Persistent asymptomatic microscopic hematuria in adolescents and young adults was associated with significantly increased risk of treated end-stage renal disease (ESRD) over a period of two decades, a 1,203,626-person retrospective study reported in the Journal of the American Medical Association (JAMA 2011;306:729-736).
While this is the most convincing evidence to date of that association, the incidence of hematuria and prevalence of ESRD in the study were very low. The findings stimulate, but do not resolve, the debate on whether broad screening for hematuria is cost-effective and should be a regular part of care.
“We don't have any information about what could be the benefits of early screening,” said senior author Ronit Calderon-Margalit, MD, MPH, of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine in Jerusalem. “The absolute risk is very low, but it is impossible to say what a doctor might have done if they knew that this is a risk marker for end-stage renal disease. That is why I'm cautious not to recommend any kind of screening at this point.”
Significantly Higher Rate
This retrospective cohort study is important for its scope. It drew on the medical records of 1.2 million Israeli Jews age 16 to 25 at the point of their fitness evaluation for mandatory military service between 1975 and 1997. It linked that information to records of patients treated for ESRD between Jan. 1, 1980, and May 31, 2010.
Symptomatic individuals were not included in the analysis, and 60% of the participants in the study were male. Persistent asymptomatic microscopic hematuria was defined by positive tests on three separate occasions.
Some 3,690 individuals (0.3%) were positive for persistent hematuria at baseline confirmation screening. An evaluation of the cohort records over 21.88 years of follow-up found a rate of treatment for ESRD that was significantly higher among those who were initially positive for hematuria (26 individuals; 0.70%) compared with those who were negative (539 individuals; 0.045%). The adjusted hazard ratio was 18.5.
“Previously, microscopic hematuria was considered a benign condition if there were no other symptoms,” Dr. Calderon-Margalit said. “This study suggests that there might be an undetectable underlying damage. It could lead to increased follow-up and treatment at an earlier stage. It might delay the need for treatment or even make it unnecessary.”
However, Dr. Calderon-Margalit readily acknowledged, “This was not a study of the utility or cost/benefit of screening.”
From Microscopic Hematuria to ESRD
Robert S. Brown, MD, a nephrologist at the Beth Israel Deaconess Medical Center and the author of the editorial that accompanied the study (2011;306:764-765), praised the research.
“It's an amazing study. They have an unrestricted population of 1.2 million people, both male and female, that they followed through their registry. That is remarkable,” he said.
“They were reasonably well studied for the time, and they produced about the best nonselective data in a single cohort population of individuals that we've ever had” to address this question.
“In the past, when there was no other evidence of renal disease other than microscopic hematuria, it was felt to be benign, but now we know that it is not so benign,” he said.
“You could say that .7 percent is pretty low over 21 years, but the patients are only in their 30s and have ESRD requiring dialysis or transplantation.”
Kevin E. C. Meyers, MBBCh, Assistant Chief of the Division of Nephrology at the Children's Hospital of Philadelphia, had a decidedly different take on the study.
“This study is probably something that is not generalizable,” he said. “Secondly, the absolute numbers of persons going into ESRD is small, 26 out of 1.2 million screened.
“And the researchers don't tell us anything about the patients—they could have other unrelated causes for going into renal failure such as trauma or sepsis, and that is why they are in ESRD. [The researchers] have no knowledge of why the patients went into end-stage. To try and associate isolated microscopic hematuria as cause and effect in these screened young adults is not supported by the authors' observations.”
For his part, Ronald J. Hogg, MD, Chief of Nephrology at Children's Hospital at Scott & White and Professor of Pediatrics at Texas A&M Health Science Center, said that the findings, as far as they go, should transfer to other Western populations when one controls for risk factors such as cholesterol and hypertension.
“The Israeli report is excellent,” he said.
However, he shared Dr. Meyers' concern about what is happening during the period from initial screening to treatment for ESRD.
“If you are just going from microscopic hematuria to ESRD twenty years later, it begs the question: What happened in the meantime? It points out, I think reasonably, that those patients should then be monitored periodically—not with very extensive tests, but certainly monitored.”
Proteinuria and Hematuria
JAMA asked Dr. Brown to comment in his editorial on whether urine dipstick screening should be routine for all patients. He acknowledged that the study's finding of a low incidence of microscopic hematuria and ultimately ESRD might not justify such screening in and of itself. “On the other hand, albumin in the urine is found much more frequently, about 8% of the time,” he said.
“It provides a much greater risk/benefit, not just for kidney disease, but particularly for cardiovascular disease, including death,” he said. “The leakage of albumin in the urine can be viewed as a marker for blood vessel disease in the body.
“I think the data should be re-reviewed by the US Preventive Services Task Force as to whether it is cost-effective to evaluate everybody at an initial evaluation and perhaps every five to 10 years.”
A new review would likely come out very differently from the previous one, he said.
“The differences from the past are better data on the amount of proteinuria one would find, the addition of the finding on hematuria, and the fact that prevention techniques for diabetes, hypertension, and other diseases that put protein in the urine have been much improved. You can delay end-stage renal disease considerably, and prior incidence of cardiovascular morbidity.”
Dr. Hogg agreed with Dr. Brown that hematuria and proteinuria “should be thought of almost in the same sense. If you are going to do one, you might as well do the other.”
Based on studies conducted in the United States and Europe some time ago, “one would have to conclude that widespread screening is not cost-effective,” he said.
But those studies are decades old, and rising incidence of obesity in the United States and a lagging curve in Europe likely have changed the population risk profile. Dr. Hogg believes new studies are merited and hopes that these new findings from Israel “add more fuel to the fire of whether we should be doing screening,” he said.
Dr. Hogg pointed to the belief among Japanese health officials that their more aggressive, long-standing policy of routine screening “has effectively reduced the number of children progressing to end-stage renal disease compared with the US. They show that things are getting worse in the US and getting better in Japan, but it is hard to take such broad strokes and make firm conclusions.”
In an earlier review article (Clin J Am Soc Nephrol 2009;4:509-515), he noted that the Asian practice of testing first morning urine yields a cleaner result.
“And the focus is more on proteinuria than hematuria,” he said. “If you just do a random urine sample during the middle of the day, you get a lot of positive protein readings that are negative on first morning collection.”
Dr. Meyers had no enthusiasm for the idea of “mass screening for isolated microscopic hematuria, especially in children, where there is very little or no comorbidity.” At best, this study “is food for thought that could lead to future studies that look at mass screening for microscopic hematuria more critically,” he said.
“It comes down to the cost-benefit of screening. If you are going to do mass screening, then it has to be with the purpose in mind of either diagnosing patients that were undiagnosed and/or being able to intervene in a meaningful way.
“I think it is far more important to be screening children and families for their poor eating habits, for obesity, for high salt intake, for undiagnosed hypertension. You are going to make far more impact with that type of screening in place than to pick up one or two patients who may or may not go on to end-stage renal disease years later.”
Perhaps it makes more sense to think of the potential value of screening for hematuria not in the narrow sense of ESRD but in a broader context of heightened risk for multiple potential diseases, including cardiovascular disease.
“Absolutely,” said Dr. Calderon-Margalit. “But we use the data we have. It is easy to use ESRD because it is such a clear-cut endpoint.” She is intrigued by the possibility of examining the hematuria screening data in light of the Israeli cancer registry.