Nothing Special   »   [go: up one dir, main page]
Previous Article in Journal
‘Optimal’ vs. ‘Suboptimal’ Haemodialysis Start with Central Venous Catheter—A Better Way to Assess a Vascular Access Service?
You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled.
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Kidney and Dialysis
Volume 4
Issue 4
10.3390/kidneydial4040019
kidneydial-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

IgA Nephropathy: What Is New in Treatment Options?

by
Roberto Scarpioni
* and
Teresa Valsania
Unit of Nephrology and Dialysis, Department of Medicine, AUSL Hospital “Guglielmo da Saliceto”, via Taverna 49, 29121 Piacenza, Italy
*
Author to whom correspondence should be addressed.
Kidney Dial. 2024, 4(4), 223-245; https://doi.org/10.3390/kidneydial4040019 (registering DOI)
Submission received: 12 July 2024 / Revised: 19 October 2024 / Accepted: 13 November 2024 / Published: 3 December 2024
Browse Figures
Figure 1
<p>The 4-Hit hypothesis of IGAN.</p> "> Figure 2
<p>Mechanism of action of SGLT2. SGLT2 inhibition affects multiple sites in the nephron. This figure summarizes the effect of SGLT2i on a single nephron. In the diabetic kidney, glomerular hyperfiltration, dependent on increased intraglomerular capillary pressure, is a detrimental process that leads to the loss of the permselective properties of the glomerular barrier to proteins, resulting in albuminuria and ESKF. In T2D patients, because of a high filtered load of glucose, reabsorption of glucose and sodium is increased in the proximal tubule via SGLT2 by up to 50%, resulting in the diminished delivery of sodium to the macula densa. Legend: ATPase = adenosine triphosphatase; GLUT2 = glucose transport 2; ESKF end-stage kidney failure; T2D: type 2 diabetes.</p> "> Figure 3
<p>ALGORITHM for the TREATMENT of IgAN nephropathy. LEGEND: acei: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; SGLT2: Sodium–GLucose coTransporter-2 inhibitor; AT1: angiotensin II receptor; Pozzi-Locatelli [<a href="#B39-kidneydial-04-00019" class="html-bibr">39</a>] or Manno [<a href="#B101-kidneydial-04-00019" class="html-bibr">101</a>] scheme, MASP: mannan-associated lectin-binding serine protease; MMF: Mycophenolate mofetil; C5: complement component C5 (the initiator of the effector terminal phase of the complement system); APRIL: A PRoliferation-Inducing Ligand; MEST-C: Oxford classification* (excluding crescents: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). Higher MEST-C scores, mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents. (* the Oxford Classification has not been validated as a tool for treatment selection).</p> ">
Versions Notes

Abstract

:
IgA nephropathy (IgAN), first described in 1968, is one of the most common forms of glomerulonephritis and can progress to end-stage kidney disease (ESKD) in 25 to 30 percent of patients within 20 to 25 years from the onset. It is histologically characterized by mesangial proliferation with prominent IgA deposition. The prognosis may be difficult to predict, but important risk factors for disease progression of kidney disease have been recognized: usually proteinuria above 0.75–1 g/day with or without hematuria, hypertension, high-risk histologic features (such as crescent formation, immune deposits in the capillary loops, mesangial deposits, glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular disease), and a reduced Glomerular Filtration Rate (GFR). In the absence of reliable specific biomarkers, current standards of care are addressed to decrease proteinuria, as a surrogate endpoint, and control blood pressure. For a long time, corticosteroids have been considered the only cure for proteinuric patients or those at risk of progression to ESKF; however, unfortunately, like other immunosuppressive agents, they are burdened with high collateral risks. Therefore, optimal treatment remains a challenge, even if, to date, clinicians have many more options available. Here, we will review the main therapies proposed, such as the stronghold of RAAS inhibition and the use of SGLT2 inhibitors; it is expected that ongoing clinical trials may find other therapies, apart from corticosteroids, that may help improve treatment, including both immunosuppressive monoclonal antibodies and other strategies. At the current time, there are no disease-specific therapies available for IgAN, because no largescale RCTs have demonstrated a reduction in mortality or in major adverse kidney or cardiovascular events with any therapy.

1. Introduction

IgA nephropathy (IgAN), first described in 1968 by the pathologist Jean Berger [1], is one of the most widespread forms of glomerulonephritis and can progress to end-stage kidney disease (ESKD) in a large number of patients, approximately 25–30 percent of patients within 20–25 years from presentation [2,3], especially when associated with proteinuria. IgAN is histologically characterized by the mesangial proliferation of IgA-containing immune complexes, triggering damage to the glomerular filtration barrier.
The prognosis may be difficult to predict, but some risk factors for progressive kidney disease have been recognized: usually persistent proteinuria above 0.75–1 g/day with or without hematuria, hypertension, high-risk histologic features (such as crescents formation, glomerulosclerosis, tubular atrophy, interstitial fibrosis, immune deposits in the capillary loops, mesangial deposits, and vascular disease), and a reduced Glomerular Filtration Rate (GFR).
IgAN can affect all people of all ages, but it is most common in young people in their second and third decades of life. The pathogenesis of IgAN may be considered as a multi-hit disease model [4,5,6,7] see Figure 1: the initial hit is represented by the increased production of mucosal-derived galactose-deficient (Gd)-IgA1, favored by genetic and/or environmental factors that lead to the formation of anti-glycan Ig antibodies (second hit) which promote the production of IgG-Gd-IgA1 circulating immune complexes (third hit). Then, the consequent deposition of immune complexes in the renal mesangial (fourth hit) causes glomerular injury through inflammation, complement activation through the lectin and alternative pathways, extracellular matrix (ECM) production, mesangial cell dysfunction, and podocyte injury. Glomerular damage is amplified by the upregulation of ET-1 and Ang II caused by the immune cell deposition complex. Kidney biopsies from IgAN patients confirmed this as ET-1 expression was directly correlated with the degree of proteinuria [8].
This pathogenetic picture is considered incomplete by some authors. Nihei et al. [9] recently postulated that bII-spectrin, an intracellular protein exposed on the surface of mesangial cells, acts as an antigen for IgA auto-antibodies, indicating IgAN as an autoimmune disease. The sera of patients with IgAN can show βII-spectrin-reactive IgA auto-Ab at a remarkable frequency, which is not found in other kidney diseases, including focal segmental glomerular sclerosis, diabetic kidney disease, and non-IgA proliferative glomerulonephritis. Children with IgAN are differently characterized, showing an initial increase in eGFR followed by a linear decline [10,11], compared with adults who usually have a linear rate of eGFR decline. In our manuscript, we will only describe adults with IgAN. The current standard of care is addressed to reduce proteinuria, avoid GFR reduction, and closely control blood pressure. Immunosuppressive agents, used in selected patients at high risk of progression, can be associated with significant side effects.
At the current time, there are no specific therapies available for IgAN, because no largescale RCTs have demonstrated a reduction in mortality or in major adverse kidney or cardiovascular events with any therapeutic intervention [12]. More recently, insights into the advancement of knowledge of the pathogenesis of IgAN have suggested novel therapeutic strategies to prevent disease progression to ESKD. Now, these are being tested in clinical trials. Clinical trials have focused on both non-immunosuppressive and immunosuppressive therapies. As it is known, KDIGO 2021 guidelines [13] recommend consideration of corticosteroids in patients with proteinuria >1 g/day, who are considered at high risk of progressive loss of kidney function, after at least 90 days of optimized supportive care. In patients with IgAN, the main goal of therapy is to prevent disease progression to end-stage kidney failure (ESKD) and reduce proteinuria, which is a surrogate endpoint in IgAN trials [11,14].
Moreover, proteinuria is an established biomarker for monitoring the progression of kidney damage, although this biomarker is not specific for IgAN.
Among 207 patients with IgAN, who were compared with another 205 patients with proteinuric kidney diseases and healthy controls [15], a fraction of Gd-IgA1 excreted into urine, originating from the glomerular deposits, was found, hypothesizing a potentially disease-specific marker of IgAN. In addition, the Kidney Health Initiative recommendations [16] indicate a reduction in proteinuria as a surrogate marker to assess a drug’s effect on the progression of kidney failure in IgAN. However, even lower levels of proteinuria (<500 mg/day) are reported to be considered as a target of therapy.
The importance of histology and microhematuria in addressing therapy in IgAN.
When is a patient with IgA at risk of progression to renal failure? When is it necessary to start therapy? What therapy is recommended? The Oxford classification of IgA [17] proposed a pathologic scoring system that suggests histologic variables (MEST-C) to independently predict kidney outcomes, using a reproducible biopsy reporting system able to predict renal disease progression, helping clinicians to identify patients who might benefit from immunosuppression [18]. The five main histological characteristics (MEST-C) were:
  • Mesangial hypercellularity
  • Endocapillary hypercellularity
  • Segmental glomerulosclerosis
  • Tubular atrophy/Interstitial fibrosis
  • Crescents
The lesions comprised mesangial hypercellularity (M0 or M1), segmental glomerulosclerosis (S0 or S1), endocapillary hypercellularity (E0 or E1), and tubular atrophy/interstitial fibrosis (T0, T1, or T2). M1 was defined by the presence of more than three cells in the most cellular mesangial area, but not adjacent to the vascular stalk, on more than 50% of the glomeruli. S1 was defined by the presence of tuft adhesion and segmental sclerosis but not global sclerosis. E1 was defined by the presence of an increased number of cells within the capillary lumina, causing narrowing. The percentage of the cortical area damaged by interstitial fibrosis of tubular atrophy, defined as T1 (26 to 50%) or T2 (50%), can be considered a risk factor for the progression of the disease, possibly suggesting the start of immunosuppressive therapy. In the original Oxford study, crescents were not found to be an independent predictor of renal outcomes; however, patients with severe renal impairment (GFR < 30 mL/min per 1.73 m2) were excluded from these studies. A working subgroup later proposed that a score of C2 (with crescents in >25% of glomeruli) further identifies patients at risk of a poor renal outcome even if treated with immunosuppression [19]. Unfortunately, there is a lack of effective tests that can predict the response to therapy and MESC. Several diagnostic tests have been proposed from multitarget measurements of the protein constituents in IgA complexes such as CD89-binding poly-IgA complex levels [20] or abnormally glycosylated IgA1 serum levels. However, these are not often available outside of research settings. The need for reliable prognostic tools has become pressing: patients with IgAN are defined to be at high risk of progression to ESKD when proteinuria is more than 0.75–1 g/day and when there is associated CKD. To confirm this, CKD stage ≥3 and proteinuria ≥1 g/day [21] are reported by some authors among 4375 patients (mean age 47.7 years, 62.7% male) with IgAN, which are associated with higher MEST-C scores, and the odds of mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents increased with CKD stage. Other authors, using an old Haas histologic classification, indicated class 4–5, poor baseline renal function, lower C3 serum levels, neutrophil-to-lymphocyte ratios, and platelet-to-lymphocyte ratios, and higher proteinuria as risk factors for poor renal outcomes [22].
Another important question, which is often not adequately considered, is the presence of microhematuria, which is common in IgAN (in 78% of patients at the time of renal biopsy) [23].
However, above all, current diagnostic tools and follow-up therapy are based on proteinuria, mesangial and endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis, and crescent (MEST-C) scores [19].
Among 125 patients affected by IgAN, 97 of them at baseline had microhematuria, defined as severe if there were ≥21 red blood cells (RBCs/hpf), moderate if there were between 3 and 20 RBCs/hpf, and absent if there were <3RBCs/hpf. An increase in the degree of microhematuria was significantly associated with an eGFR decline of −0.81 mL/min/1.73 m2 [p = 0.01] [22]. The presence of hematuria suggests that its presence at the time of renal biopsy reflects ongoing inflammation in the kidney. However, data regarding microscopic hematuria and renal outcomes are conflicting [24], even though some authors consider hematuria as an independent risk factor for eGFR decline over and above follow-up time, proteinuria, MEST-C score, and treatment [25], hypothesizing that it could identify ‘high-risk’ IgA patients. The combination of high-risk aspects, including proteinuria >1 g/day, severe hematuria (defined as ≥21 RBCs/hpf), and histological findings of E1 and C ≥ 1, should lead clinicians to suspect that the risk of renal worsening is high. T lesions, defined as the “percentage of the cortical area involved in tubular atrophy or interstitial fibrosis”, can be divided into three groups: T0 (0–25%), T1 (26–50%), and T2 (>50%). Some authors identified a strong correlation between the percentage of T lesions and eGFR. In addition, T and S lesion subtypes, such as S-NOS, global sclerotic glomeruli, segmental adherence, and perihilar glomerular sclerosis, are associated with adverse outcomes [25].
Here, we will review the main therapies available nowadays for IgAN, from the stronghold of RAAS inhibition to the use of sodium–glucose cotransporter-2 inhibitors (SGLT2i), focusing on the ongoing clinical trials that are expected to identify corticosteroid-sparing therapies and to help improve treatment of IgAN.

2. Supportive Therapy

In general, the optimal management of IgA, once the diagnosis has been made, is represented by optimal supportive therapy, namely blood pressure control, reduction of proteinuria with renin-angiotensin-aldosterone system (RAAS) inhibition, reduction of dietetic sodium intake, and following an appropriate lifestyle. Immunosuppressive therapy, reserved for IgA patients at risk of disease progression despite maximal supportive care, has been shown to improve outcomes, but is frequently associated with significant toxicity (primarily at high doses given for a prolonged duration).

2.1. Inhibition of RAAS (Renin Angiotensin Aldosteron System)

Angiotensin inhibition with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) has been demonstrated to slow the rate of progression of most proteinuric chronic kidney diseases (CKDs), an effect that is conveyed at least in part by lowering both the systemic blood pressure and the intraglomerular pressure [26,27].
Both ACEi and ARB reduce protein excretion to a greater extent than a placebo or calcium channel blocker in both normotensive and hypertensive patients [28]. Moreover, beyond the clear effects of blocking the RAAS in nephroprotection, it should be considered that the close control of blood pressure, even in IgAN, has demonstrated to preserve renal function, despite small differences in blood pressure of the order of 6–7 mm Hg [29]. Moreover, the full effect of a RAAS blockade needs time to be titrated and to demonstrate its effects. One question is whether a RAAS blockade is beneficial in normotensive IgAN patients with only moderately increased proteinuria (below 0.5 g/day). Furthermore, it is not clear whether adding ACEi plus ARB in a dual RAAS blockade exerts positive effects in IgAN patients as in other renal diseases. In fact, some years ago, smaller clinical trials demonstrated additional antiproteinuric effects in IgAN patients after the co-administration of losartan with ACEi [30]. Other meta-analysis trials in patients with glomerular diseases found a 18 to 25 percent greater reduction in proteinuria with combined ACEi and ARBs compared with monotherapy [28,31,32], although caution is advised due to the risk of hyperkalemia. However, at the current time, no randomized trials have shown benefits in kidney outcomes with combination therapy.

2.2. Obesity in IgAN

Several studies indicate a close bond between obesity and chronic kidney disease (CKD) progression, through complex mechanisms including hemodynamic changes, inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system (RAAS). Histologically, obesity-related kidney disease is characterized by glomerulomegaly, often associated with segmental glomerulosclerosis lesions. Glomerular hyperfiltration from a tubular origin is the main clinical characteristic that is associated with obesity [33]. Several studies have shown significantly worse renal outcomes among obese patients with IgA nephropathy. The impact of obesity in biopsy-proven IgAN patients was investigated by Tanaka et al. [34]. Proteinuria was significantly higher in the obese group compared to normal-weight patients, accompanied by significantly larger glomerular sizes and the ultrastructural modification of the GBM by light microscopy, conditions that contribute to increasing proteinuria.
More recently, Yuki Ariyasu et al. [35] observed that among 212 patients, obesity was associated with IgAN progression, and obesity contributed to tubular atrophy and female proteinuria. All these indications suggest that obesity should be considered as a risk factor to be controlled in supportive therapy.

2.3. Low-Salt Diet in IgAN

Some authors suggest that the urinary angiotensinogen/creatinine ratio was significantly higher in patients who consumed an ordinary salt diet (12 g/day) compared with a low-salt diet (5 g/day; p < 0.001). The sodium sensitivity index in IgAN patients positively correlated with the glomerulosclerosis score. It was suggested that the inappropriate increase of intrarenal angiotensinogen, induced by salt and associated with renal damage, contributes to the development of salt-sensitive hypertension in patients with IgA [36].

3. Immunosuppressive Therapy

Immunosuppressive therapy is nowadays suggested for high-risk patients.

3.1. Steroids

For many years, steroid therapy, in addition to blocking the RAAS, has represented an obligatory choice in IgAN patients with proteinuria and/or with worsening renal function. Glucocorticoids can act both systemically and locally as glucocorticoid receptors (GRs) that are ubiquitously expressed. In the kidney, glucocorticoids may directly interfere with both the overproduction of inflammatory mediators and also exert protective effects on podocytes via the GRs [36,37]. Patients at high risk of disease progression (despite at least three to six months of optimized supportive care) are generally considered candidates to receive immunosuppressive therapy. Immunosuppressive therapy, such as systemic glucocorticoids, likely improves short-term kidney outcomes in IgAN patients but, at the same time, has the risk of significant toxicity when administered at high doses. Randomized clinical trials (RCTs) demonstrated good results with the use of oral prednisone preceded by IV methyl-prednisolone pulses (MPP); however, the use of glucocorticoids in IgAN is controversial despite being used for decades [38]. Pozzi and Locatelli studied 86 patients with biopsy-proven IgAN, modestly compromised renal function with serum creatinine values of ≤1.5 mg/dL, and proteinuria between 1 to 3.5 g/day. Patients randomly received IV MPP daily for three days at months 1, 3, and 5, followed by oral prednisone at a dose of 0.5 mg by body weight every other day over six months. This was in addition to RASi as a supportive therapy, albeit not in all patients. Pozzi and Locatelli, after a ten-year follow-up, reported that kidney survival was significantly higher (97% in the treated group versus 53% in the control group) and that proteinuria significantly decreased from 1.9 to 0.6 g/day. No significant side effects were reported in the patients treated with steroids, apart from the development of diabetes in one patient. Only two among 43 treated patients relapsed with mild proteinuria during the FU [39,40]. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial [41], 162 proteinuric patients (>0.75 g/day) were treated for 6 months with maximization of the RAS blockade, close blood pressure control, and lifestyle modifications. Patients with CKD stages 3 and 4 (eGFR between 30 and 59 mL/min) were treated with oral prednisolone tapered to 10 mg/day after three months plus cyclophosphamide at 1.5 mg/kg/day for three months, which was then replaced by azathioprine. About 30% of participants benefited from the treatment, with proteinuria reduced to below 0.75 g/day, resulting in them being excluded from the second part of the study. The others, who did not benefit from the treatment, with proteinuria 0.75–3 g/d, were randomized to supportive therapy, including RASi or RASi, plus oral 0.5 mg/kg steroids preceded by MPP pulses for three days at months 1, 3, and 5. The addition of steroids in patients with high-risk IgAN did not significantly improve outcomes, and after 3 years, no significant difference in the annual loss of eGFR was observed between the two groups. The authors concluded that additional immunosuppressive therapy to intensive supportive care does not provide substantial benefits in decreasing eGFR > 15 mL/min/1.73 m2 (28% versus 26%) in patients with high-risk IgAN. In a retrospective analysis of the European Validation Study of the Oxford Classification of IgAN (VALIGA) study [42], 184 subjects received glucocorticoids plus RASi and another 184 patients were treated only with RASi. The steroid-treated patients showed significantly reduced proteinuria and rates of kidney function loss when proteinuria was >1 g/day, showing positive outcomes. The treatment successfully worked as the value of proteinuria increased and eGFR decreased to lower than ≤50 mL/min. Recently, Lv J. et al. [43] in the TESTING RCTrial, which enrolled 503 participants from 67 centers and had a follow-up of 4.2 years, evaluated the efficacy and adverse effects of methylprednisolone, MPP (initially 0.6–0.8 mg/kg/day, maximum 48 mg/day), in patients with IgAN, a mean eGFR = 61.5 mL/min/1.73 m2, and mean proteinuria = 2.46 g/day) who were at high risk of kidney function decline. The annual rate of loss of kidney function was −2.50 mL/min/1.73 m2 per year in patients randomized to the steroid group, compared with 4.97 mL/min/1.73 m2 per year in the placebo group (mean difference, 2.46 mL/min/1.73 m2 per year; p = 0.002. The authors concluded that treatment with a low dose of oral MPP for 6 to 9 months, compared with the placebo, significantly reduced the risk of the composite outcome of kidney function loss, kidney failure, or death due to kidney disease compared to the full dose. However, reduced-dose steroids in this study were still associated with substantial toxicity compared to the placebo, with adverse effects occurring in 10.9% of patients in the steroid group compared with 2.8% in the placebo group. In TESTING [43], as in STOP-IgAN [41], and other studies, the use of steroids was associated with significant side effects, so the risk–benefit profile of glucocorticosteroids has recently been brought into question and optimal treatment remains a challenge, even if, to date, clinicians have many more options available [13]. However, caution should be exercised in the use of steroids in patients with reduced GFR < 50 mL/min due to the side effects.

3.2. Budenoside, Oral Steroids

Considerable evidence suggests the existence of a gut–kidney axis in the pathogenesis of IgAN. There is increasing evidence for dysregulation and/or over-activation of the mucosal immune system, leading to an increase in circulating Gd-IgA1 and secretory IgA levels [6].
Budenoside is a second-generation synthetic glucocorticoid in the form of oral tablets with minimal systemic absorption and has been used for decades for the topical treatment of asthma or inflammatory bowel diseases. Budenoside represents a new way of administering steroids in IgAN, minimizing side effects. Importantly, patients treated with systemic steroids or immunosuppressants seem to have much lower levels of IgA–IgG immunocomplexes when compared with untreated patients. On the contrary, serum IgA levels did not always significantly change during treatment [19], suggesting that systemic glucocorticosteroids have little effect on mucosal production of antibodies to abnormal IgA [38]. A clinical study has been undertaken on patients with IgAN with a targeted release formulation of budesonide (TRF-budesonide), which is preferentially released in the terminal ileum, where most Peyer patches are located. Peyer patches have been recognized as being involved in the production of poorly galactosylated immunoglobulin A1 (IgA1), which has been implicated in the pathogenesis of IgAN.
In patients with IgAN, blood levels of Gd-IgA1 are increased and these can form immune complexes with IgG or IgA autoantibodies, so the mesangial accumulation of these immune complexes stimulates inflammatory and fibrotic cascades, resulting in progressive kidney injury [41,44]. In a phase 2b trial (NEFIGAN study) [45] studying 150 subjects, the effect of budenoside (Nefecon®) was tested in patients with primary IgAN at risk of progression to ESKD. Budesonide demonstrated a reduction in the urinary protein-to-creatinine ratio (UPCR) and stabilized eGFR deterioration, compared with the placebo, in 144 patients already receiving ACEi/ARBs.
The drug is now being evaluated in an ongoing phase 3 study (NEFIGARD), with a further 12-month observational follow-up period during which the study will remain blinded, to evaluate the effect of the treatment on eGFR [46]. After 9 months and maintaining all patients with stable and optimized RAS blocks, those receiving budenoside achieved a significant 27% reduction in UPCR compared to the placebo (p = 0.0003); reductions from baseline were 31% and 5% in the Nefecon and placebo groups, respectively.
In the ninth month, patients treated with Nefecon also achieved a reduction in eGFR from baseline by 0.17 mL/min/1.73 m2 compared with a decrease of 4.04 mL/min/1.73 m2 in the placebo group: this means a statistically significant 3.87 mL/min per 1.73 m2 eGFR treatment benefit (p = 0.0014) for budesonide, which was maintained at 12 months. Regarding safety, the 9-month treatment was well-tolerated, with discontinuations from treatment due to adverse events (9.3% and 1.0% in the budesonide and placebo groups, respectively) mostly due to peripheral edema, hypertension, muscle spasms, and acne.
It should be underlined that the efficacy of budenoside was compared with the placebo alone, whereas it would be interesting to compare its efficacy with systemic glucocorticoids. The route of administration of the drug and the correct selection of patients influences their efficacy and safety. It is important to note that budesonide over a 9-month treatment period did not increase the risk of infection or related hospitalizations, which is different from the results of other studies with systemic glucocorticoids (such as the STOP-IgAN study) [41].
Regulatory approval of Nefecon is now limited (United States only). The use of TRF-budesonide as an initial immunosuppressive therapy at a dose of 16 mg/day in patients with mild-to-moderate forms of IgAN, in whom systemic glucocorticoids are contraindicated or not accepted, could represent a hypothesis in the short-term, considering the long-term effects in patients with IgAN and the high costs, which are estimated to be, in the USA, more than 120 times the cost of systemic steroids.

3.3. Other Immunosuppressive Therapies

Mycophenolate Mofetil (MMF)

MMF has suppressive effects on activated T and B lymphocytes and may represent an alternative for high-risk patients unable to follow steroid therapy. However, in the literature, not many trials have been conducted on large samples. In a Chinese trial [47], 170 young IgAN patients (mean ± SD age 36.6 ± 9.4 years) with microematuria and proteinuria (mean 1.9 g/day) received MMF (1.5 g/day for 12 months, which was then tapered to a maintenance dose of 0.75 to 1 g/day for at least six months) plus (ARB), or ARB alone. Their mean baseline eGFR was 50 mL/min/1.73 m2 and after three years, only 7 versus 21% in the MMF group doubled the creatinine ratio. The numbers of ESKF and CV deaths were similar between the two groups and patients treated with MMF showed a reduced mean annual reduction in eGFR compared with patients treated with ARB (−1.2 versus −3.8 mL/min/1.73 m2).
MMF associated with a low steroid dose was not inferior to a standard dose of steroid in proteinuric (>1 g/day) patients with proliferative histologic lesions upon kidney biopsy.
In an 8-year study, a mean of 30 months of treatment with low-dose MMF (about 1.0 g/day) added to SC offered more renal benefits than SC alone and was generally well-tolerated. The MMF group showed a 77% reduction in the risks of doubling serum creatinine, ESKD, or death due to kidney or CV causes after a 3-year follow-up and had a significantly higher rate of reduction in UPCR from baseline compared with the SC group (1.2 g/day–2.1 g/day [57.1%] vs 0.5 g/day–1.7 g/day [28.2%]; p < 0.001). Interestingly, pathologic characteristics showed advanced disease, with more than 60% of patients with glomerulosclerosis >50%, hypothesizing that even in the presence of advanced renal damage, expressed by sclerotic and fibrotic lesions, immunosuppression with MMF may provide renal protection. However, on the other hand, the infection rate in patients treated with MMF was higher. Serious adverse events, nevertheless, were not statistically different. However, patients with an eGFR <50 mL/min/1.73 m2 were excluded from most IgAN trials, so KDIGO does not suggest any standard treatment guidelines for such patients. In addition, the use of low-dose MMF compared with 2 or 3 g/day resulted in lower infectious complications in patients with LES [48], so MMF could be considered a favorable option in patients with reduced eGFR and those at high risk of adverse effects with steroids. In conclusion, the use of MMF in IgAN remains open to discussion and is currently only suggested for Chinese patients as a steroid-sparing agent.

3.4. Non-Steroidal Therapies Review Based on Recent Clinical Trials

3.4.1. Sodium–GLucose coTransporter-2 Inhibitors

The physiological and pathological handling of glucose via sodium–glucose cotransporter-2 (SGLT2) in kidney damage has been moving forward, and SGLT2 inhibitors (SGLT2i) have been focused upon as a novel drug for treating diabetes.
SGLT2i improves renal glucose excretion by inhibiting renal glucose reabsorption. As a result, SGLT2i reduces plasma glucose and insulin independently, improves insulin resistance in diabetes [49], and discards excess glucose into the urine by inhibiting renal glucose reabsorption. As a result, SGLT2i reduces plasma glucose levels and avoids glucose toxicity, resulting in an improvement in insulin resistance associated with diabetes [49,50]. See Figure 2, Mechanism of action of SGLT2.
In large cardiovascular outcome trials involving patients with T2D, empagliflozin, canagliflozin, and dapagliflozin slowed the rate of decline of eGFR and reduced albuminuria, with a similar eGFR trend observed for ertugliflozin, suggesting that SGLT2i reduces intraglomerular pressure, resulting in better preservation of long-term kidney function. The same effect was also observed in patients with proteinuric chronic kidney disease (CKD) without diabetes [51].
In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial [52], participants with an eGFR 25–75 mL/min/1.73 m2 and an UPCR between 200 to 5000 mg/g (22.6–565 mg/mol) were randomized to dapagliflozin 10 mg or placebo, in addition to standard care. Results show that dapagliflozin can reduce the risk of kidney failure and prolong survival in participants with CKD and with and without T2D. The renoprotective effect of dapagliflozin was similar across the wide spectrum of patients, from subjects with UPCRs higher and lower than 1000 mg/kg and in patients with eGFRs higher and lower than 45 mL/min/1.73 m2. However, the most compromised patients, who have the highest albuminuria and lowest eGFR, may benefit most.
In the DAPA-CKD study, most patients were treated with RASi, so the renoprotective effect of dapagliflozin may be considered additive to the effect of the RAAS blockade [53]. In a sub-analysis of the aforementioned study, which included a group of 270 IgAN patients, of whom 254 (94%) had a diagnostic histological kidney biopsy to confirm the diagnosis [54], the authors demonstrated that dapagliflozin reduces the risk of the primary composite outcome (sustained ≥ 50% decline in eGFR, onset of ESKF, kidney transplantation) by 71% and the secondary kidney-specific outcomes (similar to the primary outcome without cardiovascular (CV) death; a composite endpoint of CV death or hospitalization for heart failure; and all-cause mortality) by 75%. Dapagliflozin also reduced the UPCR by 26 percent compared with the placebo and rates of adverse events were similar between the two groups. Dapagliflozin was approved in 2021 by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of CKD in adults with and without T2D.

3.4.2. Finerenone

As observed by Anders et al. [55], the GFR of participants treated with dapagliflozin in the DAPA-CKD study still reduced over time, so there is still space for other new treatments beyond a dual RAAS/SGLT2 blockade, for example, triple therapy with the addition of finerenone, a non-steroidal mineralocorticoid receptor antagonist (nsMRA), or drugs that enhance the production of novel podocytes, thus attenuating further glomerulosclerosis, nephron loss, and GFR decline. Recently, BI 690517, an enzyme that controls the final rate-limiting steps in aldosterone synthesis, was studied. In a phase II trial, Baxdrostat reduced albuminuria from baseline by −22% in CKD proteinuric patients compared with −3% in the placebo group, with a relatively good safety profile: hyperkaliemia occurred in 10% of patients in the Baxdrostat 3 mg group, in 15% of patients in the Baxdrostat 10 mg group, in 18% of patients in the Baxdrostat 20 mg group, and in 6% of those receiving the placebo. At the same time, renin–angiotensin system inhibition and empagliflozin were prescribed, suggesting an additive efficacy for CKD treatment [56,57].
Very recently, it was reported [57] that SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs) both seem to reduce albuminuria and disease progression rates in non-diabetic proteinuric CKD patients who were already taking RAASi. Four weeks of combination therapy with an SGLT2 inhibitor (dapagliflozin) plus a nsMRA (finerenone) resulted in the additive reduction in albuminuria by −36% compared with −24% and −8% with only finerenone and only SGLT2, respectively. At the same time, a significant reduction in mGFR from baseline to 8 weeks was observed in both groups, with −3 mL/min in the finerenone-alone group and −2 mL/min in the dapaglifozin-alone group, compared with a loss of −7 mL/min in association with both drugs. A safe profile in serum potassium levels with no cases of significant acute hyperkaliemia events was observed. Despite a small sample size and the absence of patients with IgAN, the data seem to be promising regarding the increase in nephroprotection in proteinuric non-diabetic patients.

3.5. Other Regimens

Sparsentan

Sparsentan is an oral, dual-selective antagonist of the angiotensin II receptor (AT1) and endothelin 1 (ET-1) receptor (ETA), with associated hemodynamic, anti-inflammatory, antifibrotic, and protective effects on podocytes in patients with IgAN [58,59]. ET-1 is the effector peptide of the endothelin system and is involved in glomerular hemodynamics. Binding to its type A receptor (ETAR), it induces inflammation and extracellular matrix production (ECM), resulting in podocyte injury with proteinuria and glomerulosclerosis [60].
In February 2023, sparsentan received conditional approval from the US Food and Drug Administration (FDA) for the reduction of proteinuria in patients with IgAN who are at risk of rapid disease progression (defined as a UPCR ≥ 1.5 g/g, approximately equal to ≥2 g/day) based on interim results from the PROTECT trial [58]. Currently, it is under review by the European Medicine Agency (EMA) and may be requested for compassionate use in IgAN patients unable to be enrolled in RCTs. PROTECT was an RCT involving 134 sites in 18 countries, studying 404 patients with biopsy-proven IgA nephropathy and proteinuria of 1 g/day or higher. In the PROTECT trial, sparsentan significantly reduced UPCRs (−49.8%, whereas P/C reduction in the irbesartan group was −15.1%), resulting in a between-group relative reduction of 41%.
Importantly, maximal RAAS inhibition was not achieved in 35 percent of patients. Rates of serious adverse events were similar in both groups (20 to 21 percent), and there were no cases of hepatotoxicity, severe edema, or heart failure. However, peripheral edema, dizziness, and hypotension (including orthostatic hypotension) were more frequent among patients treated with sparsentan and must be monitored, as also noted in our experience.

4. Complement-Targeted Therapies

Activation of the complement system occurs via three different pathways: the classical pathway, the alternative pathway, and the lectin pathway. However, although the three systems are different, numerous studies have demonstrated a close correlation between these and an interconnected pathway. The alternative pathway initially activates the typical classical and lectin pathways, and this activation is supposed to contribute up to 80% of complement activation [61]. Several inflammatory and autoimmune diseases are caused by dysregulation of the complement system [61,62]. The kidneys are sensitive to complement-mediated damage because of ultrafiltration, high blood flow, and local fluctuations in electrolytes and pH [63]. The activation (local or systemic) of the complement system in IgAN was first studied at least 50 years ago [64]. Polymeric IgA1 and immune complexes containing IgA1 can trigger both the alternative and lectin pathways, leading to the cleavage of intact C3, leading to C3a and C3b. The extent of C3 deposits in the mesangium concurs with the severity and risk of progression of IgAN.
The alternative pathway (AP) is the major activator of the complement cascade in IgAN, spontaneously triggered by the hydrolysis of C3, which is mainly deposited due to the AP. Complement 3 deposition is observed in 71–100% (∼90%) of IgAN patients. Next to glomerular IgA and C3 deposits, properdin and C5b-9 are almost always present, while C1q is typically absent [65,66].
Recent contributions have provided more information on the pathogenic involvement of Factor H-related proteins 1 and 5 (FHR1 and FHR5) in IgAN. FHRs regulate the effect of FH by interacting with ligands, inducing complement activation on cell surfaces.
FHR1 plasma levels have been demonstrated in various studies [56,63] to be significantly higher in IgAN patients than in controls, with a negative correlation between eGFR and FHR1 levels. The terminal pathway has been recognized as having an important role in the pathogenesis of IgAN: C5b-9 deposition is related to renal inflammation and progression of glomerulosclerosis [67], while mesangial C5b-9 staining is closely associated with mesangial C3 fragments. Moreover, the glomerular deposition of C5b-9 promotes podocyte damage, resulting in proteinuria [63].
Mesangial deposition of C4, particularly the C4d activation fragment, has been discovered in kidney biopsies from patients with progressive IgAN, suggesting an LP activation [68] of the lectin pathway. Fujita et al. demonstrated the glomerular deposition of mannan-binding lectin (MBL) and mannan-associated lectin-binding serine protease-1 (MASP-1) in IgAN, which co-localized with C3b and C5b-9 deposits [69]. A follow-up study showed mesangial deposits of MBL, MASP-1, and C4 in 50% of IgAN cases, and showed that IgA2 co-localized with MBL and MASP-1 in the mesangium of these patients. Other additional components of the LP, such as ficolin-2 deposition, have been proven in IgAN. Moreover, glomerular deposition of the LP is related to IgAN severity. The impressive improvements in the understanding of the role of complement in glomerulopathies, and in IgAN in particular, have led to the development and use of new complement-targeted therapies in this disease in recent years. To date, ongoing clinical trials of therapeutic complement inhibitors will provide insight into the importance of complement activity in IgA nephropathy pathogenesis, namely against factor B (iptacopan and Ionis-FB-L RX), factor D (vemircopan and pelecopan), C3 (pegcetacoplan), C5 (ravulizumab and cemdisiran), and C5a receptor 1 (avacopan) [70,71].

4.1. Narsoplimab

Among the currently promising ongoing studies with monoclonal antibodies, the OMS721 or ARTEMIS-IGAN Phase 3 Trial (NCT03608033) must be reported, which evaluated the safety and efficacy of narsoplimab in patients with IgAN. Narsoplimab is a human monoclonal antibody against mannan-associated lectin-binding serine protease-2 (MASP-2), a lectin pathway inhibitor of the complement system. The trial [72] evaluated the effect of 370 mg of OMS721 administered weekly through an IV for 12 weeks versus placebo in patients with IgA nephropathy (IgAN), using proteinuria assessed by 24 h urine protein excretion (UPE) in g/day at 36 weeks from baseline. One hundred and forty sites were involved all around the world to randomize 450 patients. The starting hypothesis was the usefulness of narsoplimab in a large series of pathologies such as thrombotic microangiopathy, HUS, lupus nephritis/IgAN, transplants, and COVID-19 acute respiratory distress syndrome. Narsoplimab leads to the inhibition of MASP-2, which is the effector enzyme of the lectin pathway. Narsoplimab has the potential to reduce thrombosis and hemolysis and limit damage to affected organs. MASP-2 is a central enzyme involved in the activation of the lectin pathway. The MASP-2 inhibitor narsoplimab has been tested in a phase 2 clinical trial in adults with severe IgAN (NCT02682407). Once-weekly IV administration of narsoplimab for 12 weeks revealed no drug-related serious adverse events.
Further 12-week courses of narsoplimab reduced proteinuria by 38% during 3 years of treatment and FU. Subjects in substudy 1 showed reduced proteinuria from 54–95% at week 18, while in substudy 2, there were no differences at week 18 between the narsoplimab and placebo groups. Eight patients who participated in the study had a median proteinuria reduction of 61%, suggesting potential efficacy in IgAN patients. Therefore, a phase 3 RCT study began (ARTEMIS-IgA Nephropathy trial, NCT03608033), with 87 designated to enroll 450 patients (225 per arm). In addition, our center participated in this study.
Patients were randomly assigned in a 1:1 ratio to weekly IV narsoplimab or placebo and, after 12 weeks and based on the progress of proteinuria, patients received additional 6-week blind treatment during the response evaluation period.
Change in proteinuria at 36 weeks was considered the primary endpoint. However, in October 2023, the trial was discontinued because treatment with narsoplimab, at the interim analysis, did not meet its primary endpoint (the reduction observed in the placebo group was far higher than data reported in other trials on IgA nephropathy).
Although the drug was well-tolerated and showed a consistent safety profile, the negative efficacy resulted in the trial being stopped.

4.2. Iptacopan

Among drugs for IgAN acting on the complement system, selective inhibition of the AP was tested as a stimulus of glomerular inflammation, with Iptacopan (LNP023) showing efficacy as an oral, selective, potent, and highly selective inhibitor of factor B of the AP.
It was tested in a phase 2 RCT study (NCT03373461) [73] on proteinuric (≥0.75 g/day) IgAN patients. The study included two parts: the first enrolled 46 patients for a 3-month period; and the second enrolled 66 patients for a 6-month period. Patients were randomly allocated to one of the four iptacopan arms [10, 50, 100 (in part 2 only), and 200 mg twice daily] and compared to the placebo, with an endpoint of reducing proteinuria and slowing disease progression.
All doses of iptacopan induced continued AP inhibition without any serious side effects. A reduction of proteinuria occurred after 6 months in the twice daily iptacopan 200 mg arm by 28% to 40% versus placebo.
A phase 3 trial (APPLAUSE, NCT04578834) [74] is currently ongoing and enrolled 470 participants with biopsy-proven IgAN and with eGFRs ≥30 mL/min/1.73m2 to evaluate the efficacy and safety of iptacopan, compared with placebo, on proteinuria reduction and slowing renal disease progression (annualized eGFR slope over 24 months).
In an interim analysis recently published, the reduction in proteinuria was supported by consistent results in secondary end point analyses. At month 9, the mean 24-h urinary protein-to-creatinine ratio was 38.3% significantly lower with iptacopan than with placebo. No unexpected safety findings with iptacopan was reported. Recently, on 6 December 2023, iptacopan was approved by the FDA as the first oral monotherapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).

4.3. Ravulizumab

Ravulizumab is a humanized monoclonal IgG2/4 kappa antibody produced in Chinese hamster ovary cells that acts as a potent and selective complement 5 inhibitor. Ravulizumab was engineered from eculizumab, another complement inhibitor, to increase its duration of action while reducing the frequency of drug administration.
Its mechanism of action is stopping terminal complement-mediated inflammation, cell activation, and cell lysis in blood disorders associated with the demolition of red blood cells, thrombosis, and impaired bone marrow function [75].
It has been studied in an ongoing multicenter, phase 2 randomized control study (NCT04564339) to evaluate its efficacy and safety in 60 adults with IgA nephropathy, with the endpoint being the percentage change in proteinuria from baseline to week 26 [76]. At 26 weeks, the investigators found proteinuria reduction to be greater in the ravulizumab group (40.3%) than in the placebo group (10.9%). In addition, the GFR was stable. Ravulizumab had a safety profile like the placebo and was effective in treatment. However, 74.4% of patients in the ravulizumab group experienced adverse events (n = 32), compared to 82.6% in the placebo group (n = 19).
A continuation of the phase 3 study, the I CAN study (ClinicalTrials.gov NCT06291376), of which we are also a part, is currently ongoing, enrolling approximately 450 participants with IgAN who are at risk of disease progression to receive an IV infusion of either ravulizumab or placebo to evaluate the variations in UPCR from baseline to week 34 and eGFR over 106 weeks.

5. New Therapies

5.1. Sibeprenlimab

New evidence supports a key role for the cytokine, a proliferation-inducing ligand (APRIL), in the pathogenesis of IgAN. APRIL belongs to the tumor necrosis factor-alpha family, which regulates B-cell-mediated immune responses and IgA production. Blocking the activity of APRIL could prevent galactose-deficient IgA1 production [77]. Sibeprenlimab (VIS649) is a humanized immunoglobulin G2 (IgG2) monoclonal antibody that blocks the biological actions of the B-cell growth factor, APRIL, preventing binding to its receptors, transmembrane activator, and calcium modulator, cyclophilin ligand interactor, and B-cell maturation antigen. The reduction in auto-antibody production caused by sibenprelimab may result in fewer immune complexes and immune deposits in the kidney, thereby limiting kidney inflammation [78]. The safety and effectiveness of an APRIL-targeted antibody was demonstrated by Mathur et al., who showed a reversible, dose-dependent decrease in serum levels of IgA, galactose-deficient IgA1, IgG, IgM, and APRIL after administration in healthy volunteers [79].
Very recently, the same group published the results of a phase 2 multicenter, double-blind RCT versus placebo with the use of sibeprenlimab in IgA patients. The authors randomly assigned 155 adult patients with biopsy-proven IgA nephropathy with UPCRs of at least 0.75 g/g and urinary protein >1 g/day, despite standard supportive therapy with ACEi or ARB for at least 3 months at the highest tolerated dose, in a 1:1:1:1 ratio to receive IV sibenprelimab at a dose of 2, 4, or 8 mg/kg of body weight, or the placebo, once a month for 12 months. At 12 months, the mean geometrical ratio reduction from baseline in the 24 h UPCR was 47.2 ± 8.2%, 58.8 ± 6.1%, 62.0 ± 5.7%, and 20.0 ± 12.6% in the sibeprenlimab 2 mg, 4 mg, 8 mg, and placebo groups, respectively. Researchers observed a consistent stabilization of kidney function, expressed as eGFR, in the groups treated with sibenprelimab. The incidence of adverse events was similar in the sibeprenlimab and placebo groups (respectively, 79% and 71%) [80]. Currently, the efficacy and safety are under investigation in an ongoing phase 3 trial, the Visionary study. This multicenter, double-blind, placebo-controlled RCT aims to evaluate the efficacy and safety of the SC administration of sibeprenlimab once a month compared to the placebo in patients with IgAN. Approximately 450 subjects from 32 countries and up to 300 sites will be randomized (1:1) to either sibeprenlimab or the placebo. A total of 26 doses will be administered to each patient.
The key primary endpoint is to compare, after 9 months of treatment, the relative change in proteinuria from baseline, measured via 24 h urine collections. The secondary endpoint is to compare the rate of change of eGFR from baseline after approximately 24 months of treatment. The study design includes a main cohort, comprising approximately 450 subjects with biopsy-confirmed IgAN and eGFRs ≥ 30 mL/min/1.73 m2, and a smaller additional exploratory cohort with biopsy-confirmed IgAN and eGFRs of 20 to <30 mL/min/1.73 m2. We are also participating in this study, which started in March 2022. As of now, no results are available; however, based on previously cited clinical trials, we hope that this therapy could be a turning point in IgA nephropathy therapies.

5.2. Ataticept

Atacicept is a fusion protein that binds the B-lymphocyte stimulator (BlyS) and the proliferation-inducing ligand (APRIL), inhibiting the maturation and class-switching of B-cells and plasma cells. In the JANUS trial, a double-blind, placebo-controlled phase II RCT [81] enrolling IgAN patients with persistent proteinuria, atacicept demonstrated an acceptable safety profile, with significant changes in 24 h proteinuria, potential stabilization of renal function, and substantial reductions in the levels of Gd-IgA1 compared with the placebo. Although it was analyzed in a small cohort of patients, it suggested an acceptable benefit–risk profile at 25 mg or 75 mg when administered via weekly subcutaneous injections. The planned treatment period was 72 weeks.
Substantial, dose-dependent reductions in serum IgA, IgG, and IgM were observed with atacicept. A phase 2B study showed that, at 24 weeks, atacicept at a dose of 150 mg reduced the mean UPCR from baseline levels by 31%, and atacicept at a dose of 75 mg led to a reduction of 7% from baseline when compared with the placebo (_ = 25%, p = 0.037). The atacicept 150 mg arm achieved a 33% reduction from baseline at week 24 and it was the only dosage that showed a statistically significantly greater reduction than the placebo (_ = 28%, p = 0.047). After 24 weeks, the atacicept 150 mg arm reduced the UPCR by 41% from baseline, compared with a 10% reduction in the placebo arm (_ = 34%, p = 0.025). It also allowed a Gd-IgA1 reduction of 60% at week 24. Regarding safety, atacicept was generally well-tolerated with a low rate (2%) of serious adverse events overall, with none in the atacicept 150 mg group. The ORIGIN phase 2b trial [82], launched on January 2024 on the heels of the phase 2 JANUS trial, showed that 106 of the 116 patients who underwent randomization completed the 72-week open-label extension period. Subjects treated with atacicept for 72 weeks demonstrated a 62% reduction in Gd-IgA1, a reduction in hematuria to 19%, and a 48% reduction in UPCR in the per-protocol analysis.

5.3. For Other Clinical Trials, Refer to Table 1

In the last few years, many companies have marketed and proposed many drugs undergoing phase 2 or 3 studies, the results of which will be available in the near future. The Table 1 below provides a complete list of therapies and trials currently underway for the treatment of IgAN.
Table 1. Immunosuppressive therapy: recent IgAN trials.
Table 1. Immunosuppressive therapy: recent IgAN trials.
DrugMechanism of ActionClinical TrialReference Number
STEROIDSPowerful immune-modulatory actionsNCT00554502, NCT01560052, VALIGA, TESTING, STOP IGAN[37,38,39,40,41,42,43]
BUDENOSIDEOral steroid, modulates mucosal B cells and plasma cells in the gutNCT01738035, NCT03643965,
NEFIGAN (phase IIB),
NEFIGARD (phase III)		[44,45]
MYCOPHENOLATE MOFETILSuppression of activated B and T lymphocytesNCT00657059, NCT00318474, MAIN[47,48]
CALCINEURIN INHIBITORSCytochrome P450 3A4 AND a P-glycoprotein inhibitor. Inhibits the synthesis of interleukinsNCT01224028, meta-analysis[83,84,85]
RITUXIMABB cells depletionNCT04525729, RITA[86]
HYDROXYCHLOROQUINE A quinoline immunomodulatory drug used to treat or prevent malaria NCT06350630[87,88,89]
SPARSENTANSelective endothelin A receptor and ARBNCT04663204[58,59]
NARSOPLIMABLectin inhibitor of complement, MASP-2NCT03608033, ARTEMIS, phase III. Early stop, no efficacy[72]
AVACOPANC5 receptor inhibitorNCT02384317[70,71]
IPTACOPANInhibitor of the alternative pathway of complementNCT04578834, APPLAUSE [73,74]
ATRASENTANSelective inhibitor of the endothelin A (ETA) receptorNCT04573478, SONAR, phase 3 ALIGN[90,91]
RAVULIZUMABSelective C5 inhibitorNCT06291376, I CAN[75,76]
SIBEPRENLIMABBlocks the biological actions of the B-cell growth factor, APRIL, preventing binding to its receptorsNCT05248646, VISIONARY RCT[77,78,79,80]
TELITACICEPTSimultaneously targets B cell maturation signals BLyS (BAFF) and APRILNCT04291781[92,93]
ATATICEPTBinds B-lymphocyte stimulator (BlyS) and a proliferation inducing ligand (APRIL) and inhibits maturation and class-switching of B-cells and plasma cellsNCT04716231 JANUS and ORIGIN phase II trials[81,82]
FOSTAMATINIBOral prodrug spleen tyrosine kinase (SYK) inhibitorNCT02112838[94]
MEZAGITAMABTargets highly CD38-expressing cells, resulting in their depletionNCT05174221 Not Provided
FELZARTAMABHuman IgG1 monoclonal CD38 antibodyNCT05021484, IGNAZ[95]
POVETACICEPTDual antagonist of the BAFF and APRIL cytokinesNCT06564142, RUBY 3 phase1b/2a[96]

5.4. Alternative Therapies

5.4.1. Tonsillectomy

Tonsillitis has been associated with proteinuria and hematuria in IgAN disease and the tonsils have, in the past, been suspected of being a source of abnormal IgA that forms immune complexes and deposits in the glomeruli.
In one randomized controlled Japanese trial [97], tonsillectomy combined with pulse steroid therapy did not demonstrate benefits over steroids alone while a retrospective European study also did not show a correlation between tonsillectomy and kidney function outcomes [98]. Therefore, tonsillectomy should not be routinely performed in most patients with IgAN despite being proposed for some Japanese patients affected by IgAN with good clinical results.

5.4.2. Fish Oil

Fish oil is a treatment option suggested for IgAN based on mixed data from largely underpowered clinical trials with a favorable safety profile [99]. However, fish oil (3.3 g/day or more omega-3 fatty acids) nowadays shows a limited role in IgA patients. It can be tried in high-risk patients with progressive disease as it may also have cardiovascular benefits; however, RTs concerning fish oil prescription in patients with IgAN have reported conflicting results.

5.4.3. Fecal Microbiota Transplantation

Finally, observations suggest that gut microbiota could be implicated in IgAN pathophysiology and fecal microbiota transplantation (FMT) has been demonstrated to be effective in the reconstruction of the intestinal microecological balance. The microbiota from patients managed to induce an increase in galactose-deficient IgA1 levels and serum BAFF and also a decrease in CD89 cell surface expression on blood CD11b+ cells, which was associated with soluble CD89 and IgA1 mesangial deposits. On the other hand, the microbiota from HC subjects led to reduced albuminuria immediately after gavage [100]. However, there is no evidence for the safety and efficacy of FMT in IgAN and a Chinese RCT is currently ongoing.
Here we suggest a algorithm for the treatment of IgAN nephropathy from a practical view of point. See Figure 3.

6. Discussion

IgAN therapy remains a difficult goal to achieve quickly but the great steps forward through continuous clinical trials, both completed and ongoing, are very encouraging.
The objectives of IgAN treatment should be to reduce glomerular inflammation and the production of Gd-IgA1 and to enhance supportive therapy as much as possible.
Strengthening supportive therapy, using glifozines with their established renoprotective effects in addition to the effect of the RAAS blockade, or by the blockade of the RAAS with the new anti-aldosterones such as finerenone, and with dual selective antagonists of the angiotensin II receptor (AT1) and endothelin 1 (ET-1) receptor (ETA), seems promising before the introduction of immunosuppressants, which is often an obligatory path in patients at high risk of progression.
Uncertainty remains in defining patients at high risk of progression of renal disease to ESKF, who are potentially eligible for immunosuppressive therapy if supportive therapy fails. Waiting for future diagnostic scenarios such as spatial proteomics and immune signatures of kidney function, which have already been tested in other pathologies but not yet used in current clinical practice, shows that we still have a long way to go with regard to non-invasive diagnostic tests.
Pending the future identification of a disease-causing gene, this could be proposed as a confirmatory test or even a replacement for renal biopsy diagnosis. However, we certainly have many more indications than we had until a few years ago, thanks to the considerable therapeutic offerings for this pathology. There are important gaps in the literature because the types of patients enrolled in RCTs often do not represent the real-life patients we visit every day in the clinics, and often important decisions on which therapy to perform are not always suggested by the guidelines. Pending the arrival of validated, new biomarkers and genetic studies for IgAN, it is reasonable to consider patients at risk of progression of renal disease as those who have microscopic hematuria (≥21 RBCs/hpf), GFR decline, proteinuria > 1 g/day (or 0.75?), and histological findings as MEST-C scores (above all with crescents).
However, the use of high doses of steroids, like other immunosuppressants, remains controversial, mostly because of the high toxicity rate, especially in cases of greater renal impairment.
Another important question is related to the time of the kidney biopsy, something that is often not thoroughly considered in many RCTs, which suggest starting immunosuppressive therapy based on kidney histological evaluations performed a long time before, sometimes years before, and are often not representative of the current picture of the disease. In fact, the Oxford classification of IgAN pays attention to differentiating between active renal lesions (E1 and C1,2) and chronic renal lesions (T1,2) [17]. In clinical trials, therapy acting on the immune system is intentionally started after a few months (from 3 to 6) of supportive therapy from the time of the kidney biopsy, as also suggested by KDIGO guidelines [13]. However, this waiting potentially gives room for acute (or active) lesions to become chronic, thus making immunosuppressive therapy less effective or no longer indicated [102]. As highlighted by various authors, a stratified analysis based on specific renal histology findings, able to evaluate the effects of treatments in a more defined way, in RCTs has not been done, because only proteinuria and loss of GFR are considered markers of therapy effectiveness.
The complement system is involved in the pathogenesis of IgAN and the flourishing of new complement-targeted therapies is very interesting, with a large number of trials in existence, despite the unsatisfactory results of drugs acting on the lectin pathway of complement so far. Finally, the risk of infections is elevated with this class of drugs, and vaccinations will likely be required.
Drugs acting on APRIL seem to be very promising, which have relegated the use of systemic steroid therapy to the background. Despite advanced disease progression in certain cases, steroids remain a cornerstone, albeit burdened by numerous side effects, especially infectious ones, with perhaps the exception of oral budesonide, which apparently has reduced side effects compared to IV high-dose steroid administration. Furthermore, the high costs of the oral steroid budenoside severely limit its possible use.
In addition to the challenging dilemma of which therapy to use and when, there remains the problem of the financial burden of new monoclonal drugs, a further obstacle in IgAN therapy given their staggering costs, which are much too high and sometimes difficult to sustain in times of severe budget reductions, where healthcare administrators prioritize short-term savings over long-term improved health. This is also partially due to the numerous therapeutic proposals that generate great expectations in such patients, mostly young patients, who often have disappointing outcomes.
In conclusion, by participating in various clinical trials on IgAN pathology, we believe that just like a dress that must be tried on and adapted to the measurements at the moment, the ideal IgA therapy should be gradual, starting from an effective support therapy, then possibly adding drugs if the proteinuria or hematuria does not reduce, the GFR worsens, or when histologic data suggest. In this case, immunosuppressive drugs or complement inhibitors could be started for high-risk patients. Considering the available literature and our first-hand experience, we picture a treatment algorithm with a rationale of gradually optimizing the therapy in a very dynamic framework, knowing that therapeutic “certainties” in the treatment of IgA could still be revised soon.

Author Contributions

Conceptualization, R.S. and T.V.; methodology, R.S. and T.V.; formal analysis, R.S. and T.V.; investigation, R.S.; data curation, R.S.; writing—original draft preparation, R.S.; writing—review and editing, R.S. and T.V.; supervision, R.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Acknowledgments

To all the medical staff of the Unit of Nephrology for the helpful suggestions and to Marco Rizzi for the efficient technical support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Berger, J.; Hinglais, N. Intercapillary deposits of IgA-IgG. J. Urol. Nephrol. 1968, 74, 694–695. [Google Scholar]
  2. Schena, F.P.; Nistor, I. Epidemiology of IgA nephropathy: A global perspective. Semin. Nephrol. 2018, 38, 435–442. [Google Scholar] [CrossRef] [PubMed]
  3. Pitcher, D.; Braddon, F.; Hendry, B.; Mercer, A.; Osmaston, K.; Saleem, M.A.; Steenkamp, R.; Wong, K.; Turner, A.N.; Wang, K.; et al. Long-term outcomes in IgA nephropathy. Clin. J. Am. Soc. Nephrol. 2023, 18, 727–738. [Google Scholar] [CrossRef] [PubMed]
  4. Currie, E.G.; Coburn, B.; Porfilio, E.A.; Lam, P.; Rojas, O.L.; Novak, J.; Yang, S.; Chowdhury, R.B.; Ward, L.A.; Wang, P.W.; et al. Immunoglobulin A nephropathy is characterized by anticommensal humoral immune responses. J. Clin. Investig. 2022, 7, e141289. [Google Scholar] [CrossRef]
  5. Coutinho, A.E.; Chapman, K.E. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol. Cell. Endocrinol. 2011, 335, 2–13. [Google Scholar] [CrossRef]
  6. Barratt, J.; Rovin, B.H.; Cattran, D.; Floege, J.; Lafayette, R.; Tesar, V.; Trimarchi, H.; Zhang, H. Why Target the Gut to Treat IgA Nephropathy? Kidney Int. Rep. 2020, 5, 1620–1624. [Google Scholar] [CrossRef]
  7. Rodrigues, J.C.; Haas, M.; Reich, H.N. IgA Nephropathy. Clin. J. Am. Soc. Nephrol. 2017, 12, 677–686. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  8. Lehrke, I.; Waldherr, R.; Ritz, E.; Wagner, J. Renal endothelin-1 and endothelin receptor type b expression in glomerular diseases with proteinuria. J. Am. Soc. Nephrol. 2001, 12, 2321–2329. [Google Scholar] [CrossRef] [PubMed]
  9. Nihei, Y.; Haniuda, K.; Higashiyama, M.; Asami, S.; Iwasaki, H.; Fukao, Y.; Nakayama, M.; Suzuki, H.; Kikkawa, M.; Kazuno, S.; et al. Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy. Sci. Adv. 2023, 9, eadd6734. [Google Scholar] [CrossRef]
  10. Barbour, S.J.; Coppo, R.; Er, L.; Russo, M.L.; Liu, Z.-H.; Ding, J.; Katafuchi, R.; Yoshikawa, N.; Xu, H.; Kagami, S.; et al. Updating the International IgA Nephropathy Prediction Tool for use in children. Kidney Int. 2020, 99, 1439–1450. [Google Scholar] [CrossRef]
  11. Coppo, R.; Lofaro, D.; Camilla, R.R.; Bellur, S.; Cattran, D.; Cook, H.T.; Roberts, I.S.; Peruzzi, L.; Amore, A.; Emma, F.; et al. Risk factors for progression in children and young adults with IgA nephropathy: An analysis of 261 cases from the VALIGA European cohort. Pediatr. Nephrol. 2017, 32, 139. [Google Scholar] [CrossRef] [PubMed]
  12. Selvaskandan, H.; Cheung, C.K.; Muto, M.; Barratt, J. New strategies and perspectives on managing IgA nephropathy. Clin. Exp. Nephrol. 2019, 23, 577–588. [Google Scholar] [CrossRef] [PubMed]
  13. Rovin, B.H.; Adler, S.G.; Barratt, J.; Bridoux, F.; Burdge, K.A.; Chan, T.M.; Cook, H.T.; Fervenza, F.C.; Gibson, K.L.; Glassock, R.J.; et al. Kidney Disease Improving Global Outcomes (KDIGO) Glomerular Diseases 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021, 100, S1–S276. [Google Scholar] [CrossRef] [PubMed]
  14. Thompson, A.; Carroll, K.; Inker, L.A.; Floege, J.; Perkovic, V.; Boyer-Suavet, S.; Major, R.W.; Schimpf, J.I.; Barratt, J.; Cattran, D.C.; et al. Proteinuria at follow-up and time-averaged proteinuria are the best assessed primary determinant of the rate of progression to ESKD demonstrated today. Clin. J. Am. Soc. Nephrol. 2019, 14, 469–481. [Google Scholar] [CrossRef]
  15. Kim, M.J.; Schaub, S.; Molyneux, K.; Koller, M.T.; Stampf, S.; Barratt, J. effect of immunosuppressive drugs on the changes of serum galactose-deficient IgA1 in patients with IgA nephropathy. PLoS ONE 2016, 11, e0166830. [Google Scholar] [CrossRef]
  16. Barratt, J.; Rovin, B.; Diva, U.; Mercer, A.; Komers, R. Implementing the kidney health initiative surrogate efficacy endpoint in patients with IgA nephropathy (the PROTECT trial). Kidney Int. Rep. 2019, 4, 1633–1637. [Google Scholar] [CrossRef]
  17. Trimarchi, H.; Barratt, J.; Cattran, D.C.; Cook, H.T.; Coppo, R.; Haas, M.; Liu, Z.H.; Roberts, I.S.; Yuzawa, Y.; Zhang, H.; et al. IgAN classification Working Group of the International IgA nephropathy Network and the Renal Pathology Society; Conference Partecipants. Oxford Classification of IgA nephropathy 2016: An update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017, 91, 1014–1021. [Google Scholar] [CrossRef]
  18. Itami, S.; Moriyama, T.; Miyabe, Y.; Karasawa, K.; Nitta, K. A Novel Scoring System Based on Oxford Classification Indicating Steroid Therapy Use for IgA Nephropathy. Kidney Int. Rep. 2022, 7, 99–107. [Google Scholar] [CrossRef]
  19. Zhang, X.; Lv, J.; Liu, P.; Xie, X.; Wang, M.; Liu, D.; Zhang, H.; Jin, J. Poly-IgA Complexes and Disease Severity in IgA Nephropathy. Clin. J. Am. Soc. Nephrol. 2021, 16, 1652–1664. [Google Scholar] [CrossRef]
  20. Caster, D.J.; Abner, C.W.; Walker, P.D.; Wang, K.; Heo, J.; Rava, A.R.; Bunke, M. Clinicopathological Characteristics of Adult IgA Nephropathy in the United States. Kidney Int. Rep. 2023, 8, 1792–1800. [Google Scholar] [CrossRef]
  21. Tsai, S.-F.; Wu, M.-J.; Wen, M.-C.; Chen, C.-H. Serologic and histologic predictors of long-term renal outcome in biopsy-confirmed IgA nephropathy (Haas classification): An observational study. J. Clin. Med. 2019, 8, 848. [Google Scholar] [CrossRef] [PubMed]
  22. Bobart, S.A.; Alexander, M.P.; Shawwa, K.; Vaughan, L.E.; Ghamrawi, R.; Sethi, S.; Cornell, L.; Glassock, R.J.; Fervenza, F.C.; Zand, L. The association of microhematuria with mesangial hypercellularity, endocapillary hypercellularity, crescent score and renal outcomes in immunoglobulin A nephropathy. Nephrol. Dial. Transplant. 2021, 36, 840–847. [Google Scholar] [CrossRef] [PubMed]
  23. Markowitz, G. Updated Oxford Classification of IgA nephropathy: A new MEST-C score. Nat. Rev. Nephrol. 2017, 13, 385–386. [Google Scholar] [CrossRef] [PubMed]
  24. Coppo, R.; Fervenza, F.C. Persistent microscopic hematuria as a risk factor for progression of iga nephropathy: New floodlight on a nearly forgotten biomarker. J. Am. Soc. Nephrol. 2017, 28, 2831–2834. [Google Scholar] [CrossRef]
  25. Haaskjold, Y.L.; Lura, N.G.; Bjørneklett, R.; Bostad, L.S.; Knoop, T.; Bostad, L. Long-term follow-up of IgA nephropathy: Clinicopathological features and predictors of outcomes. Clin. Kidney J. 2023, 16, 2514–2522. [Google Scholar] [CrossRef]
  26. Ruggenenti, P.; Perna, A.; Gherardi, G.; Garini, G.; Zoccali, C.; Salvadori, M.; Scolari, F.; Schena, F.P.; Remuzzi, G. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999, 354, 359–364. [Google Scholar] [CrossRef]
  27. Maschio, G.; Alberti, D.; Locatelli, F.; Mann, J.F.E.; Motolese, M.; Ponticelli, C.; Ritz, E.; Janin, G.; Zucchelli, P. Angiotensin-converting enzyme inhibitors and kidney protection: The AIPRI trial. J. Cardiovasc. Pharmacol. 1999, 33, S16–S20. [Google Scholar] [CrossRef]
  28. Maschio, G.; Cagnoli, L.; Claroni, F.; Fusaroli, M.; Rugiu, C.; Sanna, G.; Sasdelli, M.; Zuccalà, A.; Zucchelli, P. ACE inhibition reduces proteinuria in normotensive patients with IgA nephropathy: A multicentre, randomized, placebo-controlled study. Nephrol. Dial. Transplant. 1994, 9, 265–269. [Google Scholar] [CrossRef]
  29. Kanno, Y.; Okada, H.; Saruta, T.; Suzuki, H. Blood pressure reduction associated with preservation of renal function in hypertensive patients with IgA nephropathy: A 3-year follow-up. Clin. Nephrol. 2000, 54, 360–365. [Google Scholar]
  30. Russo, D.; Minutolo, R.; Pisani, A.; Esposito, R.; Signoriello, G.; Andreucci, M.; Balletta, M.M. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am. J. Kidney Dis. 2001, 38, 18–25. [Google Scholar] [CrossRef]
  31. Kunz, R.; Friedrich, C.; Wolbers, M.; Mann, J.F. Meta-analysis: Effect of monotherapy and combination therapy with inhibitors of the renin–angiotensin system on proteinuria in renal disease. Ann. Intern. Med. 2008, 148, 30–48. [Google Scholar] [CrossRef] [PubMed]
  32. Catapano, F.; Chiodini, P.; De Nicola, L.; Minutolo, R.; Zamboli, P.; Gallo, C.; Conte, G. Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: Meta-analysis and metaregression. Am. J. Kidney Dis. 2008, 52, 475–485. [Google Scholar] [CrossRef] [PubMed]
  33. Chagnac, A.; Herman, M.; Zingerman, B.; Erman, A.; Rozen-Zvi, B.; Hirsh, J.; Gafter, U. Obesity-induced glomerular hyperfiltration: Its involvement in the pathogenesis of tubular sodium reabsorption. Nephrol. Dial. Transplant. 2008, 23, 3946–3952. [Google Scholar] [CrossRef] [PubMed]
  34. Tanaka, M.; Yamada, S.; Iwasaki, Y.; Sugishita, T.; Yonemoto, S.; Tsukamoto, T.; Fukui, S.; Takasu, K.; Muso, E. Impact of obesity on IgA nephropathy: Comparative ultrastructural study between obese and non-obese patients. Nephron Clin. Pract. 2009, 112, c71–c78. [Google Scholar] [CrossRef] [PubMed]
  35. Ariyasu, Y.; Torikoshi, K.; Tsukamoto, T.; Yasuda, T.; Yasuda, Y.; Matsuzaki, K.; Hirano, K.; Kawamura, T.; Yokoo, T.; Maruyama, S.; et al. Analysis of the impact of obesity on the prognosis of IgA nephropathy according to renal function and sex. Clin. Exp. Nephrol. 2024, 11, 1155–1167. [Google Scholar] [CrossRef] [PubMed]
  36. Konishi, Y.; Nishiyama, A.; Morikawa, T.; Kitabayashi, C.; Shibata, M.; Hamada, M.; Kishida, M.; Hitomi, H.; Kiyomoto, H.; Miyashita, T.; et al. Relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with Iga nephropathy. Hypertension 2011, 58, 205–211. [Google Scholar] [CrossRef] [PubMed]
  37. Agrawal, S.; He, J.C.; Tharaux, P.-L. Nuclear receptors in podocyte biology and glomerular disease. Nat. Rev. Nephrol. 2021, 17, 185–204. [Google Scholar] [CrossRef]
  38. Locatelli, F.; Del Vecchio, L.; Ponticelli, C. Systemic and targeted steroids for the treatment of IgA nephropathy. Clin. Kidney J. 2023, 16 (Suppl. S2), ii40–ii46. [Google Scholar] [CrossRef] [PubMed]
  39. Pozzi, C.; Bolasco, P.; Fogazzi, G.; Andrulli, S.; Altieri, P.; Ponticelli, C.; Locatelli, F. Corticosteroids in IgA nephropathy: A randomised controlled trial. Lancet 1999, 353, 883–887. [Google Scholar] [CrossRef]
  40. Pozzi, C.; Andrulli, S.; Del Vecchio, L.; Melis, P.; Fogazzi, G.B.; Altieri, P.; Ponticelli, C.; Locatelli, F. Corticosteroid effectiveness in IgA nephropathy: Long-term results of a randomised, controlled trial. J. Am. Soc. Nephrol. 2004, 15, 157–163. [Google Scholar] [CrossRef]
  41. Rauen, T.; Eitner, F.; Fitzner, C.; Sommerer, C.; Zeier, M.; Otte, B.; Panzer, U.; Peters, H.; Benck, U.; Mertens, P.R.; et al. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N. Engl. J. Med. 2015, 373, 2225–2236. [Google Scholar] [CrossRef] [PubMed]
  42. Tesar, V.; Troyanov, S.; Bellur, S.; Verhave, J.C.; Cook, H.T.; Feehally, J.; Roberts, I.S.; Cattran, D.; Coppo, R. Corticosteroids in IgA nephropathy: A retrospective analysis from the VALIGA study. J. Am. Soc. Nephrol. 2015, 26, 2248–2258. [Google Scholar] [CrossRef]
  43. Lv, J.; Wong, M.G.; Hladunewich, M.A.; Jha, V.; Hooi, L.S.; Monaghan, H.; Zhao, M.; Barbour, S.; Jardine, M.J.; Reich, H.N.; et al. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients with IgA Nephropathy. The TESTING Randomized Clinical Trial. JAMA 2022, 327, 1888–1898. [Google Scholar] [CrossRef]
  44. Novak, J.; Barratt, J.; Julian, B.A.; Renfrow, M.B. Aberrant glycosylation of the IgA1 molecule in IgA nephropathy. Semin. Nephrol. 2018, 38, 461–476. [Google Scholar] [CrossRef]
  45. Fellström, B.C.; Barratt, J.; Cook, H.; Coppo, R.; Feehally, J.; de Fijter, J.W.; Floege, J.; Hetzel, G.; Jardine, A.G.; Locatelli, F.; et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): A double-blind, randomised, placebo-controlled phase 2b trial. Lancet 2017, 389, 2117–2127. [Google Scholar] [CrossRef] [PubMed]
  46. Barratt, J.; Lafayette, R.; Kristensen, J.; Stone, A.; Cattran, D.; Floege, J.; Tesar, V.; Trimarchi, H.; Zhang, H.; Eren, N.; et al. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int. 2023, 103, 391–402. [Google Scholar] [CrossRef]
  47. Hou, F.F.; Xie, D.; Wang, J.; Xu, X.; Yang, X.; Ai, J.; Nie, S.; Liang, M.; Wang, G.; Jia, N.; et al. Effectiveness of mycophenolate mofetil among patients with progressive IgA nephropathy: A randomized clinical trial. JAMA Netw. Open 2023, 6, e2254054. [Google Scholar] [CrossRef]
  48. Dooley, M.A.; Jayne, D.; Ginzler, E.M.; Isenberg, D.; Olsen, N.J.; Wofsy, D.; Eitner, F.; Appel, G.B.; Contreras, G.; Lisk, L.; et al. Mycophenolate versus Azathioprine as Maintenance Therapy for Lupus Nephritis. N. Engl. J. Med. 2011, 365, 1886–1895. [Google Scholar] [CrossRef] [PubMed]
  49. Jabbour, S.A.; Goldstein, B.J. Sodium glucose co-transporter 2 inhibitors: Blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int. J. Clin. Pract. 2008, 62, 1279–1284. [Google Scholar] [CrossRef]
  50. van den Heuvel, L.P.; Assink, K.; Willemsen, M.A.; Monnens, L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum. Genet. 2002, 111, 544–547. [Google Scholar] [CrossRef]
  51. Cherney, D.Z.I.; Dekkers, C.C.J.; Barbour, S.J.; Cattran, D.; Gafor, A.H.A.; Greasley, P.J.; Laverman, G.D.; Lim, S.K.; Di Tanna, G.L.; Reich, H.N.; et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): A randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol. 2020, 8, 582–593. [Google Scholar] [CrossRef] [PubMed]
  52. Wheeler, D.C.; Stefánsson, B.V.; Jongs, N. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021, 9, 22–31. [Google Scholar] [CrossRef] [PubMed]
  53. Tesar, V. SGLT2 inhibitors in non-diabetic kidney disease. Adv. Clin. Exp. Med. 2022, 31, 105–107. [Google Scholar] [CrossRef]
  54. Wheeler, D.C.; Toto, R.D.; Stefánsson, B.V.; Jongs, N.; Chertow, G.M.; Greene, T.; Hou, F.F.; McMurray, J.J.; Pecoits-Filho, R.; Correa-Rotter, R.; et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 2021, 100, 215–224. [Google Scholar] [CrossRef]
  55. Anders, H.-J.; Peired, A.J.; Romagnani, P. SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions. Nephrol. Dial. Transplant. 2022, 37, 1609–1615. [Google Scholar] [CrossRef]
  56. Tuttle, K.R.; Hauske, S.J.; Canziani, M.E.; Caramori, M.L.; Cherney, D.; Cronin, L.; Heerspink, H.J.L.; Hugo, C.; Nangaku, M.; Rotter, R.C.; et al. Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: A randomised, controlled, phase 2 trial. Lancet 2023, 403, 379–390. [Google Scholar] [CrossRef] [PubMed]
  57. Mårup, F.H.; Thomsen, M.B.; Birn, H. Additive effects of dapagliflozin and finerenone on albuminuria in non-diabetic CKD: An open-label randomized clinical trial. Clin. Kidney J. 2023, 17, sfad249. [Google Scholar] [CrossRef] [PubMed]
  58. Heerspink, H.J.; Radhakrishnan, J.; Alpers, C.E.; Barratt, J.; Bieler, S.; Diva, U.; Inrig, J.; Komers, R.; Mercer, A.; Noronha, I.L.; et al. Sparsentan in patients with IgA nephropathy: A prespecified interim analysis from a randomised, double-blind, active- controlled clinical trial. Lancet 2023, 401, 1584–1594. [Google Scholar] [CrossRef]
  59. Campbell, K.N.; Griffin, S.; Trachtman, H.; Geletka, R.; Wong, M.G. Practical Considerations for the Use of Sparsentan in the Treatment of Patients with IgAN in Clinical Practice. Int. J. Nephrol. Renov. Dis. 2023, 16, 281–291. [Google Scholar] [CrossRef]
  60. Barton, M.; Tharaux, P.-L. Endothelin and the podocyte. Clin. Kidney J. 2012, 5, 17–27. [Google Scholar] [CrossRef] [PubMed]
  61. Poppelaars, F.; Faria, B.; Schwaeble, W.; Daha, M.R. The Contribution of Complement to the Pathogenesis of IgA Nephropathy: Are Complement-Targeted Therapies Moving from Rare Disorders to More Common Diseases? J. Clin. Med. 2021, 10, 4715. [Google Scholar] [CrossRef] [PubMed]
  62. Ricklin, D.; Mastellos, D.C.; Reis, E.S.; Lambris, J.D. The renaissance of complement therapeutics. Nat. Rev. Nephrol. 2018, 14, 26–47. [Google Scholar] [CrossRef] [PubMed]
  63. Tortajada, A.; Gutiérrez, E.; de Jorge, E.G.; Anter, J.; Segarra, A.; Espinosa, M.; Blasco, M.; Roman, E.; Marco, H.; Quintana, L.F.; et al. Elevated factor H–related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy. Kidney Int. 2017, 92, 953–963. [Google Scholar] [CrossRef] [PubMed]
  64. Evans, D.J.; Williams, D.G.; Peters, D.K.; Sissons, J.G.P.; Boulton-Jones, J.M.; Ogg, C.S.; Cameron, J.S.; Hoffbrand, B.I. Glomerular Deposition of Properdin in Henoch-Schonlein Syndrome and Idiopathic Focal Nephritis. BMJ 1973, 3, 326–328. [Google Scholar] [CrossRef]
  65. Maillard, N.; Wyatt, R.J.; Julian, B.A.; Kiryluk, K.; Gharavi, A.; Fremeaux-Bacchi, V.; Novak, J. Current Understanding of the Role of Complement in IgA Nephropathy. J. Am. Soc. Nephrol. 2015, 26, 1503–1512. [Google Scholar] [CrossRef]
  66. Wu, D.; Li, X.; Yao, X.; Zhang, N.; Lei, L.; Zhang, H.; Tang, M.; Ni, J.; Ling, C.; Chen, Z.; et al. Mesangial C3 deposition and serum C3 levels predict renal outcome in IgA nephropathy. Clin. Exp. Nephrol. 2021, 25, 641–651. [Google Scholar] [CrossRef]
  67. Stangou, M.; Alexopoulos, E.; Pantzaki, A.; Leonstini, M.; Memmos, D. C5b-9 glomerular deposition and tubular α3β1-integrin expression are implicated in the development of chronic lesions and predict renal function outcome in immunoglobulin A nephropathy. Scand. J. Urol. Nephrol. 2008, 42, 373–380. [Google Scholar] [CrossRef]
  68. Segarra, A.; Romero, K.; Agraz, I.; Ramos, N.; Madrid, A.; Carnicer, C.; Jatem, E.; Vilalta, R.; Lara, L.E.; Ostos, E.; et al. Mesangial C4d Deposits in Early IgA Nephropathy. Clin. J. Am. Soc. Nephrol. 2018, 13, 258–264. [Google Scholar] [CrossRef]
  69. Endo, M.; Ohi, H.; Ohsawa, I.; Fujita, T.; Matsushita, M. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol. Dial. Transplant. 1998, 13, 1984–1990. [Google Scholar] [CrossRef]
  70. Bruchfeld, A.; Magin, H.; Nachman, P.; Parikh, S.; Lafayette, R.; Potarca, A.; Miao, S.; Bekker, P. C5a receptor inhibitor avacopan in immunoglobulin A nephropathy—An open-label pilot study. Clin. Kidney J. 2022, 15, 922–928. [Google Scholar] [CrossRef]
  71. Caravaca-Fontán, F.; Gutiérrez, E.; Sevillano, M.; Praga, M. Targeting complement in IgA nephropathy. Clin. Kidney J. 2023, 16 (Suppl. S2), ii28–ii39. [Google Scholar] [CrossRef] [PubMed]
  72. Medjeral-Thomas, N.R.; Cook, H.T.; Pickering, M.C. Complement activation in IgA nephropathy. Semin. Immunopathol. 2021, 43, 679–690. [Google Scholar] [CrossRef]
  73. Barratt, J.; Rovin, B.; Zhang, H.; Kashihara, N.; Maes, B.; Rizk, D.; Trimarchi, H.; Sprangers, B.; Meier, M.; Kollins, D.; et al. POS-546 efficacy and safety of iptacopan in iga nephropathy: Results of a randomized double-blind placebo-controlled phase 2 study at 6 months. Kidney Int. Rep. 2022, 7, S236. [Google Scholar] [CrossRef]
  74. Perkovic, V.; Barratt, J.; Rovin, B.; Kashihara, N.; Maes, B.; Zhang, H.; Trimarchi, H.; Kollins, D.; Papachristofi, O.; Jacinto-Sanders, S.; et al. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy. N. Engl. J. Med. 2024, 25. [Google Scholar] [CrossRef] [PubMed]
  75. Stern, R.M.; Connell, N.T. Ravulizumab: A novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther. Adv. Hematol. 2019, 10, 2040620719874728. [Google Scholar] [CrossRef] [PubMed]
  76. Kateifides, A.; Garlo, K.; Rice, K.; Spoerri, N.; Najafian, N. WCN23-0140 a phase 2 study evaluating the efficacy and safety of ravulizumab in patients with immunoglobulin a (Iga) nephropathy or proliferative lupus nephritis (Ln). Kidney Int. Rep. 2023, 8, S54–S55. [Google Scholar] [CrossRef]
  77. Zhai, Y.-L.; Zhu, L.; Shi, S.-F.; Liu, L.-J.; Lv, J.-C.; Zhang, H. Increased APRIL expression induces IgA1 aberrant glycosylation in IgA nephropathy. Medicine 2016, 95, e3099. [Google Scholar] [CrossRef]
  78. Castigli, E.; Scott, S.; Dedeoglu, F.; Bryce, P.; Jabara, H.; Bhan, A.K.; Mizoguchi, E.; Geha, R.S. Impaired IgA class switching in APRIL-deficient mice. Proc. Natl. Acad. Sci. USA 2004, 101, 3903–3908. [Google Scholar] [CrossRef]
  79. Mathur, M.; Barratt, J.; Suzuki, Y.; Engler, F.; Pasetti, M.F.; Yarbrough, J.; Sloan, S.; Oldach, D. Safety, tolerability, pharmacokinetics, and pharmacodynamics of VIS649 (sibeprenlimab), an APRIL-neutralizing IgG2 monoclonal antibody, in healthy volunteers. Kidney Int. Rep. 2022, 7, 993–1003. [Google Scholar] [CrossRef]
  80. Mathur, M.; Barratt, J.; Chacko, B.; Chan, T.M.; Kooienga, L.; Oh, K.-H.; Sahay, M.; Suzuki, Y.; Wong, M.G.; Yarbrough, J.; et al. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy. N. Engl. J. Med. 2024, 390, 20–31. [Google Scholar] [CrossRef]
  81. Barratt, J.; Tumlin, J.; Suzuki, Y.; Kao, A.; Aydemir, A.; Pudota, K.; Jin, H.; Gühring, H.; Appel, G. Randomized Phase II JANUS Study of Atacicept in Patients With IgA Nephropathy and Persistent Proteinuria. Kidney Int. Rep. 2022, 7, 1831–1841. [Google Scholar] [CrossRef] [PubMed]
  82. Lafayette, R.; Maes, B.; Israni, R.; Lin, C.; Wei, X.; Barbour, S.; Phoon, R.; Kim, S.G.; Tesar, V.; Floege, J.; et al. Phase 2b ORIGIN study open label extension with atacicept in patients with IgA nephropathy and persistent proteinuria: Week 72 interim analysis. Nephrol. Dial. Transplant. 2024, 39 (Suppl. S1), gfae069-0030-812. [Google Scholar] [CrossRef]
  83. Chábová, V.; Tesar, V.; Zabka, J.; Rychlik, I.; Merta, M.; Jirsa, M.; Stejskalová, A. Long term treatment of IgA nephropathy with cyclosporine A. Ren. Fail. 2000, 22, 55–62. [Google Scholar] [CrossRef]
  84. Cattran, D.C. Current status of cyclosporin A in the treatment of membranous, IgA and membranoproliferative glomerulonephritis. Clin. Nephrol. 1991, 35 (Suppl. S1), S43–S47. [Google Scholar]
  85. Song, Y.-H.; Cai, G.-Y.; Xiao, Y.-F.; Wang, Y.-P.; Yuan, B.-S.; Xia, Y.-Y.; Wang, S.-Y.; Chen, P.; Liu, S.-W.; Chen, X.-M. Efficacy and safety of calcineurin inhibitor treatment for IgA nephropathy: A meta-analysis. BMC Nephrol. 2017, 18, 61. [Google Scholar] [CrossRef]
  86. Lafayette, R.A.; Canetta, P.A.; Rovin, B.H.; Appel, G.B.; Novak, J.; Nath, K.A.; Sethi, S.; Tumlin, J.A.; Mehta, K.; Hogan, M.; et al. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction. J. Am. Soc. Nephrol. 2016, 28, 1306–1313. [Google Scholar] [CrossRef] [PubMed]
  87. Liu, L.-J.; Yang, Y.-Z.; Shi, S.-F.; Bao, Y.-F.; Yang, C.; Zhu, S.-N.; Sui, G.-L.; Chen, Y.-Q.; Lv, J.-C.; Zhang, H. Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Randomized Controlled Trial. Am. J. Kidney Dis. 2019, 74, 15–22. [Google Scholar] [CrossRef]
  88. Tang, C.; Lv, J.-C.; Shi, S.-F.; Chen, Y.-Q.; Liu, L.-J.; Zhang, H. Long-term safety and efficacy of hydroxychloroquine in patients with IgA nephropathy: A single-center experience. J. Nephrol. 2022, 35, 429–440. [Google Scholar] [CrossRef]
  89. Si, F.-L.; Tang, C.; Lv, J.-C.; Shi, S.-F.; Zhou, X.-J.; Liu, L.-J.; Zhang, H. Comparison between hydroxychloroquine and systemic corticosteroids in IgA nephropathy: A two-year follow-up study. BMC Nephrol. 2023, 24, 175. [Google Scholar] [CrossRef]
  90. Heerspink, H.J.L.; Parving, H.-H.; Andress, D.L.; Correa-Rotter, R.; Hou, F.-F.; Kitzman, D.W.; Kohan, D.; Makino, H.; McMurray, J.J.V.; Melnick, J.Z.; et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): A double-blind, randomised, placebo-controlled trial. Lancet 2019, 393, 1937–1947. [Google Scholar] [CrossRef] [PubMed]
  91. Heerspink, H.L.; Jardine, M.; Kohan, D.; Lafayette, R.; Levin, A.; Liew, A.; Zhang, H.; Glicklich, A.; Camargo, M.; King, A.; et al. POS-527 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Atrasentan in Patients with IgA Nephropathy (The ALIGN Study). Kidney Int. Rep. 2022, 7, S229–S230. [Google Scholar] [CrossRef]
  92. Dhillon, S. Telitacicept: First approval. Drugs 2021, 81, 1671–1675. [Google Scholar] [CrossRef] [PubMed]
  93. Lv, J.; Liu, L.; Hao, C.; Li, G.; Fu, P.; Xing, G.; Zheng, H.; Chen, N.; Wang, C.; Luo, P.; et al. Randomized Phase 2 Trial of Telitacicept in Patients with IgA Nephropathy with Persistent Proteinuria. Kidney Int. Rep. 2022, 8, 499–506. [Google Scholar] [CrossRef] [PubMed Central]
  94. McAdoo, S.; Tam, F.W. Role of the Spleen Tyrosine Kinase Pathway in Driving Inflammation in IgA Nephropathy. Semin. Nephrol. 2018, 38, 496–503. [Google Scholar] [CrossRef] [PubMed]
  95. Floege, J.; Lafayette, R.; Barratt, J.; Schwartz, B.; Manser, P.T.; Patel, U.D.; Pineda, L.; Faulhaber, N.; Boxhammer, R.; Haertle, S.; et al. #425 Felzartamab (anti-CD38) in patients with IgA Nephropathy—Interim results from the IGNAZ study. Nephrol. Dial. Transplant. 2024, 39, gfae069-0139-425. [Google Scholar] [CrossRef]
  96. Evans, L.S.; Lewis, K.E.; DeMonte, D.; Bhandari, J.G.; Garrett, L.B.; Kuijper, J.L.; Ardourel, D.; Wolfson, M.F.; Debrot, S.; Mudri, S.; et al. Povetacicept, an Enhanced DualAPRIL/BAFFAntagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell–Related Autoimmune Diseases. Arthritis Rheumatol. 2023, 75, 1187–1202. [Google Scholar] [CrossRef] [PubMed]
  97. Kawamura, T.; Yoshimura, M.; Miyazaki, Y.; Okamoto, H.; Kimura, K.; Hirano, K.; Matsushima, M.; Utsunomiya, Y.; Ogura, M.; Yokoo, T.; et al. A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy. Nephrol. Dial. Transplant. 2014, 29, 1546–1553. [Google Scholar] [CrossRef]
  98. Feehally, J.; Coppo, R.; Troyanov, S.; Bellur, S.S.; Cattran, D.; Cook, T.; Roberts, I.S.; Verhave, J.C.; Camilla, R.; Vergano, L.; et al. Tonsillectomy in a European cohort of 1147 patients with IgA nephropathy. Nephron 2016, 132, 15–24. [Google Scholar] [CrossRef] [PubMed]
  99. Chou, H.H.; Chiou, Y.Y.; Hung, P.H.; Chiang, P.C.; Wang, S.T. Omega-3 fatty acids ameliorate proteinuria but not renal function in IgA nephropathy: A meta-analysis of randomized controlled trials. Nephron. Clin. Pract. 2012, 121, c30–c35. [Google Scholar] [CrossRef]
  100. Lauriero, G.; Abbad, L.; Vacca, M.; Celano, G.; Chemouny, J.M.; Calasso, M.; Berthelot, L.; Gesualdo, L.; De Angelis, M.; Monteiro, R.C. Fecal Microbiota Transplantation Modulates Renal Phenotype in the Humanized Mouse Model of IgA Nephropathy. Front. Immunol. 2021, 12, 694787. [Google Scholar] [CrossRef]
  101. Manno, C.; Torres, D.D.; Rossini, M.; Pesce, F.; Schena, F.P. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol. Dial. Transplant. 2009, 24, 3694–3701. [Google Scholar] [CrossRef] [PubMed]
  102. Schena, F.P.; Cox, S.N. Is it time for personalized therapy in IgA nephropathy patients? J. Nephrol. 2023, 36, 2171–2173. [Google Scholar] [CrossRef] [PubMed]
Kidneydial 04 00019 g001
Figure 1. The 4-Hit hypothesis of IGAN.
Figure 1. The 4-Hit hypothesis of IGAN.
Kidneydial 04 00019 g001
Kidneydial 04 00019 g002
Figure 2. Mechanism of action of SGLT2. SGLT2 inhibition affects multiple sites in the nephron. This figure summarizes the effect of SGLT2i on a single nephron. In the diabetic kidney, glomerular hyperfiltration, dependent on increased intraglomerular capillary pressure, is a detrimental process that leads to the loss of the permselective properties of the glomerular barrier to proteins, resulting in albuminuria and ESKF. In T2D patients, because of a high filtered load of glucose, reabsorption of glucose and sodium is increased in the proximal tubule via SGLT2 by up to 50%, resulting in the diminished delivery of sodium to the macula densa. Legend: ATPase = adenosine triphosphatase; GLUT2 = glucose transport 2; ESKF end-stage kidney failure; T2D: type 2 diabetes.
Figure 2. Mechanism of action of SGLT2. SGLT2 inhibition affects multiple sites in the nephron. This figure summarizes the effect of SGLT2i on a single nephron. In the diabetic kidney, glomerular hyperfiltration, dependent on increased intraglomerular capillary pressure, is a detrimental process that leads to the loss of the permselective properties of the glomerular barrier to proteins, resulting in albuminuria and ESKF. In T2D patients, because of a high filtered load of glucose, reabsorption of glucose and sodium is increased in the proximal tubule via SGLT2 by up to 50%, resulting in the diminished delivery of sodium to the macula densa. Legend: ATPase = adenosine triphosphatase; GLUT2 = glucose transport 2; ESKF end-stage kidney failure; T2D: type 2 diabetes.
Kidneydial 04 00019 g002
Kidneydial 04 00019 g003
Figure 3. ALGORITHM for the TREATMENT of IgAN nephropathy. LEGEND: acei: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; SGLT2: Sodium–GLucose coTransporter-2 inhibitor; AT1: angiotensin II receptor; Pozzi-Locatelli [39] or Manno [101] scheme, MASP: mannan-associated lectin-binding serine protease; MMF: Mycophenolate mofetil; C5: complement component C5 (the initiator of the effector terminal phase of the complement system); APRIL: A PRoliferation-Inducing Ligand; MEST-C: Oxford classification* (excluding crescents: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). Higher MEST-C scores, mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents. (* the Oxford Classification has not been validated as a tool for treatment selection).
Figure 3. ALGORITHM for the TREATMENT of IgAN nephropathy. LEGEND: acei: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; SGLT2: Sodium–GLucose coTransporter-2 inhibitor; AT1: angiotensin II receptor; Pozzi-Locatelli [39] or Manno [101] scheme, MASP: mannan-associated lectin-binding serine protease; MMF: Mycophenolate mofetil; C5: complement component C5 (the initiator of the effector terminal phase of the complement system); APRIL: A PRoliferation-Inducing Ligand; MEST-C: Oxford classification* (excluding crescents: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). Higher MEST-C scores, mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents. (* the Oxford Classification has not been validated as a tool for treatment selection).
Kidneydial 04 00019 g003
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Scarpioni, R.; Valsania, T. IgA Nephropathy: What Is New in Treatment Options? Kidney Dial. 2024, 4, 223-245. https://doi.org/10.3390/kidneydial4040019

AMA Style

Scarpioni R, Valsania T. IgA Nephropathy: What Is New in Treatment Options? Kidney and Dialysis. 2024; 4(4):223-245. https://doi.org/10.3390/kidneydial4040019

Chicago/Turabian Style

Scarpioni, Roberto, and Teresa Valsania. 2024. "IgA Nephropathy: What Is New in Treatment Options?" Kidney and Dialysis 4, no. 4: 223-245. https://doi.org/10.3390/kidneydial4040019

APA Style

Scarpioni, R., & Valsania, T. (2024). IgA Nephropathy: What Is New in Treatment Options? Kidney and Dialysis, 4(4), 223-245. https://doi.org/10.3390/kidneydial4040019

Article Metrics

Back to TopTop