INTRODUCTION — IgA nephropathy is the most common cause of primary (idiopathic) glomerulonephritis in the developed world [1-4]. Although this disorder was initially thought to follow a benign course, it is now recognized that slow progression to end-stage renal disease (ESRD) occurs in up to 50 percent of affected patients [5]. The remaining patients enter a sustained clinical remission or have persistent low grade hematuria or proteinuria. However, the prognosis is quite variable and the outcome difficult to predict with accuracy in individual patients.

The classic presentation of IgA nephropathy is that of gross hematuria, often recurrent, following shortly after an upper respiratory infection [3,6]. However, the majority of patients are diagnosed following an evaluation for asymptomatic microscopic hematuria and/or mild proteinuria. Less common presentations are nephrotic range proteinuria with or without nephrotic syndrome and rapidly progressive glomerulonephritis and, rarely, malignant hypertension. The diagnosis is usually suspected based upon the clinical history and laboratory data, but can only be confirmed with a kidney biopsy, at the present time.

The prognosis and treatment of IgA nephropathy will be reviewed here. The causes, pathogenesis, and diagnosis of this disorder, and the outcomes in patients who undergo renal transplantation, are discussed separately. (See "Pathogenesis of IgA nephropathy" and "Clinical presentation and diagnosis of IgA nephropathy" and "IgA nephropathy: Recurrence after transplantation".)

PROGNOSIS — Patients with IgA nephropathy and little or no proteinuria (<500 mg/day) have a low risk of progression in the short term. However, renal insufficiency and proteinuria develop in a substantial proportion of patients over the long term, and such patients may progress to end-stage renal disease (ESRD) [5,7]. The possible role of persistent microscopic hematuria in predicting an adverse outcome in this group of patients is debated.

Frequency of progression — The natural history of patients who present with isolated hematuria (ie, without abnormal proteinuria) is not as benign as initially thought. This was demonstrated in the following studies:

• In a Chinese study of 72 consecutive patients with IgA nephropathy who underwent diagnostic biopsy because of hematuria with no or minimal proteinuria (defined as less than 0.4 g/day), patients were followed for a median of seven years [6]. Protein excretion above 1000 mg/day, hypertension, and/or impaired renal function (serum creatinine concentration ≥1.4 mg/dL [120 µmol/L]) developed in 33, 26, and 7 percent, respectively.
• In a nationwide study of 2270 patients with biopsy-proven IgA nephropathy in Japan who were surveyed three, five, and eight years after the baseline survey, 207 patients developed ESRD [8]. The seven-year cumulative incidence of end-stage renal disease was 8 and 15 percent for women and men, respectively.
• Among 93 patients with an initially normal measured glomerular filtration rate (GFR) (but usually with proteinuria), approximately one-third had a reduced GFR within five years and one-fourth progressed to ESRD within 20 years [9].

Among patients who develop proteinuria and/or elevated serum creatinine concentration, progression to ESRD is approximately 15 to 25 percent at 10 years and 20 to 30 percent at 20 years [1,2,8-11]. Higher rates of progression are seen among patients with more severely impaired kidney function. Among the 183 patients with serum creatinine ≥1.7 mg/dL (150 µmol/L) in the previously mentioned Japanese survey, the seven-year cumulative incidence of ESRD was ≥70 percent [8].

However, the rate of loss of GFR was often as low as 1 to 3 mL/min per year, a change not associated with an elevation in the serum creatinine concentration during this time period. Thus, a stable and normal serum creatinine does not necessarily indicate stable disease.

These observations are generally from patients with biopsy-confirmed IgA nephropathy in which some factor other than hematuria prompted the biopsy (such as proteinuria or an elevated serum creatinine concentration). Patients with only hematuria are often not biopsied in many countries (such as the United States).

The impact of different biopsy criteria was shown in a retrospective study that evaluated geographic differences in the clinical course of 711 patients with a biopsy diagnosis of IgA nephropathy [5]. Renal survival at 10 years was 96, 87, 64, and 62 percent in Finland, Australia, Scotland, and Canada, respectively. Better outcomes in Finland and Australia were largely attributable to the diagnosis of milder cases (eg, less proteinuria, higher creatinine clearance, lower blood pressure). This raises the possibility of lead-time bias influencing the prognosis, versus truly a better prognosis in some geographic areas compared to others [5,12]. (See "Glomerular hematuria: IgA; Alport; thin basement membrane nephropathy".)

Repeat renal biopsy has also been used to assess the frequency of progressive disease [13,14]. In one report, repeat renal biopsies were performed at five years in 73 patients with persistent proteinuria but a normal or near-normal initial serum creatinine [13]. Histologic improvement occurred in only 4 percent, with 41 percent remaining stable and 55 percent showing progressive glomerular and secondary vascular and tubulointerstitial injury.

Some patients without significant proteinuria or renal dysfunction undergo remission of abnormal laboratory findings, with reported rates ranging between 5 and 30 percent [10,12-15]. Remission may be more likely among children. This was illustrated in a study of 181 Japanese children diagnosed by renal biopsy before the age of 15 years; 30 percent had proliferative glomerulonephritis and were treated with immunosuppressive agents [16]. After a mean follow-up of seven years, 50 percent had no manifestations of disease, 36 percent had persistent hematuria with or without proteinuria, and 25 (14 percent) developed progressive disease.

Clinical predictors of progression — As in other glomerulopathies, patients who will develop progressive disease typically have one or more of the following clinical or laboratory findings at diagnosis [1,2,6,7,9,16-22]:

• Elevated serum creatinine concentration at diagnosis — Patients who reach a serum creatinine concentration ≥2.5 mg/dL (221 µmol/L) generally continue to progress.
• Hypertension — Hypertension is associated with arteriosclerosis and tubulointerstitial changes on biopsy, and usually significant proteinuria.
• Persistent protein excretion above 500 to 1000 mg/day.

The relation between increasing proteinuria and a worse prognosis is probably in part a reflection of proteinuria being a marker for the severity of glomerular disease. The rate of progression is very low among patients excreting less than 500 mg/day and is fastest among those excreting more than 3.0 to 3.5 g/day of protein [9,21,22].

The importance of the magnitude of proteinuria on the course of IgA nephropathy was evaluated in an observational study of 542 patients [22]. The rate of decline in renal function was 25-fold faster in those with sustained proteinuria of greater than 3 g/day compared to patients with protein excretion less than 1 g/day [22]. Patients who presented with protein excretion above 3 g/day who attained a partial remission (less than 1 g/day) had a similar rate of progression as patients with sustained proteinuria of less than 1 g/day. As described below, ACE inhibitors or angiotensin II receptor blockers are the preferred antiproteinuric drugs. (See 'Angiotensin inhibition' below.)

Patients who have only recurrent episodes of gross hematuria seem to be at less risk than those with persistent microscopic hematuria and proteinuria [1,23]. Why this might occur is not clear.

Acute renal failure with gross hematuria — Acute renal failure can occur during episodes of gross hematuria [24-26]. Renal biopsy in these patients reveals mesangial proliferation and segmental crescents in a small proportion of glomeruli (usually less than 25 percent) [24,26]. These findings are insufficient to account for the acute renal failure, which has been ascribed to tubular obstruction by red cell casts [24,25,27]. However, the most common histologic lesion is acute tubular necrosis, which may be induced by the iron released from lysed red cells in the tubules [24,26,27].

This form of acute renal failure is generally a benign complication; the serum creatinine concentration most commonly returns to baseline levels within several weeks to months, even if dialysis is temporarily required [24]. However, incomplete recovery of renal function has been described in up to 25 percent of affected patients [27].

Histologic predictors of progression — Although clinical features appear to be stronger prognostic indicators [18], certain findings on renal biopsy have been associated with an increased risk of progressive disease. These include glomerulosclerosis, tubular atrophy, interstitial fibrosis, immune deposits in the capillary loops as well as the mesangium, vascular disease, and crescent formation [1,10,16,20,23,28-30].

Several schema for classifying renal biopsy findings have been described that appear to correlate with prognosis; in multivariate analyses, the extent of glomerulosclerosis and tubulointerstitial disease are most commonly associated with a poor prognosis [23,31,32]. These indicators are typical of most glomerular diseases. (See "Secondary factors and progression of chronic kidney disease", section on Tubulointerstitial disease.)

Genetic associations — A number of genetic associations have been suggested to be prognostically important in patients with IgA nephropathy, but the data are often conflicting and may be confounded by the population studied.

• In some studies, progressive disease appeared more likely in patients with the DD genotype of the ACE gene, which is associated with higher plasma ACE levels, than in those with the ID or II genotype [33-35]. However, others have reported no correlation between genotype and outcome [36,37].
• The possible roles of two other genes related to the renin-angiotensin system, the angiotensinogen and angiotensin II receptor genes, have also been evaluated. No relation was found with the angiotensin II receptor genes [35,38], while conflicting data have been reported with the angiotensinogen gene [35,38,39].
• In a study of 425 Chinese patients and their families, a polymorphism of the megsin gene appeared to be associated with a faster rate of rise in serum creatinine at a two-year follow-up [40]. Upregulation of megsin (a serine protease inhibitor predominantly expressed in the mesangium) was correlated with mesangial expansion and hypercellularity.

There are conflicting findings in two Italian studies as to whether or not familial disease is associated with a worse prognosis [41,42]. The much larger series found no association between familial disease and outcome [42]. (See "Pathogenesis of IgA nephropathy", section on 'Genetic predisposition'.)

APPROACH TO THERAPY — The optimal approach to the treatment of IgA nephropathy is uncertain [43,44]. The slow rate of loss of GFR (1 to 3 mL/min per year) seen in many patients hinders the ability to perform adequate studies.

There are two separate approaches to the therapy of IgA nephropathy:

• General interventions to slow progression that are not specific to IgA nephropathy, include blood pressure control, angiotensin converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs) in patients with proteinuria. Issues related to statin therapy in patients with chronic kidney disease and serum LDL-cholesterol concentrations above goal values are discussed below and separately. (See 'Nonimmunosuppressive therapies' below and "Statins and chronic kidney disease".)

• Therapy with glucocorticoids with or without other immunosuppressive agents to treat the underlying inflammatory disease. (See 'Immunosuppressive therapy' below.)

Patient selection — Patient selection for therapy is based in part upon the perceived risk of progressive kidney disease. (See 'Clinical predictors of progression' above,:

• Patients with isolated hematuria, no or minimal proteinuria, and a normal GFR are typically not treated (and often not biopsied and identified), unless they have evidence of progressive disease such as increasing proteinuria, blood pressure, and/or serum creatinine.
• Patients with persistent proteinuria (above 500 to 1000 mg/day), normal or only slightly reduced GFR that is not declining rapidly, and only mild to moderate histologic findings on renal biopsy are managed with general interventions to slow progression and perhaps with fish oil. (See 'Nonimmunosuppressive therapies' below.)

• Patients with more severe or rapidly progressive disease (eg, nephrotic range proteinuria or proteinuria persisting despite ACE inhibitor/ARB therapy, rising serum creatinine, and/or renal biopsy with more severe histologic findings, but no significant chronic changes) may benefit from immunosuppressive therapy in addition to nonimmunosuppressive interventions to slow disease progression. (See 'Immunosuppressive therapy' below and 'Treatment' below.)

Monitoring disease activity — There are no specific markers to identify continued immunologic activity. As a result, clinical parameters are typically used, whether or not the patient is receiving immunosuppressive therapy. The major parameters that are serially monitored are the urine sediment, protein excretion, usually estimated from the protein-to-creatinine ratio, and the serum creatinine concentration.

• Hematuria — Persistent hematuria is generally a marker of persistent immunologic activity, but not necessarily of progressive disease. This finding may be a sign of a "smoldering" segmental necrotizing lesion, suggestive of "capillaritis." Hematuria alone does not require any form of therapy.
• Proteinuria — Proteinuria, rather than hematuria alone, is a marker of more severe disease [21]. Increasing proteinuria may be due to one of two factors: ongoing active disease; and secondary glomerular injury due to nonimmunologic progression. It is often not possible to distinguish between these two possibilities, except for a rapid increase in protein excretion which is only seen with active disease. Issues related to secondary factors and progression are discussed separately. (See "Secondary factors and progression of chronic kidney disease" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

Protein excretion typically falls with ACE inhibitor/ARB therapy and the degree of proteinuria is, as described below, one of the end points of such therapy. Protein excretion also may fall spontaneously, particularly during recovery from an acute episode and perhaps in children, and following effective immunosuppressive therapy.

• Serum creatinine — The serum creatinine, unless it is rapidly rising, permits an estimation of the 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 will not raise the serum creatinine for many years [9]. Thus, a stable and even normal serum creatinine does not necessarily indicate stable disease.

NONIMMUNOSUPPRESSIVE THERAPIES — There are two main nonimmunosuppressive therapies in IgA nephropathy [43,44]:

• Angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) both for blood pressure control and to slow progression of the renal disease.
• Statin therapy for lipid-lowering in selected patients to lower cardiovascular risk and possibly reduce disease progression.

Fish oil has also been studied, but its role is less clear.

Angiotensin inhibition — The progression of IgA nephropathy may be slowed by antihypertensive and antiproteinuric therapy that can minimize secondary glomerular injury [45]. ACE inhibitors and ARBs act by reducing the intraglomerular pressure and by directly improving the size-selective properties of the glomerular capillary wall, both of which contribute to reducing protein excretion [46,47].

Both observational studies [48,49] and small randomized trials [47,50,51] have provided suggestive evidence that ACE inhibitors or ARBs are more effective than other antihypertensive drugs in slowing the progressive decline in GFR in IgA nephropathy as they are in other forms of chronic proteinuric kidney disease. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

The following observations come from three randomized trials in patients with IgA nephropathy:

• In one trial, 44 patients with proteinuria (≥0.5 g/day, mean 1.9 g/day) and a serum creatinine concentration ≤1.5 mg/dL (133 µmol/L) at baseline were randomly assigned to either enalapril or antihypertensive agents other than ACE inhibitors or ARBs [50]. The target blood pressure throughout the study was <140/90 mmHg, and initially normotensive patients received a fixed dose of antihypertensive drugs. At follow-up of about six years, renal survival, defined as less than a 50 percent increase in the serum creatinine concentration, was significantly more likely in the enalapril group (92 versus 55 percent). A significant decrease in proteinuria was only observed in the enalapril group (2 g/day at baseline to 0.9 g/day at the last visit). The proteinuria decrease after one year of therapy correlated with renal survival. Blood pressure control was similar in the two groups
• In the double-blind placebo-controlled HKVIN trial, 109 Chinese patients with protein excretion ≥1000 mg/day (mean about 2.0 g/day) were randomly assigned to valsartan or placebo, and other non-ACE or non-ARB antihypertensive agents as needed to achieve a goal blood pressure of <140/90 mmHg [51]. Patients in the valsartan group had lower baseline proteinuria and achieved blood pressure. After two years, the primary end point of doubling of serum creatinine or ESRD was reached by fewer patients in the valsartan group (1 versus 4 in the placebo group), but the number of events was too small to have confidence in the results. In adjusted analyses, valsartan was associated with significant improvement in proteinuria (33 percent reduction in proteinuria compared to placebo) and a slower rate of decline in GFR (4.6 versus 6.9 mL/min per year). However, both the lower initial proteinuria and the lower sustained blood pressure in the valsartan group complicates the interpretation of the study.
• In the IgACE trial, 65 young patients (range 9 to 35 years) with moderate proteinuria (between 1 and 3.5 grams/day per 1.73 m2) and relatively preserved renal function (creatinine clearance >50 mL/min per 1.73 m2) were randomly assigned to benazepril (0.2 mg/kg per day) or placebo [52]. Only five patients were hypertensive. At a median follow-up of 38 months (range of 0 to 58 months), the primary end point (greater than 30 percent decrease in renal function) was reached by fewer patients in the treatment group (one versus five in the placebo group). However, as with the HKVIN trial, this study was underpowered to address this outcome. Nevertheless, active therapy resulted in a significantly lower incidence of the secondary composite end point (greater than 30 percent decrease of the creatinine clearance or worsening of proteinuria until the nephrotic range was reached, 3 versus 27 percent) and a higher incidence of a partial (41 versus 9 percent) or complete remission (13 versus 0 percent). Although blood pressures were higher in the placebo group in the last one to two years of the study, the effect of blood pressure on outcomes is likely to be small, given that differences were not observed in the first three years [53].

Normotensive patients who excrete less than 500 mg of protein per day are not typically treated with angiotensin inhibition. However, because most patients progress slowly over time, monitoring of the serum creatinine and protein excretion at yearly intervals is recommended. Angiotensin inhibition should be started if there is evidence of progressive disease and protein excretion above 500 mg/day.

ACE inhibitor plus ARB — The addition of an ARB to an ACE inhibitor in patients with IgA nephropathy appears to produce a further antiproteinuric effect [54,55]. This finding is consistent with meta-analyses of trials in different glomerular diseases, the largest of which found a significant 18 to 25 percent greater reduction in proteinuria with combined ACE inhibitors and ARBs compared to monotherapy [56,57].

As mentioned above, a more pronounced antiproteinuric effect is thought to be a marker for better outcomes [22]. (See 'Clinical predictors of progression' above.) Despite the greater reduction in proteinuria with combined ARB/ACE inhibitor therapy however, there are no randomized trials that have shown that this regimen improves renal outcomes. Questions have been raised about the reliability of the one trial (COOPERATE) that directly addressed the renoprotective effect of combination therapy. This issue is discussed separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease", section on COOPERATE trial.)

In addition, in the ONTARGET trial, which comprised 25,620 patients with vascular disease or diabetes, there was an increase in adverse side effects (including a possible increase in mortality) in patients who received combined therapy with an ACE inhibitor and ARB, compared to those who received monotherapy [58,59]. The ONTARGET trial is discussed elsewhere. (See "Choice of antihypertensive drug and blood pressure goal in patients at increased risk for a cardiovascular event" and "Treatment of hypertension in diabetes mellitus" and "Major side effects of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers".)

Treatment goals — The treatment goals with angiotensin inhibition are the same as those in other forms of proteinuric chronic kidney disease as described in the K/DOQI guidelines [60]. The data supporting the following recommendations are discussed in detail separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

Fish oil — The possible role of fish oil in IgA nephropathy, which might act by antiinflammatory mechanisms, is not well defined [61]. In addition to uncertain efficacy and consistency in regards to omega-3 fatty acid content, there is an associated fishy aftertaste and eructations with this treatment that often limit patient acceptance [62].

Randomized controlled trials evaluating fish oil in patients with IgA nephropathy have reported conflicting results [62-68]. The following two trials illustrate the range of findings [62,65,68]:

• In a trial from the Mayo Clinic, 106 patients with baseline creatinine clearance 80 mL/min and protein excretion of 2.5 to 3 g/day were randomly assigned to therapy with either 12 g of fish oil or a similar amount of olive oil for two years [62]. There was no difference in blood pressure control and no effect on protein excretion during the study.

At four years, patients receiving fish oil had a lower incidence of a ≥50 percent increase in the serum creatinine concentration (6 versus 33 percent in the placebo group) and a lower incidence of death or ESRD at four years (10 versus 40 percent). With follow-up extended to >6 years, benefits of continuous fish oil therapy persisted (15 versus 37 percent incidence of ESRD) [65].

• In a trial by the Southwest Pediatric Nephrology Study Group, 96 patients (mean GFR >100 mL/min per 1.73 m2 and proteinuria 1.4 to 2.2 g/day) were randomly assigned to one of three treatment arms: a purified preparation of omega-3 fatty acids (4 g/day) for two years; alternate day prednisone (60 mg/m2 per dose for three months, 40 mg/m2 per dose for nine months, and 30 mg/m2 per dose for one year); or placebo [68]. All patients with hypertension (blood pressure ≥140/90 mmHg) were treated with enalapril.

At three years, the primary outcome of a reduction in GFR to below 60 percent of the baseline value was observed more commonly in the omega-3 fatty acid treatment group (19 versus 9 percent in both the prednisone and placebo groups, respectively). This difference was not statistically significant (although the study was underpowered), and only baseline proteinuria was significantly associated with progression.

It is not clear why these trials produced different results. One potentially important factor is that the positive trial evaluated patients with more advanced disease (more proteinuria and lower creatinine clearance at baseline), and the placebo (olive oil) group had a faster rate of progression than is generally seen. On the other hand, in the negative trial, patients in the placebo group had lower baseline proteinuria, a factor that is known to be associated with a better prognosis [68].

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 [69]. When this difference was accounted for statistically, a benefit with fish oil therapy was not found to be significant, but a minor benefit was possible.

Summary — The benefit of fish oil has not been established. Furthermore, the trial designs are not applicable to current practice, since the patients were not treated with an ACE inhibitor and/or ARB and, as necessary, other drugs to recommended proteinuria and blood pressure goals. (See 'Treatment goals' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

Fish oil can be tried in addition to ACE inhibitors or ARBs in patients with protein excretion >500 to 1000 mg/day, a gradual reduction in GFR, and mild to moderate histologic lesions [70].

Lipid-lowering therapy — All patients with decreased kidney function and/or hypercholesterolemia should receive lipid-lowering therapy with a statin based upon the following rationales:

• Chronic kidney disease is associated with a marked increase in cardiovascular risk, and is now considered a coronary artery disease risk equivalent. (See "Chronic kidney disease and coronary heart disease".)

• Lipid-lowering with statins has been associated with a slower rate of loss of GFR in patients with mild to moderate CKD. (See "Statins and chronic kidney disease", section on 'Statins and CKD progression'.)

The goal LDL-cholesterol is similar to that in patients with underlying coronary heart disease. (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease".)

IMMUNOSUPPRESSIVE THERAPY — The optimal role of immunosuppressive therapy in IgA nephropathy is uncertain [43,44]. A variety of regimens have been used, mostly consisting of glucocorticoids alone or with other immunosuppressive drugs. The available studies are not conclusive since most are relatively small and have limited follow-up, and the results are sometimes conflicting [1,2,70-75].

Glucocorticoids — Most nephrologists do not treat mild, stable, or very slowly progressive IgA nephropathy with glucocorticoids (corticosteroids) or other immunosuppressive therapies, given the limited evidence of benefit and known toxicity from chronic use [76,77]. Glucocorticoid therapy should only be attempted in patients with clinical and histologic evidence of active inflammation (eg, hematuria and/or proliferative or necrotizing glomerular changes). Patients with chronic kidney disease with significant tubulointerstitial fibrosis and glomerulosclerosis are not likely to benefit from such therapy and are likely to be harmed from the side effects. (See "Major side effects of systemic glucocorticoids".)

The potential benefit of glucocorticoid therapy in IgA nephropathy has been examined in uncontrolled studies, retrospective observations, and a few relatively small, randomized controlled trials [76,78]. Furthermore, the applicability of these trials to current practice is unclear, since most trials included patients who were not routinely treated with an ACE inhibitor and/or ARB and, as necessary, other drugs to attain recommended proteinuria and blood pressure goals. (See 'Treatment goals' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

Glucocorticoid therapy for 6 to 24 months or more may be associated with a reduction in proteinuria and perhaps improved renal survival [76,78-87], although this has not been consistently noted [68]. Benefit in some of these studies was observed only among individuals with preserved kidney function (eg, creatinine clearance above 70 mL/min) [79-82]. However, other studies have found improved outcomes even among individuals with more advanced disease (eg, reduced kidney function and more significant proteinuria) [78,83,86,87].

As an example, a prospective trial from Italy included 86 adults with proteinuria (1 to 3.5 g/day) and at most mild renal insufficiency (median serum creatinine 1 mg/dL [88.4 µmol/L]) [81]. The patients were randomly assigned to supportive therapy alone, or glucocorticoids (1.0 gram of intravenous methylprednisolone for three consecutive days at the beginning of months one, three, and five, combined with 0.5 mg/kg of oral prednisolone given on alternate days for six months).

At five and ten years, the glucocorticoid treated patients had a markedly lower incidence of the primary end point, which was a doubling in the serum creatinine concentration (2 versus 21 percent at five years and 2 versus 30 percent at 10 years) [82]. The effect of ACE inhibitors was not assessed.

Another trial, which was terminated prematurely, found that therapy with glucocorticoids plus ACE inhibition was superior to ACE inhibition alone [87]. In this study, 63 patients with proteinuria of 1 to 5 g/day and excellent baseline kidney function (mean of approximately 100 mL/min per 1.72) were randomly assigned to corticosteroids (0.8 to 1 mg/kg per day for eight weeks, with a subsequent taper) plus an ACE inhibitor versus an ACE inhibitor alone. The combination regimen was associated with a significantly lower risk of kidney failure (ie, 50 percent increase in the serum creatinine) than observed with single agent therapy (one versus seven patients, relative risk 0.13, 95% CI 0.02-0.99).

However, this study has significant potential flaws, including early termination for benefit, small sample size, lack of blinding of participants and investigators, and absence of measures of compliance [88]. In addition, this was restricted to an Asian population in which the pathology and natural history might be different from other racial groups.

In contrast, the trial from the Southwest Pediatric Nephrology Study Group described above found no difference at three years between oral prednisone therapy for two years and placebo in the primary outcome of reduction in GFR to below 60 percent of the baseline value [68]. However, this trial was underpowered for the primary end-point. (See 'Fish oil' above.)

There is a subset of patients with IgA nephropathy in whom prednisone therapy appears to be more clearly beneficial: those with an acute onset of the nephrotic syndrome, little or no hematuria, preserved kidney function, minimal glomerular changes on light microscopy, and diffuse fusion of the foot processes of the glomerular epithelial cells on electron microscopy. These histologic findings are characteristic of minimal change disease, and these patients behave accordingly, frequently developing a remission with glucocorticoids and occasionally requiring cyclophosphamide for frequently relapsing proteinuria [89-91]. Mesangial IgA deposits often disappear or are greatly reduced over time [91]. (See "Treatment of minimal change disease in adults".)

Nephrotic syndrome can also occur with severe chronic IgA nephropathy and relatively advanced disease on renal biopsy. These patients do not seem to benefit from glucocorticoid therapy alone [89,90].

The role of glucocorticoids alone in the treatment of IgA nephropathy is summarized below. (See 'Treatment' below.)

Combined immunosuppressive therapy — Combined immunosuppressive therapy should only be attempted in patients with more severe active disease as defined by a more rapidly progressive clinical course and/or histologic evidence of severe active inflammation (eg, crescent formation).

Severe or progressive disease — Several trials have suggested a possible benefit from combined immunosuppressive therapy in patients with moderate to severe active disease on biopsy; however, most did not include a comparison group treated with prednisone alone [71,92-96]. In addition, the studies were primarily performed prior to the widespread use of aggressive antihypertensive and antiproteinuric therapy with ACE inhibitors and/or ARBs. (See 'Treatment goals' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

Two trials in children with moderate to severe histologic findings on renal biopsy, but normal kidney function (initial creatinine clearance >140 mL/min per 1.73 m2), evaluated complicated regimens that included heparin, warfarin and dipyridamole as well as combined immunosuppressive therapy [95,96]. No benefit was observed with these regimens compared with azathioprine and/or prednisone.

There are limited data concerning the effectiveness of cytotoxic agents in adults with progressive IgA nephropathy [76,92-94]. Some trials evaluated cyclophosphamide with warfarin and dipyridamole [92,93], a regimen that is not widely used, and one evaluated cyclophosphamide with prednisone [94]. The last trial was a single center study of 38 patients with IgA nephropathy and initially impaired renal function (but no crescents on biopsy) as defined by an initial serum creatinine concentration between 1.5 and 2.8 mg/dL (130 and 250 µmol/L, respectively) that was declining at a relatively moderate rate (by at least 15 percent over the year prior to study entry) [94]. Mean baseline protein excretion was 4.0 to 4.5 g/day.

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

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

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

Early therapy is important because improvement is rare when the baseline serum creatinine concentration is greater than 3.0 mg/dL (265 µmol/L) in the absence of crescentic glomerulonephritis [70]. In addition, immunosuppressive therapy is not indicated in the spontaneously reversible acute renal failure that may be associated with gross hematuria. (See 'Acute renal failure with gross hematuria' above.)

The role of combined immunosuppressive therapy in the treatment of severe or progressive IgA nephropathy is summarized below. (See 'Treatment' below.)

Crescentic glomerulonephritis — Uncontrolled reports in patients with crescentic, rapidly progressive glomerulonephritis suggest possible benefit from regimens similar to those used in idiopathic crescentic glomerulonephritis: intravenous pulse methylprednisolone followed by oral prednisone, intravenous or oral cyclophosphamide, and/or plasmapheresis [97-101]. Glucocorticoids may act in this setting by diminishing acute inflammatory injury rather than by correcting the abnormality in IgA production [102]. (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 [99]. After two months of therapy, there was substantial clinical improvement characterized by reductions in the serum creatinine concentration and protein excretion. However, repeat renal biopsy showed persistence of florid crescents and one-half of patients had progressive disease after therapy was discontinued.

A more prolonged course of aggressive immunosuppressive therapy was evaluated in 12 patients with crescentic, proliferative IgA nephropathy who had a mean serum creatinine concentration of 2.7 mg/dL (240 µmol/L) and protein excretion of 4 g/day at baseline [101]. The treatment regimen consisted of the following:

• Pulse methylprednisolone (15 mg/kg per day for three days)
• Oral prednisone (1 mg/kg per day for 60 days, followed by 0.6 mg/kg per day for 60 days, followed by 0.3 mg/kg per day for 60 days, with all patients on 10 mg/day at the time of repeat biopsy).
• Monthly intravenous cyclophosphamide (0.5 g/m2) for six months

After the six month course, there was significant improvement in the serum creatinine concentration (from 2.7 to 1.5 mg/dL [240 to 133 µmol/L]) and in protein excretion (from 4 to 1.4 g/day). Repeat biopsy revealed the absence of cellular crescents and endocapillary proliferation in all patients.

Throughout the three-year follow-up, all patients continued prednisone (0.15 mg/kg per day), and the blood pressure was controlled to a goal of <130/70 mmHg with ACE inhibitors and other agents as needed. Compared with 12 untreated historic controls (matched for age, gender, baseline serum creatinine concentration and histologic severity), the incidence of ESRD at three years was significantly lower in the treated group (1 of 12 [8 percent] versus 5 of 12 [42 percent]).

These limited data suggest that patients with crescentic glomerulonephritis who do not have significant chronic damage on kidney biopsy may benefit from therapy that initially includes intravenous cyclophosphamide. This is consistent with the benefit noted with a similar regimen in other forms of crescentic glomerulonephritis. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)

The role of combined immunosuppressive therapy in the treatment of crescentic IgA nephropathy is summarized below. (See 'Treatment' below.)

Other immunosuppressive agents

Cyclosporine — Cyclosporine has been investigated in small studies, and resulted in reduced proteinuria. However, its use has been limited by the associated nephrotoxicity, leading to a rise in the serum creatinine concentration that is greater than that seen in untreated patients [103,104]. Furthermore, relapse occurs soon after the drug is discontinued.

Based upon the available data, we do not use cyclosporine for the treatment of IgA nephropathy.

Mycophenolate mofetil — There are limited data concerning the efficacy of mycophenolate mofetil (MMF) in the primary treatment of progressive IgA nephropathy. Four small, prospective placebo-controlled randomized trials of the efficacy and safety of MMF in which the patients were also treated with ACE inhibitors in at least three, have produced conflicting results, ranging from no benefit [105,106] to a reduction in proteinuria [107,108]. There is no evidence (yet) that MMF will safely delay the onset of ESRD in patients with IgA nephropathy.

The conflicting results may be explained in part by differing severity of kidney disease, being less advanced in the studies demonstrating benefit. Additional trials are ongoing although one was recently stopped because of funding issues and futility given no differences observed between treated and control group [109].

A short course (less than six months) of MMF in patients with persistent proteinuria (>1.5 g/day) and well-maintained renal function (serum creatinine <1.5 mg/dL [132.6 µmol/liter]) despite maximum ACE inhibitor/ARB therapy may be considered in someone with well-preserved renal histology on biopsy. Current evidence does not support the use of MMF in patients with advanced disease (serum creatinine >2.5 to 3 mg/dL [221 and 265 µmol/L]).

OTHER POSSIBLE INTERVENTIONS — Other interventions that have been evaluated in an uncontrolled fashion include tonsillectomy, low antigen diet, antiplatelet agents, other immunosuppressive agents and intravenous immune globulin. Experience with these interventions is limited.

Tonsillectomy — Tonsillitis has been associated with hematuria and proteinuria in IgA nephropathy. It has been proposed that the tonsils are a source of abnormal IgA that forms immune complexes, and deposits in the glomeruli [110,111]. (See "Pathogenesis of IgA nephropathy".)

Several retrospective reports suggested that tonsillectomy, usually in combination with some immunosuppressive therapy, was associated with improved renal survival among patients with relatively mild renal injury [85,111-113]. Others reported no benefit of tonsillectomy [114,115]. There are no randomized trials of tonsillectomy in IGA nephropathy.

A nonrandomized study of 55 patients compared the effect of tonsillectomy plus glucocorticoid therapy to that of glucocorticoid monotherapy on the remission of proteinuria and hematuria [116]. The patients who underwent tonsillectomy did so after receiving a consultation from an otolaryngologist stating that tonsillectomy was indicated. Mean baseline protein excretion was one to 1.5 grams per day and mean baseline creatinine clearance was 95 mL/min. The following observations were made:

• In comparison to patients who received glucocorticoids alone, more patients who underwent tonsillectomy had remission of proteinuria and hematuria by 24 months (76.5 versus 41.2 percent, and 79.4 versus 17.6, respectively).
• Only one patient who received glucocorticoids alone had a doubling of serum creatinine versus no patients who underwent tonsillectomy.
• In eighteen patients who underwent a repeat biopsy 24 months after the initiation of treatment, mesangial proliferation and IgA deposition were reduced among the group that underwent tonsillectomy but not in the group that received glucocorticoids alone.
• The beneficial clinical effects of tonsillectomy on proteinuria persisted over the time of followup (mean of 54 months).

This nonrandomized study provides some evidence that tonsillectomy may be effective in inducing remission of proteinuria and hematuria in patients (who have "chronic tonsillitis") with significant IgA disease (ie, proteinuria >500 mg/day). The design of the study precludes any definitive conclusions regarding the overall efficacy of tonsillectomy in IGA nephropathy. Randomized trials are required to determine whether tonsillectomy is effective in slowing progression of disease in such patients, and to clarify the role, if any, for tonsillectomy in the absence of other indications for this procedure.

Low antigen diet — A low antigen diet consists of avoiding gluten, dairy products, eggs, and most meats [117]. The rationale for this regimen is that dietary macromolecules may be responsible for activating the mucosal IgA system. When given to 21 consecutive patients with IgA nephropathy, protein excretion fell markedly in all 12 patients whose baseline rate was more than 1000 mg/day. In addition, repeat renal biopsy showed significant reductions in mesangial IgA and complement deposition and mesangial cellularity.

The benefits in the above study have not been confirmed and a report using a gluten-free diet alone for several years was unable to document improvement in either proteinuria or renal function despite a reduction in the level of circulating IgA-containing immune complexes [118].

Intravenous immune globulin — At least part of the rationale for IVIG therapy in IgA nephropathy comes from the observation that a partial IgG deficiency, which could be corrected with IVIG, may predispose to infections that trigger flare-ups of the renal disease [119,120].

High-dose intravenous immune globulin (IVIG) has been tried in severe IgA nephropathy, characterized by heavy proteinuria and a relatively rapid decline in GFR [120]. Eleven patients (nine with IgA nephropathy and two with the related disorder Henoch-Schönlein purpura) were treated with IVIG at a dose of 1 g/kg for two days per month for three months followed by an intramuscular preparation given every two weeks for another six months. Among the benefits that were noted were a reduction in protein excretion (5.2 to 2.3 g/day), prevention of a continued reduction in GFR (loss of 3.8 mL/min per month prior to therapy versus stable GFR after therapy), and decreased inflammatory activity and IgA deposition on repeat renal biopsy.

The benefit of IVIG needs to be confirmed prospectively in a larger number of patients.

Vitamin D — Vitamin D analogs have decreased proteinuria in animal models of chronic kidney disease and in one human study of patients with chronic kidney disease of multiple etiologies [121,122]. These observations prompted the evaluation of calcitriol in patients with IgA nephropathy and proteinuria. This was a small, uncontrolled, and short-term study involving 10 patients with IgA nephropathy and persistent proteinuria despite ACE inhibitors and/or ARBs. All patients were administered twice weekly oral calcitriol (0.5 µg) [123]. At 12 weeks, proteinuria/creatinine ratio significantly decreased from 1.98 to 1.48. Blood pressure remained unchanged. Larger prospective controlled trials with much greater observation times are needed to further study the potential antiproteinuric effect of vitamin D in this setting [124].

PREGNANCY — Pregnancy is generally well tolerated in IgA nephropathy. Only women with an initial GFR below 70 mL/min, uncontrolled hypertension, or severe arteriolar and tubulointerstitial disease on renal biopsy are generally at risk for worsening renal function [125,126]. These findings are similar to those in most other renal diseases. (See "Pregnancy in women with underlying renal disease".)

ACE inhibitors or ARBs and some immunosuppressive drugs (particularly cyclophosphamide and MMF) 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 immunosuppressive drugs in pregnancy and lactation".)

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

SUMMARY AND RECOMMENDATIONS

Prognosis — Patients without significant proteinuria or renal dysfunction may undergo complete remission of abnormal clinical findings. However, most patients will have stable or slowly progressive disease.

On the other hand, patients with persistent proteinuria and/or hypertension and/or an elevated serum creatinine concentration are at significant risk for progression, with an incidence of end-stage renal disease of 20 to 30 percent at 20 years, with another 20 percent having reduced kidney function. (See 'Frequency of progression' above and 'Clinical predictors of progression' above.)

Histologic findings associated with a worse prognosis include crescent formation, which is uncommon, and, more importantly, signs of irreversible damage such as glomerular scarring, tubular atrophy, and interstitial fibrosis. (See 'Histologic predictors of progression' above.)

Acute renal failure during an episode of gross hematuria is usually reversible and the serum creatinine concentration returns to baseline but this event may leave residual histologic damage that eventually could lead to a worse long-term prognosis. (See 'Acute renal failure with gross hematuria' above.) If the episode is more severe or more prolonged than expected, a renal biopsy may be required to rule out new onset crescent formation.

Patients with concurrent mesangial IgA deposits and nephrotic syndrome with a minimal change disease pattern on renal biopsy appear to follow a course similar to minimal change disease. (See 'Glucocorticoids' above.)

Treatment

• We suggest not treating patients with isolated hematuria, no or minimal proteinuria, and a normal GFR (Grade 2C). Such patients should be periodically monitored at 6 to 12 month intervals to assess for disease progression that might warrant therapy.
• For patients with persistent proteinuria (>500 or >1000 mg/day), we recommend angiotensin inhibition with an ACE inhibitor or ARB (Grade 1A). We initiate monotherapy and target a minimum reduction in protein excretion of at least 50 to 60 percent from baseline values and a goal protein excretion of less than 500 or less than 1000 mg/day. (See 'Angiotensin inhibition' above.)

• We suggest that all patients who meet criteria for angiotensin inhibition also receive fish oil (Grade 2B). (See 'Fish oil' above.)

• We recommend that patients with persistent nephrotic syndrome and/or chronic kidney disease who have dyslipidemia be treated with a statin, primarily for cardiovascular protection (Grade 2B). (See 'Lipid-lowering therapy' above.)

• For patients with acute onset of nephrotic syndrome and minimal change disease as well as mesangial IgA deposits on renal biopsy, we recommend glucocorticoid therapy as in other patients with minimal change disease (Grade 1A). (See 'Glucocorticoids' above.)

• For patients with progressive active disease (eg, hematuria with increasing proteinuria and/or increasing serum creatinine concentration) despite the use of ACE inhibitors or ARBs, we suggest initiating therapy with glucocorticoids alone (Grade 2B). Two regimens we use are:

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

• For patients with severe disease at baseline (defined as initial serum creatinine >1.5 mg/dL [133 µmol/L]) or progressive disease with glucocorticoids alone (eg, increasing serum creatinine and/or protein excretion) who do not have significant chronic damage on kidney biopsy, we suggest therapy with oral prednisone and cyclophosphamide (Grade 2B). (See 'Severe or progressive disease' above.)

One regimen we use is:

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

• For patients with crescentic glomerulonephritis and a rapidly progressive clinical course, we suggest therapy with intravenous pulse glucocorticoids and cyclophosphamide (Grade 2B). (See 'Crescentic glomerulonephritis' above.)

One regimen we use is:

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

• If the serum creatinine or degree of proteinuria have not improved after the initial course of cyclophosphamide, we suggest a repeat biopsy to estimate the activity of the disease (eg, potential for reversal) and the amount of tubulointerstitial damage (the irreversible component) before deciding to continue immunosuppressive therapy.