What makes UpToDate so powerful?

  • over 11000 topics
  • 22 specialties
  • 5,700 physician authors
  • evidence-based recommendations
See more sample topics
Find Patient Print
0 Find synonyms

Find synonyms Find exact match

Treatment and prognosis of IgA nephropathy
UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
Treatment and prognosis of IgA nephropathy
View in Chinese
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2017. | This topic last updated: Oct 13, 2017.

INTRODUCTION — IgA 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 PROGNOSIS — Patients 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/dL with 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/min versus 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 THERAPY — The 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/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. 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 THERAPIES — There 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 nephropathy", 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 130/80 mmHg 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, 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 "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 "Indications for statins in 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. (See "Statins and chronic kidney disease", section on 'Effect on chronic kidney disease progression'.)

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 THERAPY — The 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 prednisone 0.5 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/or plasmapheresis [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 Henoch-Schönlein purpura (IgA vasculitis), where the renal biopsy findings are those of IgA nephropathy, provides indirect evidence of possible benefit [135,136]. (See "Renal manifestations of Henoch-Schönlein purpura (IgA vasculitis)", 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 INTERVENTIONS — Other 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, Henoch-Schönlein purpura [IgA vasculitis]) 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.

PREGNANCY — Pregnancy 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 underlying renal 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 "Angiotensin converting enzyme inhibitors and receptor blockers in pregnancy" and "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)

END-STAGE RENAL DISEASE — Patients who progress to end-stage renal disease can be treated with dialysis or transplantation. Issues related to recurrent disease in the transplant are discussed elsewhere. (See "IgA nephropathy: Recurrence after transplantation".)

SOCIETY GUIDELINE LINKS — Links 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 PATIENTS — UpToDate 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.)

Use of UpToDate is subject to the  Subscription and License Agreement.

REFERENCES

  1. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med 2013; 368:2402.
  2. Chapter 10: Immunoglobulin A nephropathy. Kidney Int Suppl (2011) 2012; 2:209.
  3. D'Amico G. Influence of clinical and histological features on actuarial renal survival in adult patients with idiopathic IgA nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis: survey of the recent literature. Am J Kidney Dis 1992; 20:315.
  4. Alamartine E, Sabatier JC, Guerin C, et al. Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses. Am J Kidney Dis 1991; 18:12.
  5. Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002; 347:738.
  6. Li LS, Liu ZH. Epidemiologic data of renal diseases from a single unit in China: analysis based on 13,519 renal biopsies. Kidney Int 2004; 66:920.
  7. Geddes CC, Rauta V, Gronhagen-Riska C, et al. A tricontinental view of IgA nephropathy. Nephrol Dial Transplant 2003; 18:1541.
  8. Szeto CC, Lai FM, To KF, et al. The natural history of immunoglobulin a nephropathy among patients with hematuria and minimal proteinuria. Am J Med 2001; 110:434.
  9. D'Amico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis 2000; 36:227.
  10. Berthoux F, Mohey H, Laurent B, et al. Predicting the risk for dialysis or death in IgA nephropathy. J Am Soc Nephrol 2011; 22:752.
  11. Wakai K, Kawamura T, Endoh M, et al. A scoring system to predict renal outcome in IgA nephropathy: from a nationwide prospective study. Nephrol Dial Transplant 2006; 21:2800.
  12. Rekola S, Bergstrand A, Bucht H. Deterioration of GFR in IgA nephropathy as measured by 51Cr-EDTA clearance. Kidney Int 1991; 40:1050.
  13. Johnston PA, Brown JS, Braumholtz DA, Davison AM. Clinico-pathological correlations and long-term follow-up of 253 United Kingdom patients with IgA nephropathy. A report from the MRC Glomerulonephritis Registry. Q J Med 1992; 84:619.
  14. Chacko B, John GT, Neelakantan N, et al. Presentation, prognosis and outcome of IgA nephropathy in Indian adults. Nephrology (Carlton) 2005; 10:496.
  15. Alamartine E, Sabatier JC, Berthoux FC. Comparison of pathological lesions on repeated renal biopsies in 73 patients with primary IgA glomerulonephritis: value of quantitative scoring and approach to final prognosis. Clin Nephrol 1990; 34:45.
  16. Hotta O, Furuta T, Chiba S, et al. Regression of IgA nephropathy: a repeat biopsy study. Am J Kidney Dis 2002; 39:493.
  17. Coppo R, D'Amico G. Factors predicting progression of IgA nephropathies. J Nephrol 2005; 18:503.
  18. Nozawa R, Suzuki J, Takahashi A, et al. Clinicopathological features and the prognosis of IgA nephropathy in Japanese children on long-term observation. Clin Nephrol 2005; 64:171.
  19. Lau KK, Gaber LW, Delos Santos NM, et al. Pediatric IgA nephropathy: clinical features at presentation and outcome for African-Americans and Caucasians. Clin Nephrol 2004; 62:167.
  20. Bartosik LP, Lajoie G, Sugar L, Cattran DC. Predicting progression in IgA nephropathy. Am J Kidney Dis 2001; 38:728.
  21. Hall CL, Bradley R, Kerr A, et al. Clinical value of renal biopsy in patients with asymptomatic microscopic hematuria with and without low-grade proteinuria. Clin Nephrol 2004; 62:267.
  22. Ikee R, Kobayashi S, Saigusa T, et al. Impact of hypertension and hypertension-related vascular lesions in IgA nephropathy. Hypertens Res 2006; 29:15.
  23. Donadio JV, Bergstralh EJ, Grande JP, Rademcher DM. Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy. Nephrol Dial Transplant 2002; 17:1197.
  24. Reich HN, Troyanov S, Scholey JW, et al. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol 2007; 18:3177.
  25. Izzi C, Ravani P, Torres D, et al. IgA nephropathy: the presence of familial disease does not confer an increased risk for progression. Am J Kidney Dis 2006; 47:761.
  26. Frisch G, Lin J, Rosenstock J, et al. Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial. Nephrol Dial Transplant 2005; 20:2139.
  27. Le W, Liang S, Hu Y, et al. Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population. Nephrol Dial Transplant 2012; 27:1479.
  28. Maixnerova D, Bauerova L, Skibova J, et al. The retrospective analysis of 343 Czech patients with IgA nephropathy--one centre experience. Nephrol Dial Transplant 2012; 27:1492.
  29. Zhao YF, Zhu L, Liu LJ, et al. Measures of Urinary Protein and Albumin in the Prediction of Progression of IgA Nephropathy. Clin J Am Soc Nephrol 2016; 11:947.
  30. Wilson FP, Xie D, Anderson AH, et al. Urinary creatinine excretion, bioelectrical impedance analysis, and clinical outcomes in patients with CKD: the CRIC study. Clin J Am Soc Nephrol 2014; 9:2095.
  31. Fotheringham J, Campbell MJ, Fogarty DG, et al. Estimated albumin excretion rate versus urine albumin-creatinine ratio for the estimation of measured albumin excretion rate: derivation and validation of an estimated albumin excretion rate equation. Am J Kidney Dis 2014; 63:405.
  32. Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis 1997; 29:829.
  33. Vivante A, Afek A, Frenkel-Nir Y, et al. Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA 2011; 306:729.
  34. Ibels LS, Györy AZ. IgA nephropathy: analysis of the natural history, important factors in the progression of renal disease, and a review of the literature. Medicine (Baltimore) 1994; 73:79.
  35. Bennett WM, Kincaid-Smith P. Macroscopic hematuria in mesangial IgA nephropathy: correlation with glomerular crescents and renal dysfunction. Kidney Int 1983; 23:393.
  36. Packham DK, Hewitson TD, Yan HD, et al. Acute renal failure in IgA nephropathy. Clin Nephrol 1994; 42:349.
  37. Praga M, Gutierrez-Millet V, Navas JJ, et al. Acute worsening of renal function during episodes of macroscopic hematuria in IgA nephropathy. Kidney Int 1985; 28:69.
  38. Fogazzi GB, Imbasciati E, Moroni G, et al. Reversible acute renal failure from gross haematuria due to glomerulonephritis: not only in IgA nephropathy and not associated with intratubular obstruction. Nephrol Dial Transplant 1995; 10:624.
  39. Gutiérrez E, González E, Hernández E, et al. Factors that determine an incomplete recovery of renal function in macrohematuria-induced acute renal failure of IgA nephropathy. Clin J Am Soc Nephrol 2007; 2:51.
  40. Harden PN, Geddes C, Rowe PA, et al. Polymorphisms in angiotensin-converting-enzyme gene and progression of IgA nephropathy. Lancet 1995; 345:1540.
  41. Yoshida H, Mitarai T, Kawamura T, et al. Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy. J Clin Invest 1995; 96:2162.
  42. Hunley TE, Julian BA, Phillips JA 3rd, et al. Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. Kidney Int 1996; 49:571.
  43. Suzuki S, Suzuki Y, Kobayashi Y, et al. Insertion/deletion polymorphism in ACE gene is not associated with renal progression in Japanese patients with IgA nephropathy. Am J Kidney Dis 2000; 35:896.
  44. Schena FP, D'Altri C, Cerullo G, et al. ACE gene polymorphism and IgA nephropathy: an ethnically homogeneous study and a meta-analysis. Kidney Int 2001; 60:732.
  45. Frimat L, Philippe C, Maghakian MN, et al. Polymorphism of angiotensin converting enzyme, angiotensinogen, and angiotensin II type 1 receptor genes and end-stage renal failure in IgA nephropathy: IGARAS--a study of 274 Men. J Am Soc Nephrol 2000; 11:2062.
  46. Pei Y, Scholey J, Thai K, et al. Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients. J Clin Invest 1997; 100:814.
  47. Xia YF, Huang S, Li X, et al. A family-based association study of megsin A23167G polymorphism with susceptibility and progression of IgA nephropathy in a Chinese population. Clin Nephrol 2006; 65:153.
  48. Schena FP, Cerullo G, Rossini M, et al. Increased risk of end-stage renal disease in familial IgA nephropathy. J Am Soc Nephrol 2002; 13:453.
  49. Bonnet F, Deprele C, Sassolas A, et al. Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis. Am J Kidney Dis 2001; 37:720.
  50. Syrjänen J, Mustonen J, Pasternack A. Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant 2000; 15:34.
  51. Yamamoto R, Nagasawa Y, Shoji T, et al. Cigarette smoking and progression of IgA nephropathy. Am J Kidney Dis 2010; 56:313.
  52. Daniel L, Saingra Y, Giorgi R, et al. Tubular lesions determine prognosis of IgA nephropathy. Am J Kidney Dis 2000; 35:13.
  53. Lai FM, Szeto CC, Choi PC, et al. Primary IgA nephropathy with low histologic grade and disease progression: is there a "point of no return"? Am J Kidney Dis 2002; 39:401.
  54. Weber CL, Rose CL, Magil AB. Focal segmental glomerulosclerosis in mild IgA nephropathy: a clinical-pathologic study. Nephrol Dial Transplant 2009; 24:483.
  55. Lee HS, Lee MS, Lee SM, et al. Histological grading of IgA nephropathy predicting renal outcome: revisiting H. S. Lee's glomerular grading system. Nephrol Dial Transplant 2005; 20:342.
  56. Manno C, Strippoli GF, D'Altri C, et al. A novel simpler histological classification for renal survival in IgA nephropathy: a retrospective study. Am J Kidney Dis 2007; 49:763.
  57. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Cattran DC, Coppo R, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 2009; 76:534.
  58. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Roberts IS, Cook HT, et al. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int 2009; 76:546.
  59. El Karoui K, Hill GS, Karras A, et al. Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy. II. Light microscopic and clinical studies. Kidney Int 2011; 79:643.
  60. Herzenberg AM, Fogo AB, Reich HN, et al. Validation of the Oxford classification of IgA nephropathy. Kidney Int 2011; 80:310.
  61. Shi SF, Wang SX, Jiang L, et al. Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the oxford classification. Clin J Am Soc Nephrol 2011; 6:2175.
  62. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Coppo R, Troyanov S, et al. The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults. Kidney Int 2010; 77:921.
  63. Edström Halling S, Söderberg MP, Berg UB. Predictors of outcome in paediatric IgA nephropathy with regard to clinical and histopathological variables (Oxford classification). Nephrol Dial Transplant 2012; 27:715.
  64. Tanaka S, Ninomiya T, Katafuchi R, et al. Development and validation of a prediction rule using the Oxford classification in IgA nephropathy. Clin J Am Soc Nephrol 2013; 8:2082.
  65. Zhao N, Hou P, Lv J, et al. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int 2012; 82:790.
  66. Berthoux F, Suzuki H, Thibaudin L, et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J Am Soc Nephrol 2012; 23:1579.
  67. Barratt J, Feehally J. Treatment of IgA nephropathy. Kidney Int 2006; 69:1934.
  68. Appel GB, Waldman M. The IgA nephropathy treatment dilemma. Kidney Int 2006; 69:1939.
  69. Reid S, Cawthon PM, Craig JC, et al. Non-immunosuppressive treatment for IgA nephropathy. Cochrane Database Syst Rev 2011; :CD003962.
  70. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008; 148:30.
  71. Maschio G, Cagnoli L, Claroni F, et al. ACE inhibition reduces proteinuria in normotensive patients with IgA nephropathy: a multicentre, randomized, placebo-controlled study. Nephrol Dial Transplant 1994; 9:265.
  72. Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int 2004; 65:1991.
  73. Remuzzi A, Perticucci E, Ruggenenti P, et al. Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy. Kidney Int 1991; 39:1267.
  74. Kanno Y, Okada H, Saruta T, Suzuki H. Blood pressure reduction associated with preservation of renal function in hypertensive patients with IgA nephropathy: a 3-year follow-up. Clin Nephrol 2000; 54:360.
  75. Praga M, Gutiérrez E, González E, et al. Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. J Am Soc Nephrol 2003; 14:1578.
  76. Li PK, Leung CB, Chow KM, et al. Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study. Am J Kidney Dis 2006; 47:751.
  77. Coppo R, Peruzzi L, Amore A, et al. IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J Am Soc Nephrol 2007; 18:1880.
  78. Cattran DC. Is proteinuria reduction by angiotensin-converting enzyme inhibition enough to prove its role in renal protection in IgA nephropathy? J Am Soc Nephrol 2007; 18:1633.
  79. Cattran DC, Greenwood C, Ritchie S. Long-term benefits of angiotensin-converting enzyme inhibitor therapy in patients with severe immunoglobulin a nephropathy: a comparison to patients receiving treatment with other antihypertensive agents and to patients receiving no therapy. Am J Kidney Dis 1994; 23:247.
  80. Kanno Y, Okada H, Yamaji Y, et al. Angiotensin-converting-enzyme inhibitors slow renal decline in IgA nephropathy, independent of tubulointerstitial fibrosis at presentation. QJM 2005; 98:199.
  81. Li PK, Kwan BC, Chow KM, et al. Treatment of early immunoglobulin A nephropathy by angiotensin-converting enzyme inhibitor. Am J Med 2013; 126:162.
  82. Russo D, Pisani A, Balletta MM, et al. Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 1999; 33:851.
  83. Russo D, Minutolo R, Pisani A, et al. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis 2001; 38:18.
  84. Catapano F, Chiodini P, De Nicola L, et al. Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression. Am J Kidney Dis 2008; 52:475.
  85. Retraction--Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2009; 374:1226.
  86. ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547.
  87. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372:547.
  88. Tobe SW, Clase CM, Gao P, et al. Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk: results from the ONTARGET and TRANSCEND studies. Circulation 2011; 123:1098.
  89. Donadio JV, Grande JP. The role of fish oil/omega-3 fatty acids in the treatment of IgA nephropathy. Semin Nephrol 2004; 24:225.
  90. Donadio JV Jr, Bergstralh EJ, Offord KP, et al. A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group. N Engl J Med 1994; 331:1194.
  91. Alexopoulos E, Stangou M, Pantzaki A, et al. Treatment of severe IgA nephropathy with omega-3 fatty acids: the effect of a "very low dose" regimen. Ren Fail 2004; 26:453.
  92. Donadio JV Jr, Larson TS, Bergstralh EJ, Grande JP. A randomized trial of high-dose compared with low-dose omega-3 fatty acids in severe IgA nephropathy. J Am Soc Nephrol 2001; 12:791.
  93. Donadio JV Jr, Grande JP, Bergstralh EJ, et al. The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. J Am Soc Nephrol 1999; 10:1772.
  94. Bennett WM, Walker RG, Kincaid-Smith P. Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial. Clin Nephrol 1989; 31:128.
  95. Pettersson EE, Rekola S, Berglund L, et al. Treatment of IgA nephropathy with omega-3-polyunsaturated fatty acids: a prospective, double-blind, randomized study. Clin Nephrol 1994; 41:183.
  96. Hogg RJ, Lee J, Nardelli N, et al. Clinical trial to evaluate omega-3 fatty acids and alternate day prednisone in patients with IgA nephropathy: report from the Southwest Pediatric Nephrology Study Group. Clin J Am Soc Nephrol 2006; 1:467.
  97. Ferraro PM, Ferraccioli GF, Gambaro G, et al. Combined treatment with renin-angiotensin system blockers and polyunsaturated fatty acids in proteinuric IgA nephropathy: a randomized controlled trial. Nephrol Dial Transplant 2009; 24:156.
  98. Alexopoulos E. Treatment of primary IgA nephropathy. Kidney Int 2004; 65:341.
  99. Strippoli GF, Manno C, Schena FP. An "evidence-based" survey of therapeutic options for IgA nephropathy: assessment and criticism. Am J Kidney Dis 2003; 41:1129.
  100. Laville M, Alamartine E. Treatment options for IgA nephropathy in adults: a proposal for evidence-based strategy. Nephrol Dial Transplant 2004; 19:1947.
  101. Ballardie FW. IgA nephropathy treatment 25 years on: can we halt progression? The evidence base. Nephrol Dial Transplant 2004; 19:1041.
  102. Floege J, Eitner F. Present and future therapy options in IgA-nephropathy. J Nephrol 2005; 18:354.
  103. Locatelli F, Del Vecchio L, Pozzi C. The patient with IgA glomerulonephritis--what is the role of steroid treatment? Nephrol Dial Transplant 1999; 14:1057.
  104. Lv J, Xu D, Perkovic V, et al. Corticosteroid therapy in IgA nephropathy. J Am Soc Nephrol 2012; 23:1108.
  105. Rauen T, Eitner F, Fitzner C, et al. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med 2015; 373:2225.
  106. Lv J, Zhang H, Wong MG, et al. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA 2017; 318:432.
  107. Manno C, Torres DD, Rossini M, et al. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant 2009; 24:3694.
  108. Pozzi C, Bolasco PG, Fogazzi GB, et al. Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet 1999; 353:883.
  109. Pozzi C, Andrulli S, Del Vecchio L, et al. Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J Am Soc Nephrol 2004; 15:157.
  110. Lai KN, Lai FM, Ho CP, Chan KW. Corticosteroid therapy in IgA nephropathy with nephrotic syndrome: a long-term controlled trial. Clin Nephrol 1986; 26:174.
  111. Mustonen J, Pasternack A, Rantala I. The nephrotic syndrome in IgA glomerulonephritis: response to corticosteroid therapy. Clin Nephrol 1983; 20:172.
  112. Cheng IK, Chan KW, Chan MK. Mesangial IgA nephropathy with steroid-responsive nephrotic syndrome: disappearance of mesangial IgA deposits following steroid-induced remission. Am J Kidney Dis 1989; 14:361.
  113. Woo KT, Lee GS, Lau YK, et al. Effects of triple therapy in IgA nephritis: a follow-up study 5 years later. Clin Nephrol 1991; 36:60.
  114. Walker RG, Yu SH, Owen JE, Kincaid-Smith P. The treatment of mesangial IgA nephropathy with cyclophosphamide, dipyridamole and warfarin: a two-year prospective trial. Clin Nephrol 1990; 34:103.
  115. Ballardie FW, Roberts IS. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol 2002; 13:142.
  116. Yoshikawa N, Ito H, Sakai T, et al. A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. The Japanese Pediatric IgA Nephropathy Treatment Study Group. J Am Soc Nephrol 1999; 10:101.
  117. Yoshikawa N, Honda M, Iijima K, et al. Steroid treatment for severe childhood IgA nephropathy: a randomized, controlled trial. Clin J Am Soc Nephrol 2006; 1:511.
  118. Pozzi C, Andrulli S, Pani A, et al. Addition of azathioprine to corticosteroids does not benefit patients with IgA nephropathy. J Am Soc Nephrol 2010; 21:1783.
  119. Floege J, Eitner F. Combined immunosuppression in high-risk patients with IgA nephropathy? J Am Soc Nephrol 2010; 21:1604.
  120. Kamei K, Nakanishi K, Ito S, et al. Long-term results of a randomized controlled trial in childhood IgA nephropathy. Clin J Am Soc Nephrol 2011; 6:1301.
  121. Welch TR, McAdams AJ, Berry A. Rapidly progressive IgA nephropathy. Am J Dis Child 1988; 142:789.
  122. Lai KN, Lai FM, Leung AC, et al. Plasma exchange in patients with rapidly progressive idiopathic IgA nephropathy: a report of two cases and review of literature. Am J Kidney Dis 1987; 10:66.
  123. Roccatello D, Ferro M, Coppo R, et al. Report on intensive treatment of extracapillary glomerulonephritis with focus on crescentic IgA nephropathy. Nephrol Dial Transplant 1995; 10:2054.
  124. McIntyre CW, Fluck RJ, Lambie SH. Steroid and cyclophosphamide therapy for IgA nephropathy associated with crescenteric change: an effective treatment. Clin Nephrol 2001; 56:193.
  125. Tumlin JA, Lohavichan V, Hennigar R. Crescentic, proliferative IgA nephropathy: clinical and histological response to methylprednisolone and intravenous cyclophosphamide. Nephrol Dial Transplant 2003; 18:1321.
  126. Galla JH. IgA nephropathy. Kidney Int 1995; 47:377.
  127. Maes BD, Oyen R, Claes K, et al. Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study. Kidney Int 2004; 65:1842.
  128. Chen X, Chen P, Cai G, et al. [A randomized control trial of mycophenolate mofeil treatment in severe IgA nephropathy]. Zhonghua Yi Xue Za Zhi 2002; 82:796.
  129. Tang SC, Tang AW, Wong SS, et al. Long-term study of mycophenolate mofetil treatment in IgA nephropathy. Kidney Int 2010; 77:543.
  130. Hou JH, Le WB, Chen N, et al. Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial. Am J Kidney Dis 2017; 69:788.
  131. Lai KN, Lai FM, Li PK, Vallance-Owen J. Cyclosporin treatment of IgA nephropathy: a short term controlled trial. Br Med J (Clin Res Ed) 1987; 295:1165.
  132. Cattran DC. Current status of cyclosporin A in the treatment of membranous, IgA and membranoproliferative glomerulonephritis. Clin Nephrol 1991; 35 Suppl 1:S43.
  133. Chábová V, Tesar V, Zabka J, et al. Long term treatment of IgA nephropathy with cyclosporine A. Ren Fail 2000; 22:55.
  134. Kim YC, Chin HJ, Koo HS, Kim S. Tacrolimus decreases albuminuria in patients with IgA nephropathy and normal blood pressure: a double-blind randomized controlled trial of efficacy of tacrolimus on IgA nephropathy. PLoS One 2013; 8:e71545.
  135. Shin JI, Park JM, Shin YH, et al. Cyclosporin A therapy for severe Henoch-Schönlein nephritis with nephrotic syndrome. Pediatr Nephrol 2005; 20:1093.
  136. Park JM, Won SC, Shin JI, et al. Cyclosporin A therapy for Henoch-Schönlein nephritis with nephrotic-range proteinuria. Pediatr Nephrol 2011; 26:411.
  137. Lafayette RA, Canetta PA, Rovin BH, et al. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction. J Am Soc Nephrol 2017; 28:1306.
  138. Szeto CC, Chow KM, Kwan BC, et al. Oral calcitriol for the treatment of persistent proteinuria in immunoglobulin A nephropathy: an uncontrolled trial. Am J Kidney Dis 2008; 51:724.
  139. Fishbane S, Chittineni H, Packman M, et al. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J Kidney Dis 2009; 54:647.
  140. Liu LJ, Lv JC, Shi SF, et al. Oral calcitriol for reduction of proteinuria in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis 2012; 59:67.
  141. Tomino Y, Sakai H, Hanzawa S, et al. Clinical effect of danazol in patients with IgA nephropathy. Jpn J Med 1987; 26:162.
  142. Béné MC, Faure GC, Hurault de Ligny B, de March AK. Clinical involvement of the tonsillar immune system in IgA nephropathy. Acta Otolaryngol Suppl 2004; :10.
  143. Xie Y, Chen X, Nishi S, et al. Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy. Kidney Int 2004; 65:1135.
  144. Hotta O, Miyazaki M, Furuta T, et al. Tonsillectomy and steroid pulse therapy significantly impact on clinical remission in patients with IgA nephropathy. Am J Kidney Dis 2001; 38:736.
  145. Xie Y, Nishi S, Ueno M, et al. The efficacy of tonsillectomy on long-term renal survival in patients with IgA nephropathy. Kidney Int 2003; 63:1861.
  146. Akagi H, Kosaka M, Hattori K, et al. Long-term results of tonsillectomy as a treatment for IgA nephropathy. Acta Otolaryngol Suppl 2004; :38.
  147. Komatsu H, Fujimoto S, Hara S, et al. Effect of tonsillectomy plus steroid pulse therapy on clinical remission of IgA nephropathy: a controlled study. Clin J Am Soc Nephrol 2008; 3:1301.
  148. Rasche FM, Schwarz A, Keller F. Tonsillectomy does not prevent a progressive course in IgA nephropathy. Clin Nephrol 1999; 51:147.
  149. Rasche FM, Sailer LC, Czock D, Keller F. Tonsillectomy, high dose immunoglobulins, and cyclophosphamide in progressive IgA-nephropathy. Acta Otolaryngol Suppl 2004; :32.
  150. Kawamura T, Yoshimura M, Miyazaki Y, et al. A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy. Nephrol Dial Transplant 2014; 29:1546.
  151. Zand L, Fervenza FC. Does tonsillectomy have a role in the treatment of patients with immunoglobulin A nephropathy? Nephrol Dial Transplant 2014; 29:1456.
  152. Wang Y, Chen J, Wang Y, et al. A meta-analysis of the clinical remission rate and long-term efficacy of tonsillectomy in patients with IgA nephropathy. Nephrol Dial Transplant 2011; 26:1923.
  153. Ferri C, Puccini R, Longombardo G, et al. Low-antigen-content diet in the treatment of patients with IgA nephropathy. Nephrol Dial Transplant 1993; 8:1193.
  154. Coppo R, Roccatello D, Amore A, et al. Effects of a gluten-free diet in primary IgA nephropathy. Clin Nephrol 1990; 33:72.
  155. Rostoker G, Pech MA, Del Prato S, et al. Serum IgG subclasses and IgM imbalances in adult IgA mesangial glomerulonephritis and idiopathic Henoch-Schoenlein purpura. Clin Exp Immunol 1989; 75:30.
  156. Rostoker G, Desvaux-Belghiti D, Pilatte Y, et al. High-dose immunoglobulin therapy for severe IgA nephropathy and Henoch-Schönlein purpura. Ann Intern Med 1994; 120:476.
  157. Smerud HK, Bárány P, Lindström K, et al. New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria. Nephrol Dial Transplant 2011; 26:3237.
  158. Fellström BC, Barratt J, Cook H, et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet 2017.
  159. Liu Y, Ma X, Lv J, et al. Risk factors for pregnancy outcomes in patients with IgA nephropathy: a matched cohort study. Am J Kidney Dis 2014; 64:730.
  160. Abe S. Pregnancy in IgA nephropathy. Kidney Int 1991; 40:1098.
  161. Abe S. The influence of pregnancy on the long-term renal prognosis of IgA nephropathy. Clin Nephrol 1994; 41:61.
Topic 3039 Version 41.0

Topic Outline

GRAPHICS

RELATED TOPICS

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.