Kidney Disease Screening Program in Japan: History, Outcome, and Perspectives

Special Feature: Screening Series

Enyu Imai,* Kunihiro Yamagata,† Kunitoshi Iseki,‡ Hiroyasu Iso,§ Masaru Horio,* ʈ Hirofumi Mkino, Akira Hishida,¶ and Seiichi Matsuo** Departments of *Nephrology and §Public Health, Osaka University Graduate School of Medicine, Suita, Osaka, †Department of Nephrology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Science, ʈ University of Tsukuba, Ibaraki, ‡Dialysis Unit, University Hospital of the Ryukyus, Okinawa, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, ¶First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, and **Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan

In the early 1970s, mandatory kidney disease screening was started with urinalysis in the Japanese health examination program for all workers and school-age children. In 1983, nationwide urinalysis screening in adults aged >40 yr was mandated in the community-based health examination program. Because glomerulonephritis was an endemic disease and the leading cause of end-stage renal disease in Japan until 1997, the urinalysis in the annual health examination program aimed for early detection of glomerulonephritis and early referral of patients to physicians. To the programs, measurement of serum creatinine was added for detection of chronic kidney disease in 1992 for adults aged >40 yr. Kidney disease screening and early intervention brought reduction of progressive glomerulonephritis or an increase in remission. Thus, in children and adults aged <45 yr, the number of patients with end-stage renal disease from glomerulonephritis has declined, and the mean age of patients with new end-stage renal disease has increased significantly. In 1998, the leading cause of end-stage renal disease was shifted from glomerulonephritis to diabetic nephropathy as a result of lifestyle changes in the Japanese population; however, the present comprehensive kidney disease screening in the health examination program for detection of glomerulonephritis must be continued, because even in 2005, 27.3% of newly developed end-stage renal disease was from glomerulonephritis. An additional kidney disease screening program should also be established to target patients with high risk for diabetes, hypertension, and metabolic syndrome, because 42% of newly introduced renal replacement cases were from diabetic nephropathy in 2005. Clin J Am Soc Nephrol 2: 1360–1366, 2007. doi: 10.2215/CJN.00980207

n epidemic of chronic kidney disease (CKD) is a History of Kidney Disease Screening of the worldwide health problem (1,2). It not only progress Health Examination Program in Japan A to the ESRD but also is a major risk factor for cardio- Concern about health problems in the Japanese workforce, the vascular disease (CVD) (3). Although every effort has been Ministry of Labor implemented a mandatory, nationwide, com- made to reduce CKD and the known leading causes of CKD— pany-based health examination program in 1973, including diabetes, hypertension, and metabolic syndrome—the past blood chemistry and urinalysis. In 1974, the Ministry of Edu- measures taken to treat these clinical conditions were insuffi- cation, Science and Culture initiated the mandatory school- cient. Eventually, the incidence of ESRD and CVD reached high based health examination program for school children aged 6 to in both developed and developing countries. In addition, many 18 to meet the requirement of the School Health Law. In the countries are burdened by their own endemic renal conditions program, urinalysis was performed to identify the early stage (4); IgA nephropathy (IgAN) in Asia (5); hepatitis B–related of glomerulonephritis in children. The screening, initially per- nephropathy in Asia and Africa; and HIV-associated nephrop- formed biannually, was reduced to annually in 1979. In 1983, athy in Africa, Asia, Europe, and the United States. Implement- the Ministry of Health and Welfare mandated the nationwide ing and establishing a kidney disease screening program is important to prevent CKD and particularly to detect in the community-based health examination program for adults aged Ն early stage of CKD. 40 yr by law, which included urinalysis. Since then, urinalysis in the annual health examination program has been accepted by the Japanese public. In 1992, measurement of serum creatinine level in adults aged Ն40 yr was added to both the com- Published online ahead of print. Publication date available at www.cjasn.org. pany-based and community-based annual health examination Correspondence: Dr. Enyu Imai, Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879- program for detection of CKD. The combination of urinalysis 3632; Fax: 81-6-6879-3639; E-mail: [email protected] and measurement of serum creatinine level has contributed to

Copyright © 2007 by the American Society of Nephrology ISSN: 1555-9041/206–1360 Clin J Am Soc Nephrol 2: 1360–1366, 2007 Kidney Disease Screening Program in Japan 1361 detection of early-stage CKD in Japanese adults aged Ն40 yr. workers aged 20 to 60 (11,933,703 individuals) received urinal- The kidney disease screening implemented in Japan has been ysis tests. For the adults without full-time jobs, urinalysis and systemic and nationwide, covering both school-age children blood chemistry are available in the community-based health and adults. examination program, the same as the company-based screening programs. In general, approximately half of the people Practice of the Japanese Kidney Disease eligible participate in community-based health examination Screening and Public Policy program. After the workers retire, they participate in the com- Glomerulonephritis was an endemic disease in Japan and the munity-based screening program. With urinary protein ϩ1or primary cause of ESRD until 1997 (6). Because glomerulone- more, the participants receive the second screening test for phritis is easily diagnosed with proteinuria and hematuria, urinary protein. If both tests are positive, then they receive a urinalysis in the annual health examination program was ini- diagnosis of proteinuria. tially mandated to aim for identifying the early stage of glo- For adults aged Ն40 yr, the company- and community-based merulonephritis and for the early referral to a physician. Al- health examinations are carried out more extensively. The pro- though glomerulonephritis dropped to the second leading gram includes a chest x-ray; urinalysis; and blood chemistry, cause of ESRD in 1998, glomerulonephritis continued to be a including serum creatinine, aminotransferases, uric acid, blood major cause of ESRD. Even in 2005, still 27.3% of new ESRD glucose, total cholesterol, LDL cholesterol, triglycerides, and cases involved glomerulonephritis (6). HDL cholesterol. According to the Ministry of Health, Welfare The Minister of Health, Welfare and Labor has been making and Labor, 44% of Japanese adults who were aged Ն40 yr and an extensive effort to reduce the number of patients with ESRD. did not have full-time jobs (12,983,593 individuals) participated The main strategy has been to establish an effective communi- the kidney disease screening in the health examination pro- ty-, company-, and school-based kidney disease screening gram in 2004. system. A cross-sectional study reported that prevalence of proteinuria was 4.1% (12,238 of 298,537) when urinary protein in Screening Program for Children spontaneously voided fresh urine sample was measured by In Japan, all school children receive a free urinalysis in the dipstick test, and the criteria for proteinuria was urinary pro- school-based health examination program. Urinalysis is gener- tein ϩ1 or more (approximately Ͼ30 mg/dl) (9). According to ally carried out in three stages. Proteinuria is verified by two a study conducted in 1983 in Okinawa, proteinuria and hema- consecutive positive results of the tests. The first screening is turia both tested with dipstick methods occurred in 5.3 and carried out in all school children by dipstick urinalysis. Chil- 9.0% of the general population, respectively (10). In an average dren are instructed to empty the bladder completely before 6.3-yr follow-up study, new proteinuria developed in 0.4 to sleep; the next morning, the first urine sample is brought to 0.9% of the Japanese working men, and among those with school for urinalysis. Dipstick urinalysis mainly detects protein proteinuria, 20% had persistent proteinuria and 75% received a and occult blood in urine. The second screening tests are per- diagnosis of chronic glomerulonephritis by biopsy (11). Yama- formed within 1 to 3 mo from the first screening for the children gata et al. (12) reported that newly developed proteinuria was who had proteinuria or hematuria in the first test. The child found in 0.61% of men and in 0.34% of women annually on the with two consecutive positive results receives a diagnosis of basis of community-based health examination programs for CKD, and the school physician suggests that that child see the adults aged Ն40 yr. In contrast, the prevalence of proteinuria family physician. The family physician generally checks serum was 0.01% in men and 0.19% in women of the screened popu- creatinine, urea nitrogen, uric acid, total protein, albumin, IgA, lation in the United States (13), which were 1/20 to 1/60 of the complement 3, and anti-streptolysin O. From the results, the prevalence in Japan. physician may recommend that the child see a nephrologist. The nephrologist may perform a renal biopsy if necessary. From 1983 to 1999, 29 of 270,902 children who participated in the school urinalysis screening demonstrated suspected chronic Evaluation of the Kidney Disease Screening nephritis on the basis of abnormal urinalysis and underwent Program renal biopsy (7). Of the 29 children, 14 children had IgAN Kidney Disease Screening Program for Children Has the school urinalysis screening contributed to the remis- confirmed. Pediatric IgAN occurred in 4.5 of 100,000 children sion or regression of kidney disease in children? Glomerulone- who were younger than 15 yr per year. In 2004, the patient rate phritis was the leading cause of ESRD, 68.9%, in children be- of proteinuria was 0.11% and that of hematuria was 0.83% tween 1978 and 1980. By 1999, this percentage had fallen to according to the results of school urinalysis screening. The rate 34.5% (14). The number of children with ESRD from glomeru- of children with both proteinuria and hematuria was 0.05% (124 of 246,368) in elementary school children (8). The preva- lonephritis had declined since 1974. In 1998, new ESRD oc- lence of chronic glomerulonephritis is much lower in children curred in 4 per 1 million children who were younger than 19 yr, than in adults. whereas it occurred in 15 per 1 million in the United States (15,16). The early referral and adequate intervention for glo- Screening Program for Adults merulonephritis may have reduced the occurrence of ESRD in For all workers in Japan, free urinalysis is given annually in children. Overall, the school urinalysis screening system seems company-based health examination programs. In 2004, 83% of to be working effectively. 1362 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: 1360–1366, 2007

Kidney Disease Screening Program for Adults opment of ESRD was reported by Iseki et al. (10). In the 17-yr Has the Japanese kidney disease screening program reduced follow-up study of 106,177 residents in Okinawa from 1983 to the number of dialysis patients who progress from glomerulo- 2000, 420 people developed ESRD, and the adjusted odds ratio nephritis? Is the screening program reasonably cost effective? for development of ESRD from proteinuria was 2.71. The ad- The effectiveness of the kidney disease screening system for justed odds ratio even for urinary protein ϩ1 was 1.93 in men adults was evaluated by two studies. Wakai et al. (17) reported and 2.42 in women. In addition, the study suggested that pro- that age-adjusted incidence of ESRD from chronic glomerulo- teinuria is a strong, independent predictor of ESRD, and the nephritis was decreased in both men and women since 1996 screening result of proteinuria is a key predictor for ESRD. (Figure 1). The incidence of ESRD from glomerulonephritis in Moreover, Iseki et al. (19) studied the 7-yr cumulative incidence men was 96.3 per 1 million in 1995 to 1996 and decreased to 84.0 of ESRD in 143,948 individuals of the general population in per 1 million in 1999 to 2000, whereas the incidence of ESRD Okinawa on the basis of baseline creatinine clearance (Ccr) from diabetes increased from 81.1 per 1 million in 1995 to 1996 quartile (Figure 3). The presence of proteinuria had a significant to 96.7 per 1 million in 1999 to 2000 (17). In women, the impact on the cumulative incidence of ESRD. Of individuals phenomenon was similar. The incidence of ESRD from glomer- with Ccr Ͻ50 ml/min and proteinuria, 8.5% initiated to dialy- ulonephritis was 52.7 per 1 million in 1995 to 1996 and de- sis. In contrast, of individuals who had Ccr Ͻ50 ml/min with- creased to 46.1 per 1 million in 1999 to 2000, whereas that of out proteinuria, 0.1% reached ESRD. In individuals who had diabetes increased from 38.2 per 1 million to 42.5 per 1 million, Ccr Ͼ80 ml/min without proteinuria, none developed ESRD, respectively (17). Yamagata et al. (18) reported that patients whereas in individuals with proteinuria, 1.0% developed who have glomerulonephritis and reach ESRD is at higher age ESRD. The results suggested that proteinuria is a strong indi- in Japan compared with in the United States. The mean age of cator of CKD deterioration, and screening proteinuria is also developing new ESRD from glomerulonephritis shifted signif- clinically useful for identifying the high-risk population for icantly to higher age, and the proportion of glomerulonephritis ESRD. decreased in all causes of ESRD (Figure 2). In Japan particu- Advancement in treatment of CKD also affects number of larly, new ESRD from glomerulonephritis decreased in number patients with ESRD. Angiotensin-converting enzyme inhibitors among those who were younger than 45 yr (18). have been available in Japan since 1983 and angiotensin recep- Various factors may explain the decline in the number of tor blockers (ARB) since 1998. The effects of the treatments patients with ESRD from glomerulonephritis. One reason may must be epidemiologically evaluated on CKD progression to be the reduced infection-related glomerulonephritis as a result ESRD. of improved therapeutic intervention. Poststreptococcal acute Particularly in Japan, IgAN was the most common form of glomerulonephritis and hepatitis B– and C–related glomerulo- glomerulonephritis like other Asian countries. Among patients nephritis were reduced probably by use of antibiotics and the who had primary glomerulonephritis and underwent renal appropriate prophylactic treatment after the diagnosis of hep- biopsy, 47.4% had IgAN (20). The higher incidence of IgAN in atitis; however, both types of glomerulonephritis accounted for glomerulonephritis has been a characteristic in Japan. The Jap- only a few percent in patients who underwent renal biopsy, anese kidney disease screening program has successfully de- suggesting that the decline in the infection-related glomerulo- tected milder forms of glomerulonephritis, in particular en- nephritis may have little effect on the total number of cases of demic IgAN, and has helped early intervention and perhaps newly developed ESRD. has led to a delay in the need for renal replacement therapy. A significance of proteinuria in CKD progression and devel- Specific treatments of IgAN, such as steroids (21), steroid pulse therapy (22), and tonsillectomy followed by steroid pulse therapy (23), have been widely used in patients with IgAN, as well as with angiotensin-converting enzyme inhibitor and ARB treatment in Japan. There are difficulties in interpreting the effectiveness of the kidney disease screening program from the declined number of cases of ESRD from glomerulonephritis for following reasons: (1) Significant improvement in therapy for glomerulonephritis occurred in the past 10 yr, and (2) not enough data on the effectiveness of the therapeutic intervention was accumulated in patients who were identified in the kidney disease screening. The cost-effectiveness of kidney disease screening can be evaluated in following two aspects. CKD is a risk factor not only for ESRD but also for CVD. Go et al. (24) reported that the risk for cardiovascular events increased in proportion to de- Figure 1. Change in crude incidence rates (per million popula- creased estimated GFR. Risk for CVD was evaluated in the tion [PMP]) of ESRD from all causes, diabetic nephropathy, and Japanese CKD population. Irie et al. (25) reported that relative glomerulonephritis by gender in Japan (17). Diabetes increased risk for all cardiovascular death in patients with both protein- as glomerulonephritis decreased. Data were adjusted for age. uria and GFR Ͻ60 ml/min per 1.73 m2 was 2.15-fold (95% Clin J Am Soc Nephrol 2: 1360–1366, 2007 Kidney Disease Screening Program in Japan 1363

Figure 2. Age distribution of patients who newly started maintenance renal replacement therapy in Japan (18). Each line represents a particular year from 1983 (bottom) to 1999 (top). Total number of patients with ESRD increased year by year. The mode of the age group increased year by year in total patients (A), and an apparent increment was observed in patients with glomerulonephritis (B). In contrast, only a slight increment was observed in patients with hypertension (C) and patients with diabetes (D).

confidence interval [CI] 1.28 to 3.60) higher than in patients similar between patients with ESRD from glomerulonephritis without proteinuria and with normal GFR in men and 4.00-fold and those with ESRD from diabetes, 65.8 and 65.1, respectively. (95% CI 2.62 to 6.10) higher in women. Ninomiya et al. (26) The patients with glomerulonephritis composed 43.6% of the reported in a 12-yr study that the incidence of CVD was 1.62- total hemodialysis patients, whereas those with diabetes ac- fold (95% CI 1.10 to 2.39) higher in patients with CKD com- counted for only 31.4% in 2005, although diabetes has been a pared with patients without CKD. CKD is a risk factor for CVD leading cause of ESRD (42.0% in 2005). These results depict a in the Japanese general population, although the cardiovascular characteristic of Japanese hemodialysis therapy and strongly events occurred at 9.8 in 1000 person-years in Japan (26); the support the idea that reducing ESRD that is caused by glomer- rate was 78% less than that in United States: 44.1 in 1000 ulonephritis is crucial to reducing the medical expense of dial- person-years (24). Thus, preventing CKD by kidney disease ysis therapy in Japan. screening plays a role in reduction of CVD, in turn reducing the expense of CVD treatment. Perspectives of Kidney Disease Screening The most striking aspect of Japanese dialysis therapy is that Program the longevity of hemodialysis patients is much higher in those Japan CKD initiatives with glomerulonephritis than in those with diabetes. According CKD screening in the Japanese general population is beneficial to the Japanese Society of Dialysis Therapy (6), the rates for 5-, to both individuals and the government. In fact, CKD can be 10-, 15-, and 20-yr survival were 70.1, 52.7, 40.6, and 30,8%, diagnosed by the combination of urinalysis and serum creati- respectively, in hemodialysis patients whose ESRD developed nine if accurate GFR could be estimated from serum creatinine; from glomerulonephritis. In contrast, the rates for 5-, 10-, 15-, however, data from the kidney disease screening program have and 20-yr survival were much less, 55.0, 28.0, 13.3, and 6.2%, not been fully used for prevention of CKD in Japan. Family respectively, in hemodialysis patients whose ESRD developed physicians do not always follow up with patients with protein- from diabetes, although the mean ages of entering dialysis were uria, and they do not routinely calculate estimated GFR by 1364 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: 1360–1366, 2007

Change in Policy for the Kidney Disease Screening Program As described, the kidney disease screening initially aimed to reduce glomerulonephritis in Japan; however, the leading cause of ESRD has changed to diabetes since 1998, and as the prevalence of diabetes increased, that of glomerulonephritis decreased. According to the Ministry of Health, Welfare and Labor, the prevalence of diabetes, with the definition of glyco- sylated hemoglobin Ͼ6.1%, was estimated to be 6.8% of the adult population (6.9 million) in 1997 and 7.3% (7.4 million) in 2002, and half of them were not treated. The third cause of ESRD has been hypertension since 1998 (17). In addition, metabolic syndrome has been recently recognized as a major risk factor for progressive CKD. Iseki et al. (29) reported that high body mass index was a risk for ESRD in Okinawa. In the study Figure 3. Seven-year cumulative incidence of ESRD according to of the general population, Ninomiya et al. (30) and Tanaka et al. baseline creatinine clearance (Ccr) and result of urine test for proteinuria (19). Ccr was estimated by the Cockcroft-Gault (31) reported that CKD incidence was significantly greater in equation and classified into four categories. Presence of pro- individuals with metabolic syndrome, and the cumulative in- teinuria defined by more than ϩ1 with dipstick test is a strong cidence of CKD increased in proportion to the increased num- predictor of ESRD. ber of metabolic syndrome risk factors, including hypertension, hypertriglyceridemia, low HDL cholesterol, and high blood glucose. It is interesting that triglyceride but not LDL cholesterol was a risk factor for proteinuria in Japan (32). Because the underestimating the usefulness of serum creatinine value in type of kidney disease has shifted from glomerulonephritis to early detection of CKD; therefore, the Japanese Society of Ne- diabetic nephropathy and hypertensive nephrosclerosis as a phrology launched the Japanese CKD initiatives in 2004 and a result of lifestyle change, a new screening system may be comprehensive program to promote prevention of CKD and needed. Performing kidney disease screening that is limited to the education of physicians. particular clinical conditions in a population may improve the The first task was to conduct an epidemiologic study to cost-effectiveness; however, there remains a concern that lim- survey the incidence of CKD in the Japanese general popula- iting the screening to patients with hypertension, diabetes, and tion; however, there are important problems to be solved in metabolic syndrome may not work effectively for Japanese, GFR estimation for Japanese. In general, GFR has been calcu- because the second leading cause of new ESRD, glomerulone- lated by the Cockcroft-Gault equation or by the Modification of phritis, is not associated with these conditions. Diet in Renal Disease (MDRD) Study equation; however, both There have been reports that Asian patients with diabetes are were developed in white and black individuals, so their per- predisposed to nephropathy compared with white patients formance is not adequate in the Japanese population. In fact, (33). Parving et al. (34) reported that Asian patients had a higher both Cockcroft-Gault and MDRD Study equations were found prevalence of elevated urinary albumin/creatinine ratio (55%) to overestimate GFR in Japanese, even when serum creatinine than did white patients (40.6%; P Ͻ 0.0001). Wu et al. (35) also was assayed by the noncompensated Jaffe method (27). To reported that the prevalence of microalbuminuria and mac- correct the problems we modified the four-variable MDRD roalbuminuria were 39.8 and 18.8%, respectively, among pa- Study equation with a Japanese coefficient of 0.881 for accurate tients with diabetes in Asian countries. GFR estimation (27). A subanalysis of data of Asian patients in the Reduction of With the equation, we examined the prevalence of CKD in Endpoints in NIDDM with the Angiotensin II Antagonist Lo- participants of the nationwide annual health examination pro- sartan (RENAAL) study demonstrated that ARB tend to be gram in seven prefectures of Japan using GFR estimated from more effective on Asian patients (36), particularly on Japanese the serum creatinine and with the Japanese coefficient-modi- (37), than on white patients in delaying the progression of fied MDRD Study equation (27). From the study results of diabetic nephropathy; therefore, early detection of diabetic ne- 527,594 individuals, prevalence of CKD was predicted be 19.1 phropathy and intervention of progressive diabetic nephropa- million in patients of stage 3 CKD and 200,000 in patients with thy are particularly meaningful in Japanese patients. stages 4 and 5 CKD among the general adult population using Lately, clinical relevance of microalbuminuria as a marker of adult population of 103.2 million in 2004 (9). diabetic nephropathy has drawn the attention of clinicians. Recently, we also improved the GFR estimation in Japanese According to a study (38) of the Japanese general population, using serum creatinine values determined by an enzymatic there is a high prevalence of microalbuminuria, 13.7%, in adults method and modified the isotope dilution mass spectrometry– aged Ն40 yr. As a clinical strategy to identify patients with traceable MDRD Study equation (28). To improve further the microalbuminuria and to detect early-stage diabetes–, meta- performance in GFR estimation, we have been creating an bolic syndrome–, and hypertension-related renal disease, the original equation for the Japanese using measured GFR of initial screening may be ideal; however, the initial nationwide inulin clearance. The project just completed. screening test is unrealistic because the cost is too expensive. Clin J Am Soc Nephrol 2: 1360–1366, 2007 Kidney Disease Screening Program in Japan 1365

National health insurance has been allowing quarterly mea- proteinuria screening has been practiced for Ͼ30 yr in school surement of microalbuminuria for screening of diabetic ne- children and all workers, and serum creatinine measurement phropathy since 2000. has been continued for the past 15 yr in adults aged Ն40 yr. The For early detection, a joint committee of the Japanese Diabetic incidence of ESRD from glomerulonephritis declined and the Society and the Japanese Society of Nephrology published diag- rate of early referral to the physician increased yearly; however, nostic criteria for diabetic nephropathy in 2004 (39). The commit- as a result of lifestyle changes in Japanese in the past 10 yr, the tee recommended the following procedures for diagnosis: Mi- types of kidney disease changed from glomerulonephritis to croalbuminuria is to be verified by two positive results of the three diabetic nephropathy and hypertensive nephrosclerosis. New urinary microalbumin tests. Microalbuminuria is defined by ei- kidney disease screening program for targeting patients with ther 30 to 299 mg albumin/g creatinine in spot urine or 30 to 299 diabetes, hypertension, and metabolic syndrome may be re- mg/d by 24-h urine collection. In addition, increased kidney size quired; however, keeping the present nationwide kidney dis- as observed by ultrasound and the appearance of urinary type IV ease screening system is crucial for management of major CKD collagen (8 ␮g/g Cr) in spot urine are the supportive data for the and reducing medical costs in Japan. diagnosis (39); however, Japanese national health insurance does not allow measurement of urinary microalbumin for screening of renal injury as a result of hypertensive renal disease. Although Disclosures clinical relevance of microalbuminuria in diabetes is well estab- None. lished, it is not widely recognized by physicians in Japan. 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