Hematuria

Japanese: 血尿

Concept Hematuria is a condition in which an abnormally large number of red blood cells are excreted in the urine. Therefore, hematuria is diagnosed by verifying the presence of red blood cells in the urinary sediment under a microscope. Even healthy people excrete ¹⁰⁶ red blood cells in their urine per day, which is equivalent to 3 cells/μL.
1) Microscopic hematuria:
When urinary sediment is observed under a microscope at 400x magnification, approximately one red blood cell can be seen. Therefore, excretion of more than 2-3 cells/HPF (high power field, 400x magnification) (which corresponds to 5 cells/μL) is abnormal. This is called microscopic hematuria.
2) Macroscopic hematuria or gross hematuria:
When hematuria is severe and there is more than 0.5 mL of blood in 1 L of urine, it appears red to the naked eye (this corresponds to more than 2500 blood particles/μL). This is called macroscopic hematuria. It is sometimes described as cola-colored. In acidic or old urine, the color can range from brown to black.
Pathophysiology 1. In most cases, patients themselves will notice gross hematuria based on its appearance, but microscopic hematuria is often discovered when a urine occult blood test is positive during a health check or general screening test. This is called asymptomatic hematuria (or chance hematuria, meaning hematuria discovered by chance).
The urine occult blood test using the test strip method is highly sensitive, and will be positive if there are five or more red blood cells in 1 mL of urine. However, caution is required as urine containing ascorbic acid (vitamin C) will give a false negative reaction. 2) If the occult blood test is negative but no red blood cells are found in the urinary sediment, hemoglobinuria (hemoglobinuria) due to hemolysis or myoglobinuria due to rhabdomyolysis may be the cause (Table 2-38-1).
Differential diagnosis (Table 2-38-2)
1) Causes of hematuria:
The main diseases that cause hematuria are shown in Table 2-38-2. Most cases of macroscopic hematuria are due to urinary tract diseases. However, macroscopic hematuria is also often seen in glomerular diseases such as IgA nephropathy, acute post-infectious glomerulonephritis, and microscopic polyangiitis (crescentic glomerulonephritis). Hematuria whose cause cannot be identified by routine renal and urological examinations is called idiopathic hematuria (essential hematuria). The nutcracker phenomenon occurs when the left renal vein is pinched between the aorta and superior mesenteric artery, causing an increase in left renal venous pressure, resulting in bleeding from the upper urinary tract (thought to be the renal pelvis), resulting in macroscopic hematuria.
The degree of hematuria does not necessarily correspond to the severity of the underlying disease. It is also important to note that a lesion found during the diagnostic process is not necessarily the cause of the hematuria.
2) Diagnosis of location of hematuria:
It is important to first differentiate bleeding from the urinary tract due to urological disease. For this purpose, morphological examination of red blood cells and imaging diagnosis are useful (Table 2-38-3).
a) Two-part urine test: In cases of gross hematuria, a two- or three-part urine test can, to some extent, differentiate between upper urinary tract disease, which is characterized by total hematuria or terminal hematuria, and bleeding from the lower urinary tract, which is characterized by initial hematuria.
b) Morphological examination of urinary red blood cells: More than 70% of red blood cells excreted in urine due to glomerular damage exhibit a variety of deformations, such as doughnut-shaped, helmet-shaped, or confetti-shaped (glomerular hematuria). However, deformations are rarely seen in cases of bleeding from the urinary tract (non-glomerular hematuria). The reason why glomerular hematuria exhibits a variety of deformations is thought to be due to mechanical damage caused when red blood cells pass through the glomerular basement membrane and the effects of osmotic pressure and pH when passing through the renal tubules.
c) Imaging diagnosis: Basic imaging diagnosis includes plain X-rays of the kidney, ureter and bladder (KUB), ultrasound examination of the kidney and urinary tract, and intravenous pyelography. Among these, ultrasound examination is the first screening test, as it is non-invasive and provides a large amount of information. If tumors or abnormalities in the vascular system are suspected, further tests such as CT scans, MRIs, and angiograms are performed.
d) Endoscopic examination: If bleeding from one ureter is confirmed by cystoscopy, kidney or upper urinary tract tumors or the nutcracker phenomenon (bleeding from the left kidney) are suspected. If bleeding is from both sides, there is a high possibility of an internal kidney disease.
e) Other urinary test findings: ① When hematuria and urinary protein are positive, glomerular disease should be suspected. However, even in cases of urinary tract bleeding, if 3-6 mL of blood is present in 1000 mL of urine, the qualitative test will show a positive urinary protein result. ② When a variety of findings, such as red blood cell casts, granular casts, and waxy casts, are observed in the urinary sediment, active glomerulonephritis is suspected. ③ When leukocyturia (pyuria) and bacteriuria are observed, urinary tract infection should be suspected. However, when severe inflammation is observed in the glomeruli due to vasculitis or lupus nephritis, leukocyturia should be observed. ④ If atypical cells are observed, there is a possibility of a malignant tumor in the kidney and urinary tract. ⑤ Some cases of hematuria alone are accompanied by hypercalcemia or hyperuricemia. It is speculated that microliths cause hematuria by damaging the renal tubules.
3) Renal biopsy:
If urological diseases are ruled out, differential diagnosis of internal diseases will proceed. Glomerular diseases that cause hematuria, such as IgA nephropathy, hereditary nephritis, and thin basement membrane disease, can be definitively diagnosed by renal biopsy.
4) Clinical approach to microscopic hematuria:
The incidence of microscopic hematuria in the general population is said to be 5-13%. Asymptomatic microscopic hematuria in people under 50 years of age rarely indicates a serious disease, and is often observed over time as idiopathic hematuria. In people over 50 years of age with unexplained microscopic hematuria, thorough imaging diagnosis is required to rule out the possibility of a tumor (a report has shown that malignant tumors of the urinary tract were found in 13% of patients over 50 years of age who were referred to a urology department with microscopic hematuria). [Kimura Kenjiro]

Table 2-38-1
Differentiation of Hematuria, Hemoglobinuria, and Myoglobinuria ">

Table 2-38-1

Table 2-38-2
Causes of Hematuria

Table 2-38-2

Table 2-38-3
Differential diagnosis of hematuria ">

Table 2-38-3

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

概念
　尿中に赤血球が異常に多く排泄される状態を血尿という．したがって，血尿の診断は顕微鏡で尿沈渣に赤血球を証明することにより行われる．健康人でも1日に10⁶個の赤血球が尿中に排泄されており，これは3個/μLにあたる．
1）顕微鏡的血尿（microscopic hematuria）：
尿沈渣を顕微鏡の400倍の視野で観察すると1個程度の赤血球が認められる．したがって，2～3個/HPF （high power field，400倍）（これは5個/μLにあたる）以上の排泄は異常である．これを顕微鏡的血尿という．
2）肉眼的血尿（macroscopic hematuriaまたはgross hematuria）：
血尿の程度が強く尿1 L中に血液が0.5 mL以上混じると，肉眼で赤く見える（これは2500個/μL以上に相当）．これを肉眼的血尿という．ときに，コーラ色と表現されることもある．酸性尿や古い尿では褐色から黒色となる．
病態生理
①肉眼的血尿は，その外観から患者自身が気づく場合がほとんどであるが，顕微鏡的血尿は健康診断や一般のスクリーニング検査などにおける尿潜血反応陽性が契機となって発見されることが多い．これを無症候性血尿（asymptomatic hematuriaあるいは chance hematuria，偶然に発見された血尿という意味）という．
　　試験紙法による尿潜血反応の感度は鋭敏で，尿1 mL中に赤血球が5個以上含まれていれば陽性となる．ただし，アスコルビン酸（ビタミンC）を含有する尿は反応が偽陰性となるので注意を要する．②潜血反応が陰性なのに尿沈渣で赤血球が確認されない場合は，溶血に伴う血色素尿症（ヘモグロビン尿）や横紋筋融解に伴うミオグロビン尿が考えられる（表2-38-1）．
鑑別診断（表2-38-2）
1）血尿の原因疾患：
血尿の原因になるおもな疾患を表2-38-2に示す．肉眼的血尿の多くは尿路疾患である．しかし，IgA腎症，感染後急性糸球体腎炎，顕微鏡的多発血管炎（半月体形成性糸球体腎炎）などの糸球体疾患でもしばしば肉眼的血尿がみられる．通常行われる腎・泌尿器科的検査で原因が特定できないものを特発性血尿（essential hematuria）という．ナットクラッカー現象は，左の腎静脈が大動脈と上腸間膜動脈の間に挟まれて左腎静脈圧が上昇するために上部尿路（腎盂と考えられている）から出血して肉眼的血尿が生ずるものである．　
血尿の程度と原因疾患の重症度は必ずしも一致しない．また，診断過程で見つかった病変がその血尿の原因とは限らないことに注意を要する．
2）血尿の部位診断：
泌尿器科的疾患による尿路からの出血をまず鑑別することが重要である．そのためには赤血球形態検査や画像診断が有用である（表2-38-3）．　
a）2杯分尿試験：肉眼的血尿の場合は，2杯分尿あるいは3杯分尿試験により，全血尿あるいは終末時血尿を呈する上部尿路疾患と，初期血尿を呈する下部尿路からの出血をある程度鑑別できる．
b）尿中赤血球形態検査：糸球体障害により尿中に排泄される赤血球は70％以上がドーナツ状，ヘルメット状，金平糖状などの多彩な変形を呈する（糸球体性血尿glomerular hematuria）．しかし，尿路からの出血では変形がほとんどみられない（非糸球体性血尿non-glomerular hematuria）．糸球体性の血尿が多彩な変形を示すのは，赤血球が糸球体基底膜を通過するときの機械的損傷と，尿細管を通過する際に浸透圧やpHの影響を受けることによると考えられている．
c）画像診断：腎・尿管・膀胱単純X線撮影（kidney，ureter and bladder：KUB），腎・尿路の超音波検査，経静脈性の腎盂造影が基本的な画像診断である．このなかでも超音波検査は侵襲がなく情報量も多いので，まずスクリーニングとして行う検査である．腫瘍や血管系の異常が疑われるときは，さらにCTスキャン，MRI，血管造影などの検査を行う．
d）内視鏡検査：膀胱鏡検査で片側尿管からの出血が確認されれば腎・上部尿路の腫瘍やナットクラッカー現象（左腎からの出血）などが疑われる．両側からの出血であれば内科的腎疾患の可能性が高い．
e）その他の尿検査所見：①血尿と同時に尿蛋白が陽性のときは糸球体疾患を疑う．ただし，尿路出血でも1000 mLの尿に3～6 mLの血液が混じると定性試験で尿蛋白は陽性となる．②尿沈渣にて赤血球円柱や顆粒円柱，ろう様円柱などの多彩な所見が認められる場合は，活動性の糸球体腎炎が考えられる．③白血球尿（膿尿）と細菌尿を認める場合には尿路感染を疑う．ただし，血管炎やループス腎炎などで激しい炎症が糸球体にみられる場合には，白血球尿を認める．④異形細胞を認めれば腎尿路の悪性腫瘍の可能性がある．⑤血尿単独例のなかには，高カルシウム血症や高尿酸血症を伴う例がある．微小結石が尿細管を障害して血尿の原因となることが推測される．
3）腎生検：
泌尿器科的疾患が否定される場合は内科的疾患の鑑別を進める．IgA腎症，遺伝性腎炎，菲薄基底膜病など血尿をきたす糸球体疾患は腎生検により確定診断に至る．
4）顕微鏡的血尿に対する臨床的なアプローチ：
一般住民の顕微鏡的血尿の頻度は5～13％といわれている．50歳未満の無症候性の顕微鏡的血尿では，ほとんど重篤な疾患はなく，特発性血尿として経過観察されることが多い．50歳以上の原因不明の顕微鏡的血尿は腫瘍の可能性を否定するために，画像診断をしっかりと行う必要がある（顕微鏡的血尿で泌尿器科に紹介された50歳以上の患者の13％に尿路の悪性腫瘍がみつかったという報告がある）．［木村健二郎］

表2-38-1
血尿，ヘモグロビン尿，ミオグロビン尿の鑑別">

表2-38-1

表2-38-2
血尿の原因">

表2-38-2

表2-38-3
血尿の鑑別診断">

表2-38-3

出典　内科学第10版内科学第10版について　情報

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