IgA Nephropathy: Reviewing the Evidence on Current and Future Therapies

By Seshma Ramsawak, MD, Scott Cohen, MD, Andrea Linares, DO and Corey Cavanaugh, DO

Editor’s note: This article is reprinted from the Cleveland Clinic Journal of Medicine. It is the second section of a two-part series and highlights current treatment options and those under investigation for immunoglobulin (Ig) A nephropathy. Part 1 focuses on new updates and evidence relating to pathogenesis as well as diagnosis and prognostic tools

The article in its entirety, including a full list of references, can be found here.

There has been a tremendous lag in the treatment of immunoglobulin (Ig) A nephropathy since its histologic features were first described in 1968. For decades, nephrologists have had little more than renin-angiotensin-aldosterone system (RAAS) inhibitors or corticosteroids in their treatment armamentarium. Thanks to a recent transformation in our understanding of and therapeutic approach to IgA nephropathy, in the near future, there may be more therapeutic options for IgA nephropathy than for any other glomerular disease

Proteinuria as an indicator of kidney function

The goal of therapy in IgA nephropathy, as in all kidney disease, is to prevent progression to end-stage kidney disease by decreasing the rate of GFR loss. The main therapeutic targets in IgA nephropathy include reducing proteinuria and controlling blood pressure. The severity of proteinuria remains the strongest indicator of kidney outcome. The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend reducing proteinuria to less than 1 g per day as a surrogate marker for improved kidney outcome, and consideration of immunosuppressive therapy if unable to achieve proteinuria levels lower than 1 g per day with conservative management such as RAAS blockade. However, recent large registry data have revealed that 30% of patients with time-averaged proteinuria of 0.44 to less than 0.88 g/g (of creatine) developed kidney failure within 10 years. It is therefore clear that patients with IgA nephropathy and lower degrees of proteinuria may benefit from more intensive disease management.

Currently, the goal of therapy is proteinuria of less than 0.5 g and absence of hematuria. These targets have not been well studied in a prospective therapeutic trial, however, and we do not yet know the risk or benefit of attempting to achieve such targets. Several new trials and therapeutics have emerged that require an update to our approach to diagnosis and treatment of IgA nephropathy.

Current treatment options

Nonimmunosuppressive therapy. Treatments targeting RAAS reduce proteinuria and preserve nephrons across the spectrum of glomerular diseases, including IgA nephropathy. Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers carries a strong recommendation in the most recent KDIGO guidelines, along with a target blood pressure of 120/70 mm Hg or lower and lifestyle modifications that include smoking cessation, weight reduction, salt restriction (< 2 g/day), and exercise. KDIGO guidelines no longer recommend fish oil for IgA nephropathy.

New nonimmunosuppressive therapy options include the SGLT-2 inhibitors and dual endothelin receptor and angiotensin receptor antagonists.

SGLT-2 inhibitors. There have been no dedicated trials to evaluate IgA nephropathy outcomes with the use of these agents. However, IgA nephropathy was well represented in DAPA-CKD (Dapagliflozin in Patients With Chronic Kidney Disease), a randomized controlled trial that evaluated the effect of dapagliflozin in patients with chronic kidney disease and albuminuria due to various causes. In a prespecified analysis of DAPA-CKD, 270 patients with IgA nephropathy treated with dapagliflozin had a 26% reduction in proteinuria compared with placebo. Additionally, the primary outcome (sustained decline in estimated GFR of 50% or more, end-stage kidney disease, or death from a kidney disease–related or cardiovascular cause) occurred in only six (4%) participants on dapagliflozin vs 20 (15%) on placebo (hazard ratio 0.29; 95% confidence interval [CI] 0.12–0.73), offering a 71% risk reduction. Criticisms of this trial include the lack of adequate blood pressure control with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the run-in period compared with other trials in IgA nephropathy, in addition to recruitment of older patients and exclusion of patients with recent immunosuppression use.

The safety and efficacy of the dual endothelin and angiotensin receptor antagonist sparsentan in IgA nephropathy was recently evaluated in the PROTECT (Efficacy and Safety of Sparsentan Versus Irbesartan in Patients With IgA Nephropathy) trial. In this large randomized, active-controlled study, adults with high-risk IgA nephropathy (> 1 g proteinuria per day) received sparsentan or irbesartan 300 mg daily. The primary efficacy end point was a change from baseline to week 36 in the urine protein-creatinine ratio based on a 24-hour urine sample. The sparsentan group saw a 49.8% proteinuria reduction compared with 15.1% in the irbesartan group, which was maintained until the 110-week trial ended. At two years, the estimated GFR chronic rate of change (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 rate of adverse events was similar in the two groups, with more hypotension and acute kidney injury occurring in the sparsentan group. Due to the potential hepatotoxicity and fetal toxicity of endothelin receptor antagonists, the FDA requires the Risk Evaluation and Mitigation Strategy for sparsentan, mandating liver function monitoring for patients on the drug and, for those capable of becoming pregnant, maintaining contraception while on treatment and one month after. RAAS blockers should be stopped when converting to sparsentan.

On the strength of the 36-week data showing proteinuria reduction, the FDA granted accelerated approval to sparsentan for patients with IgA nephropathy deemed high risk for progression; recently, the drug obtained full approval.

It is currently not known whether the addition of SGLT-2 inhibitors to dual endothelin receptor and angiotensin receptor antagonists or endothelin receptor antagonists will add further proteinuria reduction and estimated GFR benefit. The results of an open-label extension of the PROTECT trial are awaited.

The endothelin receptor antagonist atrasentan was recently granted accelerated approval based on findings from the phase 3 ALIGN (Atrasentan in Patients With IgA Nephropathy) trial.

Immunosuppressive therapy

Systemic corticosteroids are frequently used in IgA nephropathy, yet their role in management of this disease is controversial. Several randomized controlled trials and meta-analyses that examined corticosteroid use in IgA nephropathy have had conflicting results. Modern randomized controlled trials such as STOP-IgAN (Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy)26 and TESTING (Therapeutic Evaluation of Steroids in IgA Nephropathy Global) have best represented the use of systemic corticosteroids and their risks, which were likely underreported in older studies.

STOP-IgAN26 was a relatively small randomized controlled trial testing the safety and efficacy of immunosuppressive therapy combined with supportive care compared with supportive care alone. Immunosuppressive therapy consisted of corticosteroids for those with estimated GFR of 60 mL/min/1.73 m2 or greater, and cyclophosphamide followed by azathioprine and corticosteroids for those with estimated GFR between 30 and 59 mL/min/1.73 m2. Of the 337 patients entering the run-in phase, 106 responded to supportive care after 6 months, which included RAAS blockade, smoking cessation, and cholesterol-lowering with statins; these were not randomized. Only 5% in the supportive-care arm reported complete remission (ie, urine protein-creatinine ratio < 0.2 g/24 hours and stable renal function with a fall in estimated GFR < 5 mL/min/1.73 m2 from baseline) compared with 17% in the immunosuppressive arm. At the end of the three-year trial, there was no difference in estimated GFR between the groups. Not surprisingly, immunosuppression with corticosteroids saw higher rates of weight gain, impaired glucose tolerance, and serious adverse events such as infection. STOP-IgAN therefore solidified the value of supportive or nonimmunosuppressive care in IgA nephropathy.

The TESTING trial was a randomized clinical trial comparing oral methylprednisolone (0.6–0.8 mg/kg/day for 2 months and then tapering, with a treatment period of six to eight months) with placebo, carried out in a predominantly East Asian population. While methylprednisolone resulted in a lower likelihood of the primary end point (40% decline in estimated GFR, end-stage kidney disease, or death due to kidney failure), it came at the price of serious infections, including 2 infection-related deaths, and the investigators suspended the trial.

The trial resumed recruitment after the methyl-prednisolone dose was reduced (0.4 mg/kg/day for two months, tapered over six to nine months) and prophylactic antibiotics were mandated.29 The primary composite end point occurred in 28.8% (74 patients) of the methylprednisolone group vs 43.1% (106) of the placebo group (hazard ratio 0.53, 95% CI 0.39–0.72, P < .001) over a mean follow-up of 4.2 years. Despite the reduced steroid dose, serious adverse events were 4 times higher in the methylprednisolone group than in the placebo group: 37 vs 8 total events that occurred in 28 (10.9%) vs 7 (2.8%) participants.

Finally, targeted-release formulation (TRF) budesonide is the only immunosuppressive drug fully approved by the FDA to treat IgA nephropathy. The hypothesis is that TRF budesonide is delivered directly to the small bowel and Peyer patches, where the galactose-deficient IgA is produced, interrupting a key mediator of IgA nephropathy. In theory, because of extensive first-pass metabolism, less drug would reach the systemic circulation and limit glucocorticoid toxicity.

The NefIgArd (Efficacy and Safety of Nefecon in Patients With Primary IgA [Immunoglobulin A] Nephropathy) trial,30 a phase 3 randomized trial, evaluated TRF budesonide vs placebo in patients with proteinuria of 1 g or more over a 9-month period. TRF budesonide resulted in significantly reduced proteinuria and sustained estimated GFR benefit over a two-year follow-up. However, like other trials of systemic corticosteroids for IgA nephropathy, the proteinuria returned after TRF budesonide was stopped, and steroid-related side effects were more common in the TRF budesonide group, including weight gain, facial edema, acne, peripheral edema and hypertension.

Treatment recommendations

The landscape for treatment of IgA nephropathy has changed rapidly and will continue to change in the coming months and years. Figure presents the authors’ recommended approach, with these considerations:

1. A proteinuria threshold of 0.5 g/day is the new cutoff for warranting a biopsy, as opposed to the traditional value of 1 g/day or greater.
2. While the MEST-C score cannot be used to guide immunosuppressive therapy, we advise considering it in addition to a direct discussion with the renal pathologist who interpreted the biopsy.
3. Nonimmunosuppressive therapy should be considered in conjunction with immunosuppressive therapy.
4. There is inadequate evidence to support superiority of TRF budesonide over systemic corticosteroids, and this decision is made on a case-by-case basis.

Note that this approach can include use of mycophenolate mofetil as a corticosteroid-free immunosuppressive option. A randomized trial of 170 Chinese patients with IgA nephropathy showed mycophenolate mofetil when added to supportive care (renin-angiotensin system blockade) reduced the risk of the primary composite outcome (doubling of serum creatinine, end-stage kidney disease, or death due to kidney or cardiovascular cause) compared with supportive care alone.

Future treatment options

A variety of treatment options are under investigation for the management of IgA nephropathy targeting the different “hits” in the pathogenesis model (Table 3).

Complement inhibitors. Significant research is focused on the complement cascade, reflecting the key role of the complement system in the development of IgA nephropathy. Several complement inhibitors are being studied in phase 2 and 3 trials, with mixed results. There has been much focus on inhibition of the alternative pathway of complement, which impacts the deposition of immune complexes in the glomerulus (the fourth hit in the pathogenesis model of IgA nephropathy).

Iptacopan (LNP023), an oral factor B inhibitor that prevents the activity of the alternative pathway C3 convertase, was evaluated in 66 patients with IgA nephropathy in a phase 2 trial. At 6 months, participants who received iptacopan 200 mg twice daily had a 40% reduction in proteinuria compared with placebo. In a follow-up phase 3 trial, iptacopan showed a significant reduction in proteinuria at 9 months compared with placebo. It was recently granted accelerated approval by the FDA.

The complement inhibitor class of drugs will likely be used in cases of IgA nephropathy that are resistant to traditional treatments, including corticosteroids, and have a significant inflammatory component on kidney biopsy, or those where a steroid-sparing regimen is ideal. There is interest in correlating the intensity of C3 staining on immunofluorescence microscopy of kidney biopsies and the potential response to complement inhibition.

Inhibition of antibody-producing B cells (targeting the second and third hits in IgA nephropathy pathogenesis) has also emerged as a therapeutic target for the management of IgA nephropathy. While rituximab has not been shown to be beneficial, other B-cell receptor targets have shown some initial success, including APRIL (a proliferation-inducing ligand), BAFF (B-cell activating factor), and plasma cell receptors. APRIL and BAFF regulate B-cell survival.

APRIL may help to specifically produce IgA1 molecules by controlling the immunoglobulin class switch recombination. Several monoclonal antibodies against APRIL are currently under investigation, including sibeprenlimab, zigakibart, and atacicept. A phase 2b clinical trial of atacicept showed a significant reduction in proteinuria compared with placebo, and a phase 3 clinical trial is under way.

Antiplasma cell therapies (second and third hits in IgA nephropathy pathogenesis) are also being investigated as potential treatment options. Monoclonal antibodies to CD38 (felzartamab and mezagitamab) are being assessed in early-stage clinical trials. Larger studies are needed to assess the efficacy of this approach in the management of IgA nephropathy.

New understanding and new challenges

Advances in our understanding of the pathogenesis, prognosis, and, most important, therapeutic options for IgA nephropathy have been significant. For decades, treatment options have been limited, with many reaching end-stage kidney disease within their lifetime. Recognition of the disease still depends on urinalysis and quantification of proteinuria, but with new therapies on the horizon, there is hope that awareness will increase.

For the treating clinician, the management of IgA nephropathy is a complex clinical scenario. The four-hit model provides a blueprint for the pathogenesis, allowing targeted management of the disease, but appropriate use of novel therapies and assessment of response remain significant challenges. Among the questions to consider are the following:

• How should these drugs be combined, if at all?
• How long should each therapy be given?
• Do newer therapies result in a true reduction in the rate of end-stage kidney disease?

Also important are conversations for patients and clinicians on cost and access to therapy. Ongoing study, debate, and conversation within the nephrology community are needed to prioritize these novel therapies and develop guidelines.

The article in its entirety, including a full list of references, can be found here.

Dr. Ramsawak is a former Cleveland Clinic nephrology fellow, and Drs. Cohen, Linares and Cavanaugh staff nephrologists.