◐General Nephrology

FSGS

GN約 20 分鐘5 個章節

1.FSGS#

  • Primary FSGS<->MCD a spectrum of diseases?(有時候是FSGS沒biopsy到; 尤其FSGS多由juxtamedullary glomeruli開始sclerosis==>superficial biopsy可能miss)
    • But Tx response different and prognosis different and elevated circulating soluble urokinase plasminogen activating receptors (suPAR)(見下述pathogenesis) in primary FSGS
    • the average volume of a sclerotic lesion in FSGS is only 12.5% of total glomerular volume
      • 所以常常沒biopsy到, 如果biopsy的glomerulus <15沒看到FSGS lesions可能不能排除FSGS
  • Epidemiology
    • 佔idiopathic nephrotic syndrome的35%, 黑人更多(50%, United States)
    • 在primary GN導致的ESRD中最多(United States)
    • 東方人?(比較少, 但似乎也不少)
    • 佔ESRD的4%
  • Pathogenesis of primary FSGS
    • 可能是血漿中某些factors(circulating permeability factors?)導致podocyte and parietal epithelial cells change/damage(↑GBM permeability後-->insudation↑, hyalinosis↑, foam cells↑, podocytes edema-->obliteration of capillary lumen-->sclerosis)
      • 因為將病人血清打到老鼠身上可造成proteinuria; renal transplantation後primary FSGS常馬上復發並可用TPE(1B)...等治療; 若將recurrent FSGS的renal allograft改transplant到非FSGS的ESRD病人身上後FSGS會resolve
      • 部分 primary FSGS/MCD 活動期及移植後復發個案可測得 circulating anti-nephrin 自體抗體，效價與疾病活動度及蛋白尿平行，緩解期下降或轉陰〔Watts Sci Transl Med 2022; PMID 34732507; Hengel NEJM 2024; PMID 38804512〕
      • Circulating permeability factors
        • Soluble form of the urokinase plasminogen activating receptor (suPAR)
          • Overproduction by immature myeloid cells of the bone marrow(?)
          • 和podocyte的αvβ3 integrin有關(此integrin和foot process maturation and adehesion to GBM相關)
        • Cardiotrophin-like cytokine factor-1 (CLCF1)(?)
        • MicroRNA(功用是bind to the mRNAs of various genes and lead to their degradation==>調控mRNA)
          • miR-193a inhibited the transcript for the Wilms tumor protein (WT1) in podocytes, 而WT1和nephrin相關
  • Pathogenesis of secondary FSGS
    • 見etiology
  • Histology
    • 1°(80%)
      • Diffused foot process fusion (mean:65%foot process effacement; collapsing type甚至高達90%)
        • 小心若經過steroid Tx可能Diffuse foot process fusion會不見
        • Podocyte會detachment(vs. MCD)
    • 2°(20%)
      • Foot process fusion(多segmental, 平均20-30%)
        • 比primary FSGS較不diffused nor global
    • 註:1° or 2°切在50% foot process effacement
    • More focal change than MCD(故名FSGS嘛...)
    • 5 morphologic variants

  • not otherwise specified (NOS)(42%)(=classic)

    • Diagnosed by exclusion
    • LM:Mild mesangial hypercellularity and partial occlusion of the capillary lumens by hyaline deposits(plasma proteins 滲入abnormally permeable glomerular capillary wall(部分也因為intraglomerular hypertension?)
    • Immunofluorescence: no immune deposits; but 可有nonspecific IgM(58%) and complement (C3(35%in IgM deposit(+)) and variably C1q) in sclerotic lesions; 也可有weak non-specific mesangial deposition of IgM/C3 like MCD
      • IgM deposit似乎不影響預後; 但C3 deposit者預後較差(較不易remission)

  • Collapsing variant(11%)(有些人覺得要單獨分出來collapsing glomerulopathy而非FSGS)

    • Typically present with (segmentally or globally; tendency to global) collapsed and sclerotic glomerular capillaries, pseudocrescents(其實是hyperplastic podocytes), and severe tubulointerstitial disease(why?因為more severe proteinuria?), and implosive wrinkling and retraction of GBM
      • HIV的話:tubuloreticular structures in glomerular endothelial cells on EM(因為interferon effect, 不只HIV有(SLE也有)); microcystic renal tubular dilatation(=dilatation of tubules)(why?雖然virus是也感染了tubules)(但好像一般的collapsing FSGS也會microcystic change)
    • 大多因為HIV(also MPGN, cryoglobulinemia, IgAN, lupus like GN, MCD)/B19(也可以cryoglobulinemia)
    • I:CMV(collapsing FSGS, cryoglobulin, TIN), TB(also amyloidosis, MCD, collapsing FSGS, IgAN)
    • I:lupus/MCTD, AOSD(可Mesangial GN, collapsing FSGS, secondary amyloidosis(AA), IN), cerebral arteritis, IgAN, post-renal transplant
    • M:MM/MGUS, acute monoblastic leukemia/hemophagocytic syndrome(主要是TMA)
    • M:DM(也可一般的FSGS), drugs(interferon(可MCD/FSGS, ATN, TMA)/anabolic steroid(MCD, FSGS)/pamidronate(MCD, FSGS), sirolimus(可以TMA, collapsing FSGS, MPGN(due to TMA?), MN, IgAN(後三者少見)))
    • C:APOL1 gene, mitochondrial cytopathy(Dr.蔡:mitochondrial disease大多是用Fanconi syndrome來表現)/other genetics/也可以idiopathic
    • H:Sickle cell anemia(會hematuria(papillary necrosis), MPGN, collapsing FSGS, also一般的FSGS?)

  • Tip variant(17%)(圖見pathology)(有些人覺得是MCD的variant, 因為對steroid反應好, 預後好; 而對steroid反應不好的可能其實是early form的NOS FSGS)

    • at least one segmental lesion with adhesion between the tuft and Bowman's capsule near the origin of the proximal tubule
      • Podocytes adjacent to the consolidated segment are enlarged and contain clear vacuoles and hyaline droplets, 鄰近的proximal tubular cell也會irregular enlargement and vacuolization like podocytes change

  • Perihilar variant(26%)

    • Perihilar sclerosis and hyalinosis in >50% segmentally sclerotic glomeruli
      • 只有perihilar type要求要>50% glomerulus, 其他都只要1個即算
    • 多為secondary FSGS with increased glomerular capillary pressure, such as renal agenesis
      • Hilum壓力比較大嘛...

  • Cellular variant(3%)

    • At least one glomerulus with segmental endocapillary hypercellularity that occludes the capillary lumen; 也常有podocytes hyperplasia(所以像collapsing type)
    • 也常常severe proteinuria, 有些人認為其實是collapsing variant只是切片沒切到

  • Histology summary

Lesion type Key histologic feature Prognostic implication
FSGS NOS Segmental sclerosis (Diagnosed by exclusion) Typical course
Collapsing FSGS Collapse of tuft, podocytes hyperplasia Poor prognosis
Cellular FSGS Endocapillary proliferation, often podocytes hyperplasia Early stage lesion? Collapsing type variant?
Tip lesion Sclerosis of tuft at proximal tubule pole Better prognosis; MCD variant? FSGS NOS variant?
Perihilar variant Sclerosis and hyalinosis at vascular pole May reflect a secondary FSGS (adaptive)

2.S/S#

  • Primary 多(70-95%)用acute/subacute nephrotic syndrome表現, collapsing variant更acute, 預後較差, proteinuria常更嚴重(>10-15g/day); tip variant表現像MCD(也是acute nephrotic syndrome, proteinuria量也比較多); 1/2 hematuria(可以gross); 1/3 HTN; 1/3 Cre elevated(未必是已經chronic change, 可以因為ATN(or 因為podocytes effacement本身?))

    • Primary MCD or primary FSGS常以acute來表現, 其他GN比較chronic

  • Secondary 較多slowly increasing non-nephrotic range proteinuria(with normal serum albumin level(==>no edema and 較少dyslipidemia); 即使已經nephrotic range proteinuria也基本上是normal serum albumin level and no edema and slowly increasing renal insufficiency

  • Etiology

    • Primary(idiopathic)
    • Secondary
      • Adaptive response to glomerular hypertrophy or hyperfiltration
        • Nephron loss > 50-75%-->cause intraglomerular hypertension(RAAS system)[因為身體嘗試maintain GFR]
          • any disease casue advanced renal disease, reflux nephropathy; operation/congenital
        • Renal vasodilatation
          • DM, HTN, severe obesity(adiponectin?), anabolic steroid(renal vasodilate and direct nephrotoxicity), sickle cell anemia(medullary ischemia->vasodilatation), hypoxia, cyanotic heart disease, familial autonomic insufficiency
      • Healing(Scarring) due to previous injury(TGF-beta related)
        • any GN(ANCA, crescent GN, IgA nephropathy, SLE, MGN, TMA, Alport syndrome...)
      • Any etiology to cause podocyte injury==>Large molecules form subepithelial deposits==>Macrophage infiltrates, ECM deposits, fibrosis, TGF-B
        • Including virus(HIV, B19)==>會感染podocytes and tubules; malignancy(lymphoma(tumor antigens?->GN?, 所以也會MCD)); drugs(Heroin?, interferon, Lithium(參lithium toxicity), Pamidronate/alendronate(also cause ATN, TMA), anabolic steroid)
      • Familial/Genetic
        • 佔一大部分的steroid-resistant FSGS; 不過也有可能是steroid responsive
      • Etiology lists(也參考上面Collapsing variant)
        • I:HIV(collapsing), B19(collapsing), (also EBV(MN, FSGS, cryoglobulinemia, TIN)/CMV(collapsing FSGS, cryoglobulin, TIN)/HCV(MPGN, cryoglobuline type II多, 可MCD, collapsing FSGS, MGN, IgAN, TMA, TIN, fibrillary GN, immunotactoid GN(?)); 這三者rare)
        • I:any GN causing glomerular injury, TMA, post-renal transplantation(collapsing), AIR diseases...
        • M:lymphoma(as MCD; 其他cancers少見, 有也是case reports; RCC and thymoma多一點點), 不過MM/acute monoblastic leukemia/hemophagocytic syndrome和collapsing FSGS有關
        • M:drugs(Heroin?(collapsing), interferon(collapsing), Lithium(MCD, FSGS, cTIN, NDI), Pamidronate/alendronate(Zometa also cause tubular injury; collapsing), anabolic steroid(collapsing), anthracycline(MCD/FSGS; case reports), CNI(secondary FSGS?), Sirolimus(可以TMA, collapsing FSGS, MPGN(due to TMA?), MN, IgAN(後三者少見), 口訣:MMAC...), DM(可以collapsing FSGS?), HTN, severe obesity
        • C:congenital/familial/genetic; familial autonomic insufficiency, cyanotic heart disease, alport syndrome
          • NPHS1 gene mutation(AR, 和nephrin有關)-->glucocorticoid-resistant nephrotic syndrome
            • Congenital nephrotic syndrome of Finnish type within the first 3M
            • Steroid resistance
          • NPHS2 gene mutation(AR, 和podocin有關)-->glucocorticoid-resistant
            • Most frequent genetic cause of steroid-resistant nephrotic syndrome
            • 尤其R138Q mutation(arginine-138 to glutamine)(容易early onset FSGS(<2 y/o), more severe)
            • R229Q(Arginine-229 to glutamine)是polymorphic risk variant:削弱nephrin-podocin交互作用,↑SRNS/FSGS感受性(非保護性); 單獨R229Q外顯率低, 常需合併second hit
            • Familial and childhood-onset steroid resistant nephrotic syndrome
          • Alpha-actinin-4 gene gain of function mutation(ACTN4)(AD, 和actin有關)
            • Podocytes會有cytoplasmic electron-dense aggregates!
          • TRPC6(AD, gain of function of podocyte的Ca channel, Ca進入後激活calmodulin/calcineurin/NFAT, NFAT會破壞synaptopodin(所以CNI可治療FSGS)), INF2, MYO1E, PLCE1, LMX1B(LIM homeobox transcription factor 1β; 和Podocin and CD2AP有關; 和nail-patella syndrome(LMX1B)有關) gene.................
            • AR較多, 多出生後就發病
            • AD較少, 多adolescent or young adult發病
        • FSGS/SRNS 重要基因速查表(高頻遺傳題)
遺傳 基因(蛋白) 臨床特徵／考點
AR NPHS1(nephrin) 芬蘭型先天腎病症候群(生後3個月內重度蛋白尿, steroid無效)
AR NPHS2(podocin) 小兒 SRNS 最常見; R138Q 早發嚴重; R229Q 為風險多型性
AR PLCE1(NPHS3) 早發, 部分為 diffuse mesangial sclerosis(DMS)
AR LAMB2 Pierson syndrome(小眼球/瞳孔異常＋腎病)
AD ACTN4(α-actinin-4) EM 可見足細胞內特異電子緻密聚合體
AD TRPC6 Ca channel gain-of-function→活化 calcineurin 降解 synaptopodin(故 CNI 有非免疫的足細胞保護機轉)
AD INF2 成人 AD FSGS 最常見; 常合併 Charcot-Marie-Tooth 神經病變
AD WT1 Denys-Drash(假兩性畸形＋Wilms tumor＋DMS)／Frasier(男轉女＋性腺母細胞瘤＋FSGS)
AD LMX1B Nail-patella syndrome(指甲發育不良＋髕骨發育不全＋腸骨角＋GBM 第III型膠原沉積)
雙對偶 APOL1(G1,G2) 非洲裔; 具抗錐蟲優勢; 與 HIVAN／collapsing FSGS／高血壓腎硬化高度相關
  • 若是黑人則和APO L1 gene(chromosome 22)有關
    • APO L1 gene和hypertensive nephropathy, HIV-associated nephropathy, collapsing FSGS有關
    • Apoprotein L1和身體殺Trypanosoma brucei有關, 所以是黑人演化上select出來的
  • H:sickle cell anemia(會hematuria, MPGN, collapsing FSGS), hemophagocytic syndrome(TMA, collapsing FSGS)
  • O:advanced renal disease, reflux nephropathy
  • D/D of primary and secondary FSGS(因為和Tx有關)
  • Primary:多nephrotic syndrome + extensive foot process effacement (≥80(50?)%) + no other etiologies found
    • 符合上述條件仍不能排除congenital/genetic/familial form; 所以要詳細問FH; congenital/genetic/familial form大多早發
      • Pathology也不太能分primary or congenital/genetic/familial form; 除了NPHS1 and alpha-actinin-4 gene mutations and the disease-specific lesions of Fabry disease, Alport syndrome, and lecithin-cholesterol acyl transferase deficiency
        • 好像都是用EM分?
      • 但某些congenital form FSGS似乎也有response to steroid, 所以好像也不用硬分?
  • Secondary:多non-nephrotic range proteinuria + normal serum albumin level + segmental foot process effacement (<80(50?)%)

3.Tx#

  • General
    • Consider low-salt diet, diuretics, ACEI/ARB, pentoxifylline, statin
    • Consider PJP prophylaxis if long term steroid use(一般建議: prednisone ≥20mg/d 超過 ≥4 週(或同等累積暴露)即考慮 TMP-SMX; KDIGO GN 指引對高風險免疫抑制療程建議考慮)
    • SGLT2i: 蛋白尿性FSGS之標準支持治療(DAPA-CKD, eGFR≥20)
    • Sparsentan(雙重ETA/AT1受體拮抗劑): DUPLEX(NEJM 2023; PMID 37921461)：sparsentan 較 irbesartan 於 36 週顯著提升部分緩解率(42.0% vs 26.0%)且降低蛋白尿，惟 108 週 eGFR slope 未達顯著差異(P=0.75)〔PMID 37921461〕
    • Inaxaplin(VX-147, 首創口服小分子 APOL1 抑制劑): phase 2a(NEJM 2023; PMID 36920755)：針對帶有雙對偶 APOL1 (G1/G2) 變異之 FSGS 患者，第 13 週使 UPCR 相對基線顯著降低 47.6%〔PMID 36920755〕
  • Primary(not collapsing variant)
    • If nephrotic syndrome(if 用CNI, CsA evidence比FK506多; CsA trough 100-175 ng/mL; FK 506 12-hour trough:4-7(5-10)ng/mL)(MMF:1.5~2g/d for 6M or longer)
      • Naive
        • Predonine 1mg/kg/day(maximum 60-80mg/day) for (4)8-16W(有中國paper研究>8W全劑量的steroid並未再上升CR rate(不過steroid resistance的定義是>12-16W無PR/CR), 建議8W即可開始taper or加other drugs), then tapering
          • 看反應, 甚至可長達一年, no well evidence
            • if CR in 8-12W-->then keep for 1-2W then taper over 2-3M
              • =total course約半年
            • if PR by 12W-->taper over 3-9M
              • =total course約一年
            • Taper slowly
              • Typically ↓10mg Q2W to 0.15mg/kg/d, then ↓2.5mg Q2-4W
                • =每2週↓2顆到剩2顆, 接下來每兩週↓2.5mg/d
            • 若雖然no PR by 12-16W but decreasing proteinuria-->可keep steroid if no obvious steroid toxicity直到PR/CR再考慮taper; 也可考慮CsA(MMF if eGFR<30)
        • or CNI(MMF if eGFR<30) +/-low dose Predonine(≦15mg QD or 0.15mg/kg/d) for 12M if high risk of steroid toxicity(obesity or DM or severe osteoporosis or Age>70)
          • CNI
            • Cyclosporin:3-5mg/kg/d for 6-12M(有專家覺得應維持remission>1yr後才能taper) then slow tapered(↓25% dosage Q2M)
            • FK 506:0.1-0.2mg/kg/d for 6-12M then slow tapered(↓25% dosage Q2M)
            • 若CNI用6M沒反應-->DC
          • 但eGFR<30不用CNI, 怕會nephrotoxicity-->此時考慮MMF(劑量見上述)
            • 若eGFR<30要用CNI, 起始半劑量, 1W後check Cre, if stable or improving-->gradually titrate up and monitor Cre QW; if Cre increasing -->DC and change to MMF
        • 有一些trial發現MMF效果不輸CsA
    • Late relapse(>2M after DC steroid) after remission + no significant steroid toxicity
      • Repeat steroid course as above
    • (Late relapse(>2M after DC steroid) after remission + significant steroid toxicity) or multiple relapse
      • CNI(MMF if eGFR<30) +/- low dose Predonine for 12M
    • Steroid-dependent
      • CNI(MMF if eGFR<30)+/- low dose Predonine
        • if failed-->MMF+low dose Predonine
        • Consider Rituximab(可能和SMPDL-3b有關; 請搜尋SMPDL-3b), cytotoxic agents(Endoxan(2-2.5mg/kg/d for 8W), Chlorambucil)
          • 和MCD不同, Endoxan在此種情形不是第一線！！其evidence很少效果似乎也沒很好
    • Steroid-resistant
      • CNI(MMF if eGFR<30)+ gradually taper Predonine
        • 有一些trial發現MMF效果不輸CsA
      • No role of cytotoxic agents nor Rituximab(?)
      • Consider TPE if very high circulating permeability factors(基本上albuminuria也會很嚴重) + still severe disease(after adequate immunosuppressions)
        • TPE:level III(IIc)(Steroid resistant in native kidney)(僅一部分人有效)
          • 不過recurrent FSGS after renal transplantation是ASFA Category I, Grade 1B(與本檔§1的1B一致; native kidney的FSGS才是Category III)(不過一樣要接受其他immunosuppressions)
            • 大多study發現在recurrent FSGS after transplantation者接受TPE有70-80% remission, 不過1/3會recur after DC TPE; 但若不接受TPE, 有80%會early graft loss(<1yr)!
              • 所以應接受TPE as soon as possible if recurrent FSGS after transplantation
            • 此外也有study做prophylactic pre-transplantation or post-transplantation TPE for FSGS看起來也有好處(但尚無共識)
  • Others
    • Abatacept(?, CTLA 4 analogue(=CD80 inhibitor); 因為podocyte會表現CD80(B7-1)激活T cell; evidence少); LDL apheresis(reduction in oxidized LDL and associated inflammatory cytokines ==>reduction in proteinuria); (ACTH), pirfenidone(↓fibrosis而↓GFR decline rate; evidence少)
      • ACTH作用很複雜, 除了↑steroid之外, 也有其他機制anti-inflammation/immunomodulation, ↓lipid(!!), direct effect of podocytes(↓podocyte oxidative stress, ↓podocyte injury(podocyte上有melanocortin 1 receptor))(Brenner p1501)
  • Non-nephrotic range proteinuria with normal renal functional test
    • Obs(多indolent disease and 可能remission or stable)
  • Non-nephrotic range proteinuria with abnormal renal functional test
    • no Tx(?, 因為效果不好; 多因為secondary FSGS or previously severe primary FSGS未診斷(已經太晚了))
    • 但中國研究nonnephrotic range proteinuria 1-3.5g, 使用ACEI/ARB and steroid組比只用ACEI/ARB組可下降proteinuria and increase serum Alb level
  • 若Histology:extensive glomerulosclerosis and interstitial fibrosis(=chronic change)
    • no Tx
  • Primary(collapsing variant, non-HIV)[no prospective controlled trials, based on uptodate(clinical experience)]
    • Predonine 120mg QOD 8W, then ↓20mg Q2W到40mg QOD直到總共6M Tx; then off steroid
      • 其實和上面類似阿...上面差不多是60mg QD 8W then ↓10mg Q2W to 0.15mg/kg/d, then ↓2.5mg Q2-4W
      • If proteinuria >10g/day + Alb<2g/dL + preserved GFR
        • 同時也用CNI
    • No evidence of cytotoxic agents(Endoxan, chlorambucil)[poor efficacy of with significant side effects]
    • Consider renal transplantation
  • Secondary
    • Seldom response to immunosuppression(不過有些congenital form好像可以有response; 不過congenital form一般被當成primary吧?)
    • Seldom relapse after renal transplantation
  • Monitor
    • UPCR Q 0.5-1M in the first 2-3M, then Q1-2M

4.Response to Tx#

  • Lower likelihood of response to steroid if
    • Massive proteinuria > 10g/day
      • 多ESRD within 3yrs
    • Elevated Cre
    • Significant tubulointerstitial disease
  • Primary FSGS
    • Mean to remission:12~14M(很久, 要有耐心...)
      • vs. MCD >70%在4M內CR
    • CR, PR, no remission:20, 40, 40% (所以約60% response to immunosuppressions)(=不治療的MGN, 雖然姜醫師的經驗是MGN不治不太會remission)
      • CR者35%relapse, PR者50%relapse
    • PR者可能還是會變成ESRD
  • 註(remission definition和MCD是一樣的)
    • CR:proteinuria<0.2-0.3g/day(有些還要normal Cre and Alb>3.5g/dl)
    • PR:proteinuria↓>50% and proteinuria<3.5g/day(有些還要stable Cre)
    • Relapse:proteinuria returns to >3.5g/day after CR/PR
      • Late relapse:>2M after DC steroid
    • Steroid dependence:relapse on steroid(during tapering or on Tx) or need steroid to maintain remission(relapse <2M after DC steroid)(vs. MCD是<2W)
    • Steroid resistance:little or no reduction of proteinuria after 12-16W adequate dosage of steroid(不到PR, but 若still decreasing的狀況有點難說是不是歸在steroid resistance)

5.Prognosis of FSGS#

  • Proteinuria
    • Nephrotic syndrome
      • Spontaneous remission:<10%
        • More spontaneous remission in non-nephrotic range proteinuria and normal GFR
      • Average 5yrs renal survival:60-90%; 10yrs renal survival:30-55%(PR:75%, no remission:35%; 見下面response to Tx)
      • If Tx no response with proteinuria >10g/day, 幾乎5年內進展成ESRD
    • No nephrotic syndrome
      • If normal renal function at first
        • 10yrs renal survival:85%
  • Initial renal function
    • if Cre>1.3
      • 10yrs renal survival 27%
  • Histology
    • Worse:Interstitial fibrosis, collapsing variant, cellular variant
      • Collapsing variant renal survival
        • 1yr:75%, 3yrs:33%(vs. others:85% and 67%)
    • Better:tip lesions(more likely to respond to steroid therapy or to spontaneously remit)=>CR60%, PR15% to steroid, 有些series追蹤起來不治療也有一大部分會spontaneous remission(所以才覺得像MCD variant)
  • Response to Tx
    • PR/CR者:10 yrs renal survival:80%
    • Non-responder: 10 yrs renal survival:<50%

反向連結

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