Treatment and prognosis of IgA nephropathy

Last literature review version 16.3: October 2008 | This topic last updated:
October 17, 2008
INTRODUCTION — IgA nephropathy is the most common cause of primary
(idiopathic) glomerulonephritis in the developed world [1-4]. Although this disorder
was initially thought to follow a benign course, it is now recognized that slow
progression to end-stage renal disease (ESRD) occurs in up to 50 percent of
affected patients [5]. The remaining patients enter a sustained clinical remission or
have persistent low grade hematuria or proteinuria. However, the prognosis is quite
variable and the outcome difficult to predict with accuracy in individual patients.
The classic presentation of IgA nephropathy is that of gross hematuria, often
recurrent, following shortly after an upper respiratory infection [3,6]. However, the
majority of patients are diagnosed following an evaluation for asymptomatic
microscopic hematuria and/or mild proteinuria. Less common presentations are
nephrotic range proteinuria with or without nephrotic syndrome and rapidly
progressive glomerulonephritis and, rarely, malignant hypertension. The diagnosis is
usually suspected based upon the clinical history and laboratory data, but can only
be confirmed with a kidney biopsy, at the present time.
The prognosis and treatment of IgA nephropathy will be reviewed here. The causes,
pathogenesis, and diagnosis of this disorder, and the outcomes in patients who
undergo renal transplantation, are discussed separately. (See "Causes and
diagnosis of IgA nephropathy" and see "IgA nephropathy: Recurrence after
transplantation").
PROGNOSIS — Patients with IgA nephropathy and little or no proteinuria (<500
mg/day) have a low risk of progression in the short term. However, renal
insufficiency and proteinuria develop in a substantial proportion of patients over the
long term, and such patients may progress to end-stage renal disease (ESRD) [5,7].
The possible role of persistent microscopic hematuria in predicting an adverse
outcome in this group of patients is debated.
Frequency of progression — The natural history of patients who present with
isolated hematuria (ie, without abnormal proteinuria) is not as benign as initially
thought. This was demonstrated in the following studies:
• In a Chinese study of 72 consecutive patients with IgA nephropathy who
underwent diagnostic biopsy because of hematuria with no or minimal
 proteinuria (defined as less than 0.4 g/day), patients were followed for a
median of seven years [6]. Protein excretion above 1000 mg/day,
hypertension, and/or impaired renal function (serum creatinine concentration
≥1.4 mg/dL [120 µmol/L]) developed in 33, 26, and 7 percent, respectively.
• In a nationwide study of 2270 patients with biopsy-proven IgA nephropathy in
Japan who were surveyed three, five, and eight years after the baseline
survey, 207 patients developed ESRD [8]. The seven-year cumulative
incidence of end-stage renal disease was 8 and 15 percent for women and
men, respectively.
• Among 93 patients with an initially normal measured GFR (but usually with
proteinuria), approximately one-third had a reduced GFR within five years and
one-fourth progressed to ESRD within 20 years [9].
Among patients who develop proteinuria and/or elevated serum creatinine
concentration, progression to ESRD is approximately 15 to 25 percent at 10 years
and 20 to 30 percent at 20 years [1,2,8-11]. Higher rates of progression are seen
among patients with more severely impaired kidney function. Among the 183
patients with serum creatinine ≥1.7 mg/dL (150 µmol/L) in the previously mentioned
Japanese survey, the seven-year cumulative incidence of ESRD was ≥70 percent
[8].However, the rate of loss of GFR was often as low as 1 to 3 mL/min per year, a
change not associated with an elevation in the serum creatinine concentration
during this time period. Thus, a stable and normal serum creatinine does not
necessarily indicate stable disease.
These observations are generally from patients with biopsy-confirmed IgA
nephropathy in which some factor other than hematuria prompted the biopsy (such
as proteinuria or an elevated serum creatinine concentration). Patients with only
hematuria are often not biopsied in many countries (such as the United States).
The impact of different biopsy criteria was shown in a retrospective study that
evaluated geographic differences in the clinical course of 711 patients with a biopsy
diagnosis of IgA nephropathy [5]. Renal survival at 10 years was 96, 87, 64, and 62
percent in Finland, Australia, Scotland, and Canada, respectively. Better outcomes
in Finland and Australia were largely attributable to the diagnosis of milder cases
(eg, less proteinuria, higher creatinine clearance, lower blood pressure). This raises
the possibility of lead-time bias influencing the prognosis, versus truly a better
prognosis in some geographic areas compared to others [5,12]. (See "Glomerular
hematuria: IgA; Alport; thin basement membrane nephropathy").
Repeat renal biopsy has also been used to assess the frequency of progressive
disease [13,14]. In one report, repeat renal biopsies were performed at five years in
73 patients with persistent proteinuria but a normal or near-normal initial serum
creatinine [13]. Histologic improvement occurred in only 4 percent, with 41 percent
remaining stable and 55 percent showing progressive glomerular and secondary
vascular and tubulointerstitial injury.
Some patients without significant proteinuria or renal dysfunction undergo remission
of abnormal laboratory findings, with reported rates ranging between 5 and 30
percent [10,12-15]. Remission may be more likely among children. This was
illustrated in a study of 181 Japanese children diagnosed by renal biopsy before the
age of 15 years; 30 percent had proliferative glomerulonephritis and were treated
with immunosuppressive agents [16]. After a mean follow-up of seven years, 50
percent had no manifestations of disease, 36 percent had persistent hematuria with
or without proteinuria, and 25 (14 percent) developed progressive disease.
Clinical predictors of progression — As in other glomerulopathies, patients who
will develop progressive disease typically have one or more of the following clinical
or laboratory findings at diagnosis [1,2,6,7,9,16-22]:
• Elevated serum creatinine concentration at diagnosis — Patients who reach a
serum creatinine concentration ≥2.5 mg/dL (221 µmol/L) generally continue to
progress.
• Hypertension — Hypertension is associated with arteriosclerosis and
tubulointerstitial changes on biopsy, and usually significant proteinuria.
• Persistent protein excretion above 500 to 1000 mg/day.
The relation between increasing proteinuria and a worse prognosis is probably in
part a reflection of proteinuria being a marker for the severity of glomerular disease.
The rate of progression is very low among patients excreting less than 500 mg/day
and is fastest among those excreting more than 3.0 to 3.5 g/day of protein [9,21,22].
The importance of the magnitude of proteinuria on the course of IgA nephropathy
was evaluated in an observational study of 542 patients [22]. The rate of decline in
renal function was 25-fold faster in those with sustained proteinuria of greater than 3
g/day compared to patients with protein excretion less than 1 g/day [22]. Patients
who presented with protein excretion above 3 g/day who attained a partial remission
(less than 1 g/day) had a similar rate of progression as patients with sustained
proteinuria of less than 1 g/day. As described below, ACE inhibitors or angiotensin II
receptor blockers are the preferred antiproteinuric drugs. (See "Angiotensin
inhibition" below).
Patients who have only recurrent episodes of gross hematuria seem to be at less
risk than those with persistent microscopic hematuria and proteinuria [1,23]. Why
this might occur is not clear.
Acute renal failure with gross hematuria — Acute renal failure can occur during
episodes of gross hematuria [24-26]. Renal biopsy in these patients reveals
mesangial proliferation and segmental crescents in a small proportion of glomeruli
(usually less than 25 percent) [24,26]. These findings are insufficient to account for
the acute renal failure, which has been ascribed to tubular obstruction by red cell
casts [24,25,27]. However, the most common histologic lesion is acute tubular
necrosis, which may be induced by the iron released from lysed red cells in the
tubules [24,26,27].
This form of acute renal failure is generally a benign complication; the serum
creatinine concentration most commonly returns to baseline levels within several
weeks to months, even if dialysis is temporarily required [24]. However, incomplete
recovery of renal function has been described in up to 25 percent of affected
patients [27].
Histologic predictors of progression — Although clinical features appear to be
stronger prognostic indicators [18], certain findings on renal biopsy have been
associated with an increased risk of progressive disease. These include
glomerulosclerosis, tubular atrophy, interstitial fibrosis, immune deposits in the
capillary loops as well as the mesangium, vascular disease, and crescent formation
[1,10,16,20,23,28,29].
Several schema for classifying renal biopsy findings have been described that
appear to correlate with prognosis; in multivariate analyses, the extent of
glomerulosclerosis and tubulointerstitial disease are most commonly associated with
a poor prognosis [23,30,31]. These indicators are typical of most glomerular
diseases. (See "Secondary factors and progression of chronic kidney disease",
section on Tubulointerstitial disease).
Genetic associations — A number of genetic associations have been suggested to
be prognostically important in patients with IgA nephropathy, but the data are often
conflicting and may be confounded by the population studied.
• In some studies, progressive disease appeared more likely in patients with the
DD genotype of the ACE gene, which is associated with higher plasma ACE
 levels, than in those with the ID or II genotype [32-34]. However, others have
reported no correlation between genotype and outcome [35,36].
• The possible roles of two other genes related to the renin-angiotensin system,
the angiotensinogen and angiotensin II receptor genes, have also been
evaluated. No relation was found with the angiotensin II receptor genes
[34,37], while conflicting data have been reported with the angiotensinogen
gene [34,37,38].
• In a study of 425 Chinese patients and their families, a polymorphism of the
megsin gene appeared to be associated with a faster rate of rise in serum
creatinine at a two-year follow-up [39]. Upregulation of megsin (a serine
protease inhibitor predominantly expressed in the mesangium) was correlated
with mesangial expansion and hypercellularity.
There are conflicting findings in two Italian studies as to whether or not familial
disease is associated with a worse prognosis [40,41]. The much larger series found
no association between familial disease and outcome [41]. (See "Causes and
diagnosis of IgA nephropathy", section on Genetic predisposition).
APPROACH TO THERAPY — The optimal approach to the treatment of IgA
nephropathy is uncertain [42,43]. 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. Issues related to statin therapy in patients with chronic kidney
disease and serum LDL-cholesterol concentrations above goal values are
discussed below and separately. (See "Nonimmunosuppressive therapies"
below and see "Statins and chronic kidney disease").
• Therapy with corticosteroids with or without other immunosuppressive agents
to treat the underlying inflammatory disease. (See "Immunosuppressive
therapy" below).
Patient selection — Patient selection for therapy is based in part upon the
perceived risk of progressive kidney disease. (See "Clinical predictors of
progression" above):
• 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. (See
"Nonimmunosuppressive therapies" below).
• 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. (See "Immunosuppressive therapy" below and see "Treatment"
below).
Monitoring disease activity — There are no specific markers to identify continued
immunologic activity. As a result, clinical parameters are typically used, whether or
not the patient is receiving immunosuppressive therapy. The major parameters that
are serially monitored are the urine sediment, protein excretion, usually estimated
from the protein-to-creatinine ratio, and the serum creatinine concentration.
• Hematuria — Persistent hematuria is generally a marker of persistent
immunologic activity, but not necessarily of progressive disease. This finding
may be a sign of a "smoldering" segmental necrotizing lesion, suggestive of
"capillaritis." Hematuria alone does not require any form of therapy.
• Proteinuria — Proteinuria, rather than hematuria alone, is a marker of more
severe disease [21]. Increasing proteinuria may be due to one of two factors:
ongoing active disease; and secondary glomerular injury due to
nonimmunologic progression. It is often not possible to distinguish between
these two possibilities, except for a rapid increase in protein excretion which is
only seen with active disease. Issues related to secondary factors and
progression are discussed separately. (See "Secondary factors and
progression of chronic kidney disease" and see "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease").
Protein excretion typically falls with ACE inhibitor/ARB therapy and the degree of
proteinuria is, as described below, one of the end points of such therapy. Protein
excretion also may fall spontaneously, particularly during recovery from an acute
episode and perhaps in children, and following effective immunosuppressive
therapy.
• Serum creatinine — The serum creatinine, unless it is rapidly rising, permits
an estimation of the glomerular filtration rate. As noted above, most patients
with chronic IgA nephropathy have stable or slowly progressive disease. The
rate of loss of GFR is often as low as 1 to 3 mL/min per year, a change that
will not raise the serum creatinine for many years [9]. Thus, a stable and even
normal serum creatinine does not necessarily indicate stable disease.
NONIMMUNOSUPPRESSIVE THERAPIES — There are two main
nonimmunosuppressive therapies in IgA nephropathy [42,43]:
• Angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor
blockers (ARB) both for blood pressure control and to slow progression of the
renal disease.
• Statin therapy for lipid-lowering in selected patients to lower cardiovascular
risk and possibly reduce disease progression.
Fish oil has also been studied, but its role is less clear.
Angiotensin inhibition — The progression of IgA nephropathy may be slowed by
antihypertensive and antiproteinuric therapy that can minimize secondary glomerular
injury [44]. ACE inhibitors and ARBs act by reducing the intraglomerular pressure
and by directly improving the size-selective properties of the glomerular capillary
wall, both of which contribute to reducing protein excretion [45,46].
Both observational studies [47,48] and small randomized trials [46,49,50] have
provided suggestive evidence that ACE inhibitors or ARBs are more effective than
other antihypertensive drugs in slowing the progressive decline in glomerular
filtration rate in IgA nephropathy as they are in other forms of chronic proteinuric
kidney disease. (See "Antihypertensive therapy and progression of nondiabetic
chronic kidney disease").
The following observations come from three randomized trials in patients with IgA
nephropathy:
• In one trial, 44 patients with proteinuria (≥0.5 g/day, mean 1.9 g/day) and a
serum creatinine concentration ≤1.5 mg/dL (133 µmol/L) at baseline were
randomly assigned to either enalapril or antihypertensive agents other than
ACE inhibitors or ARBs [49]. The target blood pressure throughout the study
was <140/90 mmHg, and initially normotensive patients received a fixed dose
of antihypertensive drugs. At follow-up of about six years, renal survival,
 defined as less than a 50 percent increase in the serum creatinine
concentration, was significantly more likely in the enalapril group (92 versus 55
percent). A significant decrease in proteinuria was only observed in the
enalapril group (2 g/day at baseline to 0.9 g/day at the last visit). The
proteinuria decrease after one year of therapy correlated with renal survival.
Blood pressure control was similar in the two groups
• In the double-blind placebo-controlled HKVIN trial, 109 Chinese patients with
protein excretion ≥1000 mg/day (mean about 2.0 g/day) were randomly
assigned to valsartan or placebo, and other non-ACE or non-ARB
antihypertensive agents as needed to achieve a goal blood pressure of
<140/90 mmHg [50]. Patients in the valsartan group had lower baseline
proteinuria and achieved blood pressure. After two years, the primary end
point of doubling of serum creatinine or ESRD was reached by fewer patients
in the valsartan group (1 versus 4 in the placebo group), but the number of
events was too small to have confidence in the results. In adjusted analyses,
valsartan was associated with significant improvement in proteinuria (33
percent reduction in proteinuria compared to placebo) and a slower rate of
decline in GFR (4.6 versus 6.9 mL/min per year). However, both the lower
initial proteinuria and the lower sustained blood pressure in the valsartan
group complicates the interpretation of the study.
• In the IgACE trial, 65 young patients (range 9 to 35 years) with moderate
proteinuria (between 1 and 3.5 grams/day per 1.73 m2) and relatively
preserved renal function (creatinine clearance >50 mL/min per 1.73 m2) were
randomly assigned to benazepril (0.2 mg/kg per day) or placebo [51]. Only five
patients were hypertensive. At a median follow-up of 38 months (range of 0 to
58 months), the primary end point (greater than 30 percent decrease in renal
function) was reached by fewer patients in the treatment group (one versus
five in the placebo group). However, as with the HKVIN trial, this study was
underpowered to address this outcome. Nevertheless, active therapy resulted
in a significantly lower incidence of the secondary composite end point
(greater than 30 percent decrease of the creatinine clearance or worsening of
proteinuria until the nephrotic range was reached, 3 versus 27 percent) and a
higher incidence of a partial (41 versus 9 percent) or complete remission (13
versus 0 percent). Although blood pressures were higher in the placebo group
in the last one to two years of the study, the effect of blood pressure on
 outcomes is likely to be small, given that differences were not observed in the
first three years [52].
Normotensive patients who excrete less than 500 mg of protein per day are not
typically treated with angiotensin inhibition. However, because most patients
progress slowly over time, monitoring of the serum creatinine and protein excretion
at yearly intervals is recommended. Angiotensin inhibition should be started if there
is evidence of progressive disease and protein excretion above 500 mg/day.
ACE inhibitor plus ARB — The addition of an ARB to an ACE inhibitor in patients
with IgA nephropathy appears to produce a further antiproteinuric effect [53,54]. This
finding is consistent with meta-analyses of trials in different glomerular diseases, the
largest of which found a significant 18 to 25 percent greater reduction in proteinuria
with combined ACE inhibitors and ARBs compared to monotherapy [55,56].
As mentioned above, a more pronounced antiproteinuric effect is thought to be a
marker for better outcomes [22]. (See "Clinical predictors of progression" above).
Despite the greater reduction in proteinuria with combined ARB/ACE inhibitor
therapy however, there are no randomized trials that have shown that this regimen
improves renal outcomes. Questions have been raised about the reliability of the
one trial (COOPERATE) that directly addressed the renoprotective effect of
combination therapy. This issue is discussed separately. (See "Antihypertensive
therapy and progression of nondiabetic chronic kidney disease", section on
COOPERATE trial).
In addition, in the ONTARGET trial, which comprised 25,620 patients with vascular
disease or diabetes, there was an increase in adverse side effects (including a
possible increase in mortality) in patients who received combined therapy with an
ACE inhibitor and ARB, compared to those who received monotherapy [57,58]. The
ONTARGET trial is discussed elsewhere. (See "Choice of antihypertensive drug and
blood pressure goal in patients at increased risk for a cardiovascular event" and see
"Treatment of hypertension in diabetes mellitus" and see "Major side effects of
angiotensin converting enzyme inhibitors and angiotensin II receptor blockers").
Treatment goals — The treatment goals with angiotensin inhibition are the same as
those in other forms of proteinuric chronic kidney disease as described in the
K/DOQI guidelines [59]. The data supporting the following recommendations are
discussed in detail separately. (See "Antihypertensive therapy and progression of
nondiabetic chronic kidney disease").
Fish oil — The possible role of fish oil in IgA nephropathy, which might act by
antiinflammatory mechanisms, is not well defined [60]. In addition to uncertain
efficacy and consistency in regards to omega-3 fatty acid content, there is an
associated fishy aftertaste and eructations with this treatment that often limit patient
acceptance [61].
Randomized controlled trials evaluating fish oil in patients with IgA nephropathy
have reported conflicting results [61-67]. The following two trials illustrate the range
of findings [61,64,67]:
• In a trial from the Mayo Clinic, 106 patients with baseline creatinine clearance
80 mL/min and protein excretion of 2.5 to 3 g/day were randomly assigned to
therapy with either 12 g of fish oil or a similar amount of olive oil for two years
[61]. There was no difference in blood pressure control and no effect on
protein excretion during the study.
At four years, patients receiving fish oil had a lower incidence of a ≥50 percent
increase in the serum creatinine concentration (6 versus 33 percent in the placebo
group) and a lower incidence of death or ESRD at four years (10 versus 40 percent).
With follow-up extended to >6 years, benefits of continuous fish oil therapy persisted
(15 versus 37 percent incidence of ESRD) [64].
• In a trial by the Southwest Pediatric Nephrology Study Group, 96 patients
(mean GFR >100 mL/min per 1.73 m2 and proteinuria 1.4 to 2.2 g/day) were
randomly assigned to one of three treatment arms: a purified preparation of
omega-3 fatty acids (4 g/day) for two years; alternate day prednisone (60
mg/m2 per dose for three months, 40 mg/m2 per dose for nine months, and 30
mg/m2 per dose for one year); or placebo [67]. All patients with hypertension
(blood pressure ≥140/90 mmHg) were treated with enalapril.
At three years, the primary outcome of a reduction in GFR to below 60 percent of
the baseline value was observed more commonly in the omega-3 fatty acid
treatment group (19 versus 9 percent in both the prednisone and placebo groups,
respectively). This difference was not statistically significant (although the study was
underpowered), and only baseline proteinuria was significantly associated with
progression.
It is not clear why these trials produced different results. One potentially important
factor is that the positive trial evaluated patients with more advanced disease (more
proteinuria and lower creatinine clearance at baseline), and the placebo (olive oil)
group had a faster rate of progression than is generally seen. On the other hand, in
the negative trial, patients in the placebo group had lower baseline proteinuria, a
factor that is known to be associated with a better prognosis [67].
A meta-analysis evaluating five controlled trials, which was published before the
negative findings from the Southwest Pediatric Nephrology Study Group, attributed
much of the variability in the reported results to differences in the duration of follow-
up [68]. When this difference was accounted for statistically, a benefit with fish oil
therapy was not found to be significant, but a minor benefit was possible.
Summary — The benefit of fish oil has not been established. Furthermore, the trial
designs are not applicable to current practice, since the patients were not treated
with an ACE inhibitor and/or ARB and, as necessary, other drugs to recommended
proteinuria and blood pressure goals. (See "Treatment goals" above and see
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease").
Fish oil can be tried in addition to ACE inhibitors or ARBs in patients with protein
excretion >500 to 1000 mg/day, a gradual reduction in GFR, and mild to moderate
histologic lesions [69].
Lipid-lowering therapy — All patients with decreased kidney function and/or
hypercholesterolemia should receive lipid-lowering therapy with a statin based upon
the following rationales:
• Chronic kidney disease is associated with a marked increase in cardiovascular
risk, and is now considered a coronary artery disease risk equivalent. (See
"Chronic kidney disease and coronary heart disease").
• Lipid-lowering with statins has been associated with a slower rate of loss of
glomerular filtration rate in patients with mild to moderate CKD. (See "Statins
and chronic kidney disease", section on Statins and CKD progression.
The goal LDL-cholesterol is similar to that in patients with underlying coronary heart
disease. (See "Intensity of lipid lowering therapy in secondary prevention of
coronary heart disease").
IMMUNOSUPPRESSIVE THERAPY — The optimal role of immunosuppressive
therapy in IgA nephropathy is uncertain [42,43]. A variety of regimens have been
used, mostly consisting of corticosteroids alone or with other immunosuppressive
drugs. The available studies are not conclusive since most are relatively small and
have limited follow-up, and the results are sometimes conflicting [1,2,69-74].
Glucocorticoids — Most nephrologists do not treat mild, stable, or very slowly
progressive IgA nephropathy with glucocorticoids (corticosteroids) or other
immunosuppressive therapies, given the limited evidence of benefit and known
toxicity from chronic use [75,76]. Steroid therapy should only be attempted in
patients with clinical and histologic evidence of active inflammation (eg, hematuria
and/or proliferative or necrotizing glomerular changes). Patients with chronic kidney
disease with significant tubulointerstitial fibrosis and glomerulosclerosis are not likely
to benefit from such therapy and are likely to be harmed from the side effects. (See
"Major side effects of systemic glucocorticoids").
The potential benefit of corticosteroid therapy in IgA nephropathy has been
examined in uncontrolled studies, retrospective observations, and a few relatively
small, randomized controlled trials [75,77]. Furthermore, the applicability of these
trials to current practice is unclear, since the patients were not routinely treated with
an ACE inhibitor and/or ARB and, as necessary, other drugs to attain recommended
proteinuria and blood pressure goals. (See "Treatment goals" above and see
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease").
Corticosteroid therapy for 6 to 24 months or more may be associated with a
reduction in proteinuria and perhaps improved renal survival [75,77-85], although
this has not been consistently noted [67]. Benefit in some of these studies was
observed only among individuals with preserved kidney function (eg, creatinine
clearance above 70 mL/min) [78-81]. However, other studies have found improved
outcomes even among individuals with more advanced disease (eg, reduced kidney
function and more significant proteinuria) [77,82,85].
As an example, a prospective trial from Italy included 86 adults with proteinuria (1 to
3.5 g/day) and at most mild renal insufficiency (median serum creatinine 1 mg/dL
[88.4 µmol/L]) [80]. The patients were randomly assigned to supportive therapy
alone, or corticosteroids (1.0 gram of intravenous methylprednisolone for three
consecutive days at the beginning of months one, three, and five, combined with 0.5
mg/kg of oral prednisolone given on alternate days for six months).
At five and ten years, the steroid treated patients had a markedly lower incidence of
the primary end point, which was a doubling in the serum creatinine concentration (2
versus 21 percent at five years and 2 versus 30 percent at ten years) [81]. The effect
of ACE inhibitors was not assessed.
In contrast, the trial from the Southwest Pediatric Nephrology Study Group
described above found no difference at three years between oral prednisone
therapy for two years and placebo in the primary outcome of reduction in GFR to
below 60 percent of the baseline value [67]. However, this trial was underpowered
for the primary end-point (See "Fish oil" above).
There is a subset of patients with IgA nephropathy in whom prednisone therapy
appears to be more clearly beneficial: those with an acute onset of the nephrotic
syndrome, little or no hematuria, preserved kidney function, minimal glomerular
changes on light microscopy, and diffuse fusion of the foot processes of the
glomerular epithelial cells on electron microscopy. These histologic findings are
characteristic of minimal change disease, and these patients behave accordingly,
frequently developing a remission with corticosteroids and occasionally requiring
cyclophosphamide for frequently relapsing proteinuria [86-88]. Mesangial IgA
deposits often disappear or are greatly reduced over time [88]. (See "Treatment of
minimal change disease in adults").
Nephrotic syndrome can also occur with severe chronic IgA nephropathy and
relatively advanced disease on renal biopsy. These patients do not seem to benefit
from steroid therapy alone [86,87].
The role of corticosteroids alone in the treatment of IgA nephropathy is summarized
below. (See "Treatment" below).
Combined immunosuppressive therapy — Combined immunosuppressive
therapy should only be attempted in patients with more severe active disease as
defined by a more rapidly progressive clinical course and/or histologic evidence of
severe active inflammation (eg, crescent formation).
Severe or progressive disease — Several trials have suggested a possible benefit
from combined immunosuppressive therapy in patients with moderate to severe
active disease on biopsy; however, most did not include a comparison group treated
with prednisone alone [70,89-93]. In addition, the studies were primarily performed
prior to the widespread use of aggressive antihypertensive and antiproteinuric
therapy with ACE inhibitors and/or ARBs. (See "Treatment goals" above and see
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease").
Two trials in children with moderate to severe histologic findings on renal biopsy, but
normal kidney function (initial creatinine clearance >140 mL/min per 1.73 m2),
evaluated complicated regimens that included heparin, warfarin and dipyridamole as
well as combined immunosuppressive therapy [92,93]. No benefit was observed
with these regimens compared with azathioprine and/or prednisone.
There are limited data concerning the effectiveness of cytotoxic agents in adults with
progressive IgA nephropathy [75,89-91]. Some trials evaluated cyclophosphamide
with warfarin and dipyridamole [89,90], a regimen that is not widely used, and one
evaluated cyclophosphamide with prednisone [91]. The last trial was a single center
study of 38 patients with IgA nephropathy and initially impaired renal function (but no
crescents on biopsy) as defined by an initial serum creatinine concentration between
1.5 and 2.8 mg/dL (130 and 250 µmol/L, respectively) that was declining at a
relatively moderate rate (by at least 15 percent over the year prior to study entry)
[91]. Mean baseline protein excretion was 4.0 to 4.5 g/day.
The patients were given antihypertensive therapy as needed (but not specifically
ACE inhibitors and/or ARBs) and randomly assigned to no further therapy or to
prednisolone (40 mg per day tapered to 10 mg/day by two years) plus low-dose
cyclophosphamide (1.5 mg/kg per day) for the initial three months followed by low-
dose azathioprine (1.5 mg/kg per day) for a minimum of two years (some patients
were given azathioprine for up to six years). Blood pressure control was similar in
both groups, and immunosuppressive therapy was associated with a low incidence
of adverse effects.
Compared with the control group, the patients treated with combination therapy had
a significant reduction in protein excretion during the first six months of therapy that
persisted during follow-up (eg, reached 1.8 g/day in treatment group versus
unchanged at 4.4 g/day in controls at one year). Renal survival was significantly
higher in the treatment group at years two (82 versus 68 percent) and five (72
versus 6 percent).
These findings suggest that patients with severe or progressive disease (eg, rising
creatinine, nephrotic range proteinuria, and/or marked proliferation without
crescents) who do not have significant chronic damage on kidney biopsy may
benefit from combined immunosuppressive therapy with prednisone and
cyclophosphamide.
Early therapy is important because improvement is rare when the baseline serum
creatinine concentration is greater than 3.0 mg/dL (265 µmol/L) in the absence of
crescentic glomerulonephritis [69]. In addition, immunosuppressive therapy is not
indicated in the spontaneously reversible acute renal failure that may be associated
with gross hematuria. (See "Acute renal failure with gross hematuria" above).
The role of combined immunosuppressive therapy in the treatment of severe or
progressive IgA nephropathy is summarized below. (See "Treatment" below).
Crescentic glomerulonephritis — Uncontrolled reports in patients with crescentic,
rapidly progressive glomerulonephritis suggest possible benefit from regimens
similar to those used in idiopathic crescentic glomerulonephritis: intravenous pulse
methylprednisolone followed by oral prednisone, intravenous or oral
cyclophosphamide, and/or plasmapheresis [94-98]. Steroids may act in this setting
by diminishing acute inflammatory injury rather than by correcting the abnormality in
IgA production [99]. (See "Overview of the classification and treatment of rapidly
progressive (crescentic) glomerulonephritis").
One report evaluated the efficacy of aggressive combination therapy (including
pulse methylprednisolone, oral cyclophosphamide, and plasmapheresis) in six
patients with crescentic glomerulonephritis due to IgA nephropathy [96]. After two
months of therapy, there was substantial clinical improvement characterized by
reductions in the serum creatinine concentration and protein excretion. However,
repeat renal biopsy showed persistence of florid crescents and one-half of patients
had progressive disease after therapy was discontinued.
A more prolonged course of aggressive immunosuppressive therapy was evaluated
in 12 patients with crescentic, proliferative IgA nephropathy who had a mean serum
creatinine concentration of 2.7 mg/dL (240 µmol/L) and protein excretion of 4 g/day
at baseline [98]. The treatment regimen consisted of the following:
• Pulse methylprednisolone (15 mg/kg per day for three days)
• Oral prednisone (1 mg/kg per day for 60 days, followed by 0.6 mg/kg per day
for 60 days, followed by 0.3 mg/kg per day for 60 days, with all patients on 10
mg/day at the time of repeat biopsy).
• Monthly intravenous cyclophosphamide (0.5 g/m2) for six months
After the six month course, there was significant improvement in the serum
creatinine concentration (from 2.7 to 1.5 mg/dL [240 to 133 µmol/L]) and in protein
excretion (from 4 to 1.4 g/day). Repeat biopsy revealed the absence of cellular
crescents and endocapillary proliferation in all patients.
Throughout the three-year follow-up, all patients continued prednisone (0.15 mg/kg
per day), and the blood pressure was controlled to a goal of <130/70 mmHg with
ACE inhibitors and other agents as needed. Compared with 12 untreated historic
controls (matched for age, gender, baseline serum creatinine concentration and
histologic severity), the incidence of ESRD at three years was significantly lower in
the treated group (1 of 12 [8 percent] versus 5 of 12 [42 percent]).
These limited data suggest that patients with crescentic glomerulonephritis who do
not have significant chronic damage on kidney biopsy may benefit from therapy that
initially includes intravenous cyclophosphamide. This is consistent with the benefit
noted with a similar regimen in other forms of crescentic glomerulonephritis. (See
"Overview of the classification and treatment of rapidly progressive (crescentic)
glomerulonephritis").
The role of combined immunosuppressive therapy in the treatment of crescentic IgA
nephropathy is summarized below. (See "Treatment" below).
Other immunosuppressive agents
Cyclosporine — Cyclosporine has been investigated in small studies, and resulted
in reduced proteinuria. However, its use has been limited by the associated
nephrotoxicity, leading to a rise in the serum creatinine concentration that is greater
than that seen in untreated patients [100,101]. Furthermore, relapse occurs soon
after the drug is discontinued.
Based upon the available data, we do not use cyclosporine for the treatment of IgA
nephropathy.
Mycophenolate mofetil — There are limited data concerning the efficacy of
mycophenolate mofetil in the primary treatment of progressive IgA nephropathy.
Four small, prospective placebo-controlled randomized trials in which the patients
were also treated with ACE inhibitors in at least three, have produced conflicting
results, ranging from no benefit with mycophenolate mofetil [102,103] to a reduction
in proteinuria [104,105].
The conflicting results may be explained in part by differing severity of kidney
disease, being less advanced in the studies demonstrating benefit. Additional trials
are ongoing although one was recently stopped because of funding issues and
futility given no differences observed between treated and control group [106].
A short course (less than six months) of mycophenolate in patients with persistent
proteinuria (>1.5 g/day) and well-maintained renal function (serum creatinine <1.5
mg/dL [132.6 µmol/liter]) despite maximum ACE inhibitor/ARB therapy may be
considered in someone with well-preserved renal histology on biopsy. Current
evidence does not support the use of mycophenolate in patients with advanced
disease (serum creatinine >2.5 to 3 mg/dL [221 and 265 µmol/L]).
OTHER POSSIBLE INTERVENTIONS — Other interventions that have been
evaluated in an uncontrolled fashion include tonsillectomy, low antigen diet, and
intravenous immune globulin. Experience with these interventions is limited.
Tonsillectomy — Tonsillitis has been associated with hematuria and proteinuria in
IgA nephropathy. It has been proposed that the tonsils are a source of abnormal IgA
that forms immune complexes, and deposits in the glomeruli [107,108]. (See
"Causes and diagnosis of IgA nephropathy").
Several retrospective reports suggested that tonsillectomy, usually in combination
with some immunosuppressive therapy, was associated with improved renal survival
among patients with relatively mild renal injury [84,84,108-110]. Others reported no
benefit of tonsillectomy [111,112]. There are no randomized trials of tonsillectomy in
IGA nephropathy.
One nonrandomized study of 55 patients compared the effect of tonsillectomy plus
steroid therapy to that of steroid monotherapy on the remission of proteinuria and
hematuria [113]. The patients who underwent tonsillectomy did so after receiving a
consultation from an otolaryngologist stating that tonsillectomy was indicated. Mean
baseline protein excretion was one to 1.5 grams per day and mean baseline
creatinine clearance was 95 mL/min. The following observations were made:
• In comparison to patients who received steroids alone, more patients who
underwent tonsillectomy had remission of proteinuria and hematuria by 24
months (76.5 versus 41.2 percent, and 79.4 versus 17.6, respectively).
• Only one patient who received steroids alone had a doubling of serum
creatinine versus no patients who underwent tonsillectomy.
• In eighteen patients who underwent a repeat biopsy twenty-four months after
the initiation of treatment, mesangial proliferation and IgA deposition were
reduced among the group that underwent tonsillectomy but not in the group
that received steroids alone.
• The beneficial clinical effects of tonsillectomy on proteinuria persisted over the
time of followup (mean of 54 months).
This nonrandomized study provides some evidence that tonsillectomy may be
effective in inducing remission of proteinuria and hematuria in patients (who have
"chronic tonsillitis") with significant IgA disease (ie, proteinuria >500 mg/day). The
design of the study precludes any definitive conclusions regarding the overall
efficacy of tonsillectomy in IGA nephropathy. Randomized trials are required to
determine whether tonsillectomy is effective in slowing progression of disease in
such patients, and to clarify the role, if any, for tonsillectomy in the absence of other
indications for this procedure.
Low antigen diet — A low antigen diet consists of avoiding gluten, dairy products,
eggs, and most meats [114]. The rationale for this regimen is that dietary
macromolecules may be responsible for activating the mucosal IgA system. When
given to 21 consecutive patients with IgA nephropathy, protein excretion fell
markedly in all 12 patients whose baseline rate was more than 1000 mg/day. In
addition, repeat renal biopsy showed significant reductions in mesangial IgA and
complement deposition and mesangial cellularity.
The benefits in the above study have not been confirmed and a report using a
gluten-free diet alone for several years was unable to document improvement in
either proteinuria or renal function despite a reduction in the level of circulating IgA-
containing immune complexes [115].
Intravenous immune globulin — At least part of the rationale for IVIG therapy in
IgA nephropathy comes from the observation that a partial IgG deficiency, which
could be corrected with IVIG, may predispose to infections that trigger flare-ups of
the renal disease [116,117].
High-dose intravenous immune globulin (IVIG) has been tried in severe IgA
nephropathy, characterized by heavy proteinuria and a relatively rapid decline in
GFR [117]. Eleven patients (nine with IgA nephropathy and two with the related
disorder Henoch-Schönlein purpura) were treated with IVIG at a dose of 1 g/kg for
two days per month for three months followed by an intramuscular preparation given
every two weeks for another six months. Among the benefits that were noted were a
reduction in protein excretion (5.2 to 2.3 g/day), prevention of a continued reduction
in GFR (loss of 3.8 mL/min per month prior to therapy versus stable GFR after
therapy), and decreased inflammatory activity and IgA deposition on repeat renal
biopsy.
The benefit of IVIG needs to be confirmed prospectively in a larger number of
patients.
Vitamin D — Vitamin D analogs have decreased proteinuria in animal models of
chronic kidney disease and in one human study of patients with chronic kidney
disease of multiple etiologies [118,119]. These observations prompted the evaluation
of calcitriol in patients with IgA nephropathy and proteinuria. This was a small,
uncontrolled, and short-term study involving 10 patients with IgA nephropathy and
persistent proteinuria despite ACE inhibitors and/or ARBs. All patients were
administered twice weekly oral calcitriol (0.5 µg) [120]. At 12 weeks,
proteinuria/creatinine ratio significantly decreased from 1.98 to 1.48. Blood pressure
remained unchanged. Larger prospective controlled trials with much greater
observation times are needed to further study the potential antiproteinuric effect of
vitamin D in this setting [121].
PREGNANCY — Pregnancy is generally well tolerated in IgA nephropathy. Only
women with an initial GFR below 70 mL/min, uncontrolled hypertension, or severe
arteriolar and tubulointerstitial disease on renal biopsy are generally at risk for
worsening renal function [122,123]. These findings are similar to those in most other
renal diseases. (See "Pregnancy in women with underlying renal disease").
ACE inhibitors or ARBs and some immunosuppressive drugs (particularly
cyclophosphamide and mycophenolate mofetil) should be discontinued at the
earliest indication of pregnancy or prior to attempted conception because of risks to
the fetus. (See "Angiotensin converting enzyme inhibitors and receptor blockers in
pregnancy" and see "Use of immunosuppressive drugs in pregnancy and lactation").
END-STAGE RENAL DISEASE — Patients who progress to end-stage renal
disease can be treated with dialysis or transplantation. Issues related to recurrent
disease in patients with IgA nephropathy who progress to renal transplantation are
discussed elsewhere. (See "IgA nephropathy: Recurrence after transplantation").
SUMMARY AND RECOMMENDATIONS
Prognosis — Patients without significant proteinuria or renal dysfunction may
undergo complete remission of abnormal clinical findings. However, most patients
will have stable or slowly progressive disease.
On the other hand, patients with persistent proteinuria and/or hypertension and/or
an elevated serum creatinine concentration are at significant risk for progression,
with an incidence of end-stage renal disease of 20 to 30 percent at 20 years, with
another 20 percent having reduced kidney function. (See "Frequency of
progression" above and see "Clinical predictors of progression" above).
Histologic findings associated with a worse prognosis include crescent formation,
which is uncommon, and, more importantly, signs of irreversible damage such as
glomerular scarring, tubular atrophy, and interstitial fibrosis. (See "Histologic
predictors of progression" above).
Acute renal failure during an episode of gross hematuria is usually reversible and
the serum creatinine concentration returns to baseline but this event may leave
residual histologic damage that eventually could lead to a worse long-term
prognosis. (See "Acute renal failure with gross hematuria" above). If the episode is
more severe or more prolonged than expected, a renal biopsy may be required to
rule out new onset crescent formation.
Patients with concurrent mesangial IgA deposits and nephrotic syndrome with a
minimal change disease pattern on renal biopsy appear to follow a course similar to
minimal change disease. (See "Glucocorticoids" above).
Treatment
 • We suggest not treating 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.
• For patients with persistent proteinuria (>500 to 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
60 percent from baseline values and a goal protein excretion of less than 500
to 1000 mg/day. (See "Angiotensin inhibition" above).
• We suggest that all patients who meet criteria for angiotensin inhibition also
receive fish oil (Grade 2B). (See "Fish oil" above).
• We recommend that patients with persistent nephrotic syndrome and/or
chronic kidney disease who have dyslipidemia be treated with a statin,
primarily for cardiovascular protection (Grade 2B). (See "Lipid-lowering
therapy" above).
• For patients with acute onset of nephrotic syndrome and minimal change
disease as well as mesangial IgA deposits on renal biopsy, we recommend
steroid therapy as in other patients with minimal change disease (Grade 1A).
(See "Glucocorticoids" above).
• For 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 corticosteroids
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. (See "Glucocorticoids" above).
- 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 [133 µmol/L]) or progressive disease with
corticosteroids 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). (See
"Severe or progressive disease" above).
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.
• For patients with crescentic glomerulonephritis and a rapidly progressive
clinical course, we suggest therapy with intravenous pulse steroids and
cyclophosphamide (Grade 2B). (See "Crescentic glomerulonephritis" above).
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.