Primary glomerulonephritis

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1 2012 년 10 월 26 일 2012 년추계전공의연수강좌 일차성사구체신염 경북대학교의학전문대학원내과학교실 박선희

2 사구체신염의임상증후군 사구체신염임상증후군 급성신염증후군급속진행성사구체신염폐신증후군신증후군기저막증후군사구체혈관증후군감염병관련증후군

3 사구체신염환자의진단적접근 General category of syndrome Bedside with history and PE, Blood chemistry, Urinalysis and USG Acute vs. Subacute vs. Chronic Serology (viral markers, complement, antoantibody, ) Primary vs. secondary Clinical diagnosis Renal biopsy Pathologic diagnosis

4 For examples, Acute nephritis syndrome >> R/O IgA nephropathy R/O PSGN R/O lupus nephritis >> IgA nephropathy History and PE U/A Serology Histology

5 한국인사구체질환 : 빈도 년, 세브란스병원자료 1818 명신조직검사 MGN IgA 신증 Chang JH et al, Nephrol Dial Transplant, 2009

6 Epidemiology of GN from Japanese biopsy registry (%) IgAN Primary GN except IgAN DN Hypertensive nephrosclerosis Lupus nephritis ANCA vasculitis Infection related GN Thins GBM disease Primary GN except IgA Minor glomerular abn MGN FSGS MPGN Sugiyama H et al, Clin Exp Nephrol, 2011

7 CAUSES OF IDIOPATHIC NEPHROTIC SYNDROME IN ADULTS Incidence (%) Minimal change disease 5 10 Focal segmental glomerulosclerosis Membranous nephropathy Membranoproliferative glomerulonephritis 5 Other proliferative and sclerosing glomerulonephritides Cecil Medicine, 23rd edi.

8 사구체질환의임상양상 NEPHROTIC FEATURES NEPHRITIC FEATURES Minimal change glomerulopathy ++++ Membranous glomerulopathy Focal segmental glomerulosclerosis Fibrillary glomerulonephritis Mesangioproliferative glomerulopathy [ ] Membranoproliferative glomerulonephritis [ ] Proliferative glomerulonephritis [ ] Acute diffuse proliferative glomerulonephritis [ ] Crescentic glomerulonephritis [ ] Brenner & Rector s The Kidney, 9th edi.

9 남 /29 증례 1 C.C 건강검진에서우연히발견된현미경적혈뇨및단백뇨 P.I 평소건강하던환자로 1 개월전회사검진에서현미경적혈뇨와단백뇨가발견되어내원 흡연력없음 F.Hx 신장병의가족력없음. 당뇨, 고혈압가족력없음 P.E Ht 178cm, BW 68kg, BP 130/80 mmhg Lab 하지부종없으며그외특이소견없음 SG 1.020, Protein 2+, Glucose (-), RBC 10-20/HPF (dysmorphic RBC 80%), WBC 0-1/HPF S-cr 0.8 mg/dl 24hr proteinuria 2.4 g/day Other serologic test: U-R

10 신조직소견 Total glomeuli 20 Mesangial proliferation: 5/20 glomeruli, Segmental endocapillary proliferation: 3/20 1 glomeruli: circumferential crescent Tubular atrophy and interstitial fibrosis < 10% of the biopsy sample IgA

11 이환자의진단은? 1) Minimal change disease 2) Focal segmental glomerulosclerosis 3) Membranous glomeruloropathy 4) Membranoproliferative glomerulonephritis 5) IgA nephropathy

12 이질환의병인중 IgA 의구조적이상은? Abnormalities in the O-glycosylation of the hinge region of IgA

13 병인 Floege J, Am J Kidney Dis, 2011

14 초기평가 이차성의원인은없는가? 진행의위험이높은위험인자가있는가? 신조직검사에서나쁜예후인자가있는가?

15 관련된질환 Henoch-Schönlein purpura 이차성 IgA 신증 Neoplasia Human immunodeficiency virus infection Toxoplasmosis Seronegative spondyloarthropathy Celiac disease Dermatitis herpetiformis Crohn s disease Liver disease Alcoholic cirrhosis Ankylosing spondylitis Reiter s syndrome Mycosi fungoides Lung carcinoma Mucin-secreting carcinoma Cyclic neutropenia Immunothrombocytopenia Gluten-sensitive enteropathy Scleritis Sicca syndrome Mastitis Pulmonary hemosiderosis Berger s disease Brenner & Rector s The kidney, 9th edi. Leprosy

16 예후인자 임상적예후인자 내원시신기능단백뇨 > 1 gram/day 고혈압 발병시고령육안적혈뇨가없을때남성비만고요산혈증고지질혈증 (HyperTG) 흡연가족력 병리학적예후인자진행된사구체경화심한간질섬유화메산지움증식사구체내국소적인괴사병변반월상 > 30% 모세혈관벽의 IgA 침착간질의염증세포침윤동맥경화증

17 IgA 신증의병리소견 IgAN 의병리학적분류 Haas, Lee SMK, Lee HS, WHO classification... Oxford 분류 (M, S, E, T - MEST score)

18 이환자에서처음으로고려할치료계획은? Proteinuria 2.4g/day BP 130/80 mmhg egfr > 90 ml/min/1.73m 2 1) RAS 억제제 (ACEi or ARB) 2) 면역억제제 3) 편도선절제술 4) Omega-3 fish oil 5) 약물치료를하지않고주기적경과관찰

19 KDIGO 지침 레닌 - 안지오텐신계억제 단백뇨가하루 1gram 이상일경우 long-term ACEi 또는 angiotensin receptor blockers (ARB) 치료권고 혈압을고려하며약제증량 (1B) 단백뇨가하루 0.5 ~ 1 g/day 사이인경우 ( 소아의경우 0.5 ~ 1 g/day per 1.73m 2 ), ACEi 또는 ARB 치료고려 (2D). 내약성이좋은경우단백뇨가하루 <1g/day 일때까지용량증량 (2C) 목표혈압 - 단백뇨에따라 <1g/day : < 130/80mmHg >1g/ day : <125/75mmHg (not graded) KDIGO 지침 Strength of recommendation Quality of evidences 1 Recommend ( 권고 ) 2 Suggest ( 고려 ) A, high B, moderate C, low D very low

20 Cheng J et al, Int J Clin Pract, 2009 Renal function ACEi/ARB in IgAN: meta analysis ACEI ARB agents had statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN Proteinuria

21 Case 1 In this patient... low dose ACE inhibitor start uptitration of the drug depending on BP f/u 3 month later, BP 115/75 mmhg Protein-to-creatinine ratio 0.9 ~ 1.2 Cr 0.9~1.0 mg/dl

22 다음단계로고려할수있는치료는? 1) Steroids 2) Omega-3 fish oil 3) Mycophenolate mofetil 4) Tonsillectomy Persistent proteinuria > 1.0g/d Pathologic findings

23 Corticosteroids KDIGO 지침 1) 3~6 개월동안 ACEi 또는 ARBs 를포함한약제로 BP 를조절하며치료함에도불구하고하루 1gram 이상의단백뇨가지속되는경우 & 2) GFR > 50 ml/min/1.73m 2 인경우, 6 개월동안의스테로이드치료고려 (2C)

24 Steroids in IgA nephropathy : meta-analysis Risk reduction 80% 54% 감소 66% 감소 60% 40% 20% 0% ESRD Doubling of s-cr Zhou et al, PLoS One, 2011

25 Steroid regimen Pozzi C et al iv bolus injection of 1.0g methylprednisolone for 3 days for each at month 1, 3, 5 followed by oral steroid 0.5 mg/kg of prednisone on alternate days for 6 months Manno C et al 6-month regimen of oral prednisone starting with 0.8-1mg/kg/d for 2 months and then reduced by 0.2mg/kg/d per month for the next 4 months Pozzi C et al, Lancet, 1999 Manno C et al, Nephrol Dial Transplant, 2009

26 KDIGO 지침 Immunosuppressive agents IgA 신증에서조직소견상반월상을보이며급속진행성신염의경과를보일때스테로이드및 cyclophosphamide 병합요법고려 (2D) 사구체여과율이 < 30 ml/min per 1.73m 2 이면면역억제제사용고려하지않음 (2C) MMF 사용은고려하지않음 (2C)

27 Fish oil KDIGO 지침 3~6 개월동안 ACEi 또는 ARB 를포함한치료로혈압조절이잘되는경우지속적으로 1.0 gram 이상의단백뇨가나올때고려 (2D)

28 Omega-3 fatty acids therapy for IgAN : a meta-analysis of RCTs (n=239) Effect of omega-3 fatty acid on egfr Effect of omega-3 fatty acid on proteinuria Liu et al, Clin Nephrol, 2012 No benefit of O3FA on proteinuria and GFR or egfr Frequencies of an increase of 50% or more in s-cr and ESRD are lower significantly in IgAN patients with O3FA treatments

29 No benefit Tonsillectomy KDOQI: IgAN 에서편도선절제술은권장하지않음 (2C) 편도선절제술과스테로이드병합요법 : Tonsillectomy combined with either normal steroid or steroid pulse treatment resulted in higher remission rates with favorable long-term efficacy Tonsillectomy + steroid pulse vs. steroid pulse Wang Y, Nephrol Dial Transplant, 2011

30 Case 1 임상경과 Low dose ACEi start Titrate up to max. tolerated dose Steroid start Steroid stop ACEi keep 6 개월동안복용 PCR 2.4 BP 130/80 s-cr 0.9 mg/dl PCR BP 115/75 s-cr 1.0 mg/dl Lab (3 개월후 ) BP 125/75 PCR 0.6 s-cr 1.0mg/dL Lab (6 개월후 ) BP 120/75 PCR 0.3 s-cr 1.0mg/dL

31 Therapeutic approach in IgAN Floege J et al, J Am Soc Nephrol, 2012

32 증례 2 남 /52 C.C 2 주간의양하지부종 P.I 이전에건강하던환자로 2 주전부터서서히진행하는양하지의부종으로내원. 거품뇨가관찰됨최근감기나다른약제의복용력은없었음, 최근체중증가 4 kg F.Hx N-S P.Hx 고혈압 (-), 당뇨 (-), 결핵 (-) P.E Ht 175 cm, Wt 95kg, BMI 31 kg/m 2, BP 140/90 mmhg Ext pitting edema 3+/3+ Lab: U/A protein 4+, RBC 0-1/HPF, WBC 0-1/HPF, 24hr proteinuria 12 g/day Serum: s-alb 2.6 g/dl, total protein 5.6 g/dl, Cr 1.0 mg/dl, T-chol 433 mg/dl, TG 489 mg/dl Other serologic test U-R

33 IgG 신조직소견

34 이환자의진단은? 1) Minimal change disease 2) Focal segmental glomerulosclerosis 3) Membranous glomeruloropathy 4) Membranoproliferative glomerulonephritis 5) IgA nephropathy

35 초기평가 1. 이차성사구체신염인가? 2. 위험인자평가 면역억제제치료가필요한가?

36 MGN

37 Screening for malignancy in patients with MGN Do not perform extensive screening of malignancy in the absence of suggestive findings, such as unexplained wt loss, anemia, occult blood positive in stool exam. Screening 필요한경우 Malignancy 를의심할수있는증상을가진경우 Routine age-appropriate screening 을한적이없는경우 50세이상남자 : stool OB, colonoscopy if necessary, PSA 40세이상여자 : mammography 폐암고위험군 : Chest X-ray, Chest CT if needed

38 Primary vs. secondary MGN (pathology) Electron dense deposit on EM Tubular basement membrane staining for IgG on IF IgG subtype deposited Primary Subepithelial and intramembranous Rare IgG4 Secondary Mesangial and/or subendothelial deposits Common IgG1 and IgG3 (lupus) IgG1 and IgG2 (malignancyassociated)

39 병인 Putative antigens in the pathogenesis of idiopathic MGN M-type phospholipase A2 receptor (PLA2R) Neutral endopeptidase (NEP) Cationic bovine serum albumin Aldose reductase, manganese SOD2 M-Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy N Engl J Med, 2009

40 이환자에서처음시작할치료는? 일반적치료 1) 단백뇨의감소 : 식이단백섭취제한, ACEi or ARBs 2) 고혈압의치료 : ACEi or ARB, 염분섭취제한, 이뇨제, non-dihydropyridine CCB 3) 부종의치료 염분섭취제한 ( g) 이뇨제 Thiazide: mild edema K-sparing diuretics: useful in patients with hypokalemia Loop diuretics: moderate to severe edema Albumin infusion: useful in profound volume depletion, transient effect Ultrafiltration or dialysis: marked edema with reduced GFR

41 이환자에서처음시작할치료는? 4) 고지혈증의치료 : specific therapies that lower proteinuria, low fat and cholesterol diet, fibric acid ( TG), nicotinic acid ( cholesterol) Exchange resin, HMG co-a reductase inhibitor (most effective, TC, LDL, TG) 5) 과응고성장애 Prophylactic anticoagulant: marked reduction in s-alb (<2.5 g/dl) and additional risk for thrombosis (2C) Acute venous thrombosis: heparin warfarin

42 자연경과및예후 자연경과 : Rule of thirds 1/3 spontaneous remission 1/3 persistent proteinuria 1/3 - progress slowly to renal failure 예후인자 Older age at onset (>50 years) Male nephrotic range proteinuria (particularly >8~10 g/day) Increased s-cr at presentation

43 면역억제제는언제시작하는가? Who and When to treat? How long to wait to see in which third the patient fits?

44 KDIGO 지침 Immunosuppressive therapy Urinary protein excretion persistently exceeds 4 g/day and remains at over 50% of the baseline value, & does not show progressive decline during antihypertensive and antiproteinuric therapy during an observation period of at least 6 months (1B) The presence of severe, disabling, or life-threatening symptoms related to the nephrotic syndrome (1C), or SCr level has risen by 30% or more within 6 to 12 months from the time of diagnosis but the egfr is not less than ml/min/1.73m 2 and this change is not explained by superimposed complications (2C).

45 KDIGO 지침 Immunosuppressive therapy Initial therapy We recommend that initial therapy consist of a 6-month course of alternating monthly cycles of oral and i.v. corticosteroids, and oral alkylating agents (1B)

46 Immunosuppressive therapy KDIGO 지침 Alternative regimen We recommend that cyclosporine or tacrolimus be used for a period of at least 6 months in patients who meet the criteria for initial therapy, but who choose not to receive the cyclical corticosteroid/alkylating-agent regimen or who have contraindications to this regimen (1C)

47 6 개월후일일단백뇨 7 gram 지속시고려할치료제는? 1) 고용량스테로이드단독사용 2) Cyclosporine 치료 3) 고용량스테로이드와 chlorambucil 병용요법 4) ACEi 와 ARB 병용요법 Obesity Obesity

48 KDIGO 지침 Cyclosporine The dosage of CNIs be reduced at intervals of 4 8 weeks to a level of about 50% of the starting dosage, provided that remission is maintained and no treatment-limiting CNI-related nephrotoxicity occurs, and continued for at least 12 months (2C). CNI blood levels be monitored regularly during the initial treatment period, and whenever there is an unexplained rise in SCr level ( >20%) during therapy (not graded).

49 Case 2 임상경과 ACEi Low sodium diet & Diuretics Statin CyA start 3.5 mg/kg/day Review of recent medication change H2-blocker Non-dihydropyridine CCB 4 개월동안복용 PCR 12 BP 140/90 mmhg s-cr 1.0 mg/dl S-alb 2.3 g/dl 3 개월후 PCR 10 BP 120/75 mmhg s-cr 1.3 mg/dl S-alb 2.6g/dL CyA trough level 200 ng/ml Lab (CyA 4 개월후 ) PCR 2 BP 120/75 mmhg S-cr 2.0 mg/dl S-alb 3.4 g/dl

50 현재상태의원인으로고려할점은? 1) R/O CNI nephrotoxicity 2) R/O volume depletion a/w diuretics or intercurrent illness 3) R/O Drug-associated toxicity 4) R/O Renal vein thrombosis 5) All of the above

51 Case 2 임상경과 ACEi Low sodium diet & Diuretics Statin CyA start 3.5 mg/kg/day 4 개월동안복용 CyA reduction 2mg/kg/day CCB change Diuretics reduction H2 blocker stop CyA 3.5mg/kg/day PCR 12 BP 140/90 mmhg s-cr 1.0 mg/dl S-alb 2.3 g/dl 3 개월후 PCR 10 BP 120/75 mmhg s-cr 1.3 mg/dl S-alb 2.6g/dL Lab (CyA 4 개월후 ) BP 130/80 PCR 2 S-cr 2.0 S-alb 3.4 g/dl Lab (CyA 5 개월후 ) PCR 2.2 S-cr 1.3 S-alb 3.5 g/dl Lab (12 개월후 ) PCR 0.3 S-cr 1.2 S-alb 4.0 g/dl

52 Therapeutic approach in MGN Nephrotic proteinuria in adults Renal biopsy Recommended Approaches Diagnosis of idiopathic MN Alternate-month corticosteroids and cyclophosphamide for 6 months Months 1, 3, and 5: methylprednisolone 1 g/day IV for 3 days followed by 0.4 to 0.5 mg/kg/day orally for 27 days Months 2, 4, and 6: cyclophosphamide 2.0 to 2.5 mg/kg/day (initial dose) orally for 30 days Alternate-month corticosteroids and chlorambucil for 6 months Months 1, 3, and 5: methylprednisolone (as above) Months 2, 4, and 6: chlorambucil 0.2 mg/kg/day (initial dose) orally for 30 days Alternative Approaches Cyclosporine 3.5 mg/kg/day in two divided doses (initial dose) and low-dose prednisone for 6 to 12 months Tacrolimus monotherapy 0.05 mg/kg/day in two divided doses (initial dose), initial target trough 3 to 5 ng/ml, increase target trough to 5 to 8 ng/ml if remission not achieved within 2 months Mycophenolate mofetil 1 to 2 g/day in two to three divided doses for 6 to 24 months; attempt to taper off corticosteroids Synthetic corticotropin 1 mg IM every other week (initial dose), gradually increase to 1 mg IM twice weekly for 1 year Rituximab four weekly intravenous infusions of 375 mg/m 2

53 M/30 증례 3 C.C 건강검진에서우연히발견된단백뇨 P.I 3 년전건강검진시특이소견없었던환자로 1 개월전시행한검진에서단백뇨발견되어외래방문 최근약제복용력없음. URI 등의감염소견없었음 P.Hx : 특이소견없었음 F.Hx: 신질환의가족력은없음. 아버지, 어머니당뇨로치료중. 누나 2 명당뇨 P.E BP 150/88 mmhg, BMI 35 kg/m 2, pitting pedal edema Lab: S-Cr 1.4 mg/dl, S-albumin of 3.5 g/dl, total cholesterol 282 mg/dl 24-h urine protein of 8.2 g/day HbA1C 6.3% Serology: Negative

54 신조직소견

55 이환자의진단은? 1) Minimal change disease 2) Focal segmental glomerulosclerosis 3) Membranous glomeruloropathy 4) Membranoproliferative glomerulonephritis 5) IgA nephropathy

56 초기평가 이차성원인이있는가? 초치료는어떻게할것인가?

57 FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) 1. IDIOPATHIC OR PRIMARY FSGS 2. SECONDARY FSGS 3. SEGMENTAL GLOMERULAR SCARRING Secondary to a healed glomerulitis

58 Secondary FSGS

59 Primary vs. secondary FSGS 일차성 >> 이차성 전형적인신증후군 전자현미경에서 foot process effacement 저명 일차성 << 이차성 단백뇨양이비교적작다 (sub-nephrotic) 혈청알부민정상에가까움 전자현미경 foot process effacement 가적음 사구체비대 (glomerulomegaly)

60 Secondary FSGS

61 본증례에서초치료의목표는? 1) Aggressive BP control 2) Weight loss 3) Renin angiotensin aldosterone system inhibition 4) All of the above

62 Case 3 초치료및임상경과 ACEi + low dose thiazide diuretics Statin loop diuretics (uncontrolled edema) BP 125/80 mmhg Lab (3 개월후 ) 단백뇨 8~10g/day 로지속 s-albumin 3.0 ~ 3.5 g/dl Cholesterol levels 220 mg/dl

63 다음치료로적당한것은? 1) ACEi 최대용량까지증량 2) 면역억제제추가 3) ACEi 와 ARB 의병합요법 4) 혈장교환술

64 KDIGO 지침 Immunosuppressive agents 임상적으로신증후군을보이며 idiopathic FSGS 일때스테로이드및면역억제제치료권고 (1C). 스테로이드 : prednisone 또는 prednisolone 매일일회용법으로 1 mg/kg (maximum 80 mg) 또는격일로 2 mg/kg (a maximum dose of 120 mg) 사용고려 (2C). 초기고용량의스테로이드는최소 4 주에서최대 16 주까지사용 (2D). 완전관해이후 6 개월에걸쳐서서히감량고려 (2D). 고용량스테로이드사용이어려운경우나다른합병증 ( 예, 조절되지않는당뇨병, 정신과적문제, 심한골다공증등 ) 이우려되는경우, calcineurin inhibitors (CNIs) 를초치료로고려 (2D)

65 Steroid resistant FSGS KDIGO 지침 적어도 4 6 개월간 cyclosporine (3~5 mg/kg/d in divided doses) 투여고려 (2B) 부분관해또는완전관해에도달하는경우, 적어도 12 개월간유지한이후천천히감량할것을고려 (2D) Cyclosporine 에불내성이있는경우 mycophenolate mofetil 과 high-dose dexamethasone 병합치료고려 (2C)

66 이환자에서면역억제제치료시고려할점은? 비만 당뇨병의가족력 내원시의 HbA1C

67 Case 3 ACEi + low dose thiazide diuretics Statin loop diuretics Cyclosporin A 3.5 mg/kg/day twice daily 임상경과 Low dose Cyclosporin A 1.5 mg~2/kg/day ACEi + low dose thiazide diuretics Statin 12 개월간유지 6 개월동안서서히감량 36 개월후중단 BP 125/80 mmhg Lab (CyA 사용 2 개월후 ) 단백뇨 2.2 g/day Lab (3 개월후 ) 단백뇨 8~10g/day 로지속 s-albumin 3.0 ~ 3.5 g/dl. Cholesterol levels 220 mg/dl Lab (CyA 사용 36 개월후 ) 단백뇨 1.0 g/day S-cr 1.3 mg/dl

68 Therapeutic approach in FSGS Exclude NPHS2 mutations

69 Take home messages ACEi or ARBs is the first-line therapy in primary glomerulonephritis with significant proteinuria. General supportive treatment is important to control proteinuria, edema, hyperlipidemia and hypertension in patients with nephrotic syndrome. Start of immunosuppressive therapies could be individually determined according to the response to the initial therapy or risk factors for progression in each patient.

70 Thank you for your attention

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