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Management of IgA nephropathy: Evidence-based recommendations. The condition known as IgA nephropathy was first
identified when Berger observed mesangial staining for IgA in
healthy patients with isolated hematuria. These patients often
presented with recurrent synpharyngitic hematuria or less frequently with asymptomatic microscopic hematuria and proteinuria. Although initially considered benign, we now recognize
it as a common cause of end-stage renal failure. The overall
prognosis may be better than suggested in the literature, as
patients with mild asymptomatic hematuria are often not biopsied and, therefore, frequently are not included in published
articles. We reviewed prospective and retrospective adult studies
published after 1976 and analyzed them to produce evidencebased recommendations. Patients with proteinuria over 3 g/day,
mild glomerular changes only, and preserved renal function
(creatinine clearance over 70 ml/min) should be treated with
prednisone. Steroids reduce proteinuria (grade B recommendation) and stabilize kidney function (grade C). The combination of cyclophosphamide, dipyridamole and warfarin should
not be used (grade A), nor should cyclosporine A (grade B).
In patients with progressive disease (creatinine clearance of
less than 70 ml/min), fish oil should be given (grade B). A
tonsillectomy could reduce proteinuria and hematuria in those
patients with recurrent tonsillitis (grade D). Those with hypertension should be treated promptly with an angiotensin-converting enzyme inhibitor (grade B).
glomerular diseases, whereas in Europe, it has been reported in 10 to 30% of glomerular disease series [8]. In
the United States, the overall prevalence is approximately 10 to 15% [9], although in specific groups such
as the American Indians in the Southwest, the rate is
35% [10]. IgAN is uncommon in blacks, whether they
live in the United States or in Africa [11, 12].
Recurrence of IgAN after transplantation [13], evidence showing that IgA glomerular deposits disappear in
a kidney from an IgA donor [14], and IgA deposits observed in other organs such as skin, lungs [15], or intestines suggest that the basic abnormality in this disease
lies within the IgA immune system. IgAN patients have
been shown to have many humoral and cellular abnormalities that possibly contribute to IgA deposition in the
glomerulus [16, 17]. Fifty percent have an increase in
serum IgA at some time in the course of the disease,
which is mainly polymeric, with a shift in subclass toward
IgA1 as found in their kidney eluates [18]. High levels
of circulating immune complexes are detected, and their
presence correlates with the intensity of hematuria [19].
This article analyzed the studies published according
to their level of evidence, and based the grade of recommendations on the evidence (Fig. 1).
Natural history
The natural history of IgAN is quite variable. In up
to 23% of reported series, complete remissions occur,
even though spontaneous disappearance of immunofluorescent IgA-staining mesangial deposits has not been
described.
In terms of renal function, IgAN patients most often
follow a benign course. In those patients who do show
progressive renal impairment, this usually takes many
years. In 1991, Rekola, Bergstrand, and Bucht reported
a rate of loss of glomerular filtration rate (GFR) averaging 1 to 3 ml/min/year among patients with normal GFR
at presentation and up to 9 ml/min/year among nephrotic
patients [20]. End-stage renal disease (ESRD) developed
in 20% of cases after 10 years and in 30% after 20 years,
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Fig. 1. Decision tree for biopsy-proven IgA nephropathy (IgAN). Blood pressure in all cases
should be controlled with angiotensin converting enzyme inhibitors (ACEI).
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Author
[Reference]
Design
Treatment
Lai [27]
RCT
34
Kobayashi [28]
NCT
29
Kobayashi [29]
NRCT
46
Daily
4 months
Daily
1236 months
Daily
18 months
Follow-up
months
38
47
120
Results
P value
Level of
evidence
Renal function 5
proteinuria
Natural course 5
proteinuria
Renal function
proteinuria
in one subgroup
, 0.01
1
4
, 0.05
Abbreviations are: RCT, randomized controlled trial; NCT, non-controlled trial; NRCT, non-randomized controlled trial.
in IgAN patients (grade A recommendation). Cyclosporine A (CsA) should not be used (grade B).
Evidence. Two level 1 studies examined therapy using
the combination of cyclophosphamide, dipyridamole,
and warfarin (Table 2). Although Woo et al initially
demonstrated reduction of proteinuria and stabilization
of renal function [30], a five-year post-trial assessment
found no difference in renal function between the treatment and control groups [31]. Walker et al showed no
statistical difference in renal function in their trial, but
did show a reduction in proteinuria in the treated group
[32]. In these studies, there were no histological evaluations after treatment. Gonadal function was reduced,
making this treatment unacceptable in young patients.
As a variety of immunologic abnormalities suggest
that IgAN is an autoimmune disorder, CsA was used by
Lai, Lai, and Li in a randomized single-blind trial (level
2), shown in Table 3 [33]. The drug was used with a
plasma cyclosporine target level of 50 to 100 mg/ml in
24 patients who had proteinuria at least 1.5 g/day and a
diminished creatinine clearance, who were treated for
12 weeks. They showed a significant fall in protein excretion, accompanied, however, by a rise in serum creatinine. These changes were reversed after cessation of
treatment.
Recommendation 3. In patients with a slow progressive decline in creatinine clearance (less than 70 ml/min),
fish oil should be given (grade B recommendation).
Evidence. Deficiencies of essential fatty acids have
been detected in IgAN [34], and fish oil may favorably
influence the disease by acting on potential mediators
that stem from the initial glomerular injury. Fish oil is
rich in long-chain omega-3-polyunsaturated fatty acids
(v-3-PUFA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). These can replace arachidonic
acid and act as substrates for both lipoxygenase and
cyclooxygenase enzymes, resulting in the production of
altered and biologically less effective prostaglandins and
leukotrienes, changes in membrane fluidity, and reduced
platelet aggregability [35]. The first clinical report was a
preliminary article by Hamazaki, Tateno, and Shishido
in 1984 involving 20 IgAN patients. The treatment group
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Treatment
RCT
48
Cyclophosphamide 6 months
and
Dypiridamole, warfarin 36 months
RCT
52
Follow-up
months
Design
36
96
24
Results
P value
Level of
evidence
Proteinuria
renal function
No difference
, 0.01
Renal function 5
proteinuria
, 0.01
Table 3. Cyclosporine
Author [Reference]
Lai [33]
Design
Treatment
Follow-up
months
RCT
24
Cyclosporine 6 months
15
Results
P value
Level of
evidence
Proteinuria
renal function
, 0.05
Design
Treatment
Bennett [37]
RCT
37
Pettersson [35]
RCT
32
Donadio [38]
RCT
106
Before and
after study
11
EPA-DHA
1.8 g1.2 g daily
EPA-DHA
3.3 g1.8 g
EPA-DHA
1.8 g1.2 g
EPA-DHA
1.8 g1.2 g
Cheng [39]
Follow-up
months
24
Results
P value
Level of
evidence
1
1
24
Renal function
proteinuria 5
Slow the progression of kidney failure
10
5 0.002
1
4
Abbreviations are: RCT, randomized controlled trial; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.
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Author [Reference]
Design
Treatment
Goumenos [41]
NRCT
Retro
114
Prednisone
daily
azathioprine
24 months
Follow-up
months
Results
P value
Level of
evidence
46
Renal function
, 0.01
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Design
Coppo [49]
Maschio [50]
Cattran [51]
NRCT
RCT
NRCT
27
39
115
Bannister [52]
NRCT
23
Treatment
Follow-up
months
Captopril
Fosinopril
ACEI
26
9
29
Nifedipine
vs. ACEI
12
Results
GFR
Proteinuria
GFR
Proteinuria
5 GFR
Proteinuria with ACEI
Level of
evidence
4
3
4
2
Abbreviations are: NRCT, non-randomized controlled trial; RCT, randomized controlled trial; ACEI, angiotensin-converting enzyme inhibitor; GFR, glomerular
filtration rate.
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