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ORIGINAL ARTICLE JNEPHROL 2013; 26 ( 4) : 755- 762 DOI: 10.5301/jn.5000224 Epidemiology and mortality in dialysis patients with and without polycystic kidney disease: a national study in Taiwan Pei-Wen Lee 1, Chih-Chiang Chien 2,3,4, Wu-Chang Yang 1,5, Jhi-Joung Wang 3, Chih-Ching Lin 1,5 Pei-Wen Lee and Chih-Chiang Chien contributed equally as first authors to this work. Abstract Background: Polycystic kidney disease (PCKD) is one of the most common inherited disorders in end-stage renal disease patients. It is generally thought that the survival of PCKD patients undergoing dialysis surpasses that of general dialysis patients, but the cause of this improved survival is not clear. Methods: Using Taiwan’s national health insurance claims data, we performed a longitudinal cohort study to investigate the survival and impact of comorbidities on mortality in dialysis patients with and without PCKD. We excluded patients without diabetes mellitus (DM) in a further analysis. A Cox proportional hazards model was used to identify the risk factors for allcause mortality. The Kaplan-Meier method was used to describe overall patient survival. Results: Five hundred and one (2.25%) of 22,298 nondiabetic incident dialysis patients had PCKD. We found no significant difference in survival rates between those with and without PCKD. Being male, being over 65 years old and having congestive heart failure or cerebrovascular accident were each found to be independent predictors of mortality in the PCKD dialysis patients. Conclusions: Taiwan has a lower incidence rate of PCKD than Western countries. In Taiwan, there is little difference in the long-term survival between dialysis patients with and without PCKD. Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei - Taiwan 2 Department of Nephrology, Chi-Mei Medical Center, Tainan - Taiwan 3 Department of Medical Research, Chi-Mei Medical Center, Tainan - Taiwan 4 Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan - Taiwan 5 School of Medicine, National Yang-Ming University, Taipei - Taiwan 1 Key words: End-stage renal disease, Mortality, Polycystic kidney disease, Risk factors, Survival Introduction Polycystic kidney disease (PCKD) is one of the most common inherited disorders found in end-stage renal disease (ESRD) patients. Progressive expansion of multiple renal cysts leads to deteriorated renal function (1, 2). PCKD is found in 10% of patients with ESRD in Western countries (3) but in only 1.60% of those in Taiwan (4). Some studies have proposed that the survival of PCKD patients undergoing dialysis surpasses that of general dialysis patients (3, 5-7). However, most of these studies compared PCKD dialysis patients with a nondiabetic control group. The cause of improved survival is not clear and is presumed to stem from multiple factors, including a better hemoglobin level, which improves cardiac function, significantly lower blood pressure and use of more antihypertensive medications, especially inhibitors of the renin-angiotensin-aldosterone system (3, 7-9). Whether PCKD inherently contributes any risk or benefit to survival is uncertain. Using data from the National Health Insurance Research Database (NHIRD) in Taiwan, we designed a longitudinal cohort study of ESRD dialysis patients to uncover any influence of PCKD on survival and to determine the risk factors of mortality in nondiabetic maintenance dialysis patients with and without PCKD. © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 755 Lee et al: Mortality in PCKD patients on dialysis Materials and methods Database Taiwan’s national health insurance program, which provides compulsory universal health insurance, was first implemented in 1995. With the exception of prison inmates, all citizens are enrolled in the program. All contracted medical institutions must submit standard claim documents for medical expenses on a computerized form. Patients with ESRD are eligible for any type of renal replacement therapy free of charge and without co-payments. The data for this cohort study were obtained from the NHIRD (http://www.doh.gov.tw/statistic/index.htm [in Chinese]; http://www.doh.gov.tw/EN2006/index_EN.aspx [in English]), which is released for research purposes by the Taiwan National Health Research Institute. The NHIRD, which includes nearly all (99%) inpatient and outpatient medical benefit claims for the population of 23 million Taiwanese, is one of the largest and most comprehensive databases in the world and has been used extensively in various studies (10, 11). The NHIRD provides encrypted patient identification numbers, sex, date of birth, dates of admission and discharge, medical institutions providing services, the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic (up to 5) and procedure (up to 5) codes, and outcomes. After obtaining ethics committee approval, we used the NHIRD for ambulatory care claims and all inpatient claims, and the updated registry for beneficiaries. All of the datasets can be combined using each individual’s unique personal identification number. The study was approved by the institutional review board, and an independent data and safety monitoring board oversaw the conduct of the trial and reviewed the safety and efficacy data. Patient selection and definition Using the NHIRD, we enrolled all ESRD patients who underwent maintenance dialysis between January 1, 1999, and December 31, 2004. A patient was defined as undergoing maintenance dialysis if he or she had undergone dialysis for longer than 90 days. Patients who underwent renal transplantation before initiation of dialysis and those younger than 20 years were excluded. The remaining patients were followed up from the day of their first dialysis treatment until their death, kidney transplantation or the end of the followup period on December 31, 2008. Patient selection is shown in Figure 1. 756 Fig. 1 - Patient selection. DM = diabetes mellitus; PCKD = polycystic kidney disease. Ascertaining the demographic and comorbidity variables The patients with ESRD were stratified by the presence or absence of PCKD at the beginning of dialysis treatment. Data collected included survival status, date of death as well as demographic and comorbidity variables. Demographic variables included age and sex, and modality of initial dialysis. Baseline comorbidity variables were the major comorbidities known to affect mortality, including diabetes mellitus (DM), hypertension (HTN), congestive heart failure (CHF), coronary artery disease (CAD), cerebrovascular accident (CVA), peripheral artery disease (PAD) and malignancy. The selected comorbidities were determined based on diagnostic codes recorded on claims records from ambulatory visit or hospitalization databases at the start of the dialysis. The ICD-9-CM codes used to define these clinical conditions are shown in the Appendix. Statistical analyses Sample size estimation was performed for the whole cohort. For sample size and attrition rate, significance was set at an alpha of 0.05 (2-tailed). The study needed a power of 93.2% to yield a statistically significant result. All values were expressed as incidence proportion (%). The baseline characteristics of the groups of patients with and without PCKD were compared using Pearson chi-square tests. Age was entered as a categorical variable (20-44, 45-64 and 65 years or older). A p value <0.05 was considered significant. © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2013; 26 ( 4) : 755- 762 Overall patient survival was described using the Kaplan-Meier method. To evaluate the impact of PCKD on survival, we analyzed the differences in baseline characteristics between the patients with and without PCKD to determine which factors qualified for entry into a Cox regression model. The Cox proportional hazards model was used to identify risk factors for all-cause mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from the Cox proportional hazards models. The proportional hazards assumption was checked using log-minus-log plots of the survival function. The Cox models met the assumption of proportionality of risks. To adjust for potential confounding in the relationship between comorbidities and the risk of mortality, multivariate analysis was used to model all-cause mortality. Further interactions were tested. The complete model, which included all of the covariates listed in Table I, was used for the Cox regression analysis. Each interaction term was then included separately. The p values for each interaction term ranged from 0.134 to 0.933, none of which was significant. We used the likelihood ratio statistic to assess the goodness of fit of the model. The likelihood ratios of the null model and multivariate model were 354,931.5 and 345,923.8 for all patients and 127,048.16 and 122,467.0 for the patients without diabetes, respectively. The R-square, which we calculated according to Schemper and Stare’s formula (1996), was 18.9% for all patients, and 18.7% for the patients without diabetes. The data were analyzed using the Statistical Package for the Social Sciences (Windows version 17.0; SPSS Inc, Chicago, IL, USA). Results A total of 43,039 incident dialysis patients were evaluated in the study. Of these 603 patients had PCKD and 42,436 had other causes of ESRD. During the follow-up period, 2,100 non-PCKD and 42 PCKD patients underwent kidney transplantations. As can be seen in the summary of baseline characteristics in Table II, there was a lower proportion of women among the patients with PCKD compared than those without. Patients with PCKD had significantly lower proportions of DM and dyslipidemia, but a higher proportion of gout. We stratified the non-DM patients into whether they had or did not have PCKD (Tab. II). Of the 22,196 non-DM dialysis patients, 501 patients (2.26%) had PCKD. These patients were predominantly male (58.7%) and had a mean age of 56.4 ± 13.4 years. HTN was the most common (78.4%) comorbidity. These patients had a greater prevalence of HTN, gout and CVA than those without PCKD. The survival rates for all dialysis patients and for nondiabetic patients are shown in Figures 2 and 3, respectively. The patients with PCKD had a significantly better survival rate than those without PCKD (p<0.001, by log-rank test). However, the adjusted mortality rates of the patients with PCKD relative to those without PCKD were not significantly different (Tab. III). Because DM is an important comorbidity that greatly impacts mortality, we further excluded DM by using the restriction method. The reanalysis showed no difference in survival curves between the 2 groups. We also determined the risk factors for all-cause mortality among all PCKD patients and the nondiabetic PCKD patients by multivariate analyses. Significant risk factors for all-cause mortality in both groups were male sex, being older than 65 years, CHF and CVA (Tab. I). Discussion This nationwide representative study used Taiwan`s NHIRD to investigate the long-term survival and mortality risk of PCKD in dialysis patients. Only 1.4% of the incident dialysis patients had PCKD. We found no significant statistical difference in survival rate between the patients with and without PCKD. Being male, being 65 years or older, and having CHF or CVA were found to be independent predictors of mortality in dialysis patients with PCKD. There were substantial differences between the patients with and without PCKD, with regard to several prognostic indicators of death, including age, history of DM, dyslipidemia, CHF, CAD and PAD (Tab. II). However, we inferred a different conclusion from the multivariate adjustment. Previous reports showed that PCKD patients have a better survival after the initiation of dialysis than control patients (3, 5-7). Perrone et al (3), using data from the US Renal Data System, found a lower mortality rate in PCKD dialysis patients than in nondiabetic dialysis patients. Zeier et al (7) presumed that such an improvement might be a result of the effects of better hemoglobin levels on cardiac function. Our study found a significantly greater proportion of PCKD patients on dialysis had HTN and CVA, though they were younger. This finding was consistent with previous studies (12-15). HTN is an early and common finding in PCKD, and is possibly caused by focal ischemia resulting from cyst expansion and by increased activity of the renin-angiotensin-aldosterone system (16-18). A neurological event was the fourth most common cause of death in PCKD patients (12%). Aneurysm rupture often occurs with larger aneurysms or in patients with poorly controlled hypertension (15, 19). We also found CVA to be a significant risk factor for all-cause mortality in the PCKD patients on dialysis in Taiwan (Tab. I). Taken together, our multivariate findings suggest that ESRD patients with PCKD may not have a better survival rate than those without it. © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 757 Lee et al: Mortality in PCKD patients on dialysis TABLE I RISK FACTORS FOR ALL-CAUSE MORTALITY IN ALL AND NONDIABETIC DIALYSIS PATIENTS WITH PCKD All dialysis patients with PCKD Covariate Nondiabetic dialysis patients with PCKD Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) 1.711 (1.269-2.307)* 1.975 (1.430-2.727)* 1.734 (1.231-2.443)* 2.014 (1.415-2.865)* 1 1 1 1 45-64 1.434 (0.865-2.378) 1.391 (0.827-2.339) 1.306 (0.757-2.254) 1.273 (0.732-2.211) ≥65 4.630 (2.837-7.555)* 4.536 (2.687-7.659)* 4.458 (2.637-7.536)* 4.419 (2.555-7.645)* Diabetes mellitus (yes vs. no) 1.755 (1.268-2.430)* 1.397 (0.999-1.954) - - Hypertension (yes vs. no) 1.279 (0.884-1.850) 0.993 (0.678-1.454) 1.379 (0.909-2.091) - Dyslipidemia (yes vs. no) 0.738 (0.402-1.357) 0.544 (0.293-1.010) 0.540 (0.221-1.317) - Gout (yes vs. no) 1.222 (0.894-1.670) 0.924 (0.659-1.295) 1.092 (0.754-1.583) - Congestive heart failure (yes vs. no) 2.377 (1.648-3.429)* 2.336 (1.551-3.518)* 2.468 (1.593-3.823)* 2.481 (1.550-3.970)* Coronary artery disease (yes vs. no) 1.881 (1.359-2.603)* 1.045 (0.733-1.492) 1.862 (1.265-2.740)* 1.031 (0.686-1.551) Cerebrovascular accident (yes vs. no) 1.770 (1.212-2.585)* 1.685 (1.140-2.429)* 1.896 (1.225-2.934)* 1.871 (1.205-2.905)* Peripheral arterial disease (yes vs. no) 1.561 (0.580-4.203) 1.177 (0.429-3.228) 1.833 (0.679-4.952) - Chronic lung disease (yes vs. no) 1.873 (1.248-2.812)* 1.051 (0.677-1.633) 1.697 (1.049-2.746)* 0.918 (0.555-1.518) Chronic liver disease (yes vs. no) 1.349 (0.962-1.891) 1.350 (0.957-1.905) 1.235 (0.832-1.833) - Cancer (yes vs. no) 1.627(0.884-2.993) 1.308 (0.691-2.476) 1.261 (0.590-2.696) - Sex (male vs. female) Age at initiation of dialysis 20-44 (reference) CI = confidence interval; HR = hazard ratio; PCKD = polycystic kidney disease. *p<0.05. 758 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2013; 26 ( 4) : 755- 762 TABLE II PATIENT BASELINE CHARACTERISTICS All dialysis patients Nondiabetic dialysis patients Without PCKD (n = 42,436) With PCKD (n = 603) Without PCKD (n = 21,695) With PCKD (n = 501) No. (%) No. (%) No. (%) No. (%) 20,033 (47.2) 355 (58.9)† 9,945 (45.8) 294 (58.7)† 20-44 6,777(16) 113(18.7)* 5264 (24.3) 104 (20.8) † 45-64 18,644(43.9) 289(47.9)* 8317 (38.3) 244 (48.7) † ≥65 17,015(40.1) 201(33.3)* 8114 (37.4) 153 (30.5) † Mean age 59.15 ± 14.42 57.40 ± 13.33 56.81 ± 16.41 56.36 ± 13.40 HD 38,635 (91.1) 549 (91) 19,050 (87.9) 453 (90.4) Diabetes mellitus 20,741 (48.9) 102 (16.9)† - - Hypertension 33,373 (78.6) 484 (80.3) 14,859 (68.5) 393 (78.4)† Dyslipidemia 6,366 (15) 43 (7.1)† 1,642 (7.6) 26 (5.2)* Gout 5,607 (13.2) 114 (23.9)† 3,242 (14.9) 116 (23.2)† Congestive heart failure 8,383 (19.8) 66 (10.9)† 2,559 (11.8) 47 (9.4) Coronary artery disease 9,946 (23.4) 100 (16.6)† 3,238 (14.9) 72 (14.4) Cerebrovascular accident 5,322 (12.5) 71 (11.8) 1,635 (7.5) 53 (10.6)* Peripheral arterial disease 1,380 (3.3) 9 (1.5)* 524 (2.4) 8 (1.6) Chronic lung disease 4,707 (11.1) 54 (9) 2,201 (10.1) 42 (8.4) Chronic liver disease 7,716 (18.2) 105 (17.4) 3,812 (17.6) 83 (16.6) Cancer 2,182 (5.1) 24 (4) 1340 (6.2) 19 (3.8)* Male sex Age, years HD = hemodialysis; PCKD = polycystic kidney disease. *p<0.05; †p<0.001. DM is the leading cause of ESRD (35.3%) in Taiwan. ESRD patients with DM have a poorer survival rate than non-DM patients (20). ESRD patients with diabetic nephropathy frequently have multiple comorbid conditions that are mainly vascular in nature, including retinopathy, neuropathy and cardiovascular complications (21, 22). Our PCKD group had a much smaller proportion of DM than our non-PCKD group. After excluding the DM patients, we found no significant difference in survival rates between the 2 nondiabetic groups. The incidence of ESRD resulting from PCKD is reported to range from 6 to 8 patients per million population (PMP) in the United States (23), but only approximately 5.02 PMP in Taiwan (4). PCKD is the fourth most common cause (2.4%) of ESRD in the United States, preceded by DM (44.0%), HTN (27.9%) and chronic glomerulonephropathy (CGN) (6.7%) (10). In Taiwan, ESRD secondary to PCKD is much rarer (1.4%), and is the fifth largest cause, preceded by DM (37.31%), CGN (31.92%), HTN (6.15%) and gout (2.69%) © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 759 Lee et al: Mortality in PCKD patients on dialysis TABLE III COX REGRESSION ESTIMATES OF THE ASSOCIATION BETWEEN PCKD AND ALL-CAUSE MORTALITY FOR ALL PATIENTS AND NONDIABETIC PATIENTS Subgroup All dialysis patients Without PCKD (reference) With PCKD Fig. 2 - Kaplan-Meier survival curves for all dialysis patients with or without polycystic kidney disease (PCKD). The logrank test showed a significant difference between patients with or without PCKD (p<0.001, by log-rank test). DM = diabetes mellitus. Nondiabetic patients Without PCKD (reference) With PCKD Univariate analysis Multivariate analysis HR (95% CI) HR (95% CI) 1 1 0.719 (0.625-0.826)* 0.954 (0.829-1.098)† 1 1 0.982 (0.836-1.154) 1.040 (0.885-1.222) ‡ CI = confidence interval; HR = hazard ratio; PCKD = polycystic kidney disease. *p<0.05. † Adjusted for sex, age, dialysis modality, diabetes mellitus, hypertension, dyslipidemia, congestive heart failure, coronary artery disease, cerebrovascular accident, peripheral artery disease, lung disease, liver disease and cancer. ‡ Adjusted for sex, age, dialysis modality, hypertension, dyslipidemia, congestive heart failure, coronary artery disease, cerebrovascular accident, peripheral artery disease, lung disease, liver disease and cancer. Fig. 3 - Comparison of 10-year survival curves for nondiabetic dialysis patients with or without polycystic kidney disease (PCKD; p = 0.825, by log-rank test). (4). The prevalence of PCKD in another Asian country, Japan, is 2.1% among men and 2.7% among women (24). There may be several reasons for the difference in outcomes in ESRD patients with PCKD between Taiwan and Western countries. First, Taiwan has a lower prevalence of PCKD. In addition, the difference may be due to differences in ethnicity and a lower prevalence of diabetic nephropathy in 760 Taiwan. The possible effect of these variables on the generalizability of our results should be taken into consideration. It has been demonstrated that in affected males, female carriers and cardiac variant men with Anderson-Fabry disease, renal cysts are usually detected (25). Pisani et al reported the first case with simultaneous presence of multiple liver and kidney cysts in patients with genetically confirmed Anderson-Fabry disease (26). This could be a new association that can confound and delay the diagnosis of Anderson-Fabry disease. This study has several limitations. First, the diagnosis of comorbidities in this study relied on claims data and ICD-9-CM diagnosis codes, which may result in potential disease misclassification. Second, we assessed comorbidities on the basis of a simple classification (presence/absence), which does not take into account disease severity. Third, our study © 2012 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2013; 26 ( 4) : 755- 762 APPENDIX ICD-9-CM CODES USED TO IDENTIFY CLINICAL CONDITIONS Conditions ICD-9-CM Polycystic kidney disease 753.12-753.14 Diabetes mellitus (DM) 250.xx, 357.2, 362.0x, 366.41 Hypertension 362.11, 401.x-405.x, 437.2 Dyslipidemia 272.0, 272.2, 272.4 Gout 274.0-274.9 Congestive heart failure (CHF) 428.0-428.43, 428.9, 398.91 Coronary artery disease (CAD) 410.xx- 414.xx Cerebrovascular accident/TIA 430-438.xx Peripheral arterial disease (PAD) 440.0-440.9, 38.13-38.18, 39.22-39.26, 39.28 Chronic lung disease 490-496x, 500-505x, 506.4x Chronic liver disease 571.x Cancer 140-208 Taiwan has a low proportion of PCKD cases. The long-term survival outcomes of dialysis patients with and without PCKD are similar in Taiwan. The risk factors for mortality in PCKD dialysis patients are being male, being older than 65 years and having CHF or CVA. Financial support: This study was supported by grant CMFHR10177 from the Chi-Mei Medical Center and grant NHRI-NHIRD-99182 from the National Health Research Institutes in Taiwan. Address for correspondence: Chih-Ching Lin, MD Division of Nephrology and Department of Medicine Taipei Veterans General Hospital No. 201, Sec. 2, Shih-Pai Road Taipei, Taiwan 112, Republic of China [email protected] 3. References 2. Conclusion Conflict of interest: None. x or xx can indicate any number or no number. ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; TIA = transient ischemic attack. 1. lacked data on the duration and treatment regimens of the diseases, biochemical data and socioeconomic characteristics. These variables may exert some influence on mortality and should be considered as confounders in future studies. Torres VE, King BF, Chapman AB, et al. Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). 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Renal structure and hypertension in autosomal dominant polycystic kidney disease. Kidney Int. 1990;38(6):1177-1180. Barrett BJ, Foley R, Morgan J, Hefferton D, Parfrey P. Differences in hormonal and renal vascular responses between normotensive patients with autosomal dominant polycystic kidney disease and unaffected family members. Kidney Int. 1994;46(4):1118-1123. 18. Ecder T, Schrier RW. Hypertension in autosomal-dominant polycystic kidney disease: early occurrence and unique aspects. J Am Soc Nephrol. 2001;12(1):194-200. 19. Schievink WI, Torres VE, Piepgras DG, Wiebers DO. Saccular intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1992;3(1):88-95. 20. Yang WC, Hwang SJ. Taiwan Society of Nephrology. Incidence, prevalence and mortality trends of dialysis endstage renal disease in Taiwan from 1990 to 2001: the impact of national health insurance. Nephrol Dial Transplant. 2008;23(12):3977-3982. 21. Schroijen MA, Dekkers OM, Grootendorst DC, et al. NECOSAD Study Group. Survival in dialysis patients is not different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition. BMC Nephrol. 2011;12(1):69. 22. Rodríguéz JA, Clèries M, Vela E. Registry Committee R; Renal Registry Committee. Diabetic patients on renal replacement therapy: analysis of Catalan Registry data. Nephrol Dial Transplant. 1997;12(12):2501-2509. 23. Collins AJ, Foley RN, Herzog C, et al. US Renal Data System 2010 annual data report. Am J Kidney Dis. 2011; 57(1)(A8):e1-e526. 24. Wakai K, Nakai S, Kikuchi K, et al. Trends in incidence of end-stage renal disease in Japan, 1983-2000: age-adjusted and age-specific rates by gender and cause. Nephrol Dial Transplant. 2004;19(8):2044-2052. 25. Glass RB, Astrin KH, Norton KI, et al. Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes. J Comput Assist Tomogr. 2004;28(2):158-168. 26. Pisani A, Riccio E, Cianciaruso B, Imbriaco M. Simultaneous multicystic kidney and Anderson-Fabry disease: 2 separate entities or same side of the coin. J Nephrol. 2011;24(6): 806-808. Accepted: August 22, 2012 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428