دور المكمل في أمراض الكلى: استنتاجات من مؤتمر جدل حول أمراض الكلى: تحسين النتائج العالمية (KDIGO)

اعتلال الكلى السكري والتصلب الكبيبي البؤري المتقطع (FSGS)

مرض الكلى السكري

FSGS

الآثار السريرية لإدارة مرض الكلى السكري وFSGS

الشكل 1 | دور المكمل في أمراض الكلى المختلفة. يمكن أن يؤدي تنشيط المكمل غير المنضبط إلى التسبب أو المساهمة في إصابة الكبيبات في العديد من أمراض الكلى. (أ) الكبيبة الكلوية هي شبكة شعرية فريدة. تختلف خلايا بطانة الكبيبة الوعائية (GECs) عن معظم خلايا البطانة في أنها مسطحة بشكل استثنائي ومثقبّة بكثافة بواسطة فتحات عبر الخلايا، والتي تشكل من مساحتها السطحية. بالإضافة إلى ذلك، لأن الكبيبة تقع بين شريانيين – شريان وارد في الاتجاه العلوي وشريان صادر في الاتجاه السفلي – فإن الضغط الهيدروستاتيكي يكون مرتفعًا. تساهم هذه الخصائص، على الأقل جزئيًا، في النفاذية العالية لجدار الشعيرات الدموية الكبيبية للماء والذائبات الصغيرة، ولكن أيضًا في تعرض الكبيبة للخطر بسبب الوساطة بواسطة المكملات.

التهاب كبيبات الكلى IgA والتهاب الأوعية المرتبط بـ IgA مع التهاب الكلى

	العامل D	دانيكوبان (ALXN2040، ACH-4471)	جزيء صغير	يمنع تكوين المحولات C3 و C5 في المسار البديل	عن طريق الفم مرتين يومياً	NCT03124368 (C3G أو IC-MPGN، المرحلة 2، مكتمل) NCT03369236 (C3G أو IC-MPGN، المرحلة 2، مكتمل) NCT03459443 (C3G أو IC-MPGN، المرحلة 2، تم إنهاؤه)
	العامل D	فيميركوبان (ALXN2050، ACH0145228)	جزيء صغير	يمنع تكوين المحولات C3 و C5 في المسار البديل	شفوي	NCT05097989 (IgAN أو LN، المرحلة 2، قيد التجنيد)
	ماسپ-2	CM338	الأجسام المضادة وحيدة النسيلة	يعيق بدء مسار الليكتين	SC	NCT05775042 (IgAN، المرحلة 2، قيد التجنيد)
	ماسپ-2	نارسوبليما (OMS721)	أجسام مضادة	يعيق بدء مسار الليكتين	الرابع	NCT05855083 (متلازمة انحلال الدم اليوريمي بعد زراعة النخاع العظمي للأطفال، المرحلة 2، قيد التجنيد) NCT03205995 (aHUS، المرحلة 3، الحالة غير معروفة) NCT02682407 (C3G، IgAN، LN، MN، المرحلة 2، الحالة غير معروفة) NCT03608033 (IgAN، المرحلة 3، تم إنهاؤها)
	ماسپ-3	OMS906	أجسام مضادة	يعيق بدء مسار الليكتين	الرابع	NCT06209736 (C3G، IC-MPGN، المرحلة 2، لم يبدأ التسجيل بعد)
	رينين	أليسكيرين	جزيء صغير	يمنع انقسام C3 الذي يتم بوساطة الرينين	فموي	NCT04183101 (C3G، المرحلة 2، قيد التجنيد)

الشكل 3| مثبطات علاجية لنشاط المكمل. في المستقبل القريب، ستتوفر أدوية متعددة تستهدف نظام المكمل. من المحتمل جدًا أن يختلف تأثير الدواء اعتمادًا على عملية المرض الأساسية وعوامل محددة للمريض مثل وجود متغيرات جينية في جينات المكمل أو الأجسام المضادة الذاتية لمكونات المكمل المختلفة، مما سيجعل الطب الدقيق ممكنًا. العوامل المكتوبة بخط عريض وصلت إلى المرحلة 3 أو لاحقًا في التطوير. CD59، دفاع المكمل 59؛ DAF، عامل تسريع الانحلال؛ FB، العامل B؛ FH، العامل H؛ FI، العامل I؛ MAC، مركب الهجوم الغشائي؛ MASP، إنزيم سيرين المرتبط باللكتين المرتبط بالمانان؛ MBL، اللكتين المرتبط بالمانان؛ MCP، بروتين المساعد الغشائي؛ TAFla، مثبط انحلال الفيبرين النشط؛ THBD، جين الثrombomodulin.

الآثار السريرية

الجدول 2| مخاوف المرضى ومقدمي الرعاية، الاحتياجات غير الملباة، ووجهات النظر حول الاختبارات الجينية والخزعات المتكررة

المخاوف

• الأمراض الكلوية التي يكون فيها دور اختلال المكمل محوريًا غالبًا ما لا تتوفر لها خيارات علاج فعالة معروفة، مما يؤدي إلى فشل كلوي وخطر التكرار بعد زراعة الكلى
• يمكن أن تؤثر الأمراض الكلوية التي تتضمن فرط تنشيط المكمل بشكل عميق على الحياة اليومية للمرضى ومقدمي الرعاية، مما يحد من المشاركة في الأنشطة المهمة أو ذات المعنى
• بالنسبة للمرضى الشباب، يؤدي نقص بيانات التاريخ الطبيعي إلى عدم اليقين بشأن مسار المرض وتأثيره، مما يمكن أن يؤثر على القرارات المتعلقة بالوظيفة وتخطيط الأسرة
• الأدلة حول الإدارة الصحيحة للعديد من اعتلالات الكلى المرتبطة بالمكمل محدودة من حيث الكمية والجودة، وغالبًا ما تكون الوعي بالعلاجات المبتكرة (سواء في التجارب السريرية أو في السوق) غير كافٍ
• العوامل المعتمدة ليست متاحة عالميًا بسبب محدودية القدرة على تحمل التكاليف
• يؤخر نقص الوعي بالأمراض المرتبطة بالمكمل بين المهنيين الصحيين التشخيص ويعيق الإدارة المثلى
• نظرًا لأن العلاجات المثبطة للمكمل تزيد من خطر العدوى، فإن استخدامها على المدى الطويل قد يكون مقلقًا

الاحتياجات غير الملباة

• فهم أكثر انتشارًا وخبرة في علاج الأمراض الكلوية المرتبطة بالمكمل بين أطباء الكلى في جميع أنحاء العالم
• دراسات التاريخ الطبيعي والعلامات الحيوية في الحالات النادرة
• الوعي بالدراسات الحالية وإمكانية التسجيل بين المرضى ومقدمي الرعاية الصحية
• تصميمات التجارب التي تزيد من احتمال تلقي العلاج النشط إما من خلال نسب غير 1:1 نشط:دواء وهمي أو من خلال تمديد مفتوح
• برامج مع وصول مبكر للعلاج في الفئة العمرية المراهقة/الأطفال بمجرد إثبات السلامة
• توفر علاجات مبتكرة يُعتقد أنها أكثر فعالية من الخيارات الحالية كعلاج خط أول في أشكال المرض العدوانية
• النظر في اعتماد استراتيجيات علاج متسلسلة نظرًا لتنوع مسار المرض واستجابة العلاج داخل بعض الأمراض المرتبطة بالمكمل

الاختبارات الجينية والفحص

• الآراء والتفضيلات بشأن الفحص والاختبار الجيني متغيرة للغاية بين المرضى
• يريد بعض الأفراد معرفة أكبر قدر ممكن عن مرضهم، خاصة إذا كان التشخيص المبكر يمكن أن يؤدي إلى نتائج أفضل
• البعض الآخر لا يريد، خاصة إذا كانت المعرفة غير قابلة للتنفيذ
• ما إذا كانت وكيف يمكن أن تؤثر النتائج الجينية على التأمين أو أهلية الزرع
• المعلومات الدقيقة حول وفهم المخاطر المرتبطة بالمتغيرات الجينية للمرض أمر بالغ الأهمية
• من غير المرغوب فيه استبعاد زراعة الأعضاء من الأقارب الأحياء أو الخضوع لاختيار الأجنة بسبب أليل من غير المحتمل أن يسبب المرض
• يعد الاستشارة الجينية المناسبة والمبنية على معلومات جيدة أمرًا حيويًا، حيث يمكن أن يعاني الآباء من عبء نفسي كبير إذا قيل لهم إنهم نقلوا متغيرًا جينيًا ضارًا إلى طفلهم

خزعة متكررة في سياق تجربة سريرية

• بشكل عام، يتردد المرضى في الخضوع لخزعات متكررة، خاصة في سياق متلازمة انحلال الدم اليوريمي غير النمطية، حيث قد يكون ذلك أكثر خطورة وحيث يتم تأسيس معايير موثوقة أخرى لاستجابة العلاج (مثل عدد الصفائح الدموية، إنزيم اللاكتات ديهيدروجيناز، ومستوى الكرياتينين في المصل)
• ومع ذلك، خاصة في الأمراض الكبيبية ذات نقاط النهاية الفعالية الأقل وضوحًا وتقدم المرض بشكل أكثر تدريجي، يدرك المرضى ومقدمو الرعاية الحاجة إلى إثبات نسيجي لوكيل علاجي يؤثر على تقدم المرض وقد يكونون متحمسين للتعاون في تطوير، من خلال بيانات من خزعات متكررة، طرق تشخيص غير جراحية (مثل تقنيات التصوير الجديدة، علامات حيوية تشخيصية محسنة، وطرق خزعة سائلة)
  على وجه الخصوص، العدوى بالبكتيريا المغلفة (حيث قد يتم النظر في التطعيم و/أو المضادات الحيوية الوقائية لمثبطات المسار البديل والنهائي).

اعتلال الكلى الغشائي

الآثار السريرية

الذئبة الحمراء الجهازية (SLE)

الآثار السريرية

متلازمة الأجسام المضادة المضادة للفوسفوليبيد (APS)

الآثار السريرية

التهاب الأوعية الدموية المرتبط بـ ANCA

الآثار السريرية

TMAs، أشكال HUS المدعومة بالمكملات – المصطلحات

مشاركة المكملات والمرضية المرتبطة بها

المؤشرات الحيوية

علم الوراثة

العلاج

مرض الكلى الغشائي المناعي ومرض الكلى الغشائي التكاثري C3

الاختبارات الجينية

اختبار السيرولوجيا

الأجسام المضادة الأحادية النسيلة

العلاج

الاستنتاجات والاتجاهات المستقبلية

الملحق

المشاركون الإضافيون في المؤتمر

الإفصاحات

الشكر والتقدير

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The role of complement in kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

DIABETIC NEPHROPATHY AND FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

Diabetic kidney disease

FSGS

Clinical implications for management of diabetic kidney disease and FSGS

Figure 1 | Role of complement in various kidney diseases. Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. (a) The renal glomerulus is a unique capillary bed. The lining glomerular endothelial cells (GECs) differ from most endothelial cells in that they are extraordinarily flattened and densely perforated by transcellular fenestrae, which constitute of their surface area. In addition, because the glomerulus lies between 2 arterioles-an upstream afferent arteriole and a downstream efferent arteriole-hydrostatic pressure is high. These properties contribute, at least in part, to the high permeability of the glomerular capillary wall to water and small solutes, but also to the vulnerability of the glomerulus to complement-mediated (continued)

IgA NEPHROPATHY AND IgA-ASSOCIATED VASCULITIS WITH NEPHRITIS

	Factor D	Danicopan (ALXN2040, ACH-4471)	Small molecule	Prevents formation of C3 and C5 convertases of the alternative pathway	Oral twice daily	NCT03124368 (C3G or IC-MPGN, phase 2, completed) NCT03369236 (C3G or IC-MPGN, phase 2, completed) NCT03459443 (C3G or IC-MPGN, phase 2, terminated)
	Factor D	Vemircopan (ALXN2050, ACH0145228)	Small molecule	Prevents formation of C3 and C5 convertases of the alternative pathway	Oral	NCT05097989 (IgAN or LN, phase 2, recruiting)
	MASP-2	CM338	Monoclonal antibody	Blocks initiation of the lectin pathway	SC	NCT05775042 (IgAN, phase 2, recruiting)
	MASP-2	Narsoplimab (OMS721)	Antibody	Blocks initiation of the lectin pathway	IV	NCT05855083 (pediatric post-BMT HUS, phase 2, recruiting) NCT03205995 (aHUS, phase 3, status unknown) NCT02682407 (C3G, IgAN, LN, MN, phase 2, status unknown) NCT03608033 (IgAN, phase 3, terminated)
	MASP-3	OMS906	Antibody	Blocks initiation of the lectin pathway	IV	NCT06209736 (C3G, IC-MPGN, phase 2, not yet recruiting)
	Renin	Aliskiren	Small molecule	Blocks renin-mediated C3 cleavage	Oral	NCT04183101 (C3G, phase 2, recruiting)

Figure 3| Therapeutic inhibitors of complement activity. In the near future, multiple drugs that target the complement system will be available. It is highly likely that drug effect will vary depending on the underlying disease process and patient-specific factors such as the presence of genetic variants in complement genes or autoantibodies to different complement components, which will make precision medicine a possibility. Agents in bold have reached phase 3 or later in development. CD59, complement defense 59; DAF, decay-accelerating factor; FB, factor B; FH, factor H; FI, factor I; MAC, membrane attack complex; MASP, mannan-binding lectin-associated serine peptidase; MBL, mannan-binding lectin; MCP, membrane cofactor protein; TAFla, activated thrombin activatable fibrinolysis inhibitor; THBD, thrombomodulin gene.

Clinical implications

Table 2| Patient and caregiver concerns, unmet needs, and perspectives on genetic testing and repeat biopsies

Concerns

• Kidney diseases for which the role of complement dysregulation is pivotal often have no known effective treatment options, leading to kidney failure and risk of recurrence after kidney transplant
• Kidney diseases involving complement overactivation can have a profound impact on the daily lives of patients and caregivers, limiting participation in important or meaningful activities
• For young patients, the lack of natural history data leads to uncertainty regarding course and impact of disease, which can influence decisions on career and family planning
• Evidence on the correct management of many complement-mediated nephropathies is limited in quantity and quality, and awareness of innovative therapies (either in clinical trials or marketed) is often insufficient
• Approved agents are not universally available due to limited affordability
• Lack of awareness of complement-mediated diseases among health care professionals delays diagnosis and hinders optimal management
• Because complement blocking therapies increase the risk of infection, their long-term use is potentially concerning

Unmet needs

• A more widespread understanding of and expertise in treating complement-mediated kidney diseases among nephrologists worldwide
• Natural history and biomarker studies in rare conditions
• Awareness of existing studies and potential for enrollment among patients and health care providers
• Trial designs that increase likelihood of receiving active treatment either through ratios other than 1:1 active:placebo or through open-label extension
• Programs with early access to treatment in the adolescent/pediatric population once safety has been established
• Availability of innovative treatments judged more likely to be effective than existing options as first-line therapy in aggressive forms of disease
• Consideration for adopting serial treatment strategies given the heterogeneity of disease course and treatment response within some complementmediated diseases

Genetic testing and screening

• Opinions and preferences regarding genetic screening and testing are highly variable among patients
• Some individuals want to know as much as possible about their disease, especially if early diagnosis can lead to better outcomes
• Others do not, especially if the knowledge is not actionable
• Whether and how genetic findings could impact insurance or transplant candidacy
• Accurate information about and understanding of variant-attributable risk of disease are paramount
• Precluding a living-related transplant or undergoing embryo selection because of an allele that is unlikely to cause disease is undesirable
• Appropriate and well-informed genetic counseling is crucial, as parents can experience significant psychological burden if they are told that they transmitted a deleterious genetic variant to their child

Repeat biopsy in the setting of a clinical trial

• In general, patients are reluctant to undergo repeat biopsies, particularly in the setting of atypical hemolytic uremic syndrome, where it may be riskier and where other reliable parameters of response to treatment (e.g., platelet count, lactate dehydrogenase, and serum creatinine) are well established
• However, particularly in glomerular diseases with less well-established efficacy endpoints and a more gradual disease progression, patients and caregivers recognize the need for histologic proof of a therapeutic agent affecting disease progression and may be motivated to collaborate in developing, through data from repeated biopsies, noninvasive diagnostic approaches (e.g., novel imaging technologies, improved diagnostic biomarkers, and liquid biopsy approaches)
  particular, infections with encapsulated bacteria (where vaccination and/or prophylactic antibiotics may be considered for alternative and terminal pathway inhibitors).

MEMBRANOUS NEPHROPATHY

Clinical implications

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Clinical implications

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS)

Clinical implications

ANCA-ASSOCIATED VASCULITIS

Clinical implications

TMAs, COMPLEMENT-MEDIATED FORMS OF HUS Terminology

Complement involvement and associated pathogenicity

Biomarkers

Genetics

Treatment

C3 GLOMERULOPATHY AND IMMUNE-COMPLEX MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS Histology

Genetic testing

Serologic testing