Author Affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Urinalysis was once a standard screening test in routine health evaluation but more recently has not been advised for healthy individuals or unless patients are 60 years or older or at high risk for kidney or cardiovascular disease.1,2 Although blood tests have replaced urine tests for detecting diabetes, the urine dipstick test remains a simple means of detecting unsuspected hematuria, proteinuria, or both. Are those findings common enough, and more importantly, serious enough to warrant recommending urine dipstick testing as a simple, low-cost screening tool for asymptomatic adolescents and all adults?
“Isolated” microscopic hematuria, defined as hematuria not visible to the naked eye and unaccompanied by proteinuria, may be detected incidentally in asymptomatic individuals by a urinary dipstick test for heme and confirmed by microscopy of the urinary sediment. Microscopic hematuria may be transient and has been found to have a widely variable prevalence ranging from 0.18% to 16.1%.3 Even when microscopic hematuria persists on subsequent urinalyses, further evaluation often fails to find a cause; in these cases, the condition generally has been considered “benign hematuria” or, if familial, “benign familial hematuria.” Renal biopsies are usually not considered helpful in patients with isolated microscopic hematuria, and even when biopsies have been performed, hematuria is often unexplained by any abnormality, or histopathology may show various glomerulopathies.3 Although the short-term prognosis of unselected patients with isolated microscopic hematuria has been favorable, long-term prognosis has been unknown.
In this issue of JAMA, Vivante and colleagues4 report their findings from a longitudinal study of 1.2 million male and female adolescents and young adults, aged 16 to 25 years, who underwent urinary screening examinations and 21 years of follow-up for the development of end-stage renal disease (ESRD) treated by dialysis or kidney transplantation. In this large unselected cohort limited to Israeli Jews examined for required military service, 0.3% were initially found to have persistent asymptomatic isolated microscopic hematuria with a negative evaluation (as defined in Figure 1 in the article), a normal serum creatinine level, and the absence of proteinuria greater than 200 mg per day. During the ensuing 21 years, treated ESRD developed in 0.70% of individuals with, and 0.045% of those without, microscopic hematuria initially. The increased risk of ESRD associated with microscopic hematuria yielded an adjusted hazard ratio (HR) of 18.5 (95% confidence interval, 12.4-27.6). Among persons with microscopic hematuria, ESRD treatment was started at an earlier mean age (34 vs 38 years) and was attributed mainly to glomerulopathies.
The study documents that the prevalence of persistent microscopic hematuria in an asymptomatic young population was low and twice as frequent in male (0.4%) than female (0.2%) individuals, a point of uncertainty previously.3 Furthermore, hematuria was associated with a low but significantly increased risk for ESRD, accounting for an estimated 4.3% of treated ESRD in the Israeli Registry. The size of this study and completeness of follow-up are unique, although the inclusion of only Israeli Jews may limit applicability of the findings to other population groups, many of which have even higher rates of ESRD. It is also uncertain how many patients with microscopic hematuria might have had mild proteinuria that might now be detected as microalbuminuria.
What should the clinician do when microscopic heme is detected by a positive dipstick test result? First, confirm the hematuria by finding 2 to 5 or more red blood cells (RBCs) per high-power field by microscopic analysis of the urinary sediment on at least 2 occasions unrelated to recent menstruation, exercise, trauma, or sexual activity.3,5 The finding of acanthocytic RBCs or RBC casts would suggest a glomerular source, as may concomitant proteinuria or an elevated serum creatinine level.3,5 In patients without an apparent glomerular etiology, a urologic evaluation is advised, including radiologic imaging of the urinary tract, preferably by computed tomography scan, for all patients as well as cystoscopy and urine cytology for those with risk factors for bladder cancer or those older than 40 years5 or 50 years.3 Prior to the study by Vivante et al,4 patients with isolated microscopic hematuria and a negative evaluation were usually considered to have benign hematuria and required no follow-up. Now it seems reasonable to reevaluate such patients every 1 to 2 years for a possible increased incidence of proteinuria, hypertension, or renal insufficiency.
In the United States, because the prevalence of chronic kidney disease (CKD) is estimated to be from 70- to 200-fold greater than the prevalence of treated ESRD,6,7 perhaps an argument could be made for the inclusion of dipstick testing for hematuria as part of routine screening of young adults. However, a stronger case can be advanced by adding the advantage of simultaneously detecting unsuspected proteinuria with screening dipstick testing. Mild proteinuria, previously considered to be in the normal range but now defined as microalbuminuria by albumin-creatinine ratios of 30 to 300 mg/g,8- 10 has been associated with an increased risk for cardiovascular and all-cause mortality, in addition to the increased risk for developing CKD.8
A study from the Alberta Kidney Disease Network including more than 920 000 individuals in Canada8 found dipstick proteinuria of trace or 1+ in 7.8%, and this finding was associated with an adjusted HR of 2.1 for all-cause mortality, 2.7 for doubling of the serum creatinine level, and 1.7 for ESRD among individuals with initially normal glomerular filtration rates (GFRs) (estimated GFR >60 mL/min per 1.73 m2). In a meta-analysis of more than 1.1 million individuals,9 dipstick proteinuria of trace or greater, found in 8% overall, conferred similarly increased risks for all-cause mortality, even among those 65 years or younger with normal estimated GFRs. Likewise, measured microalbuminuria or macroalbuminuria yielded increased risks similar to those associated with mild or heavy dipstick protein levels.8,9,11
Even though a negative urinary dipstick test result for protein has a high negative predictive value for microalbuminuria (97.6%) and for macroalbuminuria (100%), the rate of false-positive urinary dipstick test results might necessitate obtaining a urine test for an albumin-creatinine ratio for confirmation.12 But because the positive predictive values of trace or 1+ dipstick protein for detecting microalbuminuria are 27% and 47%, respectively,12 and the cost of obtaining an albumin-creatinine ratio is only $15.42 based on the maximum Medicare reimbursement,13 the cost of detecting such an important prognostic indicator remains quite modest. Albuminuria is independent of estimated GFR as a predictor of mortality9 and is the strongest risk factor for CKD progression, with its associated risks of cardiovascular morbidity and mortality.10 In Taiwan, dipstick proteinuria of trace (HR, 1.70) or 1+ (HR, 2.31) was compared with smoking (HR, 1.55) as a risk factor for all-cause mortality and was estimated to be associated with life-span shortening of up to 7 years.11,14 In the United States, during a mean follow-up of 3 years, among patients with stage 3 CKD (estimated GFR, 30-59 mL/min per 1.73 m2), the rate of progression to ESRD was only 1.1%, whereas the mortality rate was 24.3%; among patients with stage 4 CKD (estimated GFR, 15-29 mL/min per 1.73 m2), ESRD occurred in 17.6% but mortality in 45.7%.10
Despite the increasing prevalence of CKD—estimated at up to 14.4% in the United States7—relatively few patients were aware of their diagnosis. Moreover, convincing data now demonstrate that proteinuria and microalbuminuria are modifiable risk factors for which therapies are available to improve the adverse outcomes of CKD progression and cardiovascular disease, particularly if treatment is begun early.6 For instance, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers may reduce the relative risk of the composite end point of ESRD, doubling of serum creatinine levels, or death by up to 40% in patients with nondiabetic nephropathy with proteinuria and by up to 20% in those with diabetic nephropathy.6 The early identification of persons at risk for CKD also should promote other healthy interventions for smoking, hypercholesterolemia, glycemic control, and reduction of sodium intake.6 The US Preventive Services Task Force has no current recommendation for CKD screening, but the topic is under consideration.15 In Japan, annual urinalysis screening for schoolchildren, working adults, and nonworkers older than 40 years has been routine since 1983, with an apparent decrease in ESRD from glomerulonephritis and an increase in the mean age of treated ESRD.16 The study by Vivante et al4 suggests that assessment of microscopic hematuria in young adults may be added to assessment of albuminuria in adults midle-aged and older as a tool to detect CKD early and potentially minimize its high costs and morbidity.
Thus, it appears that the time may have arrived for routine urine dipstick screening in adolescents and adults, at least at all initial examinations and perhaps every 5 to 10 years thereafter. The assessment of the available evidence by the US Preventive Services Task Force should help provide clinicians with additional guidance about the role of urine dipstick screening in prevention of CKD.
Corresponding Author: Robert S. Brown, MD, Nephrology Division, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Boston, MA 02215 (firstname.lastname@example.org).
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Brown RS. Has the Time Come to Include Urine Dipstick Testing in Screening Asymptomatic Young Adults?. JAMA. 2011;306(7):764-765. doi:10.1001/jama.2011.1193