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IgA nephropathy IgA nephropathy Presentation Transcript

  • Dr. Anass Ahmed Qasem
  •  History Pathogenesis Clinical Presentation Diagnosis Treatment Prognosis
  • Immunoglobulin A (IgA) nephropathy was first described by the pathologist Jean Berger and thus is sometimes called Berger’s disease.  Jean Berger published his description of glomerulo- nephritis with mesangial IgA deposition in winter 1968.
  •  History Pathogenesis Clinical Presentation Diagnosis Treatment Prognosis
  • Definition Immunoglobulin A nephropathy is defined by the presence of IgA-dominant or co-dominant mesangial immunoglobulin deposits. Lupus glomerulonephritis, which may have IgA dominant or co-dominant deposits, is excluded from this diagnostic category.Immunoglobulin A nephropathy occurs as :1- primary (idiopathic) disease, as a component of Henoch- Schِ lein n purpura small-vessel vasculitis,2- secondary to liver disease (especially alcoholic cirrhosis), and associated with a variety of inflammatory diseases including ankylosing spondylitis, psoriasis, Reiter’s disease, uveitis, enteritis (e.g., Yersinia enterocolitica infection), inflammatory bowel disease, celiac disease, dermatitis herpetiformis, and HIV infection
  • The etiology of IgA nephropathy is unknown, but infectionsand/or genetic characteristics may predispose to the developmentof kidney disease. It has also been suggested that IgA nephropathy results fromhypersensitivity to food antigens, in view of its association withceliac disease. There is, however, no evidence for widespreadhypersensitivity to food antigens in IgA nephropathy . IgA nephropathy results from dysregulation of mucosal-typeIgA immune responses. As a result, any mucosal infection or foodantigen may drive the production and release of pathogenic IgAinto the circulation where it has the propensity to deposit withinthe mesangium and trigger glomerular injury.
  • Immunoglobulin A nephropathy probably can result from multiple different etiologies and pathogenic processes, such as :(1) Abnormal structure and function of IgA molecules. (2) Reduced clearance of circulating IgA complexes.(3) Increased affinity for or reduced clearance of IgA deposits from the glomerular mesangium.(4) Excessive IgA antibody production in response to mucosal antigen exposure.(5) Increased permeability of mucosa to antigen.(6) Combinations of these factors.
  • Some secondary forms of IgA nephropathy appear to be caused by either decreased clearance of IgA from the circulation (e.g., reduced hepatic clearance caused by cirrhosis) or increased entry of IgA complexes into the circulation (e.g., caused by increased synthesis and greater access to the circulation in inflammatory bowel disease). Impaired IgA clearance  Impaired systemic clearance of IgA promotes IgA deposition in the mesangium. Persistent mesangial IgA accumulation occurs by one or both of two mechanisms: the rate of IgA deposition exceeds the mesangial clearance capacity; or the deposited IgA is resistant to mesangial clearance.
  • Systemic clearance Alterations in systemic IgA and IgA-immunecomplex clearance mechanisms will facilitate theirpersistence in the serum. The liver play an important role inIgA clearance from the circulation and radiolabeled IgAclearance studies suggest reduced hepatic clearance in IgAnephropathy. A second route of IgA clearance is throughCD89, which is the Fc receptor for IgA. IgA nephropathy isassociated with downregulated CD89 expression onmyeloid cells and decreased IgA binding to CD89.Mesangial clearance Mesangial IgA deposition is not always associated withthe development of glomerular inflammation. Furthermore,mesangial IgA deposition may be reversible.
  • However, an important pathogenic mechanism inmany patients with IgA nephropathy appears toderive from abnormally reduced galactosylation of theO-linked glycans in the hinge region of IgA1molecules.
  •  History Pathogenesis Clinical Presentation Diagnosis Treatment Prognosis
  • Epidemiology : Occur at any age but more common in children and young adult. Male > female ( 2 folds ) Genetic predisposition : IGAN1, on 6q22-q23. Susceptibility to IgA nephropathy has been associated with single-nucleotide polymorphisms (SNPs) in the E- selectin and L-selectin genes, as well as in the Polymeric Immunoglobulin Receptor (PIGR )gene. Polymorphism in the ACE and AGT genes has been associated with progression to chronic renal failure in patients with IgA nephropathy
  • A- Gross Hematuria : (40-50% ) Occur cocurrent with upper respiratory tract infection Occur 1-2 days after onset of infectious symptoms so called synpharyngitic heamaturia Loin pain , malaise , and fever are found Hypertension and peripheral oedema are rare Rare to occur after age of 40 yrs.
  • B- Asymptomatic haematuria (30-40%): Accidentally discovered on routine examinaion Protenuria is variable but less than 1gm/dayC- Nephrotic syndrome (10%): Presented with advanced glomerular disease and hypertension Maybe presented with normal kidney function and normal blood pressure where protenuria is selective (albumin)
  • D- Rapidly progressive gromerulonephritis: Occur in case of cresent IgA nephropahy Maybe due to heavy glomerular hematuria which leads o tubular occlusion ( reversible phenomenon) In elderly patients , chronic IgA nephropathyE- Chronic renal failure with hypertension
  • F- In case of HSP :Seasonal variation more on spring and autumnJoint : Joint swelling which is non migratory and non damagingIntestinal Tract : Sever abdominal pain , vomiting and melenaSkin : Purpuric eruption on lower trunk and legs
  •  History Pathogenesis Clinical Presentation Diagnosis Treatment Prognosis
  • The diagnosis of IgA nephropathy is oftensuspected on the basis of the clinical history,but can be confirmed only by kidney biopsy. A kidney biopsy is usually performed for theevaluation of suspected IgA nephropathy onlyif there are signs suggestive of more severe orprogressive disease such as protein excretionabove 0.5 to 1 g/day, elevated serum creatinineconcentration, or hypertension.
  • Light Microscopy: Immunoglobulin A nephropathy and Henoch-Schِ lein purpura nephritis ncan have any of the histologic phenotypes of immune complex–mediatedglomerulonephritis other than pure membranous glomerulopathy, including”1- No lesion by light microscopy with immune deposits by immunohistology,2- Mesangioproliferative glomerulonephritis with mesangial but noendocapillary hypercellularity.3- Focal or diffuse proliferative glomerulonephritis with endocapillary hypercellularity (with or without crescents).4- Overt crescentic glomerulonephritis with 50% or more crescents.5- Type I membranoproliferative (mesangiocapillary) glomerulonephritis .6- Focal or diffuse sclerosing glomerulonephritis
  • Light Microscopy: A variety of classification systems have been used tocategorize the light microscopic phenotypes of IgAnephropathy, such as those proposed by Kurt Lee etal(1982) and by Mark Haas (1997). Another approach isto use the same descriptive terminology that is in theWorld Health Organization (WHO) lupus classificationsystem to categorize IgA nephropathy as well as otherforms of immune complex glomerulonephritis.
  • Immunofluorescence Microscopy The sine qua non for a diagnosis of IgA nephropathy is immunohistologic detection of dominant or co-dominant staining for IgA in the glomerular mesangium. A caveat to this is that the staining for IgA should at least be 1+ on a scale of 0 to 4+ or 0 to 3+. Trace amounts of IgA are not definitive evidence for IgA nephropathy. The IgA is predominantly IgA1 rather than IgA2.
  • Rare patients have IgA nephropathy concurrent with membranous glomerulopathy, and thus their specimens show granular capillary wall IgG staining and mesangial IgA dominant staining .  Staining for IgA essentially always is accompanied by staining for other immunoglobulins and complement components (properdin , factor H and membrane attack complex). Staining for IgG and IgM often is present, but at low intensity compared to IgA.
  • A very distinctive feature of IgA nephropathycompared to other immune complex diseases is thepredominance of staining for lambda over kappa lightchains in many specimens C3 staining is almost always present and usuallyrelatively bright. However, staining for C1q isuncommon and when present is typically of lowintensity. The presence of substantial C1q should raisethe possibility of lupus nephritis with conspicuous IgAdeposition. This suspicion would be supported furtherby finding endothelial tubuloreticular inclusions byelectron microscopy and antinuclear antibodiesserologically
  • Immunofluorescence Microscopy:In case of HSP : Skin biopsy of the purpuric skin shows a leukocytoclastic vascultitis with IgA and C3 in the wall of dermal capillaries. Occasional found in clinically unaffected skin of patients with IgA nephropathy.
  • Electron Microscopy The typical ultrastructural finding is immune complex– type electron-dense deposits in the mesangium. Dense deposits most often are found immediately beneath the paramesangial glomerular basement membrane. The amount of deposits varies substantially, with occasional specimens having massive replacement of the matrix by the dense material. Capillary wall subepithelial, subendothelial, and intramembranous deposits are identified in approximately a quarter to a third of specimens with IgA nephropathy, and are more frequent in patients with Henoch-Schِ lein n purpura nephritis. Capillary wall deposits are least frequent in histologically mild disease and most frequent in histologically severe disease, especially when crescents are present.
  •  History Pathogenesis Clinical Presentation Diagnosis Treatment Prognosis
  • The optimal approach to the treatment of IgA nephropathy is uncertain. The slow rate of loss of GFR (1 to 3 mL/min per year) seen in many patients hinders the ability to perform adequate studies. There are two separate approaches to the therapy of IgA nephropathy: General interventions to slow progression that are not specific to IgA nephropathy, include blood pressure control, angiotensin converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs) in patients with proteinuria. Therapy with glucocorticoids with or without other immunosuppressive agents to treat the underlying inflammatory disease
  • Patient selection : Patients with isolated hematuria, no or minimal proteinuria, and a normal GFR are typically not treated (and often not biopsied and identified), unless they have evidence of progressive disease such as increasing proteinuria, blood pressure, and/or serum creatinine. Patients with persistent proteinuria (above 500 to 1000 mg/day), normal or only slightly reduced GFR that is not declining rapidly, and only mild to moderate histologic findings on renal biopsy are managed with general interventions to slow progression and perhaps with fish oil.
  • Patient selection : Patients with more severe or rapidly progressive disease (eg, nephrotic range proteinuria or proteinuria persisting despite ACE inhibitor/ARB therapy, rising serum creatinine, and/or renal biopsy with more severe histologic findings, but no significant chronic changes) may benefit from immunosuppressive therapy in addition to nonimmunosuppressive interventions to slow disease progression
  •  patients with isolated hematuria, no or minimal proteinuria, and a normal GFR (Grade 2C). Such patients should be periodically monitored at 6 to 12 month intervals to assess for disease progression that might warrant therapy. patients with persistent proteinuria (>500 or >1000 mg/day), we recommend angiotensin inhibition with an ACE inhibitor or ARB (Grade 1A). We initiate monotherapy and target a minimum reduction in protein excretion of at least 50 to 60 percent from baseline values and a goal protein excretion of less than 500 or less than 1000 mg/day.
  •  patients with acute onset of nephrotic syndrome and minimal change disease as well as mesangial IgA deposits on renal biopsy, we recommend glucocorticoid therapy as in other patients with minimal change disease (Grade 1A). patients with persistent nephrotic syndrome and/or chronic kidney disease who have dyslipidemia be treated with a statin, primarily for cardiovascular protection (Grade 2B).
  •  Patients with progressive active disease (eg, hematuria with increasing proteinuria and/or increasing serum creatinine concentration) despite the use of ACE inhibitors or ARBs, we suggest initiating therapy with Glucocorticoids alone (Grade 2B). Two regimens we use are: Intravenous methylprednisolone (500 to 1000 mg per dose or, in children, 7 to 15 mg/kg in children per dose to a maximum of 1000 mg) for three consecutive days at the beginning of months one, three and five, and alternate day oral prednisone (0.5 mg/kg, approximately 30 to 40 mg) for six months, then tapered to discontinuation. An alternative regimen that avoids pulse therapy can also be used, such as 2 mg/kg of prednisone (maximum 100 to 120 mg) every other day for two months, with a rapid taper to a dose of 0.5 mg/kg (approximately 30 to 40 mg) every other day for an additional four months. Prednisone is then tapered to discontinuation
  •  For patients with severe disease at baseline (defined as initial serum creatinine >1.5 mg/dL or progressive disease with glucocorticoids alone (eg, increasing serum creatinine and/or protein excretion) who do not have significant chronic damage on kidney biopsy, we suggest therapy with oral prednisone and cyclophosphamide (Grade 2B). One regimen we use is: Prednisone (1 mg/kg to a maximum 60 to 80 mg/day) for two to three months followed by a slow taper to a maintenance dose of 10 mg/day for one to two years. Cyclophosphamide (1.5 mg/kg per day) orally for three months, followed, if the serum creatinine has stabilized and protein excretion has fallen, by either azathioprine (1.5 mg/kg per day) or mycophenolate mofetil (starting with 1000 mg twice a day and tapering over time to 500 mg twice a day) for a period of one to two years as maintenance therapy.
  •  patients with crescentic glomerulonephritis and a rapidly progressive clinical course, we suggest therapy with intravenous pulse glucocorticoids and cyclophosphamide (Grade 2B). One regimen we use is: Intravenous methylprednisolone for three consecutive days (500 to 1000 mg per dose or, in children, 7 to 15 mg/kg in children per dose to a maximum of 1000 mg) followed by oral prednisone (1 mg/kg per day, maximum dose 60 to 80 mg) for two to three months, then a slow taper to a maintenance dose of 10 mg/day for one to two years. Intravenous cyclophosphamide (0.5 g/m2) monthly for at least three months followed, if the serum creatinine has stabilized and protein excretion has fallen, by either azathioprine (1.5 mg/kg per day) or mycophenolate mofetil (starting with 1000 mg twice a day and tapering over time to 500 mg twice a day) for a period of one to two years as maintenance therapy, provided the creatinine stabilized and proteinuria was reduced.
  • If the serum creatinine or degree of proteinuria have not improved after the initial course of cyclophosphamide, we suggest a repeat biopsy to estimate the activity of the disease (eg, potential for reversal) and the amount of tubulointerstitial damage (the irreversible component) before deciding to continue immunosuppressive therapy.Other lines of treatment :1. Tonsillectomy 2. Low antigen diet 3. Intravenous immune globulin 4. Vitamin D
  •  History Pathogenesis Clinical Presentation Diagnosis Treatment Prognosis
  • Factors affecting the prognosis:A- Clinical : Hypertension Absence of history of macroscopic hematuria Persistent microscopic hematuria Older age at onset of the diseaseB- Laboratory: Renal dysfunction at diagnosis in absence of acute tubular damage Proteinuria , non selective more than 0.5gm/day
  • C- Renal Histology Glomerular sclerosis Segmental glomerular necrotizing lesion or extensive cresent (>20% of glomeruli) Arteriolosclerosis Tubulointerstitial fibrosis IgG deposits in the mesangium IgA deposits in he peripheral capillary wall
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