Research and Reviews Role of Urinalysis in the Diagnosis of Chronic Kidney Disease (CKD) JMAJ 54(1): 27–30, 2011 Kunitoshi ISEKI*1 Abstract As of the end of Year 2008, 1 out of 450 people was a dialysis patient in Japan, and patients with chronic kidney disease (CKD) at stages 3 and 4 accounted for nearly 10% of the total population. An epidemiological study in Okinawa that used the introduction of dialysis treatment as the outcome revealed that the 10-year cumulative incident rate of end-stage renal disease (ESRD) was about 3% of the participants who were positive (Ն 1ϩ) for both proteinuria and hematuria, while there was hardly any difference between those who were positive for hematuria alone and those who were negative for both proteinuria and hematuria. When the incidence of ESRD (dialysis introduction) was examined in relation to the severity of proteinuria (5 grades ranging from [Ϫ] to [Ն 3ϩ]) as determined by dipstick, the cumulative incidence rate during the 17-year observation period was 16% for proteinuria (Ն 3ϩ) and about 7% for proteinuria (2ϩ). In contrast, among participants who were negative for proteinuria, the rate of dialysis introduction in 10 years is about 1 out of 1 million. The CKD Practice Guide of the Japanese Society of Nephrology recommends referral to a nephrologist when a case meets any of the following 3 criteria: 1) 0.5g/g creatinine or higher, or proteinuria (Ն 2ϩ), 2) an estimated glomerular filtration rate of less than 50ml/min/1.73m2, or 3) positive results (Ն 1ϩ) for both proteinuria and hematuria tests. Key words Chronic kidney disease (CKD), Urinalysis, Proteinuria, Hematuria, Screening, Dialysis Introduction global control measures. In Japan, universal urinalysis screening, an According to a survey of the Japanese Society ideal procedure for the early detection of CKD, for Dialysis Therapy, the number of patients on has been implemented throughout the nation dialysis exceeded 280,000 at the end of Year 2008, through mass screening such as school health which corresponds to a rate of 1 per 450 popu- checkups, health examination of adult residents, lation.1 Patients with chronic kidney disease and basic health checkups specifically designed (CKD) at stages 3 and 4 who may require dialysis for senior residents. Considering that the inci- in the future accounts for nearly 10% of the total dence of dialysis introduction due to chronic population, and the percentage increases further nephritis (IgA nephropathy), a condition often among the elderly aged 65 years or older. The diagnosed by the presence of asymptomatic pro- mortality rate due to cardiovascular disorders teinuria and hematuria, has decreased, and that is higher than the dialysis introduction rate the average age of new dialysis patients is rising, among CKD patients, meaning CKD can con- these urinalysis screening measures seem to be siderably influence the society and medical successful.2 In Specific Health Check and Guid- economy. Although it is not contagious, the ance System* for adults implemented since April World Health Organization (WHO) recognizes 2008, urinalysis was initially planned to be offered CKD as a non-infectious disease that requires as an optional test; however, an appeal led by *1 Associate Professor, Dialysis Unit, University Hospital of the Ryukyus, Okinawa, Japan ([email protected]). This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol.138, No.8, 2009, pages 1529–1531). JMAJ, January/February 2011 — Vol. 54, No. 1 27 Iseki K (%) 2.2017מ595.23xסy (ם) Proteinuria 0.8464 סr 2 (%) 3.0 3.4417מ56.708xסy (מ) Proteinuria & hematuria 100 Proteinuria 0.9705 סr 2 10 2.0 Proteinuria 1 1.0 at 7 years 0.1 Hematuria 0.01 Cumulative incidence rate of ESRD incidence rate Cumulative 0 Normal 12345678910 (Years) of ESRD incidence rate Cumulative 0.001 1153045607590105 120 135 Time after health examination Creatinine clearance (ml/min) [Cited from Iseki K, et al.3] [Cited from Iseki K, et al.5] Fig. 1 The results of urinalysis for proteinuria and hematuria in relation to the cumulative inci- Fig. 2 The relationship between renal function levels dence rate of ESRD (introduction of dialysis (creatinine clearance) and the cumulative inci- treatment) in years, obtained from mass health dence rate of ESRD (introduction of dialysis examination of residents treatment) at 7 years by the presence/absence of proteinuria, obtained from mass health exami- nation of residents Japanese Society of Nephrology (JSN) was suc- (GFR), and thus is the most important target cessful, and urinalysis has been conducted as an of treatment. standard test item. The inclusion of urinalysis as An epidemiological study was conducted in a standard item is to be reevaluated in 2013, and Okinawa from the data obtained from the par- JSN is liable to verify the effectiveness of urinaly- ticipants of mass health examination for adults sis screening by the time of the revision. There and senior residents, using the introduction of is currently no evidence to show that screening dialysis treatment as the outcome (as end-stage for proteinuria leads to a decrease in the number renal disorder, ESRD). The study revealed that of dialysis patients. A strategy study initiated in the cumulative incidence rate of ESRD in 10 April 2008 called Frontier of Renal Outcome years was about 3% in patients who were positive Modifications in Japan (commonly known as (Ն 1ϩ) for both proteinuria and hematuria, while FROM-J) is investigating the usefulness of the there was no distinct difference between those clinical care system for the prevention of who were positive only for hematuria (condition worsening of CKD patients in order to promote predominant among women of advanced age) collaborations between primary care physicians and those who were negative for both protein- (non-specialists) and nephrologists. uria and hematuria (Fig. 1).3 When the cumula- tive incidence rate of ESRD during the 17-year Clinical Significance of Proteinuria follow-up period was examined in relation to 5 grades of proteinuria ([Ϫ], [ϩ/Ϫ], [1ϩ], [2ϩ], Proteinuria refers to persistent protein excretion and [Ն 3ϩ]) as determined by dipstick, it was of 150 mg or more per day in urine. Although 16% for proteinuria (Ն 3ϩ) and about 7% for protein may be found in urine due to physiologi- proteinuria (2ϩ).4 Among those who are nega- cal reasons (e.g., strenuous exertion, after fever, tive for proteinuria, only about 1 out of 1,000,000 stress, prolonged standing, etc.), persistent uri- entered dialysis program in 10 years. Low GFR nary protein suggests the presence of disorder levels, which are common in the elderly, seldom involving the kidney and to the urinary tract. lead to dialysis treatment unless accompanied by It has long been known that the higher the proteinuria (Fig. 2).5 Since the decreases in GFR level of urinary protein, the poorer the vital prog- level due to aging were relatively mild (Ͻ0.4 ml/ nosis. Proteinuria is a factor that determines the min/1.73 m2/year) among the participants of rate of decrease in the glomerular filtration rate mass health examination, it seems unlikely that 28 JMAJ, January/February 2011 — Vol. 54, No. 1 ROLE OF URINALYSIS IN THE DIAGNOSIS OF CHRONIC KIDNEY DISEASE (CKD) aging alone was the cause for the introduction of catabolism (reduction in muscle mass), patients dialysis treatment.6 with obese nephropathy should first be guided The mean age of patients at the time of dialy- to consume sufficient calories (30–35 kcal/kg sis introduction has been increasing along with standard body weight per day). Excessive protein the increase of the elderly population and preva- intake induces glomerular hypertension and tem- lence of obesity and diabetes in Japan. In the US, porarily promotes an increase in GFR, but in the dialysis introduction rate is increasing only the long run leads to glomerular sclerosis. In the among people aged 75 years and older, while the elderly, improvement of GFR occurs gradually corresponding rates are decreasing in other age because the regulation of GFR is inadequate. groups. In Japan, a microalbuminuria screening is Fasting and dehydration (rapid and excessive covered by public health insurance only in early restriction of salt) should be avoided in all cases, cases of diabetic nephropathy. However, in a and sufficient calorie intake must be planned for survey that included the general population for those with protein-restricted diet. investigative purposes, the prevalence of micro- albuminuria was unexpectedly high, exceeding Pharmacotherapy 10% in both men and women aged 65 years or Antihypertensive therapy: In CKD patients, older, and more than 20% of those aged 75 years blood pressure should be controlled to achieve old or older were positive for microalbuminuria. the target value of less than 130/80 mmHg using mainly a renin-angiotensin system (RAS) inhibi- Referral to Nephrologists tor. When proteinuria of 1g/day or more is present, the target value should be below 125/ Annual urinalysis, and possibly a serum creati- 75 mmHg. In this regard, a RAS inhibitor is nine test, is recommended for individuals with working more like a renoprotective drug than an diabetes, hypertension, and/or obese. In addi- antihypertensive. In conditions with increased tion, differential diagnosis of CKD is necessary glomerular filtration rates (single kidney, diabe- when there is anemia, bone fracture, or cardio- tes mellitus, glomerular nephritis, puromycin vascular disorder of unknown cause. The CKD nephropathy, etc.), the use of RAS inhibitors Practice Guide by JSN recommends referral to decreases proteinuria. nephrologists if a person meets any of the follow- Diabetes mellitus: Blood glucose should be con- ing 3 criteira.7 trolled to achieve the target value of less than (1) Ն0.5g/g creatinine, or proteinuria (Ն 2ϩ) 6.5% HbA1c.