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Hematuria and proteinuria Tae-Hyun Yoo Department of Internal Medicine, College of Medicine Yonsei University, Seoul, Korea

Case I 남자 74 세, microscopic hematuria 로의뢰됨 병력상고혈압 3 년, 전립선비대증 흡연력 -, 음주력 social 증상 : dysuria +, gross hematuria + BP 126/81 mmhg, BT 36.6ºC, PR 59/min 검사소견 BUN/Cr 21.3/1.49 mg/dl Na/K/Cl/CO2 141/5.1/102/27 meq/l urine cx: - urianlysis: protein -, blood 3+, RBC 10-20/HPF urine cytology: negative, inflammatory cells

이환자에서다음으로시행하여야할가장적절한조치는? 1. Cystoscopy 2. Urine NMP22 3. 3-6 month interval regular follow up 4. 복부단층촬영 5. Renal biopsy

Causes of Isolated Hematiuria Origin < 50yrs 50 yrs Glomerular IgA IgA Thin GBM Alport s syndrome Alport s syndrome Mild focal GN Non-glomerular Nephrolithiasis Nephrolithiasis (Upper tract) Pyelonephritis Renal cell ca Cystic kidney disease Cystic kidney disease Trauma Papillary necrosis Papillary necrosis Renal infarction Tuberculosis Ritz E. N Engl J Med, 2003

Causes of Isolated Hematiuria Origin < 50yrs 50 yrs Non-glomerular Cystitis, prostitis Cystitis, prostitis Lower U-tract Bladder or ureter Bladder tumor benign polyps Prostate cancer Bladder tumor Bladder or ureter benign polyps Over anticoagulation Ritz E. N Engl J Med, 2003

Indication of cystoscopy Age over 50 Prolonged heavy phenacetin use Heavy smoking Exposure to certain dyes Long-term administration of cyclophosphamide Analgesic abusers Pelvic irradiation

Transient or persistent? Transient: Benign & without any obvious etiology in 39% of young adults 8-9% of adults >50y/o malignancy Persistent & without apparent cause: Microscopic 5% malignancy Macroscopic 20% malignancy Froom P, BMJ 1984 288;20 Britton JP, BMJ 1989, 299;1010

Case II 남자 19 세, 육안적혈뇨로내원함 병력상특이소견없음 흡연력 -, 음주력 social 증상 : 육안적혈뇨 BP 109/72 mmhg, BT 37.0ºC, PR 72/min 검사소견 BUN/Cr 11.3/0.64 mg/dl Na/K/Cl/CO2 141/4.4/103/26 meq/l WBC/Hb/Hct/Plt 5780/11.3/34.3/309,000/uL urianlysis: protein 2+, blood 3+, RBC many/hpf urine cx: negative

Rt Lt

이환자에서다음으로시행하여야할가장적절한조치는? 1. Renal biopsy 2. 3-6 month interval regular follow up 3. 복부단층촬영 4. Renal artery doppler 5. Check coagulation profiles

Nutcracker syndrome - Left renal vein entrapment between SMA and aorta - 10-20yr and middle aged woman - Hematuria, proteinuria, pain, varicocele, fatigue - PV > 80-100cm/s, ratio > 4-5 PG: 1-2mmHg - External stenting, surgical correction, gonadal v ligation, conservative tx

Case III 남자 19 세, 군대신검에서발견된혈뇨. 병력상 : 이전에소변검사를해본적은없음. 가족력상엄마도혈뇨 +, 고혈압 + 흡연력 -, 음주력 social 증상 : 없음 BP 110/70 mmhg, BT 36.8ºC, PR 92/min 검사소견 BUN/Cr 16.1/0.6 mg/dl Na/K/Cl/CO2 138/4.0/102/27 meq/l Cholesterol 127mg/dL, T.pro/alb 6.4/4.0 g/dl

Random urine analysis Protein trace RBC 2+ (5~10/HPF), WBC - (0-2/HPF) Random urine P/Cr ratio 0.09 Urine cytology -, RBC dydmorphism 20%

IgG IgA C3

이환자에서다음으로시행하여야할가장적절한조치는? 1. 면역억제재 2. Renin angiotensin system blocker 3. Antiplatelet agents 4. 저염식, 저단백식이 5. 입대

Thin basement menbrane nephropathy - GBM thickness 150nm at birth 200nm at 1year normal 200-330nm thin GBM < 200nm (?) - Hematuria, proteinuria, flank pain - Autosomal dominant trait - Benign familial hematuria, none progress renal failure - Several reports association with renal failure (0-5%) associated with COL4A3, 4, NPHS2 mutation

Case IV 여자 32 세, 5-6 개월전검진에서발견된혈뇨, 단백뇨. 병력상지난주감기기운후콜라색소변 흡연력 -, 음주력 social 증상 : 콜라색소변, 현재는 clear BP 110/70 mmhg, BT 36.8ºC, PR 86/min 검사소견 BUN/Cr 9.3/0.8 mg/dl Na/K/Cl/CO2 139/4.0/106/22 meq/l Cholesterol 132mg/dL, HBsAg/Ab -/- T.pro/alb 6.8/4.2 g/dl

Random urine analysis Protein - RBC 2+ (10~20/HPF), WBC trace (0-2/HPF) Random urine P/Cr ratio 1.48 24hour protein/albumin 1082/848mg, cr 1195mg

이환자에서다음으로시행하여야할가장적절한조치는? 1. Renal biopsy 2. 3-6 month interval regular follow up 3. 복부단층촬영 4. Renal artery doppler 5. 신동맥조영술

C3 IgA

Pathologic Diagnosis in Patients with Hematuria or Hematuria + Proteinuria Diagnosis No histologic abnormality Thin GBM disease IgA nephropathy APSGN Minimal change disease MsPGN Alport syndrome FSGS MGN MPGN Lupus nephritis Oligomeganephronia Hematuria (%) (N=289) 136 (47.1) 97 (33.6) 46 (15.9) 4 (1.4) 0 1 (0.3) 1 (0.3) 0 2 (0.7) 0 1 (0.3) 1 (0.3) Hematuria + Proteinuria (%) (N=163) 40 (24.5) 30 (18.4) 75 (46.0) 4 (2.5) 1 (0.6) 5 (3.1) 3 (1.8) 3 (1.8) 0 2 (1.2) 0 0 Kim BK et al., 2002

Case V 여자 58 세, 검진에서발견된혈뇨. 병력상 : 수년전검진상현미경적혈뇨, 당시검사하였으나특이소견없다고들었음. 최근그정도가심해졌다고함. 흡연력 -, 음주력 social 증상 : 없음 BP 110/70 mmhg, BT 37.0ºC, PR 90/min 검사소견 BUN/Cr 16.1/0.5 mg/dl Na/K/Cl/CO2 137/4.3/101/26 meq/l Cholesterol 187mg/dL, T.pro/alb 6.9/4.3 g/dl

Random urine analysis Protein - RBC 2+ (10~20/HPF), WBC - (0-2/HPF) Random urine P/Cr ratio unable (<2.5/51.4) Urine cytology -, RBC dydmorphism 10%

이환자에서다음으로시행하여야할가장적절한조치는? 1. Renal biopsy 2. 3-6 month interval regular follow up 3. 복부단층촬영 4. 24시간소변검사 (CCr, proteinuria) 5. 신동맥조영술

Follow-Up Urinalysis Yamagata K, et al (Clin Nephrol, 1996) Mass screening of 56,269 adults 432 patients with asymptomatic microscopic hematuria 134 patients with asymptomatic hematuria with proteinuria Mean follow-up: 5.8 years Follow-up urinalysis in hematuric patients 44.2%: Disappearance of hematuria 43.7%: Persistent hematuria without proteinuria 10.6%: Appearance of proteinuria 0.0%: Renal failure Follow-up urinalysis in hematuric and proteinuric patients 16.4%: Disappearance of hematuria and proteinuria 8.2%: Disappearance of proteinuria 14.9%: Development of renal failure

+ + Hematuria on urinalysis (dipstick + microscopy) Isomorphic urinary RBCs Antibiotic therapy Workup for abnormal lab + + WBC clots, pyuria + Urine culture - Repeat urinalysis X 2 + Screening laboratory studies (BUN, Cr, CBC, PT, PTT, Electro) - IVP - Cystourethroscopy - - RBC casts, Proteinuria, Dysmorphic urinary RBCs + Workup for glomerular disease No further workup RGP, Ureterorenoscopy, Ultrasonography, CT Washing cytology, Biopsy, TURP If high risk, consider CT scan; otherwise repeat urinalysis + voided urine cytology for up to 3 years Consider renal biopsy (glomerular disease) Algorithm for the Evaluation and Treatment of Hematuria

Case VI 여자 72 세, 전신부종을주소로내원함 병력상고혈압 5 년 흡연력 -, 음주력 - 증상 : 부종 BP 125/85 mmhg, BT 37.3ºC, PR 84/min 검사소견 BUN/Cr 22.2/1.57 mg/dl Na/K/Cl/CO2 138/4.4/103/22 meq/l T. Chol 250mg/dL, T.pro/alb 6.2/2.4 g/dl

Random urine analysis Protein 4+ RBC - (-/HPF), WBC - (0-2/HPF) Random urine P/Cr ratio 9.14, 24hr protein 5.4g

진단은? 1. IgA nephropathy 2. Membranous nephropathy 3. Membranoproliferative glomerulonephritis 4. Focal segmental glomerulosclerosis 5. Minimal change disease

Glomerular Proteinuria Most common cause of pathologic proteinuria Urinary loss of high molecular weight protein Usually large amount Urinary excretion of more than 2 gm per day is usually a result of glomerular disease Increased permeability due to damaged barrier

Case VII 남자 56 세, 육안적혈뇨를주소로내원. 병력상 paroxysmal nocturnal hemoglobinuria 로혈액내과경과관찰중임 흡연력 10 갑년, 음주력 social 증상 : 육안적혈뇨, BP 110/70 mmhg, BT 36.8ºC, PR 86/min 검사소견 BUN/Cr 9.3/0.8 mg/dl Na/K/Cl/CO2 139/4.0/106/22 meq/l Cholesterol 132mg/dL, HBsAg/Ab -/- T.pro/alb 6.8/4.2 g/dl

Random urine analysis Protein 4+ RBC 3+ (many/hpf), WBC - (-/HPF) Random urine P/Cr ratio 10.27 24hour urine protein 11487 mg, Cr 1786mg

이환자에서다음으로시행하여야할가장적절한조치는? 1. Renal biopsy 2. Repeat urinalysis 3. DTPA renogram 4. Renal artery doppler 5. 신동맥조영술

Measurement of Urine Protein Dipstick False positive Too long immersion Highly concentrated urine High urine ph (>7.0) Gross hematuria Contamination with pus, semen, or vaginal discharge Presence of penicillin, sulfonamides, or tolbutamide False negative Diluted urine Positively charged proteins such as Ig light chains Depends on the volume and concentration of the urine

Random urine analysis after steroid treatment Protein - RBC 3+ (10-20/HPF), WBC - (0-2/HPF) Random urine P/Cr ratio 0.55

Case VIII 남자 18 세, 신검상발견된단백뇨로의뢰됨 병력상특이소견없음 흡연력 -, 음주력 social 증상 : 없음 BP 110/70 mmhg, BT 36.6ºC, PR 72/min 검사소견 BUN/Cr 14.3/0.79 mg/dl Na/K/Cl/CO2 141/4.1/102/26 meq/l T. Chol 162mg/dL, T.pro/alb 7.6/4.9 g/dl

Random urine analysis Protein 2+ RBC - (-/HPF), WBC - (-/HPF) Random urine P/Cr ratio 1.27 24hour urine protein/alb 787/463 mg, Cr 1604mg

이환자에서다음으로시행하여야할가장적절한조치는? 1. Cystoscopy 2. Renal doppler 3. Repeat Urinalysis 4. 복부단층촬영 5. Renal biopsy

Orthostatic proteinuria - Young persons who excrete less than 2 gm per day with normal renal function - 3-5% of adolescents and young adults - Proteinuria during standing or ambulation - No impact on morbidity or mortality

+ + + Proteinuria on urinalysis (dipstick) History, P/E, and Urine microscopy Repeat dipstick X 2-3 - No need for follow up - Evidence of renal or systemic disease Test renal function and Ultrasonography - Postural protein excretion Consult to Nephrologist Consult to Nephrologist Orthostatic proteinuria Nonorthostatic proteinuria Follow up 1-2 yearly Repeat urine quantitation X 2-3 Intermittent or Orthostatic Persistent Intermittent Persistent Follow up 6-12 monthly Follow up 6-12 monthly Consult to Nephrologist Algorithm for the Evaluation of Proteinuria

Random urine analysis ( 외래 ) Protein 2+ RBC - (-/HPF), WBC - (-/HPF) Random urine P/Cr ratio 1.39 Random urine analysis ( 아침첫소변 ) Protein - RBC - (-/HPF), WBC - (-/HPF) Random urine P/Cr ratio 0.07

Asymptomatic urinary abnormality Proteinuria: 150-3000mg/day Microscopic hematuria No edema No hypertension Macroscopic hematuria attack (brown/red painless gross hematuria) with intercurrent infection

Case IX 여자 63 세, 전신부종 흡연력 -, 음주력 - 증상 : 부종 BP 135/78 mmhg, BT 36.2ºC, PR 72/min 검사소견 BUN/Cr 15.3/1.3 mg/dl Na/K/Cl/CO2 138/3.4/96/33 meq/l T. Chol 377mg/dL, T.pro/alb 3.6/2.0 g/dl

Random urine analysis Protein 4+ RBC - (-/HPF), WBC - (-/HPF) Random urine P/Cr ratio 7.79 24hour urine protein/alb 6950/4520 mg

Classification of Proteinuria Glomerular proteinuria Tubular proteinuria Overflow proteinuria Orthostatic proteinuria Benign (transient) proteinuria

Overflow Proteinuria Overproduction of low MW protein overwhelming the ability of the proximal tubule to reabsorb Variable amount of proteinuria Free light chain (Bence-Jones protein): MM Hemoglobin: Hemolysis Myoglobin: Rhabdomyolysis Lysozyme: Leukemia Amylase: Pancreatitis

Case X 여자 52 세, 지속적인신기능이상및단백뇨 병력상당뇨병, 고혈압 3 년 흡연력 -, 음주력 - 증상 : 부종 BP 150/100 mmhg, BT 36.6ºC, PR 72/min 검사소견 BUN/Cr 24.3/1.59 mg/dl Na/K/Cl/CO2 140/3.7/102/25 meq/l T. Chol 192mg/dL, T.pro/alb 5.7/2.2 g/dl

Random urine analysis Protein 4+ RBC - (-/HPF), WBC - (-/HPF) Random urine P/Cr ratio 6.74 24hour urine protein/alb 7140/5630 mg

IgG IgA

이환자에서향후치료방침으로적절한것은? 1. Heavy proteinuria 로면역억제재를고려한다. 2. 적절한치료반응을확인하기위하여 6-12 개월간격으로 24 시간요단백양을측정한다. 3. 적극적인혈당관리를통해신부전의진행을개선시킨다. 4. 단백뇨의적극적인조절을위해 Angiotensin type II receptor blocker 및 ACE inhibitor 의복합요법을고려한다. 5. 단백뇨의정도가신장의예후뿐아니라환자의예후를결정한다.

Measurement of Urine Protein (III) 24 hour urine collection (24hour urine protein) Semiquantitation of urine protein Dipstick Protein:Cr or Albumin:Cr in random or timed urine collections High degree of correlation with 24-hour urine protein excretion Useful especially in individuals in whom urine collection is difficult or impossible Useful as a screening test for renal disease in populations in which the expected prevalence of disease is high Sensitivity: 32-46% Specificity: 97-100%

Proteinuria in Chronic Kidney Disease Proteinuria at baseline is the most powerful marker for subsequent renal events. The higher the proteinuria, the greater the renal risk.

Annual changes in GFR according to albuminuria status (7.8 year follow up study) -2.3ml/min/yr -3.7ml/min/yr -5.4ml/min/yr Gaede, Nephrol Dial Transplant, 2004 19:2784-2788

The Incidence of New ESRD after 17 yr of Follow-up According to Dipstick Proteinuria Iseki et al, Kidney Int 2003;63:1468 1474

Hazard ratio RENAAL: Initial Antiproteinuric Response Renal Endpoint ESRD 2.5 2.0 2.5 2.0 1.5 1.5 1.0 1.0 0.5 0.5 0.0-90 -25 0 25 50 72 Albuminuria reduction (%) 0.0-90 -25 0 25 50 72 Albuminuria reduction (%) De Zeeuw et al., Kidney Int 2004;65:2309-2320

UAE and risk of cardiovascular and noncardiovascular mortality Hillege et al Circulation 2000