Epidemiology of IgA Nephropathy

  • Higher incidence in Pacific Asian
  • Biopsy-proved case會低估發生率, biopsy-proved的incidence為2.5 per 100,000
  • 日本 vs Tennessee的incidence (小孩): 4.5 vs 0.57 per 100,000
  • Autopsy incidence, 日本 vs Finland: 15.6% vs 1.3% (無症狀IgA deposition)
  • 歐美: 10年的eGFR減半或ESRD的比例: 27%
  • 亞洲人有increased risk of ESRD (HR=1.56)

Disease Pathogenesis in IgAN

  • Genetic + Environment
  • Multi-hit
  • Mesangial immune complex: Gd-IgA₁/anti-Gd-IgA₁-Ab (IgG)/C3
    • Gd-IgA₁: galactose-deficient IgA1
  • IgAN患者家屬25%有elevated Gd-IgA₁
  • IgA glycosylation defect, 來自genetic及environment
  • Mesangial GN→↑systemic/local RAAS and ↑complement
  • Disease progression: smoking, HTN, hyperfiltration
  • 目前並不知道Gd-IgA₁的trigger及製造場所在哪裡
  • Mice: 和細菌寄生或感染有關
  • APRIL cytokine在病人體內有升高, 可能影響是將B cell變成IgA-producing
    • APRIL gene polymorphism和IgAN susceptibility有關
    • APRIL expression也和disease progression有關
  • 補體活化在pathogenesis也很重要 (lectin pathway, defect in alternative pathway, defect in properdin and factor H)

Clinical-Pathologic Correlation in IgAN: Mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy (T), MEST and Crescents

  • Oxford classification建立自: ≥0.5 g/d of proteinuria, eGFR≥30 ml/min/1.73 m² at renal biopsy, and ≥1 year of follow-up
  • MEST (Oxford score)可預測renal outcome
    • M1: >50% of glomeruli showing mesangial hypercellularity
    • E1: any endocapillary hypercellularity
    • S1: any segmental glomerulosclerosis
    • T0, T1, and T2: fibrosis involving 1%–25%, 26%–50%, or >50%
  • Score的用意就是免去「觀察期」即可挑出high-risk of progression的患者 (傳統是用BP, proteinuria及CRE去做預測)
  • 觀察發現steroid-responsiveness可能和histology有關
  • Oxford study並未包含rapid progressive disease者
  • Any crescent也是independent的ESRD predictor
  • Score + clinical只能解釋IgAN的30%的variability in outcome

Clinical Manifestations

Common Phenotypes: Asymptomatic Hematuria and Progressive Kidney Disease

  • 子標題為2個最常見的臨床表現
  • Isolated microscopic hematuria with minimal proteinuria: 雖然整體outcome好, 但仍有少數人會發展成progressive disease, 因此還是要f/u
  • Progressive disease者的10-yr renal survival: 57%-91%

Less Frequent Manifestations

  • Synpharyngitic macroscopic hematuria (10-15%, 主要在age < 40)
  • Recurrent macroscopic hematuria: short-term outcome較佳, 但也可能來自lead-time bias
  • Proteinuria > 3 g/d不算少見, 但nephrotic syndrome很罕見
  • IgAN+MCD: 罕見但存在
  • RPGN罕見

Treatment Strategies: Current Evidence and Novel Therapies

Conservative Therapy

  • 很重要
  • STOP-IgAN trial: 有1/3病人在run-in phase, 靠著intensified conservative therapy就不再符合immunotherapy的inclusion criteria了
  • Dual RAAS blockade可再減proteinuria, 但專家不建議這麼做(due to hyperkalemia)
  • 有一個小型研究發現statin add-on也能有效降蛋白尿
  • 減肥及戒煙也可能有效

Corticosteroids

  • 早期研究支持其效果, 近年研究則懷疑其效果是否能持久
  • 第一個RCT (RAAS blockade未普及, conservative treatment也未強調)
    • N=86; vs placebo
    • Proteinuria: 1-3.5 g/d
    • CRE ≤ 1.5 mg/dL
    • Steroid: 1 g IV for 3 days at months 1, 3, and 5; PO at 0.5 mg/kg/day on alternate days for 6 months
    • 5-yr ↑CRE <50%: 81% vs 64% (P=0.05)
    • 5-yr ↑CRE <100%: 95% vs 74% (P=0.001)
    • 10-yr renal survival: 97% vs 53% (P=0.003)
    • Proteinuria改善可預測outcome
  • Single center RCT (2010 NDT)
    • N=97, biopsy-proven
    • Proteinuria ≥ 1 g/d
    • eGFR > 50/mL/min/1.73m²
    • Steroid可減少risk of renal failure, RR=0.32 (0.15-0.67, P=0.002)
    • 效果為dose-dependent, 需要> 30 mg/d或high-dose pulse
    • RAAS blockade未標準使用
  • STOP-IgAN
    • 設計: 招380個病人, 經6個月的intensive conservative therapy (RAAS blockade, BP and lipid control)後, 仍有persistent proteinuria及eGFR > 30
      • eGFR > 60: corticosteroid
      • eGFR 30-59: corticosteroid + cyclophosphamide, the azathioprine maintenance
    • Primary outcome為full clinical remission: PCR < 0.2, eGFR下降<5
    • 6個月的run-in後, 接近1/3病人無法進入trial, 162個進入 randomization
    • 3-yr remission, steroid vs placebo: 17% vs 5%, P<0.05; 但eGFR下降速度兩組沒差別
  • TESTING study 期中報告
    • 6-8個月的PO corticosteroid 0.6-0.8 mg/kg/d vs placebo
    • 預計收1300個, 追蹤5年
    • Primary outcome: composite of eGFR/ESRD/death
    • Interim analysis of 262 patients, treatment vs placebo: 8% vs 15%
    • 但治療組的serious event之RR為4.63
    • Benefit雖可能仍大過risk, 但必需小心面對, 因此研究中途暫停以修改protocol

Mycophenolate

  • Mixed result, small sample size, vs placebo
  • Guideline: against
  • 可能和lupus nephritis一樣, 有race-specific variability

Rituximab

  • Negative evidence (single small study)

Combination Therapy

  • Steroid + additional agent: 通常保留給progressive disease者
  • Mixed study results, small sample size

Novel Agents

  • Nefecon: modified formulation of oral budesonide
    • 作用在distal ileum及proximal large intestine, 減少local IgA製造
    • High first-pass, 減少systemic作用
    • NEFIGAN trial: phase IIb, 可有效減少proteinuria
  • Acthar gel: purified ACTH (NCT02382523)
  • Bortezomib (NCT01003778)
  • Fostamatinib, oral spleen TKI (NCT02112838)

Reconciling Data and the Future of Clinical Trials in IgAN

  • STOP-IgAN排除了proteinuria > 3.5 g/d者, 但這群人可能是對steroid最有response者
  • KDIGO建議: proteinuria > 3 g/d, failed conservative, 應用steroid
  • Proteinuria < 1 g/d: steroid應該沒幫助
  • Proteinuria 1-3 g/d: 灰色地帶

 2017 Apr 3;12(4):677-686.