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1、IgA Nephropathy with crescents,Nephrology Grand RoundsMarch 16th,2010Aditya Mattoo,Outline,BackgroundEpidemiologyClinical PresentationPrognosisPathogenesisHistologyTreatment Recurrence in Transplant,Background,First described by Berger et al in 1968.Characterized by predominant IgA deposition in the
2、 glomerular mesangium.Most common form of primary glomerulonephritis around the world.,Berger et al.J Urol Nephrol,74:p694,1968.,Epidemiology,Demographics,Clinical onset in second and third decades of life.80%of patients are between the ages of 16-35 years at the time of diagnosis.Male predominance
3、of 2:1 in Japan to as high as 6:1 in northern Europe and US.Asians and Caucasians more prone to develop IgAN than people of African descent.,Demographics,There appears to be a familial clustering of IgAN which shows strong family predisposition in about 10%of cases.In the U.S.,regions in Kentucky,Al
4、abama and other parts of the Southeast exhibit a higher incidence of IgAN.In other parts of the world,familial clustering of IgAN seems to be more common in Southern France and Italy.Many genetic studies are underway,trying to establish common susceptibility genes in familial IgA.,IgAN Nationwide,Ep
5、idemiology,IgAN prevalence as a percentage of primary GN:In Japan,50%of new cases of GN are IgAN(causing 40%of all ESRD).30%of new GN cases in Western Europe and Australia.10%in general US population(exception Native Americans from New Mexico with prevalence of rate of 38%)Crescentic IgAN(CIgAN)is s
6、een in approximately 7%of patients with IgAN.However,a study conducted by Shouno et al reported that by increasing the number of serial sections examined for any single biopsy specimen from the standard 20 to 100 sections,the finding of a segmental necrotizing lesion increases to 30%.,Donadio et al.
7、NEJM,347:p738,2002.Shouno et al.Acta Pathol Jpn,43:p723,1993.,Clinical Presentation,Clinical Presentation,IgAN is highly variable,both clinically and pathologically.Clinical features range from asymptomatic hematuria to RPGN.Classic flare includes painless hematuria concurrent with the onset of vira
8、l illness(e.g.pharyngitis,gastroenteritis,etc.),Clinical Presentation,Approximately 40-50%of patients present with one or recurrent episodes of gross hematuria.Another 30-40%have microscopic hematuria and usually mild proteinuria incidentally detected on a routine examination.Gross hematuria will ev
9、entually occur in 20-25%of these patients.,Clinical Presentation,Of the patients with gross hematuria secondary to IgAN,up to 40%will develop transient renal failure.Less than 10%present with either nephrotic syndrome or RPGN(characterized by edema,hypertension,and renal dysfunction).,Clinical Prese
10、ntation:Crescentic vs Non-crescentic,Ferarrio et al.3rd Congress of Nephrology,2003.,Prognosis,Prognosis,Between 5-30%of patients with mild proteinuria,hematuria or mild renal dysfunction undergo spontaneous remission of abnormal laboratory findings.A Chinese study of 72 consecutive patients with Ig
11、AN performed diagnostic biopsies on patients with hematuria,but with no or minimal proteinuria(defined as less than 0.4 g/day).After a seven year follow up period,protein excretion 1g/d,HTN,and serum Cr 1.4 mg/d developed in 33%,26%,and 7%,respectively.,Hotta et al.AJKD,39:p493,2002.Szeto et al.Am J
12、 Med.110:434,2001.,Prognosis,Approximately 25-30%of patients will reach ESRD at 10 years.Clinical risk factors associated with progressive disease are:HTN 1g/d proteinuriaMale gender Persistent microscopic hematuriaHistologic risk factors include cellular crescents and endocapillary proliferation.,D
13、onadio et al.NEJM,347:p738,2002.,Prognosis Crescentic IgAN,Some correlation between crescents and clinical risk factors exists(in one case series all patients who had at least 10%cellular crescents had hypertension and 1g proteinuria).Furthermore,prospective studies have shown that 40%of patients wi
14、th as little at 10%cellular crescents will progress to ESRD within 3 years.,Tumlin et al.Seminars in Nephrol 24:p256,2006.,pathogenesis,Pathogenesis,IgA is an antibody that plays a critical role in mucosal immunity.IgA has two subclasses(IgA1 and IgA2)and can exist in a dimeric form called secretory
15、 IgA.It exists in two isotypes,IgA1(90%)and IgA2(10%):IgA1 is found in serum and made by bone marrow B cells.IgA2 is made by B cells located in the mucosa and is the major immunoglobulin found in mucosal secretions.IgA2 provides a key first line of defense against invasion by inhaled and ingested pa
16、thogens at the vulnerable mucosal surfaces.IgA1 provides a second line of defense in the serum,mediating elimination of pathogens that have breached the mucosal surface,Pathogenesis,Panel A Normal IgA1 Molecule Panel B-Structure of carbohydrates O-linked to serine(Ser)or threonine(Thr)residues on Ig
17、A1.The IgA1 heavy chain contains a hinge region(a 19-residue sequence between CH1 and CH2,which consisted entirely of serine,threonine and proline).Glycosylation is restricted to the hinge region of IgA1.N-acetyl galactosamine(GalNAc)is O-linked to Ser or Thr residues.GalNAc is linked to Gal through
18、 the action of the enzyme 1,3-galactosyl transferase.Sialic acid is linked to Gal through an 2,3 link and to GalNac through an 2,6 link.,Donadio et al.NEJM,347:p738,2002.,Pathogenesis Mesangial Deposition,Although the pathogenesis of IgAN is not completely clear,it is well accepted that aberrant gly
19、cosylation pattern of IgA is involved.This is supported by the fact that in IgAN,mesangial deposits of IgA contain high concentrations of abnormally under-galactosylated IgA1.Furthermore it has been demonstrated that enzymatic removal of complex oligosaccharides from the hinge region of IgA1 antibod
20、ies from normal individuals significantly enhanced IgA deposition in the mesangium.,Sano et al.NDT,17:p50,2002.,Pathogenesis Mesangial Deposition,Leukocyte 1,3-galactosyl transferase activity is decreased in patients with IgAN which may be responsible for deficient galactosylation of IgA1.Abnormally
21、 glycosylated IgA has a higher tendency to self-aggregate and form complexes with IgG antibodies directed at epitopes in the hinge region of IgA1.,Novak et al.KI 62:p465,2006.Allen et al.NDT.12:p701,1997.,Pathogenesis Decreased Clearance,Leukocyte Fc-receptor for IgA(CD89)is downregulated,furthermor
22、e the receptor binding site is in the CH2 domain close the hinge(possibly affected by deficient galactosylation).Altered IgA1 clearance from circulation,particularly via the hepatic asialoglycoprotein receptor(ASGPR)whose chief ligand is the terminal galactose of IgA1(the principle site of IgA catab
23、olism).,Pathogenesis-Summary,Floege et al.JASN,11:p2395,2000.,Pathogenesis Inflammatory Response,IgA elicits a phenotypic transformation in mesangial cells in vitro,with mesangial cell proliferation and secretion of extracellular matrix component.IgA appears to stimulate the production of a variety
24、of proinflammatory and profibrotic molecules,such as interleukin-6.Increased renal expression of TGF-beta which correlates with severity of tubulointersitial damage in IgAN.,Barratt et al.Seminars in Nephrol 24:p197,2004.Taniguchi et al.Scand J of Urol Nephrol.33:p243,1999.,Pathogenesis Inflammatory
25、 Response,Studies have suggested that mesangial IgA probably activates C3,leading to the generation of C5b-9(MAC),which then promotes the production of inflammatory mediators and matrix proteins by mesangial cells.Systemically,low-grade complement activation through the alternative pathway can be se
26、en in patients with IgAN as well.,Zwriner at al.KI,51:p1257,1997.,Diagnosis,Diagnosis,The suspicion of IgAN is generally based upon the clinical history and laboratory data.The diagnosis can be confirmed ONLY by kidney biopsy demonstrating IgA deposition.Given the generally benign course of patients
27、 with IgAN who have isolated hematuria,biopsies are usually performed only if there are signs suggestive of more severe or progressive disease(HTN,proteinuria,elevated Cr,etc.),Diagnosis,A skin biopsy,looking for IgA deposition in the dermal capillaries,has not proven to be sufficiently predictive i
28、n IgAN.Plasma polymeric IgA1 levels are elevated in 30-50%of cases,but this suggestive finding is not sufficiently specific to establish the diagnosis.Circulating IgA-rheumatoid factors and IgA-immune complexes have been tested as diagnostic markers but are not specific nor can they be reliably corr
29、elated with disease activity.,Susuki at al J Clin Invest.119:p1668,2009.,Diagnosis,Increased serum levels of Gal-deficient IgA1,present in IgAN,may suggest the diagnosis.However,this assay has not been validated by testing non-IgAN patients with GN who present similarly to IgAN.Gal-deficient IgA1-sp
30、ecific IgG may be prove to be a clinically useful diagnostic marker as serum levels of IgG specific for Gal-def IgA1 are elevated in patients with IgAN.,Susuki at al J Clin Invest.119:p1668,2009.,Diagnosis,(A)Gal-deficient IgA1 incubated with IgG from healthy controls,non-IgAN disease controls and I
31、gAN patients.The rIgG from an IgAN patient served as a positive control.Serum IgG from IgAN patients bound more to Gal-deficient IgA1 compared with the IgG from disease controls or healthy controls.(B)The intensity of signal in each well was measured by densitometry as compared to rIgGSerum IgG from
32、 IgAN patients has significantly higher reactivity to Gal-def IgA1 compared with that from healthy(P 0.0001)and disease controls(P 0.0001).Serum IgG from 54 of the 60 patients with IgAN showed values greater than the 90th percentile of the values for healthy controls.(C)ROC for serum IgG binding to
33、Gal-deficient IgA1.The area under the curve is 0.9644.These data indicate a sensitivity of 88.3%and a specificity of 95.0%(D)/(E)The intensity of IgG binding to Gal-deficient IgA1 correlated with urine Pr/Cr ratio as well as with urinary IgA-IgG immune complexes.,Susuki at al J Clin Invest.119:p1668
34、,2009,Histology,Histology,The major finding on light microscopy is mesangial proliferation and matrix expansion(arrows)that can be focal,but more often seen diffusely.,Histology,Light microscopy of a glomerulus from a patient with IgAN showing increased mesangial matrix and cellularity.,Histology,H&
35、E demonstrating mesangial hypercellularity and matrix expansion.H&E with mesangial cell hypercellularity and focal area of endocapillary proliferation(bold arrow).H&E demonstrating diffuse endocapillary proliferation and mesangial hypercellularity.H&E-silver demonstrating cellular crescent with part
36、ial collapse of glomerular tuft.H&E demonstrating diffuse endocapillary proliferation and fibrinoid necrosis.Silver stain demonstrating crescent and focal glomerular tuft adhesion to Bowmans capsule.,Tumlin et al.CJASN.2:p1054,2004.,Histology,Segmental crescents are relatively common,although they m
37、ay be missed by sampling error if only a few glomeruli are obtained.(as mentioned earlier as many of 30%of IgAN on biopsy may have crescents).Although there is usually little or no glomerulosclerosis on initial biopsy,patients may eventually develop glomerulosclerosis,by which time they have clinica
38、lly advanced disease(i.e.decreased GFR and increased proteinuria).,Histology-Immunoflourescence,IF demonstrates prominent,globular deposits of IgA(often accompanied by C3 and IgG)in the mesangium and,to a lesser degree,along the glomerular capillary wall.,Histology-IF,IF demonstrating large,globular
39、 mesangial IgA deposits.Note that the capillary walls are not outlined,since the deposits are primarily limited to the mesangium.,Histology Electron Microscopy,EM typically reveals electron-dense deposits that are primarily limited to the mesangium,but may also occur in the subendothelial and subepi
40、thelial spaces.The number and size of these deposits generally correlates well with the severity of changes seen on light microscopy.,Histology-EM,Low power electron micrograph in IgAN.The primary finding is electron dense deposits that are limited to the mesangial regions(D).The glomerular basement
41、 membrane(GBM)is normal and there are no glomerular capillary wall deposits.,Histology-EM,Higher power EM with significant expansion of mesangial matrix and presence of large mesangial dense deposits(arrow).,Histology Oxford Classification,A consensus on the pathologic classification of IgA nephropa
42、thy has been developed by the International IgAN Network with the Renal Pathology Society:Mesangial hypercellularity:0=8 mesangial cells are present per mesangial area.Scores for all glomeruli are averaged and the resulting assigned hypercellularity score is either M0 if the mean score is less than
43、0.5 or M1 if the mean score is greater than 0.5.Segmental glomerulosclerosis:S1=any part of the glomerular tuft is involved in sclerosisS0 if no segmental glomerulosclerosis is present.Endocapillary hypercellularity:E1=if hypercellularity is present within the capillary lumina resulting in narrowing
44、.E0 if no hypercellularity is present within lumina.Tubular atrophy/interstitial fibrosis The percentage of the cortical area involved by tubular atrophy or interstitial fibrosis.A score of T0,T1 or T2 is given if the percentage of involved cortical area is 0-25;26-50 or 50 percent,respectively.,His
45、tology Haas Classification,Based on the histological features of 244 cases of IgAN over a 14 year period at one institution:Class I(39 cases):minimal or no mesangial hypercellularity,without glomerulosclerosisClass II(18 cases):FSGS without active cellular proliferationClass Ill(110 cases):focal pro
46、liferative GNClass IV(42 cases):diffuse proliferative GNClass V(35 cases):any biopsy showing 40%globally sclerotic glomeruli and/or 40%estimated cortical tubular atrophy or loss.,Haas et al.AJKD,29:p829,1997.,Histology Haas Classification,Haas et al.AJKD,29:p829,1997.,Histology Haas Classification,H
47、aas showed a statistically significant correlation between histologic subclass and renal survival,with an order I,II(greatest survival)Ill IV,V.,Histology Haas Classification with Crescents,Haas also reported the probability of renal survival when crescents were present in Haas subclass III and IV.,
48、treatment,Treatment,Patients with isolated hematuria,no or minimal proteinuria,and a normal GFR are typically not treated(and often not biopsied),unless they have evidence of progressive disease such as increasing proteinuria,blood pressure,and/or serum creatinine.,Treatment ACE/ARB,Patients with pe
49、rsistent proteinuria(500-1000 mg/day),mildly reduced GFR that is not declining rapidly,and only mild to moderate histologic findings on renal biopsy are traditionally managed with ACE/ARB.In one trial,44 patients with proteinuria(0.5 g/day,mean 1.9 g/day)and a Cr 1.5 mg/dL at baseline were randomly
50、assigned to either enalapril or antihypertensive agents other than ACE inhibitors or ARBs.At follow-up of about six years,renal survival,defined as 50%increase in the Cr,was significantly more likely in the enalapril group(92%versus 55%).A significant decrease in proteinuria was only observed in the
