Summary Of Progress in Treatment Of Glomerulonephritis in 2022
Feb 07, 2023
2022 has just passed, and this year, significant progress has been made in the treatment of immunoglobulin A (IgA) nephropathy and lupus nephritis (LN). Especially in the field of minimal change disease (MCD), potential new biomarkers have been discovered, which may have a huge impact on the diagnosis, treatment, and prognosis of MCD and even another immune-mediated glomerulonephritis.
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In February 2023, the journal Nature Review of Nephrology published an annual summary of the above content by American scholars, and there are 5 progress hotspots worthy of attention. This article interprets the review based on the launch of relevant new drugs in China and the progress of clinical research for readers' reference.
Progress 1: The use of glucocorticoids should be reduced in patients with IgA nephropathy
Due to unstable efficacy and safety issues, the application of glucocorticoids in patients with IgA nephropathy has been controversial.
In 2022, the TESTING study confirmed that compared with full-dose glucocorticoids, patients with IgA nephropathy should receive reduced-dose glucocorticoids. A total of 503 patients diagnosed with IgA nephropathy were included in the study. The average 24-hour urine protein was 2.46g/d, and the average estimated glomerular filtration rate (eGFR) was 61.5ml/min/1.73㎡.
It is worth noting that 75% of the patients in this study originated from China. The subjects were randomly divided into the methylprednisolone group and the placebo group. The initial dose of the methylprednisolone group was 0.6~0.8mg/kg/d, the maximum dose was 48mg/d, and the monthly reduction was 4mg/d, and antibiotics were used to prevent pneumonia. After a mean follow-up of 4.2 years, 28.8% of patients in the methylprednisolone group experienced renal composite events (40% decline in eGFR, renal failure, or death from kidney disease), compared with 43.1% in the placebo group.
Compared with the placebo group, the risk of renal function decline in the methylprednisolone group was reduced by 47% (HR=0.53 [95%CI0.39-0.72], P <0.001), and the full-dose methylprednisolone treatment regimen could reduce the risk of renal function decline by 42%. % risk of decreased renal function (HR=0.58, 95% CI, 0.41-0.81), and reduced methylprednisolone (0.4mg/kg/d, maximum 32mg/d) treatment can reduce the risk by 73% (HR= 0.27; 95% CI, 0.11-0.65). Interestingly, there were significantly fewer serious adverse events in the reduced-dose methylprednisolone group compared with the full-dose methylprednisolone group (10.9% vs 2.8%).
The TESTING study has made a great contribution to the standardized treatment of hormones for IgA nephropathy and provided solid evidence-based medical evidence for the revision of the KDIGO international guidelines for glomerulonephritis. This study once again proves that by changing the hormone therapy regimen for IgA nephropathy, it is possible to avoid drug-related adverse reactions without reducing the efficacy of glucocorticoids, which is helpful for the prognosis of patients1.
Progress 2: NEFECON treatment of IgA nephropathy significantly reduces proteinuria and delays the decline of eGFR
A series of studies have shown that intestinal mucosal immunity is an important source of IgA nephropathy. Under normal circumstances, galactose-deficient IgA1 (GD-IgA1) is mainly produced in the Peyer's patches in the terminal ileum and can be directly secreted into the intestinal tract, with only a small amount entering the systemic circulation. However, for patients with IgA nephropathy, a large amount of GD-IgA1 will stray into the systemic circulation, which is an important cause of IgA nephropathy. NEFECON (Targeted Delayed-Release Budesonide Capsules) is an ideal targeted therapy drug, which can precisely release budesonide in the terminal ileum, reduce the production of GD-IgA1, and then treat IgA nephropathy at the upstream stage of pathogenesis1.
The NeflgArd study evaluated the efficacy and safety of NEFECON in patients with IgA nephropathy. Enrolled patients were biopsy-confirmed IgA nephropathy patients with eGFR ≥ 35ml/min/1.73㎡, proteinuria ≥ 1g/d or urine protein-to-creatinine ratio (UPCR) ≥ 0.8g/g, all patients received the maximum dose of renin Angiotensin inhibitor (RASi) therapy. After 9 months, NEFECON 16 mg administered once daily significantly reduced patients' UPCR or proteinuria levels compared to placebo.
At 9 months, proteinuria levels were reduced by 34% from baseline in patients in the NEFECON group (n=97) versus 5% in the placebo group (n=102), with a 31% difference in UPCR reduction between the two groups (95 % CI, 16%~42%; p=0.0001). At the same time, the eGFR decline rate of patients in the NEFECON group was reduced (eGFR decreased by 0.17ml/min/1.73㎡ in the NEFECON group, and decreased by 4.04 ml/min/1.73㎡ in the placebo group). Notably, patients in the NEFECON group had a lower risk of adverse events and no significantly increased risk of infection1.
Previously, NEFECON had been approved for marketing by the US Food and Drug Administration, becoming the first therapeutic drug in the world to obtain indications for IgA nephropathy1. On July 15, 2022, NEFECON was also listed in the European Union (link: Nefecon was approved by EMA again, IgA nephropathy The treatment of kidney disease can be expected in the future). On December 26 of the same year, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) announced on its official website that targeted delayed-release budesonide capsules had been included in the list of priority review varieties, and the proposed indications were drugs with a risk of progression. Adult patients with primary IgA nephropathy 2.
Progress 3: Anifrolumab treatment may be beneficial to LN
More than 80% of patients with LN have high type I interferon gene signatures (High type I interferon gene signatures, IFNGS), which is more obvious in active LN. Anifrolumab is a fully human monoclonal antibody that binds to type I interferon receptor subunit 1 and blocks the activity of all type I interferons, including IFN-α, IFN-β, and IFN-ω. In theory, anifrolumab can effectively treat active LN1.
TULIP-LN was a 2-year, phase 2, randomized, placebo-controlled study. The study inclusion criteria were 18-70 years old, confirmed by renal biopsy as class II or IV LN, UPCR > 1mg/mg, eGFR ≥ 35ml/min/1.73㎡, in line with the 11 classification criteria of the American College of Rheumatology in 1997 At least 4.
The enrolled patients were randomly divided into groups according to the ratio of 1:1:1: 1) Anifrolumab basic regimen group (300mg); 2) Anifrolumab intensive regimen group (900mg for the first 3 doses, followed by 300mg/dose treatment); 3) placebo All patients were treated with glucocorticoids and mycophenolate mofetil (MMF). The primary endpoint of the study was the change of 24-hour urine protein-to-creatinine ratio (UPCR) at 52 weeks.
At week 52, there was no significant difference in 24h UPCR of patients in the Anifrolumab combination group (basic regimen + intensive regimen) compared with the placebo group (69% vs. 70%; P = 0.905), however, in the Anifrolumab group receiving Among patients with the intensive regimen, more patients (45.5% vs. 31.1%) achieved complete renal remission (definition: 24h UPCR≤0.7mg/mg, eGFR≥60ml/min/1.73㎡ or the rate of decline compared with baseline <20%; in addition, Anifrolumab was not discontinued or other restricted drugs were used).
Compared with the placebo group, fewer patients in the Anifrolumab basic regimen group achieved complete renal remission (16.3% vs 31.1%). Pharmacological analysis showed that the reason why the intensive treatment regimen was superior to the basic treatment regimen was dose-related, and perhaps the optimal effective dose of Anifrolumab was consistent with the intensive treatment regimen. In terms of adverse events, the risk of herpes zoster was higher in the anifrolumab group compared with the placebo group, while other adverse events did not differ significantly1.
Although the effect of Anifrolumab on LN needs to be further studied, this study provides great help for the selection of Anifrolumab dose and the design of future studies1. In addition, it was reported in 21 that CDE has obtained implied permission through the clinical trial application of Anifrolumab, which is intended to be developed for moderately to severely active systemic lupus erythematosus3.
Progress 4: The best time to stop maintenance immunotherapy for some LN patients maybe 2 years
LN is a relapsing disease. In long-term clinical practice, even if LN patients achieve complete renal remission and their symptoms gradually disappear, they will still receive glucocorticoid therapy for several years, that is, maintenance immunotherapy (IST). However, the optimal timing for the discontinuation of IST is still controversial.
The WIN-Lupus study is a multicenter clinical study designed to evaluate the optimal time to stop IST in patients with hyperplastic LN. Inclusion criteria include ① age ≥ 18 years; ② having received maintenance immunosuppressive therapy for 2 to 3 years; ③ using hydroxychloroquine sulfate; ④ stable remission time ≥ 12 months.
A total of 96 patients with LN were included in the study, who were randomly divided into the drug withdrawal group (continue to receive immunosuppressive therapy for more than 3 months) and continuous immunotherapy group (continue to receive immunosuppressive therapy for more than 2 years) group according to 1:1. The recurrence rate of proliferative LN was 10.4% in the continuation immunotherapy group and 25% in the discontinuation group (difference 14.8%, 95% CI [-1.9; 31.5]), the recurrence rate did not reach non-inferiority, and the time to recurrence in the two groups was No difference. In terms of SLE symptoms, there was no significant difference between the two groups of patients (P=0.034), that is, the non-inferiority endpoint was not reached in the drug withdrawal group.
In addition, the continuation of the immunotherapy group and withdrawal group were significantly higher in death (continuation of immunosuppressive treatment group: n = 0; withdrawal group: n = 0), serious kidney-related adverse events (n = 14; n = 17), infection (n = 19; n = 14) there was no significant difference; there was no significant difference between the two groups in terms of glucocorticoid dosage and creatinine level. Of note, severe SLE exacerbations (renal/extrarenal) occurred less frequently in the immunosuppressive group compared with the continued immunotherapy group (5/40 vs 14/44; P=0.035).
However, the small number of participants in this study and the short follow-up time make it difficult to draw relevant conclusions on the optimal IST withdrawal time. The researchers pointed out that in the 24-month withdrawal group, many patients did not relapse LN, and perhaps the next step of research should be to identify LN patients with a low risk of recurrence and implement an individualized and safe drug withdrawal plan1.
Progress 5: ANeA may be a revolutionary discovery for the diagnosis and treatment of MCD
The pathological basis of MCD is the destruction of the glomerular filtration barrier and the loss of the perforated membrane structure. Some scholars have found that in rodent MCD models, anti-nephrin autoantibodies (ANeA) are positive, and the better efficacy of B cell-targeted therapy may be related to ANeA.
In a study of 62 children and adults with biopsy-confirmed MCD, 29% tested positive for ANeA. In the control group with positive anti-phospholipase A2 receptor (PLA2R) antibody, only 2% of the patients tested positive for ANeA. Furthermore, the presence of circulating ANeA was positively correlated with punctate IgG staining with renin colocalization in podocytes.
In children with steroid-dependent MCD who have progressed to end-stage renal disease, massive proteinuria persists after kidney transplantation and is associated with high pre-transplant ANeA levels. More interestingly, ANeA levels gradually decrease or disappear when MCD symptoms resolve.
This discovery will have a huge impact on the diagnosis and treatment of MCD. Like the discovery of anti-PLA2R antibodies in patients with membranous nephropathy in 2009, this newly discovered antibody may be a specific antibody for some MCD patients, which can classify MCD patients. In MCD treatment, ANeA may reflect the effectiveness of treatment. Of course, these ideas will require further research in the future before they can be used in clinical practice. In short, ANeA may be a unique biomarker for MCD and its utility needs to be further explored1.
During the past year, IgA nephropathy and immunomodulatory therapies for LN remained a research focus in the field of glomerulonephritis. For IgA nephropathy-related drugs, NEFECON has been approved by many countries; although the LN study did not meet its primary endpoint, the relevant findings provide insights for future research design and treatment strategies. Finally, the discovery of the ANeA antibody will change people's understanding of the pathogenesis of MCD, thereby improving the diagnosis and treatment of MCD and benefiting patients.
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