chronic kidney disease in community-dwelling men

Kidney International, Vol. 67 (2005), pp. 2376 2382 The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men ANDREW D. RULE,DEBRA J. JACOBSON,ROSEBUD O. ROBERTS, CYNTHIA J. GIRMAN, MICHAELA E. MCGREE,MICHAEL M. LIEBER, and STEVEN J. JACOBSEN Division of Nephrology, Department of Internal Medicine; Division of Epidemiology, Department of Health Science Research; Division of Biostatistics; Department of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota; and Merck Research Laboratories, Blue Bell, Pennsylvania The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men. Background. Benign prostatic hyperplasia (BPH) and chronic kidney disease are important public health problems in older men. Previous referral-based studies disagree on whether BPH is associated with chronic kidney disease. The objective of this study was to determine the community-based association between clinical measures of BPH and chronic kidney disease. Methods. A community-based sample of 2115 white men (ages 40 79 years) was randomly selected from the Olmsted County, Minnesota population (55% participation rate) in 1990. A random subsample (N = 476) had a detailed clinical evaluation. This evaluation included a questionnaire with similar queries to the International Prostate Symptom Score (IPSS), peak urinary flow rates (uroflowmeter), postvoid residual urine volume (ultrasound), prostate volume (ultrasound), serum prostate specific antigen (PSA), and serum creatinine. Results. After adjustment for age, hypertension, diabetes, leukocyte esterase positive (possible urinary tract infection), and smoking, chronic kidney disease [serum creatinine 133 lmol/l (1.5 mg/dl)] was associated with diminished peak urinary flow rate (<15 ml/sec) by an odds ratio (OR) = 2.96 (95% CI 1.30 7.01), moderate-severe lower urinary tract symptoms (IPSS >7) by an OR = 2.91 (95% CI 1.32 6.62), and chronic urinary retention (postvoid residual >100 ml) by an OR = 2.28 (95% CI 0.66 6.68). There was no association with a prostate volume >30 ml by an OR = 0.56 (95% CI 0.22 1.37) or PSA >1.4 ng/ml by an OR = 1.17 (95% CI 0.47 2.81). Conclusion. There was a cross-sectional association between signs and symptoms of bladder outlet obstruction and chronic kidney disease in community-dwelling men. Prostatic enlargement was not associated with chronic kidney disease. Keywords: bladder neck obstruction, chronic kidney failure, creatinine, prostatic hyperplasia. Received for publication September 22, 2004 and in revised form November 30, 2004 Accepted for publication January 20, 2005 C 2005 by the International Society of Nephrology Chronic kidney disease is an important public health problem, especially in older men. Approximately 11% of adults have chronic kidney disease according to data from the third National Health and Nutrition Examination Survey (NHANES III) [1]. Men have 67% more incident advanced chronic kidney disease than women after adjusting for age, cigarette smoking, and diabetes [2]. Identified risk factors for chronic kidney disease include diabetes, hypertension, smoking, obesity, dyslipidemia, and metabolic syndrome [3, 4]. Adverse outcomes of chronic kidney disease include end-stage renal disease, cardiovascular disease, and premature death. The best way to prevent these adverse outcomes may be to identify and treat chronic kidney disease risk factors [5]. One possible risk factor for chronic kidney disease may be benign prostatic hyperplasia (BPH) [6 8]. BPH has been described as a common clinical syndrome in older men characterized by bladder outlet obstruction, lower urinary tract symptoms, and benign prostatic enlargement [9]. One quarter of men, ages 50 to 79 years, have a bladder outlet obstruction and lower urinary tract symptoms according to the Olmsted County Study of Urinary Symptoms and Health Status among Men (OCS) [10]. Technically, the diagnosis of BPH is based on histology, but performing a biopsy is impractical. Instead, the clinical syndrome, coupled with bother from symptoms, has been used primarily in making BPH treatment decisions [11]. Clinical practice guidelines disagree on serum creatinine screening among men being evaluated for lower urinary tract symptoms [11, 12]. The low prevalence of chronic kidney disease in BPH clinical trials has been a reason for recommending against serum creatinine screening [11]. However, BPH clinical trials excluded men without lower urinary tract symptoms, and were not representative of the general community. Therefore, the objective of this study was to examine the association between the clinical syndrome of BPH and risk of chronic kidney disease in community-dwelling men. 2376

Rule et al: BPH and kidney disease 2377 METHODS Many of the details of this study have been published previously [13]. Under institutional review board approval, a sampling frame of white men aged 40 to 79 years on January 1, 1990 in Olmsted County, Minnesota was constructed using the resources of the Rochester Epidemiology Project [14]. A random sample of 5135 white men were selected within age- (5 year groups) and residence- (Rochester vs. balance of Olmsted County) specific strata, and then evaluated for eligibility. Community medical records were screened to exclude men with prostate surgery, prostate cancer, bladder cancer, urethral stricture, neurogenic bladder, diabetes with documented end-organ damage, or other neurologic diseases that could affect normal urinary function other than BPH. After these exclusions, 3874 men were invited to join the study, 2115 (55%) of whom participated. Participants tended to be older or have a clinical history of BPH compared to nonparticipants [15]. These subjects completed a questionnaire regarding lower urinary tract symptom severity that was similar to the International Prostate Symptom Score (IPSS) [16]. This questionnaire also included medical history queries for diabetes, high blood pressure, and do you smoke cigarettes now. All participants had their peak urinary flow rate measured by means of a portable uroflow meter (Dantec Medical, Santa Clara, CA, USA). Of the 2115 participants, 537 (25%) were randomly selected for a detailed clinical exam, 476 (89%) of whom participated. Clinical exams performed between June 1990 and July 1991 included height, weight, serum creatinine levels, serum prostate specific antigen (PSA) levels, urine dipstick, uroflowmeter for peak flow rates, transrectal sonographic imaging for prostate volume, and transabdominal sonographic imaging for postvoid residual urine volume. The prostate volume and postvoid residual were estimated from the anteroposterior, transverse, and superoinferior diameters, using the formula for an ellipsoid, p /6 (transverse anteroposterior superoinferior) [17]. A standard urine dipstick measured proteinuria and leukocyte esterase. Trace or higher leukocyte esterase identified men with a possible urinary tract infection, a potential confounder between BPH measures and chronic kidney disease. This present study was limited to the clinical exam participants. BPH measures were divided between three obstruction measures (peak flow rates, postvoid residual, IPSS) and two prostatic enlargement measures (prostate volume, PSA). Elevated PSA in men without prostate cancer is a strong predictor of prostatic enlargement [18]. IPSS measures are both bladder outlet obstruction related (obstructive symptoms) [19] and detrusor instability related (irritative symptoms). Thus, individual analyses were done for each of the obstructive and irritative symptom queries of the questionnaire. BPH measures were also dichotomized between normal and abnormal according to standard cut points. Peak flow rate was dichotomized as 15 ml/sec versus <15 ml/sec, IPSS as 0 to 7 (nonemild) versus >7 (moderate-severe), residual urine volume as 100 ml versus >100 ml, prostate volume as 30 ml versus >30 ml, and PSA 1.4 ng/ml versus >1.4 ng/ml. Two or more obstruction-related measures (peak flow rate <15 ml/sec, IPSS >7, residual urine volume >100 ml) defined a bladder outlet obstruction. A secondary analysis using continuous BPH measures (logtransformed when appropriate) gave similar results, so only dichotomized measures were reported. Serum creatinine was measured by the modified kinetic rate Jaffe reaction method using a Hitachi 736 autoanalyzer (Hitachi, Ltd., Tokyo, Japan). Acutely ill subjects had their clinic exam rescheduled for a later date, such that all serum creatinine levels were likely to represent a stable renal function and not acute renal failure. A serum creatinine level greater than or equal to 133 lmol/l (1.5 mg/dl) was used as the definition of chronic kidney disease for several reasons. First, the 97.5th percentile for healthy men at the study laboratory was 124 lmol/l (1.4 mg/dl). Second, using this definition allowed comparisons between this study and other BPH studies that also used a serum creatinine cutoff. Third, the abbreviated Modification of Diet in Renal Disease (MDRD) equation [20] underestimates GFR in healthy persons, and may not be accurate for assessing GFR in the general population [21]. However, a sensitivity analysis was performed using the abbreviated MDRD equation in the following form: estimated GFR = 186.3 serum creatinine 1 154 age 0 203.For the sensitivity analysis, chronic kidney disease was defined by an estimated GFR <60 ml/ min/1.73m 2 [20]. A secondary analysis was also performed using urine dipstick protein trace or higher to define CKD. The distribution of BPH measures (peak urinary flow rate, IPSS, residual urine volume, prostate volume, and PSA) and comorbidities associated with kidney disease (diabetes mellitus, hypertension, smoking, and leukocyte esterase positive) were determined. Median and quartile values of continuous variables and percentages of dichotomized variables for exposures (BPH measures), covariates (comorbidities), and outcomes (serum creatinine) were calculated by chronic kidney disease status. Comparisons were made using the rank sum or chi-square test as appropriate. Odds ratios for the outcome of chronic kidney disease were calculated using logistic regression models, with each BPH measure as the exposure of interest. Confidence intervals for odds ratios were calculated using the more conservative likelihood ratio method. Age groups of 40 to 49 years (reference age group), 50 to 69 years, and 70 to 79 years were used for age adjustment.

2378 Rule et al: BPH and kidney disease Table 1. Characteristics of study cohort by chronic kidney disease (CKD) status CKD (N = 29) No CKD (N = 447) Rank sum test Median 1st Quartile 3rd Quartile Median 1st Quartile 3rd Quartile P value Characteristics Age years 59 46 73 55 47 63 0.13 Weight kg 83 76 95 86 77 96 0.52 Height cm 178 173 181 178 173 182 0.84 Serum creatinine lmol/l 133 133 141 97 88 115 <0.0001 GFR ml/min/1.73m 2a 49 46 52 71 63 79 <0.0001 Body mass index kg/m 2 27.4 24.6 28.9 27.0 25.0 30.1 0.52 CKD No CKD Chi-square P value BPH measures Slow stream (peak urinary flow <15 ml/sec) 18 (62%) 158 (35%) 0.0040 Lower urinary tract symptoms (IPSS >7) b 17 (59%) 145 (33%) 0.0041 Chronic retention (postvoid residual >100 ml) 5 (17%) 27 (6%) 0.020 Bladder outlet obstruction c 14 (48%) 90 (20%) 0.0004 Enlarged prostate (volume >30 ml) 10 (34%) 170 (38%) 0.68 Enlarged prostate (PSA >1.4 ng/ml) 11 (38%) 131 (29%) 0.33 Comorbidities Diabetes (per questionnaire) 3 (10%) 19 (4%) 0.13 Hypertension (per questionnaire) 12 (41%) 94 (21%) 0.012 Leukocyte esterase positive on dipstick 3 (10%) 18 (4%) 0.11 Current smoker 5 (18%) 57 (13%) 0.45 Combined comorbidity d 19 (66%) 158 (35%) 0.0012 a Estimated glomerular filtration rate using the abbreviated MDRD equation. b IPSS, International Prostate Symptom Score. c At least 2 of 3: peak flow rate <15 ml/sec, IPSS >7, or postvoid residual >100 ml. d Presence of either diabetes, hypertension, leukocyte esterase positive, or current smoker. Adjustment by age as a continuous variable gave similar results and was not reported. A comorbidity risk factor was defined by the presence of any of the following: diabetes, hypertension, leukocyte esterase positive, or smoking. Both age groups and comorbidity risk factors were included in multivariable models. The prevalence of chronic kidney disease was stratified by number of obstruction measures (peak flow rate <15 ml/ sec, IPSS >7, postvoid residual <100 ml) and number of prostatic enlargement measures (prostate volume >30 ml, PSA >1.4 ng/ml). The prevalence of chronic kidney disease by number of obstruction measures and by number of prostatic enlargement measures was assessed with a Mantel-Haenszel chi-square test. For all analyses, a P value less than 0.05 was considered statistically significant. All analyses were conducted using SAS version 8.2 (SAS Institute, Cary, NC, USA). RESULTS Overall, 29 (6%) of the 476 men had chronic kidney disease as defined by a serum creatinine 133 lmol/l (1.5 mg/dl). Table 1 presents the demographics, BPH measures, and comorbidity measures by chronic kidney disease status. Men with chronic kidney disease were more likely to have a slow urinary stream (P <.01), moderate-severe lower urinary tract symptoms (P <.01), and chronic urinary retention (P <.05). There was also an increased prevalence of diabetes mellitus, hypertension, and leukocyte esterase positive dipstick among men with chronic kidney disease. Four men were identified as having prostate cancer, none of which had chronic kidney disease. Exclusion of these men did not change the results. Table 2 shows the unadjusted, age-adjusted, and ageand comorbidity-adjusted odds ratios of chronic kidney disease. Peak urinary flow <15 ml/sec (slow stream) and IPSS >7 (moderate-severe lower urinary tract symptoms) were associated with an increased risk of chronic kidney disease (age- and comorbidity-adjusted, P <.05). Postvoid residual >100 ml (chronic urinary retention) showed an increased risk of chronic kidney disease, but was not statistically significant (age- and comorbidityadjusted, P =.16). Patients with bladder outlet obstruction had an increased risk of chronic kidney disease (age- and comorbidity-adjusted, P <.05). Prostate volume and PSA were not associated with chronic kidney disease. Of the individual comorbidity measures, only hypertension was significantly associated with an increased risk of chronic kidney disease (age-adjusted, P <.05). Diabetes mellitus, leukocyte esterase positive, and smoking all trended toward an increased risk of chronic kidney disease, but were not statistically significant. When all predictors (BPH measures, comorbidities, and age groups) were combined in the same multivariable model, peak urinary flow <15 ml/sec (OR = 2.63, 95% CI 1.08 6.58) remained statistically significant, but IPSS >7 (OR = 2.17, 95% CI 0.94 5.09) and postvoid residual >100 ml (OR = 2.48, 95% CI 0.72 7.33) were only borderline statistically significant.

Rule et al: BPH and kidney disease 2379 Table 2. Association between chronic kidney disease (serum creatinine 133 lmol/l) and benign prostatic hyperplasia (BPH) measures Unadjusted Age and comorbidity Potential risk factor odds ratio (OR) Age-adjusted a OR adjusted b OR BPH measure Peak flow rate <15 ml/sec 2.98 (1.39, 6.67) 2.74 (1.23, 6.35) 2.96 (1.30, 7.01) IPSS c >7 2.94 (1.38, 6.47) 2.82 (1.29, 6.34) 2.91 (1.32, 6.62) Residual urine volume >100 ml 3.23 (1.03, 8.56) 2.30 (0.69, 6.49) 2.28 (0.66, 6.68) Bladder outlet obstruction d 3.69 (1.70, 7.96) 3.40 (1.49, 7.73) 3.57 (1.54, 8.28) Prostate volume >30 ml 0.85 (0.37, 1.82) 0.60 (0.24, 1.45) 0.56 (0.22, 1.37) PSA >1.4 ng/ml 1.47 (0.66, 3.16) 1.09 (0.44, 2.60) 1.17 (0.47, 2.81) Comorbidity measure Hypertension e 2.63 (1.19, 5.66) 2.39 (1.06, 5.24) Diabetes mellitus e 2.59 (0.58, 8.25) 2.13 (0.46, 7.14) Leukocyte esterase positive 2.74 (0.61, 8.76) 2.21 (0.48, 7.44) Current smoker e 1.47 (0.48, 3.73) 1.59 (0.51, 4.13) Any comorbidity risk factor 3.46 (1.60, 7.93) 3.07 (1.40, 7.11) a Age-adjusted using age groups: 40 to 49 (reference age group), 50 to 69, and 70 to 79 years. b Adjusted for age groups and presence of any comorbidity risk factor (diabetes mellitus, hypertension, leukocyte esterase positive, or current smoker). c IPSS, International Prostate Symptom Score. d At least 2 of 3: peak flow rate <15 ml/sec, IPSS >7, or postvoid residual >100 ml. e Hypertension, diabetes mellitus, and smoking status per self-reported questionnaire; diabetics with known end-organ damage were excluded during sampling. Table 3. Association between chronic kidney disease (serum creatinine 133 lmol/l) and obstructive or irritative lower urinary tract symptoms Unadjusted odds ratio Age-adjusted b Age and comorbidity Potential risk factor a (OR) (95% CI) OR (95% CI) adjusted c OR (95% CI) Obstructive symptom score 2.42 (1.11, 5.19) 2.36 (1.06, 5.15) 2.74 (1.22, 6.10) Feeling your bladder was not empty after urinating 1.80 (0.73, 4.06) 1.76 (0.70, 4.03) 1.93 (0.76, 4.49) Stopping or starting again when urinating 1.62 (0.68, 3.57) 1.59 (0.66, 3.59) 1.93 (0.78, 4.48) Straining or pushing during urination 2.52 (0.96, 5.94) 2.50 (0.93, 5.99) 2.74 (1.00, 6.76) Smaller size or weaker force of your urinary stream 2.22 (1.04, 4.78) 2.19 (1.01, 4.79) 2.46 (1.11, 5.49) Irritative symptom score 2.11 (0.99, 4.64) 1.93 (0.90, 4.28) 1.83 (0.84, 4.09) Having to urinate more frequently then every 2 hours during the day 1.45 (0.66, 3.10) 1.34 (0.60, 2.89) 1.29 (0.58, 2.82) Feeling you can t wait to urinate 2.00 (0.94, 4.33) 1.83 (0.85, 4.01) 1.98 (0.91, 4.39) Getting up to urinate during the night 3.00 (1.35, 6.47) 2.54 (1.10, 5.69) 2.29 (0.97, 5.21) a Cut point definitions for risk factors: obstructive symptom score >4, irritative symptom score >3, individual symptom scores >1 [16]. b Adjusted using age groups: 40 to 49 (reference age group), 50 to 69, and 70 to 79 years. c Adjusted for age groups and comorbidity risk factor (diabetes, hypertension, leukocyte esterase positive, or current smoker). Table 3 shows the unadjusted, age-adjusted, and ageand comorbidity-adjusted odds ratio for chronic kidney disease by each IPSS question. The chronic kidney disease risk with obstructive symptoms (age- and comorbidity-adjusted OR = 2.74, P <.05) was slightly stronger than the risk with irritative symptoms (ageand comorbidity-adjusted OR = 1.83, P =.13). In addition, the two individual symptoms that directly describe an obstructive process: straining (age- and comorbidityadjusted OR = 2.74, P =.05) and weak stream (ageand comorbidity-adjusted OR = 2.46, P <.05), trended toward a higher risk of chronic kidney disease than the other individual symptoms. Figure 1 presents the prevalence of chronic kidney disease by number of obstruction measures. There was a significant graded relationship between the number of obstruction measures and the corresponding prevalence of chronic kidney disease (P <.0001, Mantel-Haenszel chi-square). There was no relationship between number of prostatic enlargement measures and the corresponding prevalence of chronic kidney disease (P =.74, Mantel- Haenszel chi-square). The results were similar when chronic kidney disease was defined by an estimated GFR less than 60 ml/min/ 1.73m 2.Bythis definition, 101 men (21%) had chronic kidney disease. The age- and comorbidity-adjusted odds ratio of chronic kidney disease was 2.30 (95% CI 1.44 3.69) for peak flow rate <15 ml/sec, 1.49 (95% CI 0.93 2.38) for IPSS >7, 2.65 (95% CI 1.20 5.72) for residual urine volume >100 ml, 1.01 (95% CI 0.61 1.68) for prostate volume >30 ml, and 1.45 (95% CI 0.87 2.40) for PSA >1.4 ng/ml. The age- and comorbidity-adjusted odds ratio of chronic kidney disease for patients with two or three obstruction measures compared to those with zero or one measures was 2.54 (95% CI 1.52 4.22). There was a significant graded relationship between the number of obstruction measures and the corresponding prevalence of chronic kidney disease (P <.0001, Mantel- Haenszel chi-square). An association between BPH measures and urine dipstick protein (trace or higher) was not apparent. Twenty-seven of 476 men (6%) had proteinuria, only two of which had a serum creatinine 133 lmol/l (1.5 mg/dl). The age- and comorbidity-adjusted odds ratio of

2380 Rule et al: BPH and kidney disease Prevalence, % 30% 25% 20% 15% 10% 5% 0% 3% 6% 12% 25% 0 1 2 3 Number of obstruction related measures Fig. 1. Prevalence of chronic kidney disease (SCr 133 lmol/l) by number of bladder outlet obstruction related measures (P <.0001, Mantel-Haenszel chi-square). Three different obstruction-related measures were used: International Prostate Symptom Score >7, peak urinary flow rate <15 ml/sec, and residual urine volume >100 ml. proteinuria was 1.65 (95% CI 0.72 3.90) for peak flow rate <15 ml/sec, 0.98 (95% CI 0.41 2.21) for IPSS >7, 1.32 (95% CI 0.35 4.98) for residual urine volume >100 ml, 1.02 (95% CI 0.43 2.39) for prostate volume >30 ml, and 0.98 (95% CI 0.40 2.30) for PSA >1.4 ng/ml. DISCUSSION Our study identified a positive and significant crosssectional relationship between bladder outlet obstruction and chronic kidney disease in community-dwelling men, although the absolute risk seemed to be modest. This association was present when chronic kidney disease was identified by an elevated serum creatinine, but not by dipstick proteinuria. An association between prostatic enlargement and chronic kidney disease was not present. These relationships were independent of age or other risk factors associated with kidney disease: diabetes, hypertension, leukocyte esterase positive dipstick (possible urinary tract infection), and smoking. These associations were based on three different measures related to bladder outlet obstruction (all commonly used in clinical trials) and two different measures of the prostatic enlargement. A sensitivity analysis using the MDRD equation to define chronic kidney disease gave similar results. Analyses of individual symptoms as queried in the IPSS provided additional support that bladder outlet obstruction related symptoms are risk factors for chronic kidney disease. Obstructive symptoms were more strongly associated with chronic kidney disease than irritative symptoms. This may be important because predominantly irritative symptoms motivate men to present for prostate surgery [22]. Previous studies have suggested an association between BPH and chronic kidney disease but have had more study design limitations. A community-based study of men age 50 years or older found a 2.4% prevalence of self-reported renal failure related to a prostate condition (9% reported renal failure from any cause) [23]. Most other studies have been referral-based in men presenting to a urologist. Because some of these men may have had acute renal failure from acute urinary retention, inferences about chronic kidney disease were limited. One study found a 7.7% prevalence of renal failure in men presenting for prostate surgery compared to a 3.7% prevalence in age-matched men presenting for nonprostate surgery [24]. Many studies of men with renal failure and bladder outlet obstruction show improvement in renal function in the follow-up after prostate surgery [25 27]. Case reports have also shown dialysis-dependent patients recover renal function up to a year after having prostate surgery [28]. The low occurrence of chronic kidney disease in BPH clinical trials should not be used to infer a weak association between these two disease processes. First, some clinical trials attempted to assign a single etiology (i.e., BPH vs. diabetes) to chronic kidney disease [29] when chronic kidney disease often has multiple etiologies [2 4]. Second, high serum creatinine cutoffs [up to 265 lmol/l (3.0 mg/dl)] were often used to identify cases of chronic kidney disease [30] and will miss less advanced disease. Third, men without lower urinary tract symptoms or diminished peak urinary flow rates did not meet the inclusion criteria for these trials [29]. Thus, the full spectrum of BPH disease was not represented. Finally, due to the healthy volunteer effect in clinical trials, incident chronic kidney disease may have been missed during the short duration of follow-up. Chronic kidney disease from BPH has been identified as a very rare event in prior epidemiologic studies [9]. For example, a study by Gerber et al looked at 246 consecutive men that presented to a urologist for evaluation of lower urinary tract symptoms, 26 (11%) of whom had a serum creatinine 133 lmol/l (1.5 mg/dl) [31]. Chronic kidney disease was not associated with lower urinary tract symptoms in the Gerber et al study: odds ratio = 0.76 (95% CI 0.32 1.80), but was in this study: odds ratio = 2.94 (95% CI 1.38 6.47). The odds ratios did not change with age and comorbidity adjustment in either study, so a stratified analysis was done to clarify the discrepancy. The prevalence of chronic kidney disease among men with moderate-severe symptoms (IPSS >7) in this study was 10.5%, similar to the 9.8% in the study by Gerber et al. However, the prevalence of chronic kidney disease among men with none-mild symptoms (IPSS 7) in this study was 3.8%, much less than the 12.5% in the study by Gerber et al. This would suggest that men with low symptom scores who present to a urologist may be different from men with low symptom scores in the general community.

Rule et al: BPH and kidney disease 2381 A possible mechanistic pathway by which BPH leads to chronic kidney disease could be an obstructive uropathy at the uretero-vesicular junction [32]. Chronic urinary retention leads to bladder wall thickening with trabeculations via smooth muscle hypertrophy and connective tissue infiltrates [25]. Men with chronic urinary retention often have increased bladder pressures, decreased bladder compliance, and detrusor instability, all of which have been directly associated with renal failure [6 8]. The bladder wall thickening that leads to a decline in bladder compliance can result in a functional or mechanical obstruction at the ureterovesicular junction [32]. However, evaluation for upper tract dilatation (hydronephrosis) was not done in this study. Potential limitations of our study should be noted. With a cross-sectional study design, a temporal relationship cannot be determined. It is conceivable that chronic kidney disease could be a risk factor for BPH or detrusor weakness. With only 29 cases of an elevated serum creatinine, some associations were only borderline statistically significant, particularly with multivariable adjustment. Serum creatinine levels and dipstick proteinuria were used to define chronic kidney disease instead of measured glomerular filtration rate and urinary albumin-creatinine ratios. Though serum creatinine is a widely used marker of renal function in epidemiologic studies, muscle mass and protein intake can also affect serum creatinine levels. A cohort study is needed to assess longitudinal changes in serum creatinine with respect to BPH measures and to clarify the temporal relationship. The standard dipstick may lack adequate sensitivity to identify an association between albuminuria and BPH. Because hypertension and diabetes mellitus were self-reported, they could still be a source of residual confounding. Finally, the community sample was white and predominantly middle class; inferences to other racial and socioeconomic groups should be made with caution. CONCLUSION This study demonstrated an association between bladder outlet obstruction and chronic kidney disease in men. This finding has potential importance for clinical practice and public health because benign prostatic hyperplasia and chronic kidney disease are common in older men. Obtaining a serum creatinine in men presenting for an evaluation of BPH may be reasonable to guide further evaluation or treatment decisions. A bladder outlet obstruction should also be considered in the differential diagnosis of an older man presenting with an elevated serum creatinine, even if the prostate size is normal. Future studies are needed to assess whether treatment of a bladder outlet obstructive will impact progression of chronic kidney disease. ACKNOWLEDGMENTS The authors thank the Olmsted County Study personnel for their help in this study. This study was supported, in part, by Public Health Service, National Institutes of Health research grants (DK58859, AR30582, RR000585, DK07013) and Merck Research Laboratories. Reprint requests to Dr. Steven J. Jacobsen, Department of Health Sciences Research, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. E-mail: jacobsen@mayo.edu REFERENCES 1. CORESH J, ASTOR BC, GREENE T, et al: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41:1 12, 2003 2. HAROUN MK, BERNARD GJ, HOFFMAN SC, et al: Risk factors for chronic kidney disease: A prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol 14:2934 2941, 2003 3. FOX CS, LARSON MG, LEIP EP, et al: Predictors of new-onset kidney disease in a community-based population. JAMA 291:844 850, 2004 4. CHEN J, MUNTNER P, HAMM LL, et al: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 140:167 174, 2004 5. NATIONAL KIDNEY FOUNDATION,KIDNEY DISEASE OUTCOME QUALITY INITIATIVE ADVISORY BOARD: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 39(2 Suppl 2):S1 246, 2002 6. GEORGE NJ, O REILLY PH, BARNARD RJ, BLACKLOCK NJ: High pressure chronic retention. Br Med J (Clin Res Ed) 286:1780 1783, 1983 7. STYLES RA, NEAL DE, GRIFfiTHS CJ, RAMSDEN PD: Long-term monitoring of bladder pressure in chronic retention of urine: The relationship between detrusor activity and upper tract dilatation. J Urol 140:330 334, 1988 8. COMITER CV, SULLIVAN MP, SCHACTERLE RS, et al: Urodynamic risk factors for renal dysfunction in men with obstructive and nonobstructive voiding dysfunction. J Urol 158:181 185, 1997 9. EMBERTON M, ANDRIOLE GL, DE LA ROSETTE J, et al: Benign prostatic hyperplasia: A progressive disease of aging men. Urology 61:267 273, 2003 10. JACOBSEN SJ, GIRMAN CJ, GUESS HA, et al: New diagnostic and treatment guidelines for benign prostatic hyperplasia. Potential impact in the United States. Arch Intern Med 155:477 481, 1995 11. AUA PRACTICE GUIDELINES COMMITTEE:AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol 170:530 547, 2003 12. DE LA ROSETTE JJ, ALIVIZATOS G, MADERSBACHER S, et al: EAU Guidelines on benign prostatic hyperplasia (BPH). Eur Urol 40:256 263, 2001 13. JACOBSEN SJ, GIRMAN CJ, GUESS HA, et al: Natural history of prostatism: Factors associated with discordance between frequency and bother of urinary symptoms. Urology 42:663 671, 1993 14. MELTON LJ III: History of the Rochester Epidemiology Project. Mayo Clin Proc 71:266 274, 1996 15. PANSER LA, CHUTE CG, GUESS HA, et al:the natural history of prostatism: The effects of non-response bias. Int J Epidemiol 23:1198 1205, 1994 16. BARRY MJ, FOWLER FJJ, O LEARY MP,et al: The American Urological Association Symptom Index for benign prostatic hyperplasia. J Urol 148:1549 1557, 1992 17. TERRIS MK, STAMEY TA: Determination of prostate volume by transrectal ultrasound. J Urol 145:984 987, 1991 18. ROEHRBORN CG, BOYLE P, GOULD AL, WALDSTREICHER J: Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 53:581 589, 1999 19. SCHACTERLE RS, SULLIVAN MP, YALLA SV: Combinations of maximum urinary flow rate and American Urological Association symptom index that are more specific for identifying obstructive and non-obstructive prostatism. Neurourol Urodyn 15:459 470, 1996 20. LEVEY AS, CORESH J, BALK E, et al: National Kidney Foundation

2382 Rule et al: BPH and kidney disease practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med 139:137 147, 2003 21. RULE AD, LARSON TS, BERGSTRALH EJ, et al: Using serum creatinine to estimate glomerular filtration rate: Accuracy in good healthy and in chronic kidney disease. Ann Intern Med 141:929 937, 2004 22. ROEHRBORN CG, MCCONNELL JD, SALTZMAN B, et al: Storage (irritative) and voiding (obstructive) symptoms as predictors of benign prostatic hyperplasia progression and related outcomes. Eur Urol 42:1 6, 2002 23. HUNTER DJ, BERRA-UNAMUNO A, MARTIN-GORDO A: Prevalence of urinary symptoms and other urological conditions in Spanish men 50 years old or older. J Urol 155:1965- -1970, 1996 24. HILL AM, PHILPOTT N, KAY JD, et al: Prevalence and outcome of renal impairment at prostatectomy. Br J Urol 71:464 468, 1993 25. JONES DA, GILPIN SA, HOLDEN D, et al: Relationship between bladder morphology and long-term outcome of treatment in patients with high pressure chronic retention of urine. Br J Urol 67:280 285, 1991 26. NISSENKORN I, SAVION M, SERVADIO C: Renal and bladder function recovery after prostatectomy in patients with a chronic residual urine of above 1,000 ml. Eur Urol 14:434 436, 1988 27. GHOSE RR: Prolonged recovery of renal function after prostatectomy for prostatic outflow obstruction. BMJ 300:1376 1377, 1990 28. COHEN EP, SOBRERO M, ROXE DM, LEVIN ML: Reversibility of longstanding urinary tract obstruction requiring long-term dialysis. Arch Intern Med 152:177 179, 1992 29. MCCONNELL J, ROEHRBORN CG, BAUTISTA OM, et al: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349:2387 2398, 2003 30. FLANIGAN RC, REDA DJ, WASSON JH, et al: Five-year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: A Department of Veterans Affairs cooperative study. J Urol 160:12 16, 1998 31. GERBER GS, GOLDfiSCHER ER, KARRISON TG, BALES GT: Serum creatinine measurements in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. Urology 49:697 702, 1997 32. SUTARIA PM,STASKIN DR: Hydronephrosis and renal deterioration in the elderly due to abnormalities of the lower urinary tract and ureterovesical junction. Int Urol Nephrol 32:119 126, 2000