New Data; Now What?

Sep 12 2011 Published by under Journal Club

One of the most common reasons children get sent to see me is persistent microscopic hematuria. In non-doctor-talk, they have red blood cells in their urine that can only be detected by dipstick or microscope. The prevalence of children affected is not clear, but less than 1% in most studies where at least 3 urine specimens are checked.

My approach has been fairly laid-back. Most children with significant kidney disease warranting intervention have some other indicator, such as gross hematuria (visible with the naked eye), protein in the urine, high blood pressure, and/or an abnormal glomerular filtration rate (GFR, the measurement of how the kidneys clear waste products). In the absence of these findings, or other abnormalities on blood tests, the probability of finding a treatable, progressive disorder on biopsy remains very low. These children warrant follow-up every year or two so that biopsy and treatment can be reconsidered if other signs or symptoms develop.

When the following article hit the news, I knew it would impact my life:

Persistent Asymptomatic Isolated Microscopic Hematuria in Israeli Adolescents and Young Adults and Risk for End-Stage Renal Disease.

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Vivante A, et al. JAMA 2011; 306:729-36

All Jewish Israeli adolescents and young adults must undergo medical board examination 1 year before conscription into military service. All screened participants from 1975 - 1997 were included in the study. The recruitment schema is shown at left. The investigators then linked these records to the Israeli end-stage renal disease registry to look at outcomes in these subjects.

One of the powers of this study is its numbers. Well over one million individuals underwent initial screening, and 1,199,936 ultimately did not have persistent microscopic hematuria or other risk factors for kidney disease (Control Group). Some screened individuals had diabetes or other conditions putting them at risk of kidney failure (34,243), while 3,690 (0.3%) met the criteria for isolated microscopic hematuria after multiple urinalyses with microscopic examination, kidney and bladder imaging studies, and measurement of serum creatinine level. All of these subjects visited a nephrologist who confirmed the diagnosis.

People with hematuria were twice as likely to be male as female. No differences in country of origin, blood pressure, or body size were identified at military screening.

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After a median follow-up of 20 years, end-stage kidney failure developed in 539 people without hematuria (0.045%) and in 26 patients with hematuria (0.7%), an approximately 20-fold elevation in risk.  The cause of kidney failure in hematuria patients was mostly glomerular disorders including IgA nephropathy (see table at right). Hematuria patients had lower body mass index, younger age at start of kidney failure therapy, and shorter time to kidney failure than those who developed kidney failure without preceding hematuria. Multivariate analysis revealed no mediating factors that changed these relationships.

The risk of end-stage kidney failure was 2.05 per 100,000 person-years in the Control Group and 34.0 in the hematuria group. While this represents a substantial increase in relative risk, the absolute risk remains low when compared with other chronic diseases. These hematuria patients produced 4.3% of treated end-stage kidney failure during the study period.

There are some problems with this study. First, the study population is limited, and results may not generalize to other patient groups. Second, historical evaluation techniques may not produce the same diagnoses as those of today. Intravenous pyelography was the standard for imaging in the first part of the study; ultrasound replaced it over time. Proteinuria screening has also changed; today, the more sensitive measurement of microalbuminuria might skew some patients out of the isolated hematuria group. Also, the only assessment of kidney function available was a nephrologist's statement that the serum creatinine was "normal." Calculated GFR might also have altered some of these results.

The real question is how should these data alter current medical practice? For now, I do not believe they should. The patients I see have documented persistent microscopic hematuria. We screen for a variety of systemic and glomerular disorders up front. We use state-of-the-art imaging for anatomic abnormalities, and we measure microalbuminuria to look for very low levels of proteinuria. These children then get followed-up annually, either with a primary care physician or in our office. If any other signs or symptoms of kidney disease develop, we perform a biopsy. Still, we fail to make a diagnosis or find a treatable illness in many cases.

The other question raised is the use of screening urinalysis. Data from Japan's childhood screening program suggest that an aggressive approach may reduce the risk of kidney failure due to glomerular diseases in that country. At this point, it remains unclear if more screening or biopsies would prevent enough end-stage kidney failure to justify the expense and risk of  the procedure, especially when the risk is low (even though the relative risk is high).


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