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혈뇨와단백뇨, 안심하고추적하는법 서울대학교의과대학내과학교실분당서울대학교병원신장내과 김세중 혈뇨 (hematuria) 198 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 중요한병력및이학적소견 Recent sore throat, skin infection, Weight change, Trauma, exercise, menstruation, Recent bladder catheterization Dysuria, frequency, urgency Abdominal pain, CVA pain, suprapubic pain, Medication, passage of calculus 중요한병력및이학적소견 Family History hematuria, deafness, renal failure, hypertension, hemophilia, hemoglobinopathy Physical Exam fever, arthritis, rash, nephromegaly, hypertension, CVAT 분당서울대학교병원 199

1. Drugs Analgesics Anticoagulants Anticonvulsants Antiinfective Antiinfectives Antiparkinson 2. Vegetable dyes and foods 가성혈뇨 acetoanilid, aminopyrine, ethoxazene, phenacetin mets, acetophenetidine, phenazopyridine warfarin, phenidione diphenylhydantoin, phenylsuximide azo grantrisin, azo grantanol aztrex, chloroquine, flurazolidone, metronidazole, nitrofurantoins, primaquine, pyrogallol, quinine, rifampin, sulfasalazine levodopa 3. Urinary pigment bile, melanin, porphyrins, urorosein, Serratia marscens 4. Metabolic disease alcaptonuria, urates, phosphates When the Urine is Red 가성혈뇨 vs 진성혈뇨 : dipstick 검사, microscopy Hemoglobinuria, Myoglobinuria 의감별 신성혈뇨의확인 비신성혈뇨 : 출혈부위진단 200 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 혈뇨검사법 소변의채취 morning first voided urine midstream catch Avoid catheterization 2 시간이내검사시행 냉장보관은피한다. Dipstick test False positive Hemoglobinuria Myoglobinuria High concentration of pseudoperoxidase activity (Enterobacteriaceae, staphylococci, streptococci) False-negative Ascorbic acid: missed low-grade microscopic hematuria protein, high S.G., increased nitrite High specificity and low sensitivity 분당서울대학교병원 201

혈뇨의정의 정상 : RBC output <1,000/min 혈뇨 : 1-13% prevalence in adults - microscopic >3/HPF (2-5/HPF) >3,000/min >8,000/ml - gross >10,000/min 202 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Red Urine Occult blood(+) Occult blood(-) RBC Hgb Mgb Drug, dye etc hematuria Hemoglobinuria Spun serum clear red clear U/A benzidine + + + dipstick test + RBC in urine - - microscopy + Myoglobinuria Additive data haptoglobin elevated CK urine hemosiderin aldolase 분당서울대학교병원 203

Causes of hematuria according to persistency and age 혈뇨의원인 : 신장실질질환 1) idiopathic GN: IgA N, MPGN, FSGS, thin GBM disease 2) secondary GN HBGN, LN, PSGN, Alport syndrome polyarteritis nodosa (vasculitis) 3) tubulointerstitial disease acute or chronic tubulointerstitial nephritis 204 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Microscopy Isomorphic dysmorphic Urine microscopy Erythrocytes Isomorphic: from urinary excretory system Dysmorphic: glomerular origin >80% of total erythrocytes 분당서울대학교병원 205

Dysmorphic RBC at fresh urine, s.g. >1.015 Wright stain Phase contrast microscope 일반적으로 >75% 이면 nephronal RBC cast 206 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Nephronal vs non-nephronal hematuria Nephronal Non-nephronal color dark Fresh red clot - + RBC cast + - proteinuria > ~500 mg/day < ~500 mg/day Dysmorphic RBC >80% <80% 혈뇨의원인 : 상부요로 (I) Vascular disease Renal infarction, sickle cell trait, AV malformation, Nutcracker syndrome, renal vein thrombosis, Loin pain-hematuria syndrome Cystic disease of the kidney: ADPKD 분당서울대학교병원 207

Nutcracker syndrome (renal vein entrapment syndrome) 혈뇨의원인 : 상부요로 (II) Nephrolithiasis, nephrocalcinosis Infections: pyelonephritis, Tbc Tumors: renal cell ca., angiomyolipoma Trauma (including renal biopsy) 208 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 혈뇨의원인 : 하부요로 Stone: UVJ stone, bladder stone Trauma sport-related hematuria marathon runner s hematuria Tumor: bladder ca., prostate ca. Infection: cystitis, prostatitis, urethritis, True hematuria Culture (-) Urine culture Culture (+) Check PT/aPTT CBC, platelets normal abnormal Bacterial cystitis, urethritis Tbc, pyelonephritis, proteinuria RBC RBC cast, dysm RBC RBC Coagulation disorder nephronal non-nephronal 분당서울대학교병원 209

Glomerular hematuria Isolated microscopic hematuria Proteinuria or or renal insufficiency Periodic medical F/U F/U (for (for proteinuria or or renal insufficiency) Nephrology Referral Glomerulonephritis Vasculitis Tubulointerstitial nephritis Alport syndrome Benign familial hematuria Non-nephronal hematuria Helical CT CT Referral based on on lesion Cytologic analysis of of urine Cystoscopy 50 50 Yr Yr age age or or risk risk facotors for for bladder cancer Cystoscopy <50 <50 Yr Yr of of age age without risk risk factors for for bladder cancer Workup ends 210 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Malignancy risk in Older Patients Even transient hematuria carries an appreciable risk of malignancy, Particularly in older individuals with risk factors Hematuria, often transient/gross in 23 patients over age 50: 5 had cancers of UT Another study with 1930 hematuria patients mean age 58 12%: bladder cancer 0.7%: kidney and upper tract tumors Urine cytology Urothelial cell Sensitivity 40-76% (stage, grade, expertise) High in bladder ca (~90%) Limited in upper tract TCC High false negative rate Exclude high grade tumor 15% atypical/suspicious Proved to have malignancy Cystoscopy is warranted in (+) cytology 분당서울대학교병원 211

Cystoscopy Bladder pathology diagnostic image with limited role Indication Gross hematuria and/or irritative symptoms (in the absence of UTI) High risk group High risk patients (Cystoscopy recommended) Age over 50 Prolonged heavy phenacetin use Heavy smoking Exposure to certain dyes Long-term administration of cyclophosphamide Analgesic abusers Pelvic irradiation 212 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Renal Biopsy Not recommended in isolated microscopic hematuria except, evidence of progressive disease Renal dysfunction, azotemia, etc Proteinuria Hypertension Follow Up in Undiagnosed Hematuria To exclude undiagnosed malignancies After (-) result of radiologic studies, cytology, cystoscopy Risk: 1% at 3-5 years in old age In high risk patients Periodic: urinalysis with cytology (6, 12, 24, 36 m) Yearly US and Cystoscopy (optional) To detect the glomerular disease 분당서울대학교병원 213

Hematuria itself is not dangerous unless extraglomerular bleeding is so brisk that it causes clots that obstruct the ureter May be a symptom of an underlying serious condition Particularly in age >50 단백뇨 (proteinuria) 214 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Measurement of urine protein Semiquantitative tests precipitation tests (5 to 10 mg/dl) adding 5% sulfosalicylic acid or concentrated nitric acid heating the urine and adding glacial acetic acid dipstick test (10 to 15 mg/dl) tetrabromphenol blue Comparison of Semiquantitative Methods of Measuring Urinary Protein Concentration Protein Concentration dipstick* Sulfosalicylic Acid (mg/dl) 0 0 No turbidity 1 10 Trace Slight turbidity 15 30 1+ Turbidity through which print can be read 40 100 2+ White cloud without precipitate through which heavy black lines on white background can be seen 150 350 3+ White cloud with fine precipitate through which heavy black lines cannot be seen >500 4+ Flocculent precipitate * The dipstick readings are graded from 0 to 4+ depending on the color change produced. 분당서울대학교병원 215

Protein quantification Protein:creatinine ratio >24 HU collection 24 HU collection Still widely used but time-consuming, errors of overcollection and under-collection, impractical for many patients Spot urine protein: creatinine ratio Circadian rhythm of protein excretion (lowest overnight) and fairly constant creatinine excretion over 24 hours : at the same time of the day for f/u Anti-proteinuric Barrier of GBM Charge selective barrier: negatively charged sialoglycoprotein Size selective barrier: 44A 1.200 Fractional Clearance 1.000 0.800 0.600 0.400 0.200 0.000 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Effective molecular radius Anionic Neutral Cationic 216 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Normal physiology Definition of proteinuria Proteinuria: >150 mg/day in adults Overt proteinuria >500 mg/day Nephrotic proteinuria >3.5 g/day 분당서울대학교병원 217

Albuminuria >30 mg/day Microalbuminuria: albuminuria which is not detected by routine urine dipstick test Albumin excretion between 30-300 mg/day Represents early endothelial injury in DM nephropathy or cardiovascular disease 단백뇨의접근 Proteinuria Repeat Repeat U/A U/A Proteinuria(+) Proteinuria(-) Persistent proteinuria Transient proteinuria By fever, exercise, stress W/U W/U for for Orthostatic proteinuria Pathologic Proteinuria Orthostatic Proteinuria 218 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Mechanism of proteinuria Mechanism of proteinuria 분당서울대학교병원 219

단백뇨의평가 1. Initial screening studies R/O false (+) result; highly concentrated urine, exercise, fever urinary sediment; glomerular origin associated systemic disease; DM, HBGN, LN repeat qualitative test if false (+) test or transient 2. Preliminary quantification PEP/IEP in elderly orthostatic proteinuria in young 3. Definitive kidney biopsy in glomerular proteinuria (>1 g/day), hematuria 단백뇨의종류와 Urine PEP γ β α2 α1 alb γ β α2 α1 alb Normal Glomerular proteinuria Tubular proteinuria (b2 microglobulin) Overproduction Proteinuria (multiple myeloma, hemoglobinuria, rhabdomyolysis) 220 분당서울대학교병원