IgA Nephropathy 신장내과 R4 박미나/ Prof. 임천규

<Cause of acute renal failure>

IgA nephropathy (Berger disease) In 1968 - first described by Berger and Hinglais - IgA deposition in the glomerular mesangium Now - m/c cause of glomerulonephritis in the world Highly variable, both clinically and pathologically - asymptomatic hematuria ~ RPGN Pathogenesis – incompletely understood

Epidemiology Most common cause of glomerulonephritis - 10-40% of all Bx performed for glomerular disease - greatest frequency in Asians and Caucasians 40% of all glomerular disease in Asia <-> 20% in Europe and 10% in North America => reflect regional differences in kidney Bx practice

Pathogenesis Abnormality in IgA regulation - plasma IgA :↑in 30-50% of cases - circulating IgA-containing immune complexes : parallel the course of disease - IgA-specific B and T lymphocytes ↑ following an URI Mesangial deposition of IgA antigen complexes - AbNL glycosylation of IgA1, fibronection Glomerular damage - Ag-Ab complexes bind C1 => activate classic complement pathway => C3 accumulation

Pathology Light microscopy (LM) - focal or more often, diffuse mesangial proliferation and extracellular matrix expansion - segmental necrotizing lesions with crescent formation - focal glomerular sclerosis - interstitial fibrosis, tubular atrophy, and vascular sclerosis : in advanced disease

Electron microscopy (EM) - mesangial hypercellularity and increased mesangial matrix - electron-dense deposits in the mesangium - deposits in the subendothelial and subepithelial region Immunofluorescence (IF) - IgA is deposited in a diffuse granular pattern in mesangium and occasionally in the capillary wall - IgG, C3

LM

EM IF

Pathologic classification IgA nephropathy Class I : minimal change Class II : increased mesangial cellularity Class III : focal segmental proliferation in > 50% of glomeruli Class IV : diffuse mesangial proliferation/sclerosis Class V : diffuse glomerulosclerosis in > 80%

Fig. 1 Distribution of cases of primary IgA nephropathy in adults (n = 217) and children (n = 109) according to histologic subclass

Fig. 2. Frequency of positive glomerular immunostaining for immunoglobulins, complement components, and light chains in primary IgA nephropathy. Data represent findings in 1,989 cases pooled from 13 different studies

Presenting features Gross hematuria (40-50 %) - one or recurrent episodes of gross hematuria - usually following an pharyngeal or G-I infection, vaccination, strenuous exercise - first 48-72 hours after the infection begins - about 1/3 of pts : loin pain, due to renal capsular swelling Microscopic hematuria (30-40 %) - microscopic hematuria, usually mild proteinuria - asymptomatic. detected on a routine examination

ARF (<10%) : acute renal failure with edema, HTN, oliguria - gross hematuria => tubular occlusion by RBCs - acute severe immune injury => crescentic glomerulonephritis - diffuse mesangial proliferation, glomerular hypercellularity (mesangial or endocapillary), crescent formation, necrosis in >50% of glomeruli, tubular atrophy, interstitial fibrosis, interstitial inflammation

Acute reversible renal failure with macroscopic hematuria in IgA nephropathy - Nephrol Dial Transplant.1993. - pts with IgA nephropathy shortly after bleeding Group 1(6pts) : ARF, Group 2(5pts) : no ARF - tubular RBC casts, glomerular crescents => Group1↑ - outcome : exellent ARF in IgA nephropathy - Clin Nephrol.1994. - 25(3%) of 865 pts with IgA nephropathy =>ARF - pts with ARF: higher incidence of macroscopic hematuria and RBC in tubules - pts with irreversible renal failure : >40% sclerosed glomeruli

NS (<10%) - uncommon at presentation - appear during course of the disease in 10-30% of pts - persist or spontaneously remit - diffuse proliferative glomerular or minimal-change lesions HTN - seldom occurs at initial presentation - manifests as the course of the disease lengthens or when pts develop CRF and ESRD CRF - 1-2% of all pts with IgA nephropathy develop ESRD per year

Disease progression Isolated hematuria with little or no proteinuria - low risk of progression Natural history may not be benign over the long term In many patients who progress - rate of loss of GFR : as low as 1 to 3 mL/min per yr - patients excreting more than 3.5 g of protein per day : progression rate was fastest about 9 mL/min per yr

<Clinical predictors> Predictors of progression <Clinical predictors> Strong predictor - severe proteinuria at presentation and during F/U - arterial HTN at presentation and during F/U - elevated serum creatinine at presentation Weak predictor - absence of any Hx of recurrent macroscopic hematuria - male sex - older age at presentation

<Histologic predictors> Strong predictor - widespread global and segmental glomerulosclerosis - marked tubulointerstitial lesions Weak predictor - marked extracapillary proliferation - marked arterial hyalinosis - extension of IgA deposits into the walls of peripheral capillary loops by IF

Genetic associations – DD genotype of the ACE gene => much more progression Angiotensin II receptor genes - no relation with IgA nephropathy Polymorphism in the uteroglobin gene -> disease progression Familial disease <-> sporadic cases

Treatment Strict BP control - target BP : <135/85 if proteinuria <1g/24hr <125/75 if proteinuria>1g/24hr - ACE inhibitor (or ARB) : preferred choice Rare nephrotic syndrome with minimal change on LM - high dose steroid Steroid ±cytotoxic Tx - persistent proteinuria>1g/24hr despite of RAS inhibition Fish oil : controversial

ACE inhibitors – reducing the intraglomerular pressure => reduction in protein excretion => minimize glomerular injury and disease progression Treatment of IgA nephropathy with ACEI -Praga M. 2003 - only prospective controlled trial - 44 pts with proteinuria >0.5 g/d, Cr<1.5 mg/dL => enalapril or other antihypertensive agent , F/U 6 years => renal survival, decrease in proteinuria : more in the enalapril group

ACE inhibitor plus ARB – produce an further antiproteinuric effect that might slow the loss of glomerular filtration In the major trial (COOPERATE) < Efficacy of combination therapy compared to an ACE inhibitor or ARB alone at maximal dose? > => combination Tx was associated with a significant reduction in doubling of the plasma Cr concentration or progression to ESRD and a greater antiproteinuric effect

Corticosteroids – early Tx with PDL in proliferative IgA nephropathy : proteinuria ↓, improving histologic findings - beneficial against deterioration in renal function in pts with moderate proteinuria When is PDL more clearly beneficial ? - usually with NS, little or no hematuria, minimal glomerular changes on LM, diffuse fusion of the foot processes on EM

Immunosuppressive agent - possible benefit in pts with moderate to severe disease <A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy> -J Am Soc Nephrol.1999 - PDL+ azathioprine for 2yrs - reduction in proteinuria (1.4 to 0.2g/d <->1.0 to 0.9g/d) - reduction in the degree of hematuria - change in glomeruli showing sclerosis (5.2 to 5.0% <->3.9 to 16.4%)

Fish oil (omega-3 fatty acids) - controversial and conflicting results - deficiencies of essential fatty acids in IgA nephropathy => fish oil (rich in long-chain omega-3-fatty acids,12g/d ) => reduce cytokine, eicosanoid => can be tried in progressive IgA nephropathy pts with persistent proteinuria>1g/d

< IgA nephropathy > => highly variable => clinically : asymptomatic~NS,RPGN,ARF,CRF => pathologically : mild mesangial proligferation ~ crescentic GN, glomerulosclerosis