JOURNAL CLUB

Asymptomatic Hematuria in Adolescents and Young Adults

I want to draw your attention to an interesting and informative paper (1) published in JAMA in August. Laurie Barclay from Medscape provides an excellent summary of the study. The research question is: What are the long-term consequences among adolescents and young adults of persistent asymptomatic hematuria? I believe that this paper will change our practice in evaluating and managing young patients with microscopic hematuria, i.e., we will need to re-think the “benign-ness” of “benign hematuria".

The paper adds important information on the natural history of microscopic hematuria detected in young people. In fact, the authors point out that persistent asymptomatic isolated microscopic hematuria is a frequent incidental finding on routine examination of children, adolescents, and young adults.   

There is an excellent review of this published several years back in the New England Journal of Medicine (2). How to manage these patients has been an issue for some-time. Some, including the American Academy of Pediatrics and others (2,3), do not recommend urine screening during the second decade of life, whereas others view urinalysis screening as part of a routine physical even in adolescents (4). In most everyone, microscopic hematuria is commonly screened by the urinary dipstick test, and positive results usually prompt microscopic examination, the gold standard for detecting microscopic hematuria. 

The paper is from Dr. Asaf Vivante and colleagues from Israel (1). Dr. Vivante is from the Edmond and Lily Safra Children's Hospital in Tel Hashomer, Israel, and the lead author. The study was a nationwide, population-based, retrospective cohort study using medical data from 1,203,626 persons aged 16 through 25 years (60% of whom were male) that were examined for fitness for military service between 1975 and 1997. The data from these evaluations was then linked to the Israeli treated ESRD registry. Incident cases of treated ESRD from January 1, 1980, to May 31, 2010, were included. The authors used Cox proportional hazards models to estimate the hazard ratio (HR) of treated ESRD among those diagnosed as having persistent asymptomatic isolated microscopic hematuria.  

The main outcome measure was treated ESRD onset, which was defined as the date of initiation of dialysis treatment or the date of renal transplantation, whichever came first.

The cohort comprised 1,203,626 male and female adolescents and young adults (age 16 to 25 years, 60% male) who were examined between 1975 and 1997 for fitness for military service. Of the 1,203,626 participants who met entry criteria, 3690 (0.3%; annual range, 0.1%-0.5%) were diagnosed as having persistent asymptomatic isolated microscopic hematuria, and 1,199,936 were negative for this condition. Hematuria at enrollment was twice as prevalent among male as female participants (0.4% and 0.2%, respectively). Among participants with and without persistent asymptomatic isolated microscopic hematuria, the mean age at recruitment was 17.6 (SD, 1.2) and 17.3 (SD, 1.1) years, respectively, and the duration of follow-up was 20.7 (SD, 5.9) and 21.9 (SD, 6.7) years, respectively. BMI and blood pressure values at study enrollment according to sex subcategories for both groups were similar.

The screening cohort was then linked to the Israeli-treated ESRD registry and the investigators identified incident cases of ESRD treated from January 1, 1980, to May 31, 2010.Among individuals with persistent asymptomatic isolated microscopic hematuria, the hazard ratio (HR) of treated ESRD was estimated with Cox proportional hazards models. Onset of treated ESRD was defined as the date of beginning dialysis or the date of renal transplantation, whichever came first. Mean follow-up duration was 21.88 ± 6.74 years. During follow-up, 26 individuals (0.70%) with and 539 (0.045%) without persistent asymptomatic isolated microscopic hematuria went on to have treated ESRD. Incidence rates were 34.0 and 2.05 per 100,000 person-years, respectively, and the crude HR was 19.5 (95% confidence interval [CI], 13.1 - 28.9).

The risk for ESRD linked to persistent asymptomatic isolated microscopic hematuria was similar (HR, 18.5; 95% CI, 12.4 - 27.6) in a multivariate model adjusted for age, sex, paternal country of origin, year of enrollment, body mass index, and baseline blood pressure. Compared with persons without hematuria, those with persistent asymptomatic isolated microscopic hematuria had a dramatically higher risk for treated ESRD caused by primary glomerular disease (incidence rates, 19.6 vs. 0.55 per 100,000 person-years; HR, 32.4; 95% CI, 18.9 - 55.7). However, the absolute risk was low, with the proportion of treated ESRD attributed to microscopic hematuria being 4.3% (95% CI, 2.9% - 6.4%).
A comparison of the characteristics of the patients who developed ESRD after a diagnosis of hematuria versus those without hematuria developed ESRD is worth looking at. 

Tabulated below are the main differences:

	Hematuria with ESRD%	No Hematuria but with ESRD %
Treated ESRD etiologies, %
Diabetes	3.8	20.6
Hereditary Nephritis	15.4	1.3
IgA nephropathy	15.4	5.5
Glomerular disease (excluding IgA nephropathy)	26.9	20.0
Hypertension	3.8	5.0
Cystic kidney disease	3.8	7.2
Chronic interstitial nephritis	0	2.6
Secondary glomerulonephritis or vasculitis	0	7.8
Drug induced	0	1.6
Miscellaneous conditions	11.5	3.7
Uncertain or unrecorded cause	19.2	24.5
Primary glomerular disease	57.7 (38.4-75.4)	26.9 (23.3-30.8) P=.001

Limitations

1. Generalizibility: Because military service is not mandatory for Israeli non-Jews, the study population included only Jewish recruits, for whom military service is compulsory. However, it is hard to believe that religious inclinations might influence the occurrence of hematuria, although, genetic factors – for example, a polymorphism in a gene that influences disease progression, might be conserved in Israeli Jews.

2. Longer follow-up: The follow-up was terminated before the study population reached the age at which ESRD peaks.


Bottom-line 

The study shows that young individuals with hematuria are at risk for developing end-stage renal disease later in life.

Nearly 60% of patients with hematuria presenting in adolescence or young adulthood had a primary glomerular disease. Hereditary nephritis and IgA nephropathy were common causes of kidney failure requiring dialysis.

Consequently, following up these patients, making a more definitive diagnosis by percutaneous renal biopsy and potentially treating these patients should now be seriously considered. 

The use of angiotensin blockade and optimal blood pressure management might make a difference in disease progression. As well, for patients with IgA nephropathy there is some evidence that treatment could be beneficial (for example, fish oil and/or steroids). 

On the other hand, Thomas L. Schwenk, MD from Journal Watch General Medicine makes an important point: “The number of young adults needed to be screened to detect one case of hematuria was about 330; 1 in 142 with hematuria developed ESRD, but all who screened positive for hematuria required extensive testing and follow-up. Moreover, we don't know whether early diagnosis of asymptomatic isolated microscopic hematuria leads to interventions that prevent or delay progression to ESRD in a reasonable proportion of cases”. 

Dr. Robert Brown from Beth Israel Deaconess Medical Center in Boston, Massachusetts, in an accompanying editorial (6) titled “Has the Time Come to Include Urine Dipstick Testing in Screening Asymptomatic Young Adults?” suggests 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”. He also suggests that adding screening for albuminuria would be valuable from both diagnosis and prognosis standpoints. 

Dr. Brown also adds: “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. The finding of acanthocytic RBCs or RBC casts would suggest a glomerular source, as may concomitant proteinuria or an elevated serum creatinine level. 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 years or 50 years”.  

References

1. Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E, Chaiter Y, Shohat T, Skorecki K, Calderon-Margalit R. Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA. 2011 Aug 17;306(7):729-36.

2. Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J Med. 2003 Jun 5;348(23):2330-8. Review. PubMed PMID: 12788998.

3. Woolhandler S, Pels RJ, Bor DH, Himmelstein DU, Lawrence RS. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. I.Hematuria and proteinuria. JAMA. 1989 Sep 1;262(9):1214-9.

4. American Academy of Pediatrics and Committee on Practice and Ambulatory Medicine. American Academy of Pediatrics, Committee on Practice and Ambulatory Medicine: recommendations for preventive pediatric health care. Pediatrics. 2000;105:645-646.

5. Misdraji J, Nguyen PL. Urinalysis. When--and when not--to order. Postgrad Med. 1996 Jul;100(1):173-6, 181-2, 185-8 passim.

6. Brown RS. Has the time come to include urine dipstick testing in screening asymptomatic young adults? JAMA. 2011 Aug 17;306(7):764-5.