Illicit drug use, hypertension, and chronic kidney disease in the US adult population

FEATURED NEW INVESTIGATOR Illicit drug use, hypertension, and chronic kidney disease in the US adult population SANJEEV K. AKKINA, ANA C. RICARDO, AMISHI PATEL, ARJUN DAS, LYDIA A. BAZZANO, CAROLYN BRECKLIN, MICHAEL J. FISCHER, and JAMES P. LASH CHICAGO, ILL; TOLEDO, OHIO; AND NEW ORLEANS, LA

Illicit drug use has been associated with chronic kidney disease (CKD) in select populations, but it is unknown whether the same association exists in the general population. By using data from the National Health and Nutrition Examination Survey 2005–2008, we conducted a cross-sectional analysis of 5861 adults who were questioned about illicit drug use, including cocaine, methamphetamines, and heroin, during their lifetime. The primary outcome was CKD as defined by an estimated glomerular filtration rate #60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration equation or by microalbuminuria. We also examined the association between illicit drug use and blood pressure (BP) $120/80, $130/85, and $140/90 mm Hg. Logistic regression was used to examine the association between illicit drug use and CKD and BP. Mean estimated glomerular filtration rate was similar between illicit drug users and nonusers (100.7 vs 101.4 mL/min/1.73 m2, P 5 0.4), as was albuminuria (5.7 vs 6.0 mg/g creatinine, P 5 0.5). Accordingly, illicit drug use was not significantly associated with CKD in logistic regression models (odds ratio [OR], 0.98; confidence interval [CI], 0.75–1.27) after adjusting for other important factors. However, illicit drug users had higher systolic (120 vs 118 mm Hg, P 5 0.04) and diastolic BP (73 vs 71 mm Hg, P 5 0.0003) compared with nonusers. Cocaine use was independently associated with BP $130/85 mm Hg (OR, 1.24; CI, 1.00–1.54), especially when used more during a lifetime (6–49 times; OR, 1.42; CI, 1.06–1.91). In a representative sample of the US population, illicit drug use was not associated with CKD, but cocaine users were more likely to have elevated BP. (Translational Research 2012;160:391–398) Abbreviations: BMI ¼ body mass index; CI ¼ confidence interval; CKD ¼ chronic kidney disease; eGFR ¼ estimated glomerular filtration rate; ESKD ¼ end-stage kidney disease; MEC ¼ Mobile Examination Center; NHANES ¼ National Health and Nutrition Examination Survey; OR ¼ odds ratio Sanjeev K. Akkina, MD, is an Assistant Professor of Medicine in the Section of Nephrology at the University of Illinois at Chicago. His article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, April 2011. From the Medicine/Nephrology, University of Illinois at Chicago, Chicago, Ill; Southwest Nephrology Associates, Chicago, Ill; Nephrology Consultants – Northwest Ohio, Toledo, Ohio; Tulane University School of Public Health and Tropical Medicine, New Orleans, La; Nephrology, Stroger Hospital of Cook County, Chicago, Ill; Center for Management of Complex Chronic Care, Jesse Brown VA Medical Center, Chicago, Ill.

erans Affairs Health Services Research and Development Service Career Development Award. Ana C. Ricardo was supported by the University of Illinois at Chicago Center for Clinical and Translational Science, Award Number UL1RR029879 from the National Center for Research Resources. None of the authors have a conflict of interest.

Sanjeev K. Akkina was supported by a research grant from the National Institute of Diabetes and Digestive and Kidney Diseases, Award Number K23DK084121. Michael J. Fischer was supported by a Vet-

http://dx.doi.org/10.1016/j.trsl.2012.05.008

Submitted for publication October 12, 2011; revision submitted May 24, 2012; accepted for publication May 25, 2012. Reprint requests: Sanjeev K. Akkina, MD, Section of Nephrology (M/ C 793), University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612-7315; e-mail: [email protected]. 1931-5244/$ - see front matter Ó 2012 Mosby, Inc. All rights reserved.

391

392

Translational Research December 2012

Akkina et al

AT A GLANCE COMMENTARY Akkina S, et al. Background

Illicit drug use is a common problem in the United States and has been associated with CKD in select populations, including those who already have hypertension or CKD. However, there have been no studies looking at this relationship in the general population. Translational Significance

Although various studies have shown conflicting results regarding the association of illicit drug use and CKD, our results suggest that other causes of CKD, especially those that may be reversible, should be investigated thoroughly before considering illicit drug use as the cause of kidney disease.

Illicit drug use is a significant public health problem in the United States. In 2009, it was estimated that approximately 22 million, or 8.7% of the American teenage and adult population, had recently used illicit drugs.1 Although the majority of illicit drug use was marijuana, more than 5 million of these individuals used other illicit drugs, including cocaine, heroin, hallucinogens, inhalants, and prescription drugs. The link between illicit drug use and certain medical conditions, especially cocaine and cardiovascular disease, is well established. In 2008, the American Heart Association published a scientific statement stressing the detrimental effects of cocaine on cardiovascular health.2 A substantial association was observed between cocaine use and an increased risk of a history of myocardial infarction among participants in the Third National Health and Nutrition Examination Survey (NHANES III).3 An association between illicit drug use and kidney injury is well described in case reports and case series. Methamphetamines have been associated with acute reversible kidney injury from acute tubular necrosis related to hypotension, rhabdomyolysis, disseminated intravascular coagulation, and hyperpyrexia.4-7 Although heroin use has been associated with focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis,8,9 no causal pathways have been established because of the heterogeneity of the populations and confounding factors that could better explain these lesions.10 More literature has characterized the wide spectrum of clinical complications from cocaine. Acute kidney injury as a result of cocaine-induced rhabdomyolysis,11,12 kidney infarction,13 and malignant hy-

pertension14 have been reported with recent use, and chronic use has been associated with tubular injury in animal models15 and arterial disease in humans.16 The pathophysiologic effects of cocaine on the kidney include changes in the renal hemodynamics and glomerular matrix, and induction of renal atherogenesis.10,17 Clinically, chronic cocaine use has been reported to be associated with a spectrum of kidney disorders ranging from mild renal impairment18 to end-stage kidney disease (ESKD).19,20 Although these studies show significant associations between illicit drug use and kidney disease, they were typically small and focused on specific patient populations, such as African-Americans, hypertensive men, or those with ESKD. In addition, there are small studies with conflicting findings that show no association with kidney disease21 or progression of kidney disease.22 Epidemiologic studies evaluating the relationship between illicit drug use and chronic kidney disease (CKD) in large diverse populations are lacking. The current study presents findings regarding the relationship among illicit drug use, hypertension, and CKD in a nationally representative sample of US adults. SUBJECTS AND METHODS Study cohort and design. The NHANES is a crosssectional, multistage, stratified, clustered probability sample survey of the US civilian, noninstitutionalized population, conducted by the National Center for Health Statistics. Self-reported NHANES data include demographic, socioeconomic, dietary, and healthrelated items. After informed consent, all participants undergo an in-home interview followed by extensive physical examination, and laboratory studies are performed at a Mobile Examination Center (MEC).23 We conducted a cross-sectional analysis of data from NHANES 2005–2008. The 2005–2006 survey asked all individuals aged 20 to 59 years about drug use, and the 2007–2008 survey included all individuals aged 20 to 69 years. For consistency between the 2 sets, we just used the individuals aged 20 to 59 years. We also included only those participants with complete illicit drug use questionnaire data. Therefore, the final analytic cohort consisted of 6947 individuals aged 20 to 59 years. Variables. Our primary predictor was any illicit drug use, which included methamphetamine, heroin, and cocaine. A questionnaire on illicit drug use was administered at the MEC. Eligible participants were asked: ‘‘Have you ever used cocaine, crack cocaine, heroin, or methamphetamines?’’ If they responded yes, they were asked specifically about cocaine, heroin, and methamphetamines. Among participants who admitted to cocaine and methamphetamine use, data were collected

Translational Research Volume 160, Number 6

regarding total lifetime use. The primary outcome of interest was CKD as defined by the CKD Epidemiology Collaboration equation24 for estimated glomerular filtration rate (eGFR) #60 mL/min/1.73 m2 or by the presence of microalbuminuria defined as .17 mg/g creatinine for men and 25 mg/g creatinine for women25 from a single urine sample. Values of eGFR that exceeded 200 mL/min/1.73 m2 were truncated at that level. The secondary outcomes of interest were blood pressures (BPs) $120/80, $130/85, and $140/90 mm Hg or the use of antihypertensive medications. Sociodemographic characteristics were self-reported and included age, gender, race/ethnicity (non-Hispanic white, non-Hispanic black, Mexican American, other), educational attainment (less than high school education, high school education or more), annual family income (,$20,000, $$20,000), smoking status (current smoker, nonsmoker), and alcohol use (0–2 drinks/day, .2 drinks/day). Medications for hypertension (ie, angiotensin-converting enzyme inhibitors and angiotensin receptor II blockers) were recorded from participants who had self-reported hypertension and were noted in the prescription medication questionnaire. Objective measures consisting of clinical measurements and laboratory tests were obtained during the physical examination at the MEC. Measurements included BP readings, height, and weight. A maximum of 4 BP readings were obtained in the survey for each participant, and systolic and diastolic BPs were averaged. Random spot urine samples were collected for albumin and creatinine. Urine albumin was measured by solid-phase fluorescent immunoassay. Urine and serum creatinine were measured using the Jaffe rate reaction. As recommended by the NHANES 2005–2006 analytic guidelines,26 serum creatinine from NHANES 2005–2006 were adjusted for comparison with other survey years using the following equation: standardized serum creatinine 5 20.016 1 0.978 3 NHANES 2005–2006 serum creatinine. Glycohemoglobin was measured by ion-exchange high-performance liquid chromatography.27 Statistical methods. All analyses were performed incorporating the 4-year sampling weights to obtain unbiased estimates from the complex NHANES sampling design using SAS version 9.2 (SAS Institute, Inc, Cary, NC). The standard errors for all estimates were obtained with the Taylor series linearization method as recommended in the NHANES analytic guidelines,26 and 95% confidence intervals (CIs) were calculated. Mean values were reported for normally distributed variables, and median values were reported for those not normally distributed. Chi-square tests and linear regression using SAS Survey Procedures were used to compare categoric and continuous variables,

Akkina et al

393

respectively, and by the presence of illicit drug use (any vs none). Logistic regression was used to estimate odds ratios (ORs) and 95% CIs for CKD, prehypertension, and hypertension after adjusting for age, gender, education, race (Hispanic, Black, or other vs white), family income, currently smoking, alcohol use (.2 drinks/day), marital status, and body mass index (BMI) for all analyses, whereas the CKD analysis also included glycosylated hemoglobin and anti-hypertensive medication use based on the prior literature.18,28 In previous studies using NHANES III, frequent use of illicit drugs was defined as more than 10 times during a lifetime.3,29 In the NHANES 2005– 2008 dataset, lifetime use was recorded as one of the following: once, 2 to 5, 6 to 19, 20 to 49, 50 to 99, and 1001 times. As a result, the definition of frequent use in NHANES III could not be used with the NHANES 2005–2008 dataset. For the newer dataset, we used $6 times to define a frequent user. Furthermore, heavy use of illicit drugs was associated with more chronic medical conditions compared with the general population.30 Consequently, the distribution of total cocaine or methamphetamine use was divided into infrequent, intermediate, and heavy users as defined by 1 to 5, 6 to 49, and 501 times in a lifetime. Estimates from our study are nationally representative of the noninstitutionalized US population of adults aged 20 to 59 years. For all hypotheses testing, a P value ,.05 was considered statistically significant. RESULTS

The continuous NHANES 2005–2008 included 20,497 participants (Fig 1). From these surveys, 6947 adults aged 20 to 59 years were asked about illicit drug use. Of these, 1086 were excluded for the following reasons; 779 (11%) did not complete the drug use questionnaire, and 307 (4.4%) were missing a serum creatinine or urine albumin/creatinine ratio. The final analytic cohort consisted of 5861 participants, including 1202 (22%) with some type of illicit drug use excluding marijuana and 4659 (78%) without any illicit drug use. Sociodemographic characteristics and illicit drug use. Study participants who admitted to illicit drug

use (vs those who did not) were of similar age (39.7 vs 39.6 years, P 5 0.7) but more often were male (61% vs 46%, P , 0.0001), had a lower BMI (27.7 vs 28.9, P 5 0.0003), and were of white ethnicity (76% vs 68%, P 5 0.0007) (Table I). Illicit drug users were more likely to have not completed high school (18% vs 15%, P 5 0.02), to have a family income ,$20,000 (18% vs 15%, P 5 0.04), and to be single (38% vs 32%, P 5 0.0009). Illicit drug users were also more likely to be current smokers (46% vs 21%,

394

Translational Research December 2012

Akkina et al

NHANES 2005-2008 Participants n = 20,497 No Medical Examination n = 785 Age <20 or 60 years o ld n = 12,766

Did not answer Drug Use Questionnaire n = 779 Missing serum creatinine or urine albumin/creatinine ratio n = 307 Used Cocaine, Heroin, or Methamphetamine n = 1,202 CKD n = 143

No CKD n = 1,059

No Cocaine, Heroin, or Methamphetamine n = 4,659 CKD n = 584

No CKD n = 4,075

Fig 1. Selection of study participants from the NHANES 2005–2008 dataset. CKD, chronic kidney disease; NHANES, National Health and Nutrition Examination Survey.

P , 0.0001) and to have more than 2 drinks/day (48% vs 28%, P , 0.0001). Of the 1202 participants reporting illicit drug use, 1155 (96%) admitted to cocaine use, 446 (37%) admitted to methamphetamine use, and 142 (12%) admitted to heroin use. Illicit drug use and CKD. There was no significant difference in mean eGFR (100.7 vs 101.4 mL/min/1.73 m2, P 5 0.4) or albuminuria (median 5.7 vs 6.0 mg/g creatinine, P 5 0.5) between illicit drug users and nonillicit drug users (Table II). The distribution of participants by CKD stage and level of albuminuria was also similar between illicit drug users and nonusers (Table III). There was a higher proportion of individuals with BP $130/85 mm Hg in the illicit drug user group (25.0% vs 21.1%, P 5 0.02). In unadjusted analyses, we did not find a significant association between illicit drug use and CKD (OR, 0.90; 95% CI, 0.71–1.15), as defined by an eGFR #60 mL/min/1.73 m2 or by microalbuminuria (Table IV). In an adjusted model for sociodemographic factors and comorbidities, no significant relationship between illicit drug use and CKD was observed (OR, 0.98; 95% CI, 0.75–1.27). Likewise, unadjusted and adjusted analyses of specific types of illicit drugs (e.g., cocaine, methamphetamines, and heroin) showed no association with CKD (Table IV). When we examined the relationship between CKD and the number of times an illicit drug was used during a lifetime, unadjusted analysis of cocaine use 5 times or less was associated with a lower prevalence of CKD (OR, 0.59; 95% CI, 0.38–0.90). However, the adjusted analysis

showed no significant relationship for cocaine use 5 times or less in a lifetime (OR, 0.68; 95% CI, 0.43– 1.07) or any other illicit drug use with CKD compared with no illicit drug use. We compared the characteristics of the group who had and did not have complete data regarding drug use and laboratory data. The group missing data were more likely to be non-white, to be single, to be less educated, to have less income, and to have more than 2 drinks per day. Illicit drug use and blood pressure. In our cohort, mean systolic BP was significantly higher for illicit drug users compared with nondrug users (119.6 vs 118.2 mm Hg, P 5 0.04) (Table II). Mean diastolic BP was also higher for illicit drug users compared with nonusers (72.6 vs 71.3 mm Hg, P 5 0.0003). The prevalence of prehypertension and hypertension was similar between illicit drug users and nonusers (Table III). However, the prevalence of an intermediate BP $130/ 85 mm Hg was significantly higher in illicit drug users than in nonusers (25.0% vs 21.1%, P 5 0.02). The higher prevalence was associated with cocaine use (OR, 1.24; 95% CI, 1.00–1.54, P , 0.05), especially those with a lifetime use of 6 to 49 times (OR, 1.42; 95% CI, 1.05–1.91) (Table V). Methamphetamine use was associated with prehypertension and BP $130/85 mm Hg in the unadjusted models, but these were no longer significant after adjustment for common risk factors available in the NHANES. Heroin showed no association with prehypertension and hypertension. DISCUSSION

In this study of a large representative sample of the US adult population, we did not find an association between illicit drug use and kidney function, albuminuria, or presence of CKD. This observation was consistent across all types of illicit drugs, including cocaine, methamphetamine, and heroin. However, systolic and diastolic BPs were significantly higher among illicit drug users, and the use of cocaine, especially among those with significant use during their lifetime, was independently associated with BP $130/85 mm Hg. Although an association between drug use and CKD is suggested in literature reviews,9,18,19 evidence supporting this limited and inconsistent. Vupputuri et al18 conducted a prospective cohort study of 647 patients and found that cocaine users had an increased risk for mild kidney function decline as defined by an increase in serum creatinine of $0.6 mg/dL. However, heroin or amphetamine use was not associated with a significantly increased risk of CKD. A case-control study of 716 patients with ESKD by Perneger et al19 demonstrated an increased risk of ESKD with the use

Translational Research Volume 160, Number 6

Akkina et al

395

Table I. Demographics and drug use history No drug use

Drug use

Characteristic

N

Weighted mean or % (95% CI)

n

Weighted mean or % (95% CI)

P value

Age (y) Male BMI (kg/m2) Ethnicity White Black Hispanic Other race, including multiracial Less than high school education Total family income ,$20,000 Single Current smoker .2 alcoholic drinks/d Drug use Cocaine

4659 2063 4634

39.6 (39.0–40.1) 46.3 (44.9–47.8) 28.9 (28.4–29.3)

1202 745 1196

39.7 (38.9–40.6) 60.5 (57.1–63.9) 27.7 (27.2–28.3)

0.7 ,0.0001 0.0003 0.0007

2022 1028 1410 199 1125 943 1624 1010 1329

67.9 (62.6–73.2) 12.1 (8.9–15.3) 14.4 (11.3–17.4) 5.6 (4.3–7.0) 15.4 (12.9–17.9) 14.6 (12.6–16.7) 32.0 (29.0–35.0) 21.3 (18.3–24.2) 27.7 (25.2–30.1)

666 186 309 41 311 294 489 570 601

76.1 (72.5–79.6) 7.5 (5.6–9.5) 11.9 (9.5–14.4) 4.5 (2.6–6.4) 18.3 (15.3–21.4) 17.5 (14.5–20.4) 38.2 (34.7–41.8) 46.0 (42.4–49.7) 47.8 (43.6–52.1)

-

1155

96.8 (95.3–98.4)

Methamphetamine

-

446

39.5 (33.2–45.8)

Heroin*

-

142

10.7 (8.7–12.7)

0.02 0.04 0.0009 ,0.0001 ,0.0001

Abbreviations: BMI, body mass index; CI, confidence interval. *NHANES did not report the total number of times heroin was used in a lifetime.

Table II. Clinical parameters related to chronic kidney disease by illicit drug use No drug use

Drug use Mean (95% CI)

Median (IQR)

P value

Parameter

n

Mean (95% CI)

Median (IQR)

N

CKD-EPI eGFR (mL/ min/1.73 m2) Albumin/creatinine (spot urine, mg/g) Systolic BP (mm Hg)* Diastolic BP (mm Hg)*

4659

101.4 (100.1–102.6)

-

1202

100.7 (99.0–102.3)

-

0.4

4859

-

6.0 (4.0–10.4)

1240

-

5.7 (3.9–9.0)

0.5

4565 4556

118.2 (117.5–118.9) 71.3 (70.8–71.8)

-

1181 1181

119.6 (118.4–120.8) 72.6 (71.9–73.3)

-

0.04 0.0003

Abbreviations: BP, blood pressure; CI, confidence interval; CKD-EPI eGFR, Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate; IQR, interquartile range. *Average BP reading (maximum 4 readings).

of heroin/opiates but failed to find an independent association with cocaine. An observational study of .300 hospitalized cocaine users at a large urban medical center did not find a significant association with microalbuminuria.21 Likewise, a large study of 145 asymptomatic heroin addicts who were admitted to a methadone detoxification program reported only 3 individuals with protein excretion .150 mg/day and only 1 individual with abnormal creatinine clearance.31 Our results are consistent with preliminary findings recently presented from the Chronic Renal Insufficiency Cohort Study. Bazzano et al22 examined CKD progression between illicit drug users and nonusers in these cohort. Of approximately 4000 study participants, more than 400 admitted to cocaine use over their life-

time, 146 admitted to methamphetamine use, and 58 admitted to heroin use. Illicit drug use including cocaine, methamphetamine, and heroin was not independently associated with CKD progression as defined by a 50% reduction in eGFR from baseline or development of ESKD after adjusting for demographic and clinical factors. Our analysis did find an association between cocaine use and BP $130/85 mm Hg but no significant association with any elevated BP for methamphetamine or heroin use. We examined 2 levels of prehypertension because of the increased incidence of hypertension32 and cardiovascular events33,34 in those with BP $130/ 85 mm Hg compared with individuals with BP between 120/80 and 129/84 mm Hg. The elevated BP

396

Translational Research December 2012

Akkina et al

Table III. Distribution of chronic kidney disease and blood pressure by illicit drug use No drug use

CKD (K/DOQI staging) None Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Microalbuminuria Macroalbuminuria Prehypertension $120/80 $130/85 Hypertension ($140/ 90)

Drug use P value

n

Weighted % (95% CI)

n

Weighted % (95% CI)

4075 423 107 45 4 5 491 58

88.8 (87.8–89.9) 7.4 (6.7–8.1) 2.3 (1.7–2.8) 1.3 (0.8–1.9) 0.05 (0.0–0.1) 0.06 (0.0–0.13) 9.3 (8.4–10.1) 1.0 (0.6–1.4)

1059 103 22 15 2 1 113 20

89.8 (87.4–92.3) 7.3 (5.0–9.5) 1.5 (0.7–2.3) 1.3 (0.4–2.1) 0.06 (0.0–0.15) 0.03 (0.0–0.10) 8.2 (6.2–10.1) 1.3 (0.5–2.1)

0.3 0.5

2029 975 679

45.0 (42.6–47.3) 21.1 (19.6–22.5) 14.6 (13.1–16.1)

581 301 186

48.3 (44.6–52.0) 25.0 (21.6–28.3) 15.5 (13.2–17.7)

0.1 0.02 0.5

0.7

Abbreviations: CI, confidence interval; CKD, chronic kidney disease; K/DOQI, Kidney Disease Outcomes Quality Initiative.

Table IV. Association between illicit drug use and chronic kidney disease

Any illicit drug use Cocaine (any vs none) 1–5 times vs none 6–49 times vs none 501 times vs none Methamphetamine (any vs none) 1–5 times vs none 6–49 times vs none 501 times vs none Heroin†

Unadjusted

Adjusted*

0.90 (0.71–1.15) 0.90 (0.71–1.15) 0.59 (0.38–0.90) 1.10 (0.77–1.56) 0.92 (0.60–1.43) 0.87 (0.60–1.26)

0.98 (0.75–1.27) 0.83 (0.47–1.45) 0.68 (0.43–1.07) 1.21 (0.83–1.78) 0.98 (0.62–1.55) 0.98 (0.66–1.46)

0.70 (0.35–1.40) 0.86 (0.50–1.46) 1.05 (0.53–2.09) 0.63 (0.33–1.22)

0.79 (0.38–1.61) 1.01 (0.58–1.75) 1.13 (0.05–2.32) 0.74 (0.36–1.49)

Bold values indicate P , 0.05. *Adjusted for age, gender, education, race (Hispanic, Black, or other vs white), family income, currently smoking, alcohol use (.2 drinks/day), marital status, BMI, glycosylated hemoglobin, and BP medication use. † NHANES did not report the total number of times heroin was used.

among cocaine users persisted after adjustment of BMI, which was lower in illicit drug users than nonusers. The inverse relationship between BMI and illicit drug use has been observed in multiple studies with possible explanations including malnutrition and a neural reward pathway where drugs can be substituted for food.35-37 BP $130/85 mm Hg was associated with an approximately 2-fold increase in the risk of CKD compared with individuals with optimal BP in 2 large, prospective epidemiologic studies.38,39 Several studies have shown no association with chronic hypertension and chronic cocaine use.21,40 However, several studies show organ damage, including left ventricular hypertrophy41 and re-

nal arteriosclerosis,16,42 associated with elevated BP and thought to be from the repeated vasoconstriction induced by cocaine.43 Despite the lack of association with prevalent CKD in our study, the increased risk of having BP $130/85 mm Hg observed among cocaine users may, over the long-term, contribute to the development of CKD and other cardiovascular events if left untreated. Longitudinal analyses are needed to further understand this potential relationship. To our knowledge, this is the largest study examining the association between illicit drug use and CKD in the general population. An advantage of using the continuous NHANES is the consistency and design that allows for multiple datasets to be combined to examine relatively uncommon medical conditions, such as illicit drug use and CKD. The use of a nationally representative sample also minimizes bias that may be seen in studies focusing only on subjects with CKD. However, our study is not without its own limitations. The design was cross-sectional, and therefore a temporal relationship between cocaine use and BP $130/85 mm Hg cannot be inferred. Likewise, the use of a single urine albumin measurement to define CKD is problematic because of the variability in excretion leading to the general consensus that multiple abnormal readings are needed to confirm microalbuminuria. Also, although the study population is relatively large and represents the general population, the number of individuals with CKD and hypertension was relatively small, which may introduce a type 2 error. Furthermore, we can not entirely rule out misclassification bias due to underreporting of illicit drug use because of its legal and social implications44,45; however, most studies examining the health impact of substance abuse rely

Translational Research Volume 160, Number 6

Akkina et al

397

Table V. Association between illicit drug use and hypertension Pre-hypertension BP $ 120/80 mm Hg

Any illicit drug use Cocaine (any vs none) 1–5 times vs none 6–49 times vs none 501 times vs none Methamphetamine (any vs none) 1–5 times vs none 6–49 times vs none 501 times vs none Heroin†

Hypertension BP $ 130/85 mm Hg

BP $ 140/90 mm Hg

Unadjusted

Adjusted*

Unadjusted

Adjusted*

Unadjusted

Adjusted*

1.14 (0.98–1.32) 1.14 (0.98–1.33) 0.93 (0.72–1.19) 1.24 (0.99–1.56) 1.32 (1.00–1.74) 1.33 (1.06–1.67)

1.02 (0.86–1.20) 1.07 (0.90–1.27) 0.99 (0.76–1.30) 1.32 (0.85–1.41) 1.18 (0.85–1.63) 1.12 (0.87–1.45)

1.27 (1.06–1.53) 1.27 (1.05–1.52) 0.89 (0.64–1.23) 1.48 (1.14–1.92) 1.49 (1.07–2.07) 1.44 (1.10–1.88)

1.23 (1.00–1.52) 1.24 (1.00–1.54) 0.98 (0.69–1.40) 1.42 (1.06–1.91) 1.34 (0.91–1.97) 1.33 (0.97–1.82)

1.07 (0.87–1.32) 1.06 (0.85–1.31) 1.03 (0.72–1.47) 0.87 (0.63–1.21) 1.44 (1.00–2.08) 1.14 (0.82–1.56)

1.19 (0.92–1.54) 1.20 (0.92–1.55) 1.30 (0.87–1.94) 0.98 (0.66–1.46) 1.41 (0.91–2.19) 1.26 (0.85–1.87)

1.33 (0.89–1.99) 1.38 (0.99–1.93) 1.26 (0.83–1.93) 0.90 (0.60–1.33)

1.06 (0.69–1.63) 1.11 (0.78–1.59) 1.22 (0.74–1.99) 0.84 (0.55–1.28)

1.10 (0.65–1.86) 1.53 (1.04–2.26) 1.67 (1.04–2.69) 0.92 (0.56–1.50)

1.01 (0.56–1.83) 1.40 (0.91–2.16) 1.59 (0.89–2.83) 0.89 (0.52–1.52)

1.17 (0.64–2.12) 1.23 (0.78–1.91) 0.93 (0.49–1.78) 0.92 (0.52–1.60)

1.23 (0.64–2.35) 1.48 (0.85–2.56) 0.99 (0.45–2.17) 1.30 (0.71–2.41)

Abbreviation: BP, blood pressure. Bold values indicate P , 0.05. *Adjusted for age, gender, education, race (Hispanic, Black, or other vs white), family income, currently smoking, alcohol use (.2 drinks/day), marital status, and BMI. † NHANES did not report the total number of times heroin was used.

on self-report. Moreover, our study sample does not include homeless and institutionalized people, a significant proportion of whom may use illicit drugs, because they are not included in the NHANES. CONCLUSIONS

In a large representative sample of the US adult population, we did not find a significant association between illicit drug use and CKD, but we did find an association between cocaine use and BP $130/85 mm Hg. Although our results do not support the general perception of an association between illicit drug use and CKD,46 our findings cannot exclude the possibility that illicit drug use may lead to CKD by untreated elevated BP or episodic acute kidney injury. Patients should be counseled to avoid illicit drug use for the benefit of their overall health, including the risk of elevated BP.

REFERENCES

1. Substance Abuse and Mental Health Services Administration. Results from the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings (Office of Applied Studies, NSDUH Series H-38A, HHS Publication No. SMA 10-4586 Findings). Rockville, MD; 2010. Available at: http://oas.samhsa.gov/ nsduhlatest.htm. Accessed May 31, 2012. 2. McCord J, Jneid H, Hollander JE, et al. Management of cocaineassociated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation 2008;117:1897–907. 3. Aslibekyan S, Levitan EB, Mittleman MA. Prevalent cocaine use and myocardial infarction. Am J Cardiol 2008;102:966–9.

4. Ginsberg MD, Hertzman M, Schmidt-Nowara WW. Amphetamine intoxication with coagulopathy, hyperthermia, and reversible renal failure. A syndrome resembling heatstroke. Ann Intern Med 1970;73:81–5. 5. Kendrick WC, Hull AR, Knochel JP. Rhabdomyolysis and shock after intravenous amphetamine administration. Ann Intern Med 1977;86:381–7. 6. Henry JA, Jeffreys KJ, Dawling S. Toxicity and deaths from 3,4methylenedioxymethamphetamine (‘‘ecstasy’’). Lancet 1992; 340:384–7. 7. Fahal IH, Sallomi DF, Yaqoob M, Bell GM. Acute renal failure after ecstasy. BMJ 1992;305:29. 8. do Sameiro Faria M, Sampaio S, Faria V, Carvalho E. Nephropathy associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003;18:2308–13. 9. Rao TK, Nicastri AD, Friedman EA. Natural history of heroinassociated nephropathy. N Engl J Med 1974;290:19–23. 10. Jaffe JA, Kimmel PL. Chronic nephropathies of cocaine and heroin abuse: a critical review. Clin J Am Soc Nephrol 2006;1: 655–67. 11. Roth D, Alarcon FJ, Fernandez JA, Preston RA, Bourgoignie JJ. Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 1988;319:673–7. 12. Herzlich BC, Arsura EL, Pagala M, Grob D. Rhabdomyolysis related to cocaine abuse. Ann Intern Med 1988;109:335–6. 13. Sharff JA. Renal infarction associated with intravenous cocaine use. Ann Emerg Med 1984;13:1145–7. 14. Thakur V, Godley C, Weed S, Cook ME, Hoffman E. Case reports: cocaine-associated accelerated hypertension and renal failure. Am J Med Sci 1996;312:295–8. 15. Barroso-Moguel R, Mendez-Armenta M, Villeda-Hernandez J. Experimental nephropathy by chronic administration of cocaine in rats. Toxicology 1995;98:41–6. 16. Di Paolo N, Fineschi V, Di Paolo M, et al. Kidney vascular damage and cocaine. Clin Nephrol 1997;47:298–303. 17. Nzerue CM, Hewan-Lowe K, Riley LJ Jr. Cocaine and the kidney: a synthesis of pathophysiologic and clinical perspectives. Am J Kidney Dis 2000;35:783–95.

398

Akkina et al

18. Vupputuri S, Batuman V, Muntner P, et al. The risk for mild kidney function decline associated with illicit drug use among hypertensive men. Am J Kidney Dis 2004;43:629–35. 19. Perneger TV, Klag MJ, Whelton PK. Recreational drug use: a neglected risk factor for end-stage renal disease. Am J Kidney Dis 2001;38:49–56. 20. Norris KC, Thornhill-Joynes M, Robinson C, et al. Cocaine use, hypertension, and end-stage renal disease. Am J Kidney Dis 2001;38:523–8. 21. Brecklin CS, Gopaniuk-Folga A, Kravetz T, et al. Prevalence of hypertension in chronic cocaine users. Am J Hypertens 1998; 11(11 Pt 1):1279–83. 22. Bazzano L, Balaram M, Cohan J, et al. Alcohol, tobacco and illicit drug use and progression of chronic kidney disease (CKD) [ASN Abstract: SA-PO2419]. J Am Soc Nephrol 2010;21:666A. 23. Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention [May 27, 2011]. Available at: http://www.cdc.gov/nchs/ nhanes/nhanes_questionnaires.htm; 2005. Accessed May 31, 2012. 24. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–12. 25. Warram JH, Gearin G, Laffel L, Krolewski AS. Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. J Am Soc Nephrol 1996;7:930–7. 26. Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). The National Health and Nutrition Examination Survey (NHANES) Analytic and Reporting Guidelines. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention [May 27, 2011]; Available at: http://www.cdc.gov/nchs/data/nhanes/ nhanes_03_04/nhanes_analytic_guidelines_dec_2005.pdf; 2005. Accessed May 31, 2012. 27. Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Laboratory Protocol. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention [updated May 27, 2011]. Available at: http://www.cdc.gov/nchs/nhanes/nhanes2005-2006/lab05_06.htm; 2005. Accessed May 31, 2012. 28. Munkhaugen J, Lydersen S, Wideroe TE, Hallan S. Prehypertension, obesity, and risk of kidney disease: 20-year follow-up of the HUNT I study in Norway. Am J Kidney Dis 2009;54:638–46. 29. Qureshi AI, Suri MF, Guterman LR, Hopkins LN. Cocaine use and the likelihood of nonfatal myocardial infarction and stroke: data from the Third National Health and Nutrition Examination Survey. Circulation 2001;103:502–6. 30. Fareed A, Musselman D, Byrd-Sellers J, et al. On-site basic health screening and brief health counseling of chronic medical conditions for veterans in methadone maintenance treatment. J Addict Med 2010;4:160–6.

Translational Research December 2012

31. Arruda JA, Kurtzman NA, Pillay VK. Prevalence of renal disease in asymptomatic heroin addicts. Arch Intern Med 1975;135: 535–7. 32. Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001;358:1682–6. 33. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291–7. 34. Lee M, Saver JL, Chang B, Chang KH, Hao Q, Ovbiagele B. Presence of baseline prehypertension and risk of incident stroke: a meta-analysis. Neurology 2011;77:1330–7. 35. Nazrul Islam SK, Jahangir Hossain K, Ahmed A, Ahsan M. Nutritional status of drug addicts undergoing detoxification: prevalence of malnutrition and influence of illicit drugs and lifestyle. Br J Nutr 2002;88:507–13. 36. Quach LA, Wanke CA, Schmid CH, et al. Drug use and other risk factors related to lower body mass index among HIV-infected individuals. Drug Alcohol Depend 2008;95:30–6. 37. Bluml V, Kapusta N, Vyssoki B, Kogoj D, Walter H, Lesch OM. Relationship between substance use and body mass index in young males. Am J Addict 2012;21:72–7. 38. Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med 2005; 165:923–8. 39. Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334: 13–8. 40. Braun BL, Murray DM, Sidney S. Lifetime cocaine use and cardiovascular characteristics among young adults: the CARDIA study. Am J Public Health 1997;87:629–34. 41. Brickner ME, Willard JE, Eichhorn EJ, Black J, Grayburn PA. Left ventricular hypertrophy associated with chronic cocaine abuse. Circulation 1991;84:1130–5. 42. Fogo A, Superdock KR, Atkinson JB. Severe arteriosclerosis in the kidney of a cocaine addict. Am J Kidney Dis 1992;20: 513–5. 43. Brecklin CS, Bauman JL. Cardiovascular effects of cocaine: focus on hypertension. J Clin Hypertens (Greenwich) 1999;1: 212–7. 44. Hser YI, Maglione M, Boyle K. Validity of self-report of drug use among STD patients, ER patients, and arrestees. Am J Drug Alcohol Abuse 1999;25:81–91. 45. Fendrich M, Johnson TP, Sudman S, Wislar JS, Spiehler V. Validity of drug use reporting in a high-risk community sample: a comparison of cocaine and heroin survey reports with hair tests. Am J Epidemiol 1999;149:955–62. 46. Drug Abuse and Your Kidneys. New York, NY: National Kidney Foundation [updated June 29, 2011; cited June 29, 2011]. Available at: http://www.kidney.org/atoz/content/drugabuse.cfm. Accessed May 31, 2012.