IgA Nephropathy (IgAN)

Introduction

Immunoglobulin A nephropathy (IgAN or IgA nephropathy), also known as Berger’s disease, is the most common glomerular disease in Caucasian and Asian patients (1,2). Furthermore, IgA nephropathy is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. Approximately 25-30% of IgA nephropathy patients will develop kidney failure within 20-25 years from presentation (1). In the United States, the annual incidence of IgA nephropathy is approximately 1 case per 100,000 persons (3). Most cases are sporadic; however, genetic predisposition may play a role (2). For instance, IgAN appears to be most prevalent in patients with East Asian ancestry (1). The prevalence of this disease in the Asian population is 30-60%, compared to 38% in indigenous North American patients, 20-30% in European patients, 10% in North American patients, and 2% in African American patients (4). The southeast region of Asia has the highest reported cases of IgAN (5). Notably, such testing is frequently performed in Asia with several countries having much greater screening frequency than the United States and Europe. Thus, this increased frequency may be associated with a higher identification rate and contribute to a higher prevalence.

 

IgA Nephropathy Overview

IgA nephropathy is classified as an autoimmune disease involving deposition of IgA antibodies in the kidney, specifically in the glomerular mesangium, resulting in inflammation (2,3). Inflammation in the glomeruli, also known as glomerulonephritis, results in the inability of the kidneys to filter properly (2,6).  Confirmation of a diagnosis of IgAN typically requires a kidney biopsy for both immunofluorescence staining and staging by renal histology due to a lack of noninvasive and laboratory testing that yields results specific to IgAN. Once a biopsy is completed, the MEST-C score can be utilized (1,7).

The MEST-C score measures mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and degree of crescent formation (1,2). The degree of crescent formation in IgAN patients is defined as >50% crescentic glomeruli on the kidney biopsy (8). The MEST-C score uses histological variables such as measuring the lesions, kidney tissue damage, and proliferation of cell in the kidney (9,10). All parameters in combination assist in predicting kidney outcomes (9,10). The parameters of this score are important for determining the prognosis of IgAN patients (1).

Signs and symptoms of IgAN can include dark colored urine due to hematuria, albuminuria, edema, nephrotic syndrome, and glomerulonephritis (3,11,12). Glomerulonephritis is characterized by edema, hypertension, and kidney insufficiency (2). Children and young adults with IgAN may often present with macroscopic hematuria during an upper respiratory or gastrointestinal illness (3). Older IgA patients may often present with proteinuria, microscopic hematuria, or hypertension (3). Patients with IgAN can develop end-stage kidney disease 10-20 years after diagnosis (11). Risk factors for IgA nephropathy include decreased kidney function, persistent proteinuria, and hypertension (3).

 

Treatment

There are currently no specific guidelines for IgA nephropathy treatment. However, per KDIGO treatment guidelines, it is recommended that patients be provided with optimal supportive care measures. These include blood pressure management, lifestyle modifications, and assessment of cardiovascular risk. Patients’ blood pressure and proteinuria levels should be monitored continuously for signs of disease progression. Patients with cardiovascular risk should be started on necessary interventions. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) have been used as first line therapeutic agents for IgAN associated with any proteinuria. For blood pressure management, guidelines recommend a maximally tolerated dose of an ACE inhibitor or an ARB. Controlling the blood pressure of a patient with IgA nephropathy slows chronic kidney disease progression as well as reduces cardiovascular risk (1). By controlling the patient’s blood pressure, it allows for the kidneys to continue to function properly and prevent worsening of the disease.

Sparsentan is a newer agent that has been approved by the FDA to reduce proteinuria in adults with primary IgA nephropathy at risk of rapid disease progression. Sparsentan is a dual endothelin angiotensin receptor antagonist that significantly reduced proteinuria and preserved kidney function in comparison to the ARB, irbesartan, in clinical trials. The PROTECT trial was a double-blind, randomized, active-controlled, phase 3 study, conducted across 134 clinical practice sites in 18 countries. Patients were randomized 1:1 to receive to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily). This study demonstrated that patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group with an eGFR chronic 2-year slope (weeks 6-110) of -2.7 mL/min per 1.73 m2 per year versus -3.8 mL/min per 1·73 m2 per year, respectively (difference 1.1 mL/min per 1.73 m2 per year, 95% CI 0.1 to 2.1; p=0.037). This significant reduction in proteinuria at 36 weeks was maintained throughout the study period. Adverse events occurring in greater that 10% of the sparsentan group included hyperkalemia, peripheral edema, dizziness, headache, hypotension, and hypertension (13).

Pharmaceutical quality fish oil containing high concentrations of omega-3- fatty acids have also been routinely used in patients with milder disease. Specific lifestyle modifications that should be addressed are smoking cessation, sodium restriction, weight control and exercise (1). For patients at higher risk of progression of chronic kidney disease, immunosuppressive therapy or alternatively mycophenolate mofetil have been used as treatment options. High risk of progression of chronic kidney disease is classified by proteinuria greater than 0.75-1 g/d despite 90 days of optimized supportive care (1). Immunosuppressive therapy should only be considered after patients have received maximal supportive care measures.

There have been several studies evaluating the use of immunosuppressive therapy for treatment of IgAN.  The TESTING (Therapeutic Evaluation of Steroids in IgA Nephropathy Global) randomized clinical trial studied the use of oral methylprednisolone in patients with IgA nephropathy. The primary outcome of the trial was a composite of 40% decline in eGFR, kidney failure, or death due to kidney disease. During the study, 262 participants were randomized to receive methylprednisolone (max dose 48 mg/d) or a placebo. However, due to an increased risk of serious adverse events, recruitment was discontinued after a median follow-up of 2.1 years. Serious events occurred in 20 patients (14.7%) in the methylprednisolone group compared to four patients (3.2%) in the placebo group (P = 0.001; risk difference, 11.5% [95% CI, 4.8%-18.2%]). Most serious events were due to excess infections, with 11 patients (8.1%) experiencing this in the methylprednisolone group and 0 patients in the placebo group (risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < 0.001). The primary composite outcome occurred in eight patients (5.9%) in the methylprednisolone group compared to 20 patients (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17 to 0.85]; P = 0.02; risk difference, 10.0% [95% CI, 2.5% to 17.9%]). The study concluded that the use of methylprednisolone in patients with IgAN significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease; however, it was associated with significantly increased risk of adverse events, especially infections (11).

Additionally, the Cochrane database completed a review to determine the benefits and/or harm of immunosuppression treatment for IgAN patients. The review concluded the use of immunosuppression medication probably prevents decline in GFR or doubling of serum creatinine. However, evidence on prevention of death, infection, and malignancy was sparse (14). In another study, the Intensive Supportive Care plus Immunosuppression in IgA Nephropathy trial was a multicenter, open-label, randomized control trial with a two-group parallel design. The trial had a six-month run-in phase where patients’ supportive care was adjusted based on proteinuria levels. Patients’ proteinuria levels determined if a patient received supportive care or supportive care plus immunosuppression therapy. A total of 162 were randomized to receive either supportive care or supportive care with immunosuppression. After three years, four patients (5%) in the supportive care group had full clinical remission compared to 14 patients (17%) in the supportive care with immunosuppression group (P=0.01). Additionally, a total of 22 patients (28%) in the supportive care group and 21 patients (26%) in the supportive care with immunosuppression group had a decrease in the eGFR of at least 15 mL/min/1.73 m2 (P=0.75). There was no significant difference in decline of eGFR between the two groups. The trial concluded the addition of immunosuppressive therapy in supportive care did not significantly improve the outcomes, and it was shown that there was an increased risk of adverse events (15).

However, a new agent recently received full FDA approval to reduce the loss of kidney function in adults with primary IgA nephropathy at risk for disease progression. This new agent is targeted-release budesonide, a medication that modulates B-cell numbers and activity through anti-inflammatory and immunosuppressive effects from potent glucocorticoid activity, targeting the gut-kidney axis in IgA nephropathy. This agent received full approval based on the NefIgArd trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted at 132 hospital-based clinical sites in 20 countries. Patients were randomized 1:1 to receive targeted-release budesonide 16 mg/day or matching placebo for a treatment period of 9 months, followed by a 2-week taper and a 15-month observation period off the study drug. The time-weighted average change of eGFR over two years was of –2.47 mL/min per 1.73 m2 with targeted-release budesonide compared to –7.52 mL/min/1.73 m2 with placebo. This demonstrated a statistically significant treatment benefit with targeted-release budesonide versus placebo with a difference of 5.05 mL/min/1.73 m2 between the two groups (95% CI 3.24 to 7.38, p<0.0001). Furthermore, it was found that there was 50% less deterioration of kidney function in targeted-release budesonide-treated patients compared to placebo-treated patients over the 2-year period. A maximum reduction in urine protein creatine ratio of 50% was associated with targeted-release budesonide use versus placebo at 12 months; however, this reduction was 30% at the end of the two years. Based on this finding, proteinuria may return to baseline eventually. The most common treatment emergent adverse events with targeted-release budesonide during the treatment period were peripheral edema (17%), hypertension (12%), muscle spasms (12%), acne (11%), and headache (10%). With regards to infections, the incidence of infection-related events during treatment was similar between the two groups with 35% patients in the targeted-release budesonide-group and 31% patients in the placebo group experiencing this (16).

While there are no specific guidelines for the treatment of IgAN, supportive care including blood pressure and proteinuria management with ACE inhibitors or ARBs and lifestyle modifications may be considered in these patients. Additionally, it is imperative when considering immunosuppression therapy for IgAN patients that a risk benefit analysis is evaluated to determine what is best for the patient. Newer agents such as targeted-release budesonide and sparsentan have shown promising results for management of this disease. Furthermore, investigational agents currently being evaluated for treatment of IgA nephropathy include immunomodulators (atacicept, telitacicept), complement inhibitors (avacopan, iptacopan, narsoplimab, cemdisiran, ravulizumab), endothelin A receptor inhibitors (atrasentan), and A Proliferation-Inducing Ligand (APRIL) inhibitor (sibeprenlimab).

References:

  1. Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):753-779. doi:10.1016/j.kint.2021.05.021
  2. Madan N, Hwang VJ, Yeun JY, Weiss RH. Immunoglobulin A Nephropathy and Henoch–Schönlein Purpura. In: Lerma EV, Rosner MH, Perazella MA. CURRENT Diagnosis & Treatment: Nephrology & Hypertension, 2e. McGraw Hill; 2017.
  3. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402-2414. doi:10.1056/NEJMra1206793
  4. Zhu L, Zhang H. The Genetics of IgA Nephropathy: An Overview from China. Kidney Dis (Basel). 2015;1(1):27-32. doi:10.1159/000381740
  5. Hassler JR. IgA nephropathy: A brief review. Semin Diagn Pathol. 2020;37(3):143-147. doi:10.1053/j.semdp.2020.03.001
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  7. Haaskjold YL, Bjørneklett R, Bostad L, Bostad LS, Lura NG, Knoop T. Utilizing the MEST score for prognostic staging in IgA nephropathy. BMC Nephrol. 2022;23(1):26. Published 2022 Jan 11. doi:10.1186/s12882-021-02653-y
  8. Lv J, Yang Y, Zhang H, et al. Prediction of outcomes in crescentic IgA nephropathy in a multicenter cohort study. J Am Soc Nephrol. 2013;24(12):2118-2125. doi:10.1681/ASN.2012101017
  9. Gowrishankar S, Gupta Y, Vankalakunti M, et al. Correlation of Oxford MEST-C Scores With Clinical Variables for IgA Nephropathy in South India. Kidney Int Rep. 2019;4(10):1485-1490. Published 2019 Jul 3. doi:10.1016/j.ekir.2019.06.013
  10. Firinci F, Soylu A, Sarioğlu S, Demir BK, Türkmen MA, Kavukcu S. Assessment of the effect of mesangial hypercellularity in childhood nephropathies to the clinical and laboratory findings. Ren Fail. 2014;36(6):877-882. doi:10.3109/0886022X.2014.900386
  11. Lv J, Zhang H, Wong MG, et al. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017;318(5):432-442. doi:10.1001/jama.2017.9362
  12. Iga nephropathy. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/kidney-disease/iga-nephropathy. Published November 2015. Accessed September 30, 2022.
  13. Rovin BH, Barratt J, Heerspink HJL, et al. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet. 2023;402(10417):2077-2090. doi:10.1016/S0140-6736(23)02302-4
  14. Natale P, Palmer SC, Ruospo M, et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev. 2020;3(3):CD003965. Published 2020 Mar 12. doi:10.1002/14651858.CD003965.pub3
  15. Rauen T, Eitner F, Fitzner C, et al. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med. 2015;373(23):2225-2236. doi:10.1056/NEJMoa1415463
  16. Lafayette R, Kristensen J, Stone A, et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial [published correction appears in Lancet. 2023 Sep 9;402(10405):850]. Lancet. 2023;402(10405):859-870. doi:10.1016/S0140-6736(23)01554-4

GMO-000826  Rev A  04/2024