Free water clearance (mL/min)
0.77 ± 0.07 (46±4) 3.15 ± 0.17 (189 ± 10) 9.3 ± 1.0 3.1 ± 1.1 6.1 ± 0.8
0.80 ± 0.08 (48 ± 5) 3.48 ± 0.17' (209 ± 10) 11.2 ± 1.4 4.2 ± 1.5 7.4±1.0
Baseline
0.85 (51 3.05 (183
± ± ± ± 8.8 ± 1.6 ± 6.0 ±
0.13 8)
0.35 21) 1.4 0.5 1.1
4 Hours
0.92 ± (55 ± 3.23 ± (194 ± 9.2 ± 1.8 ± 6.5 ±
0.12 7)
0.37' 22) 1.2 0.7 1.0
, P < 0.05 v baseline.
Study Design This was an open-label assessment of the acute and chronic effects of oral fenoldopam on renal function in patients with mild-to-moderate renal insufficiency who were recent renal transplant recipients receiving cyclosporine therapy. The study was approved by the Presbyterian Medical Center Investigational Review Board and the University of Pennsylvania Committee on Human Investigation. All procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki as amended in 1975 and 1983. Verbal and written informed consent were obtained from each volunteer before performing study procedures. The study consisted of five phases. During the screening/ pretreatment phase, a complete medical history; physical examination; chest x-ray; standard 12-lead electrocardiogram (ECG); hematology and clinical chemistry laboratories, including complete blood cell count, serum electrolytes, blood urea nitrogen (BUN), creatinine, glucose, calcium, phosphorous, albumin, alkaline phosphatase, total bilirubin, alanine aminotransferase, and aspartate aminotransferase; 24-hour urine collection for determination of creatinine clearance; and cyclosporine blood level determinations were performed within 2 weeks before beginning the study. A single 50-mg oral dose of fenoldopam also was administered to assess the patient's blood pressure and side effect response to the test drug. On study day A, classical inulin and P-aminohippurate (PAH) clearances6 were determined as measures ofGFR and effective renal plasma flow (ERPF), respectively, before (baseline) and after a single IOO-mg oral dose offenoldopam. Blood samples also were taken for determination of serum electrolytes, creatinine, and osmolality. Chronic dosing began after completion of the renal function tests on study day A. During the 3-week chronic dosing phase, a IOO-mg dose of oral fenoldopam was administered three times a day and office visits were scheduled on days 3, 7, and 14 for an interim history, physical examination, and laboratory assessments. This dose of fenoldopam was chosen based on previous work demonstrating that the renal vasodilatory effects were maximal within the constraints of an acceptable side effect profile for chronic dosing. 7 Cyclosporine blood levels were determined on days 7 and 14, and an ECG was obtained on day 14.
On study day B, 18 to 24 days after the initiation of chronic therapy with fenoldopam, the procedures of study 'day A were repeated. A follow-up visit, 7 to 10 days after study day B, included an interim history, physical examination, and laboratory assessments.
Statistical Evaluation All values are expressed as the mean ± SEM. A two-tailed paired Student's t test was used to assess the statistical significance of differences between baseline values and values obtained after the acute and chronic study phases.
RESULTS
Patient Population Six men who had received a renal transplant between 4 and 7 months before entering this protocol were studied. They ranged in age from 19 to 60 years, in weight from 47.6 to 97.4 kg, and in height from 165.1 to 194.3 cm. During the screening/pretreatment phase, the serum creatinine for the six patients was 150.3 ± 8.8 (range, 115 to 203) JLmol/L (1.7 ± 0.1 mg/dL) and the cyclosporine level was 86.8 ± 9.0 ng/mL (range, 49 to 110 ng/mL). The mean cyclosporine dose during the screening/pretreatment phase was 383 ± 54 mg per day (range, 250 to 600 mg) and this remained constant during the study. Five of the patients completed the study. Intravenous access to one patient could not be obtained on study day B. The six patients who entered the study tolerated the screening dose of fenoldopam. Renal Hemodynamic Effects Values of the major renal function parameters (inulin and PAR clearances, urine flow rate,
FENOLDOPAM REVERSES CYCLOSPORINE VASOCONSTRICTION
569
fractional excretion of sodium, and free water clearance) at baseline, on study day A (acute response), and on study day B (chronic response) are listed in Table 1. Whereas all values tended to increase from baseline after the 100-mg dose of fenoldopam, only PAH clearance increased significantly. This observation is consistent with the renal vasodilatory properties of the drug. Figure 1 shows the effect of fenoldopam on PAH clearance as a function of time after administration of the dose in both phases of the study. PAH clearance increased within 1 hour of administering fenoldopam and tended to peak between 2 to 3 hours after the dose. However, the PAH clearance still remained significantly elevated at the end of the 4-hour period of clearance determination. During the fourth hour of clearance
measurements on study day A, the PAH clearance was 3.48 ± 0.17 mL/s/I.73 m 2 (209 ± 10 mL/min/I.73 m 2), compared with a baseline value of 3.15 ± 0.17 mL/s/I.73 m 2 (189 ± 10 mL/min/I.73 m 2), P = 0.04. Because clearance determinations were only obtained for 4 hours, it is not possible to determine the full duration of the beneficial effect of fenoldopam after an oral dose. However, chronic administration of fenoldopam did not result in a sustained increase in ERPF, since baseline values were similar on both study days. However, there was little evidence of tolerance to repetitive administration of fenoldopam, as the renal responses on both days were similar. During the fourth hour of clearance measurements on study day B, PAH clearance increased to 3.23 ± 0.37 mL/s/I.73 m 2 (r94 ± 22
Fig 1. The effect of fenoldopam on ERPF as measured by PAH clearance. Values at 1, 3, and 4 hours after fenoldopam administration on study day A • and at 4 hours on study day B Il!il were significantly different from control (P < 0.05).
Hours after dose
Control
570
JORKASKY ET AL
mL/min/1.73 m 2), compared with a baseline value of 3.05 ± 0.35 mL/s/1.73 m 2 (183 ± 21 mL/min/1.73 m 2), P = 0.04.
possibly drug-related side effects, including mild headache and flushing, dry mouth, and occasional extrasystoles.
Other Effects
DISCUSSION
Cyclosporine exerts part of its nephrotoxic effects through renal vasoconstriction as demonstrated in both animal and human studies. So10 Although animal studies have suggested a variety of mechanisms, including excessive sympathetic nervous system activity, disturbances of prostanoid metabolism, activation of the renin-angiotensin system, and increased endothelin effect, the exact mechanism of this vasoconstriction in man is unknown. To more precisely elucidate the mechanism of cyclosporine-induced vasoconstriction in man, Conte et ai " co~ducted a study in healthy volunteers to whom they administered intravenous (IV) dopamine (2 ~g/kg/ min) following an oral dose of cyclosporine. By eliminating the confounding factor of preexisting renal disease, they concluded that the acute nephrotoxicity of cyclosporine is due to severe impairment in renal hemodynamics, with marked renal vasoconstriction, that can be reversed by low-dose dopamine infusion.
As shown in Fig 2, fenoldopam tended to decrease both SBP and DBP on both study days, with the maximal effect of -18 mm Hg (SBP) and - 6 mm Hg (DBP) noted between 75 and 90 minutes after the dose. Pulse rate increased maximally in this time period (+8 bpm). Both blood pressure and pulse rate returned to values comparable to baseline by the end of the 4-hour study periods. No adjustments in antihypertensive medication were needed during either the acute or chronic dosing phases. Fenoldopam had little effect on other parameters studied. There were no clinically significant changes in hematologic, clinical chemistry, or ECG parameters. The mean creatinine before study day B was 159.1 ± 17.7 ~mol/L(1.8 ±0.2 mg/dL), which was similar to the baseline value. Cyclosporine levels were unaffected by the coadministration of fenoldopam. The mean blood level before study day B was 72.7 ± 13.8 ng/mL. Three of the six patients studied experienced 20
1 60
! · .· . . . ··· . ·. . I
!it ..... ........... .. ... .. .. ···· ·····1
i'"
12
80
h --__-r! -- __ of -----t -
f
40- 1 - - - + - - _ + _ - - - 4 - - - + - - - + - - - - + - - + - - - - + - - - + - - - - 1 -0 . 5 0 . 0 0 .5 1. 0 1 .5 2. 0 2.5 3. 0 3.5 4.0
Hours after do s e
Fig 2. The effect of fenoldopam on supine SBP and DBP. None of the values were statistically significantly different from baseline. Systolic: -9-, study day A; 4...5 . . O ... " study day B. Diastolic: =;)=, study day A; - 6. - , study day B.
571
FENOLDOPAM REVERSES CYCLOSPORINE VASOCONSTRICTION
Following the same rationale, that an agent capable of selectively stimulating DA-l receptors in the kidney would beneficially affect renal hemodynamics, fenoldopam was studied in two rat models of cyclosporine-induced nephrotoxicity.12 Acutely, fenoldopam prevented the cyclosporineinduced reduction in renal function, measured by PAH and inulin clearances. Similarly, when cyclosporine was administered subacutely (3 days), fenoldopam increased the depressed PAH and inulin clearance values to baseline normal levels. IV fenoldopam has been shown to have natriuretic and diuretic effects in healthy volunteers l3 and to exert beneficial effects on renal function in patients with mild-to-moderate,14 refractory, 15 and severe l6 ,17 hypertension and advanced chronic renal failure. 18 This study is the first to investigate the effects offenoldopam in patients receiving cyclosporine and, in contrast to the previously mentioned studies with the drug, the oral formulation was used. Although oral fenoldopam did exert beneficial renal effects in these patients, the effects were less marked than in other types of patients who have received the IV formulation. The major effect demonstrated in this study was increased renal blood flow. Improvement was sustained for several hours after each oral dose, but returned to baseline at the end of a dosing interval. The primary difference in renal response in this study compared with other studies of fenoldopam may relate to the route of administration. Oral administration of fenoldopam is associated with high first-pass metabolism and low bioavailability.19 Systemic clearance of fenoldopam is rapid and blood levels are virtually undetectable at the end of an 8-hour dosing interval. Both of these limitations are not present when fenoldopam is administered by constant infusion. Nonetheless, the fact that favorable effects on renal blood flow and other aspects of renal function were demonstrated supports the findings of Conte et alII that the renal functional impairment due to cyclosporine is at least partially reversible with DA-l agonism. Another reason for the limited renal response
may be the condition of the transplanted kidney. It is possible that some degree of renal damage from rejection, hypertension, or recovery from ischemia may have limited the renal response to fenoldopam. A number of other pharmacologic agents have been studied in an attempt to reverse the renal vasoconstriction associated with cyclosporine use. The administration of prazosin, an a I-antagonist, did not improve renal blood flow or GFR in eight patients studied by Kiberd20 or 12 patients studied by Bantle et al. 21 Angiotensin-converting enzyme inhibitors have been studied with differing results. Curtis et aJ22 found that captopril decreased ERPF by 10% in nine patients. Conversely, Bantle et al21 demonstrated a 20% increase in ERPF in nine patients. The calcium channel blocker nifedipine did not change ERPF in one study reported by Curtis et al. 22 Thus, it has been difficult to reverse vasoconstriction with currently available drugs. Although the effect of oral fenoldopam was short-lived, a long acting DA-l agonist or an IV infusion would be expected to produce sustained renal function improvement. An IV infusion would be useful in the early posttransplant period, when cyclosporine levels tend to be the highest. This would apply to the transplanted kidney in patients receiving renal transplants, as well as to the native kidneys in recipients of other organs. On a long-term basis, an effective oral dosage form might protect against the chronic vasoconstriction associated with cyclosporine and possibly reduce the incidence of chronic nephropathy. 3 In summary, oral administration of fenoldopam, a selective DA-l agonist, to renal transplant recipients receiving cyclosporine resulted in increased renal plasma flow, sodium excretion, and urine flow. The effect persisted for at least 4 hours, but was absent at the end of the dosing interval. Although the usefulness of oral fenoldopam is limited by its low bioavailability, IV fenoldopam may be beneficial in the early posttransplant period. ACKNOWLEDGMENT The authors wish to thank Robert Samuels for skillful production of the figures and Veronica Rich for secretarial assistance.
REFERENCES I. Strom TB, Loertscher R: Cyclosporine-induced nephrotoxicity. N Eng! J Med 311 :728-729, 1984
2. Bennett WM, Pulliam JP: Cyciosporine nephrotoxicity. Ann Intern Med 99:851-854, 1983
572 3. Myers BD, Ross J, Newton L, et al: Cyclosporine-associated chronic nephrotoxicity. N Eng) J Med 311 :699-705, 1984 4. Allison NL, Dubb JW, Ziemniak JA, et al: The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics. Clin Pharmacol Ther 41:282-288, 1987 5. Day MD, Blower FR: Cardiovascular dopamine receptor stimulation antagonized by metoclopramide. J Pharrn Pharmacol 27:276-278, 1975 6. Berger EY, Farber SJ, Earle DP: Comparison of constant infusion and urine collection techniques for the measurement ofrenal function. J Clin Invest 27:710-716, 1948 7. Stote RM, Dubb JW, Familiar RG, et al: New oral renal vasodilator, fenoldopam. Clin Pharmacol Ther 34:309-315, 1983 8. Murray BM, Paller MS, Ferris TF: Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int 28:767-774, 1985 9. Curtis JJ, Dubovsky E, Welchel JD, et al: Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet 2:477-479, 1986 10. Remuzzi G, Bertani T: Renal vascular and thrombotic effects of cyclosporine. Am J Kidney Dis 13:261-272, 1989 11. Conte G, Sabbatini M, Napodano P, et al: Dopamine counteracts the acute renal effects of cyclosporine in normal subjects. Transplant Proc 20:563-567, 1988 (supp1 3) 12. Brooks DP, Drutz OJ, Ruffolo RR Jr: Prevention and complete reversal of cyclosporine A-induced renal vasoconstriction and nephrotoxicity in the rat by fenoldopam. J Pharmacol Exp Ther 254:375-379, 1990 13. Hughes JM, Ragsdale NV, Felder RA, et al: Diuresis
JORKASKY ET AL and natriuresis during continuous dopamine-1 receptor stimulation. Hypertension 11:169-174, 1988 (suppI2) 14. Murphy MB, McCoy CE, Weber RR, et a1: Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopaminel agonist fenoldopam. Circulation 76:1312-1318, 1987 15. Ruilope LM, Robles RG, Miranda B, et a1: Renal effects offenoldopam in refractory hypertension. J Hypertens 6:665669, 1988 16. White WB, Halley SE: Comparative renal effects of intravenous administration of fenoldopam mesylate and sodium nitroprusside in patients with severe hypertension. Arch Intern Med 149:870-874, 1989 17. Elliott WJ, Weber RR, Nelson KS, et a1: Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation 81 :970-977, 1990 18. Andres A, Robles RG, Alcazar JM, et a1: Diuretic and natriuretic properties offenoldopam in chronic renal failure. J Hypertens 7:S326-S327, 1989 (suppI6) . 19. Clancy A, Locke-Haydon J, Cregeen RJ, et al: Effect of concomitant food intake on absorption kinetics of fenoldopam (SK&F-82526) in healthy volunteers. Eur J Clin PharmacoI32:103-106, 1987 20. Kiberd BA: Effect ofprazosin on cyclosporine-treated renal allograft recipients. Kidney Int 37:608, 1990 (abstr) 21. Bantle JP, Paller MS, Boudreau RJ, et a1: Long-term effects of cyclosporine on renal function in organ transplant patients. J Lab Clin Med 115:233-240, 1990 22. Curtis JJ, Laskow DA, Julian BA, et a1: Nifedipine is a more effective renal vasodilator than captopril in cyclosporine transplant patients. Kidney Int 35:512, 1989 (abstr)
A
LTHOUGH THE VALUE of cyclosporine in improving both graft and patient survival in all areas of organ transplantation is widely recognized, the renal toxicity associated with its use is equally well known. 1,2 Chronic administration of cyclosporine to heart transplant recipients significantly reduces renal blood flow and glomerular filtration rate (GFR),3 effects that may be secondary to renal vasoconstriction. Consequently, a drug that could prevent or reverse renal vasoconstriction may substantially improve the renal function of patients who need long-term cyclosporine therapy following organ transplantation. The purpose of this study was to assess the acute and chronic effects of orally administered fenoldopam, a selective dopamine (DA-l) agonist known to be a renal vasodilator,4 on renal blood flow and GFR in patients receiving cyclosporine therapy following renal transplantation. METHODS
Patient Selection Six patients, 18 to 60 years old, who had received a renal transplant approximately 3 to 6 months before entry into the study were selected. These patients had to have stable serum creatinine levels of no greater than 265.20 mol/L (3.0 mg/ dL) for at least I month before entry, with no fluctuation greater than 44.20 mol/L (0.5 mg/dL) during that time. In addition, patients had to have hypertension defined as a di-
astolic blood pressure (DBP) of 90 to 105 mm Hg, and were receiving stable doses of cyclosporine (trough blood levels by whole blood high-performance liquid chromatography [HPLC) during chronic dosing between 50 and 150 ng/mL). Not more than 30 mg/d of prednisone was permitted. Excluded from the study were pregnant or lactating women or women of childbearing potential using contraceptives other than an intrauterine device (IUD); patients using other investigational drugs within 30 days of entry into the study; patients with unstable angina or evidence of myocardial infarction within 3 months of study entry; and patients with significant congestive heart failure, severe cardiac arrhythmias, or clinical or laboratory evidence of significant hepatic disease. Nonsteroidal antiinflammatory drugs, phenothiazines, and dopamine antagonists, eg, metoclopramide, had to be discontinued at least 2 weeks before the start of the study. 5 Antihypertensive medications were withheld at least 12 hours before the visit on each study day. All other concomitant medications were permissible.
From the Presbyterian Medical Center of Philadelphia and the Hospital of the University of Pennsylvania, Philadelphia, PA. This study was conducted at the Hospital of the University of Pennsylvania and Presbyterian Medical Center, Philadelphia, PA. Supported by a grant from SmithKline Beecham Pharmaceuticals, Philadelphia, PA. Address reprint requests to Diane K. Jorkasky, MD, Presbyterian Medical Center of Philadelphia, 51 N 39th St, Philadelphia, PA 19104. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/1906-0010$3.00/0
American Journal of Kidney Diseases, Vol XIX, No 6 (June), 1992: pp 567-572
567
JORKASKY ET AL
568
Table 1. Mean ± SEM Values of Major Renal Function Parameters at Baseline and at 4 Hours After the Dose of Fenoldopam on Study Days A and B Study Day A (n = 6)
Study Day B (n = 5)
Parameter
Baseline
4 Hours
Inulin clearance mL/s/1 .73 m2 (mL/min/1.73 m2 ) PAH clearance mL/s/1.73 m2 (mL/min/1 .73 m2 ) Urine flow rate (mL/min) Fractional excretion of sodium (%) Free water clearance (mL/min)
0.77 ± 0.07 (46±4) 3.15 ± 0.17 (189 ± 10) 9.3 ± 1.0 3.1 ± 1.1 6.1 ± 0.8
0.80 ± 0.08 (48 ± 5) 3.48 ± 0.17' (209 ± 10) 11.2 ± 1.4 4.2 ± 1.5 7.4±1.0
Baseline
0.85 (51 3.05 (183
± ± ± ± 8.8 ± 1.6 ± 6.0 ±
0.13 8)
0.35 21) 1.4 0.5 1.1
4 Hours
0.92 ± (55 ± 3.23 ± (194 ± 9.2 ± 1.8 ± 6.5 ±
0.12 7)
0.37' 22) 1.2 0.7 1.0
, P < 0.05 v baseline.
Study Design This was an open-label assessment of the acute and chronic effects of oral fenoldopam on renal function in patients with mild-to-moderate renal insufficiency who were recent renal transplant recipients receiving cyclosporine therapy. The study was approved by the Presbyterian Medical Center Investigational Review Board and the University of Pennsylvania Committee on Human Investigation. All procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki as amended in 1975 and 1983. Verbal and written informed consent were obtained from each volunteer before performing study procedures. The study consisted of five phases. During the screening/ pretreatment phase, a complete medical history; physical examination; chest x-ray; standard 12-lead electrocardiogram (ECG); hematology and clinical chemistry laboratories, including complete blood cell count, serum electrolytes, blood urea nitrogen (BUN), creatinine, glucose, calcium, phosphorous, albumin, alkaline phosphatase, total bilirubin, alanine aminotransferase, and aspartate aminotransferase; 24-hour urine collection for determination of creatinine clearance; and cyclosporine blood level determinations were performed within 2 weeks before beginning the study. A single 50-mg oral dose of fenoldopam also was administered to assess the patient's blood pressure and side effect response to the test drug. On study day A, classical inulin and P-aminohippurate (PAH) clearances6 were determined as measures ofGFR and effective renal plasma flow (ERPF), respectively, before (baseline) and after a single IOO-mg oral dose offenoldopam. Blood samples also were taken for determination of serum electrolytes, creatinine, and osmolality. Chronic dosing began after completion of the renal function tests on study day A. During the 3-week chronic dosing phase, a IOO-mg dose of oral fenoldopam was administered three times a day and office visits were scheduled on days 3, 7, and 14 for an interim history, physical examination, and laboratory assessments. This dose of fenoldopam was chosen based on previous work demonstrating that the renal vasodilatory effects were maximal within the constraints of an acceptable side effect profile for chronic dosing. 7 Cyclosporine blood levels were determined on days 7 and 14, and an ECG was obtained on day 14.
On study day B, 18 to 24 days after the initiation of chronic therapy with fenoldopam, the procedures of study 'day A were repeated. A follow-up visit, 7 to 10 days after study day B, included an interim history, physical examination, and laboratory assessments.
Statistical Evaluation All values are expressed as the mean ± SEM. A two-tailed paired Student's t test was used to assess the statistical significance of differences between baseline values and values obtained after the acute and chronic study phases.
RESULTS
Patient Population Six men who had received a renal transplant between 4 and 7 months before entering this protocol were studied. They ranged in age from 19 to 60 years, in weight from 47.6 to 97.4 kg, and in height from 165.1 to 194.3 cm. During the screening/pretreatment phase, the serum creatinine for the six patients was 150.3 ± 8.8 (range, 115 to 203) JLmol/L (1.7 ± 0.1 mg/dL) and the cyclosporine level was 86.8 ± 9.0 ng/mL (range, 49 to 110 ng/mL). The mean cyclosporine dose during the screening/pretreatment phase was 383 ± 54 mg per day (range, 250 to 600 mg) and this remained constant during the study. Five of the patients completed the study. Intravenous access to one patient could not be obtained on study day B. The six patients who entered the study tolerated the screening dose of fenoldopam. Renal Hemodynamic Effects Values of the major renal function parameters (inulin and PAR clearances, urine flow rate,
FENOLDOPAM REVERSES CYCLOSPORINE VASOCONSTRICTION
569
fractional excretion of sodium, and free water clearance) at baseline, on study day A (acute response), and on study day B (chronic response) are listed in Table 1. Whereas all values tended to increase from baseline after the 100-mg dose of fenoldopam, only PAH clearance increased significantly. This observation is consistent with the renal vasodilatory properties of the drug. Figure 1 shows the effect of fenoldopam on PAH clearance as a function of time after administration of the dose in both phases of the study. PAH clearance increased within 1 hour of administering fenoldopam and tended to peak between 2 to 3 hours after the dose. However, the PAH clearance still remained significantly elevated at the end of the 4-hour period of clearance determination. During the fourth hour of clearance
measurements on study day A, the PAH clearance was 3.48 ± 0.17 mL/s/I.73 m 2 (209 ± 10 mL/min/I.73 m 2), compared with a baseline value of 3.15 ± 0.17 mL/s/I.73 m 2 (189 ± 10 mL/min/I.73 m 2), P = 0.04. Because clearance determinations were only obtained for 4 hours, it is not possible to determine the full duration of the beneficial effect of fenoldopam after an oral dose. However, chronic administration of fenoldopam did not result in a sustained increase in ERPF, since baseline values were similar on both study days. However, there was little evidence of tolerance to repetitive administration of fenoldopam, as the renal responses on both days were similar. During the fourth hour of clearance measurements on study day B, PAH clearance increased to 3.23 ± 0.37 mL/s/I.73 m 2 (r94 ± 22
Fig 1. The effect of fenoldopam on ERPF as measured by PAH clearance. Values at 1, 3, and 4 hours after fenoldopam administration on study day A • and at 4 hours on study day B Il!il were significantly different from control (P < 0.05).
Hours after dose
Control
570
JORKASKY ET AL
mL/min/1.73 m 2), compared with a baseline value of 3.05 ± 0.35 mL/s/1.73 m 2 (183 ± 21 mL/min/1.73 m 2), P = 0.04.
possibly drug-related side effects, including mild headache and flushing, dry mouth, and occasional extrasystoles.
Other Effects
DISCUSSION
Cyclosporine exerts part of its nephrotoxic effects through renal vasoconstriction as demonstrated in both animal and human studies. So10 Although animal studies have suggested a variety of mechanisms, including excessive sympathetic nervous system activity, disturbances of prostanoid metabolism, activation of the renin-angiotensin system, and increased endothelin effect, the exact mechanism of this vasoconstriction in man is unknown. To more precisely elucidate the mechanism of cyclosporine-induced vasoconstriction in man, Conte et ai " co~ducted a study in healthy volunteers to whom they administered intravenous (IV) dopamine (2 ~g/kg/ min) following an oral dose of cyclosporine. By eliminating the confounding factor of preexisting renal disease, they concluded that the acute nephrotoxicity of cyclosporine is due to severe impairment in renal hemodynamics, with marked renal vasoconstriction, that can be reversed by low-dose dopamine infusion.
As shown in Fig 2, fenoldopam tended to decrease both SBP and DBP on both study days, with the maximal effect of -18 mm Hg (SBP) and - 6 mm Hg (DBP) noted between 75 and 90 minutes after the dose. Pulse rate increased maximally in this time period (+8 bpm). Both blood pressure and pulse rate returned to values comparable to baseline by the end of the 4-hour study periods. No adjustments in antihypertensive medication were needed during either the acute or chronic dosing phases. Fenoldopam had little effect on other parameters studied. There were no clinically significant changes in hematologic, clinical chemistry, or ECG parameters. The mean creatinine before study day B was 159.1 ± 17.7 ~mol/L(1.8 ±0.2 mg/dL), which was similar to the baseline value. Cyclosporine levels were unaffected by the coadministration of fenoldopam. The mean blood level before study day B was 72.7 ± 13.8 ng/mL. Three of the six patients studied experienced 20
1 60
! · .· . . . ··· . ·. . I
!it ..... ........... .. ... .. .. ···· ·····1
i'"
12
80
h --__-r! -- __ of -----t -
f
40- 1 - - - + - - _ + _ - - - 4 - - - + - - - + - - - - + - - + - - - - + - - - + - - - - 1 -0 . 5 0 . 0 0 .5 1. 0 1 .5 2. 0 2.5 3. 0 3.5 4.0
Hours after do s e
Fig 2. The effect of fenoldopam on supine SBP and DBP. None of the values were statistically significantly different from baseline. Systolic: -9-, study day A; 4...5 . . O ... " study day B. Diastolic: =;)=, study day A; - 6. - , study day B.
571
FENOLDOPAM REVERSES CYCLOSPORINE VASOCONSTRICTION
Following the same rationale, that an agent capable of selectively stimulating DA-l receptors in the kidney would beneficially affect renal hemodynamics, fenoldopam was studied in two rat models of cyclosporine-induced nephrotoxicity.12 Acutely, fenoldopam prevented the cyclosporineinduced reduction in renal function, measured by PAH and inulin clearances. Similarly, when cyclosporine was administered subacutely (3 days), fenoldopam increased the depressed PAH and inulin clearance values to baseline normal levels. IV fenoldopam has been shown to have natriuretic and diuretic effects in healthy volunteers l3 and to exert beneficial effects on renal function in patients with mild-to-moderate,14 refractory, 15 and severe l6 ,17 hypertension and advanced chronic renal failure. 18 This study is the first to investigate the effects offenoldopam in patients receiving cyclosporine and, in contrast to the previously mentioned studies with the drug, the oral formulation was used. Although oral fenoldopam did exert beneficial renal effects in these patients, the effects were less marked than in other types of patients who have received the IV formulation. The major effect demonstrated in this study was increased renal blood flow. Improvement was sustained for several hours after each oral dose, but returned to baseline at the end of a dosing interval. The primary difference in renal response in this study compared with other studies of fenoldopam may relate to the route of administration. Oral administration of fenoldopam is associated with high first-pass metabolism and low bioavailability.19 Systemic clearance of fenoldopam is rapid and blood levels are virtually undetectable at the end of an 8-hour dosing interval. Both of these limitations are not present when fenoldopam is administered by constant infusion. Nonetheless, the fact that favorable effects on renal blood flow and other aspects of renal function were demonstrated supports the findings of Conte et alII that the renal functional impairment due to cyclosporine is at least partially reversible with DA-l agonism. Another reason for the limited renal response
may be the condition of the transplanted kidney. It is possible that some degree of renal damage from rejection, hypertension, or recovery from ischemia may have limited the renal response to fenoldopam. A number of other pharmacologic agents have been studied in an attempt to reverse the renal vasoconstriction associated with cyclosporine use. The administration of prazosin, an a I-antagonist, did not improve renal blood flow or GFR in eight patients studied by Kiberd20 or 12 patients studied by Bantle et al. 21 Angiotensin-converting enzyme inhibitors have been studied with differing results. Curtis et aJ22 found that captopril decreased ERPF by 10% in nine patients. Conversely, Bantle et al21 demonstrated a 20% increase in ERPF in nine patients. The calcium channel blocker nifedipine did not change ERPF in one study reported by Curtis et al. 22 Thus, it has been difficult to reverse vasoconstriction with currently available drugs. Although the effect of oral fenoldopam was short-lived, a long acting DA-l agonist or an IV infusion would be expected to produce sustained renal function improvement. An IV infusion would be useful in the early posttransplant period, when cyclosporine levels tend to be the highest. This would apply to the transplanted kidney in patients receiving renal transplants, as well as to the native kidneys in recipients of other organs. On a long-term basis, an effective oral dosage form might protect against the chronic vasoconstriction associated with cyclosporine and possibly reduce the incidence of chronic nephropathy. 3 In summary, oral administration of fenoldopam, a selective DA-l agonist, to renal transplant recipients receiving cyclosporine resulted in increased renal plasma flow, sodium excretion, and urine flow. The effect persisted for at least 4 hours, but was absent at the end of the dosing interval. Although the usefulness of oral fenoldopam is limited by its low bioavailability, IV fenoldopam may be beneficial in the early posttransplant period. ACKNOWLEDGMENT The authors wish to thank Robert Samuels for skillful production of the figures and Veronica Rich for secretarial assistance.
REFERENCES I. Strom TB, Loertscher R: Cyclosporine-induced nephrotoxicity. N Eng! J Med 311 :728-729, 1984
2. Bennett WM, Pulliam JP: Cyciosporine nephrotoxicity. Ann Intern Med 99:851-854, 1983
572 3. Myers BD, Ross J, Newton L, et al: Cyclosporine-associated chronic nephrotoxicity. N Eng) J Med 311 :699-705, 1984 4. Allison NL, Dubb JW, Ziemniak JA, et al: The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics. Clin Pharmacol Ther 41:282-288, 1987 5. Day MD, Blower FR: Cardiovascular dopamine receptor stimulation antagonized by metoclopramide. J Pharrn Pharmacol 27:276-278, 1975 6. Berger EY, Farber SJ, Earle DP: Comparison of constant infusion and urine collection techniques for the measurement ofrenal function. J Clin Invest 27:710-716, 1948 7. Stote RM, Dubb JW, Familiar RG, et al: New oral renal vasodilator, fenoldopam. Clin Pharmacol Ther 34:309-315, 1983 8. Murray BM, Paller MS, Ferris TF: Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int 28:767-774, 1985 9. Curtis JJ, Dubovsky E, Welchel JD, et al: Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet 2:477-479, 1986 10. Remuzzi G, Bertani T: Renal vascular and thrombotic effects of cyclosporine. Am J Kidney Dis 13:261-272, 1989 11. Conte G, Sabbatini M, Napodano P, et al: Dopamine counteracts the acute renal effects of cyclosporine in normal subjects. Transplant Proc 20:563-567, 1988 (supp1 3) 12. Brooks DP, Drutz OJ, Ruffolo RR Jr: Prevention and complete reversal of cyclosporine A-induced renal vasoconstriction and nephrotoxicity in the rat by fenoldopam. J Pharmacol Exp Ther 254:375-379, 1990 13. Hughes JM, Ragsdale NV, Felder RA, et al: Diuresis
JORKASKY ET AL and natriuresis during continuous dopamine-1 receptor stimulation. Hypertension 11:169-174, 1988 (suppI2) 14. Murphy MB, McCoy CE, Weber RR, et a1: Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopaminel agonist fenoldopam. Circulation 76:1312-1318, 1987 15. Ruilope LM, Robles RG, Miranda B, et a1: Renal effects offenoldopam in refractory hypertension. J Hypertens 6:665669, 1988 16. White WB, Halley SE: Comparative renal effects of intravenous administration of fenoldopam mesylate and sodium nitroprusside in patients with severe hypertension. Arch Intern Med 149:870-874, 1989 17. Elliott WJ, Weber RR, Nelson KS, et a1: Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation 81 :970-977, 1990 18. Andres A, Robles RG, Alcazar JM, et a1: Diuretic and natriuretic properties offenoldopam in chronic renal failure. J Hypertens 7:S326-S327, 1989 (suppI6) . 19. Clancy A, Locke-Haydon J, Cregeen RJ, et al: Effect of concomitant food intake on absorption kinetics of fenoldopam (SK&F-82526) in healthy volunteers. Eur J Clin PharmacoI32:103-106, 1987 20. Kiberd BA: Effect ofprazosin on cyclosporine-treated renal allograft recipients. Kidney Int 37:608, 1990 (abstr) 21. Bantle JP, Paller MS, Boudreau RJ, et a1: Long-term effects of cyclosporine on renal function in organ transplant patients. J Lab Clin Med 115:233-240, 1990 22. Curtis JJ, Laskow DA, Julian BA, et a1: Nifedipine is a more effective renal vasodilator than captopril in cyclosporine transplant patients. Kidney Int 35:512, 1989 (abstr)
