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Shimizu, Y.; Tomino, Y.; Suzuki, Y. Therapeutic Options for IgA Nephropathy. Encyclopedia. Available online: https://encyclopedia.pub/entry/54151 (accessed on 24 June 2024).
Shimizu Y, Tomino Y, Suzuki Y. Therapeutic Options for IgA Nephropathy. Encyclopedia. Available at: https://encyclopedia.pub/entry/54151. Accessed June 24, 2024.
Shimizu, Yoshio, Yasuhiko Tomino, Yusuke Suzuki. "Therapeutic Options for IgA Nephropathy" Encyclopedia, https://encyclopedia.pub/entry/54151 (accessed June 24, 2024).
Shimizu, Y., Tomino, Y., & Suzuki, Y. (2024, January 21). Therapeutic Options for IgA Nephropathy. In Encyclopedia. https://encyclopedia.pub/entry/54151
Shimizu, Yoshio, et al. "Therapeutic Options for IgA Nephropathy." Encyclopedia. Web. 21 January, 2024.
Therapeutic Options for IgA Nephropathy
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In 1968, Jean Berger first introduced the medical world to IgA nephropathy (IgAN). Fifty-five years later, its pathogenesis is still unclear, but treatments such as renin–angiotensin–aldosterone system inhibitors (RAAS-Is), tonsillectomies, and glucocorticoids are currently used worldwide. There have been great strides in the past 20 years since the discoveries of the specific dysregulation of mucosal immunity, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1 immune complexes in patients with IgAN. According to these findings, a multi-hit hypothesis was developed, and this multi-hit hypothesis has provided several putative therapeutic targets.

IgA nephropathy RASS-Is tonsillectomy glucocorticoid

1. Introduction

IgAN, a prevalent form of primary glomerulonephritis (GN), is distinguished by the accumulation of IgA antibodies within the glomeruli. Within 10-to-20 years of being diagnosed, approximately 20–40% of patients progress to end-stage renal disease (ESRD) [1][2][3]. The discovery of galactose-deficient IgA1 (Gd-IgA1) in patients led to the proposal of a multi-hit hypothesis for the etiology of IgAN [4][5][6].

2. RAAS-Is

The RAAS is a key player in maintaining blood pressure and volume balance, and its inhibition with ACE inhibitors (ACE-Is) has proven to be an effective treatment strategy in conditions such as hypertension and congestive heart failure. The prevention of angiotensin II formation may also be advantageous in decelerating the progression of renal disease by decreasing glomerular hydrostatic pressure. This presents a hopeful therapeutic avenue for patients with IgAN, potentially enhancing outcomes and decelerating disease progression [7].
Valsartan, an angiotensin receptor blocker (ARB), has been found to significantly reduce proteinuria and slow down renal deterioration in IgAN patients [8], while enalapril, an ACE-I, has demonstrated significant improvements in renal function in proteinuric IgAN [9]. A randomized controlled trial (RCT) that tracked IgAN patients for 5 years to study the long-term renal outcomes of ACE-I/ARB therapy discovered that the treated group had lower serum creatinine, reduced proteinuria, and slower progression to ESRD compared to the control group [10]. One study on the impact of ACE-Is on tubulointerstitial fibrosis (TIF) in IgAN patients observed a slower rate of decline in creatinine clearance in the ACE-I group [11]. A controlled trial examining the response of IgAN patients to ACE-I/ARB therapy based on reduced proteinuria and its effect on the selectivity index suggested that this treatment could be beneficial for IgAN patients with renal impairment and non-selective proteinuria [12].
A combined treatment approach using prednisolone and losartan has been shown to be more effective than using prednisolone alone in decreasing proteinuria and preserving renal function in IgAN patients [13]. The combination of trandolapril and candesartan cilexetil has also been found to be more effective than verapamil in reducing the count of urinary podocytes, which could be an indicator of disease activity in adult IgAN patients [14]. Low-dose losartan significantly diminished proteinuria and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion without affecting systemic blood pressure in normotensive IgAN patients [15]. These results suggest that these medications could have a positive impact on the management of IgAN.

3. Tonsillectomies

IgAN patients frequently exhibit macroscopic hematuria following an acute tonsillar infection, leading to the proposition of a tonsillectomy as a potential treatment for IgAN. In Japan, tonsillectomies are employed in conjunction with steroid pulse therapy, and this combination has demonstrated promising outcomes. One RCT involving IgAN patients with proteinuria and low serum creatinine revealed that those who underwent a tonsillectomy and received glucocorticoid pulse therapy had significantly reduced urinary protein excretion compared to those who were administered only a glucocorticoid pulse [16]. Logistic regression analysis identified tonsillectomy and glucocorticoid pulse therapy to be significant independent factors contributing to the elimination of proteinuria. One patient in the tonsillectomy group (n = 40) and three patients in the no-tonsillectomy group (n = 40) developed diabetes during observation. No other serious complications were observed [16].
A retrospective cohort study conducted in Japan, which included 1065 IgAN patients enrolled between 2002 and 2004, implemented 1: 1 propensity score matching (to mitigate intergroup differences) for patients who underwent a tonsillectomy and those who did not. Among 153 matched pairs, the study revealed a reduced risk of the first instance of a 1.5-fold increase in serum creatinine from baseline or the initiation of dialysis in patients who were treated via a tonsillectomy. These patients also needed fewer additional treatments for one year following renal biopsy without an elevated risk for adverse events, barring temporary complications related to tonsillectomy. These findings imply that tonsillectomy could be a viable option for preventing ESRD in IgAN patients. In the entire study population (n = 1065), 59 patients had complications such as pneumonia and diabetes. No deaths occurred in the tonsillectomy group, but four deaths from malignancy, one death from obstructive lung disease, and one death from aortic dissection were observed in the no tonsillectomy group [17].
Tonsillectomies have mainly been performed in Japan, and they have been shown to be effective. In Europe, the efficacy of tonsillectomies has been questioned by many. A Hungarian study of 246 patients showed a significant prolongation of renal survival in the group of patients who underwent a tonsillectomy compared to the group of patients who did not have a tonsillectomy.

4. SGLT2 Inhibitors

DAPA-CKD trial: The DAPA-CKD trial demonstrated a reduction in the risk of transitioning to ESRD and mortality in patients with CKD, including those with IgAN. The primary endpoint was a persistent decrease in eGFR of ≥50%, ESRD, or death due to kidney disease-related or cardiovascular causes. Among the 270 IgAN subjects, 137 were administered dapagliflozin, and 133 were given a placebo. The primary outcome was observed in 4% of the dapagliflozin group and 15% of the placebo group. Compared to the placebo group, dapagliflozin reduced UACR by 26%. No significant difference was observed between the two groups in terms of medication discontinuation due to adverse drug reactions. These findings suggest that dapagliflozin can safely slow down the progression of CKD in IgAN patients. A total of six complications in the dapagliflozin group (n = 137) forced the discontinuation of the study, while in the sham group (n = 133), seven complications forced the discontinuation of the study (no significant difference). Severe complications, including death, occurred in 22 patients (16.1%) in the dapagliflozin group and 34 (25.6%) in the sham group [18].
The EMPA-KIDNEY trial expanded the range of CKD-causing diseases in which SGLT2 inhibitors could be expected to provide benefit. The primary endpoint of the EMPA-KIDNEY trial was a sustained ≥40% reduction in eGFR from basal values occurring after allocation, the introduction of renal replacement therapy (eGFR < 10 mL/min/1.73 m2), and death from cardiovascular events. Serious AEs included six cases of ketoacidosis in the empagliflozin group (0.09 patient years) and one in the sham group (0.02 patient years), as well as leg amputations in 28 patients (0.43 patient years) in the empagliflozin group and 19 patients (0.29 patient years) in the sham group. The trial was stopped early due to confirmed efficacy, limiting the analysis to all prespecified subgroups [19]. Therefore, compared to the DAPA-CKD study, the effect of dapagliflozin on IgA nephropathy was not clearly demonstrated. However, the number of patients with CKD due to glomerular disease was larger than in the DAPA-CKD study, 1669/25% (DPA-CKD study: 695/16.9%), and a large number of IgA nephropathy patients would be expected to be among these patients, indirectly suggesting an effect on IgA nephropathy patients [20].
A meta-analysis revealed that SGLT2 inhibitors diminish the risk of renal and cardiovascular events in patients with conditions such as heart failure, CKD, type II diabetes, and atherosclerotic cardiovascular risk. When compared to a placebo, SGLT2 inhibitors decreased the risk of advancing to renal disease by 37% in patients with diabetes (relative risk (RR), 0.63; 95% CI, 0.58–0.69), exhibiting a similar risk reduction effect in non-diabetic patients. Furthermore, SGLT2 inhibitors reduced the risk of acute kidney injury by 23% (0.77, 0.70–0.84) and the risk of death or hospitalization due to heart failure by 23% (0.77, 0.74–0.81) [21].

5. Glucocorticoids

Early studies have shown that glucocorticoids have long-term renoprotective effects. One study found that patients treated with intravenous methylprednisolone (mPSL) and oral prednisolone had a significantly lower rate of reaching endpoints of a 1.5- or 2-fold increase in baseline serum creatinine compared to controls. No serious AEs, such as hyperkalemia, were recorded [22]. Another study showed that oral prednisolone was renoprotective compared to controls over an 8-year observation period. No serious AEs were observed in either the combination treatment group or the ramipril monotherapy group [23].
(1) VALIGA study: The VALIGA observational cohort study analyzed data from 1147 IgAN patients from 13 European countries. The effects of various treatments, including immunosuppressive agents, on renal outcomes were assessed in a median follow-up period of 4.7 years. The results showed that immunosuppressive agents were associated with a lower risk of renal function decline (> 50% decrease in eGFR or ESRD) than no treatment or antihypertensive drugs, especially in patients with severe histological lesions or high-risk clinical features [24].
(2) STOP-IgAN trial: The STOP-IgAN trial, a randomized controlled trial (RCT), examined the effects of supportive care (SC) alone (including RAAS-Is) versus SC plus immunosuppression (IS) (corticosteroids or cyclophosphamide/azathioprine) in 162 IgAN patients with persistent proteinuria (>0.75 g/day) despite 6 months of optimized RAAS blockade. The trial did not find a significant difference between the two groups in terms of the primary endpoint of full clinical remission (proteinuria < 0.2 g/day and stable renal function) at 3 years. However, the combination of SC and IS was linked to a higher rate of partial remission (proteinuria < 0.5 g/day and stable renal function) and a slower rate of renal function decline (>15 mL/min/1.73 m2 decrease in eGFR) compared to SC alone. The immunosuppressed group had significantly more cases of infection and weight gain than the supportive care group, and one patient died of sepsis [25]
(3) TESTING and TESTING 2.0 trial: The TESTING trial was carried out on Chinese patients with IgAN who had urinary protein excretion exceeding 1 g/day and eGFR ranging from 20 to 120 mL/min/1.73 m2. The group receiving SC plus IS was administered oral mPSL for a duration of 2 months, and this treatment was gradually tapered off over a period of 6–10 months. The incidence of the primary composite endpoint was significantly lower in the SC plus-IS group compared to the SC-alone group (p = 0.02). The SC plus-IS group also exhibited lower urinary protein excretion at the endpoint (p < 0.01) and more favorable secondary endpoints (p < 0.01, p = 0.01, p = 0.01). However, the occurrence of adverse effects and severe infection was significantly higher in the SC plus-IS group (p < 0.01), leading to a shortened observation period of 2.1 years instead of 3 years [26]. Therefore, this trial found that mPSL treatment had limited benefits. However, mPSL was associated with a greater reduction in proteinuria than SC alone.
The TESTING trial demonstrated the renoprotective effect of the glucocorticoids in IgAN, but this conclusion was considered uncertain due to the shortened observation period and adverse effects of mPSL. Consequently, the TESTING 2.0 trial, with its international, multicenter, and double-blind design, was conducted on patients receiving full-dose (n = 136) and reduced-dose (n = 126) mPSL. The control patients were given a placebo. A total of 503 patients were randomized and treated with mPSL or the placebo for 2 months and weaned for 6–9 months. Over an average of 4.2 years, the composite primary endpoint occurred in 28.8% of the mPSL patients and 43.1% of the placebo patients [HR 0.53 (95% CI 0.39–0.72); p < 0.01]. The effect of full-dose mPSL was an HR of 0.58 (95% CI, 0.41–0.81), and that of reduced-dose mPSL was an HR of 0.27 (95% CI, 0.11–0.65). Nine out of eleven secondary endpoints favored mPSL treatment, including kidney failure (HR, 0.59 (95% CI, 0.11–0.65)). Adverse events were higher in cases treated with mPSL, especially in the full-dose group [27]. Therefore, oral mPSL reduced the risk of kidney function decline, kidney failure, or death due to kidney disease in high-risk IgAN cases but increased the incidence of serious adverse events, mainly with high-dose mPSL.
(4) NEFIGAN and NefIgArd trial: Budesonide (Nefecon®) is an oral glucocorticoid engineered to selectively release in the distal ileum, an area densely populated with Peyer’s patches. The NEFIGAN phase IIb double-blind placebo-controlled trial demonstrated that budesonide use resulted in a 24.4% reduction from baseline in the urinary protein-to-creatinine ratio (UPCR) compared to a placebo. Two out of thirteen serious adverse events were potentially linked to budesonide [28]. In November 2021, the US FDA granted Tarpeyo (budesonide), a targeted-release formulation capsule, accelerated approval to decrease proteinuria in adults with primary IgAN who are at risk of rapid disease progression. As part of the conditions for the accelerated approval, a study on Tarpeyo is currently underway to confirm that the drug slows down kidney function decline in patients with IgAN [29].
The NefIgArd trial was an international, phase 3, randomized, double-blind, placebo-controlled multicenter study that aimed to examine the efficacy and safety of 16 mg of Tarpeyo (budesonide) once daily versus a placebo in adult patients with primary IgAN as an adjunct to optimized RAAS-Is therapy.
After being taken orally and absorbed, budesonide is metabolized at a rate of 90% during its first pass through the liver. This process results in the formation of 6β-hydroxybudesonide and 16α-hydroxyprednisolone. However, these metabolites possess less than 1% of the corticosteroid activity compared to the original compound, budesonide [30]. Given the characteristic pharmacokinetics of budesonide, the following questions require consideration in light of the interim results: (1) Is the intestinal tract the site of pathophysiologically relevant Gd-IgA1 production? (2) Does budesonide change systemic immunity by modifying the intestinal microbiota? (3) Do small amounts of absorbed budesonide have a systemic effect?

References

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