1. IgA Nephropathy
신장내과 R4 박미나/ Prof. 임천규

2. <Cause of acute
renal failure>

3. 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

4. Epidemiology Most common cause of glomerulonephritis
% 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

5. 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

6. 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

7. 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

8. LM

9. EM IF

10. 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%

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

12. 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

13. 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 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

14. 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

15. 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

16. 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

18. 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

19. <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

20. <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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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%)

27. 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

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