Epidemiology, impact and preventive care of chronic kidney disease in Taiwannep_ 3..9

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1 Nephrology 15 (2010) 3 9 Review Article Epidemiology, impact and preventive care of chronic kidney disease in Taiwannep_ 3..9 SHANG-JYH HWANG, JER-CHIA TSAI and HUNG-CHUN CHEN Department of Medicine, Division of Nephrology, Kaohsiung Medical University Hospital, Faculty of Renal Care, Kaohsiung Medical University, College of Medicine, Kaohsiung, Taiwan KEY WORDS: chronic kidney disease, epidemiology, preventive care. Correspondence: Professor Hung-Chun Chen, Department of Medicine, Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tz-You 1st Road, Kaohsiung 807, Taiwan. chenhc@kmu.edu.tw Accepted for publication 25 February doi: /j x ABSTRACT: Chronic kidney disease (CKD) has emerged as a global public health burden. Taiwan has the highest incidence and prevalence rates of endstage renal disease (ESRD) in the world. In this review, the following key issues of CKD in Taiwan are addressed: epidemiological data, underlying diseases patterns, risk factors, public health concerns and a preventive project. Prevalence of CKD are reported to be 6.9% for CKD stage 3 5, 9.83% for clinically recognized CKD and 11.9% for CKD stage 1 5. However, overall awareness of CKD is low, 9.7% for CKD stage 1 3 and 3.5% for stage 1 5. Diabetes mellitus (43.2%), chronic glomerulonephritis (25.1%), hypertension (8.3%) and chronic interstitial nephritis (2.8%) are four major underlying renal diseases of ESRD. Older age, diabetes, hypertension, smoking, obesity, regular use of herbal medicine, family members (both relatives and spouses), chronic lead exposure and hepatitis C are associated with higher risk for CKD. Impact of CKD increases risk of allcause mortality and cardiovascular diseases, especially in those with overt proteinuria and advanced CKD stages. These impacts lead to increased medical costs. The nationwide CKD Preventive Project with multidisciplinary care program has proved its effectiveness in decreasing dialysis incidence, mortality and medical costs. It is crucially significant from Taiwan experience on CKD survey and preliminary outcome of the preventive project. Provision of a more comprehensive public health strategy and better care plan for CKD should be achieved by future international collaborative efforts and research. Chronic kidney disease (CKD) has emerged as a global public health burden for its increasing number of patients, high risk of progression to end-stage renal disease (ESRD), and poor prognosis of morbidity and mortality. 1,2 It attracts worldwide attention to its epidemiology, risk factors, treatment plans and preventive actions. 3 Estimated glomerular filtration rate (egfr) has become a standard method to evaluate CKD based on diagnostic criteria and classification by the National Kidney Foundation, USA. 4 However, the reported prevalence of CKD has varied among different countries because of the discrepancies in age, ethnic groups, survey policies and equations of egfr calculation The patterns of associated risk factors and targeting strategies are also quite diverse. Taiwan has the highest incidence and prevalence rates of ESRD in the world according to the United States Renal Data System (USRDS) Annual Data Report. 11 Thus, it is worthwhile to make explicit the epidemiology, risk factors, impact and preventive strategies for CKD in Taiwan. We hope that this approach may provide valuable lessons and experiences to many countries that are suffering from serious CKD problems and are making efforts to tackle them. In this review, we aim to address the following key issues of CKD focusing on Taiwan: epidemiological data, underlying diseases patterns, risk factors, public health concerns and a preventive project. EPIDEMIOLOGY OF CKD IN TAIWAN: A WORLDWIDE COMPARISON A nationwide, randomized, stratified survey for hypertension, hyperglycaemia and hyperlipidaemia (TW3H) by Hsu Journal compilation 2010 Asian Pacific Society of Nephrology 3

2 S-J Hwang et al. et al. reported a prevalence rate of 6.9% of CKD stage 3 5 in the subjects over 20 years-old (n = 6001). 8 The second wave follow-up study of TW3H Survey revealed 9.8% of CKD stage 1 5 (n = 5943) adjusted by age of the population in 2007 (unpubl. data, 2009). Another survey from the dataset of National Health Insurance (NHI) using disease code analysis by Kou et al. reported the prevalence of clinically recognized CKD as 9.83% and the overall incidence rate during as 1.35/100 person-years. 12 A large database of 13-year cohort commercial health examination by Wen et al. 13 later reported an overall prevalence of 11.9% of CKD stage 1 5 (n = ). The prevalence of each stage of CKD (I V) was 1.0% (I), 3.8% (II), 6.8% (III), 0.2% (IV) and 0.1% (V). Despite the differences in data sources, study subjects and definition of CKD, the prevalence of CKD ( %) in Taiwan was slightly lower than 13.1% in United States, National Health and Nutrition Examination Survey (NHANES III, ). 6 The underestimated prevalence of CKD in Taiwan might be explained by variation in sampling methods and egfr calculation system. Further worldwide epidemiological comparison on the prevalence of CKD is listed in Table 1. In Europe, the population-based Health Survey of Nord-Trondelag County (HUNT II), using the same methods as NHANES, reported a 10.2% prevalence of CKD in Norway. 7 In the Asia Pacific area, based on different published reports, the prevalence of CKD stage 3 5 or total CKD was approximately % in Japan, % in China, % in Korea, % in Thailand, % in Singapore, 4.2% in India and 11.2% in Australia. AWARENESS OF CKD A low awareness rate in contrast to high prevalence of CKD is a serious public health problem in Taiwan. Hsu et al. 8 reported an overall awareness rate of CKD of 9.7% in contrast to 6.9% prevalence rate for CKD stage 3 5. Awareness rates for each stage of CKD were 8.0% (stage 3), 25.0% (stage 4) and 71.4% (stage 5). In Wen s report, 13 the overall awareness of CKD stage 1 5 was only 3.5%. Awareness rates for each stage of CKD are 2.66% (stage 1), 2.68% (stage 2), 4.10% (stage 3), 23.67% (stage 4) and 52.40% (stage 5). Notably, low awareness in contrast to high prevalence of CKD is especially more common in subjects of low socioeconomic and educational status. This fact raises the importance of promoting awareness of CKD through patient education and an intensive screening program. For example, World Kidney Day and a public media campaign have been implemented in Taiwan since More importantly, continuing medical education is crucially needed for each level of medical physician in all specialties. We must foster the health-care professionals to learn the new concept of CKD definition and classification 4 and to provide the rational care for this rapidly growing population of CKD. HIGH INCIDENCE AND PREVALENCE OF ESRD IN TAIWAN: CURRENT STATUS AND WHY Taiwan has the highest incidence and prevalence rate of ESRD based on international comparisons of the USRDS report. 11 Based on the National Dialysis Registry by the Taiwan Society of Nephrology (TSN), Yang et al. reported that from 1990 to 2001 incidence and prevalence rates of ESRD patients increased 2.6 times from 126 to 331/million populations (pmp) and 3.46 times from 382 to 1322/pmp, respectively, from 1990 to Recent data from the Dialysis Registration of the TSN in 2007 reported haemodialysis (HD) and 4465 peritoneal cases, corresponding to a prevalence of 2288/pmp and incidence of 415/pmp, respectively. 11 The heavy burden of renal replacement therapy by dialysis was managed by a total of 1081 board-certificated nephrologists, 534 dialysis centres and HD machines. Moreover, the domestic renal transplant patients from were 2054 cases based on the data of the Bureau of National Health Insurance (BNHI). However, it was estimated that another 50% of patients received off-shore renal transplantation, mainly from China. There are several possible explanations for the high incidence and prevalence of ESRD in Taiwan. First, a major reason is that the launching of the NHI in 1995 provided free coverage for dialysis therapy without co-payment. 28 The universal coverage facilitates the utilizations of renal replacement therapy and further accelerates the inflow of dialysis patients. Second, the better health-care system may improve the survival rate of chronic diseases patients and increase the overall life expectancy. This reason is supported by the evidence that the increased ESRD population consisted of mainly elderly (>65 years) and diabetic patients in Taiwan. 27 Elderly cases constitute approximately half of the incidence of dialysis cases and diabetic cases constitute approximately 40% of the incidence of dialysis cases. Third, low transplantation rate and low mortality rate in dialysis patients further retains the numbers of the dialysis patient pool. 29 PRIMARY RENAL DISEASES OF ESRD Diabetes mellitus (DM) (43.2%), chronic glomerulonephritis (CGN) (25.1%), hypertension (8.3%) and chronic interstitial nephritis (2.8%) are four major underlying renal diseases of ESRD in DM has become the first leading cause of ESRD by outnumbering CGN since Unknown causes of ESRD are especially often reported as CGN. It implies that a significant portion of patients with hypertension and chronic interstitial nephritis might be underestimated as the underlying causes of ESRD. It needs more in-depth investigation to identify the exact pattern of primary diseases of ESRD. 4 Journal compilation 2010 Asian Pacific Society of Nephrology

3 Epidemiology of CKD in Taiwan Table 1 Epidemiology of CKD in Asian and Western countries Countries/authors Study design Samples size/period Equation of egfr Prevalence Taiwan Wen et al. 13 CS n = year: Hsu et al. 8 CS n = year: 2002 Kuo et al. 12 CS n = year: Japan Imai et al. 9 CS n = year: Iseki et al. 14 CS n = year: 2003 China Zhang et al. 15 CS n = year: not mentioned Zhang et al. 16 CS n = year: not mentioned Chen et al. 17 CS n = year: Chen et al. 18 CS n = year: Korea Kim et al. 19 CSRS n = year: 2006 Chang et al. 20 Cohort study n = year: India Singh et al. 21 CSRS n = year: Thailand Ong-Ajyooth et al. 22 CS n = year: 2004 Perkovic V et al. 23 CSRS n = year: 2000 Four-variable MDRD Total CKD: 11.9% Stage 1: 1.0% Stage 2: 3.8% Stage 3: 6.8% Stage 5: 0.1% Four-variable MDRD Stage 3 5: 6.9% ICD-9 codes Total CKD: 9.83% in 2003 Japanese four-variable MDRD Total CKD: 12.9% Stage 1: 0.6% Stage 2: 1.7% Stage 3: 10.4% Stage 4+5: 0.2% Four-variable MDRD egfr <60: 15.1% Chinese four-variable MDRD Total CKD: 13.0% Chinese four-variable MDRD Total CKD: 11.3% Albuminuria: 6.2% Reduced renal function: 5.2% Haematuria: 0.8% Chinese four-variable MDRD Albuminuria: 6.6% Haematuria: 3.8% egfr <60: 3.2% Four-variable MDRD Age-standardized prevalence of egfr 60 89: 39.4% egfr 30 59: 2.4% egfr <30: 0.14% Four-variable MDRD Total CKD: 13.7% Stage 1: 2.0% Stage 2: 6.7% Stage 3: 4.8% Stage 5: 0.0% Four-variable MDRD Total CKD: 7.2% CG and four-variable MDRD egfr (MDRD) <60: 4.2% egfr (CG) <60: 13.3% Proteinuria: 2.25% Chinese four-variable MDRD Stage 3 5: 8.45% Stage 3: 8.1% Stage 5:0.15% CG and four-variable MDRD egfr (MDRD) <60: 16.3% egfr (CG) <60: 25.5% Stage 4 (CG): 0.94% Journal compilation 2010 Asian Pacific Society of Nephrology 5

4 S-J Hwang et al. Table 1 Continued Countries/authors Study design Samples size/period Equation of egfr Prevalence Singapore Teo et al. 24 CS n = year: Shankar et al. 25 CS n = year: not mentioned Australia Chadban et al. 26 CSRS n = year: USA Coresh et al. 6 CS n = year: European Hallan et al. 7 CS n = year: Chinese four-variable MDRD and four-variable MDRD Total CKD: 75.2 vs 50.0% Stage 1: 15.2 vs 29.3% Stage 2: 56.8 vs 19.7% Stage 3: 3.0 vs 0.8% Stage 4: 0.2 vs 0.2% Stage 5: 0.0 vs 0.0% Four-variable MDRD egfr <60: 18.6% CG Proteinuria: 2.4% Haematuria: 4.6% egfr <60: 11.2% 1 indicator of kidney damage: 16% Four-variable MDRD Stage 1: 1.8% Stage 2: 3.2% Stage 3: 7.7% Stage 4: 0.35% Four-variable MDRD Total: 10.2% Stage 1: 2.7% Stage 2: 3.2% Stage 3: 4.2% National Kidney Foundation four-variable MDRD equation: 186 (creatinine) (age) (if subject is female). ICD-9: The International Classification of Disease version 9. Japanese four-variable MDRD equation: (creatinine) (age) (if subject is female). Chinese four-variable MDRD equation: 175 (creatinine) (age) (if subject is female). CG equation: (140-age) weight/ (0.814 creatinine) 0.85 (if subject is female). CG, Cockcroft-Gault; CKD, chronic kidney disease; CS, cross-sectional study; CSRS, cross-sectional study with random sampling; egfr, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease. WELL-ESTABLISHED RISK FACTORS FOR CKD The study based on NHI dataset showed that old age, diabetes, hypertension, hyperlipidaemia and female sex were associated with a higher risk of developing CKD. 12 A prospective cohort study by Wen et al. 13 further demonstrated that older age, diabetes, hypertension, smoking, obesity and regular use of herbal medicine were more common in the CKD group, and CKD is prevalent in 37.2% of the population aged over 65 years. Furthermore, hypertension, diabetes, hyperlipidaemia, smoking, obesity, low socioeconomic state and regular user of Chinese herbal drugs were significant risk factors for CKD. The association of Chinese herbal therapy with CKD and ESRD needs to be emphasized here. Herbal therapy is independently associated with risk of CKD in adults not using analgesics. 30 Intake of Chinese herbs containing aristolochic acid has been reported as the cause of advanced renal failure in Taiwan Chinese herbal products containing aristolochic acid, Mu-ton and Fangi have been banned by the Department of Health (DOH) in Taiwan since The beneficial effect of this action still needs to be observed. Additionally, the second wave of the TW3H Survey (unpubl. data, 2009) stated that metabolic syndrome exerted a 34% higher risk for CKD stage 3 5, which is similar to reports from the USA, Japan and Korea. 20,34,35 MORE POTENTIAL RISK FACTORS FOR CKD The above well-established risk factors of CKD may not explain why the high incidence and prevalence of ESRD has developed in Taiwan. Other potential risk factors needs to be further explored. First, chronic lead intoxication may play a key role in the pathogenesis of CKD in some victims of chronic exposure without obvious clinical presentations of intoxication. 36 This nephrotoxic heavy metal may accumulate and contribute to CKD silently. Reducing lead overload by administration of i.v. ethylene diamine tetra acetate has been proved to slow down the deterioration of impaired renal function. 37 Second, both hepatitis B and C are endemic diseases in Taiwan with seropositive rates of 12 15% for hepatitis B surface antigen and 3 5% for anti-hepatitis C virus in 6 Journal compilation 2010 Asian Pacific Society of Nephrology

5 Epidemiology of CKD in Taiwan general populations. It is still uncertain whether both types of chronic hepatitis may lead to higher risk of CKD. Our recent study has proved that hepatitis C but not hepatitis B acts as a significant risk factor for proteinuria and CKD. 38 It warrants more studies to investigate the association of hepatitis C with morbidity and mortality of CKD. Third, family history of CKD/ESRD has been considered a significant risk factor for CKD However, little is known about the role of family history of ESRD in the development of CKD in Taiwan. Our recent study demonstrated that higher prevalence of albuminuria and/or CKD existed not only in the first and second relatives of HD patients but also in the spouses of HD patients in comparison to their counterpart community controls. 43 It suggests that both genetic susceptibility and environmental factors may interact and contribute to the development of CKD in both genetic family members and non-genetic spouses of patients with ESRD. In sum, the above new findings have identified more potentially important risk factors for CKD. These results drive us to extend our screening program and care plan to these high-risk groups of CKD. CHALLENGES IN EGFR MEASUREMENT AND DIAGNOSIS OF CKD The varied prevalence of CKD among different countries or in different areas within the country must be interpreted with caution. These data could be influenced by many factors, such as the difference in survey design (random or purposed), study populations (general population or agespecific, or disease-specific), stages of CKD (all stages or stages of 3 5), method of creatinine measurement (Jaffe or enzymatic method and with or without standardization), equation formula for GFR calculation (Modification of Diet in Renal Disease (MDRD) or Cockcroft Gault), and the ethnicities of different races. Calculation of GFR by four-variable MDRD equation is becoming more popular because of its simplicity. However, this equation has not been fully validated in Taiwanese subjects and in different stages of CKD. Over- or underestimation of GFR will cause incorrect diagnosis of CKD. It may delay intervention in subjects with true CKD or waste resources on subjects with normal renal function. Various modified equations of GFR calculations have been developed in Asian populations. 9,10,17,24 A more accurate GFR equation for Taiwanese subjects by using inulin clearance as a standard reference is ongoing. More studies need to be validated before we can generalize this standard equation for egfr to a wider population. IMPACT OF CKD/ESRD ON PUBLIC HEALTH The major impacts of CKD on public health in Taiwan are poor prognosis of high mortality and morbidity and the increased medical expenses. A large cohort study by Wen et al. 13 has demonstrated that patients with CKD have 83% higher mortality for all-cause and 100% higher for cardiovascular diseases. Even for the subjects of CKD stage 1 2, hazard ratios (HR) for all-cause mortality were still significantly higher in those with overt proteinuria compared to those with negative proteinuria. As for the elderly population with CKD, Hwang et al. further proved that these populations had significantly higher HR of 1.5, 2.1 and 2.6 for groups with egfr of 30 44, and less than 15 ml/min per 1.73 m 2, respectively, compared to a reference group with egfr of less than 60 ml/min per 1.73 m Regarding the impact of CKD on medical care cost, CKD patients were reported to have higher chances of cardiovascular events and hospitalizations. Taiwan BNHI data showed that patients with CKD had higher rates of outpatient visits, hospitalizations and medical expenses compared to patients without CKD (unpubl. data, 2006). Based on the subset data of Taiwan BNHI of USRDS, elderly patients with CKD (>65 years) comprised 7.7% of the total elderly population but utilized 15.9% of medical costs. 29 Furthermore, medical expenses from the accompanying diseases of CKD, such as diabetes or cardiovascular disease, may aggravate the problem of soaring medical costs. Thus, medical expenses from CKD/ESRD and their comorbidities have worsened the already heavy burden of health-care economics in Taiwan and many high-epidemic CKD countries. NATIONWIDE CKD PREVENTION PROJECT AND OUTCOME In 2001, the TSN made a proposal to the DOH, Taiwan that CKD prevention and care should be placed as one of the major public health priorities. Thereafter, the nationwide CKD Preventive Project was launched under the collaboration of the TSN and Bureau of Health Promotion (BHP), DOH. An integrated CKD care program was initiated to promote the screening of high-risk populations, patient education and multidisciplinary team care. This program was developed in several leading tertiary hospitals in the first phase of the project and has now been extended to 90 institutes by Presently, more than patients with CKD have been recruited. To gear up this CKD Preventive Project, the BNHI started to provide reimbursement on comprehensive pre-esrd care for patients of CKD stage 4 5 since An intensive urinary screening program was also conducted for the family members of patients with ESRD under this project. Although the annual budget of reimbursement for CKD was only approximately $US 2 million in 2008, this policy greatly encourages the nephrologists from tertiary hospitals to primary care to conduct this integrated CKD care program. Extended coverage to patients of CKD stage 1 3 and recruitment of non-nephrologist physicians will be launched in the future. Throughout this nationwide CKD Preventive Project in Taiwan, successful experiences have been found. One study Journal compilation 2010 Asian Pacific Society of Nephrology 7

6 S-J Hwang et al. from northern Taiwan showed that a multidisciplinary predialysis education (MPE) program had significantly lower overall mortality (1.7% for MPE group vs 10.1% for non- MPE group). 44 This MPE program also reduced the incidence of dialysis (13.9% for MPE group vs 43.0% for non-mpe group) over a mean follow up of 11.7 months. Another study from southern Taiwan also proved that multidisciplinary pre- ESRD care significantly reduced medical costs for the dialysis period (mean $US vs $US /patient) and during the total observation period ($US vs $US /patient). 45 These encouraging outcomes have created a foundation of successful experiences of the CKD Preventive Project in Taiwan. More evidences for improving patients outcome and reducing health-care burden is awaited from the ongoing large-scale population, multi-centres collaborative researches on CKD Prevention and Care Plan in Taiwan supported by the Institute for Biotechnology and Medicine Industry and National Health Research Institute of Taiwan. CONCLUSION Taiwan has been recognized as an epidemic area of kidney disease with the highest incidence and prevalence rates of ESRD. Although its prevalence of CKD approximates the reported prevalence of CKD from other Asian and Western countries, it might be underestimated because of low awareness of CKD. The impact of CKD on public health burden is worsening with increasing comorbidities and mortality, and huge medical expenses. More emerging potential risk factors for CKD drive us to pay more attention to these new highrisk groups with an extended screening program. The nationwide CKD Preventive Project with multidisciplinary care program has proved its effectiveness in decreasing dialysis incidence, mortality and medical costs. Provision of a more comprehensive preventive strategy and better care plan for CKD should be achieved by future international collaborative efforts and research. CONFLICT OF INTEREST The Authors state that there is no conflict of interest regarding the material discussed in the manuscript. REFERENCES 1. El Nahas AM, Bello AK. Chronic kidney disease: The global challenge. Lancet 2005; 365: Levey AS, Atkins R, Coresh J et al. Chronic kidney disease as a global public health problem: Approaches and initiatives A position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 2007; 72: Levey AS, Schoolwerth AC, Burrows NR, Williams DE, Stith KR, McClellan W. 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