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The n e w e ng l a n d j o u r na l of m e dic i n eReview Article
Dan L. Longo, M.D., Editor
Hematuria in Adults
Julie R. Ingelfinger, M.D.
V
isible (macroscopic) hematuria, documented since ancient This article was updated on July 13, 2021,
times,1,2 is striking, particularly when there is no prior event, such as trau- at NEJM.org.
ma, dysuria due to cystitis, or flank pain with passage of a kidney stone, to N Engl J Med 2021;385:153-63.
provide a clear explanation. In contrast, nonvisible (microscopic) hematuria, or DOI: 10.1056/NEJMra1604481
Copyright © 2021 Massachusetts Medical Society.
microhematuria, may go undetected for years.2 Many patients are found to have
microhematuria when a urinalysis is performed for other reasons.
The reported prevalence of microhematuria varies greatly, from a small percent-
age of patients at screening to more than 40% in some urology clinics, probably
owing to referral bias regarding patients and their signs and symptoms.3-5 The
American Urological Association (AUA) guidelines note a prevalence ranging from
2.1 to 31.4%.5 Thus, a discussion of epidemiology per se is less important than a
consideration of individual patient circumstances and geographic region. In certain
parts of the world — for example, in northern Africa, where Schistosoma haematobium
is endemic — microhematuria is common, reflecting prevalent bladder infestation.
In addition, the causes of hematuria differ between men and women, and the
evaluation, accordingly, should reflect that difference.6-8 Furthermore, the implica-
tions of hematuria vary greatly, depending on the underlying cause. Given the
association of both visible hematuria and microhematuria with bladder and kidney
cancer, the focus of evaluation has long been to rule out cancer. Cancer is more
likely to be identified in men than in women when they are evaluated for micro-
hematuria. Worldwide, estimates of the incidence of kidney cancer are 6.0 cases
per 100,000 person-years for men and 3.1 cases per 100,000 person-years for
women, and estimates of the incidence of bladder cancer are 9.0 cases per 100,000
person-years for men and 2.2 cases per 100,000 person-years for women, accord-
ing to GLOBOCAN, a registry of data on the global incidence of cancer,9 a result
also found in a 2020 meta-analysis.10 However, evaluation in women is often de-
layed, which may contribute to worse outcomes of bladder cancer among women.
Beyond cancer, hematuria is associated with protean symptoms and causes.
This review focuses on major causes, the evaluation, and the implications of he-
maturia. Since therapy depends on the cause, treatment is not addressed here.
De tec t ion of Hem at ur i a
Urine hue normally ranges from nearly colorless, when dilute, to dark amber,
when concentrated. Red, pink, “rusty,” or brown urine may suggest hematuria but
may be due to substances besides blood. Available dipstick tests detect red cells,
as well as hemoglobin and myoglobin, necessitating microscopic examination of
the urine if a dipstick test is heme-positive, followed by other tests to confirm
hematuria and, potentially, to determine its cause.11,12
Commonly used dipstick tests incorporate a benzidine compound reduced
with a buffered organic peroxide (3,3′,5,5′-tetramethylbenzidine and diisopropyl-
benzene dihydroperoxide). When the test strip is dipped in urine that includes an
oxidizing substrate, a color reaction ensues; for example, the pseudoperoxidase
n engl j med 385;2 nejm.org July 8, 2021 153
, The n e w e ng l a n d j o u r na l of m e dic i n e
Table 1. Selected Nonheme Causes of Pigmenturia, as Compared with Red Cells or Free Hemoglobin.*
Variable Red Cells Hemoglobin Myoglobin Porphyria Bile Pigments Alkaptonuria
Urine color Red to rusty Pink to red Rusty Turns black, Brown Turns dark in
brown, or red in sunlight
sunlight
Heme test Positive Positive Positive Negative Negative Negative
Usual microscopic Red cells, No cells No red cells; Normal Normal Normal
findings casts casts may be
present
Plasma Normal Pink Normal Normal Icteric Normal
* Shown are selected endogenous causes of pigmenturia. A heme test for exogenous causes, including beets, rhubarb,
azo dye, sulfonamides, and phenolphthalein, is negative.
activity of hemoglobin will oxidize the benzi- essential.15 True microhematuria is most often
dine compound, turning the dipstick blue. Free defined as more than 2 or 3 red cells per high-
hemoglobin and myoglobin also react with the power field, and this finding should be con-
test strip, as would be expected because of their firmed on two or three separate urinalyses.16,17
molecular structure.13 Some experts suggest that if even a single urinaly-
Certain substances may lead to false positive sis is positive, a patient should have follow-up
dipstick reactions: sodium hypochlorite, peroxi- urinalyses for at least a year, so as to avoid miss-
dases from vegetable or bacterial sources, and se- ing an intermittent source of microhematuria
men. In contrast, very high ascorbic acid levels in that could signify a clinically important problem.
urine may produce false negative results. The list of Careful examination of the urinary sediment
substances that can be confused with hematuria is central to differentiating glomerular from
is lengthy (see the partial listing in Table 1). The other forms of hematuria.15 Although micro-
absence of red cells on microscopic examination of graphs of red cells crossing the glomerular base-
a “heme-positive” urine specimen suggests ei- ment membranes are as rare as hen’s teeth, red
ther that the red cells have all lysed or that iso- cells that have traversed the glomerular base-
lated hemoglobinuria or myoglobinuria may be ment membrane into the glomerular filtrate are
present. Hemoglobinuria is dipstick-positive, but much the worse for wear and appear with blebs
if it is the sole cause of the positive test, red cells and other irregularities.18 In contrast, lower uri-
will not be present in the urinary sediment. In nary tract hematuria is characterized by normal
some instances, both hematuria and hemoglobin- red cells (Fig. 1). If dysmorphic red cells are
uria are present and red cells will be identified. found, the diagnostic evaluation should first
Distinguishing blood from myoglobin in the focus on the possibility of a glomerulopathy (see
urine (which may signify rhabdomyolysis and the pragmatic algorithm in Fig. 2), particularly
may or may not be suspected, given a patient’s if casts, especially red-cell casts, are present.
history) is clinically important.14 Frequently, cen- Isolated hematuria is less likely to be associ-
trifugation is helpful, since red cells will sedi- ated with a glomerulopathy than is hematuria
ment, leaving a clear supernatant, whereas myo- with albuminuria or decreased kidney function,
globin will not. However, free hemoglobin also though IgA nephropathy and familial nephropa-
will not precipitate in a routine laboratory cen- thies may not always be characterized by albu-
trifuge. In all, the absence of red cells in the minuria.15 Bacteria in the unspun urine and in
sediment of a “heme-positive” specimen suggests the sediment suggests urinary tract infection.
that either isolated hemoglobinuria or myoglo- Crystals may suggest nephrolithiasis.
binuria may be present. Myoglobinuria can then If examination of the urinary sediment shows
be identified biochemically through ammonium normal-appearing red cells, then imaging and
sulfate precipitation, as well as through electro- urologic referral should be considered. Most
phoretic and immunologic tests. urologists will focus on imaging results and cys-
Thus, after a positive dipstick test, micro- toscopy. In patients with risk factors for cancer,
scopic examination of the urinary sediment is many urologists and guidelines would suggest
154 n engl j med 385;2 nejm.org July 8, 2021
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