On November 3-6, 2022 Eastern Time, the 2022 Annual Meeting of the American Society of Nephrology-ASN Kidney Week, the highest-level renal academic event in the world, was successfully held in the United States. The conference brought together experts and scholars in the field of nephrology from around the world, providing an excellent platform for participants to present and exchange the latest academic progress in the field. ASN’s current vision is to build a world without kidney disease (A world without kidney disease). In order to achieve this grand vision, ASN proposed three key goals: strengthen screening to identify patients with kidney disease; fairness; strengthen social attention and increase research funding for nephrology. Next, let the author take you to review this academic feast, review the hot topics in this ASN Kidney Week meeting, the new progress in research related to the complement system, and the latest therapeutic targets for kidney diseases.
Wonderful——Compilation of ASN Kidney Week Hot Spots
This session includes 4 online early education projects: covering critical illness Monitor nephrology, glomerular disease, maintenance dialysis and renal pathophysiology; 3 offline early projects: Regenerative Medicine and Bioartificial Kidney Related Research Progress Conference, Renal Pathology Fundamentals, Bedside Point-of-Care Ultrasound in Nephrology in the application. There are various forms of conferences, including basic/clinical science conferences, clinical practice conferences, translational medicine conferences, educational seminars, poster conferences, and special event conferences, etc. The content involves the application of artificial intelligence (AI) in kidney biopsy, Viewpoints and implementation challenges of individualized nutritional care for renal disease, glomerular disease: clinical, prognosis, clinical trials, etc..
This ASN Kidney Week presents refreshing new methods of kidney disease management, including the VIDAS Nephrocheck system for assessing whether acute kidney injury (AKI) occurs within 12 hours, the hepatorenal syndrome “Orphan drug” – terlipressin, and the Minuteful Kidney app, a home kidney function AI detection system. In addition to the above-mentioned new methods of kidney disease management, experts and scholars at the meeting also discussed other cutting-edge advances in kidney disease, such as xenotransplantation and new advances in genetic testing and treatment related to nephrology.
Trace to the source—complement system and kidney disease
A large part of kidney diseases are complement-related kidney diseases. Some of these kidney diseases are mainly caused by complement, some are indirectly caused by complement, and some are caused by complement.[3 ]. During this ASN Kidney Week, there was also a wonderful sharing of research progress on the complement system.
New advances in complement biomarkers
At the ASN conference A study included 149 patients with suspected lupus nephritis (LN), who underwent renal biopsy and collected urine complement activation products (CAPs) C5a, C5b-9 and Ba factors, and compared CAPs levels with clinical and histological data. Spearman correlation analysis was carried out, and the results proved that C5b-9 in urine was the best indicator for detecting LN histological activity.
Complement-targeted drug therapy progress
Treatment of kidney disease Traditional therapies such as glucocorticoids and immunosuppressants have low response rates and significant adverse reactions in some diseases or phenotypes. The important biological functions of the complement system make it an important and potential therapeutic target. Therapies targeting complement activation have the potential to achieve therapeutic goals by reducing tissue inflammation and immune responses.
A phase II clinical study evaluated the effects of Cemdisiran (an investigational RNA interference therapy targeting complement C5) in patients with IgA nephropathy. The primary endpoint was the change from baseline to week 32 in the 24-hour urine protein/creatinine ratio (UPCR). The results of exploratory studies showed that compared with the control group, Cemdisiran couldReduce serum complement C5 and urine protein levels in IgAN patients. Compared with the baseline, at week 32, the serum complement C5 level in the Cemdisiran group decreased by 98.7%, 24-hour UPCR decreased by 37.4%, and the annual eGFR decline rate in the Cemdisiran group was slower than that in the control group. This study shows that blocking complement by Cemdisaran can reduce renal inflammatory injury in IgAN patients.
There is also a phase II clinical study evaluating the effect of oral selective factor B inhibitor Iptacopan on urinary protein and complement biomarkers in IgAN. In the study, IgAN patients (n=112) were randomized to receive placebo or different doses of Iptacopan. Post-hoc analyzes of Parts 1 and 2 showed that the trial met its primary endpoint: 31% (80% CI: 23% reduction in UPCR from baseline) in the Iptacopan arm (using a dose of 200 mg bid) at 3 and 6 months, respectively , 39%) and 41% (31%, 49%). Studies have shown that Iptacopan reduces urinary protein in IgAN patients by inhibiting the bypass pathway. A phase III clinical study of Iptacopan in the treatment of atypical hemolytic uremic syndrome (aHUS) is currently recruiting.
Phase II clinical trials of the efficacy and safety of IONIS-FB-LRx, which can reduce the production of complement factor B, in the treatment of IgAN are underway. The median 24-hour UPCR of the subjects decreased by 44% at week 29 compared with the baseline. In addition, the phase III international multi-center clinical study aimed at evaluating the new complement intervention drug Crovalimab targeting C5 in the treatment of atypical hemolytic uremic syndrome (aHUS) is also recruiting patients .
The drugs for complement-targeted therapy in the ASN kidney cycle include factor D inhibitor ALXN2050, complement C5 inhibitor Ravulizumab, CD40 ligand inhibitor Tegoprubart and so on. As an important link in the pathogenesis of kidney disease, the complement system is believed to play a role in the field of disease prediction in the future and provide new targets for the treatment of kidney disease.
Thriving——Explore new targets for kidney disease treatment
The treatment of kidney disease is flourishing. In addition to the complement system mentioned above, there are more drugs with other therapeutic targets that are worth looking forward to.
To explore the effect of sodium glucose cotransporter-2 (SGLT2) inhibitors on the renal and cardiovascular health of patients with chronic kidney disease (especially non-diabetic patients, and patients with low levels of renal function), EMPA- The KIDNEY trial included 6,609 patients at risk of progression of kidney disease, who were treated with the SGLT2 inhibitor empagliflozin 10 mg/d or placebo. The results showed that empagliflozin reduced the risk of cardiovascular disease death by 28%. A meta-analysis of renal outcomes from large randomized clinical trials of SGLT2 inhibitors included 13 trials and found that SGLT2 inhibitors safely reduced the risk of renal disease progression by about 40% and the risk of AKI by almost a quarter one.
Oxidative stress can promote the development and progression of diabetic nephropathy. In a phase II trial, 140 patients with type 2 diabetes and CKD were randomized to receive a NADPH oxidase inhibitor Isuzinaxib or placebo treatment for 12 weeks. Although the UACR level of patients in the Isuzinaxib group decreased by 21%, there was no significant difference compared with the control group (P=0.046). However, in subgroup analysis, for patients with eGFR<45ml/min/1.73m2, compared with the control group, the UACR level of patients in the Isuzinaxib group was significantly reduced by 47% ( P=0.0197). KIM-1 (a urinary marker of kidney injury) was significantly decreased in the Isuzinaxib group (P=0.0128).
IgAN is the most common primary glomerular disease, and its treatment strategy is also thriving. BION-1301 is a novel humanized monoclonal antibody (mAb) that binds to and blocks proliferation-inducing ligand (APRIL), and has a potential mechanism for changing the disease process of IgAN (disease-modifying MOA). APRIL binds to the receptor B-cell maturation antigen (BCMA) and the transmembrane activator and calcium-regulated cyclophilin-ligand interacting factor (TACI) on B cells, driving IgA class switching and the proliferation/proliferation of IgA-producing plasma cells survive. By blocking the action of APRIL and its receptor, BION-1301 depletes galactose-deficient IgA1 (Gd-IgA1) and blocks the generation of pathogenic immune complexes. The interim data disclosed in this ASN further demonstrate the potential therapeutic effect of BION-1301 on IgAN patients.
The interim study results of cohort 1 showed that after BION-1301 treatment, the 24h-UPCR geometric mean decreased by 48.8% (n=8) and 66.9% (n=8) at weeks 24, 52 and 100, respectively. ) and 71.0% (n=2); 7 of 8 patients (88%) who completed the 52-week visit had a UPCR reduction of more than 50%. At the same time, pathogenic Gd-IgA1 was reduced by more than 70% (n=6) and more than 80% (n=2) at weeks 52 and 88, respectively. Indicating that BION-1301 can sustainably and significantly reduce urine protein in IgAN patients with residual proteinuria and cause pathogenic Gd-IgA1 depletion in IgAN patients who are still at risk of disease progression after receiving optimized standard therapy. The potential for action provides valid validation .
Endothelin A (ETA) receptor antagonist Atrasentan’s efficacy and safety in IgAN phase II clinical AFFINITY interim results are impressive, the results show that the standard treatment ( The maximum tolerated and stable dose of RASi) was added to the treatment of IgAN patients with Atrasentan. After 24 weeks, the average urinary protein of the patients was reduced by 54.7%, and the safety and tolerance were good , about Atrasentan Phase III ALIGN study for the treatment of IgAN is also under active .
In addition, there are many “newcomers” in the field of kidney disease treatment, such as the apoptosis signal-regulated kinase 1 inhibitor Selonsertib, ETA and angiotensin II type 1 (AT1) receptor dual blocker Sparsentan, Atacicept targeting BAFF and APRIL, etc. , adding new vitality to the treatment of kidney disease.
Summary and Outlook
This ASN Kidney Week brings together experts and scholars in the field of nephrology from around the world , bringing many new breakthroughs and cutting-edge advances in the field of nephrology. Some researches have integrated emerging technologies such as big data, AI, and genetic engineering, giving new vitality to the field of kidney disease. As an important part of the pathogenesis of kidney disease, the complement system brings new biological markers and therapeutic targets for the treatment of kidney disease, such as urine C5b-9 detection, and targeted complement drugs Cemdisiran and Iptacopan. New targets for the treatment of kidney disease are also in full bloom, and various related drug researches are carried out around the world. For example, the SGLT2 inhibitor Empagliflozin and the oxidative stress regulator Isuzinaxib have shown remarkable therapeutic potential. In the field of IgAN treatment, drug research is also thriving: in the research of BION-1301 and Atrasentan applied to IgAN, the results of significantly reducing urinary protein are eye-catching. We look forward to the early launch of BION-1301 and Atrasentan for the treatment of IgAN, bringing new hope to IgAN patients with limited clinical treatment options and unmet needs, and injecting new vitality into the field of renal disease treatment. It is believed that with people’s in-depth exploration of the field of nephrology and the vigorous development of nephrology medicine, the dream of “building a world without kidney disease” will surely come true.
Professor Zhao Minghui
Professor and Chief Physician of Peking University
Director of Peking University Institute of Nephrology
Asia-Pacific Nephrology Standing director of the Society of Diseases; Chairman of the Nephrology Committee of the Chinese Preventive Medicine Association; Vice Chairman of the Nephrology Branch of the Chinese Medical Association; Chairman of the Beijing Immunology Society
Main research fields Immunoinflammatory pathogenesis for renal disease. Winner of the National Science Fund for Distinguished Young Scholars. Presided over major projects of the National Natural Science Foundation of China. Published 470 SCI papers with an H index of 61.
Won the National Science and Technology Progress Award twice. He won the Servia Award of the French National Academy of Medical Sciences, the Wu Jieping-Paul Janssen Medical Pharmacy Award, and the China Youth Science and Technology Award.
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14. 2022 ASN Kidney Week Discloses the latest data, BION- 1301 treatment significantly reduces urinary protein levels in patients with IgA nephropathy. https://mp.weixin.qq.com/s/6o2pLHaYVflUilbGUwBZwg
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