Wolters Kluwer Health UpToDate

• Clinicians
• Patients
• Institutions
• Educators
• Subscribe
• Wolters Kluwer Health Clinical Solutions

Official reprint from UpToDate^® www.uptodate.com
©2012 UpToDate^®

Print | Back

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 (click here) ©2012 UpToDate, Inc.

Treatment and prognosis of IgA nephropathy

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2012. | This topic last updated: Jan 19, 2012.

INTRODUCTION — IgA nephropathy is the most common cause of primary (idiopathic) glomerulonephritis in the developed world [1-4]. Although this disorder was initially thought to follow a benign course, it is now recognized that slow progression to end-stage renal disease occurs in up to 50 percent of affected patients [5], 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. The prognosis is difficult to predict with accuracy in individual patients, but 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: the classic presentation with gross hematuria, often recurrent, following shortly after an upper respiratory infection; and persistent asymptomatic microscopic hematuria with or without mild to moderate proteinuria [3]. The diagnosis may be suspected in patients with the classic presentation, but must be confirmed by 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) have a low risk of progression, at least in the short term. However, proteinuria and renal insufficiency develop in a substantial proportion of patients over the long term [5-10]. 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 [1,2,9-12].

The rate of progression is typically slow with the 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 [13,14]. 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 [13]. Histologic improvement occurred in only 4 percent, with 41 percent remaining stable and 55 percent showing progressive glomerular and secondary vascular and tubulointerstitial injury. 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. Patients with only hematuria are often not biopsied in many countries, such as the United States, but should be monitored periodically but progression to protein 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 [5]. 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 [5,15].

Clinical predictors of progression — As in other glomerulopathies, patients who will develop progressive disease typically have one or more of the following clinical or laboratory findings at diagnosis, each of which is a marker for more severe disease [1,2,6-10,16-23]:

• Elevated serum creatinine concentration
• Hypertension
• Persistent protein excretion above 1000 mg/day

Reduced GFR — A reduction in glomerular filtration rate (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 [1,9,10,20,21,23,24]. 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) [9]:

• 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 [8,18,22]. The magnitude of this effect was illustrated in a prospective study of 332 patients with IgA nephropathy [8]. 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 [22]. 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 relation 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 3.0 to 3.5 g/day [8-10,18,21-23,25].

The importance of the magnitude of proteinuria and its persistence on the course of IgA nephropathy was evaluated in the prospective cohort study of 332 patients (mean age 36±15 years) cited above [8]. The incidence of dialysis and 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). 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 the observational study of 542 patients with IgA nephropathy (mean age 38±13 years) who were followed for a mean 6.5 years [22]:

• 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 1.73m2 per month), with a hazard ratio for the development of end-stage renal disease during the study of 10. Patients with protein excretion between 1 and 3 g/day were at intermediate risk (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).
• The prognosis in patients who presented with protein excretion below 1 g/day at presentation varied with the course of proteinuria over time. Renal survival was very high in patients who had a 1 to 2 g/day increase in proteinuria and progressively decreased with greater increases in proteinuria (figure 3).

In a study from China, patients with less than 500 mg/day had significantly better outcomes than patients excreting 500 to 1000 mg/day [25]. However, data regarding the effect of lowering proteinuria to different levels was not provided, in contrast to the above study (figure 2). Thus, the better prognosis in patients with protein excretion below 500 mg/day could simply have reflected less severe disease or better blood pressure control.

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 [9]. 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.

As described below, an ACE inhibitor or angiotensin II receptor blocker is the preferred initial drug to reduce protein excretion and slow the rate of disease progression. (See 'Angiotensin inhibition' below.)

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 [1,26]. In addition, isolated persistent hematuria (ie, with little or no proteinuria) at presentation may be associated with progressive disease over time [6,9,10,27]. 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 [6]. 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 [27]. 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 [11,13-16,28]. 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 [16]. After a mean follow-up of seven years, 50 percent had no manifestations of disease, 36 percent had persistent hematuria with or without proteinuria, and 14 percent developed progressive disease.

Acute renal failure with gross hematuria — Acute renal failure can occur during episodes of gross hematuria in patients with IgA nephropathy [29-32]. Renal biopsy in these patients reveals mesangial proliferation and segmental crescents in a small proportion of glomeruli (usually less than 25 percent) [29,31,32]. These findings are insufficient to account for the acute renal failure, which has been ascribed to tubular obstruction by red cell casts [30,31,33]. 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 [30,32,33].

The serum creatinine concentration typically returns to baseline levels within several weeks to months, although dialysis may be temporarily required [30]. However, incomplete recovery of renal function was noted in 9 of 36 patients (estimated mean GFR after recovery 38 mL/min versus 89 mL/min) [33]. Significant risk factors for lack of complete recovery included duration of gross hematuria longer than 10 days, age greater than 50 years, decreased estimated GFR 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 [34-36]. However, others have reported no correlation between genotype and outcome [37,38].
• 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 [36,39], while conflicting data have been reported with the angiotensinogen gene [36,39,40].
• 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 [41]. 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 [23,42]. The much larger series found no association between familial disease and renal outcomes [23]. (See "Pathogenesis of IgA nephropathy", section on 'Genetic predisposition'.)

At present, none of the genetic associations has proven utility in determining prognosis and making treatment decisions.

Other risk factors — Other potentially modifiable risk factors for progressive disease include obesity [43], hypertriglyceridemia and hyperuricemia [44], and smoking [45].

Histologic predictors of progression — Although clinical features appear to be stronger prognostic indicators [18], 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. [1,10,11,16,20,23,26,46-48].

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 [26,49,50]. These indicators are typical of most glomerular diseases [51,52]. (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 [51,52]. 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 [53], a North American cohort [54], and a Chinese cohort [55]. The predictive value of each of the histologic variables appears to be similar in adults and children [56]. 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.

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 scoring system that estimates the risk of dialysis or death at 10 and 20 years was developed in a prospective study of 332 patients with IgA nephropathy followed for a mean of 12 years [8]. 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 [8,13].

The incidence of death or dialysis at 10 and 20 years for specific ARR scores was [8]:

• 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 [22], 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.)

APPROACH TO THERAPY — The optimal approach to the treatment of IgA nephropathy is uncertain [57,58]. The slow rate of loss of 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:

• 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). In addition, statin therapy may be beneficial in patients with chronic kidney disease and serum LDL-cholesterol concentrations above goal values. (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 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 managed with nonimmunosuppressive therapies to slow progression and perhaps with fish oil. (See 'Nonimmunosuppressive therapies' below.)
• Patients with more severe or rapidly progressive disease (eg, nephrotic range proteinuria or proteinuria persisting despite ACE inhibitor/ARB therapy, rising serum creatinine, and/or renal biopsy with more severe histologic findings, but no significant chronic changes) may benefit from immunosuppressive therapy in addition to nonimmunosuppressive interventions to slow disease progression. (See 'Immunosuppressive therapy' below.)
• The Oxford histologic classification system may improve the ability to select patients with the worst prognosis at the time of renal biopsy [56]. This classification may also permit the identification of features such as endocapillary proliferation that provide an indication of responsiveness to immunosuppressive therapy. This was suggested in another retrospective report from the Oxford classification in which patients with endocapillary proliferation who received immunosuppressive therapy had a markedly lower rate of decline in glomerular filtration rate than those who did not receive immunosuppressive therapy [51]. A similar trend was noted in another cohort [54]. However, such an observation does not prove cause-and-effect. (See 'Oxford classification of IgA nephropathy' above.)

Monitoring disease activity — There are no specific markers to identify continued immunologic activity. As a result, clinical parameters are typically used, whether or not the patient is receiving immunosuppressive therapy. The major parameters that are serially monitored are the urine sediment, serum creatinine concentration or estimated glomerular filtration rate, 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, 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, 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 "Measurement of urinary protein excretion", section on 'Urinary ratios'.)
  
  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 only seen 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 typically falls with therapy with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker 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 glomerular filtration rate (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 [10]. 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 [57,58]:

• 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) has also been studied, but its role is 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 comparable degree compared with placebo or the dihydropyridine calcium channel blocker amlodipine [59,60], an effect that is seen in normotensive as well as hypertensive patients [61]. In contrast, the non-dihydropyridine calcium channel blockers diltiazem and verapamil also lower protein excretion [62] 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 [63]. 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 [64]. (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 comes 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 [65]. 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 [66].

Another randomized trial, IgACE, compared benazepril to placebo in 65 young patients (range 9 to 35 years) with IgA nephropathy, moderate proteinuria (1.0 to 3.5 g/day per 1.73 m2), and relatively preserved renal function (creatinine clearance >50 mL/min per 1.73 m2) were randomly assigned to benazepril (0.2 mg/kg per day) or placebo [67]. 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 [68].

Benefit from angiotensin inhibition was also seen in two observational studies [69,70]. 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 [69]. 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 1.0 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.

The authors and reviewers of this topic do not agree on which patients might 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 [59,71,72]. 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 [60,73]. 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 to 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 [74]. 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 [75]. 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) [76]; 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 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) [77].
• 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. In 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 [8,22].
  
  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 'ACE inhibitor plus ARB'.)

The authors of this topic suggest the use of combination ACE inhibitor and ARB therapy if the proteinuria goal of less than 500 mg/day or less than 1 g/day is not reached with monotherapy at the maximum recommended dose. In contrast, the reviewers of this topic cite the potential harm and lack of evidence of improved renal outcomes and would add other antiproteinuric drugs (eg, diltiazem or verapamil, and an aldosterone antagonist) rather than combination therapy. (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 [22] (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 0.72 versus 0.03 mL/min per 1.73m2 per month in patients with protein excretion 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 idiopathic membranous nephropathy", section on 'Risk factors for progressive idiopathic MN' and "Treatment of primary focal segmental glomerulosclerosis", section on 'Degree of proteinuria'.)
• 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 immunosuppressive 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, and is considered a coronary artery disease risk equivalent. The goal LDL-cholesterol is similar to that in patients with underlying coronary heart disease. (See "Chronic kidney disease and coronary heart disease", section on 'Statin therapy' and "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease".)

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 CKD 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 antiinflammatory mechanisms, is not well defined [78]. 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 [79].

Randomized trials evaluating fish oil in patients with IgA nephropathy have reported conflicting results [79-86]. The following 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 [79]. There was no difference in blood pressure control and no effect on protein excretion during the study.
  
  At four years, patients receiving fish oil had a lower incidence of a ≥50 percent increase in the serum creatinine concentration (6 versus 33 percent in the placebo group) and a lower incidence of death or end-stage renal disease (ESRD) at four years (10 versus 40 percent). With follow-up extended to more than 6 years, the benefits of continuous fish oil therapy persisted (15 versus 37 percent incidence of ESRD) [82].

• In a trial by the Southwest Pediatric Nephrology Study Group, 96 patients (mean glomerular filtration rate [GFR] >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 [85]. 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).

A meta-analysis evaluating five controlled trials, which was published before the negative findings from the Southwest Pediatric Nephrology Study Group, attributed much of the variability in the reported results to differences in the duration of follow-up [87]. When this difference was accounted for statistically, a benefit with fish oil therapy was not statistically significant, but a minor benefit was possible. A Cochrane meta-analysis of four trials including both discussed trials showed no beneficial effect on fish oil on renal outcomes including serum creatinine, creatinine clearance, or change in proteinuria [59].

In summary, a benefit from fish oil has not been clearly established. Furthermore, the trial designs are not applicable to current practice, since the patients were not treated with an angiotensin inhibitor and, as necessary, other drugs to attain recommended proteinuria and blood pressure goals. (See 'Proteinuria and blood pressure goals' above.)

Fish oil can be tried in addition to ACE inhibitors or ARBs in patients with protein excretion above 1 g/day, a gradual reduction in GFR, and mild to moderate histologic lesions [88]. 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 immunosuppressive therapy IgA nephropathy is uncertain [57,58]. A variety of regimens have been used, mostly consisting of antiinflammatory 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 [1,2,88-91]. For patients with stable or slowly progressive disease, angiotensin inhibition is initiated prior to immunosuppressive therapy.

Immunosuppressive therapy should only be attempted in patients with clinical (hematuria plus an increased serum creatinine or proteinuria above 1.0 to 1.5 g/day after maximal antiproteinuric therapy) and histologic evidence (eg, proliferative or necrotizing glomerular changes) of active inflammation. (See 'Proteinuria and blood pressure goals' above.)

Indications for immunosuppressive 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 [92,93].

Immunosuppressive therapy should be considered only in patients with clinical (hematuria with an elevated or increasing serum creatinine and/or protein excretion above 1.0 to 1.5 g/day despite maximum antiproteinuric therapy) and morphologic features (eg, active inflammation with necrotizing glomerular lesions) suggesting an adverse renal prognosis. The authors and reviewers of this topic disagree on the proteinuria threshold for initiating immunosuppressive therapy. Some use a threshold of above 1 g/day and some use a threshold of above 1.5 g/day.

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 [24]. However, such patients who have proteinuria may still benefit from angiotensin inhibition. (See 'Angiotensin inhibition' above and 'Histologic predictors of progression' above.)

Glucocorticoids — The potential benefit of glucocorticoid therapy in IgA nephropathy has been examined in uncontrolled studies, retrospective observations, and a few relatively small, randomized controlled trials [92,94]. The applicability of these trials to current practice is unclear, since most trials included patients who were not routinely treated with an ACE inhibitor or ARB and, as necessary, other drugs to attain recommended proteinuria and blood pressure goals. With the exception of patients described later in this section who appear to have minimal change disease as the cause of nephrotic syndrome, we use glucocorticoids in combination with angiotensin inhibition, not glucocorticoids alone. (See 'Proteinuria and blood pressure goals' above.)

Glucocorticoids alone — Glucocorticoid therapy for 6 to 24 months or more may be associated with a reduction in proteinuria and perhaps improved renal survival [92,94-104], although this has not been consistently noted [85]. Benefit in some of these studies was observed only among individuals with preserved kidney function (eg, creatinine clearance above 70 mL/min) [95-98]. However, other studies have found improved outcomes even among individuals with more advanced disease (eg, reduced glomerular filtration rate and more proteinuria) [94,99,102,103].

As an example, a prospective trial from Italy included 86 adults with moderate proteinuria (1 to 3.5 g/day) and at most mild renal insufficiency (median serum creatinine 1.0 mg/dL [88 micromol/L]) [97]. The patients were randomly assigned to supportive therapy alone or glucocorticoids (1.0 g of intravenous methylprednisolone for three consecutive days at the beginning of months one, three, and five, combined with 0.5 mg/kg of oral prednisolone given on alternate days for six months). At five and ten years, the 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 five years and 2 versus 30 percent at 10 years) [98]. The effect of ACE inhibitors was not assessed.

There is a subset of patients with IgA nephropathy in whom glucocorticoid therapy 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 cyclophosphamide for frequently relapsing proteinuria [105-107]. Mesangial IgA deposits often disappear or are greatly reduced over time [107]. It is possible that these patients have minimal change disease and that the presence of IgA deposits is unrelated, particularly in Asian patients [105,107]. (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'.)

Nephrotic syndrome can also occur in patients with severe chronic IgA nephropathy and relatively advanced disease on renal biopsy. These patients do not seem to benefit from glucocorticoid therapy [105,106].

Glucocorticoids plus angiotensin inhibitors — Simultaneous treatment with glucocorticoids plus an angiotensin inhibitor is preferred to glucocorticoids alone and may be superior to angiotensin inhibitors alone [103,108]. In a multicenter trial from Italy, combined treatment with ramipril and a six month course of prednisone provided greater benefit in preventing progression of kidney disease compared with ramipril alone among 97 patients with IgA nephropathy, protein excretion >1 g/day (mean 1.6 g/day), and estimated glomerular filtration rate (GFR) >50 mL/min per 1.73 m2 (mean 99 mL/min) [108].

At a follow-up of up to eight years, the following significant benefits were noted with combined therapy:

• A lower rate of the primary end point of doubling of the serum creatinine or end-stage renal disease (4 versus 27 percent).
• A lower rate of end-stage renal disease (2 versus 14 percent).
• The median urine protein excretion was higher with ramipril monotherapy at 6 months, 1 year and 2 years, but not at 3, 4, and 5 years of followup.

In multivariate analysis, the baseline serum creatinine and degree of proteinuria predicted the risk of achieving the primary outcome as described above in many other studies. (See 'Clinical predictors of progression' above.)

In this trial, glucocorticoids and angiotensin inhibitors were given simultaneously. We do not typically recommend simultaneous initiation of therapy since it would not be possible to detect whether any reduction in protein excretion was due to glucocorticoid therapy and/or to angiotensin inhibition. We usually recommend initial therapy with angiotensin inhibition for proteinuria unless the patient has more severe disease requiring immunosuppressive therapy. Once a stable response has been obtained, the second drug can be added. (See 'Indications for immunosuppressive therapy' above.)

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 [89,109-113]. 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 [92,109-111,114]. Two trials, which are discussed below, evaluated prednisone with either cyclophosphamide followed by azathioprine [111] or with azathioprine alone [114]. 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) [111]. Mean baseline protein excretion was 4.0 to 4.5 g/day.

The patients were given antihypertensive therapy as needed (but not specifically ACE inhibitors and/or ARBs) and randomly assigned to no further therapy or to prednisolone (40 mg per day tapered to 10 mg/day by two years) plus low-dose cyclophosphamide (1.5 mg/kg per day) for the initial three months followed by low-dose azathioprine (1.5 mg/kg per day) for a minimum of two years (some patients were given azathioprine for up to six years). Blood pressure control was similar in both groups, and immunosuppressive therapy was associated with a low incidence of adverse effects.

Compared with the control group, the patients treated with combination therapy had a significant reduction in protein excretion during the first six months of therapy that persisted during follow-up (eg, reached 1.8 g/day in treatment group versus unchanged at 4.4 g/day in controls at one year). Renal survival was significantly higher in the treatment group at years two (82 versus 68 percent) and five (72 versus 6 percent).

These findings suggest that patients with severe or progressive disease (eg, rising creatinine, nephrotic range proteinuria, and/or marked proliferation without crescents) who do not have significant chronic damage on kidney biopsy may benefit from combined immunosuppressive therapy with prednisone and cyclophosphamide [57].

Early therapy is important because improvement is rare when the baseline serum creatinine concentration is greater than 3.0 mg/dL (265 micromol/L) in the absence of crescentic glomerulonephritis [88]. In addition, immunosuppressive therapy is not indicated in the spontaneously reversible acute renal failure that may be associated with gross hematuria. (See 'Acute renal failure with gross hematuria' above.)

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 creatinines ≤2.0 mg/dL (177 micromol/L) and protein excretion >1.0 g/day were treated with glucocorticoids (a 3-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) [114]. 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 2.0 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 angiotensin converting enzyme inhibitor or angiotensin receptor blocker at the onset and therefore were not receiving the current standard of care [115]. 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 [112,113]. 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 [112]. 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) [116].
• In the second trial, 80 children were randomly assigned to prednisolone, azathioprine, warfarin, and dipyridamole or to prednisolone alone [113]. At 2-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 [117-121]. Glucocorticoids may act in this setting by diminishing acute inflammatory injury rather than by correcting in the factors responsible for IgA production and deposition [122]. (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 [119]. 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 [121]. 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.)

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 [24,123], particularly in patients with advanced fibrotic disease [24], to a reduction in proteinuria and a decrease in rate of decline in GFR [124,125]. Additional trials are ongoing [126]. 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.

A short course (less than six months) of MMF may be considered in patients with hematuria, persistent proteinuria (>1.5 g/day) and a serum creatinine <1.5 mg/dL (133 micromol/L) despite maximum therapy with an angiotensin inhibitor in patients without marked glomerular or tubulointerstitial fibrosis on renal biopsy. Current evidence does not support the use of MMF in patients with advanced disease (serum creatinine >2.5 mg/dL [221 micromol/L]) [24].

MMF is associated with increased fetal risk and should not be used in women who are or might become pregnant. (See "Mycophenolate mofetil: Pharmacology and adverse effects when used in the treatment of rheumatic diseases", section on 'Pregnancy'.)

Cyclosporine — Cyclosporine has been investigated in small series of patients with IgA nephropathy. Although proteinuria may be reduced, the use of cyclosporine 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 [127,128]. In addition, relapse occurs soon after the drug is discontinued.

Based upon the available data, we do not use cyclosporine 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, where the renal biopsy findings are those of IgA nephropathy, provides indirect evidence of possible benefit [129,130]. (See "Renal manifestations of Henoch-Schönlein purpura", section on 'Renal disease'.)

OTHER POSSIBLE INTERVENTIONS — Other interventions that have been evaluated in an uncontrolled fashion include tonsillectomy, a low antigen diet, intravenous immune globulin, and wormwood [59]. Other drugs, such as vitamin D analogs [131-133], phenytoin [59], antiplatelet agents [59], and danazol [134] 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 [135,136]. (See "Pathogenesis of IgA nephropathy", section on 'Regulation of IgA synthesis'.)

Several retrospective studies [101,136-138] and at least one prospective study [139] 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 benefit following tonsillectomy [140,141]. Randomized trials have not been performed.

In the prospective study of 55 patients, the effect of tonsillectomy plus pulse glucocorticoid therapy was compared with pulse glucocorticoid monotherapy alone [139]. The patients who underwent tonsillectomy did so after receiving a consultation from an otolaryngologist stating that tonsillectomy was indicated. Mean baseline protein excretion was 1.0 to 1.5 g/day and the mean baseline creatinine clearance was 95 mL/min. The following findings were noted:

• The patients who underwent tonsillectomy had significantly higher rates of remission of proteinuria and hematuria at two years after therapy (77 versus 41 percent, and 79 versus 18 percent, respectively). The beneficial clinical effects of tonsillectomy on proteinuria persisted through a mean follow-up of 54 months.
• In 18 patients who underwent a repeat biopsy at two years, mesangial proliferation and IgA deposition were reduced to a significantly greater degree in the patients who underwent tonsillectomy.

A meta-analysis of 4 case-control studies, including this one from Japan demonstrated a lower rate of end-stage renal disease among patients who had tonsillectomy plus glucocorticoids compared to nonoperative therapy with a pooled odds ratio of 0.22 (95% CI 0.11-0.44) [142]. The rate of clinical remission at 5 and 10 years was higher in the tonsillectomy group.

These findings provide some evidence supporting the efficacy of tonsillectomy in patients with "chronic tonsillitis" and significant IgA nephropathy (ie, proteinuria >1 g/day). Randomized trials are required to confirm that tonsillectomy is effective in slowing progression of IgA nephropathy and to clarify the role, if any, for tonsillectomy in the absence of other indications for this procedure, since the improvements observed may have been due to glucocorticoid therapy rather than removal of the tonsils.

Low antigen diet — A low antigen diet consists of avoiding gluten, dairy products, eggs, and most meats [143]. 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 [144].

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 [145].

High-dose IVIG has been tried in severe IgA nephropathy, characterized by heavy proteinuria and a relatively rapid decline in GFR [146]. Eleven patients (nine with IgA nephropathy and two with the related disorder Henoch-Schönlein purpura) were treated with IVIG at a dose of 1 g/kg for two days per month for three months followed by an intramuscular preparation given every two weeks for another six months. 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.

Wormwood — The herbal drug, wormwood (Artemisia absinthium), may inhibit inflammatory cytokines such as tumor necrosis factor-alpha and nuclear factor-kappa B. One study examined the effect of wormwood (1.8 g/day for six months) on protein excretion in ten patients with biopsy-proven IgA nephropathy, a creatinine clearance greater than 90 mL/min; and protein excretion >500 and <3500 mg/day despite angiotensin inhibition [147]. At six months, the mean urine protein-to-creatinine ratio decreased from 2.3 to 0.3. The reduction in proteinuria persisted for six months after stopping the herbal supplement. The creatinine clearance remained unchanged. The long-term effects of wormwood on the course of IgA nephropathy have not been evaluated.

PREGNANCY — Pregnancy is generally well tolerated in patients with IgA nephropathy and a normal or near normal glomerular filtration rate (GFR). 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 [148,149]. (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 "Use 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".)

SUMMARY AND RECOMMENDATIONS

• 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 that 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 endocapillary proliferation. It has been validated in numerous cohorts. (See 'Histologic predictors of progression' above.)
• The optimal approach to the treatment of IgA nephropathy is uncertain since definitive randomized trials have not been performed. Our approach is as follows:

• We recommend not treating patients with isolated hematuria, no or minimal proteinuria (less than 500 to 1000 mg/day), and a normal glomerular filtration rate. Such patients should be periodically monitored at 6 to 12 month intervals to assess for disease progression that might warrant therapy such as increases in proteinuria or serum creatinine. (See 'Patient selection' above.)
• For patients with persistent proteinuria greater than 1000 mg/day, we recommend angiotensin inhibition with an ACE inhibitor or ARB with a goal below 1000 mg/day. Some experts initiate an ACE inhibitor or an ARB in patients with proteinuria greater than 500 mg/day with a goal of less than 500 mg/day. (See 'Angiotensin inhibition' above.)
• Fish oil can be tried in addition to an ACE inhibitor or ARB in patients with protein excretion above 1000 mg/day, a gradual reduction in GFR, and mild to moderate histologic lesions. (See 'Fish oil' above.)

• We recommend the addition of immunosuppressive therapy with glucocorticoids to angiotensin inhibition in patients with an elevated or increasing serum creatinine and/or protein excretion above 1.0 to 1.5 g/day despite maximum antiproteinuric therapy, with the exception of patients with substantial chronic fibrotic changes. We do not use glucocorticoids without angiotensin inhibition and we recommend not using immunosuppressive therapy in patients with chronic fibrotic disease as described above. (See 'Indications for immunosuppressive therapy' above and 'Lack of benefit in chronic fibrotic disease' above.)
  
  Two glucocorticoid regimens we use are:

• Intravenous methylprednisolone (500 to 1000 mg per dose or, in children, 7 to 15 mg/kg in children per dose to a maximum of 1000 mg) for three consecutive days at the beginning of months one, three and five, and alternate day oral prednisone (0.5 mg/kg, approximately 30 to 40 mg/day) for six months, then tapered to discontinuation. (See 'Glucocorticoids' above.)
• An alternative regimen that avoids pulse therapy can also be used, such as 2 mg/kg of prednisone (maximum 100 to 120 mg) every other day for two months, with a rapid taper to a dose of 0.5 mg/kg (approximately 30 to 40 mg) every other day for an additional four months. Prednisone is then tapered to discontinuation.

• For patients with severe disease at baseline (defined as initial serum creatinine >1.5 mg/dL [133 micromol/L]) or progressive disease (eg, increasing serum creatinine and/or protein excretion) with glucocorticoids alone who do not have significant chronic damage on kidney biopsy, we suggest therapy with oral prednisone and cyclophosphamide. (See 'Severe or progressive disease' above.)
  
  One regimen we use is:

• Prednisone (1 mg/kg to a maximum 60 to 80 mg/day) for two to three months followed by a slow taper to a maintenance dose of 10 mg/day for one to two years.
• Cyclophosphamide (1.5 mg/kg per day) orally for three months, followed, if the serum creatinine has stabilized and protein excretion has fallen, by either azathioprine (1.5 mg/kg per day) or mycophenolate mofetil (starting with 1000 mg twice a day and tapering over time to 500 mg twice a day) for a period of one to two years as maintenance therapy.

• For patients with crescentic glomerulonephritis and a rapidly progressive clinical course, we recommend therapy with intravenous pulse glucocorticoids and cyclophosphamide as used in other forms of crescentic glomerulonephritis. (See 'Crescentic glomerulonephritis' above.)
  
  One regimen we use is:

• Intravenous methylprednisolone for three consecutive days (500 to 1000 mg per dose or, in children, 7 to 15 mg/kg in children per dose to a maximum of 1000 mg) followed by oral prednisone (1 mg/kg per day, maximum dose 60 to 80 mg) for two to three months, then a slow taper to a maintenance dose of 10 mg/day for one to two years.
• Intravenous cyclophosphamide (0.5 g/m2) monthly for at least three months followed, if the serum creatinine has stabilized and protein excretion has fallen, by either azathioprine (1.5 mg/kg per day) or mycophenolate mofetil (starting with 1000 mg twice a day and tapering over time to 500 mg twice a day) for a period of one to two years as maintenance therapy, provided that the serum creatinine stabilized.

• For patients with acute onset of nephrotic syndrome and minimal change disease as well as mesangial IgA deposits on renal biopsy, we recommend glucocorticoid therapy as in other patients with minimal change disease. (See 'Glucocorticoids' above.)
• Acute renal failure 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 to months. However, acute renal failure 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 at a maximum of one week, we suggest a repeat renal biopsy to exclude crescentic disease. (See 'Acute renal failure with gross hematuria' above.)
• Chronic kidney disease from any cause is associated with a marked increase in cardiovascular risk. Statin therapy may lower cardiovascular risk but there is no evidence that it slows the rate of progression of renal disease. (See 'Lipid-lowering therapy' above.)

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

Topic 3039 Version 17.0

Wolters Kluwer Health | Facts & Comparisons® | Medi-Span® | ProVation® Order Sets | ProVation® Medical | Pharmacy OneSource® | Medicom | Lexicomp

Wolters Kluwer Health | UpToDate

TOPIC OUTLINE

GRAPHICS

RELATED TOPICS