Suzanne K. Swan

The effects of fenoldopam, a selective dopamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects

OBJECTIVE Acute renal failure, frequently a consequence of renal vasoconstriction and subsequent renal ischemia, is a common problem for which no proven preventive or therapeutic agents exist. Fenoldopam is a new, selective, dopamine-1 receptor agonist that causes both systemic and renal arteriolar vasodilation. In hypertensive patients, fenoldopam rapidly decreases blood pressure, increases renal blood flow, and maintains or improves the glomerular filtration rate. We sought to determine a dose of fenoldopam that increases renal blood flow without inducing hypotension in normotensive patients and to explore the role of volume status (sodium replete vs. deplete) in these effects. DESIGN Randomized, double-blind, placebo-controlled, cross-over study. SETTING Clinical research unit. PATIENTS Fourteen normal male volunteers. INTERVENTIONS Renal plasma flow (para-aminohippurate clearance) and glomerular filtration rate (inulin clearance) were measured during three fixed, escalating doses of fenoldopam (0.03, 0.1, and 0.3 Lg/kg/min) on both a high-sodium and a low-sodium diet. MEASUREMENTS AND MAIN RESULTS Fenoldopam significantly increased renal plasma flow in a dose-dependent manner compared with placebo: 670 + 148 vs. 576 + 85 mUmin at 0.03 iLg/kg/min; 777 + 172 vs. 579 + 80 mUmin at 0.1 tig/kg/min; and 784 + 170 vs. 592 + 165 mUmin at 0.3 ilg/kg/min (p < .05 fenoldopam vs. placebo at all three doses). Glomerular filtration rate was maintained. At the lowest dose (i.e., 0.03 ILg/kg/min), significant renal blood flow increases occurred without changes in systemic blood pressure or heart rate. At 0.1 and 0.3 Lgl/kg/ min, systolic blood pressure did not change, but diastolic blood pressure was slightly lower in the fenoldopam group than in the placebo group: 62.5 + 6.4 vs. 63.6 + 2.6 mm Hg, respectively, at 0.3 tg/kg/min (p < .05). None of the effects of fenoldopam were altered by volume status. CONCLUSIONS Fenoldopam increased renal blood flow in a dose-dependent manner compared with placebo, and, at the lowest dose, significantly increased renal blood flow occurred without changes in systemic blood pressure or heart rate. These findings will be useful in designing future studies exploring the role of fenoldopam in preventing or treating renal failure in patients who are not hypertensive.

Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial

A new intravenous (i.v.) iron compound, sodium ferric gluconate complex in sucrose (Ferrlecit, R&D Laboratories, Inc, Marina Del Rey, CA), was administered over 8 consecutive dialysis days in equally divided doses to a total of either 0.5 or 1.0 g in a controlled, open, multicenter, randomized clinical study of anemic, iron-deficient hemodialysis patients receiving recombinant human erythropoietin (rHuEPO). Effectiveness was assessed by increase in hemoglobin and hematocrit and changes of iron parameters. Results were compared with historically matched controls on oral iron. High-dose i.v. treatment with 1.0 g sodium ferric gluconate complex in sucrose resulted in significantly greater improvement in hemoglobin, hematocrit, iron saturation, and serum ferritin at all time points, as compared with low-dose i.v. (0.5 g) or oral iron treatment. Despite an initial improvement in mean serum ferritin and transferrin saturation, 500 mg i.v. therapy did not result in a significant improvement in hemoglobin at any time. Eighty-three of 88 patients completed treatment with sodium ferric gluconate complex in sucrose: 44 in the high-dose and 39 in the low-dose group. Two patients discontinued for personal reasons. The other three discontinued because of a rash, nausea and rash, and chest pain with pruritus, respectively. In comparison with 25 matched control patients, adverse events could not be linked to drug therapy, nor was there a dose effect. In conclusion, sodium ferric gluconate complex in sucrose is safe and effective in the management of iron-deficiency anemia in severely iron-deficient and anemic hemodialysis patients receiving rHuEPO. This study confirms the concepts regarding iron therapy expressed in the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) that hemodialysis patients with serum ferritin below 100 ng/mL or transferrin saturations below 18% need supplementation with parenteral iron in excess of 1.0 g to achieve optimal response in hemoglobin and hematocrit levels.

Pharmacodynamics Pharmacodynamics of a Novel Designer Natriuretic Peptide, CD‐NP, in a First‐in‐Human Clinical Trial in Healthy Subjects

CD‐NP is a novel chimeric natriuretic peptide (NP) consisting of the 22‐amino‐acid (AA) human C‐type natriuretic peptide (CNP), a venodilating peptide with limited renal actions and minimal effects on blood pressure, and the 15‐AA C‐terminus of Dendroaspis NP (DNP). The rationale for the design of CD‐NP was to enhance the renal actions of CNP, the ligand for natriuretic peptide receptor‐B, but without inducing excessive hypotension. Here we report the first‐in‐human studies for CD‐NP, which represent the first successful clinical testing of a chimeric NP demonstrating in normal human volunteers that CD‐NP possesses cyclic guanosine monophosphate—activating, natriuretic, and aldosterone‐suppressing properties without inducing excessive hypotension, laying the foundation for additional studies on this first‐in‐class new cardiovascular therapeutic in human heart failure, which are now underway worldwide.

Safety and Pharmacokinetic Profile of Gadobenate Dimeglumine in Subjects With Renal Impairment

RATIONALE AND OBJECTIVES To determine the safety and pharmacokinetics of gadobenate dimeglumine in a group of subjects with moderate or severe renal impairment. METHODS The safety and pharmacokinetic profile of gadobenate dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast agent for MRI, were evaluated in a placebo-controlled, double-blind, multicenter trial. Subjects with moderate or severe renal impairment (creatinine clearances of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intravenous bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and fecal samples (up to 216 hours) were assayed for total Gd3+ content by inductively coupled plasma atomic emission spectroscopy. Gd3+ blood concentration/time data were analyzed nonparametrically and parametrically using the software program WinNonlin VI.1. RESULTS Mean (SD) values for Gd3+ area under the curve, blood clearance, steady-state volume of distribution, renal clearance, and creatinine clearance for the moderate group were 862 (392) micrograms.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min. Values for the severe group were 1347 (366) micrograms.h/mL, 31 (7) mL/min, 19 (6) L, 22 (7) mL/min, and 21 (8) mL/min. No Gd(3+)-related adverse events occurred. Mean values for Gd3+ recovery in urine and feces for moderate and severe groups were 74% and 6%, and 69% and 8% of the dose, respectively. Linear regression analysis demonstrated a significant relation between the level of renal function and blood clearance of Gd3+. CONCLUSIONS Although mean blood clearance and renal clearance values progressively declined with increasing degree of renal impairment, based on the safety profile and the fact that the administered dose was double the standard dose used for MRI purposes, there appears to be no need for dose reduction in this population.

Pharmacologic profile of diaspirin cross-linked hemoglobin in hemodialysis patients

Various hemoglobin compounds have been evaluated as potential oxygen-carrying, blood volume expanders, but toxicity has prevented clinical application. Diaspirin cross-linked hemoglobin (DCLHb) represents a modified hemoglobin compound that is derived from human red blood cells and maintained in a tetrameric configuration by cross-linkages between the two alpha chains of the hemoglobin molecule. In a randomized, placebo-controlled, single-blind, cross-over trial, DCLHbs safety and pharmacologic parameters were evaluated in 18 subjects receiving chronic hemodialytic therapy. A 30-minute infusion of 25, 50, or 100 mg/kg DCLHb or placebo was given at the start of routine hemodialysis. One week later, the alternate treatment (placebo or DCLHb) was administered. Maximum plasma hemoglobin concentrations and terminal half-life values were calculated for each dosage group. Dialysate was collected and assayed for hemoglobin. Changes in systolic and diastolic blood pressure from baseline and the volume of hypertonic saline administered for treatment of hypotension during hemodialysis were measured. The maximum plasma hemoglobin concentrations increased with DCLHb dose and occurred at the end of DCLHb infusion. The mean (+/- SD) terminal half-life ranged from 2.1 +/- 1.0 hours in the 25 mg/kg DCLHb group to 4.3 +/- 1.4 hours in the 100 mg/kg group, but did not differ significantly between groups. Mean baseline plasma hemoglobin corrected areas under the plasma concentration-time curves increased from 89 to 1,136 mg/hr/dL across the fourfold dose range. Diaspirin cross-linked hemoglobin was not dialyzable as none was detected in dialysate. The maximum increase in systolic blood pressure from baseline increased significantly with DCLHb dose compared with placebo (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Etoricoxib in Patients with Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase‐2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end‐stage renal disease requiring hemodialysis) following administration of single 120‐mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long‐term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease.

Renal Effects of Conivaptan, Furosemide, and the Combination in Patients With Chronic Heart Failure

BACKGROUND Loop diuretics, though often effective for treating congestion, have significant limitations. Discovering ways to limit exposure to loop diuretics while achieving effective decongestion is an important goal of current clinical research in heart failure (HF). Vasopressin antagonists are effective in removing large amounts of water, but not salt, in HF. Few data exist about the detailed renal and hormonal effects of these agents compared with or in combination with loop diuretics. This study investigated the renal and neurohormonal effects of loop diuretics, the mixed vasopressin antagonist conivaptan, and the combination in patients with chronic stable HF. METHODS AND RESULTS In 8 patients with chronic stable HF on standard medical treatment, heart rate, arterial pressure, systemic vascular resistance, and cardiac output (the latter 2 by using impedance cardiography), as well as glomerular filtration rate (iothalamate clearance), renal blood flow (para-aminohippurate clearance), urinary volumes and urinary sodium, plasma catecholamines, renin activity, arginine vasopressin, and B-type natriuretic peptide were assessed before and at hourly intervals for 4 hours after receiving furosemide, conivaptan, or the combination on 3 different study days at a minimum of 1-week intervals. There were no significant effects of conivaptan, furosemide, or the combination on any hemodynamic variable, neurohormonal level, renal blood flow, or glomerular filtration rate. Conivaptan and furosemide similarly increased urine volumes; the effect of the combination was significantly greater. Furosemide, but not conivaptan, increased urinary sodium excretion, and the combination was significantly greater than after furosemide alone. CONCLUSIONS Without adversely affecting important hemodynamic variables, neurohormones, renal blood flow, or glomerular filtration rate, conivaptan significantly augmented both the diuretic and the natriuretic response to furosemide in patients with chronic HF. These results may have implications for the design of furosemide-sparing regimens in the treatment of acute HF.

Fellows’ Forum in Dialysis edited by Mark A. Perazella: Does Uremia Protect against the Demyelination Associated with Correction of Hyponatremia during Hemodialysis? A Case Report and Literature Review

Rapid correction of chronic hyponatremia is known to cause demyelination syndromes, which are attributed to the rapid shift of water out of the brain. In uremic patients with hyponatremia, depending on the dialysate sodium concentration and delivered Kt/V, serum sodium levels may be rapidly corrected inadvertently during the hemodialysis (HD) session. It is not known whether uremic patients are as susceptible to the development of demyelination as patients with normal renal function. Since urea diffuses slowly across the blood–brain barrier, it can act as an effective osmole between plasma and the brain if levels are changed abruptly. During HD, blood urea levels drop suddenly and significantly and cerebral edema may develop (dialysis disequilibrium syndrome). This effect may counteract the fluid shift out of the brain during correction of hyponatremia. Therefore, theoretically, uremic patients may be less prone to develop demyelination. We present a patient with renal failure whose hyponatremia was corrected rapidly during HD to illustrate the potential problem. The patient tolerated rapid correction of hyponatremia without sustaining any neurologic damage. We performed a literature search looking for similar case reports and reviewed the scientific evidence behind the above hypothesis.

Effect of Impaired Renal Function and Haemodialysis on the Pharmacokinetics of Aprepitant

AbstractBackground: The neurokinin NK1-receptor antagonist aprepitant has demonstrated efficacy in preventing highly emetogenic chemotherapy-induced nausea and vomiting. Objective: The objective of the present study was to investigate the effects of impaired renal function on the pharmacokinetics and safety of aprepitant. Subjects and methods: A total of 32 patients and healthy subjects were evaluated in this open-label, two-part study. Pharmacokinetic parameters after a single oral dose of aprepitant 240mg were measured in eight patients with end-stage renal disease (ESRD) requiring haemodialysis, eight patients with severe renal insufficiency (SRI [24-hour creatinine clearance <30 mL/min/1.73m2]) and 16 healthy and age-, sex- and weight-matched subjects (controls). Results: In ESRD patients, the area under the plasma concentration-time curve (AUC) from 0 to 48 hours (AUC48) for aprepitant was on average approximately 36% lower than that observed in control subjects (ratio [ESRD patients/healthy controls] of geometric means = 0.64), but the 90% confidence interval 0.52, 0.78 for the ratio of true mean AUC48 fell within the predefined target interval of 0.5, 2.0. Also in ESRD patients, there was no statistically or clinically significant difference in unbound aprepitant AUC (which may be more clinically relevant than total aprepitant AUC) when compared with healthy control subjects. Aprepitant pharmacokinetic parameters in ESRD patients were clinically similar when haemodialysis was initiated at 4 hours or 48 hours after aprepitant administration. In SRI patients, the ratio (SRI patients/healthy controls) of aprepitant AUC from zero to infinity (AUC∞) geometric mean value was 0.79 with a 90% confidence interval of 0.56, 1.10. On average, in SRI patients the principal aprepitant pharmacokinetic parameters (AUC∞, initial maximum plasma concentration [Cmax], time to initial Cmax, and apparent elimination half-life) were not statistically different from those obtained in healthy control subjects. Aprepitant was generally well tolerated in both ESRD and SRI patients. Conclusion: The results of this study demonstrate that ESRD, haemodialysis and SRI have no clinically meaningful effect on aprepitant pharmacokinetics. Therefore, no dosage adjustment of aprepitant is warranted in SRI or ESRD patients.

Diuretic Strategies in Patients with Renal Failure

SummaryA thorough understanding of the clinical pharmacology of diuretic agents, particularly loop diuretics, is crucial in patients with abnormal (and those with normal) renal function. Renal insufficiency represents a pathophysiological state characterised by diuretic resistance.Diuretic resistance is defined as a diminished pharmacological response, or diminished natriuresis, to a given dose of a diuretic. The phenomenon of diuretic resistance is demonstrated by a shift in the dose-response curve relating urinary diuretic excretion rates (dose) with sodium excretion (response). Pharmacokinetic factors underlie the diuretic resistance observed in patients with renal failure. Diminished renal blood flow and sodium filtration, accumulation of organic acids that inhibit tubular secretion of the diuretic, and inadequate cumulative sodium excretion to meet patients’ needs contribute to the diuretic-resistant state. In contrast, the pharmacological response of remnant (i.e. remaining) nephrons to diuretic agents remains intact.The time course of delivery of diuretics to their intraluminal site of action is an independent determinant of natriuretic response. An administration regimen that continuously maintains effective rates of excretion of diuretics into the urine would be expected to cause a greater overall natriuretic effect than the same amount of diuretic administered in intermittent doses. Thus, diuretic administration strategies that take account of the altered pharmacological responses in patients with renal failure are necessary to provide effective and safe treatment. Additionally, such strategies warrant revision by the prescribing physician as renal function changes over time.