Abstract

Objective. NSAIDs are commonly prescribed to control gout attacks in patients with hyperuricaemia. We investigated risk factors for NSAID-induced acute kidney injury (AKI) in patients with hyperuricaemia.

Methods. We identified 328 patients with hyperuricaemia treated with NSAIDs at Seoul National University Hospital between December 1998 and January 2008 to investigate risk factors for NSAID-induced AKI. The risk factors evaluated included age, sex, BMI, comorbidity, NSAID COX-2 selectivity, baseline glomerular filtration rate (GFR), serum uric acid, serum albumin, haemoglobin level, ratio of blood urea nitrogen and serum creatinine and the use of allopurinol. After extracting possible risk factors through univariate analysis, multivariate logistic regression analysis was performed with backward selection to derive a risk model for NSAID-induced AKI in patients with hyperuricaemia.

Results. Thirty (9.1%) NSAID users developed AKI. Univariate analysis revealed that old age (P = 0.008), low GFR (P = 0.001), low serum albumin (P < 0.001) and low haemoglobin levels (P < 0.001) were possible risk factors. Multivariate logistic regression analysis showed that low baseline GFR [odds ratio (OR) 4.86, 95% CI 1.27, 18.55, P = 0.021, for GFR 15–29 vs ≥60 ml/min/1.73 m2] and low serum albumin (OR 4.43, 95% CI 1.82, 10.80, P = 0.001, for albumin ≤4 vs >4 g/dl) are risk factors for NSAID-induced AKI in patients with hyperuricaemia.

Conclusion. Low GFR and low serum albumin are risk factors for AKI in hyperuricaemic patients treated with NSAIDs. Our results suggest that NSAIDs should be used with caution in patients with low serum albumin.

Introduction

In recent years, the prevalence of gout and hyperuricaemia has increased in the general population along with the prevalence of elderly and obese individuals [1]. NSAIDs, which are among the most commonly prescribed over-the-counter drugs, are the primary medications recommended to control gout attacks in patients with hyperuricaemia [2]. Despite the well-established efficacy of NSAIDs in controlling gout attacks, these drugs have several possible adverse effects and can cause acute kidney injury (AKI) [3–5].

AKI affects 2.5 million people per year in the USA and can lead to longer hospital stays, increased health-care costs and greater mortality among hospitalized patients [5, 6]. Several risk factors for AKI have been suggested, including age, BMI, baseline renal function, acute or chronic circulatory failure and prior invasive procedures or high-risk surgery [7, 8]. The NSAID-induced AKI was reported to be associated with pre-existing diseases causing low-renal perfusion such as congestive heart failure and liver cirrhosis, pre-existing renal disease, concomitant use of nephrotoxic drugs and old age [9–12]. However, the risk factors for NSAID-induced AKI have not yet been fully evaluated in patients with hyperuricaemia despite common use of NSAIDs in this group of patients.

Patients and methods

This is a retrospective cohort study investigating risk factors for NSAID-induced AKI in patients with hyperuricaemia. All information was retrieved by reviewing medical records. Patients were eligible for this study if they had a history of serum uric acid >7.0 mg/dl, glomerular filtration rate (GFR) ≥15 ml/min/1.73 m2, were ≥18 years old, were prescribed an NSAID at Seoul National University Hospital between December 1998 and January 2008, and underwent relevant laboratory tests within 4 weeks before and after administration of an NSAID. In some patients, serum uric acid was <7.0 mg/dl when the NSAID was prescribed. There were 2889 cases where an NSAID was prescribed in patients with hyperuricaemia. After excluding repeated cases and cases with insufficient baseline data and end-stage renal disease, we were able to enrol 328 patients into the final analysis.

The primary end-point of the study was development of AKI. AKI was classified into Risk, Injury, Failure, Loss and End-stage kidney disease, according to the RIFLE classification scheme [13]. These classifications were based on changes in GFR, serum creatinine (Cr) or urine output. Criteria for risk were a >25% decrease in GFR or 1.5-fold increase in Cr, for injury were a >50% decrease in GFR or 2-fold increase in Cr and for failure were a >75% decrease in GFR or Cr level >4 mg/dl. Loss was defined as complete loss of kidney function for at least 4 weeks, and end-stage kidney disease as loss of function for >3 months. Baseline values were defined as the last value before NSAIDs were administered. Values after NSAID administration were defined as the lowest value within 4 weeks after administration of an NSAID. Urine output data were not available. GFR was calculated using the modification of diet in renal disease (MDRD) study equation [14].

Candidate explanatory variables included demographic variables (age and sex), BMI, comorbidities (hypertension and diabetes mellitus), Cyclooxygenase (COX)-2-selectivity of NSAIDs, laboratory data [baseline GFR, serum uric acid, serum albumin, haemoglobin, ratio of blood urea nitrogen (BUN) and Cr] and the use of allopurinol. Baseline renal function was classified as Stage 1 (GFR ≥ 90 ml/min/1.73 m2), Stage 2 (GFR 60–89 min/ml/1.73 m2), Stage 3 (GFR 30–59 ml/min/1.73 m2) or Stage 4 (GFR 15–29 ml/min/1.73 m2) [15]. Patients with GFR <15 ml/min/1.73 m2 were excluded at enrolment since the purpose of the study was to monitor changes in GFR. The BUN/Cr ratio was included as a surrogate marker for dehydration and intravascular volume status and serum albumin was used as an indicator of synthetic liver function.

The Institutional Review Board (IRB) of Seoul National University Hospital approved this study. Informed consent was not required by the IRB based on the minimal risk to patients and the impracticality of acquiring informed consent.

Statistical analysis

Univariate analysis was performed to detect the crude risk factors associated with AKI. Student's t-test was applied for continuous variables and Pearson's chi-square test was used for categorical variables. With development of AKI as the primary end-point, the following risk factors were evaluated: patient age, sex, BMI, presence of hypertension, presence of diabetes mellitus, COX-2 selectivity of NSAIDs, baseline GFR, baseline serum uric acid, serum albumin, haemoglobin, ratio of BUN and Cr and use of allopurinol.

After selecting candidate risk factors (age, serum albumin, haemoglobin and baseline GFR) based on univariate analysis, multivariate logistic regression analysis was performed to reveal adjusted risk factors for NSAID-induced AKI. Backward selection was applied to select the most significant risk factors and to exclude factors causing collinearity. P < 0.05 was considered statistically significant. All data were analysed by SPSS-17.0 for Windows.

Results

Patient demographics

The baseline characteristics of enrolled patients are summarized in Table 1. Among 328 patients, 211 (64.3%) were enrolled from the outpatient clinic and the remaining were from the inpatient service. Mean (s.d.) age was 57.9 (14.1) years and 92.0% of patients were male. The mean (s.d.) uric acid level was 7.4 (2.4) mg/dl, Cr was 1.3 (0.5) mg/dl and the GFR was 66.7 (18.7) ml/min/1.73 m2. A total of 328 (73.1%) patients received NSAID treatment for gout attacks. NSAIDs prescribed included aceclofenac, etodolac, ketorolac, sulindac, lornoxicam, meloxicam, piroxicam, tenoxicam, dexibrofen, fenoprofen, ibuprofen, ketoprofen, naproxen, celecoxib and nabumetone.

Table 1

Baseline characteristics of patients (n = 328)

Characteristic Patients (n = 328) 
Age, mean (s.d.), years 57.9 (14.1) 
Male/female, n (%) 298 (90.9)/30 (9.1) 
BMI, mean (s.d.) (n = 114) 24.4 (3.0) 
Outpatient/inpatient, n (%) 211 (64.3)/117 (35.7) 
Diagnosis, n (%)  
    Gout 266 (81.1) 
    Hyperuricaemia 62 (18.9) 
Comorbidities, n (%)  
    Hypertension 167 (50.9) 
    Diabetes mellitus 53 (16.2) 
NSAID type, n (%)  
    COX-2 selective 44 (13.4) 
    COX-2 non-selective 284 (86.6) 
Reasons for medication, n (%)  
    Gout attack 210 (64.0) 
    Chronic gout 30 (9.2) 
    Other reasons 88 (26.8) 
Concomitant medication, n (%)  
    Allopurinol 72 (22.3) 
    Benzbromarone 10 (3.0) 
Laboratory findings, mean (s.d. 
    Haemoglobin, g/dl 13.5 (2.3) 
    BUN, mg/dl 18.6 (9.8) 
    Creatinine, mg/dl 1.3 (0.5) 
    Uric acid, mg/dl 7.4 (2.4) 
    Total cholesterol, mg/dl 179.7 (39.3) 
    Albumin, g/dl 4.1 ((0.5) 
    GFR, ml/min/1.73 m2 66.7 ((18.7) 
Characteristic Patients (n = 328) 
Age, mean (s.d.), years 57.9 (14.1) 
Male/female, n (%) 298 (90.9)/30 (9.1) 
BMI, mean (s.d.) (n = 114) 24.4 (3.0) 
Outpatient/inpatient, n (%) 211 (64.3)/117 (35.7) 
Diagnosis, n (%)  
    Gout 266 (81.1) 
    Hyperuricaemia 62 (18.9) 
Comorbidities, n (%)  
    Hypertension 167 (50.9) 
    Diabetes mellitus 53 (16.2) 
NSAID type, n (%)  
    COX-2 selective 44 (13.4) 
    COX-2 non-selective 284 (86.6) 
Reasons for medication, n (%)  
    Gout attack 210 (64.0) 
    Chronic gout 30 (9.2) 
    Other reasons 88 (26.8) 
Concomitant medication, n (%)  
    Allopurinol 72 (22.3) 
    Benzbromarone 10 (3.0) 
Laboratory findings, mean (s.d. 
    Haemoglobin, g/dl 13.5 (2.3) 
    BUN, mg/dl 18.6 (9.8) 
    Creatinine, mg/dl 1.3 (0.5) 
    Uric acid, mg/dl 7.4 (2.4) 
    Total cholesterol, mg/dl 179.7 (39.3) 
    Albumin, g/dl 4.1 ((0.5) 
    GFR, ml/min/1.73 m2 66.7 ((18.7) 

Development of AKI

AKI developed in 30 (9.1%) of the NSAID users. The mean (s.d.) duration from NSAID prescription to detection of AKI was 2.1 (1.1) weeks. Classified according to the RIFLE criteria, 22 (73.3%) patients belonged to the risk group, 3 (10.0%) patients to the injury group and 5 (16.7%) patients to the failure group. All patients in the failure group gradually recovered renal function after stopping medication.

Risk factors for AKI

Univariate analysis is summarized in Table 2. Patients who developed AKI were older [64.4 (12.8) vs 57.2 (14.1) years, P = 0.008] and had decreased baseline renal function (P = 0.001) compared with those who did not develop AKI. The risk of AKI progressively increased as baseline renal function deteriorated. AKI developed in 5.5% of the 218 patients with Stage 1 or 2 renal functions, but in 14.6% of the 96 patients with Stage 3 and 28.6% of the 14 patients with Stage 4. Baseline serum albumin and haemoglobin levels were significantly lower in the AKI group. However, sex, BMI, presence of comorbidities (hypertension and diabetes mellitus), COX-2 selectivity of NSAIDs, baseline serum uric acid and the ratio of BUN to Cr did not differ between the AKI and non-AKI groups. Multivariate logistic regression analysis revealed that low baseline GFR [odds ratio (OR) 4.86, 95% CI 1.27, 18.55, P = 0.021, for GFR 15–29 vs ≥60 ml/min/1.73 m2] and low serum albumin (OR 4.43, 95% CI 1.82, 10.80, P = 0.001, for albumin ≤4 vs >4 g/dl) were significant risk factors for NSAID-induced AKI after adjusting for confounding variables and excluding collinear variables (Table 3).

Table 2

Univariate analysis of NSAID-induced AKI in patients with hyperuricaemia

Variables AKI (−) (n = 298) AKI (+) (n = 30) P-value 
Age, mean (s.d.), years  57.2 (14.1) 64.4 (12.8) 0.008 
Sex, n (%)    
    Male 273 (91.6) 25 (8.4) 0.173 
    Female  25 (83.3)  5 (16.7)  
BMI, mean (s.d.), kg/m2 (n = 114)  24.5 (3.1) 23.7 (2.4) 0.406 
Hypertension, n (%)    
    Yes 148 (49.7) 19 (63.3) 0.153 
    No 150 (50.3) 11 (36.7)  
Diabetes mellitus, n (%)    
    Yes  49 (16.4)  4 (13.3) 0.659 
    No 249 (83.6) 26 (86.7)  
NSAID type, n (%)    
    COX-2-selective NSAID  40 (13.4)  4 (13.3) 0.989 
    COX-2- non-selective NSAID 258 (86.6) 26 (86.7)  
Baseline GFR (%), ml/min/1.73 m2    
    15–29  10 (3.4)  4 (13.3) 0.001 
    30–59  82 (27.5) 14 (46.7)  
    ≥60 206 (68.1) 12 (40.0)  
Serum uric acid, mean (s.d.), mg/dl   7.4 (2.4)  7.3 (2.5) 0.981 
Serum albumin, mean (s.d.), g/dl   4.1 (0.5)  3.6 (0.5) <0.0001 
Haemoglobin, mean (s.d.), g/dl  13.7 (2.2) 12.2 (2.6) <0.0001 
Ratio of BUN/Cr, mean (s.d. 14.4 (4.8) 15.1 (5.3) 0.398 
Allopurinol, n (%)    
    Yes  67 (22.5)  6 (20.0) 0.755 
    No 231 (77.5) 24 (80.0)  
Variables AKI (−) (n = 298) AKI (+) (n = 30) P-value 
Age, mean (s.d.), years  57.2 (14.1) 64.4 (12.8) 0.008 
Sex, n (%)    
    Male 273 (91.6) 25 (8.4) 0.173 
    Female  25 (83.3)  5 (16.7)  
BMI, mean (s.d.), kg/m2 (n = 114)  24.5 (3.1) 23.7 (2.4) 0.406 
Hypertension, n (%)    
    Yes 148 (49.7) 19 (63.3) 0.153 
    No 150 (50.3) 11 (36.7)  
Diabetes mellitus, n (%)    
    Yes  49 (16.4)  4 (13.3) 0.659 
    No 249 (83.6) 26 (86.7)  
NSAID type, n (%)    
    COX-2-selective NSAID  40 (13.4)  4 (13.3) 0.989 
    COX-2- non-selective NSAID 258 (86.6) 26 (86.7)  
Baseline GFR (%), ml/min/1.73 m2    
    15–29  10 (3.4)  4 (13.3) 0.001 
    30–59  82 (27.5) 14 (46.7)  
    ≥60 206 (68.1) 12 (40.0)  
Serum uric acid, mean (s.d.), mg/dl   7.4 (2.4)  7.3 (2.5) 0.981 
Serum albumin, mean (s.d.), g/dl   4.1 (0.5)  3.6 (0.5) <0.0001 
Haemoglobin, mean (s.d.), g/dl  13.7 (2.2) 12.2 (2.6) <0.0001 
Ratio of BUN/Cr, mean (s.d. 14.4 (4.8) 15.1 (5.3) 0.398 
Allopurinol, n (%)    
    Yes  67 (22.5)  6 (20.0) 0.755 
    No 231 (77.5) 24 (80.0)  
Table 3

Multivariate-adjusted ORs for NSAID-induced AKI in patients with hyperuricaemia

Variable OR (95% CI) P-value 
Baseline albumin, g/dl   
    ≤4 4.43 (1.82,10.80) 0.001 
    >4 1.00 – 
Baseline GFR, ml/min/1.73 m2   
    15–29a 4.86 (1.27,18.55) 0.021 
    30–59a 2.69 (1.17, 6.17) 0.019 
    ≥60 1.00 – 
Variable OR (95% CI) P-value 
Baseline albumin, g/dl   
    ≤4 4.43 (1.82,10.80) 0.001 
    >4 1.00 – 
Baseline GFR, ml/min/1.73 m2   
    15–29a 4.86 (1.27,18.55) 0.021 
    30–59a 2.69 (1.17, 6.17) 0.019 
    ≥60 1.00 – 

aWhen combined (GFR is between 15 and 59 ml/min/1.73 m2), OR for AKI is 2.68 (95% CI 1.1, 6.17) with a P-value of 0.020.

Discussion

In this study, we found that patients with hyperuricaemia are especially susceptible to AKI if they have low serum albumin and low baseline renal function. Considering that low GFR and low effective circulatory volume are major risk factors of AKI in the general population, our results suggest that the risk factors in hyperuricaemic patients are similar to those in the general population. To the best of our knowledge, this is the first study to investigate the risk factors for NSAID-induced AKI in patients with hyperuricaemia.

AKI developed in 9.1% of patients who started an NSAID. A severe form of AKI, acute renal failure, occurred in 1.2% of patients. The incidence of AKI (9.1%) was higher in this study than that previously reported for the general population (0.47–4.6%) [16, 17]. The higher incidence of AKI in our study may be a result of different population characteristics (ethnicity, age, sex, etc.), the use of different criteria to define AKI or inclusion of patients with more comorbidities than other studies. Our patient group is deviated to a more severe group than the general population since all the patients were enrolled from a tertiary hospital. Furthermore, our patient group might be composed of more complicated patients, because we enrolled only those who needed repeated blood tests before and after administration of NSAIDs.

The incidence of AKI progressively increased as baseline renal function deteriorated: 5.5% of those with GFR >60 ml/min, 14.5% of those with GFR between 30–59 ml/min and 28.6% of those with GFR <30 ml/min developed AKI. These results suggest that special care should be taken when NSAIDs are administered to hyperuricaemic patients if their baseline GFR is <60 ml/min. Low GFR is closely associated with hyperuricaemia. According to one study, each increase of 1 mg/dl in serum uric acid is associated with a 7–11% increase in incident chronic kidney disease [18].

Low serum albumin was a significant risk factor for AKI in this study. An independent association of low serum albumin and AKI has been reported. In meta-analysis of the relationship between hypoalbuminaemia and AKI, Wiederman et al. [19] reported that the OR for AKI was 2.34 with a 95% CI of 1.74, 3.14. Furthermore, AKI patients with hypoalbuminaemia showed higher ORs for death than those without hypoalbuminaemia (OR 2.47, 95% CI 1.51, 4.05). Serum albumin can protect against renal injury through several pathways. It can adsorb nephrotoxic agents such as amikacin [20], facilitate the growth of renal tubular cells [21] or activate cellular signalling pathways [22].

The effects of COX-2-selective NSAIDs on AKI risk are controversial. Meta-analysis of randomized controlled trials showed that rofecoxib increased risk for AKI [23], but a nested case–control study showed decreased risk with selective COX-2 inhibitors compared with non-selective inhibitors [24]. COX-2-selective and non-selective NSAIDs showed no difference in AKI risk in this study. The negative result of this study may come from the low statistical power of the study, but our results suggest that great care should be taken when NSAIDs are prescribed to patients with hyperuricaemia whether they are COX-2-selective or not [11, 16, 17, 25].

NSAID-induced AKI can result from direct nephrotoxicity, such as acute interstitial nephritis, or from indirect nephrotoxicity through inhibition of prostaglandins [26]. While direct toxicity can develop from an unpredictable immunological response, inhibition of prostaglandins can develop in most patients, especially when the renin–angiotensin system is activated [3, 11]. The mechanism of AKI was not the focus of this study, but inhibition of prostaglandins might play a major role in the development of AKI, considering the rare occurrence of acute interstitial nephritis with NSAID use.

Fortunately, NSAID-induced AKI is known to be reversible within 1 week of discontinuation of the offending agent [11]. The reversibility is consistent with our results. However, it is still desirable to avoid AKI since AKI can lead to a progressive decline in renal function in some patients leading to a need for renal replacement therapy in 6% of patients [27], and can interfere with management of comorbidities and cause discomfort to patients.

The mean (s.d.) level of serum uric acid in the present study's patient population was 7.4 (2.4) mg/dl. This rather low score comes from the fact that we included patients with gout who were taking allopurinol for hyperuricaemia control, and some patients showed transiently low uric acid levels during gout attacks. It is well known that uric acid levels can be lowered during gout attacks [28, 29].

There are several limitations of the present study. First, the number of patients may not have been sufficient to identify all possible risk factors. Many candidates were excluded because there were not enough consecutive data for analysis. Second, compliance of patients taking NSAIDs was not measured in this study. However, we assume a high compliance rate considering the intense pain associated with gout attacks. Incomplete information is an inevitable limitation of retrospective studies. Third, not all comorbid diseases and conditions associated with AKI could be evaluated. However, we tried to include as many potential risk factors as possible and used surrogate markers if direct data were not available. For example, the ratio of BUN to Cr was included to represent intravascular volume status.

In conclusion, we found that low serum albumin and low GFR are significant risk factors for AKI when NSAIDs are administered to patients with hyperuricaemia. These findings suggest that NSAIDs should be used with care in hyperuricaemic patients with low serum albumin levels.

graphic

Acknowledgements

We deeply appreciate statistical assistance by Medical Research Collaborating Center of Seoul National University College of Medicine.

Funding: This work was supported by a grant of the Korean Healthcare Technology Research and Development project, Ministry of Health and Welfare, Republic of Korea (A084204).

Disclosure statement: The authors have declared no conflicts of interest.

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