Nephrology for the people: Presidential Address at the 42nd Regional Meeting of the Japanese Society of Nephrology in Okinawa 2012
- First Online:
The social and economic burdens of dialysis are growing worldwide as the number of patients increases. Dialysis is becoming a heavy burden even in developed countries. Thus, preventing end-stage kidney disease is of the utmost importance. Early detection and treatment is recommended because late referral is common, with most chronic kidney disease (CKD) patients remaining asymptomatic until a late stage. Three-quarters of dialysis patients initiated dialysis therapy within 1 year after referral to the facility. Since its introduction in 2002, the definition of CKD has been widely accepted not only by nephrologists but also by other medical specialties, such as cardiologists and general practitioners. Japan has a long history of general screening for school children, university students, and employees of companies and government offices, with everybody asked to participate. The urine test for proteinuria and hematuria is popular among Japanese people; however, the outcomes have not been well studied. We examined the effects of clinical and laboratory data from several sources on survival of dialysis patients and also predictors of developing dialysis from community-based screening (Okinawa Dialysis Study, OKIDS). At an early CKD stage, patients are usually asymptomatic; therefore, regular health checks using a urine dipstick and serum creatinine are recommended. The intervals for follow-up, however, are debatable due to the cost. CKD is a strong risk factor for developing cardiovascular disease and death and also plays an important role in infection and malignancies, particularly in elderly people. People can live longer with healthy kidneys.
KeywordsSurvival Predictor Chronic kidney disease (CKD) End-stage kidney disease (ESKD) Proteinuria
Although kidney disease patients can survive without kidney function, dialysis is a life-saving procedure. However, many complications related to chronic kidney disease (CKD) have not been resolved, including cardiovascular disease (CVD), mineral and bone disorders (CKD-MBD), and infection . Nephrology is a relatively new sub-specialty in the field of internal medicine, and we are still learning the extent of how the kidneys support the body. The social and economic burdens of dialysis are growing worldwide as the number of patients increases. Dialysis is becoming a heavy burden even in developed countries. Thus, preventing end-stage kidney disease (ESKD) is of the utmost importance. Early detection and treatment is recommended because late referral is common, with most CKD patients remaining asymptomatic until a late stage. According to the annual report from the Japanese Society for Dialysis Therapy (JSDT), three-quarters of dialysis patients initiated dialysis therapy within 1 year after referral to the facility .
CKD is clinically defined by the presence of albuminuria and/or a decrease in kidney function for >3 months. Since its introduction in 2002, the definition of CKD has been widely accepted not only by nephrologists but also other medical specialties, such as cardiologists and general practitioners. Japan has a long history of universal screening for school children, university students, and employees of companies and government offices. The urine test for proteinuria and hematuria is popular among Japanese people; however, the outcomes have not been well studied.
Okinawa dialysis study (OKIDS)
Risk factors for death in chronic dialysis patients (modified from Iseki et al. CEN2004 )
Primary renal disease (diabetes, nephrosclerosis)
Predialysis comorbid conditions (cardiovascular disease, malignancies)
High coronary artery calcification score
Hyper- and hypophosphatemia
Several randomized controlled trials, such as the treatment of anemia using an erythropoietin-stimulating agent [21, 22] and statin treatment [23, 24], have failed to show an improvement in survival. Hypertension is a major risk factor for death and cardiovascular disease in dialysis patients, but the effect of lowering blood pressure in this high-risk patient group is uncertain. We examined the effect of an angiotensin receptor blocker on survival . In a multicenter prospective, randomized, open-label, blinded-endpoint trial, we assigned 469 patients on chronic hemodialysis (HD) with hypertension to receive the angiotensin receptor blocker olmesartan (n = 235) or a treatment other than an angiotensin receptor blocker or angiotensin-converting enzyme inhibitor (n = 234). Lowering blood pressure with an angiotensin receptor blocker did not significantly lower the risk of major cardiovascular events or death among patients with hypertension on chronic HD .
Two community-based registries for ESKD patients and general screening have been available to us [27, 28]. The Okinawa General Health Maintenance Association (OGHMA) has been performing universal screening annually in Okinawa. Since 1983, they have filed records in the computer registry. With full collaboration of the physicians and medical staff, we were able to match subjects who participated in the screening and later developed ESKD. Because the area consists of sub-tropical islands, the ESKD or CKD stage 5 patients reside exclusively in Okinawa. After verifying the databases from 1983 (n = 106,182) and 1993 (n = 143,948), we analyzed the relationship between commonly measured laboratory variables and ESKD [27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40]. The total number of identified ESKD patients was 420 from 1983 to 2000.
Risk factors for the development of ESKD (modified from Iseki et al. CEN2005 )
Past history of cardiovascular disease
Family history of cardiovascular disease
Clinical and laboratory variables
Obesity, metabolic syndrome
Only a few studies outside Japan have examined the effect of microhematuria on developing ESKD. Microhematuria is relatively common, particular in elderly women. Compared to proteinuria, the risk of microhematuria was significant, but showed a weak dose–response relationship. The absolute risk of microhematuria was low but was a statistically significant predictor of ESKD . Notably, microhematuria is a risk factor for developing proteinuria; if combined with proteinuria, the risk of developing ESKD is even higher compared to having proteinuria alone .
The Japanese Society for Dialysis Therapy (JSDT)
The early initiation of dialysis has been practiced worldwide, and the mean initial estimated glomerular filtration rate (eGFR) is becoming higher than ever before [45, 46, 47]. The eGFR threshold for starting dialysis is not available. According to the JSDT, the survival was best at around eGFR 4–6 ml/min/1.73 m2 [48, 49]. The effect of confounding variables other than age and diabetes is unknown, and we need more data to determine the eGFR threshold. Most Japanese nephrologists rely on the research group criteria supported by the Ministry of Health, Welfare, and Labor, which use eGFR and the presence of uremic symptoms. The threshold for manifesting ‘uremic symptoms’ is variable between patients. Judging the ‘right timing’ would be determined ideally by the physician, patient, and family. Continuing conservative management without dialysis is an alternative option for elderly patients.
The Japanese Society of Nephrology (JSN)
The JSN has published the ‘Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney Disease’ in 2007, 2009, and 2012 . The “Evidence-based Practice Guideline for the treatment of CKD” was published in 2009 and will be updated in 2013 . The JSN has been raising awareness of CKD on World Kidney Day, which is on the second Thursday in March. Importantly, Japanese patients generally have a lower eGFR compared to American patients. Therefore, an eGFR ≥60 ml/min/1.73 m2 is considered to be normal for someone who is otherwise healthy. Albuminuria can only be measured and reimbursed for patients with early-stage diabetic kidney disease in Japan. Instead, the JSN advocates using dipstick proteinuria or measuring the daily amount of proteinuria.
JSN criteria for referring CKD patients to a nephrologist (cited from ref. )
Proteinuria (≥2+ by dipstick proteinuria)
Combined proteinuria and hematuria (both 1+ and over by dipstick proteinuria)
Low eGFR (<50 ml/min/1.73 m2): <60 ml/min/1.73 m2 (if age <40 years) and <40 ml/min/1.73 m2 (if age ≥70 years)
Kidney Disease: Global Outcomes Improving Outcomes
Since the introduction of the concept of CKD, the definition has been challenged with several criticisms: (1) the classification was too simple, (2) lack of key outcomes of CKD, and (3) significance of testing eGFR and albuminuria. In this setting, the KDIGO-Controversies Conference was held from October 4–6, 2009 in London . We offered the dataset, including serum creatinine and dipstick proteinuria, for the conference. After the conference, the CKD classification was slightly modified and expressed as ‘the CKD heat map’. The clinical impacts of eGFR and albuminuria were investigated for several major outcomes [57, 58, 59, 60, 61].
To further examine the significance of the classification, the KDIGO CKD prognosis consortium (PC) was organized. We are privileged that the Okinawa 1983/1993 cohorts were involved in the KDIGO-PC. The phase 2 analyses have already been completed for seven major topics, such as hypertension, diabetes, gender, ethnicity, age, CKD epidemiology collaboration, and cystatin C [62, 63, 64]. The significance of a low eGFR and albuminuria was confirmed for all-cause mortality and cardiovascular mortality. The relative risks of these markers were similar, but the absolute risks were different based on age, sex, and the presence of diabetes or hypertension. Currently, there will be an additional 13 topics in the Phase 3 step to be studied soon. The new KDIGO ‘Clinical Practice Guideline’ will be published shortly .
CKD patients are at risk of developing acute kidney injury due to contrast media, nephrotoxic drugs, surgery, and dehydration. CKD is a strong risk factor for developing CVD and death and also plays an important role in infection and malignancies, particularly in elderly people. People can live longer with healthy kidneys.
Japan is a front runner in ‘the new society’ of a world where the elderly population (≥65 years) is the most prevalent, reaching 30 % in 2020 . Moreover, the total population is decreasing. Japan is the leader of medicine for an aged society and the science of ageing. We need further studies on the natural history of CKD progression and GFR trajectory . High-quality observational studies could promote basic science and stimulate the invention of new treatments for CKD. The mechanisms of age-related GFR decline are entirely unknown, and we have no way to delay the process. Further research on the role of CKD along with other medical conditions, such as infection, mental disorders, CKD-MBD, and malignancies is needed, especially among the elderly population. CKD campaigns in public and medical communities should be continued in order to delay, if not prevent, the development of ESKD. Many cases of CKD are left unrecognized, but the condition can be treated even at late stages, so screening is always beneficial.
The author acknowledges the staff from Ryukyu University, the Okinawa Dialysis Study, and the Okinawa General Health Maintenance Association for their invaluable help and encouragement. Data management and verification and the statistical analyses were performed by Ms. C Iseki and Professor O. Morita from Fukuoka University. Grant support was from the Ministry of Education, Culture, Sports, Science and Technology in Japan (K. Iseki), the Health and Labor Sciences Research Grants for ‘Research on the positioning of chronic kidney disease (CKD) in specific health check and guidance in Japan” (20230601), and the Ministry of Health, Labor and Welfare of Japan (T. Watanabe). Part of this study was supported by Health and Labor Sciences Research Grants for ‘Design of the effective CKD medical cooperation system linked up with health guidance based on assessment of an individual’s risk by specific health checkup’ (12103111) from the Ministry of Health, Labor and Welfare of Japan.
Conflict of interest
The author has no conflict of interest to declare.
- 1.K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–S266Google Scholar
- 2.Nakai S, Iseki K, Itami N, et al. An overview of regular dialysis treatment in Japan (as of December 31, 2010). Ther Apher Dial. 2012.Google Scholar
- 19.Iseki K. Reverse epidemiology in chronic hemodialysis patients. Nephrol Front. 2007;6:82–3.Google Scholar
- 26.Iseki K, Arima H, Kohagura K, Komiya I, Ueda S, Tokuyama K, Shiohira Y, Uehara H, Toma S. Effects of ARB on mortality and cardiovascular outcomes in patients with long-term haemodialysis: a randomized controlled trial. Nephrol Dial Transplant. 2013 (in press).Google Scholar
- 29.Iseki K, Ikemiya Y, Fukiyama K. Blood pressure and risk of end-stage renal disease in a screened cohort. Kidney Int. 1996;49(Suppl 55):S69–71.Google Scholar
- 31.Iseki K, Ikemiya Y, Fukiyama K. Predictors of end-stage renal disease and body mass index in a screened cohort. Kidney Int. 1997;52(Suppl 63):S169–70.Google Scholar
- 50.Japanese Society of Nephrology. Clinical practice guidebook for diagnosis and treatment of chronic kidney disease. Tokyo: Tokyo Igakusha; 2012.Google Scholar
- 51.Japanese Society of Nephrology. Evidence-based practice guideline for the treatment of CKD. Tokyo: Tokyo Igakusha; 2009.Google Scholar
- 65.KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013Google Scholar
- 66.Imai E. The coming age of geriatric nephrology. Clin Exp Nephrol (Epub Nov 8, 2012)Google Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.