Laboratories, Inc., Deerfield, Illinois) by slow intravenous ... Med Tech, Inc., Elwood, Kansas) was administered ..... Macy did not measure osmolality of serum or ...
Nephrotoxicity of Amphotericin B in Dogs: A Comparison of Two Methods of Administration S.I. Rubin, D.R. Krawiec, H. Gelberg and R.D. Shanks
functional impairment, less severe systemic signs, and less renal damage Two methods of administration of than rapid bolus administration amphotericin B were compared for without supplemental fluids. their ability to produce nephrotoxicity in 12 dogs. Six dogs received six RESUME alternate day doses of amphotericin B: 1 mg/kg administered as a rapid bolus Cette experience portait sur 12 in 25 mL 5% dextrose in water. Another six dogs received alternate chiens et elle visait a comparer deux day treatments of the same dose of methodes d'administration de l'amamphotericin B in 1 L 5% dextrose in photericine B, relativement a la water over 5 h. Both treatment groups production d'effets nephrotoxiques. experienced significant reductions in Les six du groupe I resurent, a tous les glomerular filtration rate, as measured deux jours et a six reprises, en by inulin clearance, 24 h endogenous injection intraveineuse d'une duree de creatinine clearance, serum creatinine cinq heures, 1 mg/kg d'amphotericine and serum urea. This reduction in B, diluee dans 1000 mL d'une solution glomerular filtration rate was most aqueuse contenant 5% de dextrose. marked in the group receiving the drug Les six du groupe II recurent par as a rapid bolus. The inulin clearances ailleurs, a tous les deux jours et a six decreased from 3.54 ± 0.30 mL/min/ reprises, en injection intraveineuse kg (X ± SEM) on day 0 to 1.15 ± 0.25 d'une duree de seulement trois mL/min/kg on day 12 in the slow minutes, 1 mg/kg d'amphotericine B, infusion group and from 3.24 ± 0.25 diluee dans 25 mL d'une solution mL/min/kg on day 0 to 0.46 ± 0.11 aqueuse contenant 5% de dextrose. mL/min/kg on day 12 in the rapid Les 12 chiens afficherent une baisse bolus group. Renal lesions character- significative du taux de filtration istic of amphotericin B administration glomerulaire, comme le demontrerent were observed in all dogs tested. The le test de clairance a linuline, celui de dogs which received amphotericin B as la clairance quotidienne de la creatia rapid bolus had a significantly nine endogene, ainsi que la determinagreater number of tubular lesions than tion de la creatinine et de lure'e the slow infusion group. Systemic side seriques. Cette baisse du taux de effects, such as vomiting, diarrhea and filtration glomerulaire se revela weight loss, were observed in both beaucoup plus marquee, chez les treatment groups but were most severe chiens du groupe II. La clairance de in the rapid bolus group. This study linuline passa de 3,54 ± 0,30 mL/ demonstrates that the administration min/kg (X ± SEM), au jour 0, a of amphotericin B by slow infusion seulement 1,15 ± 0,25 mL/min/kg, le with supplemental fluids causes less 12e jour, chez les chiens du groupe I, ABSTRACT
alors qu'elle passa de 3,24 ± 0,25 mL/ min/kg, au jour 0, a seulement 0,46 ± 0,11 mL/min/kg, le 12e jour, chez ceux du groupe II. Des lesions renales, caracteristiques de l'administration d'amphotericine B, se retrouverent chez tous les chiens eprouves a cette fin. Ceux du groupe II afficherent un nombre significativement plus eleve de lesions tubulaires que ceux du groupe I. Des effets secondaires tels que vomissement, diarrhee et perte de poids affecterent tous les chiens, mais ils se reve'lrent beaucoup plus severes chez ceux du group II. Cette experience demontre par consequent que l'administration lente d'amphotericien B, dans beaucoup de liquide, cause moins d'alterations fonctionnelles, moins de signes cliniques marques et moins de lesions renales que son administration rapide, dans peu de liquide.
INTRODUCTION
Amphotericin B (AMB) has been the drug of choice for the treatment of systemic mycoses for over twenty years. Therapy usually involves the administration of multiple doses of AMB until the disease is in remission or an arbitrary cumulative dose is achieved. Amphotericin B therapy may result in reversible or irreversible renal dysfunction (1). The greatest limitation for treatment with AMB is the nephrotoxicity it produces (2). Nephrotoxicity from AMB may be lessened by extending the interval
Department of Veterinary Clinical Sciences (Rubin, Krawiec), Department of Veterinary Pathobiology (Gelberg) and Department of Animal Sciences (Shanks), Univerity of Illinois at Urbana-Champaign, Urbana, Illinois 61801. Present address of Dr. Rubin: Department of Veterinary Internal Medicine, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N OWO. This work was supported by a grant from Solvay-Veterinary Incorporated, Princeton, New Jersey. Submitted November 20, 1987.
Can J Vet Res 1989; 53: 23-28
23
between doses. Delays in completion of the regimen, however, reduce the therapeutic effectiveness in potentially life-threatening fungal disease and/or, significantly add to the time and cost of treatment. Well-defined methods of administration of AMB in either veterinary or human medicine have not been established. For human use it is usual to dissolve the drug in 500 mL of 5% dextrose in water (D5W), and to administer it by intravenous infusion over a period of 2 to 6 h (3). In veterinary medicine, there are two popular methods of administration of AMB. These include a rapid bolus of AMB diluted in 20 to 30 mL of D5W given intravenously over 1 to 3 min or diluting the AMB in 500 or 1000 mL of D5W and administering it by slow infusion over 4 to 6 h. These two methods are based on experimental studies in the dog, clinical experience and data obtained from studies in humans. There also have been several recommendations for doses of AMB. Single dose recommendations range from 0.15 to 1.0 mg/ kg in a rapid intravenous bolus or by slow infusion. Total cumulative doses range from 4 to 25 mg/ kg (4-8). There are no reports from studies that have determined the precise amount of AMB needed for a clinical cure. There have been a limited number of studies that compare the method of administration of AMB in producing renal toxicity. Butler administered AMB on a daily or alternate-daily basis to dogs at doses ranging from 0. 125 to 4.0 mg/ kg of body weight (4). The AMB was diluted in 1 to 5 mL of D5W and given intravenously over 3 to 5 min. An elevation of serum urea nitrogen (SUN) occurred in all dogs given the AMB for four days or longer. The rise in SUN was less prompt in dogs given alternate-day injections compared to those dogs given daily injections. Long-term survival was noted to be improved on the alternate-day regimen compared to daily treatment. A dog receiving a double-dose of 1.0 mg/kg of body weight on alternate days survived longer than a dog given 0.5 mg/kg daily. Butler also administered AMB with 500 mL of D5W, and found that "renal intoxication" was slightly reduced, although he did not elaborate 24
on how he assessed this reduction in toxicity. Butler suggested that the slight reduction in renal intoxication achieved by large daily intravenous infusions of D5W did not compensate for the hazard, trouble and expense added by such treatment (4). He recommended that for the treatment of canine systemic mycoses that AMB be administered at a dose of 0.25 to 0.5 mg/kg three times weekly until a cumulative dose of 10 to 25 mg/ kg was reached (4). It has not been proven that the nephrotoxicity of AMB can be lessened by administering it with large volumes of fluid over several hours. Some authors have advocated a rapid infusion of AMB in small volumes of D5W (7,8). This study was therefore undertaken in dogs to determine if a difference in nephrotoxicity exists between administration of AMB slowly with a large volume of fluid, or rapidly in a small volume of fluid. MATERIALS AND METHODS DOGS
Twelve mixed-breed, conditioned dogs were used. The dogs were all normal as determined by physical examination and hematological, biochemical and renal function tests. Prior to the administration of AMB, kidney function was evaluated in all dogs. These procedures allowed each animal to serve as his own control. The renal function evaluation process included the measurement of serum creatinine (SC), serum urea nitrogen (SU), sodium, potassium, chloride, calcium, phosphorus, total protein, albumin, 24 h endogenous creatinine clearance (Ccr), inulin clearance (Cn), urinalysis and urine osmolality. A test was performed to screen for Dirofilaria immitis microfilaremia (Difil test, Evsco Pharmaceutical Corporation, Buena, New Jersey). In addition, a preexperimental renal biopsy was performed percutaneously using the keyhole technique (9). Treatments commenced after a seven to ten day rest following renal biopsy. The dogs were housed indoors and maintained on dry dog food (Wayne Dry Dog Food, Wayne Pet Food Division, Continental Grain Company, Chicago, Illinois) and water. All
dogs were males and weighted from 12.2 to 24.1 kg. EXPERIMENTAL DESIGN
Dogs were randomly assigned to either group I (n = 6), or group II (n = 6). The dogs in group I received AMB at a dose of 1 mg/kg diluted in 1 000 mL of D5W (five percent dextrose injection, USP, Travenol Laboratories, Inc., Deerfield, Illinois) by slow intravenous infusion over a period of 5 h (3.33 mL/min), every other day for six treatments. Group I dogs were kept in a canine restraint sling (Dog Torso Sling Suit and Dog Sling Frame, Alice King Chatham Medical Arts, Los Angeles, California) during the infusion to facilitate a proper rate of infusion. The dogs in group II received AMB at a dose of 1 mg/ kg diluted in 25 mL of D5W over a period of 3 min, every other day for six treatments. The total cumulative dose of 6 mg/kg for both groups was chosen because it is the minimum accepted dose necessary to treat most systemic mycotic diseases in the dog (10). Throughout the experimental period, except day 6 when inulin clearances were performed, each dog was kept in a metabolism cage where urine could be collected over a 24 h period for determination of creatinine. At the end of each 24 h period, the bladder was emptied by catheterization. The dogs were fed once daily and water was provided ad libitum. Water consumption was measured. Physical examinations were performed daily. Activity, appetite, water consumption and character of excretions were monitored. BIOCHEMICAL, HEMATOLOGICAL AND RENAL FUNCTION STUDIES
Complete blood counts, packed cell volumes, serum biochemistry determinations (Hycel Super-Seventeen, Hycel Inc., Houston, Texas), urine osmolality and endogenous creatinine clearances were measured every other day on the day following treatment with AMB. Complete blood counts (CBC) and packed cell volumes (PCV) were performed by the Clinical Pathology Laboratory of the Veterinary Medicine Teaching Hospital, University of Illinois. Urine osmolality was determined by freezing point
depression (Advanced Wide Range Osmometer, 3WII, Advanced Instruments, Inc., Needham Heights, Massachusetts). Inulin clearances were measured prior to treatment (Day 0) and on days 6 and 12 posttreatment. The measurement of serum creatinine was based on the Jaffe reaction. This reaction was performed after the adsorption of creatinine to Lloyd's reagent, an aluminum silicate which separates creatinine from other noncreatinine chromogens (11). Urinary creatinine concentration was determined in a manner similar to serum creatinine concentration, except that Lloyd's reagent was not used. The inulin clearance test was employed as a measure of glomerular filtration rate (GFR). Inulin (Inulin and sodium chloride injection, USP, 10 percent solution, American Critical Care, McGaw Park, Illinois) was infused in a concentrated priming dose to a plasma concentration of approximately 25 mg/ dL and then infused at a rate that maintained a constant plasma concentration. In order to minimize collection errors associated with low urine volumes, hypertonic mannitol (Mannitol, 20% solution, Med Tech, Inc., Elwood, Kansas) was administered intravenously at a rate sufficient to maintain a serum concentration of 5 mOsm/ L. A priming dose of 20% mannitol solution, (219 mg/ kg) was given with the inulin. The priming dose of inulin and mannitol was injected intravenously over a period of approximately 3 min. Immediately following the injection of the priming dose, a constant infusion of inulin and mannitol was maintained using a peristaltic infusion pump. The concentrations of inulin and mannitol were adjusted with lactated Ringer's solution (Lactated Ringer's solution, USP, Travenol Laboratories, Inc., Deerfield, Illinois) in order to deliver a rate of 2 mL per min. Thirty minutes after priming, there were three timed collection periods (10-15 min each), for each clearance study. Samples were analyzed for inulin by a modification of the simplified anthrone method (12). PATHOLOGY
Fixed renal biopsy specimens were processed in a routine manner,
embedded in paraffin, sectioned at 2 and 5 A and stained with hematoxylineosin and periodic acid-Schiff. Sections were examined by light microscopy, and any animal with significant lesions prior to onset of the experimental period was withdrawn from the study. At the termination of the study (Day 13), animals were euthanized by barbiturate overdose followed by exsanguination. The kidneys were removed immediately, incised, and immersion fixed in 10% buffered formalin. Tissue sections were processed as for the biopsy specimens. Tissues were coded and the code was not deciphered until all tissues were examined. Each kidney section was examined by light microscopy. Tubular damage was quantitated by examining 1 cm2 of each 5 , tissue section at 400x and counting the number of mineralized foci within tubules. The sum of the scores from the right and left kidney was averaged, yielding a score equal to the number of mineralized foci per cm2 of renal cortex. Quantitated separately were other changes including necrosis without mineralization, protein or other casts, tubular ectasia, thickened basement membranes and tubular reepithelialization. For these latter changes a numerical score was assigned by anatomic location as follows: Glomerulus: tuftal adhesions, mineralization, thickening of Bowman's capsule, increased cellularity of glomerular tuft or Bowman's capsule, infraglomerular reflux, glomerular atrophy. 0 = no lesions present. I = changes mild and scattered; contain one or two of above. 2 = changes moderate and scattered; contain two or three of above. Interstitium: inflammatory cell influx. 0 = not present or not associated with tubular lesions. I = changes mild and associated with tubular lesions. 2 = changes moderate and associated with tubular lesions and extends into intertubular areas. Pelvis: 0 no lesions present. l=mild mononuclear cell influx.
2 = mild mixed mononuclear and polymorphonuclear cell influx. STATISTICAL ANALYSIS
Analysis of variance using a repeated-measures design was performed using a computer statistical package (SAS Institute, Box 8000, Cary, North Carolina) to detect differences between treatment groups. The statistical model included treatment, dogs within treatments, time and time-treatment interaction. The mean square for the time-treatment interaction was used as the appropriate denominator in the F ratio for testing treatment. Differences among days were tested with a Bonferroni (Dunn) t-test with a significance level of 0.05 (alpha = 0.05). Histopathological changes between the two treatment groups were compared using a t-test for unpaired data. Results were considered significant if either treatment or time-treatment interaction was at a value of p < 0.05. RESULTS All initial laboratory values were within normal ranges. Renal morphology was normal in all biopsy specimens. Analysis of variance indicated a significant difference among days for Ccr, SC and SU with the p value less than 0.0001 in each case. Bonferroni multiple t-tests also showed there were significant differences among days for SC, Su, CCr and C1. (Figs. 1-4). In general days 0 and 2 were significantly different from days 4, 8, 10 and 11 for SU and CCr and from days 8, 10 and 11 for SC. For Cin, days 0, 6 and 12 were all significantly different from each other. Significant reductions in Cin, Ccr and increases in SC and SU concentrations occurred in both treatment groups following administration of AMB (Figs. 1-4). Pretreatment values for C1. were within the range accepted for healthy animals (13,14). Glomerular filtration rate declined progressively following treatment with AMB as determined by CIn and there was a significant difference in GFR between treatments as determined with an unpaired t-test, with lower values observed in group II. Inulin clearance decreased from 3.54 ± 0.30 mL/min/kg on day 0 to
25
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TREATMENT DAY
Fig. 3. Change in serum creatinine in dogs administered amphotericin B by fast (n = 6) and slow (n = 6) methods. Values are expressed as X ± SEM. Bonferroni multiple t-tests indicate that days 0 and 2 are significantly different from days 8, 10 and 11.
Fig. 5. Change in serum osmolality in dogs administered amphotericin B by fast (n = 6) and slow (n = 6) methods. Values are expressed as X± SEM. Fig. 1. Flow curves in three healthy ponies
through the experimental period. Both treatment groups experienced an abrupt decrease in osmolality of urine following the initiation of AMB treatment (Fig. 6). No other significant biochemical abnormalities were identified. There were no significant abnormalities in hematological parameters throughout the experimental period.
lesions, with greater number of lesions observed in group II. There were no differences between treatment groups with respect to glomerular, interstitial or pelvic lesions. Glomerular, interstitial and pelvic lesions were mild and
PATHOLOGY
There were no gross lesions. The histopathological lesions are summarized in Table I. Tubular lesions were extensive and could be most easily quantified. Generally, those kidneys having the greatest number of mineralized foci also had more necrosis, ectasia and reepithelialization. Statistical analysis showed a significant difference between the two treatment groups in the number of tubular
during quiet respectively.
scattered.
CLINICAL FINDINGS
All dogs in treatment groups I and II survived the experiment. Following the administration of AMB, both treatment groups became polyuric. Both treatment groups showed a progressive reduction in appetite throughout the experimental period. Anorexia was more profound in the rapid infusion group. Vomiting and diarrhea were occasionally observed between infusions, most frequently in dogs of group IT. Dogs in group II appeared depressed at the end of the experiment. Both treatment groups experienced progressive weight loss throughout the experimental period.
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Fig. 2. Change in creatinine clearance in dogs administered amphotericin B by fast (n = 6) and slow (n = 6) methods. Values are expressed as X ± SEM. Bonferroni multiple t-tests indicate that days 0 and 2 are significantly different from days 4, 8, 10 and 11.
26
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0
2
4
6
8
'I 10
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TREATMENT DAY
Fig. 4. Change in serum urea in dogs administered amphotericin B by fast (n = 6) and slow (n = 6) methods. Values are expressed as X ± SEM. Bonferroni multiple t-tests indicate that days 0 and 2 are significantly different from days 4, 8, 10 and 11.
Ul z
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Fig. 6. Change in urine osmolality in dogs administered amphotericin B by fast (n = 6) and slow (n = 6) methods. Values are expressed as X ± SEM.
TABLE I. The Effect of Amphotericin Infusion Method on Renal Morphology in Dogs Infusion Method Fast (Group II)a Slow (Group I)' Renal Morphology * 191.17 ± 37.89 *84.50 ± 19.74 Number of mineralized foci per cm2 1.50 ± 0.22 1.33 ± 0.21 Glomerular lesions score 1.00 ± 0.0 1.33 ± 0.21 Interstitial lesion score 0.67 ± 0.42 1.33 ± 0.21 Pelvic lesion score aValues are expressed as mean + SEM Differences between the treatment groups determined by t-test for unpaired data (* = p < 0.05)
There were, however, no significant differences between the experimental groups.
DISCUSSION
This study was designed to compare the nephrotoxic effects of two techniques for clinical administration of AMB in dogs. We not only compared the effects of slow infusion versus rapid infusion of AMB on nephrotoxicity since the treatment groups also differed in the amount of fluids that were received with the AMB. Animals in both treatment groups experienced adverse reactions from the AMB. These included anorexia, vomiting, and diarrhea and were most pronounced in group II. These side effects and others have been previously reported to occur in humans (17) and dogs (18). In our experiments, both treatment groups experienced a significant progressive weight loss throughout the course of the experiment. This weight loss is a significant finding in healthy dogs treated with AMB and has been reported previously (19). Glomerular filtration rate (GFR) was measured by Cin and Ccr. In addition, SU and SC concentrations were used as crude indices of GFR. The greatest advantage of determining Cln and Ccr over SC or SU is that Ci, and Ccr detect the presence of reduced renal function before elevations in SU or SC may be detected. We suggest that the decreases in CIn and CCr and elevation of SC and SU concentrations in these dogs was caused by the AMB. These findings have been previously reported by others (20-23). The decrease in GFR was likely secondary to a decrease in renal blood flow and appeared to be a dose-related phenomenon, although the progres-
sion may also have been the result of a single insult from the first or second dose. The differences between treatments suggest that in the dog a rapid infusion of AMB in a small volume of fluid will cause a more severe decline in GFR than will a slow infusion with a large volume of fluid. Our study did not differentiate whether it was the slow administration of drug, or the larger volume of fluid used that lessened the renal toxicity. Fields did not find significant differences in nephrotoxicity in humans when he compared rapid (45 min) infusions of AMB to slow (5 h) infusions (24). No mention was made regarding supplemental fluid support. Butler found a slight reduction in "renal intoxication" in the dog when AMB was diluted in 500 mL of D5W and administered over an unstated period compared to diluting AMB in 5 mL of D5W and administering it over 3 to 5 s (18). Defects in renal concentrating ability secondary to amphotericin Binduced renal failure have been reported in both humans and dogs (25). Macy did not measure osmolality of serum or urine in his study, but noted the development of hyposthenuria following AMB administration (19). The progressive rise in serum osmolality in treatment group II is reflective of dehydration (26). The histopathological changes seen are similar to those previously reported in humans and dogs (19,2729). There was a significant difference between treatment groups in the number of tubular lesions present. A more severe renal histopathological response was seen in dogs given the rapid bolus infusion of AMB. Tubular damage with nephrocalcinosis was the most frequently reported renal lesion associated with the administration of AMB in humans and animals (27). It
was suggested that the nephrocalcinosis was initiated by calcification within the amorphous material of tubular casts, possibly accelerated by the alkaline urinary pH secondary to renal tubular acidosis (27). Extrusion of calcified casts from atrophic tubules may cause interstitial calcification (25). Tubular calcification is significant because it renders the corresponding obstructed nephrons nonfunctional (25). Therefore it would seem prudent to administer the AMB in a fashion which has the least potential of causing permanent renal impairment, i.e. with a large volume of fluid in a slow infusion. In conclusion, although both AMB administration methods produced nephrotoxicity, there was a significant difference in the degree of nephrotoxicity between these two methods of administration. This is supported by the greater reductions in GFR observed in group II as measured by CI. and Ccr, SC and SU. In addition, a significantly greater number of renal tubular lesions were observed in the group II dogs. The dogs receiving the rapid infusion and small volume of fluid also demonstrated more severe systemic signs such as weight loss, vomiting, anorexia and dehydration, as compared to the slow-infusion group that received a larger volume of fluid. It is not known whether the difference between the two treatment groups was a result of the rate of drug infusion or the additional fluids received by the group I dogs. When the drug is used clinically, animals receiving AMB by rapid bolus infusion do not usually receive additional fluids. It may be argued that an astute clinician would give the patient supplemental fluids when the problems of vomiting, dehydration and azotemia developed. This is not always the case. On the basis of these experimental findings, we recommended that for the treatment of systemic fungal infections, AMB be administered slowly in 1 L of D5W over a minimum period of 5 h.
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