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1、Nephrology Grand Rounds March 16th, 2010 Aditya MattooOutlineBackgroundEpidemiologyClinical PresentationPrognosisPathogenesisHistologyTreatment Recurrence in TransplantBackgroundFirst described by Berger et al in 1968.Characterized by predominant IgA deposition in the glomerular mesangium.Most commo
2、n form of primary glomerulonephritis around the world.Berger et al. J Urol Nephrol, 74:p694, 1968.DemographicsClinical 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 of 2:1 in Japan to as high as 6:1 in northe
3、rn Europe and US.Asians and Caucasians more prone to develop IgAN than people of African descent.DemographicsThere 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, Alabama and other parts of the Southeast exh
4、ibit 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 NationwideEpidemiologyIgAN prevalence as a percentag
5、e 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 seen in approximately 7% of pa
6、tients 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. NEJM, 347:p738, 2002. Sho
7、uno et al. Acta Pathol Jpn, 43:p723, 1993.Clinical PresentationIgAN 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 viral illness (e.g. pharyngitis, gastroenteri
8、tis, etc.)Clinical PresentationApproximately 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 eventually occur in 20- 25% of these p
9、atients.Clinical PresentationOf 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 Presentation: Crescentic vs Non-cre
10、scenticCrescentic IgANNoncrescentic IgANP valueNumber of patients35229 Sex male/female26/9147/82NSMean age years33 12.532 13NSSerum creatinine mg/dL1.3 0.51.2 0.4NSProteinuria g/day2.3 2.11.1 1.21g/d, HTN, and serum Cr 1.4 mg/d developed in 33%, 26%, and 7%, respectively. Hotta et al. AJKD, 39:p493,
11、 2002. Szeto et al. Am J Med. 110:434, 2001.PrognosisApproximately 25-30% of patients will reach ESRD at 10 years. Clinical risk factors associated with progressive disease are: HTN 1g/d proteinuria Male gender Persistent microscopic hematuriaHistologic risk factors include cellular crescents and en
12、docapillary proliferation.Donadio et al. NEJM, 347:p738, 2002.Prognosis Crescentic IgANSome 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 ha
13、ve shown that 40% of patients with as little at 10% cellular crescents will progress to ESRD within 3 years.Tumlin et al. Seminars in Nephrol 24:p256, 2006. PathogenesisIgA is an antibody that plays a critical role in mucosal immunity. IgA has two subclasses (IgA1 and IgA2) and can exist in a dimeri
14、c form called secretory 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 inva
15、sion by inhaled and ingested pathogens at the vulnerable mucosal surfaces. IgA1 provides a second line of defense in the serum, mediating elimination of pathogens that have breached the mucosal surfacePathogenesisPanel A Normal IgA1 Molecule Panel B - Structure of carbohydrates O -linked to serine (
16、Ser) or threonine (Thr) residues on IgA1.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 the a
