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1
Prevalence and risk factors for aminoglycoside nephrotoxicity in the ICU 1
2
João F. P. Oliveira 1
3
Carolina A. Silva 1 4
Camila D. Barbieri 1 5
Giselle M. Oliveira 1
6
Dirce M. T. Zanetta 2
7
Emmanuel A. Burdmann 1 *
8
9
1 Division of Nephrology, Hospital de Base, São José do Rio Preto Medical School, Av. 10
Brigadeiro Faria Lima, 5416, São José do Rio Preto, SP, Brazil., 15090-000. 11
2 Dirce M. T. Zanetta is currently at the School of Public Health, University of Sao Paulo, 12
Departamento de Epidemiologia, sala 212, Av. Dr. Arnaldo 715, Sao Paulo, SP, Brazil, 13
01246-904 14
15
* Address correspondence to: 16
Emmanuel A. Burdmann 17
Sao Jose do Rio Preto Medical School 18
Av. Brigadeiro Faria Lima 5416 19
São Jose do Rio Preto, SP 20
Brazil, 15090-000 21
Phone: 55-17-32015712 22
Fax: 55-17-32162227 23
E-mail: [email protected] 24
Copyright © 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.01430-08 AAC Accepts, published online ahead of print on 13 April 2009
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Running title 26
Aminoglycoside nephrotoxicity 27
Keywords 28
Aminoglycoside; nephrotoxicity; acute kidney injury; acute renal failure; risk factors. 29
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Abstract 30
In order to assess the prevalence of, and risk factors, for aminoglycoside nephrotoxicity in 31
the ICU, we evaluated 360 consecutive patients starting aminoglycosides therapy in the 32
ICU with a baseline calculated GFR (cGFR) ≥ 30 ml/min/1.73 m2. Among these patients, 33
209 (58%) developed aminoglycoside-associated nephrotoxicity (acute kidney injury - 34
AKI, decrease in cGFR > 20% from baseline), while 151 did not (non-AKI). Both groups 35
had similar baseline cGFR. The AKI group developed a lower cGFR nadir (45 ± 27 vs. 79 36
± 39 ml/min/1.73 m2, p < 0.001), was older (56 ± 18 y vs. 52 ± 19 y, p = 0.033), had a 37
higher prevalence of diabetes (19.6% vs. 9.3%, p = 0.007), treatment with other 38
nephrotoxic drugs (51% vs. 38%, p = 0.024) and used iodinated contrast more frequently 39
(18% vs. 8%, p = 0.0054), showed higher prevalence of hypotension (63% vs. 44%, p = 40
0.0003), shock (56% vs. 31%, p < 0.0001), and jaundice (19% vs. 8%, p = 0.0036). 41
Mortality was 44.5% in the AKI and 29.1% in the non-AKI groups (p = 0.0031). A logistic 42
regression model identified as significant (p<0.05) independent factors affecting 43
aminoglycoside-associated nephrotoxicity: baseline cGFR < 60 ml/min/1.73 m2 (OR 0.42), 44
diabetes (OR 2.13), treatment with other nephrotoxins (OR 1.61) or iodinated contrast (OR 45
2.13), and hypotension (OR 1.83). 46
In conclusion, AKI was frequent among ICU patients receiving an aminoglycoside, and it 47
was associated with high mortality. The presence of diabetes, hypotension, use of other 48
nephrotoxic drugs, and iodinated contrast were independent risk factors for the 49
development of aminoglycoside-associated nephrotoxicity.50
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Introduction 51
52
Aminoglycosides are potent bactericidal antibiotics that are highly effective against 53
Gram-negative bacterial infections. They have been increasingly used as Gram-negative 54
organisms have become progressively more resistant to beta-lactam antibiotics and 55
fluoroquinolones (8). In fact, they were recently found to be prescribed in 12.1% of the 56
cases in which an antibiotic was necessary in the ICU (10).
Aminoglycosides are 57
administered by parenteral route, have low albumin plasma binding, and are freely 58
eliminated by glomerular filtration and reabsorbed by the proximal tubule (26). A fraction 59
of the filtered load of the antibiotic binds to megalin, a receptor from the brush border of 60
proximal tubule segments S1 and S2, which then transports it to the interior of the tubule 61
cells (25). Their half-life in the renal cortex is estimated to range between 30 and 700 hours 62
(1). 63
The most important adverse effects of aminoglycosides are nephrotoxicity, 64
ototoxicity, and, more rarely, neuromuscular blockade. Renal injury can occur in a 65
substantial number of patients receiving aminoglycoside, and whether it occurs depends on 66
the patients’ clinical conditions and interactions with other nephrotoxic drugs (26). The 67
most usual clinical presentation for aminoglycoside nephrotoxicity is non-oliguric acute 68
kidney injury (AKI), which occurs following 7-10 days of therapy (1,26). Aminoglycoside-69
associated kidney injury may manifest as a decrease in the glomerular filtration rate, 70
enzymuria, aminoaciduria, glycosuria, hypomagnesemia, hypocalcemia, and hypokalemia. 71
Fanconi-like and Bartter-like syndromes, as well as impaired renal concentrating 72
mechanisms, have also been described (15,19,26). 73
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Several risk factors have been identified in aminoglycoside nephrotoxicity, 74
including the presence of co-morbidities, volume depletion, liver dysfunction, sepsis, renal 75
dysfunction, hypokalemia, hypomagnesemia, advanced age, prolonged therapy, type of 76
aminoglycoside, frequency of aminoglycoside dosing, elevated serum aminoglycoside 77
concentration, timing of aminoglycoside administration, simultaneous medications, and 78
interaction with other nephrotoxic drugs (5,34). However, the majority of published studies 79
(2,5,24,27,29,30,32) did not evaluate several of the most important risk factors 80
simultaneously, had small sample sizes, or did not use appropriate statistical methods for 81
risk factor assessment. In addition, few studies analyzed intensive care unit (ICU) patients. 82
Therefore, the aim of the present study was to assess the prevalence of 83
aminoglycoside nephrotoxicity in a large cohort of ICU patients, and identify the 84
independent risk factors associated with the development of renal injury. 85
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Patients and methods 86
87
This study was carried out through a retrospective cohort analysis of the patients 88
admitted to a clinical-surgical ICU (24 beds) of a tertiary university hospital over a period 89
of three consecutive years. The study was approved by the local Ethics Committee (Sao 90
Jose do Rio Preto Medical School, Sao Jose do Rio Preto, Brazil). 91
The ICU patients included in the study were ≥ 18 years old, they had begun 92
aminoglycoside use (amikacin or gentamicin) in the ICU, they had been taking the 93
antibiotic for at least four days, and they had a calculated GFR (cGFR) ≥ 30ml/min/1.73m2 94
at the time they began taking the aminoglycoside. Patients were treated with a single daily 95
dose of aminoglycoside and the initial doses were 3 to 5 mg/kg/day of gentamicin and 10 to 96
15 mg/kg/day of amikacin. Dose adjustments were performed using the calculated GFR 97
(cGFR). If cGFR was < 10 ml/min gentamicin was given every 72 hours and if the cGFR 98
was between 10 and 50 mL/min gentamicin was given every 48 hours. Regarding amikacin 99
if cGFR was < 10 ml/min, 50% of the recommended dose was given every 48 hours and if 100
the cGFR was between 10 and 50 mL/min, 50% of the recommended dose was given every 101
24 hours 102
The GFR was calculated using the abbreviated MDRD formula, which includes sex, 103
ethnicity, age, and serum creatinine level (17). 104
Nephrotoxicity was defined as a decrease of 20% or more from the baseline cGFR 105
during aminoglycoside use. According to this definition, patients were divided into two 106
groups: those with nephrotoxicity (AKI) and those without nephrotoxicity (non-AKI). 107
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The following variables were assessed: sex, age, baseline cGFR (using baseline 108
serum creatinine) and nadir cGFR (using peak serum creatinine), time of AKI diagnosis, 109
the presence of oliguria (< 400 ml/day), the presence of previous renal disease (clinical 110
report of renal calculi, glomerulonephritis, urinary tract infection, nephrotic syndrome and 111
nephritic syndrome), the presence of diabetes mellitus (clinical report), the presence of 112
cardiovascular disease (clinical report of hypertension, coronary disease, or stroke), the 113
presence of hypovolemia/dehydration (skin and mucosa appearance; heart rate > 120 bpm; 114
and at least one of the following: abundant vomiting, diarrhea, gastric tube drainage > 2 115
L/day, or severe bleeding during the 24 hours preceding aminoglycoside use), occurrence 116
of shock (need for vasopressors), the occurrence of hypotension (systolic blood pressure < 117
80mmHg or a 40% decrease in the customary blood pressure), jaundice (jaundice and/or 118
total bilirubin > 2 mg/dl), the simultaneous use of other drugs, specifically nephrotoxic 119
drugs (NSAIDs, vancomycin, cephalothin, amphotericin B, cisplatin, cyclosporine, 120
tacrolimus), iodinated contrast and furosemide, metabolic acidosis (pH < 7.30 and 121
bicarbonate < 20 mEq/L), hypokalemia (potassium < 3.0 mEq/l), hepatic failure (based on 122
three of six criteria: serum SGOT > 2 times normal, total bilirubin > 2.5mg/dl, albumin < 123
3.0g/dl, increase in serum alkaline phosphatase, prothrombin time > 15 s, ascites), the 124
duration of aminoglycoside use, and mortality. 125
126
Statistical analysis 127
Results are reported as a percent (%) or mean ± standard deviation (SD). Univariate 128
analysis was performed using a two-tail, non-paired, Student’s t-test, Mann-Whitney test, 129
or Fischer test, as appropriate. 130
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The variables that were statistically significant, based on univariate analysis, or 131
considered clinically important were analyzed by multivariate analysis using a logistic 132
regression model. The initial model included the following variables (with the reference for 133
each indicated in parentheses): age (< 60 years); sex (male); baseline cGFR (≥ 60 134
ml/min/1.73m2); time of aminoglycoside use (< 10 days); type of aminoglycoside used 135
(amikacin); and the presence of cardiovascular disease, diabetes, acidosis, hypovolemia, 136
hypotension, jaundice, furosemide use, iodinated contrast use, and use of other nephrotoxic 137
drugs (with the reference being the absence of these variables or non-use of the drug). 138
Shock was not included because it showed a strong correlation with hypotension (0.76). 139
Two-way interactions between terms of interest were removed simultaneously from 140
the initial model and were evaluated by likelihood ratio test (chunk test). As a group, the 141
interaction terms were not statistically significant and were not included in the final model 142
(p = 0.97). 143
Backward variable selection was used serially to remove non-significant factors. 144
The variables that, when excluded, introduced a change in parameter estimates greater than 145
10% were re-introduced to the model to account for confounding. The goodness-of-fit of 146
the model was assessed using the Hosmer and Lemeshow test. The Wald test was used to 147
assess significance of variables in the model. The level of significancy was established as p 148
< 0.05. 149
The data were analyzed using EPI-Info [version 6.04 (2001); CDC, Atlanta, GA, 150
USA] and BMDP [version PC90 (1990 IBM PC/MS-DOS); BMDPRL Statistical Software, 151
Los Angeles, CA, USA). 152
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Results 153
154
A total of 980 patients using aminoglycoside were identified during the time period 155
analyzed. Among them, 402 had all of the clinical information necessary for the study, and 156
360 fulfilled the inclusion criteria. Just over half (209, 58%) of these 360 patients 157
developed acute kidney dysfunction 6.7 ± 3.1 days after beginning aminoglycosides 158
therapy. When the two aminoglycosides were analyzed separately the prevalence of 159
nephrotoxicity was similar: 60% for gentamicin and 56.7% for amikacin. Only three of 160
these 209 patients (1.41%) presented oliguria. The AKI group was older than the non-AKI 161
group: 56 ± 18 y vs. 52 ± 19 y (p < 0.003). The frequency of males was similar in both the 162
AKI (58.3%) and non-AKI (52.3%) groups. 163
The baseline cGFR was similar in both groups (88.6 ± 42.4 ml/min/1.73 m2
for AKI 164
vs. 84.0 ± 42.2 ml/min/1.73 m2
for non-AKI). The cGFR nadir, as expected, was lower in 165
the AKI group (44.6 ± 26.9 ml/min/1.73 m2
vs. 79.4 ± 38.7 ml/min/1.73 m2 in non-AKI, p 166
< 0.001). In the AKI group, the serum creatinine increased from a baseline value of 1.0 ± 167
0.4 mg/dL to a peak value of 2.2 ± 1.3 mg/dL (p < 0.001). 168
When the patients were categorized by baseline cGFR, using 60 ml/min/1.73 m2 as 169
the threshold, it was found that patients with a baseline cGFR < 60 ml/min/1.73 m2 170
received a lower daily dose of amikacin than patients with baseline cGFR ≥ 60ml/min/1.73 171
m2: 0.78 ± 0.27 g vs. 0.94 ± 0.24 g, respectively (p = 0.0003). Both groups of GFR received 172
a similar daily amount of gentamicin. Among the patients with a baseline cGFR < 60 173
ml/min/1.73 m2, 49.5% developed AKI (50/101 patients), compared to 61% (159/259 174
patients) among the patients with cGFR ≥ 60ml/min/1.73 m2 (p = 0.0438). 175
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The AKI group received a lower daily amount of amikacin (0.86 ± 0.25 g in AKI 176
versus 0.95 ± 0.24 g in non-AKI, p = 0.0467), and both groups received similar daily 177
amounts of gentamicin (0.22 ± 0.01 in AKI versus 0.21 ± 0.01 g in non-AKI). 178
The AKI and non-AKI groups were similar in terms of the number of days that they 179
used the aminoglycosides (9.4 ± 4.6 d vs. 9.9 ± 4.5 d), the proportion of individuals who 180
used furosemide (40% vs. 30%, p = 0.059), the furosemide dosage used (51 ± 20 mg vs. 51 181
± 26 mg), and the frequency of acidosis (49% vs. 40%) and hypokalemia (22% versus 182
24%). The proportion of individuals using other nephrotoxic drugs (vancomycin, , 183
cyclosporine, cephalosporin, amphotericin B) was higher in the AKI group (51% vs. 38%, 184
p = 0.024), as was the proportion using iodinated contrast (18% vs. 8%, p = 0.005). 185
The AKI group showed a higher frequency of co-morbidities: diabetes (19% vs. 186
9.3%, p = 0.007), jaundice (19% vs. 9%, p = 0.0036), and liver dysfunction (7.6% vs. 2%, p 187
= 0.0175). Although previous cardiovascular disease was also more frequent among AKI 188
patients, this result did not reach statistical significance (47% vs. 37%, p = 0.067). 189
AKI patients had a higher frequency of hypovolemia (44% vs. 27%, p = 0.001), 190
hypotension (63% vs. 44%, p = 0.003), and shock (56% vs. 31%, p < 0.001). 191
The time of stay at the ICU was similar for both groups (16.1 ± 9.9 d vs. 15.5 ± 11 192
d). Mortality rate was significantly higher in the AKI group (44.5% vs. 29.1%, p = 0.0031). 193
194
Logistic regression 195
Logistic regression identified a baseline cGFR < 60 ml/min/1.73m2 as an independent 196
protective factor against AKI [OR 0.42 (95% CI 0.24 – 0.72, p = 0.02)]. The independent 197
risk factors for AKI were diabetes [OR 2.13 (95% CI 1.01 – 4.49, p = 0.046)], use of 198
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iodinated contrast [OR 2.13 (95% CI 1.02 – 4.43, p = 0.043)], hypotension [OR 1.83 (95% 199
CI 1.14 – 2.94, p = 0.012)], and the simultaneous use of other nephrotoxic drugs [OR 1.61 200
(95% CI 1.00 – 2.59, p = 0.048). 201
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Discussion 202
203
The prevalence of aminoglycoside nephrotoxicity reported by clinical studies varies 204
widely depending on the characteristics of the analyzed population and the criteria used to 205
diagnose renal injury. Most of the published series estimate that it occurs in 10-20% of 206
cases. The reliability of this estimate is hindered by the lack of uniform criteria for defining 207
AKI in the various studies. Absolute increases (0.5-1.5 mg/dL) or relative increases (25-208
100 %) in serum creatinine have been used for AKI diagnosis (3,12,18,31,35). When an 209
increase in serum creatinine of 0.5 mg/dl or more was used as a diagnostic criterion, 29% of 210
ICU patients were found to have aminoglycoside-associated nephrotoxicity (30). In the 211
present study of critically ill patients, the use of a more sensitive definition of renal injury, 212
i.e. a 20% decrease in cGFR, identified a much higher prevalence (58%) of 213
aminoglycoside-associated nephrotoxicity. We should recognize, however, that the most 214
widely used equations for GFR measurement, as MDRD and Cockroft-Gault have not been 215
validated yet in ICU patients. On the other hand, using the most recent definitions for AKI, 216
90.91% of the 209 patients identified as AKI in the current study will fit in the “Risk” 217
category or higher (50% increase in baseline creatinine) for RIFLE (Risk, Injury, Failure, 218
Loss, End Stage Kidney Disease) and 92.34% will fit in stage 1 or higher (a creatinine 219
increase of 0.3 mg/dl or higher from baseline or 50 to 100% increase in baseline creatinine) 220
for AKIN (Acute Kidney Injury Network) classification (4,21). 221
A noteworthy finding of this study is that those patients developing nephrotoxicity 222
had significantly higher mortality when compared to patients with stable renal function. 223
Indeed, emerging evidence suggests that even minor changes in serum creatinine are 224
associated with increased in-patient mortality (7,21). Information on the influence of 225
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aminoglycoside nephrotoxicity on patient mortality is scarce. A peak serum creatinine > 1.2 226
mg/dl was associated with higher mortality (based on univariate analysis) in febrile 227
neutropenic patients receiving gentamicin (6). When cirrhotic septic patients were treated 228
with ceftazidime or with netilmicin plus mezlocillin in a prospective, randomized trial, 229
renal failure was present at the time of death in 8% of the patients treated with ceftazidime, 230
compared with 56% of the patients treated with netilmicin (p < 0.05) (20). 231
In the present study, the majority of risk factors potentially connected to 232
aminoglycoside nephrotoxicity were studied in a large cohort of patients, using an adequate 233
statistical methodology. Diabetes as a co-morbidity, the presence of hypotension, the 234
simultaneous use of iodinated contrast, and the simultaneous use of other nephrotoxic drugs 235
emerged as independent risk factors for the development of AKI. On the other hand, a 236
baseline glomerular filtration rate < 60 ml/min/1.73 m2 was identified as an independent 237
protection factor. Although hypotension and other nephrotoxic drugs might themselves be 238
the cause of AKI in some of the studied patients, the timing of the renal injury development 239
and the fact that only 1.44% of the patients were oliguric are strongly indicative of 240
aminoglycoside-associated renal injury. 241
Data on the influence of diabetes as a risk factor for AKI in patients treated with 242
aminoglycoside are contradictory. Diabetic rats were protected against renal injury in an 243
experimental model of aminoglycoside nephrotoxicity (9,33). This protection was attributed 244
to osmotic diuresis, which decreased tubular absorption of aminoglycosides and, 245
consequently, their concentrations in the renal cortex (9,33). When the hyperglycemic state 246
was corrected by insulin, the animals lost their protection against aminoglycoside-247
associated nephrotoxicity (11). In a clinical study involving 86 elderly patients, diabetes 248
was associated with increased aminoglycoside nephrotoxicity. In this study, 9.3% of 249
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patients receiving aminoglycoside developed nephrotoxicity, and diabetes mellitus was 250
identified by logistic regression as a risk factor for aminoglycoside-associated kidney injury 251
(2). On the other hand, a study of 249 elderly patients receiving amikacin or gentamicin did 252
not find diabetes to be a risk factor for nephrotoxicity, based on logistic regression analysis 253
(29). Similarly, stepwise discriminant analysis of 214 patients treated with gentamicin or 254
tobramycin did not identify diabetes as a risk factor for aminoglycoside nephrotoxicity 255
(24). In the present study, diabetes was clearly identified as a risk factor for 256
aminoglycoside-associated nephrotoxicity. 257
In contrast to the question of the association of diabetes, hypotension and shock 258
have been constantly identified, both experimentally and clinically, as risk factors for 259
aminoglycoside-associated AKI (24,32,36). These conditions cause renal hypoperfusion 260
and ischemia. Aminoglycosides interfere with synthesis of energy molecules increasing the 261
risk of kidney injury during an ischemic episode. Moreover, ischemia alters membrane 262
lipids, thus enhancing accumulation of aminoglycosides in the proximal tubular cells 263
(23,37). In the present study, hypovolemia, hypotension, and shock occurred significantly 264
more often in the AKI group based on the univariate analysis, but only hypotension was an 265
independent factor for nephrotoxicity in the logistic regression analysis. 266
Iodinated contrast is widely used, so it is likely to be administered to patients 267
receiving aminoglycoside. This combination of treatments is potentially synergistic, since 268
contrast agents and aminoglycosides together harm renal hemodynamics and tubular cell 269
function. In fact, it is recommended that aminoglycoside not be used less than 24 hours 270
before iodinated contrast administration (14). In one of the few series analyzing contrast as 271
a risk factor for aminoglycoside nephrotoxicity, AKI was observed in 15% of the 88 272
patients studied, and univariate analysis did not identify contrast as a risk factor for its 273
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development (27). On the other hand, the present study of a large cohort found that the use 274
of contrast significantly increased the risk of AKI in patients treated with aminoglycosides. 275
The simultaneous use of aminoglycosides and other potentially nephrotoxic drugs 276
has been shown to increase the risk of aminoglycoside-associated kidney injury. Indeed, 277
this synergistic action has been demonstrated in patients and in animal studies. Clinical 278
studies have implicated several drugs in this synergy, such as vancomycin, amphotericin B, 279
piperacillin, cephalosporins, foscarnet, allopurinol, NSAIDs, inhibitors of angiotensin-280
converting enzyme, cyclosporine, and cisplatin (5,16,27,28,34). Consistent with these 281
results the simultaneous use of aminoglycoside with vancomycin, cyclosporine, 282
cephalosporin or amphotericin B significantly increased the risk of AKI. 283
Chronic kidney disease has been pointed as a risk factor for aminoglycoside 284
nephrotoxicity. These patients have a potentially higher risk of accidental aminoglycoside 285
over-dosing due to mis-estimation of the necessary dose correction. In addition, they have 286
less renal reserve, and their ability to recover from renal injury is impaired. Nevertheless, 287
published results are conflicting. Paterson found a baseline creatinine clearance of 39.6 288
mL/min in patients developing aminoglycoside-associated nephrotoxicity, compared to 289
46.7 mL/min in patients that did not develop kidney dysfunction. However, this difference 290
was not statistically significant. In the same paper, a logistic regression model identified 291
elevated baseline serum creatinine as a risk for aminoglycoside nephrotoxicity (27). 292
Another study examined the case records of 1,154 patients for whom pre- and post-293
treatment serum creatinine values were available from phase II and phase III studies with 294
amikacin. The prevalence of nephrotoxicity (change in serum creatinine) was 8.7%, and 295
one of the factors related to nephrotoxicity was elevated initial serum creatinine (16). In an 296
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analysis of 1,489 patients treated with aminoglycoside, baseline renal dysfunction was 297
identified as a risk factor for nephrotoxicity in the univariate analysis, but this was not 298
confirmed in the multiple logistic regression (5). Two different studies assessing 299
aminoglycoside nephrotoxicity in 96 and 249 patients, respectively, did not recognize 300
initial serum creatinine or decreased GFR as risk factors for kidney injury in the logistic 301
regression analysis (13,29). Finally, higher initial creatinine clearance was associated with 302
an increased risk of nephrotoxicity. Moore et al. reviewed 214 case reports of two 303
randomized clinical trials involving gentamicin or tobramycin. Patients who developed 304
kidney failure were found to have higher initial creatinine clearance (70 ± 5 vs. 58 ± 3 305
ml/min/1.73m2, p = 0.04), which was confirmed as a risk factor by stepwise discriminant 306
analysis (24,32). This last report is consistent with the results of the present study. 307
Although the cGFR mean was similar for both groups, a baseline GFR < 60 ml/min/m 2 308
conferred significant protection against aminoglycoside nephrotoxicity. It is possible that a 309
moderate decrease in the glomerular filtration rate, associated with an adequate antibiotic 310
dose correction, allowed a lower load of aminoglycoside to reach the tubular lumina, thus 311
decreasing tubular reabsorption and cortical accumulation of the antibiotic. One way to 312
reconcile these contradictory results is to conclude that in previous studies reporting 313
increased risk of aminoglycoside nephrotoxicity in patients with CKD, the patients suffered 314
more severe baseline renal injury, as reflected in lower baseline GFRs, and this made the 315
kidneys more vulnerable to subsequent insults. It is also reasonable to assume that a 316
decrease in baseline GFR may urge the ICU team to prescribe a lower dose of 317
aminoglycoside; this would protect the tubule cells against a high luminal concentration of 318
antibiotic. In fact, when we analyzed the amikacin dose in terms of baseline cGFR, we 319
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found that patients with a baseline cGFR < 60 ml/min/1.73 m2 received a lower dose of 320
antibiotic as compared with patients with a baseline cGFR ≥ 60 ml/min/1.73 m2. 321
In conclusion, aminoglycoside-associated nephrotoxicity occurred frequently and 322
was associated with high mortality in the ICU patients in this study. A baseline GFR < 60 323
ml/min/1.73 m2 was an independent protective factor against aminoglycoside-associated 324
nephrotoxicity, while diabetes, hypotension, simultaneous use of iodinated contrast, and 325
simultaneous use of other nephrotoxic drugs were independent risks factor for the 326
development of nephrotoxicity. These data indicate that if an appropriated correction of the 327
dose of the drug delivered is used, decreased baseline GFR it is not a risk factor for 328
aminoglycoside-associated nephrotoxicity. Moreover, these results strongly suggest that 329
aminoglycoside should be avoided or used with extreme caution in hypotensive and/or 330
diabetic patients or patients receiving other nephrotoxic drugs, including iodinated contrast, 331
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Acknowledgements 333
EAB and DMTZ are partially supported by grants from The National Council for 334
Scientific and Technological Development (CNPq, Brazil). 335
Part of this work was presented at the American Society of Nephrology meeting in 336
2005 and published as an abstract in the J Am Soc Nephrol 16:539A, 2005. 337
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Conflict of interest 338
The authors have no potential conflict of interest to disclose regarding the data in 339
this manuscript. 340
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References 341
342
1. Appel GB. 1990. Aminoglycoside nephrotoxicity. Am J Med. 88:16S-20S. 343
2. Baciewicz AM, Sokos DR, Cowan RI. 2003. Aminoglycoside-associated 344
nephrotoxicity in the elderly. Ann Pharmacother. 37:182-186. 345
3. Bates DW, Su L, Yu DT, Chertow GM, Seger DL, Gomes DR, Dasbach EJ, 346
Platt R. 2001. Mortality and costs of acute renal failure associated with 347
amphotericin B therapy. Clin Infect Dis. 32:686-693. 348
4. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis 349
Quality Initiative workgroup. 2004. Acute renal failure - definition, outcome 350
measures, animal models, fluid therapy and information technology needs: the 351
Second International Consensus Conference of the Acute Dialysis Quality Initiative 352
(ADQI) Group. Crit Care. 8:R204-R212. 353
5. Bertino JS Jr, Booker LA, Franck PA, Jenkins PL, Franck KR, Nafziger AN. 354
1993. Incidence of and significant risk factors for aminoglycoside-associated 355
nephrotoxicity in patients dosed by using individualized pharmacokinetic 356
monitoring. J Infect Dis. 167:173-179. 357
6. Bianco TM, Dwyer PN, Bertino JS Jr. 1989. Gentamicin pharmacokinetics, 358
nephrotoxicity, and prediction of mortality in febrile neutropenic patients. 359
Antimicrob Agents Chemother. 33:1890-1895. 360
7. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. 2005. Acute 361
kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc 362
Nephrol. 16:3365-3370. 363
on June 27, 2018 by guesthttp://aac.asm
.org/D
ownloaded from
21
8. Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, Louie A. 364
2007. Back to the future: using aminoglycosides again and how to dose them 365
optimally. Clin Infect Dis. 45:753-760. 366
9. Elliott WC, Houghton DC, Gilbert DN, Baines-Hunter J, Bennett WM. 1985. 367
Experimental gentamicin nephrotoxicity: effect of streptozotocin-induced diabetes. 368
J Pharmacol Exp Ther. 233:264-270. 369
10. Erbay A, Bodur H, Akinci E, Colpan A. 2005. Evaluation of antibiotic use in 370
intensive care units of a tertiary care hospital in Turkey. J Hosp Infect. 59:53-61. 371
11. Gouvea W, Roth D, Alpert H, Kelley J, Pardo V, Vaamonde CA. 1994. Insulin 372
reverses the protection given by diabetes against gentamicin nephrotoxicity in the 373
rat. Proc Soc Exp Biol Med. 206:445-453. 374
12. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. 1983. Hospital-375
acquired renal insufficiency: a prospective study. Am J Med. 74:243-248. 376
13. Koo J, Tight R, Rajkumar V, Hawa Z. 1996. Comparison of once-daily versus 377
pharmacokinetic dosing of aminoglycosides in elderly patients. Am J Med. 378
101:177-183. 379
14. Lameire NH. 2006. Contrast-induced nephropathy - prevention and risk reduction. 380
Nephrol Dial Transplant. 21 (Suppl 1):i11-23. 381
15. Landau D, Kher KK. 1997. Gentamicin-induced Bartter-like syndrome. Pediatr 382
Nephrol. 11:737-740. 383
16. Lane AZ, Wright GE, Blair DC. 1977. Ototoxicity and nephrotoxicity of 384
amikacin: an overview of phase II and phase III experience in the United States. Am 385
J Med. 62:911-918. 386
on June 27, 2018 by guesthttp://aac.asm
.org/D
ownloaded from
22
17. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. 1999. A more 387
accurate method to estimate glomerular filtration rate from serum creatinine: a new 388
prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern 389
Med. 130:461-470. 390
18. Levy EM, Viscoli CM, Horwitz RI. 1996. The effect of acute renal failure on 391
mortality: A cohort analysis. JAMA. 275:1489-1494. 392
19. Martinez-Salgado C, López-Hernández FJ, López-Novoa JM. 2007. Glomerular 393
nephrotoxicity of aminoglycosides. Toxicol Appl Pharmacol. 223: 86-98. 394
20. McCormick PA, Greenslade L, Kibbler CC, Chin JK, Burroughs AK, 395
McIntyre N. 1997. A prospective randomized trial of ceftazidime versus netilmicin 396
plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients. 397
Hepatology. 25:833-836. 398
21. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin 399
A; Acute Kidney Injury Network. 2007. Acute Kidney Injury Network: report of 400
an initiative to improve outcomes in acute kidney injury. Crit Care. 11:R31. 401
22. Melnick JZ, Baum M, Thompson JR. 1994. Aminoglycoside-induced Fanconi’s 402
syndrome. Am J Kidney Dis. 23:118-123. 403
23. Molitoris BA, Meyer C, Dahl R, Geerdes A. 1993. Mechanism of ischemia-404
enhanced aminoglycoside binding and uptake by proximal tubule cells. Am J 405
Physiol. 264:F907-F916. 406
24. Moore RD, Smith CR, Lipsky JJ, Mellits ED, Lietman PS. 1984. Risk factors for 407
nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med. 100:352-408
357. 409
on June 27, 2018 by guesthttp://aac.asm
.org/D
ownloaded from
23
25. Nagai J, Tanaka H, Nakanishi N, Murakami T, Takano M. 2001. Role of 410
megalin in renal handling of aminoglycosides. Am J Physiol Renal Physiol. 411
281:F337-F344. 412
26. Oliveira JFP, Cipullo JP, Burdmann EA. 2006. Aminoglycoside nephrotoxicity. 413
Braz J Cardiovasc Surg. 21:444-452. 414
27. Paterson DL, Robson JM, Wagener MM. 1998. Risk factors for toxicity in 415
elderly patients given aminoglycosides once daily. J Gen Intern Med. 13:735-739. 416
28. Prins JM, Weverling GJ, de Blok K, van Ketel RJ, Speelman P. 1996. 417
Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing 418
schedule and guidelines for monitoring therapy. Antimicrob Agents Chemother. 419
40:2494-2499. 420
29. Raveh D, Kopyt M, Hite Y Rudensky B, Sonnenblick M, Yinnon AM. 2002. 421
Risk factors for nephrotoxicity in elderly patients receiving once-daily 422
aminoglycosides. QJM. 95:291-297. 423
30. Schentag JJ, Cerra FB, Plaut ME. 1982. Clinical and pharmacokinetic 424
characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients. 425
Antimicrob Agents Chemother. 21:721-726. 426
31. Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G. 1987. 427
Risk factors and outcome of hospital-acquired acute renal failure. Clinical 428
epidemiologic study. Am J Med. 83:65-71. 429
32. Smith CR, Moore RD, Lietman PS. 1986. Studies of risk factors for 430
aminoglycoside nephrotoxicity. Am J Kidney Dis. 8:308-313. 431
on June 27, 2018 by guesthttp://aac.asm
.org/D
ownloaded from
24
33. Teixeira RB, Kelley J, Alpert H, Pardo V, Vaamonde CA. 1982. Complete 432
protection from gentamicin-induced acute renal failure in the diabetes mellitus rat. 433
Kidney Int. 21:600-612. 434
34. Verpooten GA, Tulkens PM, Molitoris BA. 2003. Aminoglycosides and 435
vancomycin. p151-162 .In De Broe ME, Porter GA, Bennett WM, Verpooten GA. 436
Clinical Nephrotoxins. 2nd
ed. Dordrecht Kluwer Academic Publisher. 437
35. Zahar JR, Rioux C, Girou E, Hulin A, Sauve C, Bernier-Combes A, Brun-438
Buisson C, Lesprit P. 2006. Inappropriate prescribing of aminoglycosides: risk 439
factors and impact of an antibiotic control team. J Antimicrob Chemother. 58:651-440
656. 441
36. Zager RA. 1988. Gentamicin nephrotoxicity in the setting of acute renal 442
hypoperfusion. Am J Physiol. 254:F574-F581. 443
37. Zager RA. 1992. Gentamicin effects on renal ischemia/reperfusion injury. Circ Res. 444
70:20-28. 445
on June 27, 2018 by guesthttp://aac.asm
.org/D
ownloaded from