IgA nephropathy: Treatment and prognosis

INTRODUCTION — IgA nephropathy (IgAN) is the most common cause of primary (idiopathic) glomerulonephritis in resource-abundant settings [1].

The treatment and prognosis of IgAN will be reviewed here. Other aspects of IgAN are discussed separately:

●(See "IgA nephropathy: Pathogenesis".)

●(See "IgA nephropathy: Clinical features and diagnosis".)

●(See "IgA nephropathy: Recurrence after transplantation".)

●(See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

PRETREATMENT CONSIDERATIONS

Risk factors for disease progression — Although IgA nephropathy (IgAN) was initially thought to follow a benign course, it is now recognized that slow progression to end-stage kidney disease (ESKD) occurs in 25 to 30 percent of patients within 20 to 25 years of presentation (see 'Prognosis' below). The remaining patients enter a sustained clinical remission or have persistent low-grade hematuria and/or proteinuria. Although the prognosis may be difficult to predict in some individuals, important risk factors for progressive kidney disease have been identified:

●Proteinuria above 1 g/day – Several observational studies have documented the importance of the magnitude of proteinuria and its persistence on the course of IgAN [2-11]. The rate of progression is very low among patients excreting less than 1 g/day and is greatest among those excreting more than 3 to 3.5 g/day. As an example, in an observational study of 542 patients with IgAN who were followed for a mean of 6.5 years, the rate of decline in kidney 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 0.04 mL/min/1.73 m² per month) [7]. Patients who presented with proteinuria above 3 g/day who attained a partial remission (less than 1 g/day) had a similar rate of progression to kidney failure as those with sustained proteinuria from presentation of less than 1 g/day. The relationship between increasing proteinuria and a worse prognosis is related at least in part to proteinuria being a marker for the severity of glomerular disease.

However, some studies suggest that proteinuria of less than 1 g/day by itself does not guarantee a good outcome or indicate that treatment is not needed [11-13]. In one study, for example, up to one-third of patients with high-risk histologic features, especially those with significant hematuria, had proteinuria less than 1 g/day and eventually experienced reduced kidney function [12]. Data from another large cohort study of patients with IgAN from the United Kingdom suggest that low-grade proteinuria that is untreated or is unresponsive to supportive therapies may be associated with poor long-term outcomes [11]. (See 'Goals of therapy' below and 'Prognosis' below.)

●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 [2,5,7]. In a prospective study of 332 patients with IgAN, the cumulative incidence of dialysis or death was much higher in patients with hypertension (defined in this study 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) [2]. Similar findings were reported in another study of 542 patients with IgAN, in which a higher mean arterial pressure was associated with a higher risk of progressive kidney disease, an effect that was seen at all levels of proteinuria [7].

●Reduced GFR – A reduction in glomerular filtration rate (GFR), as manifested by an elevated serum creatinine concentration or lower estimated GFR (eGFR) at diagnosis or during the course of the disease, is associated with a worse kidney prognosis [3,4,6,8,13-17].

●Hematuria – Studies evaluating the relationship between hematuria and progressive disease have yielded conflicting results [9,18-24]. However, in many of these studies, the analysis of hematuria was performed only at the onset of disease or at an isolated point in the disease course. Studies with longitudinal follow-up of hematuria, in which fresh urine was examined by experienced personnel, have shown an association between persistent microscopic hematuria and a higher risk of progressive disease. As an example, a cohort study that followed 112 patients with IgAN for a mean of 14 years found that the proportion of patients reaching ESKD or a 50 percent reduction in kidney function was higher among those with persistent hematuria compared with those with no or minimal hematuria (30 and 37 versus 11 and 15 percent, respectively) [25]. Patients who had remission of hematuria had slower rates of kidney function decline. A higher degree of microscopic hematuria has also been associated with worse kidney outcomes [26]. However, no prospective studies have shown a benefit of therapy directed at reducing hematuria (independent of proteinuria) on disease progression. Some UpToDate contributors to this topic believe that the combination of hematuria and proteinuria represents active immunologic disease and is a risk for kidney disease progression.

●Histologic predictors of progression – Although clinical features appear to be stronger prognostic indicators [5], certain findings on kidney biopsy in patients with IgAN have been associated with 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 [4,8,14,15,27-32]. Inclusion of recent pathologic findings adds to the accuracy of prognostication, over and above clinical features alone, when assessed at the time of kidney biopsy. (See 'Assessment of risk' below.)

The revised Oxford classification of IgAN is used to score kidney biopsies on the basis of five histologic variables: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C). Each of these variables has been shown to individually predict kidney outcome, independent of clinical data. Combining these variables with cross-sectional clinical data at the time of biopsy provides similar prognostic value as that obtained with two years of follow-up clinical data [33]. The utility of the Oxford classification in guiding therapy such as immunosuppression remains uncertain. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Oxford classification of IgAN'.)

Other potentially modifiable risk factors for progressive disease include obesity [34], hypertriglyceridemia and hyperuricemia [35], smoking [36], and other concomitant kidney disease.

Assessment of risk — Prior to therapy, all patients with IgAN should have an individual assessment of their risk of progressive disease, which can be estimated using the International IgA Nephropathy Prediction Tool (IIgAN-PT) [37-39]. Among adults, this risk prediction tool (available for use online or as a mobile app) calculates the five-year risk of a 50 percent decline in eGFR or progression to ESKD, based upon the following readily available clinical and histologic variables at the time of kidney biopsy:

●Estimated GFR

●Blood pressure

●Proteinuria

●Age

●Race/ethnicity (White, Japanese, Chinese, or other)

●Prior use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)

●Oxford classification of IgAN MEST histology scores

●Immunosuppression use at or prior to biopsy

The presence or absence of glomerular crescents on kidney biopsy is not included in the IIgAN-PT as their inclusion did not improve prediction accuracy [37,38]. Similarly, the presence or absence of hematuria is not included in the IIgAN-PT.

The IIgAN-PT has been updated (also available for use online) to enable a similar risk assessment to be performed at one or two years after kidney biopsy [39].

The IIgAN-PT has also been adapted for use in children with IgAN [40], who have a different disease trajectory compared with adults [41-45]. In contrast with adults, who usually have a linear rate of eGFR decline, children experience an initial increase in eGFR, which may last up to several years, followed by a linear decline similar to that seen in adults [40]. Given the slow progression in children that occurs before reaching the eGFR decline observed in adults, the IIgAN-PT risk prediction tool was modified for children to calculate the five-year risk of a 30 percent decline in eGFR or ESKD, which is analogous to the risk of a 50 percent decline in eGFR in adults. (See 'Children' below.)

The IIgAN-PT may not be applicable to all populations. As an example, a study that attempted to validate the tool in an Indian cohort found that the IIgAN-PT underestimated the risk of disease progression across all risk groups [46].

There is no uniform consensus for the threshold of five-year risk above which an individual patient is considered at high risk of progression. The risk estimate derived from the IIgAN-PT can be used in discussions with patients regarding outcomes. In the choice of treatment, other factors must also be considered, including the potential toxicities of therapy and patient characteristics that may increase the risk of treatment-related toxicity. The IIgAN-PT cannot be used to determine the likely impact of any particular treatment regimen. (See 'Approach to therapy' below.)

Goals of therapy — In patients with IgAN, the primary goal of therapy is to prevent disease progression to ESKD. Unlike many other forms of glomerular disease, achievement of this goal is primarily through nonimmunosuppressive strategies (supportive care) rather than immunosuppressive therapies. However, some patients who are at high risk for progressive disease as well as those with variant forms of IgAN may require immunosuppressive therapy. (See 'Approach to therapy' below.)

●Reduction in proteinuria – We aim for a reduction in proteinuria to less than 1 g/day and, if possible, to less than 0.5 g/day in all adult patients with IgAN. Proteinuria ≥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 'Risk factors for disease progression' above). Among patients who present with proteinuria of 3 g/day or more, reducing proteinuria to <1 g/day results in a similar rate of progression to kidney failure as in patients with sustained proteinuria from presentation of <1 g/day (figure 1).

Importantly, a reduction in proteinuria to <1 g/day is considered a valid surrogate for improved kidney outcome in patients with IgAN [47-49]. This was shown in an analysis of data from 13 controlled trials, which found an association between treatment effects on percent reduction in proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death [47]. Trials included in this analysis generally targeted a reduction in proteinuria to <1 g/day. (See 'Monitoring and modifying therapy' below.)

●Improvement in the urinary sediment – We aim for resolution of microscopic hematuria in all patients with IgAN since persistent hematuria has been associated with progressive disease and resolution of hematuria has been associated with improved kidney outcomes [25,26]. However, the utility of isolated hematuria as a surrogate marker for treatment efficacy independent of proteinuria or eGFR has not been proven.

INITIAL THERAPY FOR PRIMARY IGA NEPHROPATHY

Approach to therapy — The approach to initial therapy for adults with primary IgA nephropathy (IgAN) who do not have a variant form (such as IgAN with apparent minimal change disease, IgAN with acute kidney injury [AKI], and IgAN with rapidly progressive glomerulonephritis [RPGN]) is presented below. Variant forms of IgAN may require specific immediate therapy and are discussed elsewhere in this topic. The management of secondary causes of IgAN, children with IgAN, and IgA vasculitis (IgAV) nephritis is also discussed separately. (See 'Patients with variant forms of IgA nephropathy' below and 'Secondary IgA nephropathy' below and 'Children' below and "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations", section on 'Management of IgAV nephritis'.)

In general, the management of primary IgAN focuses on optimized supportive care, including blood pressure control to optimal targets, reduction of proteinuria with renin-angiotensin system inhibition, and lifestyle modifications as appropriate. Immunosuppressive therapy, which has been shown to improve outcomes in patients with IgAN but has significant toxicity (particularly at high doses given for a prolonged duration), should be reserved only for patients who remain at high risk for progression to end-stage kidney disease (ESKD) despite maximal supportive care. Our approach to initial therapy, which is largely consistent with the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines [50], is as follows:

●We score the patient's kidney biopsy (performed up to two years before) using the Oxford classification of IgAN MEST-C score. In patients who have clinical risk factors for disease progression (eg, proteinuria ≥1 g/day), the presence of active proliferative lesions (ie, higher M and/or E scores) or crescents (higher C score) may be an indication to treat more aggressively [51,52]. By contrast, patients with more chronic lesions (ie, higher T scores) are less likely to be responsive to immunosuppressive therapy. No threshold value for these variables has been shown in prospective studies to be a reliable indicator of treatment benefit. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Oxford classification of IgAN'.)

●We assess the patient's risk of progressive disease using the International IgA Nephropathy Prediction Tool (IIgAN-PT; available for use online or as a mobile app), which calculates the five-year risk of a 50 percent decline in estimated glomerular filtration rate (eGFR) or progression to ESKD based upon clinical and histologic variables measured at the time of kidney biopsy [37,38]. An updated prediction tool can also be used to evaluate risk at one or two years after biopsy [39]. Neither prediction tool includes crescents in their evaluation. We use this risk assessment in our discussions with patients regarding treatment and outcome. However, as discussed above, this tool cannot be used to predict the likely response to any particular treatment regimen. (See 'Assessment of risk' above.)

●We initiate and optimize supportive care, which consists of blood pressure control, reduction of proteinuria with maximally tolerated renin-angiotensin system blockade (either an angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), treatment of dyslipidemia (if present), and lifestyle modification (such as dietary sodium and protein restriction, smoking cessation, weight control, and exercise as appropriate). In some patients, particularly those with an eGFR ≥20 or ≥30 mL/min/1.73 m² [53,54], use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor may be added to this supportive regimen. Supportive care should be continued for a minimum of three months and ideally six months unless the patient has evidence of rapid disease progression. During this period, we monitor urine protein excretion, serum creatinine (with calculation of eGFR), and a urinalysis (to assess hematuria) every one to three months depending upon the clinical severity at presentation. (See 'Supportive care in all patients' below.)

●After three to six months of optimized supportive care (or sooner if the patient has signs or symptoms of rapid disease progression), we stratify patients into the following categories of risk based upon an assessment of proteinuria:

•High risk – Patients with proteinuria ≥1 g/day despite at least three to six months of optimized supportive care are considered to be at high risk for progressive disease. Some contributors to this topic consider patients with proteinuria ≥2 g/day to be at "very high risk" of progressive disease. In patients at high or very high risk, we treat with immunosuppressive therapy (ie, glucocorticoids) plus supportive care, as discussed below. (See 'Immunosuppressive therapy in high-risk patients' below.)

Some UpToDate contributors of this topic consider the presence of persistent microscopic hematuria as an additional feature to promote the use of immunosuppressive therapy. (See 'Risk factors for disease progression' above.)

•Lower risk – Patients with proteinuria <1 g/day after three to six months of optimized supportive care are considered to be at lower risk of progressive disease. Such patients generally should not receive immunosuppressive therapy but should continue optimized supportive care indefinitely with routine monitoring. Some patients with proteinuria <1 g/day and significant microscopic hematuria (eg, 2+ or greater on urine dipstick) may still develop progressive loss of kidney function, especially if the kidney biopsy demonstrates active inflammation (eg, Oxford classification M1, E1, S0, T0, C1). In such patients, immunosuppressive therapy may be indicated. (See 'Supportive care in all patients' below and 'Monitoring and modifying therapy' below.)

Supportive care in all patients — All patients with IgAN should receive optimized supportive care, which consists of reduction of proteinuria with an ACE inhibitor or ARB, blood pressure control, treatment of dyslipidemia, and lifestyle modification (such as dietary sodium and protein restriction, smoking cessation, weight control, and exercise as appropriate). Patients with persistent proteinuria despite treatment with an ACE inhibitor or ARB can also be treated by adding an SGLT2 inhibitor or, alternatively, switching from the ACE inhibitor or ARB to sparsentan.

Angiotensin inhibition — For all patients with IgAN and proteinuria ≥0.5 g/day, we recommend treatment with either an ACE inhibitor or ARB. Some experts would administer an ACE inhibitor or ARB to selected patients with proteinuria <0.5 g/day in the absence of hypertension, such as those with a solitary kidney, low birth weight, or persistent severe hematuria. Angiotensin inhibition with an ACE inhibitor or ARB slows the rate of progression of most proteinuria chronic kidney diseases (CKD), 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 "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors'.)

●In patients who are initially normotensive, we generally start with a low dose (eg, lisinopril 2.5 to 10 mg once daily or losartan 25 to 50 mg once daily) and titrate the dose gradually (eg, every two to four weeks) as tolerated to the maximum recommended dose to target an absolute proteinuria goal of <1 g/day and, if possible, to <0.5 g/day. Careful monitoring in initially normotensive patients is important, as such patients may be more prone to complications related to volume depletion (eg, from heat or illness) and may be at risk for the development of acute kidney injury. Higher starting doses may be appropriate for patients who are initially hypertensive. The maximal tolerated dose will often be less than the recommended maximal dose for a particular agent.

●Among patients who do not achieve the proteinuria goal with an ACE inhibitor or ARB at the maximum recommended dose for at least three and up to six months, and whose blood pressure is not lowered to levels associated with symptoms, we add other antiproteinuric or renoprotective therapies (such as an SGLT2 inhibitor) rather than administer combination therapy with an ACE inhibitor and ARB [55]. (See 'SGLT2 inhibitors' below.)

Clinical trials supporting the efficacy of angiotensin inhibition in patients with IgAN are limited [56-59], 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 proteinuria CKD. ACE inhibitors and ARBs both significantly reduce protein excretion to a greater degree when compared with placebo or the dihydropyridine calcium channel blocker amlodipine [60,61], an effect that is seen in normotensive as well as hypertensive patients [62]. By contrast, the non-dihydropyridine calcium channel blockers diltiazem and verapamil also lower protein excretion [63] and can be added if the therapeutic goals are not reached with angiotensin inhibition alone.

●The best data supporting greater clinical efficacy of angiotensin inhibition compared with other antihypertensive drugs on kidney outcomes in IgAN come from a trial in which 44 patients with proteinuria (≥0.5 g/day, mean 1.9 g/day) and a serum creatinine concentration ≤1.5 mg/dL (133 micromol/L) at baseline were randomly assigned to either enalapril or antihypertensive agents other than ACE inhibitors or ARBs [56]. The target blood pressure was <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 a mean of approximately six years, kidney survival, defined as a <50 percent increase in the serum creatinine concentration, was higher 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 declines after one year of therapy correlated with kidney survival. Another small, randomized trial showed benefit from valsartan therapy compared with placebo [57].

●Another randomized trial, IgACE, compared benazepril with placebo in 65 young patients (range 9 to 35 years) with IgAN, moderate proteinuria (1 to 3.5 g/day/1.73 m²), and relatively preserved kidney function (creatinine clearance >50 mL/min/1.73 m²) [58]. Only five patients were hypertensive. At a median of 38 months, the primary endpoint (>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 lower incidence of the secondary composite endpoint (>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 [64].

●The addition of an ARB to an ACE inhibitor in patients with IgAN produces a further antiproteinuric effect in short-term studies [60,65,66]. 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 [61,67]. However, there are no randomized trials that have shown that combination therapy improves kidney outcomes in patients with proteinuric CKD. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Combination of ACE inhibitors and ARBs'.)

It is unclear if angiotensin inhibition improves outcomes in patients with IgAN with moderately increased albuminuria (30 to 300 mg/day) and normal blood pressure, given the lack of randomized trials in this specific patient population.

The clinical trials supporting the efficacy of angiotensin inhibition in proteinuric CKD in general are discussed in detail separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD' and "Treatment of diabetic kidney disease".)

SGLT2 inhibitors — Patients with IgAN and proteinuria should receive treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors. This approach is similar to that for other patients with CKD and proteinuria, as discussed elsewhere. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)

The optimal time to initiate therapy with an SGLT2 inhibitor in patients with IgAN is uncertain. We typically start an SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) in patients who have persistent proteinuria ≥500 mg/day in spite of treatment with a maximally tolerated dose of ACE inhibitor or ARB for at least three to six months.

Although the majority of trials demonstrating kidney protective benefits have been performed in proteinuric patients with diabetic kidney disease, there are data suggesting that these benefits also extend to nondiabetic proteinuric patients, including those with IgAN [53,68]. As an example, in a prespecified analysis of 270 participants with IgAN in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, the primary composite endpoint (sustained decline in eGFR of ≥50 percent, ESKD, or death from a kidney disease-related or cardiovascular cause) occurred in six patients (4 percent) receiving dapagliflozin compared with 20 (15 percent) receiving placebo, a benefit that was independent of baseline proteinuria [68]. Dapagliflozin also reduced the urine albumin-to-creatinine ratio by 26 percent relative to placebo. Rates of adverse events were similar between the two groups. Dapagliflozin has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of CKD in adults with and without type 2 diabetes.

Dual endothelin angiotensin receptor antagonists — Sparsentan is an oral, single-molecule, selective antagonist of the angiotensin II receptor (AT₁) and endothelin 1 (ET-1) receptor (ET_A). ET-1, primarily though activation of ET_A, has been implicated in podocyte injury, proteinuria, fibrosis, and progression of chronic kidney disease [69,70]. Sparsentan has received conditional approval by the FDA for reduction of proteinuria in patients with IgAN at risk of rapid disease progression (defined as a urine protein-to-creatinine ratio [UPCR] ≥1.5 g/g, approximately equal to ≥2 g/day) [71].

Existing data do not yet support the use of sparsentan as initial supportive therapy for IgAN (ie, as a replacement for maximally tolerated angiotensin inhibition with or without SGLT2 inhibition). We consider sparsentan as an alternative option to reduce proteinuria (and possibly delay disease progression) in patients with IgAN who have persistent proteinuria ≥1 g/day in spite of optimal treatment with an ACE inhibitor or ARB and an SGLT2 inhibitor for at least three to six months. If sparsentan is used, the ACE inhibitor or ARB should be discontinued. The anticipated benefits are somewhat uncertain, as there are no data directly comparing sparsentan with the combination of an ACE inhibitor or ARB plus an SGLT2 inhibitor in patients with IgAN. Combination therapy with an SGLT2 inhibitor and sparsentan is under evaluation (NCT03762850, NCT05856760).

The efficacy and safety of sparsentan were evaluated in a phase III trial that randomly assigned 404 adults with biopsy-proven IgAN, an eGFR ≥30 mL/min/1.73 m², and persistent proteinuria >1 g/day in spite of three months of optimized supportive care (including maximally tolerated ACE or ARB therapy) to sparsentan 400 mg once daily or irbesartan 300 mg once daily [72,73]. At baseline, mean proteinuria was 1.8 g/day and mean eGFR was approximately 57 mL/min/1.73 m². Of note, maximal renin-angiotensin system inhibition was not achieved in approximately 37 percent of patients. Patients receiving sparsentan had a greater reduction in proteinuria from baseline to week 110 (-42.8 versus -4.4 percent) and were more likely to achieve complete remission of proteinuria (proteinuria <0.3 g/day; 31 versus 11 percent). The eGFR two-year chronic slope (from weeks 6 to 110) was -2.7 mL/min/1.73 m²/year with sparsentan and -3.8 mL/min/1.73 m²/year with irbesartan (difference 1.1 mL/min/1.73 m²/year, 95% CI 0.1-2.1). The composite of kidney failure (confirmed 40 percent eGFR reduction, ESKD, or all-cause mortality) occurred in 9 percent of patients on sparsentan and 13 percent of those on irbesartan, but this difference was not statistically significant. Rates of serious treatment-related adverse events were similar between the groups (35 to 37 percent); however, hypotension (including orthostatic hypotension), dizziness, and acute kidney injury were more frequent among patients receiving sparsentan.

Given the potential risks of hepatotoxicity and known risks of serious birth defects associated with sparsentan (and other endothelin receptor antagonists, such as bosentan, atrasentan, and macitentan), the FILSPARI Risk Evaluation and Mitigation Strategy (available from Travere Therapeutics as required by the FDA: FILSPARI REMS) was created as a restricted drug distribution program. Clinicians, patients, and pharmacies must enroll in the program before the drug can be prescribed. It is a condition of the FILSPARI REMS program to measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin before initiating treatment and monthly for the first 12 months and then every three months during treatment. For patients who can become pregnant, pregnancy testing is required before treatment initiation, during treatment, and one month after discontinuation of treatment. Patients who can become pregnant must use effective contraception before treatment initiation, during treatment, and for one month after discontinuation of treatment.

Blood pressure control — The blood pressure goals with angiotensin inhibition and other antihypertensive therapies (drugs and dietary salt restriction) in patients with IgAN are similar to those in other causes of proteinuric CKD (table 1). These goals and how they can be attained are discussed in detail elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Patients with chronic kidney disease'.)

Limited role for fish oil — We do not routinely give fish oil as part of supportive care to all patients with IgAN. However, fish oil (3.3 g/day or more of prescription strength omega-3 fatty acids, not over-the-counter food supplements) can be tried in patients at high risk for disease progression (see 'Approach to therapy' above) as long as it is not used to the exclusion of other therapies that are proven to be effective (such as renin-angiotensin inhibitors). Fish oil may have cardiovascular benefits and is unlikely to be harmful, although an associated fishy aftertaste and eructations with this treatment often limit patient acceptance [74]. A benefit from fish oil has not been clearly established, and randomized trials evaluating fish oil in patients with IgAN have reported conflicting results [74-81].

Other measures — Other supportive measures include lifestyle modification (dietary sodium and protein restriction, weight control, smoking cessation, and exercise as appropriate) and treatment of dyslipidemia, if present. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. These issues are discussed in greater detail elsewhere:

●Dietary sodium and protein restriction (see "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake')

●Weight control (see "Obesity in adults: Overview of management")

●Smoking cessation (see "Overview of smoking cessation management in adults")

●Physical exercise (see "Exercise for adults: Terminology, patient assessment, and medical clearance" and "Exercise prescription and guidance for adults")

●Lipid lowering (see "Lipid management in patients with nondialysis chronic kidney disease" and "Lipid abnormalities in nephrotic syndrome")

●Treatment of edema (see "Overview of the management of chronic kidney disease in adults", section on 'Volume overload')

Immunosuppressive therapy in high-risk patients — Patients with IgAN who are considered to be at high risk of disease progression (ie, proteinuria ≥1 g/day despite at least three to six months of optimized supportive care) (see 'Approach to therapy' above) should generally receive immunosuppressive therapy. Immunosuppressive therapy (ie, systemic glucocorticoids) likely improves short-term kidney outcomes among patients with IgAN but has the potential for significant toxicity if given in high doses without antimicrobial prophylaxis. Treatment-related toxicity may be more likely among those with certain clinical characteristics, such as an eGFR <50 mL/min/1.73 m², diabetes, obesity, severe osteoporosis, latent infection (eg, viral hepatitis, tuberculosis), active peptic ulcer disease, or uncontrolled psychiatric illness. (See 'Systemic glucocorticoids as first-line therapy' below.)

However, we do not give immunosuppressive therapy to patients if they have evidence of severe and irreversible kidney damage (eGFR <30 mL/min/1.73 m² for >3 months, small echogenic kidneys on kidney ultrasound, or evidence of severe interstitial fibrosis, tubular atrophy, or glomerulosclerosis on kidney biopsy), since immunosuppressive therapy is unlikely to be effective in such patients [16]. In such patients, we continue to administer supportive care and discuss future options for kidney replacement therapy.

There are limited data on factors that predict the response to immunosuppressive therapy in patients with IgAN. In one study of 621 Chinese patients with biopsy-proven IgAN who were at high risk for disease progression (≥1 g/day of proteinuria despite optimized supportive care with renin-angiotensin system inhibition) and received immunosuppressive therapy (mostly mycophenolate mofetil [MMF] in combination with glucocorticoids or alone) for a median of 18 months, higher levels of CD206⁺ and CD68⁺ macrophage infiltration within glomeruli on kidney biopsy were associated with a 40- and 13-fold increased probability of response to immunosuppression, respectively, when compared with lower levels [82]. Combining the intensity of macrophage infiltration with clinical data and the MEST-C score had an area-under-the-curve (AUC) of 0.87 for predicting response to immunosuppression. Of note, patients with AKI or an eGFR ≤30 mL/min/1.73 m² were excluded from the study. While these findings may help identify patients who will benefit from immunosuppression, additional validation in other patient populations is needed. There are no data from randomized trials showing that MEST-C scores can predict the response to immunosuppressive treatment.

The use of immunosuppressive therapy in patients with variant forms of IgAN, such as IgAN with apparent minimal change disease or IgAN with RPGN, is discussed elsewhere in this topic. (See 'IgA nephropathy with apparent minimal change disease' below and 'IgA nephropathy with rapidly progressive (crescentic) glomerulonephritis' below.)

Systemic glucocorticoids as first-line therapy — For patients who are at high risk of disease progression (see 'Approach to therapy' above), we suggest treatment with systemic glucocorticoids plus supportive care rather than supportive care alone. All patients receiving systemic glucocorticoid therapy should also receive antibiotic prophylaxis to prevent Pneumocystis pneumonia. Dosing and duration of glucocorticoid therapy for IgAN are discussed below. (See 'Choice of regimen' below and 'Treatment-related toxicity' below.)

Glucocorticoids should be used with caution or avoided in patients with diabetes, obesity, latent infections (eg, viral hepatitis, tuberculosis), active peptic ulcer disease, severe osteoporosis, or uncontrolled psychiatric illness. For patients who cannot tolerate or who do not wish to receive oral systemic glucocorticoids, an oral targeted-release formulation of the glucocorticoid budesonide (TRF-budesonide) or MMF is an alternative option. Trials evaluating TRF-budesonide use have shown a low frequency of severe adverse events (particularly infections) although some side effects (such as hypertension, edema, and acne) suggestive of systemic glucocorticoid exposure were more frequent with TRF-budesonide than with placebo. There are no data directly comparing the efficacy and safety of TRF-budesonide with those of moderate-dose systemic glucocorticoids. Supportive data for MMF come from trials that included only limited patient populations. Alternatively, patients can be encouraged to participate in a clinical trial, if feasible. (See 'Alternatives to systemic glucocorticoids' below.)

The efficacy and safety of systemic glucocorticoid therapy in patients with IgAN have been evaluated in several randomized controlled trials and meta-analyses [83-90]. The best data come from the following two large randomized trials, in which patients uniformly received renin-angiotensin inhibitors:

●In the Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP IgAN) trial, 162 patients with IgAN, eGFR of ≥30 mL/min/1.73 m², and proteinuria of 0.75 to 3.5 g/day despite six months of comprehensive supportive therapy (that included ACE inhibitors, ARBs, or both, targeting a blood pressure of <125/75 mmHg) were randomly assigned to continue supportive care alone or to receive immunosuppression in addition to supportive care [84]. Mean eGFR and proteinuria at baseline were 57 mL/min/1.73 m² and 1.6 g/day, respectively, in the supportive care arm and 61 mL/min/1.73 m² and 1.8 g/day, respectively, in the immunosuppression arm; patients were not stratified by Oxford MEST-C scores due to the wide variation in time between biopsy and entry into the trial. Of the 82 patients assigned to immunosuppressive therapy, 55 had an eGFR that was ≥60 mL/min/1.73 m² and received glucocorticoid monotherapy (intravenous [IV] methylprednisolone 1 g/day for three days at the start of months 1, 3, and 5, and oral prednisolone 0.5 mg/kg per 48 hours on the other days [86]), and 27 had an eGFR that was 30 to 59 mL/min/1.73 m² and received combination immunosuppression (a tapering daily dose of oral prednisolone combined with oral cyclophosphamide 1.5 mg/kg/day for three months followed by azathioprine 1.5 mg/kg/day until month 36). At three years, the rate of full clinical response (ie, a decrease in protein-to-creatinine ratio to <0.2 g/g plus preservation of eGFR) was higher with immunosuppressive therapy (17 versus 5 percent) [84]. However, this result was due primarily to a proteinuria decrease in patients who were treated with glucocorticoid monotherapy; the change in eGFR was similar between those who did and did not receive immunosuppression. Also, patients receiving immunosuppression had a higher rate of infections, impaired glucose tolerance, and weight gain. At 10 years of follow-up, there were no significant differences in the rates of ESKD or eGFR loss >40 percent between the groups [91].

●The Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING) evaluated the efficacy and safety of high-dose oral glucocorticoids versus supportive therapy alone in 262 patients with IgAN, eGFR of 20 to 120 mL/min/1.73 m², and proteinuria of ≥1 g/day after at least three months of supportive therapy (blood pressure control with maximally tolerated ACE inhibitor or ARB therapy) [85]. At baseline, mean eGFR was 59.4 mL/min/1.73 m² and mean proteinuria was 2.40 g/day. Patients were randomly assigned to oral methylprednisolone (0.6 to 0.8 mg/kg/day) or placebo for two months, followed by a monthly dose taper for a total treatment duration of six to eight months; supportive therapy was continued in all patients. The primary endpoint was a composite of ESKD, death due to kidney failure, or a 40 percent decrease in eGFR. The study was terminated early because of an interim analysis showing an excess of serious adverse effects (mostly serious infection) in the methylprednisolone arm (14.7 versus 3.2 percent); consequently, only 262 of the planned 750 patients were recruited at the time of study discontinuation.

Following recommendations of an external data monitoring committee concerning safety, a decision was then made to revise the trial protocol to recruit 241 additional patients to receive a reduced dose of oral methylprednisolone (0.4 mg/kg/day, maximum dose 32 mg/day) or placebo, with ongoing follow-up of all trial participants, including those in the original high-dose cohort (total of 503 patients) [90]. All subsequent participants also received antibiotic prophylaxis for pneumocystis pneumonia for the first three months of the treatment period. Mean eGFR at baseline for the entire cohort was 61.5 mL/min/1.73 m² and mean proteinuria was 2.46 g/day. At a mean of 4.2 years, the primary endpoint occurred in fewer patients in the glucocorticoid group than the placebo group (29 versus 43 percent). Although there was no significant difference in deaths due to kidney failure or from any cause between the groups, the risk of ESKD was lower in the glucocorticoid group (hazard ratio 0.59, 95% CI 0.40-0.87). In addition, the annual rate of loss of kidney function was lower among those receiving glucocorticoids (2.50 versus 4.97 mL/min/1.73 m² per year). However, serious adverse events (mostly hospitalization or severe infection) were more frequent in the glucocorticoid-treated group compared with placebo (11 versus 3 percent). This excess was primarily observed in patients receiving high-dose rather than reduced-dose glucocorticoids; rates of serious adverse events were similar between the reduced-dose glucocorticoids and placebo groups.

These findings suggest that reduced doses of oral, systemically acting glucocorticoids combined with antibiotic prophylaxis lower the risk of ESKD in patients with IgAN without the serious adverse events associated with higher doses of glucocorticoids. Given the relatively homogeneous patient population studied (75 percent were Chinese and 5 percent were White), however, these study findings may not necessarily be generalizable to all patients with IgAN throughout the world. In addition, the rate of loss of kidney function in the placebo arm of this trial (-4.97 mL/min/1.73 m²) was considerably greater than that reported for patients receiving supportive care only in the STOP IgAN trial (-1.57 mL/min/1.73 m²) and other trials that primarily enrolled White patients with IgAN [84,92]. These differences in the rate of progression in the placebo arm of these trials may reflect differences in baseline proteinuria, Oxford MEST-C score, or other ancestry-related factors, and do not necessarily invalidate the findings [93].

There are few trials directly comparing systemic glucocorticoids to other immunosuppressive therapies in patients with IgAN. One trial that compared prednisone (IV pulses combined with an oral regimen) plus azathioprine with prednisone alone found no added benefit and potential harm with azathioprine [94]. (See 'Other regimens' below.)

Choice of regimen — There is no consensus about the best oral systemic glucocorticoid regimen for IgAN. Some experts prefer a moderate-dose regimen similar to the reduced-dose glucocorticoid regimen used in the TESTING trial [90], whereas other experts prefer a higher-dose regimen. Any one of several regimens (table 2) is acceptable in patients with IgAN. There are no data directly comparing the efficacy and safety of these different regimens.

We aim for a total duration of six months of glucocorticoid therapy. In most of these regimens, the initial dose of glucocorticoids is maintained for a minimum of two months, at which time the dose is tapered over four months if the patient shows signs of an initial response to treatment (eg, ≥25 percent reduction in proteinuria and stable or improved kidney function). If an initial response to treatment is not seen at two months, tapering should be individualized to the patient's response, risk of disease progression, and tolerability of the regimen. (See 'Monitoring and modifying therapy' below.)

Treatment-related toxicity — Immunosuppressive therapy with prolonged moderate- to high-dose oral glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures. These adverse effects and the recommended prophylactic regimens are discussed elsewhere:

●For prevention of Pneumocystis jirovecii pneumonia (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV")

●For minimizing glucocorticoid-induced bone loss and other adverse effects (see "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Major adverse effects of systemic glucocorticoids")

Alternatives to systemic glucocorticoids — For patients who are unable to tolerate or do not wish to take systemic glucocorticoids, TRF-budesonide and MMF are alternative options for initial immunosuppressive therapy.

Targeted-release budesonide — An oral targeted-release formulation of the glucocorticoid budesonide (TRF-budesonide) has been designed to release the drug in the distal ileum (ileocecal region), where most Peyer patches are located. Mucosal B lymphocytes localized within Peyer patches are postulated to be a source for the production of poorly galactosylated immunoglobulin A₁ (IgA₁), which has been implicated in the pathogenesis of IgAN. Budesonide is reported to have a 90 percent hepatic clearance at first liver passage, limiting its systemic circulation. (See "IgA nephropathy: Pathogenesis", section on 'IgA1 O-glycosylation'.)

The role of TRF-budesonide in the treatment of IgAN has not yet been fully defined. Some UpToDate contributors to this topic would use TRF-budesonide as initial immunosuppressive therapy in patients with IgAN in whom systemic glucocorticoids are contraindicated or who do not wish to take systemic glucocorticoids. However, other UpToDate contributors would not use TRF-budesonide as initial therapy given its higher cost and the lack of evidence showing superior efficacy and safety over moderate-dose oral glucocorticoids. Some of these contributors would reserve this agent for patients who do not respond to or cannot tolerate a six-month course of moderate-dose oral glucocorticoids and who have a persistent UPCR ≥1.5 g/g or proteinuria ≥2 g/day. However, the efficacy and safety of TRF-budesonide in this clinical setting remain unknown. If TRF-budesonide is used in such patients, treating clinicians should evaluate for signs of glucocorticoid toxicity prior to starting therapy. If evidence of glucocorticoid toxicity is present, it may be preferable to wait for at least six months. However, waiting six months would potentially put the patient at increased risk of disease progression, and some authors would rather switch to a different therapy (eg, MMF) than wait. If TRF-budesonide is used, the patient should be closely monitored for adverse effects of prolonged glucocorticoid administration. (See 'Monitoring and modifying therapy' below.)

TRF-budesonide is administered as 16 mg/day for nine months (table 2).

The safety and efficacy of TRF-budesonide were evaluated in a randomized, placebo-controlled phase 3 trial (NefIgArd) of 364 patients with IgAN, an eGFR of ≥35 to ≤90 mL/min/1.73 m², and persistent proteinuria despite three months of optimized ACE inhibitor and/or ARB therapy [95,96]. Median proteinuria (UPCR) and eGFR at baseline were 1.26 g/g and 55 mL/min/1.73 m², respectively. A higher proportion of patients in the TRF-budesonide group had a history of diabetes or were identified as prediabetic compared with the placebo group (48 versus 31 percent). Patients were randomly assigned to TRF-budesonide 16 mg/day or placebo for nine months; all patients continued to receive optimized renin-angiotensin system blockade. Treatment with TRF-budesonide, compared with placebo, resulted in an overall greater reduction in UPCR from baseline at nine months (34 versus 5 percent decrease), an effect that was maintained at 12 and 24 months. At two years, eGFR in the TRF-budesonide group decreased from baseline by 6.1 mL/min/1.73 m² compared with a decrease of 12 mL/min/1.73 m² in the placebo group. Fewer patients in the TRF-budesonide group reached a composite of 30 percent reduction in eGFR or kidney failure (12 versus 21 percent). Rates of treatment-emergent adverse events, including infection, were similar between the groups although rates of adverse events leading to discontinuation of treatment were higher in the TRF-budesonide group (9 versus 2 percent). Hypertension, peripheral and facial edema, muscle spasms, and acne were more frequent in the TRF-budesonide group compared with placebo, possibly suggesting a systemic glucocorticoid effect of TRF-budesonide.

Limitations of this phase 3 study include its lack of patient stratification by Oxford MEST-C score at the time of randomization. In addition, for unclear reasons, patients assigned to the placebo group, particularly those with a baseline UPCR ≥1.5 g/g, had a more rapid decline in eGFR than patients receiving supportive care only in other large randomized trials such as the STOP IgAN trial [84]. Additional studies will be required to establish the role for TRF-budesonide in patients with IgAN, particularly in comparison with moderate-dose, oral, systemic glucocorticoids or other generic forms of delayed-release budesonide. The hypothesis that TRF-budesonide exerts its beneficial effects on the course of IgAN via local effects on Peyer patches in the distal ileum remains unproven.

Other FDA-approved, generic preparations of enteric-coated budesonide (such as those prescribed for inflammatory bowel disease) have not been evaluated in randomized trials in patients with IgAN but have shown some benefit in reducing proteinuria in a few uncontrolled studies [97,98].

Mycophenolate mofetil — MMF is an alternative option for high-risk patients who are unable to tolerate or do not wish to receive oral glucocorticoids, although supportive data come from trials that included only limited patient populations. Some contributors to this topic use MMF as initial therapy in high-risk patients who have both proteinuria and microscopic hematuria, while others use MMF in high-risk patients who continue to have disease progression despite treatment with glucocorticoids. If MMF is used, we start with 500 mg twice daily and titrate the dose to 1000 mg twice daily over several weeks as tolerated. We treat initially for four to six months. If eGFR or proteinuria worsen during this time, we discontinue treatment. If eGFR and proteinuria remain stable or improve, we continue treatment for one year and then taper the dose (eg, by 250 mg every two weeks or by 500 mg every month) to discontinuation.

There are limited data concerning the efficacy of MMF in the primary treatment of progressive IgAN [16,99-104]. The best data come from an open-label trial in 170 Chinese patients with IgAN and persistent proteinuria (between 0.75 and 3.5 g/day) in spite of three months of optimized supportive care (including maximally tolerated ARB therapy) who were randomly assigned to MMF (1.5 g/day for 12 months, then tapered to maintenance dose of 0.75 to 1 g/day for at least six months) plus supportive care or supportive care alone [104]. At baseline, mean proteinuria was 1.9 g/day, mean eGFR was 50 mL/min/1.73 m², and microscopic hematuria was present in 100 percent of patients. At three years, fewer patients in the MMF group experienced a doubling of serum creatinine (7 versus 21 percent), while rates of ESKD and death due to cardiovascular cause were not significantly different between the groups. Patients receiving MMF had a lower mean annual loss of eGFR than those receiving supportive care (-1.2 versus -3.8 mL/min/1.73 m²). Rates of serious adverse events were comparable between the groups.

Patients in the trial who did not require kidney replacement therapy were followed after the trial for a median of 60 months and continued to receive supportive care. Those in the MMF group either discontinued MMF or received a maintenance dose of MMF based upon clinician judgment or patient preference. During this posttrial phase, mean annual loss of eGFR was -7.1 mL/min/1.73 m² in patients in the supportive care group, -6.1 mL/min/1.73 m² in patients in the MMF group who discontinued MMF, and -4.1 mL/min/1.73 m² in patients in the MMF group who continued MMF.

Another trial that compared the combination of MMF and lower-dose prednisone (0.4 to 0.6 mg/kg/day) with full-dose prednisone (0.8 to 1 mg/kg/day) in Chinese patients with clinically and histologically active IgAN found no difference in complete remission rates at 6 and 12 months, suggesting a glucocorticoid-sparing effect of MMF [102].

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

Other regimens — Several other immunosuppressive agents have been evaluated for the treatment of IgAN: calcineurin inhibitors (CNIs), rituximab, cytotoxic agents, and others. We do not routinely use any of these agents as initial therapy for IgAN given the lack of clear evidence supporting their efficacy in this patient population [88]. Evidence for these therapies is presented below:

●Calcineurin inhibitors – CNIs such as cyclosporine and tacrolimus have been investigated in small studies of patients with IgAN [105-107]. A meta-analysis of seven randomized controlled trials comparing the use of CNIs (in combination with glucocorticoids) with glucocorticoids alone or placebo found higher rates of complete remission of proteinuria with CNI therapy but no differences in serum creatinine or eGFR between the groups. In addition, patients receiving CNI therapy had an increased risk of adverse events (relative risk 2.21, 95% CI 1.52-3.21) including gastrointestinal and neurologic symptoms or hirsutism.

●Rituximab – The efficacy of rituximab was evaluated in a small open-label trial that randomly assigned 34 patients with IgAN to rituximab or no rituximab; all patients were maintained on ACE inhibitor and/or ARB therapy [92]. At baseline, median proteinuria (2.1 g/day) and serum creatinine (1.4 mg/dL) were similar between treatment groups; however, median eGFR was lower in patients assigned to rituximab (40 versus 61 mL/min/1.73 m²). At 12 months, there was no difference in the change in proteinuria or change in kidney function from baseline between the two groups. Although treatment with rituximab resulted in the successful depletion of CD19+ B cells at both 6 and 12 months, there were no differences in serum levels of galactose-deficient (Gd)-IgA₁ or IgG autoantibodies against Gd-IgA₁ between the groups at baseline and at 12 months. No patients experienced serious adverse events, but mild adverse effects occurred more frequently among rituximab-treated patients. Rituximab may be beneficial for patients with IgA vasculitis (IgAV) nephritis [108], but at present it has no role in treatment of IgAN. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations", section on 'Alternative therapies'.)

●Cyclophosphamide – Combined therapy with prednisone plus oral cyclophosphamide followed by maintenance therapy with azathioprine has been examined for the initial treatment of IgAN. Although one small trial of patients with moderately progressive (noncrescentic) disease reported a higher rate of kidney survival with this regimen compared with supportive care alone [109], these findings were not confirmed in the larger STOP IgAN trial cited above [84]. The use of cyclophosphamide in patients with IgAN is generally reserved for those with rapidly progressive disease [110]. (See 'IgA nephropathy with rapidly progressive (crescentic) glomerulonephritis' below.)

●Azathioprine – The addition of azathioprine to glucocorticoids does not appear to provide further benefit compared with glucocorticoids alone. This was shown in a multicenter randomized trial in which 207 patients with a serum creatinine ≤2 mg/dL (177 micromol/L) and protein excretion >1 g/day were treated with glucocorticoids with or without azathioprine (1.5 mg/kg per day for six months) [94]. At a median of 4.9 years, there was no difference in kidney survival time (defined as the time to a 50 percent increase in plasma creatinine from baseline). Major side effects were more frequent among those who received azathioprine compared with those who did not (17 versus 6 percent). This trial is limited by the fact that fewer than one-half of patients were treated with an ACE inhibitor or ARB at the onset and therefore were not receiving the current standard of care.

●Leflunomide – Leflunomide is an immunosuppressive agent that inhibits pyridine synthesis and is used for the treatment of rheumatoid arthritis. Data from one open-label, randomized trial of 85 patients with progressive IgAN suggested that combined therapy with leflunomide and low-dose prednisone for 12 months, compared with high-dose prednisone, had a similar efficacy at preventing disease progression with fewer serious adverse effects [111,112].

●Hydroxychloroquine – Hydroxychloroquine is an immunomodulatory drug that has been evaluated for the treatment of IgAN. Although data are limited to small, randomized controlled trials in Chinese patients, hydroxychloroquine may help to reduce proteinuria when added to treatment with angiotensin inhibition [113,114]. The long-term benefits on progression of CKD are unknown. In addition, the benefit of adding hydroxychloroquine to patients receiving immunosuppressive therapy is unknown.

Investigational agents — A number of novel investigational agents for therapy of IgAN are being evaluated in clinical trials, including immunomodulators (such as atacicept [115] and telitacicept [116]), complement inhibitors (such as avacopan, iptacopan, narsoplimab, cemdisiran, and ravulizumab), endothelin A receptor inhibitors (such as atrasentan), and A Proliferation-Inducing Ligand (APRIL) inhibitors (such as sibeprenlimab).

●APRIL inhibitors – A Proliferation-Inducing Ligand (APRIL) is critical for mucosal B cell survival, maturation, proliferation, and IgA class switch recombination and has been implicated in the pathogenesis of IgAN. Serum levels of APRIL are increased in IgAN and correlate with disease severity. (See "IgA nephropathy: Pathogenesis", section on 'Source and regulation of Gd-IgA1 production in IgAN'.)

The efficacy and safety of sibeprenlimab, a humanized monoclonal antibody against APRIL, were evaluated in a phase II trial in which 155 patients with biopsy-proven IgAN, an eGFR ≥30 mL/min/1.73 m², and persistent proteinuria ≥1 g/day in spite of three months of optimized supportive care (including maximally tolerated ACE or ARB therapy) were randomly assigned to intravenous sibeprenlimab (2, 4, or 8 mg/kg of body weight) or placebo once monthly for 12 months [117]. Approximately 6 percent of patients in the trial were receiving treatment with an SGLT2 inhibitor. At baseline, the placebo group had a higher median baseline eGFR (68 versus 56 to 64 mL/min/1.73 m²), more severe proteinuria (2.13 versus 1.47 to 1.93 g/day), and a higher mean percentage of crescents on kidney biopsy than the sibeprenlimab groups. At 12 months, patients receiving sibeprenlimab had a greater, dose-dependent reduction from baseline in 24-hour UPCR (47, 59, and 62 percent with sibeprenlimab 2 mg, 4 mg, and 8 mg, respectively, versus 20 percent with placebo). The mean change from baseline in eGFR was -2.7, 0.2, -1.5 mL/min/1.73 m² with sibeprenlimab 2 mg, 4 mg, and 8 mg, respectively, compared with -7.4 mL/min/1.73 m² in the placebo group. Rates of serious adverse events were similar among the groups. A larger phase III trial (NCT05248646) is in progress.

Adjunctive therapies

●Tonsillectomy – Tonsillitis has been associated with hematuria and proteinuria in IgAN. It has been proposed that the tonsils are a source of abnormal IgA that forms immune complexes and deposits in the glomeruli [118,119]. However, aside from such patients who require tonsillectomy for conventional reasons, the available evidence suggests that tonsillectomy should not be routinely performed in most patients with IgAN [120]. However, tonsillectomy (with or without pulsed glucocorticoids) has been performed in Japan for some patients with IgAN with successful results. (See "IgA nephropathy: Pathogenesis", section on 'Source and regulation of Gd-IgA1 production in IgAN'.)

Several retrospective studies [119,121-123] and at least one prospective study [124] suggest that tonsillectomy, usually in combination with some immunosuppressive therapy, is associated with improved kidney outcomes in patients with IgAN and relatively mild kidney injury. However, other studies reported no overall benefit following tonsillectomy [125-127]. Nearly all studies of tonsillectomy in patients with IgAN were performed in Asian populations, and whether the ancestry of such patients or their underlying histology (eg, Oxford MEST-C scores) determines in part the response to various forms of therapy, including tonsillectomy, is unknown.

●Other interventions – Other interventions that have been evaluated in patients with IgAN include a low-antigen diet [128], gluten-free diet [129], intravenous immune globulin [130], and other drugs, such as vitamin D analogs [131-133], phenytoin [60], antiplatelet agents [60], and danazol [134], but data are limited.

Monitoring and modifying therapy — All patients who are receiving treatment for primary IgAN should be closely monitored for clinical response to therapy. We monitor serum creatinine and eGFR, urine total protein excretion (by urine protein-to-creatinine ratio from either a spot urine sample or a several-hour [8 to 24 hours] urine protein collection), and the urinalysis (for assessment of hematuria) every two to three months. Some experts perform more frequent monitoring (eg, at least monthly) in patients receiving immunosuppressive therapy.

●Patients receiving immunosuppressive therapy – In high-risk patients who are receiving immunosuppressive therapy (most commonly oral glucocorticoids), we determine the clinical response to treatment after four to six months of therapy and modify treatment as follows:

•If the patient has proteinuria <1 g/day and stable or improved kidney function, we continue to taper glucocorticoids and completely discontinue glucocorticoid therapy at six months. Such patients should continue supportive care measures indefinitely, unless contraindicated. Some contributors to this topic would add MMF 500 to 1000 mg twice daily for four to six months if the patient has persistent proteinuria >0.5 g/day and hematuria (ie, >10 red blood cells [RBC]/high-power field [hpf]).

•If the patient has persistent proteinuria ≥1 g/day, but proteinuria has decreased ≥50 percent from its peak value and kidney function is stable or improved, we continue to taper glucocorticoids and completely discontinue glucocorticoid therapy at six months. Although such patients have not achieved the goal for reduction in proteinuria, additional glucocorticoid therapy is unlikely to be of benefit. Most contributors to this topic would add MMF 500 to 1000 mg twice daily for four to six months if, in addition to the proteinuria, the patient has persistent hematuria (ie, >10 RBC/hpf). Supportive care measures should be continued indefinitely, unless contraindicated, and patients should be monitored for signs of increasing proteinuria.

•If the patient has persistent proteinuria ≥1 g/day without a ≥50 percent reduction in proteinuria from its peak value or has worsening kidney function, we administer a four- to six-month trial of MMF at 500 to 1000 mg twice daily and either discontinue glucocorticoids or continue low-dose glucocorticoids for the duration of MMF therapy, although there is no high-quality evidence to support this approach. Other authors would give a pulse of intravenous methylprednisolone 1 g. If the patient has persistent proteinuria ≥2 g/day, some authors would switch to an oral targeted-release formulation of budesonide (TRF-budesonide) (see 'Targeted-release budesonide' above). If there is persistent proteinuria ≥1 g/day and persistent hematuria (ie, >10 RBC/hpf) or worsening kidney function after six months of MMF, we obtain a repeat kidney biopsy.

●Patients not on immunosuppressive therapy – In patients who are receiving supportive care only and develop an increase in proteinuria of >50 percent and to >1 g/day or a sustained increase in serum creatinine greater than that expected from use of an ACE inhibitor or ARB, we perform a kidney biopsy to evaluate the need for more aggressive therapy.

SPECIAL POPULATIONS

Patients with variant forms of IgA nephropathy

IgA nephropathy with apparent minimal change disease — For patients with IgA nephropathy (IgAN) with apparent minimal change disease, we suggest glucocorticoid therapy using an approach similar to that used for patients with primary minimal change disease. These patients differ from other IgAN patients since they have extensive podocyte foot process effacement on electron microscopy and only mesangial electron-dense deposits. (See "Minimal change disease: Treatment in adults".)

There is a subset of patients with IgAN in whom glucocorticoid therapy alone is clearly beneficial: those with acute onset of the nephrotic syndrome, little or no hematuria, preserved kidney function, minimal glomerular changes on light microscopy, and diffuse fusion of the foot processes of the glomerular epithelial cells on electron microscopy. These histologic findings are characteristic of minimal change disease, and these patients behave similarly, usually going into remission with glucocorticoid therapy and occasionally requiring other immunosuppressives for frequently relapsing proteinuria [135-137]. Mesangial IgA deposits often disappear or are greatly reduced over time [137]. It is possible that these patients have minimal change disease and that the presence of IgA deposits is unrelated [135,137]. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Associated conditions'.)

IgA nephropathy with acute kidney injury — Acute kidney injury (AKI) can occur during episodes of gross hematuria in patients with IgAN [138-141]. In such patients, immediate management should focus on supportive care for AKI. If there is no clear evidence of reversal of AKI at a maximum of one week, a kidney biopsy should be performed to exclude the possibility of crescentic disease, which can present similarly but has a different prognosis and requires immediate therapy. (See "Overview of the management of acute kidney injury (AKI) in adults" and 'IgA nephropathy with rapidly progressive (crescentic) glomerulonephritis' below.)

Kidney biopsy in patients with IgAN and AKI reveals mesangial proliferation and segmental crescents in a small proportion of glomeruli (usually less than 25 percent) [138,140,141]. These findings are insufficient to account for the AKI, which has been ascribed to tubular obstruction by red cell casts [139,140,142]. 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 [139,141,142].

The serum creatinine concentration typically returns to baseline levels within several weeks to months, although dialysis may be temporarily required [139]. However, incomplete recovery of kidney function was noted in 9 of 36 patients (mean estimated glomerular filtration rate [eGFR] after recovery was 38 versus 89 mL/min/1.73 m²) [142]. Significant risk factors for lack of complete recovery included duration of gross hematuria longer than 10 days, age greater than 50 years, decreased eGFR at baseline, and more severe tubular necrosis on kidney biopsy.

IgA nephropathy with rapidly progressive (crescentic) glomerulonephritis — Among patients with IgAN, rapidly progressive glomerulonephritis (RPGN) is defined as a ≥50 percent decline in eGFR over three months or less, not explained by other reversible causes (such as drug toxicity, prerenal disease, or urinary obstruction), and the presence of crescents on kidney biopsy. A precise threshold for glomerular crescent involvement used to define crescentic IgAN has not been clearly established; we consider >30 percent crescent involvement to be a marker of risk for rapid progression. For patients with IgAN who have RPGN, we suggest treatment with cyclophosphamide and glucocorticoids using an approach similar to that used for patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)

A kidney biopsy is required to establish the diagnosis and will typically demonstrate mesangial and endocapillary hypercellularity and a high proportion of glomeruli affected by crescents with areas of focal necrosis. However, the presence of crescents in a kidney biopsy in the absence of a decline in eGFR does not indicate a diagnosis of rapidly progressive IgAN. Similarly, a decline in eGFR in the absence of crescents on biopsy should not be treated as RPGN. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Establishing the diagnosis' and "IgA nephropathy: Clinical features and diagnosis", section on 'Pathology'.)

The treatment of RPGN in patients with IgAN has not been evaluated in randomized trials. Observational data suggest possible benefit from regimens similar to those used in idiopathic RPGN: intravenous pulse methylprednisolone followed by oral prednisone, intravenous or oral cyclophosphamide, and/or plasmapheresis [143-147], although the benefit of plasmapheresis is controversial. Glucocorticoids may act in this setting by diminishing acute inflammatory injury rather than by correcting the factors responsible for IgA production and deposition [148].

The prognosis of RPGN in patients with IgAN is generally poor. In a multicenter cohort study of 113 patients with crescentic IgAN (88 with RPGN), 57 patients (50 percent) received glucocorticoids and immunosuppressive agents, including 43 (38 percent) who received pulse methylprednisolone plus cyclophosphamide [149]. Overall kidney survival at years 1, 3, and 5 after kidney biopsy were 57, 46, and 30 percent, respectively. Multivariate analysis found that initial serum creatinine was the only independent predictor of end-stage kidney disease (ESKD; hazard ratio 1.32, 95% CI 1.10-1.57); the percentage of crescents on biopsy did not associate with ESKD.

Pregnant patients — Pregnancy is generally well tolerated in patients with IgAN and a normal or near-normal glomerular filtration rate (GFR) [150]. As with most other chronic kidney diseases (CKD), the risk of worsening kidney disease with pregnancy is increased in women with an initial GFR below 70 mL/min, uncontrolled hypertension, or severe arteriolar and tubulointerstitial disease on kidney biopsy [151,152]. (See "Pregnancy and contraception in patients with nondialysis chronic kidney disease".)

Angiotensin inhibitors and some immunosuppressive drugs (particularly cyclophosphamide and mycophenolate mofetil [MMF]) should be discontinued at the earliest indication of pregnancy or prior to attempted conception because of risks to the fetus. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy" and "Safety of rheumatic disease medication use during pregnancy and lactation".)

Children — The optimal approach to therapy in children with IgAN is uncertain, and guidelines are lacking [153]. Establishing a clear approach to treatment is complicated by the varying clinical presentations among children (from mild microscopic hematuria to acute nephritic syndrome and nephrotic-range proteinuria) as well as by a different disease trajectory when compared with adults [40,154] (see 'Assessment of risk' above). Children are usually diagnosed at an early stage of disease, frequently have more active lesions (mesangial and endocapillary hypercellularity and crescents) and fewer chronic changes on kidney biopsy, and generally have a higher potential for recovery than adults. Assessment of risk in children with IgAN is critical to avoid overtreatment in mild cases and to provide more intensive treatment in patients with potentially progressive disease over a long-term life expectancy.

Our approach in children with IgAN is as follows:

●We assess the risk of progressive disease based upon clinical and pathological features. We score the patient's kidney biopsy using the Oxford classification of IgAN MEST-C score, if not already performed. We also use the International IgA Nephropathy Prediction Tool (IIgAN-PT; available for use online or as a mobile app) to calculate the five-year risk of a 30 percent decline in eGFR or progression to ESKD based upon clinical and histologic variables measured at the time of kidney biopsy [40]. Some experts also consider persistent severe microscopic hematuria to be a risk factor for disease progression [155]. We use this risk assessment in our discussions with caregivers and children regarding treatment and outcome. (See 'Assessment of risk' above and "IgA nephropathy: Clinical features and diagnosis", section on 'Oxford classification of IgAN'.)

●All children with IgAN with proteinuria ≥0.2 g/day/1.73 m² should receive supportive care, including an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) at maximally tolerated doses and blood pressure control to ≤50 percentile for age and height. As in adults, supportive care should be continued for at least three to six months before deciding upon additional therapy. During this period, we monitor a spot urine protein-to-creatinine ratio, serum creatinine (with determination of eGFR), and a urinalysis for evaluating microscopic hematuria every one to three months depending upon the clinical severity at presentation. (See 'Supportive care in all patients' above.)

●We consider the following patients to be at high risk for disease progression:

•Children with persistent proteinuria >0.5 g/day/1.73 m² (or >0.5 g/g creatinine) despite at least three months of optimized supportive measures.

•Children who present with active and severe lesions on kidney biopsy (high MEST-C scores) and proteinuria >1 g/day/1.73 m²; such patients often have severe microscopic hematuria.

●In children with IgAN who are considered to be at high risk for progressive disease, we suggest glucocorticoid therapy plus supportive care rather than supportive care alone [156-158]. We typically administer glucocorticoids for a total duration of six months, similar to glucocorticoid regimens in adults, although the duration may be individualized to the patient. The potential benefits of moderate doses of glucocorticoids have not yet been investigated in children with IgAN. Glucocorticoid therapy exceeding six months is discouraged to limit side effects on psycho-social responses and growth. (See 'Immunosuppressive therapy in high-risk patients' above.)

Children who are not considered to be at high risk for progressive disease are generally not treated with immunosuppressive therapy and should receive supportive care indefinitely. Regular follow-up is needed since relapses may occur.

●Children with IgAN with RPGN generally have poor outcomes, similar to adults with rapidly progressive IgAN. In such patients who have >30 percent glomerular crescent involvement associated with signs of rapid decline in eGFR, we suggest treatment with oral cyclophosphamide and glucocorticoids, although supportive evidence is limited [149,156,157]. (See 'IgA nephropathy with rapidly progressive (crescentic) glomerulonephritis' above.)

●In children with IgAN, the goal for reduction in proteinuria is <0.2 g/day/1.73 m² (or <0.2 g/g creatinine). This is lower than the proteinuria target in adults (0.5 to 1 g per day). (See 'Goals of therapy' above.)

Data evaluating the efficacy of immunosuppressive therapy in children with IgAN are limited [156-165], and there are few randomized trials. Evidence mostly from retrospective studies has shown that glucocorticoids, alone or combined with other immunosuppressive agents, may improve eGFR and reduce proteinuria [156-160].

SECONDARY IGA NEPHROPATHY — Secondary IgA nephropathy (IgAN) has been attributed to a variety of clinical conditions, including cirrhosis and other forms of severe liver disease, celiac disease, HIV infection, and other disorders. The optimal treatment approach for these forms of secondary IgAN is not well established. In general, therapy should be directed at the underlying primary disease. In certain conditions, such as celiac disease and inflammatory bowel disease, addressing the underlying disease has led to improvement in urinary abnormalities (eg, proteinuria and microscopic hematuria) or clearance of mesangial IgA deposits [129,166]. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Associated conditions'.)

PROGNOSIS — Patients with IgA nephropathy (IgAN) who have little or no proteinuria (less than 500 mg/day) have a low risk of progression. However, progressive proteinuria and kidney function impairment develop in a substantial proportion of patients over the long term [2-4,11,13,167-169]. Among patients who develop overt proteinuria and/or elevated serum creatinine concentration, progression to end-stage kidney disease (ESKD) is approximately 15 to 25 percent at 10 years and 20 to 30 percent at 20 years [3,4,14,27,170,171].

The rate of progression is typically slow with the glomerular filtration rate (GFR) often falling by as little as 1 to 3 mL/min per year, a change not associated with an elevation in the serum creatinine concentration in the short term. Thus, a stable and normal serum creatinine concentration does not necessarily indicate stable disease. The frequency with which this occurs has been evaluated in studies in which repeat kidney biopsy was used to assess the frequency of progressive disease [172,173]. In one report, repeat kidney biopsies were performed at five years in 73 patients with persistent proteinuria and a normal or near-normal initial serum creatinine [172]. 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.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Initial therapy in adults – In general, the management of primary IgA nephropathy (IgAN) focuses on optimized supportive care, including blood pressure control to optimal targets, reduction of proteinuria with renin-angiotensin system inhibition, and lifestyle modifications as appropriate. Immunosuppressive therapy, which has been shown to improve outcomes in patients with IgAN but has significant toxicity, should be reserved only for patients who remain at high risk for progression to end-stage kidney disease (ESKD) despite maximal supportive care and those with variant forms of progressive disease. Our approach to initial therapy in patients who do not have a variant form of IgAN is as follows (see 'Approach to therapy' above):

•Risk assessment – We score the patient's kidney biopsy using the Oxford classification of IgAN MEST-C score, if not already performed, and assess the patient's risk of progressive disease at the time of biopsy using the International IgA Nephropathy Prediction Tool (IIgAN-PT; available for use online or as a mobile app). (See 'Assessment of risk' above.)

•Supportive care in all patients – We initiate and optimize supportive care in all patients. For patients with IgAN and proteinuria ≥500 mg/day, we recommend treatment with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) (Grade 1B). Other supportive care measures include blood pressure control and lifestyle modification (such as dietary sodium restriction, smoking cessation, weight control, and exercise as appropriate). For all patients with IgAN, we suggest moderate dietary protein restriction (Grade 2C). Patients with persistent proteinuria despite treatment with an ACE inhibitor or ARB for at least three and up to six months can be treated by adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor or, alternatively, switching from the ACE inhibitor or ARB to sparsentan. (See 'Supportive care in all patients' above.)

•Immunosuppressive therapy in high-risk patients – For patients with IgAN who are considered to be at high risk of disease progression (ie, proteinuria ≥1 g/day despite at least three months of optimized supportive care), we suggest treatment with oral systemic glucocorticoids plus supportive care rather than supportive care alone (Grade 2B). Some experts prefer a moderate-dose glucocorticoid regimen, whereas others prefer a higher-dose regimen; any one of several regimens (table 2) is acceptable. We aim for a total duration of six months of glucocorticoid therapy. For patients who cannot tolerate or who do not wish to receive high-dose glucocorticoids, targeted-release budesonide (TRF-budesonide) or mycophenolate mofetil (MMF) is an alternative option. Alternatively, the patient can be encouraged to participate in a clinical trial if feasible. (See 'Immunosuppressive therapy in high-risk patients' above and 'Systemic glucocorticoids as first-line therapy' above.)

•Monitoring – All patients who are receiving treatment for primary IgAN should be closely monitored for clinical response to therapy. We monitor serum creatinine and estimated glomerular filtration rate (eGFR), urine protein excretion (by spot urine protein-to-creatinine ratio or 24-hour urine protein collection), and the urinalysis every two to three months. Some experts perform more frequent monitoring (eg, at least monthly) in patients receiving immunosuppressive therapy. We aim for a reduction in proteinuria to less than 1 g/day in all adult patients with IgAN. (See 'Monitoring and modifying therapy' above.)

●Variant forms of IgAN

•IgAN with apparent minimal change disease – For patients with IgAN with apparent minimal change disease, we suggest glucocorticoid therapy using an approach similar to that for patients with primary minimal change disease (Grade 2C). (See 'IgA nephropathy with apparent minimal change disease' above.)

•IgAN with acute kidney injury (AKI) – In patients with IgAN with AKI, immediate management should focus on supportive care for AKI. If there is no clear evidence of reversal of AKI at a maximum of one week, a kidney biopsy should be performed to exclude the possibility of crescentic disease. (See 'IgA nephropathy with acute kidney injury' above.)

•IgAN with rapidly progressive (crescentic) glomerulonephritis (RPGN) – For patients with IgAN who have RPGN, we suggest treatment with cyclophosphamide and glucocorticoids (Grade 2C); the approach is similar to that used for patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. (See 'IgA nephropathy with rapidly progressive (crescentic) glomerulonephritis' above.)

●Children with IgAN – The optimal approach to therapy in children with IgAN is uncertain, and guidelines are lacking. All children with IgAN with proteinuria ≥0.2 g/day/1.73 m² should receive supportive care, including an ACE inhibitor or ARB at maximally tolerated doses and blood pressure control to ≤50 percentile for age and height. In children with IgAN who are considered to be at high risk for progressive disease, we suggest glucocorticoid therapy plus supportive care rather than supportive care alone (Grade 2C). (See 'Children' above.)