News
Article
To claim CE credit for this activity, please visit https://www.pharmacytimes.org/courses/preventing-progression-in-iga-nephropathy-a-managed-care-focus-on-emerging-therapies
ABSTRACT
Immunoglobulin A nephropathy (IgAN) is an autoimmune disease that is the most common cause of glomerulonephritis. In IgAN, the glomeruli are impaired by deposits of IgA-complexes in the kidney, which leads to the progression of chronic kidney disease, often resulting in end-stage renal disease requiring dialysis or kidney transplantation. This progression is associated with impaired health-related quality of life and a significant economic burden. Better overall patient outcomes have been seen in patients who are diagnosed and receive treatment earlier in the disease process. Supportive therapy is the mainstay of treatment, but there have also been recent advances with targeted therapies that may provide additional therapeutic options to meet treatment goals. Managed care professionals are well positioned to design clinical programs and pathways to promote earlier diagnosis, better efficacy and safety monitoring, and timely access to targeted therapies to slow progression, reduce kidney damage, and delay or prevent end-stage renal disease.
Am J Manag Care. 2023;29(suppl 3):S31-S43. https://doi.org/10.37765/ajmc.2023.89344
Disease Overview
Immunoglobulin A nephropathy (IgAN), also known as Berger disease, is a progressive autoimmune kidney disease and the most common primary glomerular disease in the world.1 Initially identified by French pathologist Dr Jean Berger in the 1960s, IgAN is characterized as a kidney disease having glomerular “intercapillary deposits of IgA-IgG.”2 These antibody deposits in the kidney result in a chronic renal inflammation that leads to the development of blood (hematuria) and protein (proteinuria) in the urine with progression to end-stage renal disease (ESRD) in 40% to 53% of patients within 20 years of diagnosis.1,3 Although IgAN is the most common kidney disease in the world, there is no validated tool to predict disease progression. However, based on data from risk prediction models and studies, the presence of specific clinical and demographic risk factors may be predictive of kidney outcomes in patients with IgAN. The most robust risk factors identified include estimated glomerular filtration rate (eGFR), blood pressure, and proteinuria at diagnosis.4-6 Uncontrolled hypertension (HTN) and proteinuria over time has been associated with disease progression; however, a reduction in proteinuria to less than 1 gram/day has demonstrated improved prognosis regardless of peak proteinuria.4 Currently, 2 products have been FDA approved for the treatment of IgAN-mediated proteinuria; however, with a better understanding of the disease pathogenesis, new therapeutic approaches are currently in development.7 Managed care professionals need to understand the underlying pathophysiology of IgAN and the management of this disease process as treatment options become available.
Epidemiology
The global incidence of IgAN among adults is estimated to be 2.5 cases per 100,000 person-years with an early age of onset, frequently presenting in the second or third decade of life.3 In the United States, the incidence of IgAN is estimated to be 1.29 cases of every 100,000 individuals or 4236 adults and children diagnosed annually.3 Men are twice as likely to be affected than women and IgAN is more prevalent among persons of Asian descent, followed by Caucasians, with rare occurrence in individuals of sub-Saharan African ancestry.2,8 The prevalence of IgAN varies widely among ethnic groups and while this variability may be partially explained by differences in health screening policies and biopsy practices between these regions, genetics is likely a strong contributor.2 In 1 study evaluating 251 patients from the southeastern United States with IgAN, the median age at diagnosis was 36.9 years with a demographic of 69% male and 95% Caucasian. Due to the progressive nature of the disease process, life expectancy was reduced by 10.1 years, with a median observed age of death at 65.7 years compared to a median expected age at death of 75.8 years. Eighty-three percent of the deaths occurred after progression to ESRD.9 A population-based cohort study of more than 3600 individuals with biopsy-confirmed IgAN conducted in Sweden found a 53% increase in all-cause mortality compared to a matched control group. The absolute death rate was moderately increased among patients after progression to ESRD, corresponding to a 6-year reduction in life expectancy. The study also found that mortality was not increased in the pre-ESRD period, which may be a compelling reason for early treatment to stabilize the disease process and delay progression to ESRD.10 It is clear that the clinical course of IgAN is influenced by several factors, such as the presence of HTN at baseline, level of kidney function, and amount of proteinuria and hematuria. Thus, it is well accepted that the disease progression of IgAN is highly variable. Early diagnosis of IgAN provides an opportunity to impact modifiable risk factors such as HTN and proteinuria, which have subsequent improvements in outcomes of patients with IgAN. In 1 study evaluating outcomes of patients with biopsy-proven IgAN, control of HTN and proteinuria reduced the risk of death or dialysis.11
Pathophysiology
IgAN is an autoimmune disease where the glomeruli are increasingly damaged by the accumulation of IgA deposits in the glomerular mesangium, leading to chronic inflammation.12 Glomerular injury persists and results in disruptions in the filtration barrier, leading to hematuria and proteinuria. As glomerular injury through chronic inflammation continues, progressive glomeruli necrosis leads to kidney failure.8,13 IgAN is characterized best by the “multi-hit hypothesis,” which outlines 4 specific factors that, when combined, create the pathophysiologic environment for kidney injury (Figure 114).4,15 These factors include (1) an increased circulating level of galactose-deficient immunoglobulin A1 (Gd-IgA1); (2) presence of antiglycan antibodies targeting Gd-IgA1; (3) circulating immune complexes containing Gd-IgA1; and (4) mesangial deposition of Gd-IgA1-antiglycan IgG immune complexes.4,8,15
IgA is the second most predominant of the 5 immunoglobulins and has the greatest production rate. IgA has 2 subtypes, IgA1 and IgA2, with IgA1 constituting 80% of the total. While both have different roles, IgA1 has an important role in maintaining mucosal homeostasis in multiple tissues, which includes the respiratory and gastrointestinal systems. This is accomplished by responding to abnormalities to the common antigens presented to the mucosal tissue and thus protects the body from foreign substances such as bacteria and viruses.8
The pathogenesis of IgAN begins with the synthesis of a poorly galactosylated form of human IgA1, resulting in an imbalanced increase in circulating Gd-IgA1.4,12 The next step in the disease process is the stimulation of an immune-mediated event such as a viral or bacterial infection that results in the production of antibodies directed to the Gd-IgA1. The recruitment of IgG to the abnormal IgA results in the formation of an immune complex that deposits in the kidneys, triggering an inflammatory response.4 These complexes activate the production of extracellular matrix and the release of proinflammatory cytokines and chemokines, which ultimately result in kidney damage.16,17 The activation of a complement system in the glomeruli amplifies the inflammatory cascade and potentiates progressive tissue injury.15,17 Clinically, the glomerular injury leads to the presence of hematuria and proteinuria in the urine.4 Over time, the damage may cause scarring of the nephrons with eventual progression to ESRD and the need for dialysis or kidney transplant.8 The site of immune complex formation is still unclear; however, evidence suggests the importance of circulating factors. The support for circulating factors comes from the isolation of circulating immune complexes identical to glomerular immune deposits, the recurrence of IgAN in some patients after kidney transplant and the observation that donor kidneys containing IgA deposits transplanted into patients with ESRD from other causes results in the deposits disappearing within weeks.4
Direct and indirect immune-mediated kidney disease
Elevated levels of circulating Gd-IgA1 alone are not sufficient to cause IgAN. Healthy relatives of patients with IgAN also exhibit high levels of circulating Gd-IgA1 levels compared with unrelated controls. Therefore, this necessitates that other events are required to stimulate an immune-mediated response that would convert the presence of Gd-IgA1 into a clinical nephritis and that a strong genetic correlation exists in the overproduction of Gd-IgA1 among patients with IgAN. The activation of an immune-mediated production of antibodies against the Gd-IgA requires an instigating event, the cause of which has been the subject of ongoing investigation and debate. One such hypothesis suggests that an immune-mediated response may be elicited by the exposure of certain bacteria or viruses that may express antigenic GalNAc-containing epitopes on their surfaces responsible for exacerbations of hematuria or proteinuria following mucosal infections. Another hypothesis follows from the observation that IgA1 immune complex deposits in the kidney share similarities with normal mucosal IgA1, including the galactose deficiency, which supports the role of a renal-gut connection in the pathogenesis of IgAN.12 Therefore, it has been proposed that after encountering antigens in the mucosa, IgA-expressing plasmablasts may produce Gd-IgA1 in the systemic circulation rather than the intended mucosal target. This immune dysregulation appears to present the antigenic stimulation necessary for the antiglycan antibody production and the eventual immune complex formation characterizing the genesis of the IgAN disease process.4
Risk factors
Risk of developing IgAN is higher in individuals with the following characteristics8:
Genetic factors significantly contribute to the pathogenesis of IgAN. The serum level of Gd-IgA1 is a heritable trait in diverse racial and ethnic groups. As many as 75% of patients with IgAN have serum Gd-IgA1 level above the 90th percentile for healthy controls, while 30% to 40% of first-degree relatives have similarly high levels.13 In most families, IgAN follows autosomal dominant transmission with incomplete penetrance.18
Diagnosis
IgAN can only be diagnosed by kidney biopsy. Histologic evaluation of the kidney tissue reveals the diagnostic hallmark of IgAN as a predominance of IgA immune complex deposits with or without IgG and IgM in the glomerular mesangium.4 Complement component C3 is co-localized with IgA in greater than 90% of biopsies with IgAN.2 Patients in early stages of the IgAN process may seek a consultation with a nephrologist when experiencing persistent and visible hematuria usually during or after an upper respiratory tract infection or gastrointestinal illness.9,13 Tests for proteinuria and hematuria are often the first diagnostic features to indicate presence of an underlying IgAN disease process, in addition to a positive family history and clinical examination. Urine protein-to-creatinine ratio (UPCR) and eGFR may be calculated to evaluate kidney function. However, renal biopsy remains the only definitive method to confirm IgAN diagnosis but its ability to independently predict prognosis is less certain.19 Currently, eGFR and proteinuria are the only prognostic biomarkers for IgAN. The International IgAN Prediction Tool is a valuable resource to quantify risk of progression and incorporates clinical information at the time of biopsy, including eGFR, blood pressure, and proteinuria. However, it cannot be used to determine the impact of a specific treatment regimen.6,19
Disease progression
The progression of symptoms across individuals with IgAN is variable.13 In the early stages of IgAN, there may be no detectable symptoms and may be silent for years or decades. The most common clinical presentation is microhematuria and moderate proteinuria with relatively preserved kidney function. Macroscopic hematuria and proteinuria following an upper respiratory tract infection may be typical of disease presentation among children or adults in the early stage of the disease process.8 While the presence of hematuria is the most common clinical finding in IgAN, the development of sustained proteinuria is predictive of the increasing risk of kidney disease progression. The strongest prognostic risk factor in IgAN is the presence of sustained proteinuria, typically levels greater than 1 gram/day.12 The presence of HTN is associated with a negative prognostic factor and has a robust association with an increased risk of eGFR loss.12,13,19 According to Kidney Disease Improving Global Outcomes (KDIGO) guidelines, the risk of progression toward ESRD of a patient with IgAN is determined by the mean proteinuria during follow-up, eGFR, and blood pressure.6,12,19
The eGFR is directly correlated to disease stage in patients with chronic kidney disease (CKD). An eGFR of greater than 60 mL/min/1.73m2 indicates the presence of kidney disease and less than 30 mL/min is indicative of ESRD.20 At diagnosis, results of 1 study found 53% of participants progressed to ESRD within 20 years and 39% died. The life expectancy was reduced by about 10 years.9Figure 2 demonstrates the correlation between the time of progression to ESRD and death with the at-risk patients for both survival curves identified at 5-year intervals.9
As mentioned previously, elevated serum Gd-IgA1 levels alone are not enough for individuals to develop clinical manifestation of renal disease, and therefore, other factors must be necessary for the expression of the disease.13 It is theorized that respiratory or intestinal infections may trigger the onset of the disease. Clinical observations regarding the onset of disease include a connection between mucosal inflammation of the gastrointestinal or respiratory tract and nephritis. The direct or indirect implication of mucosal immunity in the risk of IgAN has led to the exploration of the gut-kidney axis and its role in IgAN.14 Mucosal tissues excrete IgA into the system every day, more than all other antibodies combined. The gut-associated lymphoid tissue (GALT) secretes 15% of the body’s total IgA production (3-5 grams/day), and a normal gut produces 80% of all immunoglobulin-producing cells in the body. IgA in the mucus layer functions as an immune defense by preventing microbes from binding to the epithelial layer and excretes them. The GALT contains Peyer patches that extend into the submucosal layer; about half of the Peyer patches are found in the distal ileum. The IgA from the Peyer patches is believed to contribute to the serum levels of Gd-IgA1 (Figure 1). This emerging understanding of the gut-kidney axis confirms known secondary causes of IgAN that include gastrointestinal diseases such as celiac disease and inflammatory bowel disease.21
Clinical presentation
The clinical course of IgAN is highly variable, ranging from asymptomatic non-progressive disease to highly aggressive disease.13 In its most benign presentation, IgAN can be asymptomatic and resolve spontaneously.8 In the clinical setting, the most common clinical presentation is microhematuria and moderate proteinuria with a relatively well-preserved kidney function and is usually preceded by an infection.12 Rarely patients may present with nephrotic range proteinuria leading to edema in the legs, feet, and ankles and foamy urine.8 Over a period of 10 to 20 years with IgAN, as many as 40% of patients will present with signs and symptoms consistent with ESRD, including HTN, edema, fatigue, reduced urine output, weight loss, sleep disturbance, failure to concentrate, dark skin, and muscle cramps. Complications associated with advanced disease include HTN, chronic or acute renal disease, cardiovascular disease (CVD), nephrotic syndrome, and Henoch-Schönlein purpura.8 Generally, rapid progression is rare.22 CKD may be evident if UACR is greater than 30 mg/gram and/or eGFR is less than 60 mL/min/1.73m2.8
Treatment
Treatment goals and prognosis
IgAN carries a significant mortality risk and is highly correlated to the development of ESRD.2 Early diagnosis facilitated by access to health care and treatment of IgAN may delay progression of disease and extend the lifespan of individuals diagnosed with IgAN.9 As IgAN is a rare disease, data are limited to specifically evaluate the question of health-related quality of life (HRQOL). However, in 1 systematic review, 11 studies were identified to evaluate the burden of illness.3 Those data revealed that patients with IgAN have a significant symptom burden in early kidney disease before the initiation of dialysis. The United States had the largest proportion of patients in later stages of CKD. Finally, the conversion of patients from earlier stages of kidney disease to ESRD leads to a further decline in HRQOL. Therefore, the goal of treatment in IgAN is to prevent or delay progression of disease to ESRD and preserve kidney function. This is accomplished by the application of therapeutic interventions that control HTN, remove extra fluid volume in the body, reduce inflammation, and lower serum cholesterol.8,19
Patients who progress to ESRD may receive renal replacement therapy in the form of dialysis treatment or kidney transplant. One study found that of 132 patients with ESRD, 53 received dialysis and 79 received 1 or more kidney transplants. Time to survival for dialysis patients averaged 5.5 years, while the 50% transplant survival interval for first renal transplant was 10.5 years.9 Patients of all glomerulonephritis subtypes are at risk of recurrence post-transplant with the prevalence of recurrence estimated between 3% and 15%.3 IgAN is one of the most common recurrent reasons for glomerulonephritis after renal transplant with recurrence occurring late with a cumulative incidence of 15% at 15 years posttransplant. Up to 40% of these patients may lose their transplanted kidney with IgAN as the primary reason in 60% of those patients. The recurrence occurs mostly in younger patients or in those exhibiting rapid progression of the original disease.23
Supportive care is the mainstay of treatment for IgAN. As nonspecific modifiers such as uncontrolled HTN and proteinuria potently impact the disease course, it is critical that supportive care targeting either of these processes should first be initialized and optimized in all patients with IgAN at risk for progressive disease.19
Supportive Care
The KDIGO clinical practice committee issued recommendations for the treatment of IgAN and other glomerular kidney diseases.19 The initial management of IgAN includes initiation of optimized supportive care measures to control blood pressure and reduce proteinuria and CV risk.19,22 It is well-described that blood pressure increases at very early stages in patients with IgAN with significant activation of the renin-angiotensin-aldosterone system (RAAS) in the kidneys of these patients.22 Recent recommendations from KDIGO suggest target systolic blood pressure less than 120 mm Hg in most patients. Therefore, the primary objective of therapeutic management of IgAN involves initiating either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for all patients with a proteinuria above 0.5 gram/day regardless of the presence of HTN.19 Doses of ACE inhibitors or ARBs should be optimized by titrating to the maximal tolerated dose with caution in those who are normotensive.
Sodium restriction to less than 2 grams per day is a critical dietary modification for successful strategies for management of HTN. Additional dietary modifications such as diets low in saturated fat and cholesterol and moderate protein intake may contribute to preserving kidney function and delaying disease progression (Table 18,19,22). A series of smaller clinical trials have suggested that omega-3 fatty acid supplementation may play a role in lowering blood pressure and reducing inflammation, thereby slowing kidney damage.8,24
As previously mentioned, research suggests a relationship between the gut-mucosal immune system and the role of gluten and probiotics in patients with IgAN. Case reports of celiac disease and IgAN link gluten as the potential cause for the underlying inflammatory process. In celiac disease, gluten ingestion elicits an immune-mediated response leading to zonulin overexpression, causing a cascade of inflammatory events leading to increased intestinal permeability. The increasing gut permeability can cause molecules such as gliadin and mucosal IgA to cross the gut barrier, causing the body to mount an immune response to these substances. A pilot study, evaluating the effects of a gluten-free diet on patients with IgAN with no sign of celiac disease, found a reduction in proteinuria and hematuria with no concomitant decline in kidney function in patients over a period of 4 years. The use of probiotics has also been useful in modulating the intestinal microbiota and as a result has demonstrated anti-inflammatory and anti-oxidative effects. It has also been efficient in preventing enteric infections and inflammatory and malignant diseases. In the context of kidney health, the consumption of probiotics could improve the barrier function, leading to a reduction in inflammatory markers.14
Immunosuppressive Therapy
The KDIGO guidelines outline a strategy for patients who have persistent proteinuria despite optimized supportive care for a minimum of 3 months (Figure 322). The algorithm focuses on the assessment of proteinuria as a key treatment target in determining patient prognosis, progression of kidney damage, and in guiding treatment decisions in patients with IgAN. Other than proteinuria and eGFR, no other validated prognostic biomarkers for IgAN exist.19 For those with eGFRs greater than or equal to 30 mL/min/1.73/m2 and an evaluation of toxicity risk, corticosteroids may be initiated to decrease the inflammatory response responsible for the IgAN disease process.19 Immunosuppressive drugs should be considered only in patients who remain at high risk of CKD progression as defined by persistent elevated proteinuria (>0.75 – 1 gram/day) despite at least 90 days of optimal treatment that includes achievement of maximally tolerated RAAS inhibition with either ACE inhibitors or ARBs.19
Corticosteroids
High-dose corticosteroids are controversial and generally only prescribed for a few months in select patients. Recent studies have documented evidence to show benefits with either oral or intravenous corticosteroids.25,26 The TESTING study compared oral methylprednisolone to placebo with the initial study protocol halted due to deaths in the methylprednisolone group.25 The protocol was adjusted with a lower targeted dose and the study continued. The results demonstrated that treatment with methylprednisolone caused a 46% reduction in the composite primary end point (40% decline in eGFR, kidney failure, or death due to kidney disease). However, the methylprednisolone group had an increased risk of serious adverse effects compared with placebo (10.9% vs 2.8%).25 Another study compared a pulse intravenous methylprednisolone regimen combined with alternate-day oral steroids to full-dose, daily oral methylprednisolone.26 Both groups showed reductions in proteinuria; however, the incidence of adverse effects was higher in the full-dose, oral methylprednisolone group.26 While corticosteroids may offer some clinical benefit, the intervention is associated with significant adverse effects leading to increased morbidity and mortality and increased health care costs.25-29
Based on KDIGO guidelines, patients at high risk for progression despite optimal supportive care may be considered for a 6-month course of corticosteroid therapy after a discussion regarding risks versus benefits with the patient, particularly those with an eGFR less than 50 mL/min/1.73m2. However, the 2021 KDIGO guidelines also state: “Clinical benefit of corticosteroids in IgAN is not established and should be given with extreme caution or avoided entirely in the situations.” The situations refer to comorbidities such as eGFR less than 30 mL/min/1.73m2, diabetes mellitus (DM), obesity, and others.19
Non-corticosteroid Immunosuppressants
The use of non-corticosteroid immunosuppressants in IgAN has shown a lack of benefit and their use is generally not supported.19 However, there is some limited evidence for the use of non-glucocorticoid immunosuppressants in combination with glucocorticoids for more severe cases of IgAN.19 As IgAN has been acknowledged as an autoimmune-mediated disease, some treatment approaches have targeted B-cell depletion as a therapeutic approach.22 An open-label study evaluating use of rituximab in combination with the standard of care that included an RAAS inhibitor (RAASi) found no significant improvement in kidney function or proteinuria levels compared with the standard of care over 1 year.30 Mycophenolate mofetil (MMF), a B-cell lymphocytic, has been studied in various trials, producing conflicting results.22 Three studies conducted in Chinese patients with IgAN and proteinuria have shown beneficial effects. In an initial trial conducted in Beijing, 62 patients with severe IgAN and proteinuria greater than 2 grams/day received MMF and study results demonstrated improvements in proteinuria and serum lipid levels. Another study based in Hong Kong conducted in 40 patients with IgAN and persistent proteinuria of greater than 1 gram/day despite RAASi found that 6 months of treatment with MMF resulted in significant reduction in proteinuria and improved kidney survival at 6-year follow-up compared with RAASi alone. Results of a multicenter randomized controlled trial conducted in China found 6 months of MMF plus low-dose corticosteroids noninferior to standard-dose corticosteroids among the 174 patients with IgAN presenting with proliferative lesions and proteinuria greater than 1 gram/day. Steroid-related adverse effects were found to be lower in the MMF combination treatment group.22 The trials among non-Chinese patients demonstrated no clear benefit of MMF.19,22 Therefore, KDIGO guidelines support use of MMF as a steroid-sparing agent only in Chinese patients in whom corticosteroids would be considered.19
Based on KDIGO guidelines, treatment with azathioprine is not recommended as evidence of efficacy as monotherapy or in combination with glucocorticoids is lacking. In both children and adults, cyclophosphamide is also not recommended but may be considered in combination with glucocorticoids for rapidly progressive IgAN per the KDIGO guidelines.19
Hydroxychloroquine, an antimalarial agent, has been widely used in patients with immune-mediated disorders such as rheumatoid arthritis and systemic lupus erythematosus. The beneficial effects of hydroxychloroquine may relate to inhibition of Toll-like receptor (TLR)-9, which has shown to be upregulated in the pathogenesis of experimental IgAN-like mice models. Nevertheless, a small, short-term randomized controlled trial in Chinese patients demonstrated reduction in proteinuria in patients with proteinuria of 0.75 to 3.5 grams/day despite optimized RAASi.22 KDIGO guidelines support use of hydroxychloroquine for Chinese patients at high risk of progression despite optimized supportive care.19
Targeted Pharmacologic Treatments
Delayed-release budesonide
Delayed-release budesonide (Tarpeyo) oral capsules, the first FDA-approved treatment for IgAN, are designed to deliver corticosteroid treatment directly to mucosal B cells in the ileum, to downregulate production of the Gd-IgA1 antibodies responsible for the IgAN disease process.7 Delayed-release budesonide’s approval and related indication has been approved under the FDA’s accelerated approval pathway for rare diseases, which was based on achieving its primary end point of reduction in proteinuria in part A of the NeflgArd pivotal phase 3 trial (NCT03643965). The NefIgArd trial was a randomized, double-blind, multicenter study in patients with biopsy-proven IgAN, eGFR greater than or equal to 35 mL/min/1.73m2, and proteinuria (defined as either ≥1 gram/day or UPCR ≥0.8 gram/gram) who were on a stable dose of maximally tolerated RAASi therapy.31 Patients were randomized in a 1:1 fashion to receive either delayed-release budesonide 16 mg once daily or placebo and treated for 9 months followed by a 2-week taper of either delayed-release budesonide 8 mg once daily or placebo. The primary end point in part A was the percentage reduction in UPCR at 24 hours over 9 months compared with baseline, while the primary end point in part B is the eGFR at 2 years.7,21 It has not yet been established if delayed-release budesonide slows the progressive decline of kidney function since part B results have not been published yet. This delayed-release formulation is indicated to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a UPCR greater than or equal to 1.5 grams/gram.7,32
The results of Part A of the NefIgArd trial demonstrated that patients on optimized RAASi who received delayed-release budesonide (n = 97) showed a statistically significant, 27% reduction in UPCR at 9 months compared with placebo (n = 102). Baseline reductions of proteinuria were 34% versus 5% with delayed-release budesonide and placebo, respectively. Subgroup analysis suggested that the most benefit was achieved in those who were on maximally tolerated RAASi but did not achieve maximum allowed dose of RAASi. Patients in the delayed-release budesonide group also had a significantly slower decline in eGFR. This benefit was greater in patients with a UPCR higher than or equal to 1.5 grams/gram at baseline. See Table 2 for additional primary and secondary results at 9 and 12 months.31 The most common adverse effects experienced (≥5%) in this study were HTN, peripheral edema, muscle spasms, acne, dermatitis, weight gain, dyspnea, facial edema, dyspepsia, fatigue, and hirsutism.7,31 These data are encouraging but reflect short-term results and will require longer-term studies to determine durability of response and safety.
Selective Dual Endothelin Angiotensin Receptor Antagonist
On February 17, 2023, sparsentan (Filspari), was granted accelerated approval to reduce proteinuria in adults with IgAN at risk of rapid disease progression (UPCR ≥1.5 grams/gram).33,34 Sparsentan is a once-daily oral dual endothelin angiotensin receptor antagonist that is the first non-immunosuppressive agent to be approved for IgAN.33 Preclinical data have demonstrated that blockade of both endothelin type A and angiotensin II type 1 pathways reduces proteinuria and prevents glomerulonephritis and mesangial cell proliferation in forms of rare CKD. This approval was based on the PROTECT study, in which a total of 404 adult patients with persistent proteinuria despite ACE inhibitor or ARB treatment were randomized 1:1 to receive once-daily oral doses of either sparsentan or irbesartan. Topline interim results from the ongoing PROTECT trial show that proteinuria was reduced by 49.8% from baseline in those receiving sparsentan compared with 15.1% in those receiving irbesartan after 36 weeks (P <.0001). Results from the confirmatory end point analysis of sparsentan’s effect on eGFR slope after 110 weeks is expected in the 4th quarter of 2023.33 Patients completing the open-label extension period of the PROTECT study may be able to enroll in a randomized, controlled, open-label substudy evaluating sparsentan used in combination with dapagliflozin.35 Sparsentan is also being studied for the treatment of focal segmental glomerulosclerosis in the United States and Europe.33
The most common adverse effects (≥5%) in the PROTECT study were peripheral edema, hypotension, dizziness, hyperkalemia, and anemia.33,34 Sparsentan does carry a Blackbox warning for hepatotoxicity and embryo-fetal toxicity, so is only available through a Risk Evaluation and Mitigation Strategy.34 Monitoring of liver aminotransferases and bilirubin prior to initiation and of aspartate transaminase and alanine aminotransferase monthly for the first year and then every 3 months is recommended. Animal data demonstrated birth defects, so pregnancy testing and effective contraception for patients who could become pregnant is required prior, during, and for 1 month after therapy. Sparsentan is contraindicated to be used concurrently with ARBs, endothelin receptor antagonists, or aliskiren.34
Emerging Targeted Pharmacologic Treatments
The limitations of currently available treatments and emphasis on supportive care highlight an unmet need for safer and more effective pharmacologic therapy for IgAN. Fortunately, there are several promising therapies (Table 32,36-41) being studied that target novel pathways in IgAN. Most of the studies of investigational agents include patients with optimized supportive care after several weeks to months, yet still need treatment to manage IgAN symptoms and prevent kidney function decline. Two agents, dapagliflozin and empagliflozin, have large randomized controlled trial study results available and are discussed in more detail below.
SGLT2 inhibitors
With clinical data demonstrating the reduction of CKD progression, the sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a promising emerging treatment approach in patients with high-risk IgAN.22 SGLT2 inhibitors have been FDA approved to reduce the risk of kidney disease in patients with DM or at risk of CVD.42,43 While these agents have not yet been approved for the treatment of IgAN, SGLT2 inhibitors have demonstrated improvements in kidney outcomes in patients without DM. 42,43
In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin, an SGLT2 inhibitor, reduced the risk of kidney failure and prolonged survival in 4304 participants with CKD with and without type 2 DM.42 Patients with eGFR 25-75 mL/min/1.73m2 and UACR 200-5000 mg/gram (22.6-565 mg/mol) were randomized to dapagliflozin 10 mg or placebo, as an adjunct to standard of care. The primary outcome was a sustained decline in eGFR of 50% or more, ESRD, or death from CV or kidney causes. The DAPA-CKD trial included 270 participants with IgAN, 137 of whom were randomized to receive dapagliflozin and 133 to placebo and followed for a median of 2.1 years. The primary outcome occurred in 6 (4%) of the participants on dapagliflozin and in 20 (15%) in the placebo arm (HR, 0.29; CI 95%, 0.12-0.73) Mean rates of eGFR decline with dapagliflozin and placebo were –3.5 and –4.7 mL/min/1.73m2/year, respectively. Dapagliflozin reduced the UACR by 26% relative to placebo. In the prespecified analysis of patients with IgAN, dapagliflozin was associated with fewer serious adverse effects compared with placebo, and no new safety findings in this population. Study results found that use of dapagliflozin was associated with a significant reduction in the frequency of the primary outcome; and in the IgAN cohort, dapagliflozin use resulted in a slowing of the rate of kidney decline and a reduction in albuminuria.42
Additional insight into the role of SGLT2 inhibitors in the treatment of IgAN will be provided by the ongoing EMPA-KIDNEY trial (Study of Heart and Kidney Protection with Empagliflozin) designed to assess the effects of treatment with empagliflozin (10 mg once daily) in a broad range of patients with underlying CKD, including 817 (12%) with IgAN at baseline.22,43 The trial was designed to evaluate the effect of empagliflozin on patients without DM but with an eGFR 20-45 mL/min/1.73m2 regardless of the level of albuminuria or an eGFR 45-90 mL/min/1.73m2 with UACR ratio of at least 200 at screening. Patients were optimally treated with an RAASi if deemed clinically appropriate. Empagliflozin led to a 28% reduction in the risk of progression of kidney disease or death from CV compared with placebo, with no major safety concerns in this population of patients (wide range of kidney function, levels of albuminuria, and causes of CKD).43 Future publications will allow for a deeper understanding of the intervention in those patients with IgAN.
A recent meta-analysis of SGLT2 inhibitor trials found that the use of SGLT2 inhibitors, in addition to the established CV benefits, demonstrated benefits in modifying the risk of kidney disease progression and acute kidney injury in patients with CKD or heart failure irrespective of DM status, primary kidney disease (including IgAN), or kidney function.44 Two of the studies, previously mentioned (DAPA-CKD, EMPA-Kidney) identified a subset of the population with IgAN. The combined dataset demonstrates a consistent finding, slowing the progression of kidney disease. Additional sub-analysis and follow-up of these studies will need to be conducted to determine the duration of the effect of empagliflozin reducing proteinuria and minimizing the progression of kidney decline in patients with IgAN.43
Managed Care
Treatment Costs of IgAN
While economic evidence in IgAN remains sparse, management of ESRD is a major cost driver to the US health care system, underscoring the need for treatments that slow the progression of kidney disease and maintain HRQOL.45 An estimated 15% of the US population is afflicted with CKD, accounting for approximately 37 million Americans, and an ESRD prevalence among the highest in the world at 2242 cases per million population in 2018.46 The risk of CKD is even greater in adults with comorbidities such as DM, CVD, heart failure (HF), and HTN.47 CKD is associated with a significant economic burden with health care costs that increase substantially with each CKD stage progression.45,48 Most recent data from the CDC estimated 2019 Medicare costs for CKD exceeded $87 billion and were more than $37 billion to treat ESRD.49 The average annual Medicare expenditures for patients undergoing dialysis is estimated to be $85,000 for outpatient-based, in-center hemodialysis compared with $69,000 for in-home–based peritoneal dialysis.45 Studies evaluating the economic burden of IgAN are limited but data from a study in British Columbia, Canada, demonstrated consistent use of prednisone over a 13-year period.50 Chronic exposure to systemic corticosteroids is associated with increased health care utilization and costs, regardless of dose.51 A study of microsimulation model of health care costs and utilization provides some insight on how to apply cost-effectiveness analysis in CKD.52 This model used IgAN as a reference disease state and demonstrated that costs increased as CKD progressed. Thus, considering new strategies is warranted to reduce systemic exposure from corticosteroids and slow the progression of kidney disease in IgAN.
The natural history of IgAN leads to ESRD in up to 14% to 40% of patients over 20 years.53,54 A retrospective analysis of health care usage patterns and cost in patients with CKD found that of the 146,132 patients identified by serum creatinine, a total of 14.5% (n = 21,252) had CKD.47 Of those, approximately half had CKD without CVD, DM, or HF. Among patients with CKD, the stages of disease progression as measured by eGFR categories differed based on comorbidity burden. Mean annual total health care costs were 31% higher among patients with CKD only ($7334; 95% CI, $6746 to $8003) compared with those without CKD ($5631; 95% CI, $5497 to $5768). In the presence of DM, CVD, or HF, health care costs of all types were substantially greater. Inpatient costs were higher for patients with CKD and substantially higher among those with comorbidities such as DM, CVD, or HF with inpatient costs accounting from 44% (CKD and DM) to 55% (CKD and HF) of total costs. Most of the direct health care costs for CKD were associated with dialysis. Inpatient admissions were the largest contributor to cost even in the early stages of CKD, ranging from 35% to 56% in the eGFR category representing mild to moderate decline. Health care costs associated with inpatient admission continued to rise with worsening kidney function, reaching 40% to 65% of total costs when dialysis treatment became more prevalent. This study demonstrates that patients with CKD and comorbidities contribute to higher economic costs to manage disease progression. The therapeutic management of patients with CKD regardless of comorbidities should focus on slowing the progression of kidney disease. In conclusion, total costs of care increase as kidney function declines and early detection and treatment may improve patient outcomes and reduce health care utilization and expenditure.47 The most compelling data to support this come from a study that demonstrated that effective control of proteinuria and HTN reduced the risk for death or dialysis in patients with IgAN.11
A retrospective cohort study of 52,599 adults with CKD and type 2 DM using claims data was conducted to evaluate cost estimates for CKD management and major CKD complications.55 Medical costs associated with CKD management, renal replacement therapies, and major CKD complications (eg, myocardial infarction, stroke, HF, atrial fibrillation, and hyperkalemia), and death were assessed in 4-month cycles. The estimated 4-month CKD management costs ranged from $7725 for stage 1 to 2 disease to $11,879 for stage 5 (without renal replacement therapies), with high additional costs for dialysis and kidney transplantation ($87,538 and $124,271, respectively). The acute event costs were $31,063 for HF, $21,087 for stroke, and $21,016 for myocardial infarction in the first 4 months after the incident event, which all decreased substantially in subsequent 4-month cycles. The acute event costs of atrial fibrillation and hyperkalemia were $30,500 and $31,212 with hospitalization, and $5162 and $1782 without. The costs associated with CV-related death, renal-related death, and death from other causes were $17,031, $12,605, and $9000.55 The results of this study support findings from previously conducted retrospective studies evaluating the economic impact of progressive kidney disease and the corresponding rise in health care resource utilization in the United States.48 These studies further demonstrate the need for early detection and treatment to minimize progression of CKD to reduce health care costs incurred by this patient population.55 This assertion is supported by recent data that estimated a 33% cost reduction over 3 years when patients with CKD were treated with an SGLT2 inhibitor compared with standard treatment alone.56 This benefit was realized as a result of reduced CKD progression and incidence of cardiorenal events.
Managed Care’s Role in Steering Course of Early, Effective Treatment
Early-stage CKD is usually asymptomatic and may go undiagnosed until the disease is in the more advanced stages.57 Under-recognition of the prevalence of CKD among patients in the earlier stages of the disease and the complexities associated with comorbidities may lead to an underestimation of the total costs associated with CKD. Retrospective economic analysis demonstrates health care costs begin to accrue in the earlier stages of CKD.45 Care management programs that promote the early detection and treatment of the underlying kidney disease process would not only contribute to a reduction in health care expenditure for renal replacement therapies but would also yield improvements in morbidity and mortality by slowing disease progression.57 Kidney biopsy remains the gold standard for diagnosis of IgAN, yet the earliest clinical sign remains hematuria. Urinalysis is an effective screening tool for detection of urinary markers that suggest glomerular injury and in fact is used as part of the National Kidney Foundation Kidney Early Evaluation Program (NKF KEEP).58 This has been recently supported by investigators in Japan who demonstrated cost savings for mass screening of the population using dipstick urinalysis for hematuria.59 Early access to effective antihypertensives can prevent or delay the onset of higher-cost treatments, such as dialysis and kidney transplantation.60 Community-based screening programs implemented as part of a population health-based intervention through health plan providers may be instrumental in identifying high-risk patients to allow for early medical interventions designed to slow the progression of CKD.57,61 Finally, there are evaluations of novel biomarkers such as Gd-IgA1, Gd-IgA1 antibodies, and Gd-IgA1 immune complexes that may provide additional clinical tools to screen patients for IgAN.62 The cost-effectiveness of these biomarkers was recently assessed, which showed a reduction in overall medical expenses.54
CareFirst Blue Cross Blue Shield of Maryland (CareFirst) as part of a pilot patient-centered medical home program implemented a quality improvement program from July 1, 2015, to June 30, 2017, to identify patients at high risk for CKD and enroll them in a care plan according to risk stratification.61 While not specific for IgAN, the CKD program enlisted a multidisciplinary clinical team to identify members with conditions that place them at risk of CKD to screen, stage, and monitor for care coordination and kidney-related services. These services included kidney testing, patient education on lifestyle modifications, disease awareness, nephrologist referral, and initiation of medical interventions as appropriate. A total of 7420 individuals were enrolled in the study and while there was no significant change in eGFR testing, a small increase in UACR testing occurred (31.3%-33.0%; P = .0020) More significantly, the study authors concluded a reduction in hospital admission and 30-day readmissions per 1000 patients for patients in the CKD class 3 (moderate), CKD class 4 (moderate-severe), and CKD class 5 (severe) risk stratification stages (Table 461). These same categories of patients exhibited a cost savings in medical per member per month of $276.80 for CKD class 3 and $480.79 for CKD class 5. The authors conclude that long-term changes in the rates of patients receiving dialysis may take time to present in a population, but improvements in hospitalization and readmission rates demonstrate the short-term benefits for both the patient and the payer. CKD class 3 and 5 exhibited a per-member, per-month cost savings in the first year of the program. This prospective screening program demonstrates the benefit of implementing community-based care management programs to improve patient care and outcomes and reduce health care costs.61
In addition to considering screening and early detection interventions, medication management and provider and patient education can help mitigate risks of medication-related disease and improve chronic disease management. Medication management is a critical need because polypharmacy is often a concern for patients with CKD and patients receiving renal replacement therapy. It is not unusual for patients to take 10-12 medications, resulting in an average pill burden of 19 pills per day, to manage their kidney disease and other comorbidities.60 The complex medication regimens place patients on dialysis at risk for medication-related problems and drug interactions. Improving medication management in this vulnerable population may reduce the risk for medication-related hospitalizations and adverse drug reactions and improve overall patient outcomes. A medication management approach as part of a broader care management program may also be effective in reducing avoidable health care costs and improve the overall quality of care among patients with CKD.60 Provider and patient education built on evidence-based best practices and recommended guidelines are the foundation of disease management programs and clinical care programs. As IgAN has a variable course, the disease-state management program consists of regular follow-up to assess blood pressure and conduct a urinalysis for hematuria and proteinuria. Patients should be educated to regularly monitor their blood pressure as it remains a critical factor to reduce the progression of kidney disease. Since supportive care includes RAASi, patients should be counseled on sick day protocols, and pregnancy planning for women of childbearing age. Disease management programs support optimal patient care and outcomes, and they can be promoted in a population health setting. Patient education should include information on diet, physical activity, body weight reduction, smoking cessation, analgesic use, and dietary modifications.22 Provider education can include supportive care guidelines, including information on optimizing pharmacotherapy with recommended dosing guidelines.
HRQOL and Impact on IgAN
The symptom burden for patients with IgAN is considerable, with pain and fatigue reported most frequently.3 Evidence of the impact of IgAN on HRQOL has been limited. In 1 systematic literature review of IgAN, 8 studies reporting HRQOL were evaluated and results showed that proteinuria was associated with poorer HRQOL and depression, and patients with glomerulonephritis reported worse mental health compared with healthy controls or patients undergoing hemodialysis.3 The physical and mental health effects documented in patients undergoing dialysis in CKD can also provide some insight into QOL for those with IgAN. The Cure Glomerulonephropathy Network (CureGN) study is utilizing patient-reported outcomes to assess HRQOL in adult and pediatric patients with 4 primary glomerular diseases, including IgAN.63 Across demographics and age groups, presence of edema has been associated with worse HRQOL. Despite the role of disease duration, use of immunosuppressants, and biological markers such as eGFR or proteinuria in determining disease severity, none of these measures was significantly associated with worsening HRQOL in the study. The CureGN study emphasizes the importance of patient-reported outcomes in the evaluation and management of patients as well as identifies edema as a potential HRQOL measure for clinical trials of new therapies.63
Access to novel therapies for IgAN
Timely addition of newly approved treatments to national treatment guidelines supported by a well-designed pharmacy benefit structure and formulary coverage can support patient access to immediate treatment. Early detection and treatment have been shown to slow the progression of kidney disease and delay the need for renal replacement therapies.11 However, access to appropriate, effective treatments, especially early access to medications through the FDA’s accelerated approval pathway, requires overcoming barriers such as formulary coverage, step therapy, prior authorization, and financial toxicity related to high out-of-pocket costs or lack of adequate health insurance coverage. As new drug entities become available, health plans conduct complex formulary decisions to determine if the agent will be covered and what, if any, restrictions are imposed. In 1 analysis, there were significant inconsistencies across different health plans on coverage decisions.64 Pharmacy benefit managers (PBMs) complicate the decision-making process because they play an intermediate role between the drug manufacturers and health plans that offer rebates to the PBM that are not always passed through to the health plan or patient.
Published guidelines for the management of IgAN have established management strategies that provide health plans with a well-defined algorithm for decision-making.19 For example, if a patient was not receiving an ACE inhibitor or ARB, coverage of a newer therapy could be denied unless the medication was contraindicated (eg, hypersensitivity, pregnancy) or not tolerated. Plans would also expect to see data to document UPCR to help decide on formulary coverage. As these guidelines are widely available, one would expect that health plans would consistently apply them. However, in the case example of delayed-release budesonide, an independent review of several national payer coverage decisions was initiated. This review revealed that delayed-release budesonide requires the patient to meet specific clinical criteria and these criteria vary across plans.65-68 The IgA Nephropathy Foundation has created a patient community to provide resources for patients and providers.69 These resources include but are not limited to information on the disease, guide for making treatment decisions, dietary advice (cookbook), and a list of active and recruiting clinical trials in which eligible patients may participate.69
Conclusion
IgAN is the most common glomerular disease and an important cause of kidney failure. Because of the critical interaction between an intrinsic antigen, Gd-IgA1, and circulating antibodies, IgAN is considered an autoimmune disease. Current KDIGO treatment guidelines recommend early detection and initiation of supportive care treatment regimens that optimize the use of antihypertensives that block RAAS in favor of corticosteroid treatments to delay the progression to CKD and ESRD. Health care utilization and costs increase proportionally to advancing kidney decline with current total Medicare cost estimates exceeding $124 billion in the United States. Delayed-release budesonide and sparsentan offer targeted treatments for IgAN. Advances in understanding the molecular basis of the pathogenesis may lead to earlier diagnosis, better monitoring of the clinical course or response to treatment, and ultimately, targeted therapy. Emerging targeted therapies being evaluated in clinical trials may provide more therapeutic options to treat IgAN.
Author affiliation: Darren W. Grabe, PharmD, is Associate Professor and Chair in the Department of Pharmacy Practice at the Albany College of Pharmacy and Health Sciences, Albany, NY.
Funding source: This activity is supported by an educational grant from Travere Therapeutics.
Author disclosure: Dr Grabe has no relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.
Address correspondence to: Darren.Grabe@acphs.edu
Medical writing and editorial support provided by: Shetal Desai, PharmD
REFERENCES