Summary of GN secondary causes

1.Type of GN#

2.FSGS(all)#

• （FSGS 之次發原因、感染、藥物、血液疾患及詳細遺傳基因清單，完整彙整於本檔 §1 表格，以及專章 FSGS §2 之「FSGS/SRNS 重要基因速查表」）
• APOL1-mediated kidney disease (AMKD)：非洲裔帶有 G1/G2 雙風險等位基因者，顯著增加高血壓腎硬化、HIVAN 及 collapsing FSGS 之發病風險〔PMID 20647424〕

3.Secondary MGN（次發 membranous pattern）#

• 標靶抗原與次發病因關聯(2020-2025新考點)：
  • NELL-1(~5-10%)：與惡性腫瘤(多固態腫瘤)及外源性含硫製劑(lipoic acid 硫辛酸、傳統草藥、NSAID)強相關；IgG1 主
  • EXT1/EXT2：與自體免疫/SLE 強相關(尤 LN class V)，多為年輕女性，預後佳〔PMID 31061139〕
  • THSD7A(~1-5%)：約 20% 合併惡性腫瘤
  • SEMA3B：見於小兒膜性腎病最常見抗原
  • FAT1：造血幹細胞移植後(GVHD 相關)
  • CNTN1：合併慢性脫髓鞘多發性神經病變 (CIDP)
• I:HBV(較常見於小孩, 和HBeAg and anti-HBeAg Ab的immunocomplex(所以C1q(+))沉積在subepithelial/subendothelial/mesangial area有關(所以HBeAg seroconversion有可能MGN就spontaneous resolve, 但成人常不resolve); 有microscopic hematuria, 可hypocomplements, negative PLA2R Ab(但一小部分HBV, HCV, malignancy related MGN也可以anti-PLA2R Ab(+)...); 可cryoglobulin, MPGN, IgAN(due to chronic liver disease?)), HCV, syphilis(因為Treponemal antigen deposits in glomerulus, MGN>MCD), EBV, malaria(MPGN, cryoglobulinemia, MGN)
• 沒有HIV(HIV多collapsing FSGS, 可MCD, MPGN/cryoglobulin/lupus like GN/IgAN, AIN(AIN可能是因為virus, drugs...)), 有的話可能是因為HBV or syphilis

4.SLE type V(10-20% lupus nephritis)(type V: 可hypocomplement但不常見)#

• I:SLE type V(10-20% lupus nephritis為type V; 可hypocomplements但不常見, 所以MCTD也會MGN但奇特的是MCTD都IgG3(-))
• Sjogren's syndrome(可MGN(rare), MPGN, 其他GN(rare), amyloidosis(AA), cryoglobulinemia, IN(多chronic IN with NDI, type I RTA(also II), hypokalemia...), RTA type I(25% sjogren可有一點type I RTA, 大多mild) and II [RTA主要是因為IN導致的tubular injury]; 也可以Bartter's syndrome, Gitelman's syndrome(=2M GN+...)), RA(可MGN, MPGN, mesangial GN, 可IgAN, secondary amyloidosis(AA), drugs related(NSAID, MTX, CsA, Golds(1-3%MGN; 也可MCD)), vasculitis(=3M GN+IgA類+...)), autoimmune thyroiditis(因為Ab+thyroglobulin沉積在subepithelial site; 可MGN, 可MPGN), GVHD(MGN>MCD; 可能是donor lymphocytes打glomerular Ag, 治療和iMN一樣; MGN多發生在post-HSCT後8-14M且within 2M after GVHD(+)); post renal transplantation(可recurrence(typical 1yr after renal transplantation); 也可以de novo MGN(多比recurrent MGN晚開始); 不過uptodate建議Rituximab>Endoxan in renal transplantation的MGN(和chronic ABMR有關)); sarcoidosis(35-50% renal involvement; 多non-caseating granulomatous AIN+vitamin D related nephrocalcinosis and nephrolithiasis; 可GN(rare, 可MGN, MPGN, IgAN, crescent (口訣:MMAC)...); 可obstructive uropathy(lymph nodes, retroperitoneal fibrosis, stones, direct ureter involvement)); IgG-4 disease(TIN>>>MGN/mesangial GN/MPGN/MCD/IgAN/HSP/amyloidosis(AA); 也會hypocomplements雖然機制不太清楚, 因為IgG4不太激活complements)(=4M GN+IgA類)
• M:(5-20% Pts of MN, 尤其>65y/o; 原因是tumor Ag deposits in glomerulus->Ab接上去->激活complements; 也有可能是malignancy表現出的Ag和podocyte Ag一樣, 如有report說tumor表現THSD7A):多為solid cancer尤其lung(26%), prostate(15%), GI...; hematologic malignancy(14%, CLL, lymphoma...)也可但較少見; 診斷MN時大多是clinically apparent cancer
• M:NSAID(MCD>MGN), anti-TNF alpha(可new lupus nephritis, MGN, pauci-immune GN, crescent GN, MGN), bucillamine, Penicillamine(7%; MGN>MCD; 可crescent GN), Tiopronin(結構像Penicillamine), Gold(1-3%; MGN>MCD)[大多是治療RA的藥], captopril, probenecid, Mercury(MGN>>MCD; also tubular dysfunction)...
  • 多使用drugs後6-12M出現, 不過也可以3-4年才出現; 停藥後多9-12M resolution, 也可以upto 2-3 years(因為slow clearance of subepithelial immune deposits and slow remodeling of the disorganized GBM; podocytes類的回復比較慢...)

5.IgAN/HSP#

• (感覺呼吸道/腸胃道疾病, HIV/lymphoma, liver疾病等會產生IgA或是IgA無法代謝的疾病就可能IgA deposit-->其中某些人會IgA nephropathy)
• I:HCV, HIV, disseminated TB, dermatitis herpetiformis
• I:RA, celiac disease(1/3 Pts腎臟會堆積IgA但大多無IgA nephropathy; 如果IgA nephropathy有腸胃道症狀要小心Celiac disease, HSP), IBD, seronegative arthritis(特別是AS), GPA(可能是因為常upper airway infection), IgG-4 disease, sarcoidosis
• M:SCLC, HL and T cell lymphoma(本身產生IgA?)
• M:smoking(呼吸到刺激?), sirolimus(可以TMA, collapsing FSGS, MPGN(due to TMA?), MN, IgAN(後三者少見; 和sarcoidosis口訣都是MMAC, 雖然C不同))
• O:Chronic liver disease(含HBV/HCV...), liver cirrhosis(因為IgA removal by the Kupffer cells下降; 很多Pts腎臟會堆積IgA但大多無IgA nephropathy)
• C:在Africa and central America有familial IgAN(大多為AD with incomplete penetrance)

6.PSGN/IRGN#

• 1.PSGN from GAS, 不過group C, group G streptococcus也有案例

7.MPGN#

• (簡單來說就是許多慢性感染, 許多AIR, MGUS/MIDD, TMA)
• I:chronic infection, 尤其HCV(HBV也可); 其他的virus(HIV...)/bacteria(mycoplasma(MCD, MPGN), abscess, IE, osteomyelitis, shunt nephritis...)/fungus/parasites(P. malariae(可MN), schistosoma, toxoplasma(可AIN)...) chronic infection也可
  • URI也可以誘發MPGN(應該是本來體質就有問題??)
  • 回思IE可MPGN(其實應該算是IRGN)...
  • PSGN廣義來說也算MPGN的一種(不過應該沒有double contour?)
• HCV:typically shows granular deposition of IgM, C3, and both κ and λ light chains +/- IgG; C1q is typically negative(may also be seen with other viral infections)
• I:尤其LN(less often=>Sjögren's syndrome or systemic sclerosis(因為malignant HTN而TMA?) or RA or IgG-4 disease or sarcoidosis or APS(因為TMA?)) or autoimmune thyroiditis(可MGN, MPGN)
• D/D
  • SLE會"full house" pattern, including IgG, IgM, IgA, C1q, C3, κ and λ light chains
  • TMA immunofluorescence是(-)的
• M:monoclonal gammopathy(尤其LCDD, monoclonal IgG disease; 小心MM, CLL, B cell lymphoma)(所以MIDD可以有MPGN pattern, 但大多是nodular pattern); Rares: NHL, RCC, melanoma
  • monoclonal gammopathy:characterized by deposition of monotypic κ or λ light chains but not both. MPGN associated with heavy-chain deposition may show immunoglobulin deposition(heavy-chain isotypes) in the absence of either light chain(=HCDD?)
• M:chronic and healed TMA/TTP/HUS
• C:complement dysregulation(尤其complement factor H deficiency)(也是一種TMA), complement deficiency(C2 or C3) +/- partial lipodystrophy, α1-Antitrypsin deficiency(也和AAV相關)

8.Cryoglobulinemia#

• Type I(10-15%)
  • Monoclonal Ab:多為IgG or IgM; 但也可以是IgA or light chain
    • 非IC deposit-->no decreased complement but可hyperviscosity syndrome
    • From
      • M(B cells系列):(MM, WM, CLL...) >>> MGUS
• Type II(mixed cryoglobulinemia)(50-60%)
  • Polyclonal IgG and monoclonal IgM(against the IgG; =rheumatoid factor)
    • IC deposit in BV-->vasculitis(small vessel leukocytoclastic vasculitis)-->C4↓↓, C3↓
    • From
      • I(主):HAV, HBV, HCV, EBV, CMV(collapsing FSGS, cryoglobulinemia, TIN), HIV, B19, IE, streptococcus, fungus, malaria, Ameba
      • I:SLE, Sjogren, RA, PAN
      • M:B cell lymphoma, solid cancers
        • HCV>>>AIR>idiopathic>LPD>other infections
• Type III(也是mixed cryoglobulinemia)(25-30%)
  • Polyclonal IgG and polyclonal IgM
    • IC deposit in BV-->vasculitis(small vessel leukocytoclastic vasculitis) -->C4↓↓, C3↓
    • From(不就和type II一樣???)
      • I:as above, 尤其HCV(仍多)

9.TMA#

• 詳見專章TMA(TTP-aHUS and secondary)
• 小心有一些是drugs related:
  • 劑量依賴毒性:CNI(CsA/FK506), mTORi(sirolimus), gemcitabine, mitomycin C, cisplatin, bleomycin, anti-VEGF/TKI(bevacizumab, sunitinib, sorafenib)
  • 免疫媒介/idiosyncratic:quinine, ticlopidine, clopidogrel
  • (註:minocycline, hydralazine, procainamide, isoniazid是drug-induced lupus和AAV的藥, 不是TMA的藥, 勿混淆)

10.LN / AAV#

• (註:LN 本身次發於 SLE；drug-induced lupus 如 minocycline, hydralazine, procainamide, isoniazid…；以下為 AAV 的 ANCA 分型/次發成因)
• 1.比較少c-ANCA和p-ANCA都(+), 除了cocaine(with levamisole(cutting agent in cocaine) contamination) user導致的vasculitis
• 2.c-ANCA(more ENT and respiratory tract involved)
  • GPA(90%(+); c:75-80%, p:10-15%)
  • α1-Antitrypsin deficiency(?, α1-Antitrypsin是in vivo PR3 inhibitor)
• 3.P-ANCA(more 肺腎skin involved; 註:P-ANCA較易resistance but較少relapse)
  • EGPA(50%(+); c:15%, p:35%), MPA(70-90%(+); 多p-ANCA)
  • Renal limited vasculitis(=idiopathic crescent GN; 90%(+), c:10%, p:80%)
  • Anti-GBM disease(10-40%(+); 多p-ANCA)
• 4.Atypical P-ANCA(IFA(+), ELISA(-))
  • 註:有發現AAV Pts似乎和cancer association, 但是是based on case reports/series, 所以證據不強
  • SLE(p:20-30%) and other AIR diseases...
    • LN若為crescent GN有30% P-ANCA(+), 其他的immunocomplex GN若是crescent GN也有25% P-ANCA(+)
  • UC/PSC(p:40-70%), CD(p:10-27%), AIH
  • Cystic fibrosis
  • IE/bacteremia/TB/aspergillus...(感染相關)
  • Drugs induced vasculitis(PTU, -mazole, Apresoline(SLE相關), procainamide(SLE相關), isoniazid(SLE相關), minocycline(SLE相關), allopurinol, phenytoin, penicillamine, rifampicin, Cefotaxime, indomethacin, clozapine...)
    • PTU:30% Pts, 多months~yrs出現p-ANCA(+)(因為PTU累積在neutrophil並bind and alter MPO antigen), 但有vasculitis的僅占一小部分, DC drugs後大多會recovery
    • 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
  • 小心GPA/MPA有report of concurrent other GN(anti-GBM disease, MGN(crescents maybe due to concurrent anti-GBM or ANCA disease), IgAN, PSGN, LN)
    • 有IgAN, PSGN因為AAV其實部分和infection有關?
    • 也可以反過來..., 這些crescent immunocomplex GN 25%合併ANCA(+)(註:若是non-crescent immunocomplex GN其ANCA(+)<5%)

11.Anti-GBM disease#

• 誘發/次發成因：吸菸(誘發肺出血)、碳氫化合物/有機溶劑暴露、呼吸道感染、ESWL 體外震波碎石或腎外傷、Alemtuzumab 治療後
• 遺傳關聯：易感 HLA-DRB1*15:01、DR4；保護 HLA-DRB1*01 與 DRB1*07
• 詳見Anti-GBM disease

12.Congo red and thioflavine-T#

• 1.Fibrillary GN
  • negative(nonamyloid) fibrillar glomerular deposition diseases
    • DNAJB9 為特異性免疫染色標記（Andeen JASN 2018; PMID 29097624）〔PMID 29097624〕
    • 可和HCV相關
    • AIR(15%)
      • most often CD, SLE, Graves' disease, ITP
      • 可和anti-GBM disease相關
    • Monoclonal gammopathy(17%)
    • Malignancy(23%)
      • 可以發生在GN前 or 後10年
  • 2.Immunotactoid glomerulopathy
    • 大多有monoclonal gammopathy with restricted light chains(either k or λ)
    • 所以要小心survey lymphoproliferative disorders(尤其CLL or B cell lymphoma)
    • 但似乎HCV or cryoglobulinemia or anti-GBM disease or SLE也可immunotactoid glomerulopathy
• Fibronectin glomerulopathy
  • Autosomal dominant congenital disease(亞洲人有)
• Collagenofibrotic glomerulopathy
  • AR
    • More frequently in adult Indian populations in a sporadic, non-familial manner
• Nail-patella syndrome
  • Autosomal dominant congenital disease
• Amyloidosis
  • 1.AL
    • 可with MM, P(PNS, ANS)OE(pituitary, thyroid, adrenal↓)MS, WM(註:IgM-associated AL amyloidosis, 較少cardiac involvement), lymphoplasmacytic lymphoma, NHL, CLL
  • 2.AA
    • I
      • TB(amyloidosis(AA), also MCD, collapsing FSGS, IgAN), leprosy, COPD, cystic fibrosis, subacute IE, osteomyelitis, chronic pyelonephritis, skin ulcers
      • Whipple's disease
      • HBV(?)
    • I(60%)
      • RA(常>15yrs), IBD/sero (-) spondyloarthropathy, FMF(familial Mediterranean fever), AOSD, SLE(rare, 原因未知, 不過 SAA level抽起來確實比RA低), vasculitis(Giant cell arteritis, Takayasu arteritis, Behcet's diseases, PAN), IgG-4 related diseases
        • RA以前常有glomerular AA depositions and 常常ESRD
          • 隨著治療進步,現在不常見, 因為大多發生在poor controlled, seropositive, long-standing and 有 extraarticular manifestation的RA
        • RA可cresent GN(uncommon), 可能因為RA本身造成的GN or amyloid fibril-induced ruptures in the capillary loops
    • 其他AL, AA也可以crescent GN但是很少見
  • M
    • 尤其HL, RCC
    • 可Hairy cell leukemia, castleman disease
    • 可Lung/GI/GU adenocarcinoma, hepatic adenoma, BCC
  • Others
    • Drugs abuser(感染相關?)
    • Gout(case report)

13.MIDD#

• 大多還是from MM(LCDD or LHCDD都約50%有MM, HCDD約25%有MM), 不過也可from WM, CLL, nodal marginal zone lymphoma or chronic infection or autoimmune