初始治疗选择
1. 双重免疫抑制治疗
组成：糖皮质激素（GC）+ 一种主要免疫抑制剂
适用于：大多数患者，尤其是轻至中度蛋白尿或肾损伤者。
选择如下：
霉酚酸酯（MMF）或肠溶霉酚酸钠（EC-MPS）
环磷酰胺（IV 或口服）
剂量与用法
霉酚酸酯（MMF）：
起始剂量：0.5 g 每日2次，第2周增加至 1 g 每日2次。
若耐受良好，可进一步增至 2.5–3 g/天。
若有胃肠道不良反应（如恶心、腹泻），可替换为肠溶霉酚酸钠（EC-MPS）：1 g MMF ≈ 720 mg EC-MPS。
治疗持续6个月。
环磷酰胺：
短疗程低剂量方案：IV环磷酰胺 500 mg 每2周一次，共6次（Euro-Lupus方案）。
长疗程高剂量方案：IV环磷酰胺 0.5–1 g/m² 每月一次，共6个月（NIH方案）。
口服环磷酰胺：1–1.5 mg/kg 每日，逐渐增至 2 mg/kg，维持2–4个月。
2. 三重免疫抑制治疗
组成：糖皮质激素（GC）+ 两种免疫抑制剂
适用于：重度蛋白尿（≥3 g/天）、复发性LN或需快速激素减量的患者。
推荐组合
贝利木单抗（Belimumab）+ MMF 或环磷酰胺
贝利木单抗抑制B细胞存活因子BLyS，特别适用于同时有狼疮关节炎或复发风险高的患者。
剂量：10 mg/kg IV每2周一次（前三次），随后每4周一次；或皮下400 mg每周一次，4周后改为200 mg每周一次。
钙调神经磷酸酶抑制剂（CNI, 如Tacrolimus或Voclosporin）+ MMF
Tacrolimus（他克莫司）：
起始剂量1–2 mg 每日2次，依据蛋白尿变化调整剂量。
血药浓度目标：5–7 ng/mL。
Voclosporin（伏克洛司他）：
剂量：23.7 mg 每日2次，无需监测血药浓度。
注意：eGFR <45 mL/min/1.73 m²者慎用。
Tacrolimus比环孢素不良反应少，推荐优先使用。
糖皮质激素的剂量和减量
初始治疗：IV甲基强的松龙 250–1000 mg 每日1–3天，以快速控制炎症。
口服维持：起始 0.3–0.5 mg/kg/天（最大剂量40 mg/天），逐步减量至 ≤7.5 mg/天（优选 ≤5 mg/天），持续3–6个月。
关键点
低剂量激素与高剂量激素疗效相当，但感染等副作用显著减少。
激素单药治疗效果较差，不推荐单用。
治疗方案的选择依据
病理严重程度：
活动性新月体病变、快速肾功能恶化：优选高剂量IV环磷酰胺。
轻中度活动性：MMF方案较耐受性好。
蛋白尿水平：
≥3 g/天：CNI（如Tacrolimus或Voclosporin）+ MMF 可能更佳。
复发风险：贝利木单抗可减少LN复发。
肾功能受损（eGFR<45 mL/min/1.73 m²）：避免CNI，优选MMF或环磷酰胺。
生育需求：MMF对生育影响小于环磷酰胺，但妊娠期间需停止使用MMF。
依从性问题：患者不愿服药时，可选择IV环磷酰胺。
治疗成本与药物可得性：新药（如贝利木单抗、Voclosporin）成本高，部分国家供应有限。
临床研究证据
MMF与环磷酰胺疗效比较：
ALMS研究：MMF与IV环磷酰胺在24周肾脏反应率相当（56% vs 53%）。
Meta分析：MMF和环磷酰胺在缓解率、ESKD风险和感染发生率方面无显著差异，但MMF导致脱发更少。
三重免疫抑制的优势：
加用贝利木单抗或CNI可提高肾脏完全反应率，尤其是在高蛋白尿患者中。
快速记忆方法
1. 治疗选择口诀
“轻中激素配MMF，蛋高三药CNI；新月恶化环磷救，贝利复发性关节益。”
轻中度患者：糖皮质激素 + MMF。
高蛋白尿：三药方案，优选CNI + MMF。
活动性新月体病变或快速恶化：环磷酰胺。
贝利木单抗：适合复发风险高或伴关节炎者。
2. 糖皮质激素口诀
“冲击甲强三天足，口服减量控副毒。”
3. 药物特点口诀
“MMF肠胃副作用多，环磷脱发需避孕；CNI降蛋优护肾，贝利控复炎症松。”
治疗建议
LN治疗需结合个体病情制定最佳方案。
治疗应在专科医生指导下进行，并关注药物副作用及长期随访。
Detailed Summary of Initial Immunosuppressive Therapy for Lupus Nephritis (LN)
Overview of Treatment Choices
Treatment for lupus nephritis (LN) is guided by the activity and severity of kidney involvement, biopsy findings, and individual patient factors such as comorbidities, fertility concerns, adherence, and drug availability. Below are the key considerations:
Active lesions (e.g., Class III, IV, or mixed Class V LN): Immunosuppressive therapy is recommended.
Chronic lesions only (e.g., extensive fibrosis, tubular atrophy without active inflammation): Immunosuppression is generally not indicated; supportive care for CKD is preferred.
Extra-renal manifestations of systemic lupus erythematosus (SLE) (e.g., CNS disease, myocarditis): Extra-renal disease severity may influence therapy selection.
Initial Treatment Options
1. Dual Immunosuppressive Therapy
Components: Glucocorticoids (GC) + One primary immunosuppressive agent
Recommended for most patients with mild-to-moderate proteinuria or kidney involvement.
Agents:
Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS)
Cyclophosphamide (IV or oral)
2. Triple Immunosuppressive Therapy
Components: Glucocorticoids (GC) + Two immunosuppressive agents
Suitable for patients with severe proteinuria (≥3 g/day), recurrent flares, or those requiring rapid GC taper.
Regimens:
Belimumab + MMF or cyclophosphamide
Belimumab targets B-cell survival factor (BLyS) and is effective for reducing LN relapses and SLE-associated arthritis.
Calcineurin inhibitor (CNI, e.g., tacrolimus or voclosporin) + MMF
CNIs help reduce proteinuria and preserve kidney function, especially in severe LN.
Dosing and Administration
1. Mycophenolate Mofetil (MMF)
Initial dose: 0.5 g twice daily; increase to 1 g twice daily after one week.
Target dose: 2.5–3 g/day (adjust based on tolerance).
Substitute with EC-MPS if gastrointestinal side effects occur (1 g MMF ≈ 720 mg EC-MPS).
Treatment duration: Typically 6 months.
2. Cyclophosphamide
Short-course, low-dose regimen (Euro-Lupus regimen): IV 500 mg every 2 weeks, 6 doses.
Long-course, high-dose regimen: IV 0.5–1 g/m² every month, 6 doses.
Oral cyclophosphamide: 1–1.5 mg/kg daily, titrated to a maximum of 2 mg/kg for 2–4 months.
3. Calcineurin Inhibitors (CNI)
Tacrolimus:
Dose: 1–2 mg twice daily, adjusted based on proteinuria response.
Blood trough levels: 5–7 ng/mL.
Voclosporin:
Dose: 23.7 mg twice daily; no monitoring of drug levels required.
Avoid in patients with eGFR <45 mL/min/1.73 m² unless benefits outweigh risks.
4. Belimumab
IV: 10 mg/kg every 2 weeks for 3 doses, then every 4 weeks.
Subcutaneous: 400 mg weekly for 4 weeks, then 200 mg weekly.
5. Glucocorticoids
Induction: IV methylprednisolone 250–1000 mg daily for 1–3 days.
Maintenance: Oral prednisone 0.3–0.5 mg/kg/day (max 40 mg/day), taper to ≤7.5 mg/day within 3–6 months.
Factors Influencing Treatment Choice
Severity of kidney pathology:
Severe crescentic lesions or rapidly progressive renal failure: High-dose IV cyclophosphamide.
Mild-to-moderate activity: MMF preferred for better tolerability.
Proteinuria level:
≥3 g/day: Triple therapy with CNI + MMF may be more effective.
History of LN flares: Belimumab reduces recurrence risk.
Impaired kidney function (eGFR <45 mL/min/1.73 m²): Avoid CNIs; consider MMF or cyclophosphamide.
Fertility concerns: MMF preferred over cyclophosphamide.
Adherence issues: IV cyclophosphamide may improve compliance.
Cost and drug availability: Newer agents like belimumab and voclosporin may be expensive or inaccessible in some regions.
Supporting Evidence
MMF vs. Cyclophosphamide:
ALMS trial: Renal response at 24 weeks was comparable between MMF (56%) and cyclophosphamide (53%).
Meta-analyses suggest similar efficacy for remission, ESKD risk, and infection rates, but MMF causes fewer side effects (e.g., alopecia).
Triple Therapy:
Adding belimumab or CNI improves renal response, particularly in patients with high proteinuria.
Rapid Memory Aids
1. Treatment Selection Mnemonic
“Dual for mild, Triple for severe. CNI for protein, Cyclo for flare.”
Dual therapy: For mild-to-moderate LN.
Triple therapy: For severe LN or high proteinuria.
CNI: Preferred in high-proteinuria cases.
Cyclophosphamide: Used for severe, rapidly progressive disease.
2. Glucocorticoid Taper Mnemonic
“Pulse high, taper low.”
Start with IV methylprednisolone pulses, then taper oral prednisone.
3. Drug Characteristics Mnemonic
“MMF milder, Cyclo stronger; CNI cuts protein, Belimumab stops relapse.”
Treatment Recommendations
Treatment should be personalized based on kidney biopsy findings, clinical severity, and patient-specific factors.
Long-term follow-up is crucial to monitor treatment response and minimize adverse effects.
参考文献
UpTodate
KDIGO LN Guidelines
