Case Discussion < Presentation of Case > 　　A 56-year-old man sought medical attention at the nephrology clinic because of frothy urine, weight gain (3 kg/2 months) and severe pedal edema in the past two months. He had been diagnosed as having type 2 diabetes mellitus (DM) and essential hypertension for 3 years, for which he regularly received amlodipine, metformin, and glyburide. His blood pressure was usually maintained around 130/80 mmHg and the latest HbA1C was 7.2% 2 months earlier before this evaluation, when an annual adult health check did not reveal microalbuminuria or diabetic retinopathy; and the serum creatinine (Cr) level was 1.3 mg/dl. On evaluation, he was found to have overt proteinuria, and the blood urea nitrogen (BUN) and Cr level was 48 and 3.9 mg/dl, respectively (See laboratory). The chest radiography and first colonoscopy were reportedly normal. He denied taking non-prescribed medications, herbs, or a history of recent travel. He used to exercise 30 minutes, every 3 days weekly. There was no cough, hemoptysis or dyspnea. A diagnosis of acute renal failure with nephrotic syndrome was made and he was admitted. Upon admission, physical examination revealed a modest obese but well-developed man. The heart rate was 80 beats per minute, the temperature 36.8℃, and the blood pressure 138/88 mmHg. The conjunctiva was not pale and sclera not icteric. The heart beats were regular and there were no cardiac murmurs. Auscultation of the lungs showed bibasilar crackles. Abdominal exam was normal. Pitting edema graded 4+ was noted at bilateral legs. No skin lesion was found. Digital rectal exam was unremarkable. Laboratory evaluation yielded normal electrolyte levels and blood cell counts. The renal function was BUN/Cr 50/3.9 mg/dl. The urine analysis revealed 4+ proteinuria and some intact RBC but without RBC casts or atypical cells. Twenty-four urine protein analysis revealed a nephrotic-range proteinuria of 5.0 g/day. The renal sonography revealed bilateral parenchymal renal disease with symmetric kidney size. < Laboratory and Image Study > 1. CBC/DC: Day after admission WBC K/μL Hgb g/dL Hct % Plt K/μL Band % Seg % Eos % Lym % OPD 7.5 12.1 36.2 410 N/A (not available) N/A N/A N/A Admission 7.6 11.9 34.2 422 0 72 2.1 3.9 Discharge 7.67 12.5 36.6 420 N/A N/A N/A N/A ESR (admission): 60 mm/h 2. Biochemistry: Day after hospitalization BUN mg/dl Cre mg/dl Na mmol/l K mmol/l Ca mmol/l AST U/l ALT U/l Albumin mg/dl T-Bil mg/dl AC sugar mg/dl HbA1C OPD 48 3.8 139 4.6 2.36 36 32 3.3 0.8 N/A N/A Admission 50 3.9 137 5.1 2.42 N/A N/A N/A N/A 92 7.3 Day 7 56 4.1 138 4.4 N/A N/A N/A N/A N/A N/A N/A Discharge 50 4.0 138 3.9 N/A N/A N/A 3.6 N/A 100 N/A Cholesterol (at OPD): 300 mg/dl Table 3. Urine analysis Date Appearance Specific gravity pH Protein (mg/dl) Glucose Ketone Occult blood OPD pink, clear 1.010 6.5 >300mg/dl -- -- + Admission pink, clear 1.010 6.5 >300mg/dl -- -- + Discharge pink, clear 1.010 6.5 >300mg/dl -- -- + Date Urobilinogen Bilirubin RBC WBC Epithelial cells Cast Bacteria OPD 0.1 -- >50 5-10 -- Granular -- Admission 0.1 -- >50 <5 -- Granular -- Discharge 0.1 -- >50 <5 + Granular -- 4. Serology studies: HBcAg(-), HBsAg(-), Anti-HBs(+), anti-HCV(-), HIV(-), rheumatoid factor(RF)(-), Anti-nuclear antibody(ANA)(-), cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA)(-), perinuclear-ANCA (p-ANCA)(-), cryoglobulin(-), anti-glomerular basement membrane (anti-GBM)(-), normal C3 and C4 levels 5. Serum- and urine protein electrophoresis: no dysproteinemia 6. Renal ultrasonography: Normal kidney size with increased echogenecity compared to the liver. No tumor or hydronephrosis is seen. The prostate is mildly enlarged. 7. Renal biopsy summary: Focal glomerular cellular crescents and mild to moderate fibrosis are noted. Interstitial lymphocytes and plasma cells infiltration with interstitial fibrosis is present. Tubular atrophy is noted. There is no remarkable change of small arterioles. Congo red staining is negative. No definite pathologic change of diabetic nephropathy is noted. Immunofluorescence stain reveals intense segmental mesangial and linear staining for IgG (especially IgG4) and C3 but no positive glomerular staining for IgA, IgM, C1q, kappa or lambda light chain. Electron microscopy (EM) reveals extensive podocyte foot-process effacement with focal detachment from the capillary tuft, mesangial, subendothelial and intramembranous deposits. In high magnification of EM, in nonbranching, randomly oriented fibrillar deposits with an average diameter of 20 nm are noted. Since there is no typical pathologic change of diabetic nephropathy, diabetic nephropathy is less likely. Crescentic fibrillary glomerulopathy should be considered. < Course and Treatment > 　　The nephrotic syndrome (NS) was treated with diuretics accordingly, and amlodipine was replaced by irbesartan for hypertension and proteinuria. Because of his rapidly deteriorating renal function in the past two months, he was initially treated with intravenous methylprednisolone and cyclophosphamide. Follow-up ophthalmic exam showed no findings of diabetic retinopathy. His renal function deteriorated slightly during the initial course of diuretic and irbesartan therapy, which subsequently stabilized. Renal biopsy was performed and the pathology suggested the diagnosis of crescentic fibrillary glomerulonephritis (FGN). The immunosuppressants were subsequently changed to prednisolone and mycophenolate mofetil. He was discharged and enrolled in the chronic kidney disease education program and was followed as an outpatient. 　　Nephrotic syndrome (腎病症候群)代表了腎絲球出現病變導致蛋白自尿中流失，診斷腎病症候群，基本上是依據病患出現proteinuria (>3.5 g/day)、hypoalbuminemia (<3.5 g/dl)、edema及hypercholesterolemia，但部份病患的表現會有變異。在年紀大的病患出現腎病症候群時，最先要考慮的疾病為membrane nephropathy (MN)，在所有年齡的成年人，尤其是40至60歲，MN是腎病症候群最常見的原因，MN又可根據病因再分為原發或次發。60歲以後，腎病症候群的原因以multiple myeloma和amyloidosis更為常見。雖然惡性腫瘤是次發membrane nephropathy的原因之一，且一直被強調為老年人membrane nephropathy的重要鑑別診斷，甚至部分病患惡性腫瘤的初始表現是腎病症候群，但因為惡性腫瘤的發生率同時也隨著年齡的增加而增加，現今並無有力的證據證明老年人membrane nephropathy與惡性腫瘤之間的必然相關性。儘管如此，惡性腫瘤仍然是臨床醫師見到老年人membrane nephropathy時必須考慮的原因之一。此外由於此病患罹患DM，且DM也是次發membrane nephropathy的原因之一，因此DM nephropathy導致的腎病症候群也須列入考慮，但一般來說，DM nephropathy進展為慢性，一般約10到15年才會出現overt proteinuria，此病患血糖控制不錯，且之前並無microalbuminuria或diabetic retinopathy病史，因此DM nephropathy導致腎病症候群的可能性較低。另外病患也出現acute renal failure (ARF)，在老年人出現ARF，第一需先排除post-renal obstruction，但超音波已排除此可能性，此外實驗數據也較支持intrinsic renal disease導致之可能性。另外還要考慮在腎病症候群出現ARF的原因包括體液喪失導致pre-renal azotemia、感染導致acute tubular necrosis、腎臟疾病本身所導致如membrane nephropathy接著產生crescentic nephritis、bilateral renal vein thrombosis或有使用NSAID、diuretics或ACEI等。但這些鑑別診斷在此病患的可能性都較低或需要進一步以腎臟切片幫忙診斷，因此我們安排了腎臟切片。 　　 Fibrillary glomerulonephritis (FGN)在臨床上並不常見，平均診斷年紀介於45至65歲，白人及女性有較高的發生率， 大部分原因不明，但少部分與惡性腫瘤、dysproteinemia或自體免疫疾病有關。不過2011年分析66個病患的case series(目前最大)反而指出惡性腫瘤(25%，尤其是carcinoma)及自體免疫疾病(15%，多為Crohn’s disease、SLE、Graves’disease及idiopathic thrombocytopenic purpura )佔大部分，該文作者認為不應將FGN歸類為idiopathic，更應該查明可能的主要病因。在分類上FGN屬於一群統稱為fibrillary glomerulopathy的疾病，這群疾病的特色為其特殊的超微結構(ultrastructure)，主要是在腎絲球內出現nonbranching fibril的沈積，不同疾病之間在光學顯微鏡下表現類似，但在電子顯微鏡下則有不同的超微結構沈積。這群疾病包括如amyloidosis、light chain disease、cryoglobulinemia、systemic lupus erythematosus、diabetic fibrillosis、immunotactoid glomerulopathy及FGN等。其中將有關amyloidosis、immunotactoid glomerulopathy及FGN的區分列于Table 1。由於FGN的病患在腎絲球都會有IgG與complement的沈積，因此FGN的致病機制被認為是這些immune complex進一步進行fibrillogenesis有關，這也可說明為何FGN與自體免疫疾病有關，但目前並無腫瘤抗原被偵測到。 　　 FGN多以腎病症候群伴隨(或無)腎功能異常表現，唯一的診斷方法為腎臟切片。根據目前最大的case series，病理切片在光學顯微鏡下表現以mesangial proliferative/sclerosing glomerulonephritis最多，其次為membranproliferative glomerulonephritis，有時可見到crescent出現，尤其是腎功能異常的病患。所有的檢體都可在腎絲球染到IgG，尤其是IgG4。電子顯微鏡下FGN的fibril直徑大小約為amyloidosis的fibril的兩倍，約12至30 nm(多為20 nm)。另外和amyloidosis不同之處為FGN的Congo Red染色為陰性。 　　整體來說，FGN的預後並不好，四年內有將近一半的病患進展到ESRD，而接近43%的病患為chronic kidney disease。目前FGN並無証實有效的治療，其中少數達到remission的病患的特色為較年輕(<40歲)、腎臟切片時腎功能是正常的、切片並無明顯的纖維化。相對的，年紀大、切片時腎功能異常、切片時24小時proteinuria量高及有明顯的腎絲球纖維化，則可想而知為預後不良的因子。所以發病時的年紀、切片時Cr及proteinuria的值及腎絲球纖維程度是目前最重要的預後因子。一旦進展到end-stage renal disease，病患的處置與其他疾病並無差異，根據2009年的預後研究，腎移植是安全可靠且術後復發風險低的治療。 < References > 1. Comprehensive Clinical Nephropathy, 3rd Edition 2. Glomerular Disease in the Elderly, Geriatric Nephrology Curriculum, American Society of Nephrology, 2009 3. Clin J Am Soc Nephrol 2011;6:775-84. 4. Nephrol Dial Transplant 2004;19:2166-70. 5. Kidney Int 2009;75:420-7. 繼續教育考題 1. (D) 在評估 Nephrotic syndrome (腎病症候群)時，何者不是診斷標準？ A Proteinuria (>3.5 g/day) B Hypoalbuminemia (<3.5 g/dl) C Edema D Urinalysis with RBC casts 2. (B) 在年紀大的病患出現腎病症候群時，需要考慮的疾病不包括？ A GI tract carcinoma B IgA nephropathy C Amyloidosis D Multiple myeloma 3. (A) 當腎病症候群的病患出現acute renal failure時需要考慮的原因包括？ A Post-renal cause due to obstruction B Pre-renal cause due to fluid loss C Intrinsic renal cause due to underlying renal disease D All of them 4. (B) 針對fibrillary glomerulonephritis (FGN)在臨床上的敘述，何者正確？ A Mostly presented with nephrotic syndrome B Associated to underlying autoimmune diseases C Mostly occurs in young population D Male predominant 5. (C) 有關fibrillary glomerulonephritis與amyloidosis的比較，何者不正確？ A Differs in size of fibril deposit B Differs in Congo Red stain C Differs in renal presentation D Differs in immunoglobulin deposition 6. (D) 有關fibrillary glomerulonephritis的敘述，何者不正確？ A With intra-glomerular nonbranching fibril deposition B Associated with malignancy and autoimmune diseases C Renal transplantation is by far the most effective therapy D Almost all the samples were stained positive for IgG2 答案解說 ( D ) Nephrotic syndrome (腎病症候群)代表了腎絲球出現病變導致蛋白自尿中流失，診斷腎病症候群，基本上是依據病患出現proteinuria (>3.5 g/day)、hypoalbuminemia (<3.5 g/dl)、edema及hypercholesterolemia，但部份病患的表現會有變異。Urine RBC casts是nephritic syndrome的特徵。 ( B ) 在所有年齡的成年人，尤其是40至60歲，MN是腎病症候群最常見的原因，MN又可根據病因再分為原發或次發。60歲以後，腎病症候群的原因以multiple myeloma和amyloidosis更為常見。雖然惡性腫瘤是次發membrane nephropathy的原因之一，且一直被強調為老年人membrane nephropathy的重要鑑別診斷，甚至部分病患惡性腫瘤的初始表現是腎病症候群，但因為惡性腫瘤的發生率同時也隨著年齡的增加而增加，現今並無有力的證據證明老年人membrane nephropathy與惡性腫瘤之間的必然相關性。儘管如此，惡性腫瘤仍然是臨床醫師見到老年人membrane nephropathy時必須考慮的原因之一。IgA nephropathy主要是以gross hematuria表現，有時確實可伴隨proteinuria或腎功能異常，但IgA nephropathy主要仍以年輕人為主。 ( A ) 在臨床上，所有acute renal failure都需先排除post-renal cause後，才考慮其他原因，因此腎臟或腹部超音波檢查可以為主要的篩檢工具。在腎病症候群出現acute renal failure要考慮的原因包括體液喪失導致pre-renal azotemia、感染導致acute tubular necrosis、腎臟疾病本身所導致如membrane nephropathy接著產生cresentic nephritis、bilateral renal vein thrombosis或有使用NSAID、diuretics或ACEI等。 ( B ) Fibrillary glomerulonephritis (FGN)在臨床上並不常見，多以腎病症候群伴隨(或無)腎功能異常表現，平均診斷年紀介於45至65歲，白人及女性有較高的發生率， 大部分原因不明，但少部分與惡性腫瘤、dysproteinemia或自體免疫疾病有關。不過2011年分析66個病患的case series(目前最大)反而指出惡性腫瘤(25%，尤其是carcinoma)及自體免疫疾病(15%，多為Crohn’s disease、SLE、Graves’disease及idiopathic thrombocytopenic purpura )佔大部分。 ( C ) 電子顯微鏡下FGN的fibril直徑大小約為amyloidosis的fibril的兩倍，約12至30 nm(多為20 nm)(Figure 1)，另外和amyloidosis不同之處為FGN的Congo Red染色為陰性。Amyloidosis的immunoglobulin deposition為monoclonal light chain (mostly λ)，而FGN則為polyclonal (mostly IgG4)及偶爾monoclonal IgGκ，但兩者的表現皆以nephrotic syndrome為主。(See Table 1) ( D ) Fibrillary glomerulonephritis與惡性腫瘤(25%，尤其是carcinoma)及自體免疫疾病(15%，多為Crohn’s disease、SLE、Graves’disease及idiopathic thrombocytopenic purpura )相關。電子顯微鏡下FGN的fibril直徑大小約為amyloidosis的fibril的兩倍，約12至30 nm(多為20 nm)。FGN多以腎病症候群伴隨(或無)腎功能異常表現，唯一的診斷方法為腎臟切片，所有的檢體都可在腎絲球染到IgG，尤其是IgG4。FGN的預後並不好，目前並無証實有效的治療，一旦進展到end-stage renal disease，病患的處置與其他疾病並無差異，根據2009年的預後研究，腎移植對是安全可靠的治療且術後復發風險低。