◐General Nephrology

Lupus nephritis(LN)

GN約 20 分鐘2 個章節

1.Lupus nephritis#

  • Epidemiology

    • 60% SLE Pts(35% SLE with nephritis at the time of diagnosis)
    • Non-white, younger(<33y/o) and males比較容易有nephritis earlier in the course of SLE
      • SLE診斷後5年內產生LN機率華人約50% 黑人約42% 白人約23%
        • 註:白人治療的預後也比較好(較多CR; 見下述Prognosis; 相反的, MGN則為東方人預後較好)
    • For [(no active sediments) and (proteinuria<0.5g/day)] monitor
      • U/A, UPCR, Cre Q3-6M(Q3M if anti-DsDNA(+) or hypocomplement者)

  • Indication for renal biopsy

    • SLE with any of one
      • Daily urine protein>0.5g/day
      • Active urinary sediment(RBC>=5HPF and suspect renal origin(dysmorphic)) or cellular casts
      • Rapidly rising Cre without other causes(多表crescent) or slowly rising Cre(表type VI or possible low-grade disease activity)
        • 這些indication主要是要抓出type III/IV and V(I, II, VI不用治療(不過II如果nephrotic syndrome則Tx as MCD/FSGS); III/IV/V要治療, but III/IV和V治療不同); 另外也看crescent程度(可能要治療較兇猛); 也看是不是已經stage VI(沒救了,不用治); 也看是不是有superimposed other diseases
        • Isolated nephrotic syndrome 看起來像type V可以其實是type III, IV(?)
        • 很輕微的nephritis像type I/II可以其實是type III
        • 很嚴重的nephritis看起來像type III/IV可以看有沒有其他concurrent disease與是否有crescent
    • Repeat biopsy
      • 若有上述情況(SLE with any of one)repeat biopsy有>50%會由one histologic pattern changed to another pattern
      • Indication
        • Worsening of proteinuria despite treatment for proliferative GN(III/IV)可以repeated biopsy看是否也有type V
          • Concurrent type III/IV+V is best treated with MMF + CNI(voclosporin 或 tacrolimus) + steroid 之 multitarget 三合一治療(完全緩解率顯著較高)
        • Active sediments+rapidly rising Cre
          • 看有沒有crescent formation
        • Slowly rising Cre or persistent proteinuria
          • 看是否已經是type VI or 是secondary FSGS or 還有active的成分可救(=目前藥物不夠力)
            • 如果沒有active的成分, 那用ACEI/ARB就是最好的Tx
        • Suspected other superimposed etiologies
      • Successfully treated diffuse proliferative disease who develop a recurrent active sediment-->不一定要repeat biopsy因為多為recurrent disease, 不過也有人會要biopsy看chronicity
      • 若原本是type V with recurrent proteinuria不一定要repeat biopsy, 因為蠻常見的(尤其如果是用CNI者), 不過若有懷疑有type III/IV成分則要repeat biopsy
        • 所以治療好之後recurrence不一定要repeat biopsy, 因為很常見?

  • Pathogenesis

    • Anti-DNA immune complex formation
      • Deposits in mesangium, subendothelium
        • Communicating with vascular space-->complement pathway-->proliferative GN(nephritis syndrome)
      • Deposits in subepithelium
        • MGN(podocytes damage)
    • 也可direct attack GBM, tubular BM, mesangium
    • 有各種不同Ab, 不同Ag, 形成不同immunocomplex, 不同nephritis程度...所以結果多變
    • Some points
      • 懷孕中or postpartum period, lupus nephritis容易flare up, 可能是因為estrogen, prolactin, cytokines...等的關係

  • Classification(renal biopsy希望有≧25(有點困難...)個glomerulus)

    • 有overlap; 一部分因為variation in sampling, 一部分因為會evolve from one form to another(either spontaneously or after Tx)(統計上type V 10年有35%會combined type III/IV and V, 但type V好像一開始就有50%concurrent type III/IV?)
    • Drugs induced lupus
      • such as minocycline, hydralazine(Apresoline), procainamide, isoniazid...
        • 上述4個藥物也和AAV相關
        • Captopril, β-blockers, diltiazem, hydrochlorothiazide, methyldopa, penicillamine, sulfasalazine, sulfonamides, nitrofurantoin, rifampin, chlorpromazine, practolol, phenytoin, carbamazepine, quinidine, PTU, lithium, PAS, glyburide, interferon α, and TNF-α blockers...也都有reports
      • Renal involvement不常見,不過還是可以proliferative GN or nephrotic syndrome
        • Brenner(p1403):(DLE)Central nervous system and renal involvement are relatively uncommon
        • 不過Apresoline好像比較容易renal involvement??
          • Apresoline:會有DLE and ANCA-associated vasculitis; 後者常有anti-DsDNA, high titer P-ANCA, renal involvement, 常需要immunosuppressive Tx and DC drugs
      • Lab
        • >95%有anti-histone Ab
          • (Brenner p1403)against a complex of the histone dimer H2A-H2B and DNA and other histone components
            • 註:(Brenner p1403)一般的SLE也會有anti-histone Ab, 但其打的是(H1 and H2B)
        • Anti-DsDNA, hypocomplements比一般的SLE少見
    • Class I(Minimal mesangial LN)
      • Clinical
        • Normal U/A, normal renal function
      • Pathology
        • LM:normal
        • Immunofluorescence and EM: mesangial immune deposits
    • Class II(Mesangial proliferative LN)
      • Lupus podocytopathy(狼瘡足細胞病; 2018 ISN/RPS 與近年 KDIGO 正式描述)
        • 臨床: SLE 病人急性發作之典型 nephrotic syndrome
        • 病理: LM 正常(像 class I)或僅系膜增生(像 class II), 無內皮增生/毛細血管壁病變; IF 只有 mesangial 沉積(無 subendothelial/subepithelial); EM 廣泛 foot process effacement(≥50-70%)
        • 鑑別: 須排除 class III/IV/V 與藥物/感染引起的次發 MCD
        • 治療與預後: 對 steroid 反應極佳(1mg/kg/d, 75-90% 於 4-8 週 CR), 但復發率高(~50%); steroid-dependent/frequent relapse 可加 CNI 或 Rituximab
      • Clinical
        • 多有microscopic hematuria and/or subnephrotic proteinuria; 少HTN
        • 不應有renal insufficiency nor nephrotic syndrome
          • 不過可有Extensive podocyte effacement without immune deposits(如同MCD or FSGS; 可能是因為cytokine or lymphokine or T cell dysregulation?)(很少見)
            • 此時就可以有nephrotic syndrome, consider Tx as MCD/FSGS
      • Pathology
        • LM:mesangial hypercellularity or mesangial matrix expansion(but no endocapillary proliferations visible by LM)
        • Immunofluorescence
          • Full house granular deposits of mesangium (IgG, IgA, IgM, C3, C1q 皆呈陽性沉積)〔Heptinstall's Pathology of the Kidney, 8th ed, 2023; Weening JJ et al. JASN 2004; PMID 14747370〕
          • IF/EM可有一點點subendothelial or subepithelial deposits(需小心分辨type III/IV/V)
        • EM
          • Glomerular endothelial cells可有tubuloreticular structures(同HIV nephropathy)
          • Granular electron-dense deposits in mesangium
          • IF/EM可有一點點subendothelial or subepithelial deposits(需小心分辨type III/IV/V)
    • Class III(Focal proliferative LN) (因為sampling的關係, 有時候是class IV但是看起來是class III, 所幸治療是一樣的)
      • Clinical
        • 多有hematuria and proteinuria(可nephrotic syndrome), 有些人有HTN, 有些人會renal insufficiency(回思上面說看起來很輕微的nephritis也可以是type III)
          • 若<25% glomeruli involved and segmental proliferation without necrosis則progressive renal dysfunction is unlikely
      • Pathology
        • LM:<50% glomerulus involved
          • Endocapillary +/- extracapillary(crescent) GN +/- necrotizing +/- mesangial abnormalities
          • 分segmental/global(小於或大於50% tufts in a glomerulus); 幾乎都是segmental(<50% tufts)
          • Active/chronic(sclerosing)(A, C)[其實目前A/C(active/chronic)已被modified NIH activity/chronicity index取代; 見下面modified NIH activity/chronicity index]
            • A:active lesions
              • 又叫focal proliferative lupus nephritis
            • A/C:active and chronic lesions
              • 又叫focal proliferative and sclerosing lupus nephritis
            • C:chronic inactive lesions with scarring
              • 又叫focal sclerosing lupus nephritis
        • Immunofluorescence and EM: (uniform involvement; 和LM不同)immune deposits in the subendothelial space and mesangium
    • Class IV(Diffuse proliferative LN)(most common)
      • Clinical
        • 都有hematuria and proteinuria, 很常見HTN, nephrotic syndrome and renal insufficiency
        • Active disease多有decreased C3/C4 and elevated anti-DsDNA
      • Pathology
        • LM:>50% glomerulus involved
          • Endocapillary +/- extracapillary(crescent) GN +/- necrotizing +/- mesangial abnormalities
          • 2018 ISN/RPS 修訂要點(Kidney Int 2018; PMID 29459092)：
            • 取消 Class IV-S (分節性) 與 IV-G (球性) 次分型：因跨觀察者一致性差且無獨立預後差異，統一為 Class IV (diffuse LN)
            • 全面改以修訂版 NIH 活動度指數 (Activity Index, 0-24分) 與慢性化指數 (Chronicity Index, 0-12分) 評估所有增生型病變，取代舊版 A, A/C, C 分類
            • 歷史備註：舊文獻之 22% IV-G 有新月體、或 severe segmental 合併之 IV-Q 現均以 NIH 活動度與新月體百分比量化
        • Immunofluorescence and EM
          • (uniform involvement) granular immune deposits in the subendothelial space and mesangium
          • If diffuse wire loop(其實就是因為subendothelial depositions太多讓GBM變得超級厚) deposits, but no glomerular proliferation, 也算class IV(uptodate原文:The presence of diffuse wire loop deposits, but with little or no glomerular proliferation, is also considered class IV disease)

Light micrograph showing proliferative lupus nephritis

Subendothelial deposits and tubuloreticular inclusions in lupus nephritis

  • Class V(Lupus membranous nephropathy) (10-20% of LN; 50% concurrent with proliferative disease)(統計上type V 10年有35%會combined type III/IV and V)
    • Clinical
      • 類似MN, 所以多有nephrotic syndrome +/- microscopic hematuria +/- hypertension
      • Cre大多normal or mildly elevated
        • 若significant hematuria and cellular casts-->suggests concurrent proliferative disease
      • 可no serology titers of SLE nor systemic presentation of SLE
        • 少Low C3, low C4, anti-dsDNA Ab(僅7, 7, 21 %)
    • Pathology
      • LM:
        • as iMN(但LN(V)基本上多有一些mesangial cell proliferation and mesangial matrix expansion)
      • Immunofluorescence and EM
        • 不同iMN處見(MGN-Primary vs. secondary MGN)

Light micrograph showing lupus membranous nephropathy

Lupus Nephritis, Class V

  • Class VI(Advanced sclerosing LN)(4% of LN)
    • Clinical
      • Slowly progressive deterioration of RFT with proteinuria and relatively bland sediments
    • Pathology
      • Global sclerosis >90% glomeruli without residual activity
        • Represents healing of prior inflammatory injury
      • No need of Tx==>as CKD care

2.NIH Activity/Chronicity Score (Modified)#

  • Other renal pathology

    • Vascular disease
      • TMA[(可能因為APS) or Ab to ADAMTS13)], vasculitis, atheroembolic disease and atherosclerosis
        • 1/3 SLE有Vaso-occlusive lesions(其實SLE約有1/4有aPL)
      • Subendothelial deposit could cause fibrinoid necrosis with vascular narrowing----->RAAS-->severe hypertension(本身也再導致傷害?)
        • worse prognosis
      • Renal vein thrombosis(尤其nephrotic+APS者)
    • TIN(基本上有lupus nephritis應該都有一些TIN)
      • 回思也可以有anti-TBM Ab
      • 偶爾可以沒GN但有TIN
      • IFTA和prognosis有關
      • 可以type I RTA
    • Collapsing glomerulosclerosis
      • 多combined with active lupus flare
        • >50%於2年內ESRD
      • 和APOL1 gene相關
    • 可以長得像ANCA GN(prominent necrosis and crescent with minimal/absent endocapillary proliferation nor subendothelial deposits)

  • Tx

    • General
      • ACEI/ARB if proteinuria >0.5g/day; goal:proteinuria <0.5-1g/day, 至少<3.5g/day and ↓>50%
        • KDIGO 2024 反應定義(Fig 11; PMID 38182286)：
          • CR (完全緩解)＝24h 尿 PCR <0.5 g/g (或 mg/mg) 且 eGFR 穩定(基線 ±10-15% 內)，於 6-12M 內達成 (部分可 >12M)
          • PR (部分緩解)＝PCR 自基線下降 ≥50% 且 <3.0 g/g 伴 eGFR 穩定，於 6-12M 內達成；6-12M 內未達 PR/CR 者定義為 no kidney response
          • PERR (Primary Efficacy Renal Response)＝PCR ≤0.7 g/g 且 eGFR 下降 ≤20%，為 BLISS-LN 等試驗之特定複合終點，【絕對不可與 KDIGO CR 混用】
          • 註：歷史文獻與早期試驗之 CR 定義（如尿蛋白 <0.33-1g/d、Cre<1.2-1.4）互有出入，當代腎專考試與臨床評估一律以 KDIGO 2024 標準為準
      • Pentoxifylline(證據有限之蛋白尿輔助; 非常規)
      • Statin
      • Plaquenil(HCQ)≤5mg/kg/day(以實際體重計; AAO 2016/KDIGO 2024)
        • 眼科檢查:開始1年內做baseline, 之後每年檢查(用滿5年後必查, 高危險[劑量>5mg/kg、腎功能差、合用tamoxifen、老年]更早)
      • Others as CKD management(含SGLT2i, eGFR≥20+蛋白尿, KDIGO 2024)
    • Immunosuppressions
      • For type III/IV
        • Induction(1A)
          • (Endoxan(0.5g Q2W6 IF(但此劑量沒trials用在severe proliferative GN) or 0.5-1g/m2 Q1M6(dosage看打完Nadir WBC調整(多打完的10-14天nadir) or oral Endoxan 1-1.5mg/kg/day for 2-4M) or MMF(dosage如同type V的induction)) with steroid(pulse(if severe) 250-1000mg QD 3 days, then 0.5-1mg/kg/day, steroid dosage給多少或如何taper目前無consensus)

  • Endoxan or MMF皆為第一線, 不過未來要懷孕(Endoxan減少生育能力)或是黑人(MMF maybe more effective)考慮用MMF為第一線 (但MMF會畸胎, 已懷孕不能用, 所以用MMF理論上要避孕)

  • Endoxan fail則用MMF, MMF fail則用Endoxan(1B)

    • fail=resistant=no CR/PR for 6M
    • 若Endoxan and MMF都fail, consider Rituximab(2C) or (MMF+FK506 0.075 mg/kg/day)

  • (FK506 4mg/day+MMF 1g/day+Steroid) vs. (Endoxan 0.5-1g/m2 Q1M*6+steroid)看起來short term outcomes(6M)前者CR rate較高 but more infection?(→ 見下大圖multitarget比較; Reference:Multitarget therapy for induction treatment of lupus nephritis: a randomized trial(2015))

  • FK506 vs. MMF vs. Endoxan short term outcomes(6M)看起來沒差異

    • Reference:Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis(2012)
      • 2020s標靶治療(KDIGO 2024 LN首次更新納入兩種新核准藥；Kidney Int 2024; PMID 38182299)〔PMID 38182299〕
        • Belimumab(BLISS-LN, NEJM 2020; PMID 32937045; FDA核准): 加於MMF/標準治療↑renal response; KDIGO 2024建議active class III/IV induction可考慮MMF+belimumab+steroid triple therapy〔PMID 32937045〕
        • Voclosporin(AURORA-1, Lancet 2021; PMID 33971155; FDA核准): CNI類, 加於MMF↑CR rate(52W: 41% vs 23%)〔PMID 33971155〕
        • Obinutuzumab(Gazyva; REGENCY, NEJM 2025; PMID 39927615): type II anti-CD20, 加於標準治療76W CR率較佳(46.4% vs 33.1%)〔PMID 39927615〕

  • Maintenance

  • [MMF 0.5-2g/day(可慢慢taper) or AZA 2mg/kg/day(upto 150-200mg/day)] + Steroid 0.05-0.2 mg/kg/day(可以很小心很慢的taper off steroid, 不過也有人維持很低劑量如<=5mg/day) for (2yrs or longer(<2yrs more relapse, 歐洲guideline說至少3年以上)); KDIGO 2024 PP 10.2.3.2.4：proliferative LN 的「誘導＋合併維持」總療程應 ≥36 個月(從開始治療起算，不是從達成 CR 起算)；維持期 MMF 約 750-1000 mg BID〔KDIGO 2024 LN; PMID 38182286〕(MMF vs AZA比較→ 見下大圖維持段)

    • 若Pt想懷孕則不能用MMF要用AZA; 若MMF and AZA都不能用則用CNI
    • CNI relapse rate等同於AZA

  • 大圖(reference:Induction and Maintenance Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis of Randomized Trials)

  • for proliferative LN, induction

  • MMF+CNI seemed better than MMF alone and IV Endoxan; however, MMF+CNI was not superior to CNI alone

  • for proliferative LN, maintenance

  • MMF 或 AZA 優於靜脈 cyclophosphamide 維持(MAINTAIN 與 ALMS 兩大 RCT 共識); MMF vs AZA 效果相近但 MMF relapse 較少

  • DFPP used in Class IV-G(A)看起來可以改善short-term outcome but not long term outcome; 目前無證據支持常規使用(KDIGO 2024不建議), 僅個案/研究

  • For type IV+V(Tx based on the proliferative lesion)

  • FK506+MMF+Steroid better?

  • For pure type V

  • 目前沒有好的RCT, 有些專家認為全部都要治療, 因為iMN有high rate of spontaneous remission but lupus MN不會spontaneously remit(所以有人認為UPCR>1g就要immunosuppression)

  • Uptodate:Tx in (any of one) (2B)

  • (Nephrotic syndrome) or (proteinuria >3.5g/day after ACEI/ARB without nephrotic syndrome)

  • Increased Cre

  • Uptodate建議induction

  • 第一線MMF(0.5g BID 1W->1g BID 1W->1.5g BID (1g TID if 1.5g BID intolerance) for 6M) + Steroid (60mg/day, ↓10mg/day Q2W to 40mg/day, then↓5mg/day Q2W to 10mg/day; 繼續taper if 很stable) (2C)

  • 第二線{CNI[(CsA initial 100mg BID, titrate to trough 150-250 ng/mL(=mcg/L) and a reduction in proteinuria; if Cre↑1.3-1.5X or >0.3mg/dl, decrease 25% dose) or (FK506 initial 1-2mg BID, titrate to trough 5-10ug/L and a reduction in proteinuria, reduce dose if elevated Cre)] or Endoxan[(0.5g Q2W*6 IF) or (1-1.5mg/kg/day <=6M)]} + Steroid

  • Post-hoc study

    • MMF=Endoxan; Endoxan比CNI少relapse

  • Tx 3M仍惡化-->換藥; Tx 6M仍未改善-->換藥

    • proteinuria的改善速度會比較慢(active sediments改善比較快)

  • Uptodate建議maintenance

  • MMF 1g BID for 2-3 yrs then slowly tapered

    • 若是failed induction of MMF才改(CNI or Endoxan), 則maintenance用CNI for 2yrs then tapered
      • taper期間 or taper off後relapse仍可考慮用同樣的藥物

  • Consider Baktar for PJP prophylaxis if predonine ≧20mg/d and will be >1M

  • 一開始就可以開始吃而不是等到滿1個月再吃

  • Osteoporosis surveillance and prophylaxis

  • Monitor

    • Q2-4W for 3M , then Q2-3M
      • 含CBC, LFT, U/A, UPCR, Cre, C3, C4(趨勢比絕對值重要), (anti-DsDNA)
      • 註:serum complements and anti-DsDNA level和renal disease activity有關但是和longterm prognosis無關

  • Prognosis

    • Predicting CR
      • White race(回思MGN是亞洲人預後比較好), lower baseline Cre, stable Cre after 4W Tx, lower baseline proteinuria, lower chronicity index on renal biopsy
    • Risk factors for progression to ESRD
      • Black, elevated Cre, HTN, nephrotic range proteinuria, Hct<26%(表示SLE activity大? or 表示CKD?), crescent, TIN, TAIF, delayed Tx, frequent relapse, no remission
    • Relapse
      • 多within 5yrs after induction Tx, average 8%/yr(depends on maintenance Tx and CR/PR); but 50%(!!!) proliferative LN who initially achieve CR會relapse after tapering and DC maintenance Tx
        • Mild relapse可將maintenance Tx restart or 加量
        • Moderate-severe relapse要re-induction, 之前若是Endoxan induction者大多改用MMF以免cumulative toxicity(回思Endoxan total dosage建議<200mg/kg)
    • Type III/IV
      • 10-30% ESRD
    • Pure type V
      • 35% develop concurrent proliferative disease within 10yrs
      • 10 yr renal survival:72-98% (10年約10% ESRD)
    • LN with ESRD
      • Obs study:active clinical lupus:由55% at initiation of RRT變成6.5% at 5yrs after RRT(且多剩mild to moderate S/S), serology markers也由80%->22%
        • 有些study覺得SLE活動並未減低, 可能有bias of Obs study
      • 若要renal transplantation, acute renal failure最好先洗3-6M with ≦10mg/day predonine (因為看是否會回復且等SLE activity↓); 不過若是progressive course to ESRD without active lesions(renal biopsy) and without activity of SLE則不用先洗3-6M即可去做renal transplantation
        • After renal transplantation, 2-10% recurrence of LN, 多發生在10yrs內, 大多比原本的LN輕微(因為immunosuppressants用很強嘛...), graft loss rate<2-4%

反向連結

General Nephrology · 腎專考試筆記 · 僅供學習參考