< Presentation of Case >
An 18-year-old college student had been otherwise well was transferred from the student health center for further investigation of his proteinuria and hematuria. This young man denied any noticeable symptom in the recent six months and denied any systemic disease or taking any medication. A week before this assessment, he visited the student health center for his “foamy urine” and was found to have mild to moderate proteinuria and hematuria by the dipstick test of a random urine sample. He was therefore suggested to have an advanced check at the nephrology clinic. He was not sure about for how long this “foamy urine” had been noticed but he recalled having trace or mild proteinuria when he tested his urine sample using a dipstick test in a biology laboratory class a year earlier. However, he did not seek medical attention. There was no history of exposure to heavy metal, toxic chemical substances or Chinese herbal remedies. He did not smoke or consume alcohol. He did not recall any family history of kidney disease except for hypertension in his father's side.
At the outpatient clinic, physical examination revealed a well-developed young man without ill-looking. His height was 178 cm and weight 65 kg. The heart rate was 80 bpm, temperature 36.8 ℃, and blood pressure 142/88 mmHg. The conjunctiva was not pale and sclera not icteric. The heart beat was regular without murmurs. Auscultation of the lung fields was normal. No remarkable finding was found in the abdomen. There was no lower leg edema.
< Laboratory and Image Study >
1. CBC and differential count
Day after admission |
WBC
K/μL |
Hgb
g/dL |
MCV
fL |
MCHC
% |
Hct
% |
Plt
K/μL |
Band
% |
Seg
% |
Lym
% |
OPD-1 |
6.62 |
13.5 |
91 |
32 |
39.6 |
420 |
0 |
68 |
2.2 |
On admission |
6.68 |
13.7 |
92 |
33 |
39.8 |
425 |
N/A |
N/A |
N/A |
OPD-2 |
6.66 |
13.6 |
94 |
33 |
39.8 |
425 |
N/A |
N/A |
N/A |
N/A: not applicable
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 |
Uric acid
mg/dl |
Albumin
g/dl |
OPD-1 |
28 |
2.1 |
137 |
4.2 |
10.3 |
3.8 |
24 |
24 |
6.8 |
3.8 |
On admission |
27 |
2.1 |
137 |
4.1 |
10.1 |
3.9 |
N/A |
N/A |
N/A |
N/A |
OPD-2 |
28 |
2.2 |
139 |
4.0 |
10.2 |
3.8 |
N/A |
N/A |
N/A |
3.9 |
OPD-3 |
29 |
2.3 |
140 |
4.1 |
10.2 |
3.8 |
N/A |
N/A |
N/A |
N/A |
3. Urinalysis
Date |
Appearance |
Specific gravity |
pH |
Protein
(mg/dl) |
Glucose |
Ketone |
Occult blood |
OPD-1 |
yellow, clear |
1.004 |
6.5 |
100 |
-- |
-- |
+ |
On admission |
yellow, clear |
1.002 |
6.7 |
100 |
-- |
-- |
+ |
OPD-2 |
yellow, clear |
1.003 |
6.6 |
100 |
-- |
-- |
+ |
Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial cells |
Cast |
Bacteria |
OPD-1 |
0.1 |
-- |
15 |
-- |
-- |
granular & RBC |
-- |
Admission |
0.1 |
-- |
15 |
-- |
-- |
granular & RBC |
-- |
OPD-2 |
0.1 |
-- |
15 |
-- |
-- |
granular & RBC |
-- |
24 hour urine total protein amount: 1.1 g/day
4. Serology study: C3: 42 (80 to 178 mg/dl), C4: 30 (12 to 42 mg/dl), CH50: 65 (142 to 279 CH50 units/ml), c-ANCA: negative, p-ANCA: negative, Rheumatoid factor: negative, ANA: negative, C3NeF: positive, Anti-HBc: negative, Anti-HBs: positive, Anti-HCV: negative, cryoglobulin: negative, serum and urine electrophoresis: negative
5. Renal sonography: Bilateral kidneys are of normal size. No obvious cystic lesion or mass was identified. Compatible with parenchymal renal disease.
6. Renal pathology: By light microscopy, capillary walls are thickening. Glomerular and mesangial hypercellularity is noted. Increase of mesangial matrix and matrix interposition is noted. Eosinophilic deposits are found within the glomerular basement membrane. No crescent and interstitial fibrosis is found. Immunofluorescence staining shows intense C3 deposition along the capillary wall and in the mesangial region. By electron microscopy, highly electron-dense material depositions in the segmental and continuous patterns are within the lamina densa of the basement membrane of the capillary wall and mesangium. It is compatible with dense deposit disease.
< Course and Treatment >
Based on the history (proteinuria and hematuria), hypertension and urinalysis (RBC casts), glomerulonephritis was the most likely diagnosis. Among various glomerulonephritis, the membranoproliferative glomerulonephritis type II (MPGN II) was highly suspected because of the low complement concentration (low C3 and CH50). Since MPGN II is a relatively rare disease and drusen may develop in some individuals with MPGN II (also known as dense deposit disease). The patient underwent the ophthalmologic exam, which did not reveal drusen. In order to further confirm the diagnosis, he was admitted for renal biopsy and the pathologic report further confirmed the diagnosis of MPGN II. Angiotensin II receptor blocker was begun to control high blood pressure and proteinuria, and pentoxifylline for chronic kidney injury. He was also under special diet education and modification to meet his daily need. He was now under regular follow-up at clinic.
< Analysis >
Membranoproliferative glomerulonephritis (MPGN)是一群在臨床及病理上有著類似表現的疾病，這些疾病可為原發性(primary, idiopathic)或次發 (secondary)於如感染、腫瘤、自體免疫疾病或慢性肝病等。原發性的MPGN又可分為一至三型，皆與補體系統(complement system)異常相關。第一型(classic MPGN)是最常見的，以immue complex的subendothelial deposition與classic complement pathway的活化為主。第二型與血清中的免疫球蛋白及C3 nephritic factor (C3NeF)有關。至於第三型則歸類為第一型的變異型，主要以subepithelial deposition為特色。在此病例我們將主要討論第二型MPGN。
造成MPGN II的原因是由於alternative complement pathway不受控制的活化。而alternative complement pathway不受控制的活化的原因是由於C3 nephritic factor (C3NeF)。因為C3NeF是IgG的自體免疫抗體，而C3NeF可穩定C3 convertase (C3bBb)防止其被分解，進而造成alternative complement pathway的持續活化，也進而導致C3被持續消耗而引起hypocomplementemia。在臨床上，MPGN II與另外兩種疾病相關，acquired partial lipodystrophy (APD)及macular degeneration。APD的病患在血中也可發現C3NeF，進而導致complement-mediated adpocyte lysis，及其後續alternative complement pathway的活化。至於macular degeneration與MPGN II之間，則是透過兩者都和factor H的變異而相關。臨床上，MPGN主要影響小孩及年輕成人，但沒有男女之間的差異。MPGN一般多為idiopathic，但當發生在成人時，則要考慮與HCV及cryoglobulinemia的相關性。因此對於本病患，我們也檢測了HCV及cryoglobulinemia，不過結果都呈陰性。MPGN II 病患的表現可以為腎病症候群(40-70%)、急性腎炎症候群(20-30%)、無症狀的蛋白尿及(或)血尿(20-30%)與反覆發作肉眼可見的血尿(10-20%)等。約有一半的病患在被診斷前會有呼吸道感染症狀、約三分之ㄧ會出現高血壓，約一半的病患在診斷時已有腎功能異常，如此病例。MPGN的三型並不能以臨床表現分別，然而根據腎外表現則可輔助診斷。如眼睛出現drusen或伴隨APD則考慮MPGN II。Drusen是在眼內Bruch's membrane的黃白色沉積物，由於眼球的choriocapillaris-Bruch’s membrane-retinal pigment epithelial interface在結構上十分類似腎絲球的capillary tuft-glomerular basement membrane-glomerular epithelial interface，因此drusen可見於某些MPGN II的病患，尤其是進展到末期腎病變的病患。但與macular degeneration所產生的drusen之間的不同處在於，MPGN II出現drusen的時間要較macular degeneration早，約為10至20歲之間。此外，雖然三型MPGN都會表現hypocomplementemia，但彼此之間的表現類型還是有所不同。在第一型及cryoglobulinemic MPGN (次發性)，主要是classic complement pathway的活化，因此可見到正常或低下的C3、低下的C4及低下的CH50；第二型則是alternative complement pathway的活化，可見到低下的C3、正常的C4及低下的CH50。至於第三型則以altrnative 與terminal pathway活化引起，可見到低下的C3、正常的C4及低下的C5到C9。另外一項MPGN II的實驗診斷特徵為約有80%的病患呈現C3NeF陽性，因此這也是一項有用的診斷輔助工具，不過並不是每一個實驗室都有能力從事此項檢驗。臨床上診斷MPGN II最主要的方法為腎臟切片。組織學上可見到程度不等的glomerular hypercellularity、血管壁增厚及mesangial matrix增生，但這些都不具特異性。最重要的檢查發現是要在電子顯微鏡下，在basement membrane內見到連續或不連續的緊密沉積，正因為此特徵，MPGN II才會又名dense deposit disease，而dense deposit disease也更較MPGN能傳神的描述此病的特徵。至於沉積物的成分尚未確定，不過已知的是，這些沉積物並非immune complex。
臨床上MPGN II的自發性緩解(remission)不常見，加上目前並無有效的療法，最後幾乎都會進展到末期腎病變，在診斷後的十年內，就已有約一半以上的病患進展到末期腎病變。治療方面，目前並無特定治療方法，所以一切都是以症狀治療為主。基本上就是依一般慢性腎病原則處理，但由於多發生在年輕人，因此營養、生長、飲食、心理建設、慢性腎病教育及定期追蹤都是相當重要的。進展到末期腎病變後，可以接受透析治療或腎臟移植，但MPGN II的病患在移植後的復發機會相當高，曾被報告有80至90%的復發機會，且至少15%的移植腎會在5年內失去功能，因此是否要接受移植端看病患當時狀況決定。
< References >
- Primer on Kidney Diseases. 4th edition.
- J Am Soc Nephrol 2005;16:1392-1404.
- Pediatr Nephrol 2010;25:1409-18.
|
Case Discussion
繼續教育考題