NTRODUCTIONIgA nephropathy is the most common cause of primary

(idiopathic) glomerulonephritis in the developed world [1-6]. Although this

disorder was initially thought to follow a benign course, it is now recognized that
slow progression to end-stage renal disease occurs in up to 50 percent of
affected patients [7], often over 20 to 25 years of observation. The remaining
patients enter a sustained clinical remission or have persistent low-grade
hematuria and/or proteinuria. Although the prognosis may be difficult to predict in
some individuals, important risk factors for progressive renal disease have been
identified. (See 'Clinical predictors of progression' below.)
There are two major clinical presentations of IgA nephropathy: gross hematuria,
often recurrent, following shortly after an upper respiratory infection or athletic
exertion; and persistent asymptomatic microscopic hematuria with or without mild
to moderate proteinuria [5]. The diagnosis requires a kidney biopsy, which, as
described below, often provides prognostic information. (See "Clinical
presentation and diagnosis of IgA nephropathy" and 'Histologic predictors of
progression' below.)
The renal prognosis and treatment of IgA nephropathy will be reviewed here. The
pathogenesis of IgA nephropathy and the outcomes in patients who undergo
renal transplantation are discussed separately. (See "Pathogenesis of IgA
nephropathy" and "IgA nephropathy: Recurrence after transplantation".)

RENAL PROGNOSISPatients with IgA nephropathy who have little or no

proteinuria (less than 500 to 1000 mg/day) usually have a low risk of progression.
However, progressive proteinuria and renal insufficiency develop in a substantial
proportion of patients over the long term [7-12]. Among patients who develop
overt proteinuria and/or an elevated serum creatinine concentration, progression
to end-stage renal disease is approximately 15 to 25 percent at 10 years and 20
to 30 percent at 20 years [3,4,11-14].
The rate of progression is typically slow with the glomerular filtration rate (GFR)
often falling by as little as 1 to 3 mL/min per year, a change not associated with
an elevation in the serum creatinine concentration in the short term. Thus, a
stable and normal serum creatinine concentration does not necessarily indicate
stable disease. The frequency with which this occurs has been evaluated in
studies in which repeat renal biopsy was used to assess the frequency of
progressive disease [15,16]. In one report, repeat renal biopsies were performed
at five years in 73 patients with persistent proteinuria and a normal or near-
normal initial serum creatinine [15]. Histologic improvement occurred in only 4
percent, with 41 percent remaining stable and 55 percent showing progressive
glomerular and secondary vascular and tubulointerstitial injury. An increase in
serum creatinine to more than 1.5 mg/dL (133 micromol/L) was associated with
major pathologic lesions.
These observations and those in the following sections 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. In many countries, such as the United States, patients
who have only hematuria are often not biopsied. However, such individuals
should be monitored periodically because progression to proteinuria and
impaired renal function can occur. (See 'Hematuria without proteinuria' below.)
The potential impact of biopsy criteria on prognosis was evaluated in a
retrospective study that evaluated geographic differences in the clinical course of
711 patients with a biopsy diagnosis of IgA nephropathy [7]. Renal survival at 10
years was 96, 87, 64, and 62 percent in Finland, Australia, Scotland, and
Canada, respectively. The better outcomes in Finland and Australia were largely,
although not completely, attributable to the diagnosis of milder cases (eg, less
proteinuria, higher creatinine clearance, and/or lower blood pressure). This raises
the possibility of lead-time bias influencing the prognosis, as opposed to a better
prognosis in some geographic areas compared with others [7,17].
Clinical predictors of progression — Patients with IgA nephropathy who
develop progressive disease typically have one or more of the following clinical
or laboratory findings at the time of diagnosis, each of which is a marker for more
severe disease [3,4,8-12,18-25]:
●Elevated serum creatinine concentration
●Hypertension (>140/90 mmHg)
●Persistent (eg, for more than six months) protein excretion above
1000 mg/day
Reduced GFR — A reduction in GFR, as manifested by an elevated serum
creatinine concentration at diagnosis or during the course of the disease, is
associated with a worse renal prognosis [3,11,12,22,23,25,26]. The magnitude of
the effect of reduced GFR on prognosis was illustrated in a study from Japan of
2270 patients with IgA nephropathy in which the cumulative incidence of end-
stage renal disease at seven years varied directly and markedly with the serum
creatinine (SCr) at diagnosis (p value for the trend <0.001) [11]:
●SCr ≤1.25 mg/dL (111 micromol/L) – 2.5 percent
●SCr 1.26 to 1.67 mg/dL (111 to 147 micromol/L) – 26 percent
●SCr >1.68 mg/dL (>148 micromol/L) – 71 percent
Hypertension — When present at diagnosis, hypertension or a significant
elevation in blood pressure (eg, from 100/60 to 130/80 mmHg) is predictive of a
worse outcome [10,20,24]. The magnitude of this effect was illustrated in a
prospective study of 332 patients with IgA nephropathy [10]. The cumulative
incidence of dialysis or death was much higher in patients with hypertension
(defined as >140/90 mmHg) at disease discovery compared with those without
hypertension (15 versus 3 percent and 41 versus 6 percent at 10 and 20 years,
respectively).
Similar findings were noted in a second prospective study of 542 patients with
IgA nephropathy [24]. A higher mean arterial pressure was associated with a
higher risk of progressive renal disease, an effect that was seen at all levels of
proteinuria. However, as described in the next section, the degree of proteinuria
was the most important predictor of renal outcome.
It is thought that the adverse prognosis associated with hypertension is primarily
related to its being a marker of more severe glomerular disease. However, if
untreated, hypertension can directly contribute to progressive kidney disease.
(See 'Proteinuria and blood pressure goals' below and "Antihypertensive therapy
and progression of nondiabetic chronic kidney disease in adults", section on
'Blood pressure goal'.)
Protein excretion above 1 g/day — The relationship between increasing
proteinuria and a worse prognosis is related at least in part to proteinuria being a
marker for the severity of glomerular disease. The rate of progression is very low
among patients excreting less than 1000 mg/day and is greatest among those
excreting more than 3 to 3.5 g/day [10-12,20,23-25,27,28].
The importance of the magnitude of proteinuria and its persistence on the course
of IgA nephropathy has been evaluated in several observational studies:
●In a prospective cohort study of 332 patients, the combined incidence of
dialysis or death was significantly higher for patients with protein excretion of
1 g/day or more compared with those excreting less than 1 g/day (17 versus
3 percent and 41 versus 10 percent at 10 and 20 years, respectively) [10].
This study also confirmed the above observation that sustained proteinuria
less than 1 g/day could be used as a practical definition of partial remission
in IgA nephropathy. Over the long term, the incidence of dialysis or death
was much lower in patients who achieved a reduction in protein excretion to
less than 1 g/day with treatment compared with those with persistent protein
excretion above this level (2 versus 29 percent and 2 versus 67 percent at 10
and 20 years, respectively).
●Similar findings were noted in an observational study of 542 patients with
IgA nephropathy who were followed for a mean of 6.5 years [24]. The rate of
decline in renal function was 24 times faster in patients with sustained
proteinuria of more than 3 g/day compared with patients with persistent
 protein excretion below 1 g/day (0.72 versus 0.03 mL/min per 1.73 m2 per
month) (figure 1). 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 to renal failure as patients with sustained proteinuria from
presentation of less than 1 g/day (figure 2).
●In a study from China, patients with less than 500 mg/day had significantly
better outcomes than patients excreting 500 to 1000 mg/day [27]. However,
data regarding the effect of lowering proteinuria to different levels were not
provided, in contrast to the above study (figure 2). Thus, the better prognosis
in patients with protein excretion below 500 mg/day could have reflected less
severe disease or better blood pressure control.
Among patients with IgA nephropathy, proteinuria measured by any method is
predictive of disease progression. A spot urine albumin-to-creatinine ratio (ACR)
may be better at predicting disease progression than other methods of
quantifying proteinuria. One study of 438 Chinese patients with IgA nephropathy
compared the association of urine ACR, urine protein-to-creatinine ratio (PCR),
and 24-hour urine protein excretion (UPE) with disease severity and progression
[29]. In all patients, urine ACR and PCR were quantified at the time of kidney
biopsy; 24-hour UPE was measured within a few days of the procedure. All three
tests correlated well with the severity of chronic kidney disease (CKD), presence
of hypertension, and extent of tubular atrophy and interstitial fibrosis on kidney
biopsy. Urine ACR, compared with PCR and 24-hour UPE, was slightly better at
predicting disease progression (a composite end point of ≥30 percent reduction
in estimated GFR [eGFR], end-stage renal disease, or death).
However, the association between the urine ACR and prognostic outcomes may
be confounded by the fact that low urinary creatinine excretion is an independent
predictor of end-stage renal disease and death [30]. A low urinary creatinine
excretion can cause a spurious increase in urine ACR, but not 24-hour UPE. In
this setting, it may be difficult to differentiate the adverse prognostic implications
of high urinary albumin excretion versus low urinary creatinine excretion. A urine
ACR corrected for estimated creatinine excretion may improve the accuracy of
albuminuria assessment [31].
Even the degree of proteinuria by dipstick at the baseline evaluation has
predictive value. This was demonstrated in a report from Japan of 2270 patients
with biopsy-proven IgA nephropathy who were surveyed three, five, and eight
years after the baseline survey [11]. The seven-year cumulative incidence of
end-stage renal disease was 0.7 percent in patients who had no or trace
proteinuria at presentation compared with 6.4, 18.3, and 30.9 percent in patients
with 1+, 2+, and 3+ proteinuria at presentation. The urine albumin concentration
ranged from less than 30 mg/dLwith a negative or trace positive dipstick to
300 mg/dL or more with a 3+ dipstick.
Acute onset of nephrotic syndrome — Nephrotic-range proteinuria can occur
in more severe IgA nephropathy and is an adverse predictor of prognosis.
However, some patients have an acute onset of nephrotic syndrome and renal
biopsy reveals only mild mesangial proliferation, with the most prominent finding
being diffuse fusion of the foot processes on electron microscopy, similar to that
seen in minimal change (picture 1). Furthermore, many of these patients behave
as if they have minimal change disease, as remission of the nephrotic syndrome
can be induced with glucocorticoid therapy. Whether these patients actually have
IgA nephropathy is unclear. IgA nephropathy may also overlap with membranous
nephropathy. (See "Clinical presentation and diagnosis of IgA nephropathy",
section on 'Minimal change disease and membranous
nephropathy'and "Treatment of minimal change disease in adults", section on
'Glucocorticoid therapy'.)
Hematuria without proteinuria — Patients who have recurrent episodes of
gross hematuria without proteinuria are at low risk for progressive kidney disease
compared with patients who have persistent microscopic hematuria and
proteinuria [3,32]. In addition, isolated persistent hematuria (ie, with little or no
proteinuria) at presentation may be associated with progressive disease over
time [8,11,12,33]. The following observations are illustrative:
●In a study from China, 72 consecutive patients with IgA nephropathy who
underwent renal biopsy because of hematuria with no or minimal proteinuria
(defined as less than 0.4 g/day) were followed for a median of seven years
[8]. Protein excretion above 1 g/day, hypertension, and impaired renal
function (serum creatinine ≥1.4 mg/dL [120 micromol/L]) developed in 33, 26,
and 7 percent, respectively.
●A study from Israel found persistent asymptomatic isolated microscopic
hematuria (proteinuria less than 200 mg/day) in 3690 young adults (0.3
percent of 1.2 million eligible individuals) who were examined for fitness for
military service [33]. At a mean follow-up of 16 years, treated end-stage renal
disease occurred significantly more often than in those without hematuria
(0.70 versus 0.05 percent, adjusted hazard ratio 18.5). Four of the 26
patients had progressive disease had IgA nephropathy on renal biopsy.
Some patients with isolated hematuria (ie, no significant proteinuria or renal
dysfunction at presentation) undergo remission of abnormal laboratory findings,
with reported rates ranging from 5 to 30 percent [13,15-18,34]. Remission
appears to occur most often in 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 [18]. 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 14 percent developed progressive disease.
Acute kidney injury with gross hematuria — Acute kidney injury (AKI) can
occur during episodes of gross hematuria in patients with IgA nephropathy [35-
38]. Renal biopsy in these patients reveals mesangial proliferation and segmental
crescents in a small proportion of glomeruli (usually less than 25 percent)
[35,37,38]. These findings are insufficient to account for the AKI, which has been
ascribed to tubular obstruction by red cell casts [36,37,39]. 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, possibly acting via the local
generation of toxic oxygen free radicals [36,38,39].
The serum creatinine concentration typically returns to baseline levels within
several weeks to months, although dialysis may be temporarily required [36].
However, incomplete recovery of renal function was noted in 9 of 36 patients
(estimated mean GFR after recovery was 38 mL/minversus 89 mL/min) [39].
Significant risk factors for lack of complete recovery included duration of gross
hematuria longer than 10 days, age greater than 50 years, decreased eGFR at
baseline, and more severe tubular necrosis on renal biopsy.
One concern in such patients with known IgA nephropathy is that transformation
to crescentic disease, which has a different prognosis and requires immediate
therapy, can present in a similar fashion. We suggest renal biopsy if, at a
maximum of one week, there is no clear evidence of reversal of the acute
episode. (See 'Crescentic glomerulonephritis' below.)
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
(population stratification):
●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, compared with patients who have the ID or II genotype [40-42].
However, others have reported no correlation between genotype and
outcome [43,44].
●The possible role of two other genes related to the renin-angiotensin
system, the angiotensinogen and angiotensin II receptor genes, has also
been evaluated. No relation was found with the angiotensin II receptor genes
[42,45], while conflicting data have been reported with the angiotensinogen
gene [42,45,46].
●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 two-year follow-up [47]. Upregulation of megsin (a serine
protease inhibitor predominantly expressed in the mesangium) correlated
with mesangial expansion and hypercellularity.
There were conflicting findings in two Italian studies as to whether or not familial
disease is associated with a worse prognosis [25,48]. The much larger series
found no association between familial disease and renal outcomes [25].
(See "Pathogenesis of IgA nephropathy", section on 'Genetic predisposition'.)
At present, none of these genetic associations has proven utility in determining
prognosis and making treatment decisions. However, other genetically
determined factors, such as the level of circulating galactose-deficient IgA
immunoglobulin, may be related to prognosis. (See 'Serologic predictors of
progression' below.)
Other risk factors — Other potentially modifiable risk factors for progressive
disease include obesity [49], hypertriglyceridemia and hyperuricemia [50], and
smoking [51].
Histologic predictors of progression — Although clinical features appear to be
stronger prognostic indicators [20], certain findings on renal biopsy in patients
with IgA nephropathy have been associated with an increased risk of progressive
disease. These include both markers of more severe inflammatory disease,
such as crescent formation and immune deposits in the capillary loops in addition
to the mesangial deposits that are present in all patients, and markers of chronic
fibrotic disease such as glomerulosclerosis, tubular atrophy, interstitial fibrosis,
and vascular disease. [3,12,13,18,22,25,32,52-54].
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 [32,55,56]. These indicators are typical of most glomerular
diseases [57,58]. (See "Secondary factors and progression of chronic kidney
disease", section on 'Tubulointerstitial fibrosis'.)
Oxford classification of IgA nephropathy — A consensus on the pathologic
classification of IgA nephropathy has been developed by the International IgA
nephropathy Network Group working in collaboration with the Renal Pathology
Society [57,58]. In order to develop this classification, clinical data and renal
biopsies were obtained from 265 patients who were followed for a median of five
years. Repeated analysis by several pathologists identified histologic variables
that were consistently interpreted with a high degree of reproducibility. In a
retrospective analysis, the following variables correlated with adverse renal
outcomes independent of the clinical features at baseline and the degree of
proteinuria and blood pressure control during follow-up:
●Mesangial hypercellularity
●Segmental glomerulosclerosis
 ●Endocapillary hypercellularity
●Tubular atrophy/interstitial fibrosis

The Oxford classification has been validated in a European cohort [59], a North
American cohort [60], and a Chinese cohort [61]. The predictive value of each of
the histologic variables appears to be similar in adults and children [62,63]. A
potential weakness of this classification system is that it does not include
crescents or necrotizing lesions, as too few of these lesions were found in the
data set due to inclusion and exclusion criteria. In addition, the prognostic value
of the Oxford classification is diminished in treated patients.
Based upon these observations, the consensus recommendation is that every
biopsy report of IgA nephropathy should include numerical scores based upon
the presence or absence of these variables. A suggested scoring system and the
definitions of the above histologic variables are presented elsewhere.
(See "Clinical presentation and diagnosis of IgA nephropathy", section on 'Oxford
classification of IgA nephropathy'.)
There are no data on the utility of the Oxford classification, independent of
clinical parameters (eg, reduced glomerular filtration and proteinuria above
1 g/day) for determining appropriate therapy. (See 'Patient selection' below.) It
appears that the addition of a classification of glomerular pathology adds
accuracy to prognostication, over and above clinical assessment.
Absolute renal risk score — A prediction score that estimates the five-year risk
of developing end-stage renal disease was developed in a Japanese cohort of
698 untreated patients and then validated in a separate cohort of 702 patients
[64]. Patients were assigned points according to two clinical risk factors and three
of the four Oxford classification criteria:
●24-hour urine protein excretion (0 for <0.5, 4 for 0.5 to 0.99, 6 for 1 to 3.5, or
9 points for 3.5 grams or more)
●eGFR (0 for ≥60, 1 for 30 to 59, 4 for 15 to 29, or 9 points for
<15 mL/min/1.73 m2)
●Mesangial hypercellularity (0 if M0 or 2 points if M1)
●Segmental glomerulosclerosis (0 if S0 or 4 points if S1)
●Tubular atrophy/interstitial fibrosis (0 if T0, 6 if T1, or 10 points if T2)

The five-year incidence of end-stage renal disease varied widely according to the
prediction score; as examples, the incidence was less than 1 percent for patients
whose score was 8 points or less and greater than 50 percent for patients whose
score was 23 points or more.
Another scoring system that estimates the risk of end-stage renal disease or
death at 10 and 20 years was developed in a smaller European study of 332
patients with IgA nephropathy followed for a mean of 12 years [10]. At the time of
diagnosis, patients were assigned an absolute renal risk (ARR) score of 0 to 3
depending upon the presence of hypertension (1 point), protein excretion
≥1 g/day (1 point), and a global optical score (GOS) on renal biopsy ≥8 (1 point).
The GOS is a measure of the severity of glomerular, vascular, tubular and
interstitial lesions observed on the initial biopsy; a value ≥8 represents severe
pathological lesions [10,15].
The incidence of death or dialysis at 10 and 20 years for specific ARR scores
was [10]:
●ARR score of 0 – 2 and 4 percent
●ARR score of 1 – 2 and 9 percent
●ARR score of 2 – 7 and 18 percent
●ARR score of 3 – 29 and 64 percent

However, as noted by the authors and described in earlier papers [24], reducing
protein excretion and treating hypertension significantly improves outcomes.
Thus, it appears that persistence of these risk factors is the most relevant issue
for patient prognosis. (See 'Protein excretion above 1 g/day' above
and 'Proteinuria and blood pressure goals' below.)
Serologic predictors of progression — Compared with healthy subjects
without IgA nephropathy, patients with IgA nephropathy have an increase in the
proportion of aberrantly galactosylated IgA1 (also called galactose-deficient IgA1
[Gd-IgA1]) O-glycoforms in the serum. These aberrantly galactosylated IgA1
molecules are thought to be involved in the pathogenesis of IgA nephropathy.
(See "Pathogenesis of IgA nephropathy", section on 'Poor O-galactosylation of
IgA1'.)
Higher serum levels of aberrantly galactosylated IgA1 may correlate with a higher
likelihood of developing progressive renal failure [65]. In addition, a study of 97
patients with IgA nephropathy of varying severity found that higher titers of
autoantibodies specific for aberrantly galactosylated IgA1 corresponded to both
the absolute renal risk score (mentioned above) and the risk of end-stage renal
disease or death [66]. Thus, testing for either galactose-deficient IgA in the
serum or autoantibodies against abnormal IgA1 molecules may prove to be a
useful prognostic tool in patients with IgA nephropathy.

APPROACH TO THERAPYThe optimal approach to the treatment of IgA

nephropathy is uncertain [67,68]. The slow rate of loss of glomerular filtration rate
(GFR) seen in many patients (1 to 3 mL/min per year) hinders the ability to
perform adequate studies. (See 'Renal prognosis' above.)
There are two approaches to the therapy of IgA nephropathy [2]:
●General interventions to slow progression that are not specific to IgA
nephropathy, including blood pressure control and, in patients with
proteinuria, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II
receptor blockers (ARBs). (See 'Nonimmunosuppressive therapies' below.)
●Therapy with glucocorticoids with or without other immunosuppressive
agents to treat the underlying inflammatory disease.
(See 'Immunosuppressive therapy' below.)
The general interventions are used in all patients at risk for progression (ie, with
proteinuria), while immunosuppressive therapy is used in selected patients.
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 (less than 500 to
1000 mg/day), and a normal GFR are typically not treated and often not
biopsied and therefore not identified as having IgA nephropathy. However,
these patients should be periodically monitored at 6- to 12-month intervals
since there is an appreciable rate of progressive disease as manifested by
increases in proteinuria, blood pressure, and/orserum creatinine.
(See 'Hematuria without proteinuria' above.)
●Patients with persistent proteinuria (above 1 g/day or perhaps above
500 mg/day), a normal or only slightly reduced GFR that is not declining
rapidly, and only mild to moderate histologic findings on renal biopsy are
initially managed with nonimmunosuppressive therapies to slow progression.
Adding fish oil supplements at this stage can be considered.
(See 'Nonimmunosuppressive therapies' below.)
●Patients with more severe or rapidly progressive disease (eg, nephrotic-
range proteinuria or proteinuria persisting despite three to six months of
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.)
●The Oxford histologic classification system may improve the ability to
identify patients with a poor renal prognosis at the time of renal biopsy in
untreated patients [62]. This classification may also allow the identification of
features that are steroid responsive. This was suggested in the original
Oxford classification and also seen in the North American IgA nephropathy
validation study, in which patients with endocapillary proliferation who
received immunosuppressive therapy (largely corticosteroids) had a
markedly lower rate of decline in GFR than those who did not receive this
 therapy [57]. However, such an observation does not prove cause-and-
effect. (See 'Oxford classification of IgA nephropathy'above.)
Monitoring disease activity — There are no specific serologic 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, serum creatinine concentration or estimated glomerular filtration rate
(eGFR), and protein excretion.
●Hematuria – Persistent hematuria is generally a marker of persistent
immunologic activity, but not necessarily of progressive disease. Hematuria
alone does not require any form of therapy but monitoring over time is
essential since some patients develop proteinuria and progressive disease.
(See 'Hematuria without proteinuria' above.)
●Proteinuria – Protein excretion above 1 g/day is a marker of more severe
disease and is a major risk factor for disease progression unless the degree
of proteinuria is reduced. (See 'Protein excretion above 1 g/day' above.)
Because of the prognostic importance of the degree of proteinuria, we
suggest an initial 24-hour urine collection for both protein and creatinine. The
completeness of the 24-hour urine collection can be estimated from the rate
of creatinine excretion. Normal values of creatinine excretion vary with age:
in patients under the age of 50 years, 20 to 25 mg/kg estimated lean body
weight in men and 15 to 20 mg/kg estimated lean body weight in women;
and, in patients between the ages of 50 and 90 years, there is a progressive
50 percent decline in creatinine excretion (to as low as 10 mg/kg estimated
lean body weight in men). (See "Assessment of kidney function", section on
'Limitations of using creatinine clearance'.)
If the initial 24-hour urine collection seems complete, then the rate of protein
excretion is probably an accurate estimate. In this setting, the urine protein-
to-creatinine ratio on this specimen can be related to the total amount of
proteinuria, and the urine protein-to-creatinine ratio on a random specimen
can subsequently be used to monitor the degree of proteinuria, as long as
muscle mass appears stable. (See "Assessment of urinary protein excretion
and evaluation of isolated non-nephrotic proteinuria in adults".)
Increasing proteinuria may be due to ongoing active
disease and/or 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 usually
associated with active disease. Issues related to secondary factors and
progression of any cause of proteinuric chronic kidney disease are discussed
separately. (See "Secondary factors and progression of chronic kidney
disease" and "Antihypertensive therapy and progression of nondiabetic
chronic kidney disease in adults".)
 Protein excretion often falls with therapy with an ACE inhibitor or an ARB,
and the degree of proteinuria is one of the major end points of such therapy.
Protein excretion also may fall spontaneously, particularly during recovery
from an acute episode, following effective immunosuppressive therapy, and
perhaps in children. (See 'Angiotensin inhibition' below.)
●Serum creatinine – The serum creatinine concentration, unless it is rapidly
rising, permits an estimation of the GFR. 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 may
not raise the serum creatinine level to above normal values for a number of
years [12]. Because of a compensatory rise in single-nephron GFR among
less injured glomeruli, a stable normal serum creatinine level or estimated
total kidney eGFR does not necessarily indicate stable disease.
(See 'Reduced GFR' above.)

NONIMMUNOSUPPRESSIVE THERAPIESThere are two main

nonimmunosuppressive therapies in IgA nephropathy [67,68]:
●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 (with elevated LDL
cholesterol) to lower cardiovascular risk. No evidence is available to show
that such therapy slows the rate of progression of renal disease.
Fish oil (omega-3 fatty acids prescription strength and quality) and tonsillectomy
have also been studied, but their roles are less clear.
Angiotensin inhibition — Angiotensin inhibition with an ACE inhibitor or ARB
slows the rate of progression of most proteinuric chronic kidney diseases, an
effect that is mediated at least in part by lowering both the systemic blood
pressure and the intraglomerular pressure, thereby minimizing both proteinuria
and secondary glomerular injury (ie, not due to the primary glomerular disease
itself). (See "Secondary factors and progression of chronic kidney disease",
section on 'Intraglomerular hypertension and glomerular hypertrophy'.)
The clinical trials supporting the efficacy of angiotensin inhibition in proteinuric
chronic kidney disease in general are discussed in detail separately.
(See "Antihypertensive therapy and progression of nondiabetic chronic kidney
disease in adults", section on 'Effect of renin-angiotensin system inhibitors on
progression of CKD' and "Treatment of diabetic kidney disease", section on
'Preservation of renal function'.)
Efficacy — Clinical trial data supporting the efficacy of angiotensin inhibition in
patients with IgA nephropathy are limited, but it is presumed that the
mechanisms of secondary progression (ie, progression not due to the activity of
the underlying disease) are similar to those in other forms of proteinuric chronic
kidney disease. ACE inhibitors and ARBs significantly reduce protein excretion
(to a similar degree) when compared with placebo or the dihydropyridine calcium
channel blocker amlodipine [69,70], an effect that is seen in normotensive as well
as hypertensive patients [71]. By contrast, the non-dihydropyridine calcium
channel blockers diltiazem and verapamil also lower protein excretion [72] and
can be added if the therapeutic goals are not reached with angiotensin inhibition
alone. (See 'Proteinuria and blood pressure goals' below.)
The antiproteinuric effect is mediated by both a reduction in intraglomerular
pressure and improvement in the size-selective properties of the glomerular
capillary wall [73]. Angiotensin inhibitors also lower the blood pressure, and there
is evidence that a goal blood pressure below 130/80mmHg is associated with
improved renal outcomes [74]. (See "Secondary factors and progression of
chronic kidney disease", section on 'Intraglomerular hypertension and glomerular
hypertrophy'.)
The best data supporting greater clinical efficacy of angiotensin inhibition
compared with other antihypertensive drugs on renal outcomes in IgA
nephropathy come from a trial in which 44 patients with proteinuria
(≥0.5 g/day, mean 1.9 g/day) and a serum creatinine concentration
≤1.5 mg/dL(133 micromol/L) at baseline were randomly assigned to
either enalapril or antihypertensive agents other than ACE inhibitors or ARBs
[75]. The target blood pressure was less than 140/90 mmHg, and initially
normotensive patients received a fixed dose of antihypertensive drugs. Blood
pressure control throughout the study was similar in the two groups. 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) and a significant decrease in proteinuria was only
observed in the enalapril group (2 g/day at baseline versus 0.9 g/day at the last
visit). The proteinuria decline after one year of therapy correlated with renal
survival. Another small randomized trial showed benefit from valsartan therapy
compared with placebo [76].
Another randomized trial, IgACE, compared benazepril with placebo in 65 young
patients (range 9 to 35 years) with IgA nephropathy, moderate proteinuria (1 to
3.5 g/day per 1.73 m2), and relatively preserved renal function (creatinine
clearance >50 mL/min per 1.73 m2) [77]; patients were randomly assigned to
benazepril (0.2 mg/kg per day) or placebo. Only five patients were hypertensive.
At a median follow-up of 38 months, the primary end point (greater than a 30
percent decrease in creatinine clearance) was reached by only a few patients
and significant efficacy could not be determined. However, benazepril therapy did
result in a significantly lower incidence of the secondary composite end point
(greater than 30 percent decrease in 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 of
proteinuria (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 was probably small since differences were not observed
in the first three years [78].
Benefit from angiotensin inhibition was also seen in two observational studies
[79,80]. As an example, a report from the Toronto Glomerulonephritis Registry
retrospectively identified 115 patients with IgA nephropathy who had proteinuria
of at least 1 g/day and were followed for 3 to 121 months [79]. The 27 patients
who were treated with an ACE inhibitor, when compared with the 55 patients
treated with other antihypertensive drugs, had the following significant benefits: a
slower rate of loss of creatinine clearance (0.4 versus 1 mL/min per month), a
longer time to loss of one-third of creatinine clearance, and a higher frequency of
remission of proteinuria (18.5 versus 1.8 percent). When compared with the 33
patients who were not treated with antihypertensive drugs, the patients treated
with an ACE inhibitor had the same rates of fall in creatinine clearance and
progression to renal failure and a higher rate of remission of proteinuria, despite
having more severe histologic changes on renal biopsy and a higher initial serum
creatinine.
By contrast, angiotensin inhibition does not appear to be beneficial in non-
proteinuric patients or those with low levels of protein excretion. This was shown
in a trial of 60 Chinese patients with IgA nephropathy, proteinuria below
500 mg/day, normal kidney function, and blood pressure below 140/90 mmHg
who were randomly assigned to ramipril (2.5 mg/day) or placebo [81]. After five
years, there were no differences in the incidence of proteinuria or hypertension
and no differences in the rate of kidney function decline. However, it is unknown
whether or not a benefit would have been identified with longer periods of follow-
up.
The authors and reviewers of this topic do not agree on the level of proteinuria
below which patients do not require angiotensin inhibition. Some would treat all
patients with protein excretion of 500 mg/day or more. Others would treat all
patients with protein excretion of 1 g/day or more, but not those with protein
excretion below 1 g/day. This issue is discussed below. (See 'Proteinuria and
blood pressure goals' below.)
Combination of ACE inhibitor and ARB — The addition of an ARB to an ACE
inhibitor in patients with IgA nephropathy produces a further antiproteinuric effect
in short-term studies [69,82,83]. This finding is consistent with meta-analyses of
trials in different proteinuric glomerular diseases, which found a significant 18 to
25 percent greater reduction in proteinuria with combined ACE inhibitors and
ARBs compared with monotherapy [70,84]. As mentioned above, a more
pronounced antiproteinuric effect to below 1 g/day is a marker for better
outcomes. (See 'Protein excretion above 1 g/day' above.)
Despite these observations, the clinical role of combined therapy in the treatment
of IgA nephropathy is uncertain for the following reasons:
●In most of the clinical trials of proteinuria, combined therapy was compared
with the usual dose rather than a higher dose of a single agent.
●Despite the greater reduction in proteinuria with combined therapy, there
are no randomized trials that have shown that this regimen improves renal
outcomes in patients with proteinuric chronic kidney disease. The one trial
(COOPERATE) that showed benefit from combination therapy has been
retracted by the publisher due to concerns about the reliability of the data
[85]. This issue is discussed separately. (See "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults", section on
'Combination of ACE inhibitors and ARBs'.)
●In the ONTARGET trial, which included 25,620 mostly older patients with
vascular disease or diabetes, there was an increase in adverse side effects
(including a possible increase in mortality) in patients who received
combination therapy with an ACE inhibitor and ARB, compared with patients
who received monotherapy [86]. There was also an adverse effect on renal
outcomes with combination therapy in ONTARGET. Although combination
therapy reduced proteinuria, it was associated with a significantly higher rate
of doubling of the serum creatinine or requirement for dialysis (2.5 versus 2.1
percent with monotherapy at a median follow-up of 4.7 years, hazard ratio
1.24, 95% CI 1.01-1.51) [87]; the increase in renal risk was much greater in
the subset of 608 patients who, at baseline, had proteinuria and an estimated
glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m2 (4.8
versus 2.8 percent per year with monotherapy, hazard ratio 1.63, 95% CI
1.05-2.51) [88].
●The applicability of these observations to IgA nephropathy is unclear since
the patient populations are so different. ONTARGET was a trial of patients at
high cardiovascular risk who had mean age of 66 years. By contrast, the
mean age of patients with IgA nephropathy is much lower (eg, mean 36 to 38
years in two large series described above), and affected patients would
usually be at lower cardiovascular risk [10,24].
The ONTARGET trial is discussed in detail elsewhere. (See "Major side
effects of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers", section on 'Combination of ACE inhibitors and
 ARBs' and "Antihypertensive therapy and progression of nondiabetic chronic
kidney disease in adults", section on 'Combination of ACE inhibitors and
ARBs' and "Treatment of hypertension in patients with diabetes mellitus",
section on 'Avoid combination renin-angiotensin system inhibition'.)
The authors and reviewers of this topic do not agree on whether combination
therapy with ACE inhibitors and ARBs should be used in patients with IgA
nephropathy. Among patients who do not achieve the proteinuria goal (ie, less
than 500 to 1000 mg/day) with monotherapy at the maximum recommended
dose, both the authors and the reviewers would first add other antiproteinuric
therapies (eg, sodium restriction, a diuretic, diltiazem or verapamil, and/or a
mineralocorticoid receptor antagonist) rather than combination therapy with an
ACE inhibitor and ARB. However, should these measures also fail to attain the
proteinuria goal, the authors of this topic suggest that combination ACE inhibitor
and ARB therapy in younger, nondiabetic patients with IgA nephropathy is worth
considering. By contrast, the reviewers of this topic cite the potential harm and
lack of evidence of improved renal outcomes and therefore would not use
combination therapy, even in this selected group. (See "Antihypertensive therapy
and progression of nondiabetic chronic kidney disease in adults", section on
'Effect of antihypertensive drugs on proteinuria'.)
Proteinuria and blood pressure goals — The proteinuria and blood pressure
goals with angiotensin inhibition and other antihypertensive therapies (drugs and
salt restriction) in patients with IgA nephropathy are similar to those in other
causes of proteinuric chronic kidney disease. These goals and how they can be
attained are discussed in detail elsewhere. (See "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults", section on
'Proteinuria goal' and "Antihypertensive therapy and progression of nondiabetic
chronic kidney disease in adults", section on 'Blood pressure goal'.)
IgA nephropathy has some relatively unique features that support attaining a
proteinuria goal of less than 1 g/day in all patients, if possible [24] (see 'Protein
excretion above 1 g/day' above):
●The renal prognosis is progressively worse in IgA nephropathy when protein
excretion exceeds 1 g/day, particularly if persistently above 3 g/day (rate of
loss of glomerular filtration rate [GFR] was 0.72 versus 0.03 mL/min per 1.73
m2 per month in patients with protein excretion of below 1 g/day) (figure 1).
This is in contrast to many other causes of proteinuric chronic kidney
disease, such as membranous nephropathy and primary focal segmental
glomerulosclerosis, in which persistent subnephrotic proteinuria is a predictor
of a relatively good renal prognosis. (See "Focal segmental
glomerulosclerosis: Treatment of primary focal segmental
 glomerulosclerosis", section on 'Degree of proteinuria' and "Treatment of
idiopathic membranous nephropathy", section on 'Prognosis'.)
●Among patients who present with proteinuria of 3 g/day or more, reducing
protein excretion to less than 1 g/day results in a similar rate of progression
to renal failure as in patients with sustained proteinuria from presentation of
less than 1 g/day (figure 2).
In some patients, it is not possible to get below 1 g/day with antiproteinuric
therapy alone. The indications for the addition of immunosuppressive therapy are
discussed below. (See 'Indications for glucocorticoid therapy' below.)
The authors and reviewers of this topic do not agree on the degree of proteinuria
that, independent of hypertension, warrants angiotensin inhibitor therapy. Some
would treat all patients with protein excretion of 500 mg/day or more to a goal
below 500 mg/day as long the patient tolerates angiotensin inhibitor therapy (eg,
absence of a substantial rise in serum creatinine or potassium or hypotension
associated with the initiation of therapy). Others would treat all patients with
protein excretion of 1 g/day or more as tolerated, but not those with protein
excretion below 1 g/day. However, occasional patients with protein excretion
below 1 g/day progress slowly over time. As a result, 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 (rising
proteinuria and/or serum creatinine) with a goal protein excretion of less than
500 mg/day. Independent of protein excretion, angiotensin inhibitors can also be
used to treat hypertension.
The issue of whether to use, if necessary, combination ACE inhibitor and ARB
therapy or one of these agents plus other antihypertensive drugs that can lower
protein excretion is discussed in the preceding section. (See 'Combination of
ACE inhibitor and ARB' above.)
The adverse prognostic effect of high rates of protein excretion in IgA
nephropathy applies primarily to chronic persistent proteinuria and not
necessarily to patients with the acute onset of nephrotic syndrome in whom
mesangial proliferation and IgA deposits may be accompanied by histologic
findings of minimal change disease (particularly diffuse foot process fusion on
electron microscopy). Such patients often go into remission with glucocorticoid
therapy, a response similar to that with minimal change disease alone.
(See 'Acute onset of nephrotic syndrome' above.)
Lipid-lowering therapy — Chronic kidney disease is associated with a marked
increase in cardiovascular risk. The use of statins in patients with chronic kidney
disease is discussed elsewhere. (See "Lipid management in patients with
nondialysis chronic kidney disease" and "Secondary prevention of cardiovascular
disease in end-stage renal disease (dialysis)" and "Chronic kidney disease and
coronary heart disease", section on 'Statin therapy'.)
Although some studies suggested a possible benefit of statin therapy on the
progression of chronic kidney disease, such an effect was not seen in a meta-
analysis and a subsequent large randomized trial (SHARP) that included 6247
patients with chronic kidney disease not requiring dialysis. Statin therapy should
not be used for this purpose. The supportive data are presented in detail
elsewhere.
Fish oil — The possible role of fish oil (prescription strength omega-3 fatty acids
not over-the-counter food supplements) in patients with IgA nephropathy, which
might act by anti-inflammatory mechanisms, is not well defined [89]. In addition to
uncertain efficacy and consistency in omega-3 fatty acid content, there is an
associated fishy aftertaste and eructations with this treatment that often limit
patient acceptance [90].
Randomized trials evaluating fish oil in patients with IgA nephropathy have
reported conflicting results [90-97]. A Cochrane meta-analysis of four trials
including the two major trials discussed below showed no overall beneficial effect
of fish oil on renal outcomes including serum creatinine, creatinine clearance, or
change in proteinuria, although small benefits were possible [69]. The two largest
trials illustrate the range of findings:
●In the largest and best quality trial from the Mayo Clinic, 106 patients with a
mean baseline creatinine clearance of 82 mL/min and protein excretion of
2.5 to 3.2 g/day were randomly assigned to therapy with either 12 g of fish oil
or a similar amount of olive oil for two years [90]. There was no difference in
blood pressure control and no significant 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 end-stage renal
disease at four years (10 versus 40 percent). With follow-up extended to
more than six years, the benefits of continuous fish oil therapy persisted (15
versus 37 percent incidence of end-stage renal disease) [93].
●In a trial by the Southwest Pediatric Nephrology Study Group, 96 patients
(mean GFR of >100 mL/min per 1.73 m2 and estimated protein excretion
from the urine protein-to-creatinine ratio of 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 [96]. 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
Mayo Clinic trial evaluated patients with more advanced disease (more
proteinuria and lower creatinine clearance at baseline). In addition, partial
remission, defined by reductions in proteinuria, was not considered in these
trials [57].
In summary, a benefit from fish oil has not been clearly established. However,
fish oil (3.3 g/day or more) can be tried in patients with risk factors for
progression as long as it is not used to the exclusion of other therapies that are
proven to be effective [2,98]. Fish oil may have cardiovascular benefits and is
unlikely to be harmful. (See "Fish oil and marine omega-3 fatty acids".)

IMMUNOSUPPRESSIVE THERAPYThe optimal role of anti-inflammatory

therapy in IgA nephropathy is uncertain [67,68]. A variety of regimens have been
used, mostly consisting of anti-inflammatory doses of glucocorticoids alone or in
combination 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 [3,4,98-101]. For patients with stable or slowly
progressive disease, angiotensin inhibition is initiated prior to
immunosuppressive therapy.
Indications for glucocorticoid therapy — The indications for the use of
glucocorticoids alone or in combination with other immunosuppressive drugs in
patients with IgA nephropathy are not well defined, and one must take into
account the potential toxicity of these drugs. Most nephrologists do not treat mild,
stable, or very slowly progressive IgA nephropathy with glucocorticoids or other
immunosuppressive therapies [102,103].
In general, we suggest anti-inflammatory therapy with glucocorticoids in patients
with clinical features supporting active disease and progression, which include
hematuria in addition to one or more of the following:
●A progressively declining glomerular filtration rate (GFR)
●Persistent proteinuria above 1 g/day after maximal antiproteinuric therapy
with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II
receptor blockers (ARBs) for three to six months
●Morphologic evidence of active disease based upon kidney biopsy (eg,
proliferative or necrotizing glomerular changes)
However, we suggest not treating with glucocorticoids in patients with chronically
elevated serum creatinine or histologic evidence of prominent glomerulosclerosis
and tubulointerstitial atrophy or fibrosis. (See 'Lack of benefit in chronic fibrotic
disease' below.)
Combined immunosuppressive therapy can be considered in patients with more
severe disease as defined by a more rapidly progressive clinical
course and/or histologic evidence of severe active inflammation (eg, crescent
formation). (See 'Combined immunosuppressive therapy' below.)
In addition, patients with acute onset of nephrotic syndrome and diffuse foot
process fusion on renal biopsy are treated as if they have minimal change
disease. (See 'Acute onset of nephrotic syndrome' above and "Treatment of
minimal change disease in adults".)
Lack of benefit in chronic fibrotic disease — Patients with a chronically
elevated serum creatinine level of 2.5 mg/dL (221 micromol/L) or greater and
prominent glomerulosclerosis and tubulointerstitial atrophy or fibrosis on renal
biopsy are not likely to benefit from immunosuppressive therapy and may be
harmed from adverse drug effects. In a randomized trial of 32 such patients, the
renal outcomes were not improved with mycophenolate mofetil compared with
placebo [26]. However, such patients who have proteinuria may still benefit from
angiotensin inhibition. (See 'Angiotensin inhibition' above and 'Histologic
predictors of progression' above.)
Glucocorticoids as sole immunosuppressive/anti-inflammatory
therapy — With the exception of patients described later who appear to have
minimal change disease as the cause of nephrotic syndrome (rather than IgA
nephropathy), we use glucocorticoids only after angiotensin inhibition has failed
to lower proteinuria to goal. In addition, angiotensin inhibition is continued in
combination with the glucocorticoids, rather than being replaced by
glucocorticoids. (See 'Patients with apparent minimal change disease' below.)
The potential benefit of glucocorticoid therapy in IgA nephropathy was examined
in a 2012 meta-analysis of nine randomized trials including 536 patients with
proteinuria (above 1 g/day) and relatively preserved renal function [104]. The
primary end point of the analysis was a renal event, defined as a doubling of
serum creatinine, a 50 percent decline in GFR, or end-stage renal disease,
depending upon the study. The nine trials were heterogenous with respect to the
glucocorticoid regimen (eg, high- versus low-dose, short- versus long-term),
duration of follow-up (6 months to 10 years), the use of a placebo control, and
concurrent therapy with ACE inhibitors. The major findings were as follows:
 ●Glucocorticoid therapy significantly reduced the incidence of renal events
compared with the control (2.4 versus 15 percent; relative risk reduction 0.32
[95% CI 0.15 to 0.67]). Glucocorticoids were also beneficial when only end-
stage renal disease events were considered.
●The two trials in which glucocorticoids combined with ACE inhibitors were
compared with ACE inhibitors alone produced findings consistent with the
overall result (2.5 versus 19 percent of patients having renal events),
suggesting that the addition of glucocorticoids to ACE inhibitors may be
beneficial in patients with proteinuria and preserved renal function.
●The benefit of therapy was greater in trials that used higher doses of
glucocorticoids and when treatment with glucocorticoids lasted less than 12
months. By contrast, baseline renal function (serum creatinine above or
below 1.1 mg/dL [97.2 micromol/L]) and baseline proteinuria (above or below
2 g/day) had no apparent effect on whether or not glucocorticoid therapy was
beneficial.
●Adverse events were more likely to occur with glucocorticoid therapy (24
versus 13 percent of patients experiencing an adverse event), although the
majority of these adverse events were weight gain and cushingoid features.
In addition to the small number of events, the confidence in the findings of this
meta-analysis is diminished by several additional concerns: eight of the nine
trials used open-label designs; six of the nine trials failed to report that
randomization was concealed; and four of the nine trials failed to use an
intention-to-treat analysis.
Since the publication of this meta-analysis, there have been two additional trials
evaluating the benefit and risks of glucocorticoids in IgA nephropathy:
●In one trial (Supportive Versus Immunosuppressive Therapy of Progressive
IgA Nephropathy [STOP-IgAN] trial), 162 patients with IgA nephropathy,
estimated GFR (eGFR) of ≥30 mL/min/1.73 m2, and proteinuria of 0.75 to
3.5 g/day despite six months of comprehensive supportive therapy (that
included ACE inhibitors, ARBs, or both, targeting a blood pressure
of <125/75 mmHg) were randomly assigned to continue supportive care or to
receive immunosuppression in addition to supportive care [105]. Of the 82
patients assigned to immunosuppressive therapy, 55 had an eGFR that was
≥60 mL/min/1.73 m2 and received glucocorticoid monotherapy (1 g of
intravenous methylprednisolone for three consecutive days at the beginning
of months 1, 3, and 5, combined with 0.5 mg/kg of oral prednisolone given on
alternate days), and 27 had an eGFR that was 30 to 59 mL/min/1.73 m2 and
received combination immunosuppression (a tapering daily dose of
oral prednisone combined with 1.5 mg/kg/day of oral cyclophosphamide for
three months followed by 1.5 mg/kg/day of azathioprine until month 36).
At three years, the rate of full clinical response (ie, a decrease in protein-to-
creatinine ratio to <0.2 g/g plus preservation of eGFR) was higher with
immunosuppressive therapy (17 versus 5 percent) [105]. This result was due
primarily to a proteinuria decrease in patients who were treated with
glucocorticoid monotherapy: a decrease in protein-to-creatinine ratio to
<0.2 g/g at three years occurred in 11 percent of patients who received
supportive care only, 31 percent of those who received glucocorticoid
monotherapy, and 11 percent of those who received combination
immunosuppression. By contrast, the change in eGFR was similar between
those who did and did not receive immunosuppression. Also, patients
receiving immunosuppression had a higher rate of infections, impaired
glucose tolerance, and weight gain.
Although this trial suggests that immunosuppressive therapy might not help
preserve kidney function in patients with IgA nephropathy, the findings are
not directly applicable to our treatment suggestions (see 'Indications for
glucocorticoid therapy' above). The inclusion of patients with less severe
proteinuria (ie, <1 g/day) and possibly patients with chronic fibrotic disease
(no morphologic data was reported) may have obscured a beneficial effect of
glucocorticoid monotherapy. In addition, the study was not powered to find a
benefit from glucocorticoid monotherapy on preservation of GFR.
Treatment with cyclophosphamide, which was not beneficial in this trial,
should be reserved for patients who have crescentic IgA nephropathy.
(See 'Crescentic glomerulonephritis' below.)
●A second randomized, controlled trial (Therapeutic Evaluation of Steroids in
IgA Nephropathy Global [TESTING] study) evaluated the efficacy and safety
of oral glucocorticoids versus supportive therapy alone in 262 patients with
IgA nephropathy, eGFR of 20 to 120 mL/min/1.73 m2, and proteinuria of
>1 g/day after at least three months of supportive therapy (blood pressure
control with maximally tolerated ACE inhibitor or ARB therapy) [106]. At
baseline, mean eGFR was 59.4 mL/min/1.73 m2 and mean proteinuria was
2.40 g/day. Patients were randomly assigned to oral methylprednisolone (0.6
to 0.8 mg/kg/day with a maximum dose of 48 mg/day) or placebo for two
months, followed by a monthly 8 mg/day dose taper for a total treatment
duration of six to eight months; supportive therapy was continued in all
patients. The initial primary endpoint was a composite of end-stage renal
disease (ESRD), death due to renal failure, or a 50 percent decrease in
eGFR; the eGFR component was later changed to a 40 percent decrease in
eGFR. Safety outcomes included serious infection, new-onset diabetes,
gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular
events.
Although the trial intended to enroll 750 patients from five different countries,
the study was terminated early because of an excess of serious adverse
effects reported in the methylprednisolone arm; consequently, only 262
 patients from two countries (>95 percent China, remainder from Australia)
were recruited at the time of study discontinuation. At a median of 2.1 years,
serious adverse events (mostly serious infection) occurred in 14.7 percent of
patients who received methylprednisolone compared with 3.2 percent of
those who received placebo. The primary renal endpoint occurred in fewer
patients in the glucocorticoid group than the placebo group (5.9 versus 15.9
percent, respectively); however, given the premature termination of the study
and short follow-up, definitive conclusions about the benefit of treatment
could not be drawn. In addition, given the homogeneous patient population
studied (more than 95 percent Asian), the study findings, particularly the high
rate of serious adverse events, are not necessarily generalizable to all
patients with IgA nephropathy. Other trials evaluating similar doses of
glucocorticoids in patients with IgA nephropathy have not reported such high
rates of serious adverse events [107].
Given the uncertainty about the optimal dosing of glucocorticoids in the
treatment of IgA nephropathy, another clinical trial evaluating the efficacy
and safety of lower doses of oral glucocorticoids compared with a placebo
control (TESTING Low Dose Study [NCT01560052]) is in progress.
Glucocorticoid regimen — The two largest trials included in the meta-analysis
described above treated patients with glucocorticoids for six months and are
briefly described here:
●A randomized trial from Italy included 86 adults with moderate proteinuria (1
to 3.5 g/day) and, at most, a mild reduction in GFR (median serum creatinine
1 mg/dL [88 micromol/L]) [108]. The patients were randomly assigned to
supportive therapy alone or glucocorticoids (1 g of
intravenous methylprednisolone for three consecutive days at the beginning
of months 1, 3, and 5, combined with 0.5 mg/kg of oral prednisolone given on
alternate days for six months). ACE inhibitors were not used routinely in this
trial. At 5 and 10 years, the glucocorticoid treated patients had a significantly
lower incidence of the primary end point, which was a doubling in the serum
creatinine concentration (2 versus 21 percent at 5 years and 2 versus 30
percent at 10 years) [109].
●Another multicenter trial from Italy randomly assigned 97 patients with IA
nephropathy, protein excretion greater than 1 g/day (mean 1.6 g/day),and
eGFR greater than 50 mL/min per 1.73 m2 (mean 99 mL/min per 1.73 m2) to
combined therapy with ramipril and a six-month course of prednisone (0.8 to
1 mg/kg per day for two months followed by monthly dose reductions of
0.2 mg/kg per day during the next four months) or to ramipril alone [107].
Prednisone therapy reduced the rate of the primary end point of doubling of
the serum creatinine or end-stage renal disease (4 versus 27 percent) at
 eight years. Prednisone also reduced the incidence of end-stage renal
disease (2 versus 14 percent).
We agree with the 2012 KDIGO guidelines that either of these two glucocorticoid
regimens is acceptable in patients with IgA nephropathy who are selected for
immunosuppressive therapy [2].
Patients with apparent minimal change disease — There is a subset of
patients with IgA nephropathy in whom glucocorticoid therapy alone is clearly
beneficial: those with 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 similarly, usually going into
remission with glucocorticoid therapy and occasionally requiring other
immunosuppressives for frequently relapsing proteinuria [110-112]. Mesangial
IgA deposits often disappear or are greatly reduced over time [112]. It is possible
that these patients have minimal change disease and that the presence of IgA
deposits is unrelated, particularly in Asian patients [110,112]. (See 'Acute onset
of nephrotic syndrome' above and "Clinical presentation and diagnosis of IgA
nephropathy", section on 'Minimal change disease and membranous
nephropathy' and "Treatment of minimal change disease in adults", section on
'Glucocorticoid therapy'.)
Combined immunosuppressive therapy — Combined immunosuppressive
therapy can be considered in patients with more severe 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 disease on biopsy; however, most of these trials did not include a
comparison group treated with prednisone alone [99,113-117]. In addition, the
studies were primarily performed prior to the widespread use of aggressive
antihypertensive and antiproteinuric therapy with ACE inhibitors or ARBs.
(See 'Angiotensin inhibition' above and 'Proteinuria and blood pressure
goals' above.)
There are limited data concerning the effectiveness of cytotoxic agents in adults
with progressive IgA nephropathy [102,113-115,118]. Two trials, which are
discussed below, evaluated prednisone with either cyclophosphamide followed
by azathioprine [115] or with azathioprine alone [118]. Trials with more
complicated regimens have been evaluated in children. (See 'Severe disease in
children' below.)
Glucocorticoids plus cyclophosphamide followed by azathioprine — The
efficacy of initial therapy with glucocorticoids plus cyclophosphamide followed by
maintenance therapy with azathioprine was evaluated in 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 micromol/L, respectively) that was
declining at a relatively moderate rate (by at least 15 percent over the year prior
to study entry) [115]. Mean baseline protein excretion was 4 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 followed by azathioprine [67].
Early therapy is important because improvement is rare when the baseline serum
creatinine concentration is greater than 3 mg/dL (265 micromol/L)in the absence
of crescentic glomerulonephritis [98]. In addition, immunosuppressive therapy is
not indicated in the spontaneously reversible acute renal failure that may be
associated with gross hematuria. (See 'Acute kidney injury with gross
hematuria' above.)
Glucocorticoids plus azathioprine — The addition of azathioprine does not
appear to provide further benefit compared with glucocorticoid alone. This was
shown in a multicenter randomized trial in which 207 patients with a serum
creatinine ≤2 mg/dL (177 micromol/L) and protein excretion >1 g/day were
treated with glucocorticoids (a three-day pulse of methylprednisolone in months
1, 3, and 5 in addition to oral prednisone0.5 mg/kg every other day) with or
without azathioprine (1.5 mg/kg per day for six months) [118]. At a median follow-
up of 4.9 years, there was no difference in renal survival time, defined as the time
to a 50 percent increase in plasma creatinine from baseline. Protein excretion
decreased in both groups from a median of 2 to 1.3 g/day during the first year of
follow-up, but there was no between-group difference. Major side effects were
more frequent among those who received azathioprine compared to those who
did not (17 versus 6 percent, respectively).
This trial is limited by the fact that fewer than one-half of patients were treated
with an ACE inhibitor or ARB at the onset and therefore were not receiving the
current standard of care [119]. In addition, there was no run-in period during
which supportive therapy was optimized. Thus, low-risk patients who may have
responded to nonimmunosuppressive therapy may have been included in the
trial, possibly obscuring a potential benefit of azathioprine in patients who were at
high risk for progression.
The role of combined immunosuppressive therapy in the treatment of severe or
progressive IgA nephropathy is summarized below.
Severe disease in children — Two trials from the Japanese Pediatric IgA
Nephropathy Study group evaluated children (mean age 12 years) with newly
diagnosed severe disease defined as diffuse mesangial proliferation on renal
biopsy, with crescents in 22 percent of glomeruli and sclerosis in 5 percent of
glomeruli [116,117]. Despite the marked pathologic changes, the mean creatinine
clearance was normal (approximately 150 mL/min per 1.73 m2), mean urinary
protein excretion was approximately 1.2 g/day, and the mean blood pressure
was 115/65 mmHg. Both trials supported a benefit from combination
immunosuppressive therapy:
●In the first trial, 78 children were randomly assigned to heparin-warfarin
and dipyridamole alone or with prednisolone and azathioprine for two years
[116]. The outcomes at the end of the trial were significantly better in the
children treated with the regimen that included prednisolone and azathioprine
(group 1) compared with heparin-warfarin and dipyridamole alone (group 2):
mean urinary protein excretion and serum IgA levels fell in group 1 but was
stable in group 2; and the percent of glomeruli with sclerosis was stable in
group 1 and increase in group 2. The blood pressure and serum creatinine
remained normal in all but one patient. In a 10-year follow-up study that
included 74 of the 78 children, end-stage renal disease had developed in
fewer patients who received prednisolone and azathioprine compared with
control therapy (5 versus 14.7 percent, respectively) [120].
●In the second trial, 80 children were randomly assigned
to prednisolone, azathioprine, warfarin, and dipyridamole or to prednisolone
alone [117]. At two-year follow-up, patients treated with combination therapy
 had a significantly higher rate of achieving the primary end point of
disappearance of proteinuria (less than 0.1 g/m2 per day; 92 versus 74
percent) and had no change in the percentage of sclerotic glomeruli
compared with an increase from 3 to 15 percent with prednisolone alone.
Crescentic glomerulonephritis — The treatment of crescentic, rapidly
progressive glomerulonephritis in patients with IgA nephropathy has not been
evaluated in randomized trials. Observational data 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/orplasmapheresis [121-125]. Glucocorticoids may
act in this setting by diminishing acute inflammatory injury rather than by
correcting in the factors responsible for IgA production and deposition [126].
(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 [123]. 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 IgA nephropathy who had a mean serum
creatinine concentration of 2.7 mg/dL (240 micromol/L) and protein excretion of
4 g/day at baseline [125]. 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, and 0.3 mg/kg per day for 60 days; all patients were 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 were significant reductions in the serum
creatinine concentration (2.7 to 1.5 mg/dL [240 to 133 micromol/L]) and in protein
excretion (4 to 1.4 g/day). Repeat renal 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 less than 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 end-stage renal disease 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 'Summary and
recommendations' below.)
Unclear role for other immunosuppressive agents — In addition to the above
regimens, mycophenolate mofetil and cyclosporine have been evaluated for the
treatment of IgA nephropathy.
Mycophenolate mofetil — There are limited data concerning the efficacy
of mycophenolate mofetil (MMF) in the primary treatment of progressive IgA
nephropathy. Three small, prospective placebo-controlled randomized trials
evaluated the efficacy of MMF therapy; the patients were also treated with ACE
inhibitors. The trials had conflicting results, ranging from no benefit [26,127],
particularly in patients with advanced fibrotic disease [26], to a reduction in
proteinuria and a decrease in rate of decline in GFR [128,129]. Another trial that
compared the combination of MMF and lower-dose prednisone (0.4 to
0.6 mg/kg/day) with full-dose prednisone (0.8 to 1 mg/kg/day) found no difference
in complete remission rates at 6 and 12 months [130]. Some of the authors and
reviewers of this topic would consider the use of MMF in selected patients and
some would not use it in any patients. In addition, the KDIGO clinical practice
guidelines do not recommend the use of MMF as first-line therapy [2].
MMF is associated with increased fetal risk and should not be used in women
who are or might become pregnant. (See "Mycophenolate: Overview of use and
adverse effects in the treatment of rheumatic diseases", section on 'Pregnancy'.)
Calcineurin inhibitors — Cyclosporine and tacrolimus have been investigated
in small series of patients with IgA nephropathy [131-134]. Although proteinuria
may be reduced, the use of these agents 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 [131,132,134]. In addition, relapse
may occur soon after the drug is discontinued.
Based upon the available data, we do not use these drugs for the treatment of
IgA nephropathy pending further studies showing benefit. The observation
that cyclosporine appears to be effective treatment of nephrotic-range proteinuria
in IgA vasculitis (Henoch-Schönlein purpura), where the renal biopsy findings are
those of IgA nephropathy, provides indirect evidence of possible benefit
[135,136]. (See "IgA vasculitis (Henoch-Schönlein purpura): Renal
manifestations", section on 'Approach in children'.)
Rituximab — We do not routinely use rituximab in the treatment of patients with
IgA nephropathy. As mentioned above, increased circulating levels of aberrantly
galactosylated IgA1 (also called galactose-deficient IgA1 [Gd-IgA1]) and
autoantibodies against Gd-IgA1 are associated with an increased risk of disease
progression. B cell-depleting therapies such as rituximab have been used in the
treatment of other renal diseases mediated by autoantibodies and could
theoretically remove the autoantibodies that drive the progression of IgA
nephropathy. (See 'Serologic predictors of progression' above.)
The efficacy of rituximab was evaluated in a small open-label randomized trial of
34 patients with biopsy-proven IgA nephropathy (with <50 percent
glomerulosclerosis or interstitial fibrosis), proteinuria of >1 g/day, and estimated
GFR (eGFR) or measured creatinine clearance of <90 and >30 mL/min per 1.73
m2 [137]. Patients were randomly assigned to rituximab (two infusions of 1 g
administered two weeks apart, followed by an identical course six months later;
17 patients) or no rituximab (17 patients); all patients were maintained on ACE
inhibitor and/or ARB therapy. At baseline, median proteinuria (2.1 g/day) and
serum creatinine (1.4 mg/dL) were similar between treatment groups; however,
median eGFR was lower in patients assigned to rituximab (40 versus
61 mL/min per 1.73 m2). At 12 months, there was no difference in the change in
proteinuria or change in renal function from baseline between the two groups.
Although treatment with rituximab resulted in the successful depletion of CD19+
B cells at both 6 and 12 months, there were no differences in serum levels of Gd-
IgA1 or IgG autoantibodies against Gd-IgA1 between the groups at baseline and
at 12 months. No patients experienced serious adverse events, but mild adverse
effects occurred more frequently among rituximab-treated patients.

OTHER POSSIBLE INTERVENTIONSOther interventions that have been

evaluated in an uncontrolled fashion include tonsillectomy, a low-antigen diet,
intravenous immune globulin, and wormwood [69]. Other drugs, such as vitamin
D analogs [138-140], phenytoin [69], antiplatelet agents [69], and danazol [141]
have also been evaluated, but data are 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
[142,143]. However, aside from such patients who require tonsillectomy for
conventional reasons, the available evidence suggests that tonsillectomy
should not be routinely performed in patients with IgA nephropathy [2].
(See "Pathogenesis of IgA nephropathy", section on 'Source and regulation of
pathogenic IgA synthesis'.)
Several retrospective studies [143-146] and at least one prospective study [147]
suggest that tonsillectomy, usually in combination with some immunosuppressive
therapy, is associated with improved renal outcomes in patients with IgA
nephropathy and relatively mild renal injury. However, other studies reported no
overall benefit following tonsillectomy [148-150].
The best data come from a randomized trial of 72 patients from Japan with IgA
nephropathy, protein excretion 1 to 3.5 g/day (mean, 1.6 g/day), and serum
creatinine ≤1.5 mg/dL (≤132.6 micromol/L) [150]. Approximately half of the
patients were taking angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs) at baseline. All patients received
oral prednisolone (0.5 mg/kg) for six months plus 500 mg of
intravenous methylprednisolone for three days at baseline and then again at
months 2 and 4. Those assigned tonsillectomy underwent the operation one to
three weeks before the onset of glucocorticoid therapy. The following results
were observed at 12 months:
●Remission rates (defined as reduction of proteinuria to <0.3 g/g creatinine
and hematuria to <5 cells per high-powered field) were nonsignificantly
higher in the tonsillectomy group (approximately 50 versus 30 percent)
●The proportion of patients achieving proteinuria of <0.3 g/g creatinine was
nonsignificantly larger with tonsillectomy (approximately 60 versus 40
percent)
In addition to the small sample size, limited statistical power, and short duration
of follow-up, some patients crossed over to the alternative treatment group, some
initiated ACE inhibitor or ARB therapy during the course of follow-up (which could
bias the results), and nearly 20 percent of patients were either discontinued or
lost to follow-up [151]. Thus, larger randomized trials with a lower risk of bias and
extended follow-up are required before tonsillectomy can be recommended in
patients with IgA nephropathy.
The available long-term follow-up data in patients undergoing tonsillectomy come
solely from nonrandomized studies. A meta-analysis of four case-control studies,
for example, demonstrated a lower rate of end-stage renal disease among
patients who had tonsillectomy plus glucocorticoids compared with nonoperative
therapy with a pooled odds ratio of 0.22 (95% CI 0.11-0.44) [152]. The rate of
clinical remission at 5 and 10 years was higher in the tonsillectomy group.
Nearly all studies of tonsillectomy in patients with IgA nephropathy were
performed in Asian populations, and whether the ancestry of such patients
determines in part the response to various forms of therapy, including
tonsillectomy, is unknown.
Low-antigen diet — A low-antigen diet consists of avoiding gluten, dairy
products, eggs, and most meats [153]. 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 was markedly reduced or fell into the normal range in 11 of the 12
patients whose baseline rate was more than 1 g/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 did not demonstrate improvement in
either proteinuria or renal function despite a reduction in the level of circulating
IgA-containing immune complexes [154].
Intravenous immune globulin — At least part of the rationale for
intravenous immune globulin (IVIG) therapy in IgA nephropathy comes from the
observation that partial IgG deficiency, which could be corrected with IVIG, may
predispose to infections that could trigger flare-ups of the renal disease [155].
High-dose IVIG has been tried in severe IgA nephropathy, characterized by
heavy proteinuria and a relatively rapid decline in glomerular filtration rate (GFR)
[156]. Eleven patients (nine with IgA nephropathy and two with the related
disorder, IgA vasculitis [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. IVIG
therapy was associated with 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 in a larger number of patients.
Budesonide — An oral targeted-release formulation of the
glucocorticoid budesonide (TRF-budesonide) has been designed to release the
drug in the ileocecal region where Peyer patches are located. Mucosal B
lymphocytes localized within Peyer patches are postulated to be a source for the
production of aberrantly galactosylated IgA1, which has been implicated in the
pathogenesis of IgA nephropathy. (See "Pathogenesis of IgA nephropathy",
section on 'Poor O-galactosylation of IgA1'.)
Based upon the results of an early pilot study [157], the safety and efficacy of
TRF-budesonide was evaluated in a randomized, double-blind, placebo-
controlled phase 2b trial of 149 patients with IgA nephropathy, estimated GFR
(eGFR) of ≥45 mL/min/1.73 m2, and persistent proteinuria (urine protein-to-
creatinine ratio [UPCR] of >0.5 g/g or 24-hour urine protein excretion of
≥0.75 g/day) despite six months of optimized ACE inhibitor and/or ARB therapy
[158]. Patients were randomly assigned to TRF-budesonide at 8 mg/day, TRF-
budesonide at 16 mg/day, or placebo for nine months; all patients continued to
receive optimized renin-angiotensin system blockade. Treatment with TRF-
budesonide, compared with placebo, resulted in a greater reduction in UPCR
from baseline at 9 and 12 months (20 and 28 percent decrease for 8 mg/day and
16 mg/day, respectively, versus 0.4 percent increase for placebo at 12 months).
At nine months, eGFR remained stable among patients treated with TRF-
budesonide but decreased among those treated with placebo. Body weight,
blood pressure, and hemoglobin A1c did not change significantly from baseline
among patients treated with TRF-budesonide compared with placebo; however,
the rate of glucocorticoid-related adverse events was much greater among
patients who received TRF-budesonide, including the development of Cushingoid
features in approximately 40 percent, suggesting that the drug is systemically
absorbed. Limitations of this study include lack of a formal statistical analysis of
the primary end point at nine months; a high dropout rate among patients in the
TRF-budesonide treatment groups (22 and 29 percent for 8 mg/day and
16 mg/day, respectively, versus 8 percent for placebo), primarily due to adverse
events; and a short study duration that precluded assessment of long-term
outcomes.
Additional studies will be required to establish a role for TRF-budesonide in
patients with IgA nephropathy, particularly in comparison with low-dose oral
bioavailable glucocorticoids.

PREGNANCYPregnancy is generally well tolerated in patients with IgA

nephropathy and a normal or near-normal glomerular filtration rate (GFR) [159].
As with most other chronic kidney diseases, the risk of worsening renal disease
with pregnancy is increased in women with an initial GFR below
70 mL/min,uncontrolled hypertension, or severe arteriolar and tubulointerstitial
disease on renal biopsy [160,161]. (See "Pregnancy in women with nondialysis
chronic kidney disease".)
Angiotensin inhibitors 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 "Adverse effects of angiotensin
converting enzyme inhibitors and receptor blockers in pregnancy" and "Safety of
rheumatic disease medication use during pregnancy and lactation".)

END-STAGE RENAL DISEASEPatients who progress to end-stage renal

disease can be treated with dialysis or transplantation. Issues related to recurrent
disease in the transplant are discussed elsewhere. (See "IgA nephropathy:
Recurrence after transplantation".)

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Glomerular disease in adults".)

INFORMATION FOR PATIENTSUpToDate offers two types of patient

education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on "patient
info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: IgA nephropathy (The Basics)")

SUMMARY AND RECOMMENDATIONS

Background
●IgA nephropathy is the most common cause of primary (idiopathic)
glomerulonephritis in the developed world. Slow progression to end-stage
renal disease occurs in up to 50 percent of affected patients, often over 20 to
25 years of observation. The remaining patients enter a sustained clinical
remission or have persistent low-grade hematuria and/or proteinuria.
(See 'Introduction' above.)
●Clinical predictors of progression of IgA nephropathy include elevated
serum creatinine, hypertension, and persistent protein excretion above
1000 mg/day. Patients who have recurrent episodes of gross hematuria
without proteinuria are at low risk for progressive kidney disease.
(See 'Clinical predictors of progression' above.)
 ●Histologic findings on renal biopsy in patients with IgA nephropathy have
been associated with an increased risk of progressive disease. These
include both markers of more severe inflammatory disease, such as crescent
formation, and immune deposits in the capillary loops in addition to the
mesangial deposits that are present in all patients, and markers of chronic
fibrotic disease such as glomerulosclerosis, tubular atrophy, interstitial
fibrosis, and vascular disease. The Oxford classification is a pathologic
classification that identified several variables that correlated with adverse
renal outcomes independent of the clinical features, including mesangial
proliferation, endocapillary proliferation, segmental glomerulosclerosis, and
tubulointerstitial fibrosis. It has been validated in numerous cohorts.
(See 'Histologic predictors of progression' above.)
●Acute kidney injury can occur in patients during episodes of gross
hematuria. This is usually due to acute tubular necrosis, and the serum
creatinine concentration typically returns to baseline levels within several
weeks. However, acute kidney injury can also represent transformation to
crescentic disease, which requires immediate therapy. Among patients with
IgA nephropathy who have an acute deterioration of renal function that does
not improve within a maximum of a week's observation, we suggest a repeat
renal biopsy to exclude crescentic disease. (See 'Acute kidney injury with
gross hematuria' above.)
Management
●There are two major approaches to the therapy of IgA nephropathy
(see 'Approach to therapy' above):
•Nonimmunosuppressive therapies to slow progression, including blood
pressure control and, in patients with proteinuria, angiotensin-converting
enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs); and
fish oil. (See 'Nonimmunosuppressive therapies'above.)
•Immunosuppressive therapy with glucocorticoids, with or without other
immunosuppressive agents, to treat the underlying inflammatory
disease. (See 'Immunosuppressive therapy' above.)
●Patients with isolated hematuria, no or minimal proteinuria (less than 500 to
1000 mg/day), and a normal glomerular filtration rate (GFR) are typically not
treated and often not biopsied and therefore not identified as having IgA
nephropathy. However, these patients should be periodically monitored at 6-
to 12-month intervals since there is an appreciable rate of progressive
disease as manifested by increases in proteinuria, blood
pressure, and/or serum creatinine. (See 'Hematuria without
proteinuria' above.)
●Patients with persistent proteinuria (above 1 g/day or perhaps above
500 mg/day), a normal or only slightly reduced GFR that is not declining
rapidly, and only mild to moderate histologic findings on renal biopsy
are initially managed with nonimmunosuppressive therapies to slow
progression. The sequence of nonimmunosuppressive therapy is as follows
(see 'Nonimmunosuppressive therapies' above):
•Angiotensin inhibition with either an ACE inhibitor or ARB. The goals of
therapy with an ACE inhibitor or ARB are a urinary protein excretion
below 500 mg/day or 1 g/day and a blood pressure less
than 130/80 mmHg. (See 'Angiotensin inhibition' above and 'Proteinuria
and blood pressure goals' above.)
•Fish oil (3.3 g/day or more), which can be tried in patients with protein
excretion above 1 g/day despite three to six months of therapy with an
ACE inhibitor or ARB. Fish oil may have cardiovascular benefits and is
unlikely to be harmful. (See 'Fish oil' above.)
●We suggest anti-inflammatory therapy with glucocorticoids in patients with
clinical features supporting active disease and progression, which include
hematuria in addition to one or more of the following (see 'Indications for
glucocorticoid therapy' above and 'Glucocorticoids as sole
immunosuppressive/anti-inflammatory therapy' above):
•An increasing serum creatinine
•Persistent proteinuria above 1 g/day after maximal antiproteinuric
nonimmunosuppressive therapies
•Morphologic evidence of active disease based upon kidney biopsy (eg,
proliferative or necrotizing glomerular changes)
•However, we suggest not treating with glucocorticoids in patients with a
chronically elevated serum creatinine or morphologic evidence of
prominent glomerulosclerosis and tubulointerstitial atrophy or fibrosis
(see 'Lack of benefit in chronic fibrotic disease' above)
●Either of the following two regimens is acceptable in patients with IgA
nephropathy who are selected for glucocorticoid therapy (see 'Glucocorticoid
regimen' above):
•Intravenous methylprednisolone, 1 g, for three consecutive days at the
beginning of months 1, 3, and 5, combined with 0.5 mg/kg of
oral prednisolone given on alternate days for six months
•Prednisone, 0.8 to 1 mg/kg per day, for two months followed by monthly
dose reductions of 0.2 mg/kg per day during the next four months
●Combined immunosuppressive therapy can be considered in patients with
more severe disease as defined by a more rapidly progressive clinical
course and/or histologic evidence of severe active inflammation (eg, crescent
formation). Various combinations of immunosuppressive drugs have been
used in such patients. (See 'Combined immunosuppressive therapy' above.)
●There is a subset of patients with IgA nephropathy who present with 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. Such patients with acute onset of nephrotic syndrome and diffuse
foot process fusion on renal biopsy are treated as if they have minimal
change disease. (See 'Acute onset of nephrotic syndrome' above
and "Treatment of minimal change disease in adults".)
●There are no specific serologic markers to identify continued immunologic
activity in IgA nephropathy. 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 serum creatinine
concentration or estimated glomerular filtration rate (eGFR), and protein
excretion. (See 'Monitoring disease activity' above.)