Roccatello et al. [1] investigated the effectiveness and safety of mycophenolate mofetil (MMF) in combination with corticosteroids, compared to a 6-month course of glucocorticoids alone, in a group of 30 patients with proteinuric immunoglobulin A nephropathy (IgAN) who had active renal lesions (including proliferative endocapillary and extracapillary lesions and fibrinoid necrosis) identified through kidney biopsy. All patients received renin-angiotensin system blockers (RASBs) at the maximum tolerated dose as supportive therapy. The retrospective study demonstrated a significant reduction in proteinuria in both patient groups, with the mean follow-up period being 18.7 months for the first group receiving MMF in combination with corticosteroids, and 21.5 months for the group treated with corticosteroids alone. At the end of the follow-up period, the authors obtained a cumulative sparing dose of 6 g of corticosteroids in the group of patients who received the combined therapy (MMF and corticosteroids). The study is limited by its retrospective design and the small number of patients included. However, it highlights two important points: first, the central importance of kidney biopsy in determining therapy for IgAN patients, and second, the potential for MMF to reduce the overall dose of corticosteroids required for treatment. An international group of nephrologists dedicated 6 years (2004–2009) to developing the Oxford classification of the renal lesions in kidney biopsy from IgAN patients. Briefly, the classification is based on the grade of histological lesions as mesangial proliferation (M0,1), endocapillary proliferation (E0,1), glomerular sclerosis (S0,1) and tubulointerstitial lesions (T0,1,2). Eight years later, in 2017, the classification was revised and extracapillary proliferative lesions (C0,1,2) were included [2]. Thus, active renal lesions (E1 and C1,2) were differentiated from chronic renal lesions (T1,2). Unfortunately, the renal lesions were not considered in the first and second release of the KDIGO guidelines [3]. It is recommended that all patients receive intensive supportive therapy (renin-angiotensin system blockers) for at least 3–6 months following kidney biopsy. If the patient remains proteinuric (excreting more than 1 g per day) after this period, corticosteroids may be added to the treatment regimen. This means that active renal lesions become chronic in IgAN patients after 3 months of supportive therapy without immediate immunosuppressive therapy. This non-appropriate procedure has been adopted in all randomized clinical trials (RCTs) in the last 10 years, as shown in Table 1. The time lapse between the kidney biopsy and the randomization procedure fluctuated between 3 and 6 months of supportive therapy. All biopsy-proven IgAN patients (with active or chronic renal lesions) who were enrolled in those studies had chronic renal lesions because active renal lesions were not immediately treated with immunosuppressive therapy. There are several points to consider with this therapeutic approach. Firstly, corticosteroids may not be necessary for treating proteinuric IgAN patients with chronic renal lesions after supportive therapy. Newer drugs such as gliflozins and endothelin angiotensin receptor antagonists, when combined with RASBs, may effectively reduce proteinuria [4, 5]. Secondly, these drugs do not have to be limited to IgAN patients alone, but may also be used to treat other biopsy-proven chronic glomerular diseases. For example, sparsentan was initially shown to be effective and safe in patients with focal and segmental glomerular sclerosis [6] before being tested in IgAN patients [5]. Additionally, it is worth mentioning the targeted-release formulation, budesonide (Nefecon), a corticosteroid that has been shown to reduce proteinuria in IgAN patients. However, it is uncertain whether this drug can also reduce active renal lesions. It would be valuable to investigate the potential of Nefecon when combined with an antiproteinuric drug in treating IgAN patients with active renal lesions following kidney biopsy. Unfortunately, this hypothesis cannot be proved by the NEFIGAN and NEFIgArD studies because all patients received RASBs alone for at least 3 months before Nefecon therapy.

Is it time for personalized therapy in IgA nephropathy patients?

Schena, Francesco Paolo
;
Cox, Sharon Natasha
2023-01-01

Abstract

Roccatello et al. [1] investigated the effectiveness and safety of mycophenolate mofetil (MMF) in combination with corticosteroids, compared to a 6-month course of glucocorticoids alone, in a group of 30 patients with proteinuric immunoglobulin A nephropathy (IgAN) who had active renal lesions (including proliferative endocapillary and extracapillary lesions and fibrinoid necrosis) identified through kidney biopsy. All patients received renin-angiotensin system blockers (RASBs) at the maximum tolerated dose as supportive therapy. The retrospective study demonstrated a significant reduction in proteinuria in both patient groups, with the mean follow-up period being 18.7 months for the first group receiving MMF in combination with corticosteroids, and 21.5 months for the group treated with corticosteroids alone. At the end of the follow-up period, the authors obtained a cumulative sparing dose of 6 g of corticosteroids in the group of patients who received the combined therapy (MMF and corticosteroids). The study is limited by its retrospective design and the small number of patients included. However, it highlights two important points: first, the central importance of kidney biopsy in determining therapy for IgAN patients, and second, the potential for MMF to reduce the overall dose of corticosteroids required for treatment. An international group of nephrologists dedicated 6 years (2004–2009) to developing the Oxford classification of the renal lesions in kidney biopsy from IgAN patients. Briefly, the classification is based on the grade of histological lesions as mesangial proliferation (M0,1), endocapillary proliferation (E0,1), glomerular sclerosis (S0,1) and tubulointerstitial lesions (T0,1,2). Eight years later, in 2017, the classification was revised and extracapillary proliferative lesions (C0,1,2) were included [2]. Thus, active renal lesions (E1 and C1,2) were differentiated from chronic renal lesions (T1,2). Unfortunately, the renal lesions were not considered in the first and second release of the KDIGO guidelines [3]. It is recommended that all patients receive intensive supportive therapy (renin-angiotensin system blockers) for at least 3–6 months following kidney biopsy. If the patient remains proteinuric (excreting more than 1 g per day) after this period, corticosteroids may be added to the treatment regimen. This means that active renal lesions become chronic in IgAN patients after 3 months of supportive therapy without immediate immunosuppressive therapy. This non-appropriate procedure has been adopted in all randomized clinical trials (RCTs) in the last 10 years, as shown in Table 1. The time lapse between the kidney biopsy and the randomization procedure fluctuated between 3 and 6 months of supportive therapy. All biopsy-proven IgAN patients (with active or chronic renal lesions) who were enrolled in those studies had chronic renal lesions because active renal lesions were not immediately treated with immunosuppressive therapy. There are several points to consider with this therapeutic approach. Firstly, corticosteroids may not be necessary for treating proteinuric IgAN patients with chronic renal lesions after supportive therapy. Newer drugs such as gliflozins and endothelin angiotensin receptor antagonists, when combined with RASBs, may effectively reduce proteinuria [4, 5]. Secondly, these drugs do not have to be limited to IgAN patients alone, but may also be used to treat other biopsy-proven chronic glomerular diseases. For example, sparsentan was initially shown to be effective and safe in patients with focal and segmental glomerular sclerosis [6] before being tested in IgAN patients [5]. Additionally, it is worth mentioning the targeted-release formulation, budesonide (Nefecon), a corticosteroid that has been shown to reduce proteinuria in IgAN patients. However, it is uncertain whether this drug can also reduce active renal lesions. It would be valuable to investigate the potential of Nefecon when combined with an antiproteinuric drug in treating IgAN patients with active renal lesions following kidney biopsy. Unfortunately, this hypothesis cannot be proved by the NEFIGAN and NEFIgArD studies because all patients received RASBs alone for at least 3 months before Nefecon therapy.
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