Complement-mediated kidney diseases (CMKD) are chronic, rare, complex, and progressive diseases that present with inflammatory response to the cause kidney damages in patients with an overly active immune system.1 They include diseases such as C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), and Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN).2-5 Activation of the alternative pathway has been implicated as a primary driver of these conditions.6 Although presented with similar characteristics and overall survival rate, CMKDs have differences in genetic or acquired abnormalities, and histological features, which depends on the timing of kidney biopsy and disease activity or chronicity.7-8
C3G has an estimated incidence of about 1-3 per 1,000,000 and prevalence as low as 5 per 1,000,000.9 Previous survey of patients with C3G by the National Kidney Foundation revealed that many patients were misdiagnosed and were not treated for their renal symptoms for years.10 Prognosis for patients with CMKD is poor. In the case of C3G, about half the adult patients and ~70% of children progress to end-stage kidney disease within 10 years.11 Despite kidney transplantation, C3G often recur and contribute to poor allograft survival rates in nearly half of the patients.12 Understanding the dysregulation of the alternative complement pathway and its subtypes including post-transplant recurrence, progression to end-stage kidney diseases and prevalence in children and young adults will help clinicians better identify and classify patients with a CMKD.
Patients living with CMKD can experience a variety of symptoms, which may include proteinuria, hematuria, debilitating fatigue, edema, anxiety, and chronic infections as some of the most bothersome symptoms and complications. Improvement in quality-of-life symptoms are priorities from a patient’s perspective.13-14
Optimal treatment strategy for CMKDs has not been established due to multiple factors, such as difficulty carrying out large randomized controlled trials due to disease rarity, lack of availability to perform genetic testing in community settings, and heterogenous nature of disease, but many in clinical trials are showing promise.9 Survey data found that while nearly 60% of patients were interested in participating in clinical trials, only 18% of patients did.10 This suggested the need for educational efforts to bring additional or previously unrecognized disease symptoms to light. Oral corticosteroids and immunosuppressants can be used in patients at high risk of disease progression, but these often come with significant side effects.14-15
Knowledge gaps remain in identifying which patients will benefit most from current treatment and emerging targeted therapies. Careful evaluation of clinical trial data and up to date scientific publications as they emerge, as well as the determination of the disease drive through genetic testing and complement assays are crucial for developing optimal treatment plan for patients with complement-mediated kidney diseases.
References:
- Thurman JM. (2020) Complement and the Kidney: An Overview. Adv Chronic Kidney Dis.27(2):86-94.
- Smith R, et al. (2019) Nat Rev Nephrol. 15:129–43.
- Schena F, et al. (2020) Int J Mol Sci. 21:525.
- Wong EKS et al. (2018) Semin Immunopathol.40(1):49-64.
- Boyd J, et al. (2012) Kid Int. 81:833–43.
- Poppelaars F, Thurman JM. Complement-mediated kidney diseases. Mol Immunol. 2020;128:175-187.
- Kovala M, Seppälä M, Räisänen-Sokolowski A, Meri S, Honkanen E, Kaartinen K. Diagnostic and Prognostic Comparison of Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3 Glomerulopathy. Cells. 2023;12(5):712.
- Ravindran A, Fervenza FC, Smith RJH, De Vriese AS & Sethi S C3 glomerulopathy: ten years' experience at Mayo Clinic. Mayo Clin. Proc 93, 991–1008 (2018)
- Estebanez BT, Bomback AS. C3 Glomerulopathy: Novel Treatment Paradigms. Kidney Int Rep (2023)
- Feldman DL, Bomback A, Nester C. VOICE OF THE PATIENT: Report of Externally-Led Patient-Focused Drug Development Meeting on Complement 3 Glomerulopathy (C3G).; 2018. https://www.kidney.org/sites/default/files/C3G_EL-PFDD_VoP-Report_3-29-18.pdf
- Bomback AS, Santoriello D, Avasare RS, et al. C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int 2018; 93(4):977–985.
- Mehdi A, Taliercio JJ. C3 glomerulopathy. CCJM. 2023;90(6 suppl 1):e1-e4.
- Gonzalez A, et al. (2020) Am J Kidney Dis. S0272-6386(20)30719-8.
- Zhao Y, et al. (2020) J Int Med Res. 48(1):300060519898008.
- Rauen T, Wied S, Fitzner C, et al. After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy. Kidney Int. 2020;98(4):1044-1052.