Activity Transcript

Dana Rizk, MD: Hello. My name is Dana Rizk. I am an adult nephrologist at the University of Alabama in Birmingham. I have a research interest in glomerular diseases, and in particular, IgA nephropathy. Welcome to this lecture on understanding IgA nephropathy evolving insights into disease state, pathophysiology as a foundation for novel treatment options.

In today's program, I will discuss advances in understanding the pathophysiology of as a rare immune complex-mediated disease, the role of the mucosal immune system in IgA nephropathy, including the link between the mucosal infections and disease flares, what we refer to as the gut-kidney axis, mechanisms behind localized effects and low systemic bioavailability of novel gut-directed therapies compared with standard corticosteroids, and novel therapies targeting the gut-kidney axis and latest clinical data on their efficacy and safety.

The diagnosis of IgA nephropathy relies on a kidney biopsy. And characteristically, what you would find is the presence of a dominant or co-dominant IgA deposition, primarily in the mesangial area of the glomeruli on the biopsy. This IgA deposit is primarily of the IgA1 subclass. In humans, there are 2 subclasses of immunoglobulin A, IgA1 and IgA2, and the difference between the 2 is this extended hinge region. The presence of less galactose sugar on the hinge region is characteristic of patients with IgA nephropathy, hence referred to as galactose-deficient IgA1.

Primary IgA nephropathy is considered to be an autoimmune disease that affects the kidneys, but may begin at the mucosal surfaces, in particular, the gut. The gut-kidney axis is therefore considered to play a key role in the pathophysiology of the disease. The mucosa in the gut, as you can imagine, is exposed to many antigens from food and bacteria, and the gut-associated lymphoid tissue, or GALT, contains specialized lymphoid tissue, including Peyer's patches, which are concentrated mostly in the distal ileum. These provide mucosal surveillance, and lead to production of mucosal-type immunoglobulin A.

Mucosal immunoglobulin A has a poorly galactosylated hinge region, and is often secreted as a dimer, and mucosal IgA1 is secreted directly into the gut, so typically only small amounts are found in the systemic circulation. Most mucosal IgA1 is produced by B-cells with input from T-cells. In some genetically-predisposed individuals, mishandling of mucosal antigens may lead to activation of naive B-cells in the Peyer's patches. These cells ultimately mis-traffic to the bone marrow, and likely other systemic sites, and aberrantly secrete mucosal-type IgA1 into the systemic circulation, raising the level of galactose-deficient IgA1 in the blood.

This can then subsequently trigger the formation of auto-antibodies, again, in the right susceptible individual, the auto-antibodies can be of the IgA or IgG subtype. We think that the IgG auto-antibody plays a larger pathogenic role. They react to the galactose-deficient IgA-1, leading to the formation of immune complexes in the circulation. These ultimately deposit in the kidney glomerular mesangium, leading to mesangial cell proliferation, increased extracellular matrix synthesis, infiltration of inflammatory cells, fibrosis, and podocyte injury and loss.

This cascade of events ultimately leads to glomerular and tubulo-interstitial injury and fibrosis, resulting in proteinuria and progressive decline in renal function. In fact, up to half of the patients diagnosed with IgA nephropathy can progress to end-stage kidney disease within 20 years of their kidney biopsy diagnosis.

Genome-wide associations in large cohort of patients identified several genetic variants that associate with an increased risk of disease development. Among the high-risk alleles are some that are related to mucosal immunity. Several alleles have been identified, including the CARD9 locus. The risk variant in that particular locus is associated with an increased risk of inflammatory bowel disease, demonstrated in previous genome-wide association studies (GWAS) studies. Other loci of importance are located on chromosome 22, including genes known as LIF and OSM, encoding 2 related cytokines, again, previously implicated in mucosal immunity and inflammation. These studies were also replicated in a large GWAS study, using Chinese cohorts in which 2 additional genome-wide significant loci, encoding again genes related to mucosal immunity were identified.

This really puts in perspective the gut-kidney axis, and this is something we as clinicians have observed for a long time. In fact, when your patients have upper respiratory infections or a gastrointestinal (GI) tract infection, they often present with a surge in inflammatory response and gross hematuria clinically. So IgAN pathophysiology, as best we understand it today, starts with the priming of naive B-cells to class switch to IgA antibody secreting cells in the gut-associated lymphoid tissue upon exposure to again, mucosal bacteria or maybe food pathogens. These mucosally-activated IgA1 committed B-cells are then displaced into the bone marrow, where they secrete high levels of mucosal type IgA- into the systemic circulation. The secretion of mucosal type IgA1 in the systemic compartment is further increased by toll-like receptor ligation. In susceptible individuals, this accumulation of mucosal type IgA1 in systemic sites provide the antigenic stimulus for auto-antibody formation. Both IgG and IgA auto-antibodies react to the poorly galactosylated IgA1 hinge region, forming pathogenic immune complexes. Data suggests that IgG auto-antibodies may play a bigger pathogenic role. These immune complexes deposit in the glomerular mesangium through a combination of mesangial trapping, and increased affinity of mucosal type IgA1 with extracellular matrix components, leading to mucosal type IgA1 induced renal injury.

Patients with IgA nephropathy can progress relatively slowly over many years. However, there's a subgroup of them that are at high risk of progression. Studies have identified pathologic features that increase the risk of disease progression, and clinical features that include an abnormal kidney function at the time of diagnosis, as well as the presence of proteinuria. In these patients, we need to escalate treatment to prevent progression to end-stage kidney disease. Traditionally, patients would be started on a course of systemic [cortico]steroids. However, recent data in the last 10 years put in perspective the risk associated with [cortico]steroid use. The STOP-IgAN trial randomized patients to receive supportive care vs corticosteroids in patients with a preserved estimated glomerular filtration ratio (eGFR) of over 60 mL/min/1.73 m², or corticosteroids with cyclophosphamide and azathioprine in the group with an eGFR between 30 and 59 mL/min/1.73 m².

The STOP-IgAN trial identified several important findings. Number one, the importance of supportive care. In fact, after the run-in period during which the supportive care was optimized, 34% of patients ended up having a proteinuria of less than 0.75 g/d, hence not qualifying for the immunosuppressive treatment. The second important finding is that corticosteroids were associated with a high rate of clinical remission at the expense of more serious adverse events. And proteinuria improved with corticosteroids, however, long-term follow-up showed that this did not translate into kidney function preservation. In fact, after 10 years of follow up, no difference was seen between the supportive care with immunosuppression vs the supportive care alone in IgA nephropathy.

In parallel with the IgAN trial, the TESTING-1 study was a multi-centered double-blind placebo-controlled trial that assigned patients with IgA nephropathy to either supportive care or corticosteroid treatments. Here again, patients went through a 3-month run-in period, during which the renin-angiotensin system (RAS) blockade were optimized. They subsequently were randomized to either corticosteroids or supportive care if their proteinuria remained above 1 g/day, and their eGFR remained between 20 and 120 mL/min/1.73 m². The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. And there were predefined safety outcomes that the investigators were looking for, including severe infections, GI hemorrhage, fracture, and cardiovascular events. The study had to be terminated early, and the Data Safety Monitoring Board held further enrollment until they were able to review the data due to safety concerns. The preliminary data from the TESTING-1 study, however, showed that the steroid group had better decline in urine protein based on a 24-hour urine collection. It also showed preliminary results suggesting that the eGFR was better preserved in the steroid group.

With these encouraging preliminary data, the Data Safety Monitoring Board recommended resumption of enrollment, however, changed the inclusion criteria, and raised the lower limit of the eGFR up to 30 [mL/min/1.73 m²]. They also recommended a lower [cortico]steroid dose up to methylprednisolone dose of 0.4 mg/kg/day, along with antibiotic prophylaxis against pneumocystis pneumonia. This was an event-driven study, and again, the primary outcomes were a 40% decline in eGFR, end-stage kidney disease, or kidney-related death. Other outcomes included change in urine protein to creatinine ratio and eGFR at 6 and 12 months.

Among patients with IgA nephropathy and proteinuria with more than 1 g/day, oral methylprednisolone significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. There was an increased risk of adverse events, including infections, mostly seen in the high dose [cortico]steroids that was used early in the TESTING trial.

Following these 2 landmark studies, the KDIGO guidelines updated the recommendations. Patients with IgA nephropathy at high risk of progression, after maximally supportive care that included the increase in RAS blocker use to maximally tolerated doses or maximally allowable doses, had to be then referred to clinical trials if they remained at high risk of progression. And the use of corticosteroid systemically was moved further down the treatment algorithm.

With a better understanding of the IgA nephropathy pathogenesis, and the FDA guidance to use proteinuria outcome as a surrogate for kidney function decline over time, there has been a significant increase in the interest to test new therapies for IgA nephropathy treatment. We're going to focus today on therapies related to mucosal immunity. In particular, we will go over the targeted-release formulation of budesonide, as well as other immunomodulators, including hydroxychloroquine.

In a phase 2 clinical trial that was double blind randomized placebo control, patients with proteinuria, despite being on optimized RAS blockade, were randomized to receive oral hydroxychloroquine vs placebo for a total treatment period of 6 months. Patients had to have a proteinuria between 0.75 and 3.5 g/day and had to have a relatively preserved eGFR of more than 30 mL/min/1.73 m². Primary outcome was a percentage change in proteinuria from baseline to 6 months. They also looked at secondary outcomes, including the percentage change in proteinuria from baseline to 2 and 4 months, respectively. And the frequency of patients with a 50% decrease in proteinuria, and a percentage change in eGFR.

Sixty participants with a mean eGFR of 53.8 mL/min/1.73 m², and a median urine protein excretion of 1.7 g/day were recruited. The percentage change in proteinuria at 6 months was significantly different between the hydroxychloroquine group and the placebo group, with 48.4% decline in proteinuria in the hydroxychloroquine group vs a 10% increase in the placebo group, with a very significant P value. At 6 months, the median proteinuria level was significantly lower in the hydroxychloroquine group than in the placebo group, on the order of 0.9 gram vs 1.9 gram in the 2 groups, respectively. No serious adverse events were recorded during this study in either group. The short treatment period and the lack of post-withdrawal observations, of course, limit conclusions about the long-term renal protective effect, and the efficacy and safety of the study. An ongoing phase 3 study testing the value of hydroxychloroquine use in IgA nephropathy patients at high risk of progression is currently ongoing.

How about localized [cortico]steroids? Budesonide is a corticosteroid with potent glucocorticoid activity and weak mineralocorticoid activity, that undergoes substantial first pass metabolism, therefore limiting the systemic exposure of patients to [cortico]steroids. Budesonide delayed-release capsule is thought to work on the gut-kidney axis, modulating a key pathogenic step in IgA nephropathy.

So how does it work? The specially designed capsule delivers treatment to the area of the ileum, where the Payer's patches are found in high concentration, and mucosal B-cells are located. Mucosal B-cells express glucocorticoid receptors and produce galactose deficient IgA1 antibodies. Through anti-inflammatory and immunosuppressive effects at the glucocorticoid receptor, budesonide can modulate B-cell numbers and activity.

After promising results from the phase 2 trial, the efficacy and safety of targeted budesonide in patients with primary IgAN was tested in a phase 3 trial design. In this study, patients with biopsy-proven IgA nephropathy within 10 years of enrollment were included if they had an eGFR of 35 mL/min/1.73 m² or higher, and a UPCR of at least 0.8 gram per gram, or a 24-hour urine protein more than 1 g/day. They were subsequently randomized to receive targeted budesonide at 16 mg/day vs placebo for a total of 9 months, followed by a 3-month follow-up period. This constituted part A of the study. Part B, which is still ongoing, is a post-approval confirmatory results, verifying the clinical benefit of targeted budesonide, and confirming the long-term renal protection, using an NKF-FDA-EMA suggested eGFR based endpoint over 2 years.

201 patients with IgA nephropathy were ultimately enrolled in the study and randomized to targeted budesonide vs placebo. The key baseline characteristics included a median UPCR of 1.26 gram per gram, which translated into a median proteinuria of 2.26 gram per 24 hours. 58% of the cohort had at least 2 grams or higher on a 24-hour urine collection, and a median eGFR of 55 mL/min/1.73 m². All patients were on optimized RAS blockade. The results of the part A study were very promising, and in favor of the treatment arm. At 9 months, patients receiving budesonide experience a 27% reduction when compared to the placebo group. The eGFR results presented here are preliminary, and data from the Part B study that would be more conclusive are awaited.

From a safety perspective, 86.6% of patients receiving targeted budesonide reported treatment emergent adverse events compared to 73% in the placebo group. Most of these were mild or moderate. There were no severe infections requiring hospitalization, and importantly, no death reported.

There are limitations to this study. Most of the patients included have been White. And although the disease mechanism and the budesonide efficacy are expected to be similar across different ethnic origins, these positive results will need to be confirmed in a more diverse patient population. Contemporaneous biopsies were not required for entry into the study, preventing the association of histologic features with the indications for, and or response to treatment. Another limitation of the study is that the postulated location of, and mechanism of action of budesonide, which distinguishes it from other formulations of systemic budesonide albeit appealing is still speculative at this time.

Understanding how budesonide, once deployed at the gut-associated lymphoid tissue level, modulates the different components of the pathogenic cascade in IgA nephropathy, may allow the identification of novel biomarkers to better inform the future use of targeted budesonide in clinical practice. Such mechanistic studies are currently ongoing, and we look forward to communicating their results in the near future.

So, in conclusion, IgA nephropathy is a rare progressive autoimmune disease. The mucosal immune system, including the gut-kidney axis play a pivotal role in IgA nephropathy development. The localized effect, and low systemic bioavailability of novel gut-directed treatments are differentiators from systemic immunosuppressive drugs, such as corticosteroids. Targeted-release formulation-budesonide is the first disease modifying therapy conditionally approved for patients with primary IgA nephropathy at risk of end stage kidney disease, showing clinically important improvements in urine protein to creatinine ratios, urine albumin to creatinine ratios, and early encouraging eGFR data, compared with optimized supportive care alone.

I thank you for participating in this activity.

This transcript has not been copyedited.