This lecture was conducted during the Nephrology Unit
Grand Ground by Medical Student rotated under
Nephrology Division under the supervision and
administration of Prof. Jamal Al Wakeel, Head of Nephrology
Unit, Department of Medicine and Dr. Abdulkareem Al
Suwaida, Chairman of Department of Medicine. Nephrology
Division is not responsible for the content of the
presentation for it is intended for learning and /or education
purpose only.
The management of
IgA nephropathy
“ what was, what is and what will be “
Presented by:
Dr. Abdullah Al-Mutairi
Medical Student
August 2008
Introduction
Was first described by berger and hinglais in 1865
Soon became the most common primary GN
Caused by glomerular IgA deposition
Demography
Onset in the second and third decades
Male > female ( 2 : 1 )
More common in Whites and Asians
Rare in blacks
Incidence
20 – 40% in Japan and Australia
2 -10 % in USA and Canada
High prevalence = routine screening for urinary abnormalities and
low threshold for biopsy
Low prevalence = in USA no biopsy is done for asymptomatic
hematuria
Etiology
IgA deposition is found in association with many diseases
( 2ndy IgA nephropathy )
eg. Liver cirrhosis, celiac, HIV infection
However, the cause primary IgA nephropathy is
still unknown
Presentation
40 -50 % present with gross hematuria
(usually post URTI )
30 – 40 % present with microscopic hematuria and
Protienuria ( usually incidentally discovered )
Less than 10 % present with nephrotic syndrome or RPGN
Pathogenesis
35 % of IgA nephropathy patients transplanted with new kidneys
had recurrence
Patients transplanted with kidneys from IgA nephropathy donors,
showed disappearance of the deposits
Therefore, IgA nephropathy is a systemic disease rather than a
disease of the kidney alone
Pathogenesis
High IgA deposits does not it self cause the disease
Rather, it is related to multiple palying factors,
1- Abnormal IgA immune complexes, polymeric IgA that
are more likely to deposit in the mesangium
( galactosylation, sialation )
2- Abnormal systemic immune response to antigens
3- Impaired clearance ( hepatic , mesangial clearance )
Pathogenesis
Provocative factors;
- Infections ( staph.aurues, CMV, Toxoplasma )
- Food antigen ( as in celiac )
These trigger the abnormal immune response, in the genetically
predisposed patients
leading to the production of the pathogenic IgA
complexes in the bone marrow, which in turn deposit
in the mesangium
Pathogenesis
Deposited IgA leads to ;
IL-6 which switches on the inflammatory cascade
C3 (local complement activation) - inflammation
TGF – Beta – mesangial proliferation
PDGF – Beta – mesangeal proliferation
Histopathology
Light microscopy,
focal or diffuse mesangial proliferation
other findings, segmental sclerosis/necrosis and crescents
Electron microscopy,
electron dense deposits within the mesangium
Immunofluorescence,
predominant IgA deposition
( Co-deposition of IgG,IgM,C3,lambda, and kappa light chains )
The management - 1
Approach to
therapy
Approach to Rx
There is no cure
However, measures to slow the progression are available .
The treatment is based upon multiple factors that predicts
progression to more severe disease
Approach to Rx
Clinical predictors of progression
initial creatinine > 2.5 mg/dL ( 221 umol/L )
if 150umol/l ,ESRD >70% at 7yrs
hypertension
protein excretion 500 – 1000 mg/day ( 55%)
indicates active and progressive disease
thus, used for monitoring disease activity
Approach to Rx
Histologic predictors of progression
glomerulosclerosis
tubular atrophy
interstitial fibrosis
vascular disease
crescents
Approach to Rx
Genetic predictors
DD genotype of ACE gene
upregulation of megsin gene
The management - 2
Treatment
Treatment
General interventions
ACE inhibitors / ARB’s
Statins
?? Fish oil
Immunosuppressive therapy
Other interventions
Corticosteroids
Cyclophosphamide
Cyclosporin, cellecept
Tonsillectomy
Low antigen diet
IV immunoglobulins
ACE inhibitors
known to reduce proteinuria through its effect on The
size-selective properties of the glomerular capillary wall.
Clin Nephrol 200;54:360
As in other CKDs, it slows the progression of the reduction
in GFR.
Am J Kidney Dis 2006;47:751
ACE inhibitors
Praga et al ( 44 pt, creatinine >133 umol/l, prot > 1.9 g/day)
came to a conclusion in a randomized controlled trial
that enalapril had better effect on renal survival ( 92 % ) and
reduction in proteinuria in a six years follow-up when
compared to other anti-hypertensives
J Am Soc Nephrol 2003;14:1578
ACE inhibitors
In HKVIN trial 109 patients were studied over 2 years,
Protein 2g/day
Few patients in the Valsartan group reached the primary
end point ( doubling of creatinine or ESRD )
There was significant improvement in proteinuria ( 33% reduction )
and slower reduction in GFR ( 4.6 Vs 6.9 ml/min/yr )
as compared to placebo and other antihypertensives
Am J Kidney Dis 2006;47:751
ACE inhibitors
In the IgACE trial ( 65 patients over 38 months )
The primary end point ( > 30% decrease in renal function )
was reached by fewer patients in the Benazepril group
Also lower incidence of secondary composite end point
( > 30% decrease in CR clearance or worsening of protienuria
to reach nephrotic range )
Higher rate of partial or complete remission
J Am Soc Nephrol 2007;18:1880
ACE/ARB combination
The COOPERATE trial ( 263 patients, 60% IgAN )
combination versus monotherapy
Trandolapril (3mg/day) and losartan
Combination had better results in
reduction in creatinine concentration + progression to ESRD
(11% Vs 23% )
antiprotinuric effect (76% Vs 43% )
Lancet 2003;361:117
Fish oil
( omega-3 fatty acids )
Mechanism unknown, ?? Anti-inflammatory
Evidence on benefit is conflicting
Mayo clinic trial ( 106 patients , 12 g fish oil )
At 2 yrs - No difference in BP and protein excretion
At 4 yrs – lower creatinine increase ( 6 Vs 33 % )
lower death or ESRD ( 10 Vs 40 % )
> 6 yrs – persisting benefit ( 15 Vs 37 % )
N Eng J Med 1994;331:1194.
Fish oil ( omega-3 fatty acids )
A meta-analysis published in 1997 , concluded that fish has only
minor benefit
J Am Soc Nephrol 1997;8:1739.
However, a pediatric study by Hogg et al. failed to show this
benefit in more advanced disease
Clin J Am Soc Nephrol 2006;1:467
Statins
As CKD is CAD equivalent, then statins can be used to reduce risk
circulation 2003;108:2154
Statins decreases loss of GFR in in mild to moderate CKD
J Am Soc Nephrol 2006;17:2006
Target LDL is similar to that for IHD- < 100 mg/dl (2.5 mmol/l)
J Am Soc Nephrol 2003;14:2556
Immunosuppressive
therapy
Steroids only
Use of steroids from 6 -24 months decreases protein excretion
and improves renal survival
Clin Exp Nephrol 2004;8:237
Italian study ( 86 patients follow up for 5 and 10 yrs )
protein 3.5 g/day, creatinine 88.4
methylpred 1 g/day IV for the 3 days of minth 1,3 and 5
Combined with prednisolone 0.5 mg/kg/day on alternate
days for 6 months
Decreased primary end points ( doubling creatinine)
2 Vs 21% at 5 yrs
2 Vs 30 % at 10 yrs
Lancet 1999;353:883
Steroids only
However, the southwest pediatric group study,
( prednisolone Vs placebo ) showed
no difference at 3 yrs, in reduction of GFR < 60 % of baseline
Clin J Am Soc Nephrol 2006;1:467
So still unclear role, hence steroids are kept for diseases with
proven active inflammation
Clear benefit in acute nephrotic syndrome with histopath showing
minimal change disease
Am J Kid Dis 1989;14:361
Combined Rx
This is only attempted for severe active disease or RPGN
Studies showed possible benefit
but these – did not compare with steroids alone
were published prior to the widespread use of ACE
Limited data
Combined Rx
Ballardie et al.( single center, controlled prospective trial of 38 pt )
patients = initial creatinine 130 – 250 umol/l that
was increasing with rate of 15%/yr
protein excretion 4- 4.5 g/day
no crescents
( So severe or progressive disease )
Given = prednisolone 40mg/day tapered to 10mg/day by 2 yrs
cyclophosphamide 1.5 mg/kg/day x 3months then
azathioprine 1.5mg/kg/day x 2yrs
Combined Rx
Treatment group had
decreased protein excretion in the 1st 6 months,
( 4.4g to 1.8g/day ) which persisted during 1yr follow up
renal survival higher ( 82 Vs 68 % at 2 yrs )
( 72 Vs 6 % at 5 yrs )
J Am Soc Nephrol 2002;13:142
Thus, patients with severe or progressive disease , without chronic
renal damage on biopsy will benefit from combined
immunosuppression
Combined Rx
Crescentric disease, tumlin et al. studied 12 patients
mean creatinine 240 umol/l
protein excretion 4g/day
Given pulse methylpred 15mg/kg/day x 3days
prednisolone 1mg/kg/day x 2months, then 0.6mg/kg/day
x 2months, then 0.3 mg /kg/day x2months
cyclophosphamide 0.5mg/m2 x 6months
Combined Rx
At end of the 6 months
Creatinine improved ( 240 to 133 umol/l)
Protein excretion reduced ( 4 to 1.4 g/day)
renal Bx showed absence of crescents and proliferation
With 3 yrs follow up ( prednisolon 0.15mg/kg/day + ACE)
incidence of ESRD was lower ( 8 Vs 42 % in control )
Same results to other forms of crescentric GN
However, still needs study
Nephrol Dial Transplant 2003;18:1321
Other Immunosuppressive Rx
Cyclosporine –
small studies showed reduction in protein excretion
but nephro-toxicity, increases creatinine > untreated
relapse soon after stopping Rx
Clin Nephrol 1991;35 Suppl 1:S43
Mycophenolate Mofetil ( MMF ) 4 small prospective, randomised trials with conflicting results
still being studied
Other Interventions
Tonsillectomy
tonsillitis associated with hematuria and proteinuria in IgAN
so, thought to be the site of abnormal IgA fromation
some retrospective reports showed improved renal survival
Am J Kidney Dis 2001;38:736
Acta Otolaryngol Suppl 2004; 38
others showed no benefit
Acta Otolaryngol Suppl 2004;32
Other Interventions
Low antigen diet
a diet free from gluten, dairy products, eggs and
most meats
proposed that some food antigens triggers the abnormal
mucosal IgA system
when this was applied in 1 study a dramatic reduction in
protein excretion was noted
renal Bx showed reduction in IgA and complement
deposition and decreased cellularity
Nephrol Dial Transplant 1993;8:1193
But still unconfirmed
Other Interventions
IV IG –
It was observed that IgG is deficient in IgA nephropathy
thus, predispose to infections leading to flare up of the disease
Clin Exp Immunol 1989;75:30
Rostoker et al. studied 11 patients with high dose of IVIG
( 1g/kg 2 days/month x 3months, then im inj /2wks x6 months
- Reduction in proteinuria ( 5.1 to 2.3 g/day )
- Improve GFR ( from rate of 3.8 ml/month loss to stable GFR )
- Decreased inflammation and IgA deposition on Bx
Ann Intern Med 1994;120:476
Still need more studies
Suggestions
Suggestion
Isolated hematuria, normal GFR - follow every 6 months
treat if progress
Persistant proteinuria > 500-1000mg/day
treat with ACE inhibitors, goal protein excretion
reduction by 60% from baseline
if target not reached combine with ARBs
Can use fish oil with ACE inhibitors
Persistant nephrotic syndrome or CKD give statin
Suggestions
Acute onset nephrotic syndrome with minimal change dis and
IgA deposition start steroids
Progressive active dis ( hematuria, increasing proteinuria, and
increasing creatinine) despite ACE /ARB start steroids alone
- methylpred 1g x3days at month 1,3 and 5
with pred alternate days 0.5 mg/kg x 6 months
then taper to stop
- pred 2mg/kgevry other day x 2months then 0.5 mg/kg
every other day x 4 months then taper to stop
Suggestions
Initially severe( creatinine > 133 umol/l) or progressive eventhough
on steroids ( increasing creatinine or proteinuria ) with no
chronic damage on Bx , then add cyclophosphamide
pred 1mg/kg x3months then taper to 10mg/day x 2 yrs
with cycloph 1.5 mg/kg orally x 3months then
maintainance with
either immuran 1.5 mg/kg
or cellecept 1g BD tapering to 500mg BD x 2 yrs
Suggestion
Crescentric GN and RPGN use pulse steroids with cyclophos
Methylpred 500-1g x 3days then pred 1mg/kg x 3months then
taper to 10mg/day x 2 yrs
With cyclophos 0.5 mg/m2 IV monthly x 3 months then
maintainance with
either immuran 1.5mg/kg
or
cellecept 1g bd tapering to 500mg bd X 2yrs
Thanks