< Presentation of Case >
A 18-year-old man who had been otherwise well was found to have microscopic hematuria during a health check on admission to a college. The repeat urine dipstick tests remained positive for 1+ to 2+ microscopic hematuria 2 weeks and 4 weeks later, respectively. He was referred to the Nephrology outpatient clinic where a detailed urine analysis showed glomerular microscopic hematuria without proteinuria (see laboratory results). He had no history of gross hematuira, dysuria, urinary frequency, burning sensation on urination, or recent episodes of respiratory tract infection. He denied having un-protected sex or multiple sexual partners, or urethral discharge. He did not take herbs, medication, or chemical agents. He did not consume alcohol or smoke. There was a family history of essential hypertension. His mother reported that one of the patient’s paternal uncles seemed to have an at least 10-year history of hematuria, but she was not aware of the etiology or his current renal function. The physical examination revealed a well-developed young man without ill-looking or distress. The body height was 180 cm and weight 70 kg. The heart rate was 74 bpm, the temperature 36.7 ℃, and the blood pressure 124/68 mmHg. There was no pale conjunctiva or icteric sclera. The heart beat was regular without murmurs. Auscultation of the lung fields was normal. Examinations of the abdomen and limbs were normal.
< Laboratory and Image Study >
1. CBC
| Day after admission |
WBC
K/μL |
Hgb
g/dL |
Hct
% |
MCV
fL |
MCHC
% |
Plt
K/μL |
OPD |
7.12 |
14.9 |
44.8 |
94 |
34 |
420 |
2. Biochemistry
| Day after admission |
BUN
mg/dl |
Cre
mg/dl |
Na
mmol/l |
K
mmol/l |
Ca mg/dl |
P
mg/dl |
GOT
U/l |
GPT
U/l |
Albumin
g/dl |
OPD |
18 |
0.8 |
139 |
4.4 |
10.1 |
3.8 |
34 |
32 |
4.4 |
3. Urinalysis
| Date |
Appearance |
Specific gravity |
pH |
Protein
(mg/dl) |
Glucose |
Ketone |
Occult blood |
College health center |
yellow, clear |
N/A |
N/A |
N/A |
-- |
-- |
++ |
OPD |
yellow, clear |
1.005 |
6.8 |
-- |
-- |
-- |
++ |
Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial cells |
Cast |
Bacteria |
College health center |
N/A |
-- |
N/A |
N/A |
N/A |
N/A |
N/A |
OPD |
0.1 |
-- |
>80 |
<5 |
Few |
-- |
-- |
Urine RBC morphology: dysmorphic
N/A denotes non applicable
4. Serology study: Anti-nuclear antibody (ANA): negative, Anti-neutrophil cytoplasmic antibody (ANCA): negative, Anti-HBc: negative, Anti-HBs: positive, Anti-HCV: negative
5. Renal sonography: Negative finding
< Course and Treatment >
Because of the presence of dysmorphic RBC, microscopic hematuria of glomerular origin was highly considered. Further inquiry revealed that his uncle’s hematuria was described as a “familial benign hematuria” and no renal biopsy was performed. Based on the clinical presentation, results of serologic investigations and a family history, thin basement-membrane nephropathy or Alport syndrome was suspected. The ophthalmology examination showed no abnormality, which made Alport syndrome less like. Renal biopsy was suggested, which the patient declined; however, the patient agreed to skin biopsy and genomic DNA sequencing. The amount of type IV collagen α3, α4 and α5 chains was maintained in the skin sample. Additionally, subsequent sequencing reveals a heterozygous missense mutation in alpha 4 type IV collagen precursor (COL4A4) gene. Thus, a diagnosis of thin basement-membrane nephropathy (TBMN) was made and he kept annual follow- up at the Nephrology clinic for urine analysis and renal function without any specific treatment.
< Analysis >
Microscopic hematuria在臨床上十分常見，一般可先依尿中紅血球的形態來區分屬於腎絲球性或非腎絲球性血尿，之後再依年齡來做初步鑑別診斷 (Figure 1)。在排除掉結石、感染及腫瘤等之後，在小孩及成人常見的持續性血尿主要原因，包括thin basement-membrane nephropathy (TBMN)、IgA nephropathy及Alport syndrome，而TBMN是其中最常見的。持續性血尿的操作型定義為至少檢測出兩次以上的血尿，而TBMN則甚至需要兩次血尿中間至少需間隔2年的診斷條件。持續性血尿的盛行率在同時考慮小孩及成人時約為6%，可能是遺傳性的，也可能是偶發性的，但不管遺傳性或偶發性的持續性血尿，通常都需要接受腎臟切片才可能鑑別診斷病因，不過若腎功能穩定、血尿無逐漸惡化、無或極輕微且無惡化蛋白尿時，就不一定需要積極進行腎臟切片。雖然遺傳性的持續性血尿可從家族史下手，且家中或已有被確定診斷的病例，不過即使遇到有家族史的持續性血尿也不可掉以輕心，以免遺漏可能潛藏的其他病因。
TBMN可在任何種族或任何年紀(1歲至86歲都被報告過)發生，部份報告指出以女性居多，其預估盛行率約1%，但因為大部分的病患都未被診斷出，所以其盛行率並不十分可信。TBMN屬於自體顯性遺傳，乃是因為type IV collagen異常導致，約有三分之二的TBMN病患家族中會至少有一位也有持續性血尿。另外三分之一的TBMN病患則是因為de novo mutation所導致的，因此此類TBMN病患沒有明顯的家族史，不過其下一代則有50%的機會發生TBMN。由於TBMN屬於遺傳性疾病，因此TBMN(為non-progressive hematuria)有時會被誤稱為familial hematuria，不過為了與Alport syndrome(也為一種familial hematuria，可為自體顯性、自體隱性、或X染色體遺傳，但為progressive hematuria，預後與TBMN不同)區分，所以目前多已改稱thin basement-membrane nephropathy。
臨床上TBMN的典型特徵為persistent microscopic glomerular hematuria (dysmorphic RBC)，這也是大部分病患的唯一表現，但有些病患也可能有非常輕微的non-progressive proteinuria，不過總體腎臟功能是正常的，且預後相當好。在光學顯微鏡下TBMN病患的glomeruli幾乎是正常的，或許有些許mesangial cellular proliferation及matrix expansion，但是所有光學顯微鏡下的表現都不具特異性。標準的診斷方法為在電子顯微鏡下見到典型均一性變薄的glomerular basement membrane (GBM)，不過早期的Alport syndrome也會出現變薄的GBM，因此TBMN和早期的Alport syndrome較難以區分。此外TBMN病患呈現的是”均一性”變薄(uniformly thinned)的GBM，而正常小孩或minimal change nephrosis的小孩則偶爾以”局部性”變薄(focally thinned)為主。另外病理及臨床上診斷要注意的是，GBM變薄有時也會出現在製作不當的檢體，進而導致誤判，所以必須要在檢體的不同區域進行確認以排除檢體不良的可能。GBM的厚度在出生時約為150 nm，1歲時約為200 nm，到11歲時會達到成人的標準(成人男性約370±50 nm，成人女性約320±50 nm)，WHO提出成年人的GBM至少須達到250 nm，而2到11歲的小孩至少須達到180 nm，但是因為不同的報告提出不同的標準，所以目前尚未有公認標準。不過簡單來說，當GBM的厚度小於200 nm時就要高度懷疑考慮TBMN了。臨床上約有5%至20%的TBMN病患一生至少會發生一次macroscopic hematuria，尤其是在運動後或感染後，不過由於macroscopic hematuria也可以是IgA nephropathy及Alport syndrome的主要表現，因此鑑別診斷十分重要。
臨床上有時不易區分TBMN、IgA nephropathy或Alport syndrome，因為三者都可以persistent microscopic hematuria表現。但IgA nephropathy或Alport syndrome通常會伴隨較具特異性的表現或腎外表現，如IgA nephropathy會以persistent microscopic hematuria及在上呼吸道感染後48至72小時出現gross hematuria為主要表現，此外腎臟切片的免疫螢光染色也有助區分TBMN及IgA nephropathy；而Alport syndrome則可出現hearing loss、lenticonus或retinopathy，最終可導致renal failure，不過早期的Alport syndrome十分不易與TBMN區分，甚至有學者認為伴隨progressive proteinuria及腎功能惡化的TBMN，其實是未被診斷出的Alport syndrome。除了以腎臟切片伴隨電子顯微鏡檢查外，免疫組織化學 (immmunohistochemical analysis) 與遺傳分析也是確定診斷的重要工具。免疫組織化學分析可經由皮膚切片之後針對collagen進行螢光染色， X染色體隱性遺傳及自體隱性遺傳之Alport syndrome的type IV collagen α3、α4與α5 chains的量會減少或缺乏，而TBMN的type IV collagen α3、α4與α5 chains則維持正常。遺傳性TBMN在COL4A3及COL4A4會帶有heterozygous mutations，然而自體隱性遺傳之Alport syndrome則在COL4A3及COL4A4有homozygous或compound mutations，80%的X染色體隱性遺傳之Alport syndrome則在COL4A5可發現mutations。
目前雖然並沒有針對TBMN的標準治療，不過由於TBMN的預後都相當好，因此其實也不需要特定治療，曾有報告追蹤TBMN病患達30年，病患腎功能也無惡化。不過也有少數報告指出TBMN也可能產生腎功能惡化，但是如前所述，許多學者認為這些惡化的”TBMN”很可能其實是未被診斷出的Alport syndrome，所以雖然TBMN的預後都相當好，但還是建議臨床醫師需定期追蹤。
< References >
- Comprehensive Clinical Nephrology 4th edition
- J Am Soc Nephrol 17:813-822, 2006
- Arch Pathol Lab Med.2009; 133:224-232
- N Engl J Med 2003;348:2330-8
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Case Discussion
繼續教育考題