Rhabdomyolysis accounts for 5-7% of all cases of acute renal failure in the USA . Approximately one-third of patients with rhabdomyolysis will develop acute renal failure . Several mechanisms are thought to contribute to myoglobinuric acute renal failure :
(a) Myoglobin-associated vasoconstriction of the renal vessels.
(b) Mechanical obstruction of renal tubules by myoglobin and pigmented granular casts.
(c) Renal tubular cytotoxic effects of myoglobin.
(d) Renal cortical adenosine triphosphate depletion.
(e) Renal hypoperfusion associated with fluid sequestration in injured muscle.
(f) Activation of the endotoxin-cytokine cascade.
Current treatment or prophylaxis of myoglobin-associated acute renal failure comprises aggressive crystalloid administration, mannitol and alkalinization of the urine . These treatments are effective only if initiated promptly. To date, the role of experimental treatment strategies such as iron chelation [4,5] administration of free radical scavengers  and manipulation of nitric oxide induced vasodilation [6,7] in the prophylaxis or treatment of myoglobinuric acute renal failure are unproven.
In a rat model of myoglobinuric acute renal failure, pretreatment with dopexamine or dopamine significantly improved the course of acute renal failure, with better survival after treatment with dopexamine . In an observational report by Shimazu and colleagues, dopamine 3 μg kg−1 min−1 did not confer a renoprotective effect in victims of crush injury .
Fenoldopam is a highly selective agonist at peripheral dopamine (DA1) receptors . Renal effects include vasodilation and inhibition of sodium-potassium adenosine triphosphatase, which results in increased renal blood flow, diuresis and natriuresis . In dogs, low doses of fenoldopam (0.125 μg kg−1 min−1) produced diuresis and natriuresis without causing a decrease in blood pressure . In dogs with spontaneous renal failure as well as in those with normal renal function, renal plasma flow increased by 100% after administration of fenoldopam either intravenously (i.v.) (0.5 μg kg−1 min−1) or orally (10 mg kg−1) . Also, in dogs in whom renal ischaemic injury was induced by a 90 min of infrarenal aortic cross-clamping, administration of fenoldopam (0.1 μg kg−1 min−1) decreased proximal tubular sodium reabsorption and increased creatinine clearance and urinary output without causing hemodynamic instability . The administration of fenoldopam (0.1 μg kg−1 min−1) before aortic cross-clamping in patients undergoing elective aortic surgery was associated with a preservation of creatinine clearance, which was not seen in those patients receiving placebo .
Our hypothesis was that fenoldopam, by virtue of renal vasodilatory, diuretic and renal oxygen-sparing effects, would have a renoprotective effect in the setting of rhabdomyolysis. To test this hypothesis, we compared the effects of i.v. administration of fenoldopam (0.1-1.0 μg kg−1 min−1) or saline on renal blood flow and renal tubular function in anaesthetized dogs in whom myoglobinuric acute renal failure had been induced by the administration of intramuscular (i.m.) glycerol 50% (10 mL kg−1). Intramuscular hypertonic glycerol causes muscle cell necrosis with release of myoglobin, intravascular haemolysis and, consequently, haemoglobinaemia and haemoglobinuria . The best imitation of the renal failure, which develops after crush injury in humans, is obtained by the i.m. injection of glycerol in rats. This model has been widely used for studying myoglobinuric acute renal failure .
The experiment was carried out by licensed investigators in compliance with the Cruelty to Animals Act 1876 (Department of Health, Ireland). Ten 18-month-old Labrador dogs (seven females, three males; mean weight 20.5 ± 4.3 kg) were fasted for a minimum of 12 h. Of 10 dogs studied, one was subsequently excluded because it had not been fasted before commencing the experiment.
After premedication with morphine (0.5 mg kg−1) subcutaneously, general anaesthesia was induced with pentobarbital 30 mg kg−1 via a cannula in the right long saphenous vein (inserted under local anaesthesia), and maintained thereafter using pentobarbital 6 mg kg−1 h−1 i.v. After tracheostomy, positive pressure ventilation was initiated (animal ventilator, Palmer, London, UK) using oxygen-enriched air and adjusted to maintain an end-tidal carbon dioxide partial pressure of 4.6-5.3 kPa (Morgan Capnograph®; PK Morgan, Gillingham, Kent, UK). Fractional inspired oxygen concentration (FiO2) was adjusted to maintain PaO2 > 12 kPa. Electrocardiography lead II (SE 40001®; electromedical multichannel amplifier; Southern Electric Laboratories, North Selfetham, Middlesex, UK; closed down) was recorded and core body temperature (homeothermic blanker control unit and probe, Harvard Apparatus, Edenbridge, Kent, UK) was measured continuously with a rectal temperature probe and maintained between 36.5 and 37.5°C.
The right carotid artery was cannulated (internal diameter 1.7 mm) to facilitate sampling of blood and continuous measurement of arterial pressure. The right external jugular vein was cannulated (internal diameter 1.7 mm) for administration of fenoldopam or saline. A small midline incision was made in the lower abdomen and bilateral ureteric catheters (internal diameter 0.8 mm) inserted for urine collection. Each dog was then turned onto its right side and an incision made in the left flank to expose the renal artery, around which a perivascular transonic flow probe (3RS probe®; Linton Instrumentation, Diss, Norfolk, UK) was placed. Before application, each probe used in the study was calibrated in vitro using physiological saline 0.9%. A stabilization period of 60 min was allowed after these procedures had been completed.
Continuously measured variables were heart rate (HR), mean arterial pressure (MAP), left renal artery blood flow (RBF), end-tidal CO2 partial pressure and intratracheal pressure. These variables were displayed and recorded by using a K2G® digital recorder (Astro-Med, Slough, UK). Acid-base status and oxygenation were measured at hourly intervals throughout the experiment (pH blood-gas analyser IL 1306®; Instrumentation Laboratory, Milan, Italy). This device performed an automatic two-point calibration before and at 2 h intervals during the experiment.
After a stabilization period (60 min), glycerol 50% (10 mL kg−1) was administered i.m. distributed equally between the right and left hind leg. An infusion of fenoldopam or saline was commenced 30 min after glycerol injection and continued for 3 h. A dose finding study was performed in each animal receiving fenoldopam. The infusion of fenoldopam commenced at 0.1 μg kg−1 min−1 and was doubled at intervals of 5 min, until a 10% decrease in MAP from baseline occurred or if 1.2 μg kg−1 min−1 was achieved. The dose before that associated with this decrease was administered for the remainder of the experiment. No other fluid was administered to either group. The experiment was divided into five periods:
• Stabilization period before injection of glycerol (60 min).
• Glycerol injection i.m. and the subsequent 30 min, i.e. until the appropriate infusion was commenced.
• 0-60 min after commencement of the appropriate infusion.
• 60-120 min after commencement of the infusion.
• 120-180 min after commencement of the infusion.
Heart rate, MAP and renal blood flow in the left renal artery were documented at intervals of 15 min. The mean recorded for each period in the experiment was taken to represent that period. Urine was collected from each kidney and the volume measured and recorded for each period. At the mid-point of each stage, blood sampling from the arterial cannula was performed for determination of: plasma creatinine concentration (Pcreat), plasma sodium concentration (PNa+) and plasma osmolality (Posm). Blood sampling for the purpose of estimation of serum malondialdehyde concentration (a measure of lipid peroxidation) was carried out: midway through the stabilization period, 15 min after i.m. glycerol, and at 30 and 150 min after commencement of the fenoldopam or saline infusion. For each of the five periods, the urine was analysed for determination of: urinary creatinine concentration (Ucreat), urinary sodium concentration (UNa+), and urinary pH and urinary osmolality (Uosm). Creatinine clearance (CrCl), fractional excretion of sodium (FENa) and free water clearance (FWC) were derived using the following formulae:
• CrCl = [Ucreat × urine flow (mL min−1)]/Pcreat
• FENa = [UNa+/PNa+ × 100%]/Ucreat/Pcreat
• FWC = urine volume (mL h−1) − osmolar clearance
• Osmolar clearance = [Uosm × urine volume (mL h−1)]/Posm
At the end of the experiment, both renal pedicles were ligated and the kidneys removed. Each dog received a lethal overdose of potassium chloride.
Analysis of serum for malondialdehyde
Serum malondialdehyde concentrations were measured by high-performance liquid chromatography (HPLC) as described by Bull and Marnett . This technique entails reverse-phase, ion-pairing, isocratic elution by HPLC.
Blood samples drawn were freshly processed. After centrifugation at 2000 g for 15 min at 4°C, separated serum underwent a protein precipitation step, followed by centrifugation at 2000 g for 15 min at 4°C. The supernatant was then filtered through a 0.2 μm filter and stored at −85°C until analysed.
The chromatography system comprises a Varian Prostar® diode array UV-vis PDA 330 detection system complete with a solvent delivery module and autosampler. Twenty microlitres of the prepared serum sample were injected onto the HPLC described above, equipped with a Guard column (Supelguard Discovery 18®; 2 cm × 4.0 mm, 5 μm) and an analytical column (Discovery C-18®; 25 cm × 4.6 mm, 5 μm, both Supelco, Bellefonte, PA, USA). The malondialdehyde was separated by isocratic elution of a mobile phase comprising acetonitrile 14% in 50 mmol myristyl trimethylammonium bromide (Sigma-Aldrich chemicals) and 1 mmol Na2HPO4, adjusted to pH 6.8 at a flow rate of 1.0 mL min−1. The effluent was monitored at 267 nm and compared with standard curves, which were derived by the acid hydrolysis of tetramethoxypropane and linear regression analysis of the result of integration of absorption against time. Concentration was checked by spectrophotometry according to Csallany and colleagues , with ε = 34 000 mol−1 cm−1 (molar extinction coefficient). Area units were derived by Varian Star® chromatography workstation software (version 5.3).
Recovery experiments demonstrated a detection rate of >90% of added amount. In the range 15 pmol to 80 nmol, the relationship was linear and the lower reliable detection limit for malondialdehyde was 15 pmol per injectate, corresponding to concentrations of 1.5 μmol to 8 mmol in serum.
Preparation of the kidney for light microscopy
Each kidney was cut longitudinally, sectioned and fixed in formalin. The kidneys were then sectioned into 3-5 μm, stained with haematoxylin and eosin, and examined under light microscopy. On pathological review of the sections, there was no evidence of swelling or vacuolation of cells, cell necrosis or tubular mitoses. The only changes noted were tubular dilatation, peritubular capillary congestion and vascular dilatation. These changes were then semiquantatively assessed and graded as: 0 = absent; 1 = mild; 2 = moderate; and 3 = severe.
The data were analysed using unpaired two-tailed t-tests or Fisher's exact test as appropriate. P < 0.05 was taken as being statistically significance.
The two groups of Labradors (each approximately 18 months old) were similar in terms of weight (placebo 21.2 ± 1.1 kg, fenoldopam: 23.4 ± 3.0 kg; P = 0.2) and gender (placebo m:f = 1:3; fenoldopam m:f = 1:4). Of the 10 dogs studied, one (fenoldopam group) was subsequently excluded because it transpired after completion of the experiment that it had not been fasted before commencement. Urinary pH was not measured at 1 and 3 h after commencement of infusion in one dog in the fenoldopam group because an inadequate volume of urine was produced.
During the third hour of infusion, HR was greater in the fenoldopam group (173 ± 9 beats min−1) than in the control group (153 ± 9 beats min−1) (P = 0.013) and MAP decreased compared with baseline in the fenoldopam group (120 ± 9 versus 134 ± 8 mm Hg; P = 0.04), but not in the control group. Left RBF decreased to a similar extent in the two groups (Table 1).
Urinary output, fractional excretion of sodium, plasma creatinine, urinary pH and urinary osmolality were similar in the two groups throughout the study (Table 2).
Following i.m. glycerol administration, creatinine clearance decreased in both groups. However, the magnitude of the decrease was greater in the dogs that received fenoldopam. This achieved statistical significance during the first and second hour of infusion. Creatinine clearances at these times (fenoldopam versus placebo) were 12.7 ± 11.5 versus 31.3 ± 9.9 mL min−1 (P = 0.04) and 8.5 ± 5.3 versus 20.1 ± 7.4 mL min−1 (P = 0.03), respectively (Fig. 1). Following commencement of the infusion, free water clearance increased significantly in the fenoldopam group from a baseline value of −51 ± 20.7 to −21.8 ± 19 mL h−1 (P = 0.048), −19 ± 18.8 mL h−1 (P = 0.034) and −11 ± 9.8 mL h−1 (P = 0.004) during the first, second and third hours, respectively. There was no such increase in the control group.
During the first and second hours of infusion, respectively, plasma osmolality was greater in the fenoldopam group than control (339 ± 8 versus 322 ± 14 mOsm kg−1, P = 0.05; and 347 ± 4 versus 338 ± 4 mOsm kg−1, P = 0.02) (Table 2).
A great increase (140-fold) in serum malondialdehyde occurred in one dog in the fenoldopam group. This increase occurred 30 min after commencement of the fenoldopam infusion (Table 3).
On pathological review (light microscopy), evidence of renal injury consistent with rhabdomyolysis was seen in all nine animals. The frequency and severity of this injury was similar in both groups (Table 4).
Administration of fenoldopam significantly worsened the resulting renal injury. Using this canine model of myoglobinuric acute renal failure, creatinine clearance decreased to a markedly greater extent in dogs that received fenoldopam (0.1-1.0 μg kg−1 min−1). A very great increase in serum malondialdehyde (marker of lipid peroxidation) occurred in one dog that received fenoldopam.
In myoglobinuric acute renal failure, renal vasoconstriction - a consequence of intravascular volume depletion and altered release of vasoactive compounds (such as nitric oxide, endothelin, tumour necrosis factor, adenosine and platelet-activating factor) - markedly reduced renal blood flow. This reduces glomerular filtration rate and may also produce ischaemic tubular injury. Myoglobin precipitation within distal tubules produces cast formation and possibly intratubular obstruction. Following proximal tubular uptake via endocytosis, myoglobin exerts direct cytotoxic effects .
Multiple interrelationships exist between these injury pathways and serve to amplify the evolving tissue damage. For example, renal vasoconstriction markedly potentiates the cytotoxic effects of myoglobin. Cast formation accentuates proximal tubular cell haem uptake, increasing the potential for direct cytotoxicity. If tubular cell death results, the necrotic debris worsens cast formation .
In recent years, investigations into the pathogenesis of rhabdomyolysis-induced acute renal failure have attempted to define the mechanisms by which myoglobin exerts its cytotoxicity. The toxic effect of myoglobin is thought to result from intracellular-free iron release and the resulting formation of free radicals [4,5]. Using this iron source, the Haber-Weiss reaction results in the generation of the potent oxidant hydroxyl radical (OH•) . Thus, it appears that the direct proximal tubular cytotoxicity of myoglobin in rhabdomyolysis is mediated by the formation of reactive oxygen species. Lipid peroxidation is the oxidative deterioration of polyunsaturated lipids. Polyunsaturated fatty acids are those that contain two or more carbon-carbon double bonds. The membranes that surround cells and organelles contain large amounts of polyunsaturated fatty acid side-chains. Initiation of lipid peroxidation is caused by attack upon a lipid of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene (-CH2−) group. Hydroxyl radicals can initiate peroxidation and therefore cell and organelle damage readily. Malondialdehyde is a breakdown product that arises largely from peroxidation of polyunsaturated fatty acids and is used as a measure of the extent of lipid peroxidation .
In our study, three of four dogs in the placebo group and three of five dogs in the fenoldopam group had a detectable rise in malondialdehyde concentration during the course of the experiment. However, the rise in malondialdehyde in one dog in the fenoldopam group was of the order of 140-fold (from 48 to 7089 pmol L−1) from baseline. The largest rise in the placebo group was from 0 to 97 pmol L−1 from baseline to midway through the first hour of infusion, and 97 pmol L−1 was the largest value recorded in any animal in the placebo group (Table 3). Both the deleterious effect of fenoldopam on creatinine clearance and the marked elevation of malondialdehyde in one dog that received fenoldopam were unexpected results. It is possible that fenoldopam may increase the generation of reactive oxygen species and thus aggravate tubular injury and the decrease in creatinine clearance. There are two possible explanations as to how fenoldopam could augment a 'reperfusion'-type injury by increasing the generation of free radicals and therefore lead to a worsening of renal function in rhabdomyolysis.
By decreasing the extent of vasoconstriction during reperfusion, fenoldopam may increase renal blood flow, oxygen delivery and thus generation of reactive oxygen species. However, in this model opposing factors on renal vasomotor tone coexist: vasodilatation (fenoldopam-mediated DA1 effect) and vasoconstriction (direct effect of myoglobin and that induced by fluid sequestration) as referred to in points (a) and (e) of the introduction (page 711). The observed changes in renal blood flow therefore represent a culmination of these effects. As several of the mechanisms of myoglobinuric acute renal failure described result in ischaemia, it is possible that the dogs studied received fenoldopam at a time that partial reperfusion was underway. Under normal conditions, about 1% of the electrons that pass along the transport chain stray away and react with molecular oxygen. The rate of this electron escape is directly proportional to the partial pressure of oxygen. In situations of high oxygen availability, the capacity of scavenger mechanisms that 'mop up' free radicals may be overwhelmed. This explanation is unlikely to account for our findings, as renal blood flow was similar in both groups. However, the renal blood flow measurement represented gross flow (rather than distribution of flow) in one renal artery and gave no indication of changes that may have been occurring in the renal microcirculation. In anaesthetized dogs, fenoldopam has been shown to increase renal blood flow relatively more in the medulla than in the cortex .
Another possible explanation whereby fenoldopam could augment the production of free radicals may lie in its metabolic breakdown pathway. Fenoldopam is structurally similar to dopamine. The oxidation of the catecholamines dopamine, norepinephrine and epinephrine leads to the formation of ortho-quinone derivatives which are subsequently cycled to o-quinones . The o-quinones can then take one of two pathways:
• Antioxidant pathway involving reductive conjugation with glutathione to yield unreactive glutathione conjugate.
• Pro-oxidant pathway involving one electron reduction to o-semiquinones.
o-Semiquinones are reoxidized in the presence of dioxygen, giving rise to redox cycling in which very small amounts of catechol o-quinones can generate large amounts of reactive oxygen species. Generation of reactive oxygen species in this way has been postulated to be involved in neurodegeneration in the mesolimbic and nigrostriatal systems and thus in the aetiology of schizophrenia and Parkinson's disease . Fenoldopam may undergo a similar breakdown pathway to catecholamines and therefore promote generation of reactive oxygen species. Boppana and colleagues in an in vitro determination of the metabolites of fenoldopam by high-performance liquid chromatography found that the 8-sulphate derivative was indeed oxidized to the o-quinone .
These findings are consistent with previous unreported observations in a rat model of renal ischaemia-reperfusion injury, where fenoldopam, when present at the time of reperfusion, caused a significant worsening of renal function assessed by glomerular filtration rate (inulin clearance). Allopurinol (α xanthine oxidase inhibitor) attenuated the deleterious effects of fenoldopam in the same model. Our findings are inconsistent with those of Gomez-Garre and colleagues who found that in rats with acute renal failure induced by intramuscular injection of glycerol 50% pretreatment with dopamine or dopexamine attenuated the abrupt falls in glomerular filtration rate and renal plasma flow (measured by inulin and para-aminohippuric acid clearance). Dopexamine had additional effects in that it also increased urine flow and survival .
Animal models have displayed a clear difference between species. Southard and colleagues showed that human and canine kidneys have a similar superoxide dismutase:xanthine oxidase ratio 40 times greater than that in the rat .
In our study, fenoldopam increased free water clearance compared with baseline during the 3 h infusion. Free water clearance was greater in the fenoldopam group compared with the control group during the first and third hours of infusion. This is in keeping with previous studies in human beings in which fenoldopam has consistently been shown to increase free water clearance [27-29].
Urinary pH was decreased in the control group from baseline at all time points after i.m. glycerol injection, but was similar between groups at each time point. The lowest urinary pH recorded was 6.3 (in the control group during the first hour of infusion), which is above the threshold of 6.0 below which animals have been shown invariably to develop acute renal failure [30,31].
The weaknesses of our study include the small number of dogs studied. In addition, because there are multiple mechanisms of myoglobin-induced renal injury, this might permit a beneficial effect of fenoldopam on one of these mechanisms to be masked by its deleterious effect on others. We studied a single timing regimen of fenoldopam administration (i.e. commencing 30 min after the i.m. injection of glycerol). It is possible that if given before i.m. glycerol, fenoldopam may have conferred a protective effect. A relatively small range of doses (0.4-0.8 μg kg−1 min−1) was administered. It is unlikely that a dose of fenoldopam sufficient to cause haemodynamic instability could be used clinically (even if a renoprotective effect had been demonstrated). The adequacy of the model in causing a renal injury was evidenced by the marked decrease in creatinine clearance which occurred in the control group (Fig. 1). Based on these findings, fenoldopam administration appears to worsen renal function in dogs with rhabdomyolysis. Further investigation will be necessary to determine the mechanism of this effect and if it has applicability to other types of ischaemic renal injury.
We thank Mr K. McDonnell (Technician, University College Cork), the Physiology Department (University College Cork), Ms L. O'Reagan and Ms H. Keefe (Histopathology Department, Cork University Hospital) for assistance during the study. We also thank Neurex/Elan Pharmaceutical for its support in carrying out this investigation.
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