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Front and center: burden of disease and unmet needs

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Limitations in managing C3G and primary IC-MPGN

In C3G and primary IC-MPGN, the broad range of patient types can add to the challenges of management. These rare glomerular diseases span across age (from childhood through adulthood) and kidney status (native or post-transplant).1-4

Current management approaches

Across the broad range of patient types, 3 key markers of disease activity are common5:

Management approaches are limited and do not effectively address the underlying complement overactivation driving disease activity.1,5,6
Patients’ symptoms are typically managed with a variety of antiproteinuric, antihypertensive, and immunosuppressive drugs with variable efficacy.5
Goal: typically used first line to reduce proteinuria and control blood pressure1
Associated with significant renal survival in a French multicenter retrospective study of pediatric and adult patients with C3G or primary IC-MPGN (P<0.0001)7
Goal: to limit inflammatory effects of complement overactivation and/or reduce risk of kidney rejection in transplant patients1,8
Conflicting data on efficacy—some studies report impact on renal survival; others report no change in progression to ESKD1,8
Goal: to remove autoantibodies and mutated proteins associated with disease9
Must be used in conjunction with immunosuppressive therapy for blocking antibody production9
Robust data are lacking; occasional case reports describe favorable outcomes when a mutated protein is causally implicated1
Goal: to address inflammation from complement overactivation8
C5 inhibition primarily affects C3G pathogenesis through an anti-inflammatory effect rather than directly targeting the complement overactivation that underlies disease. Limited efficacy has been observed with C5 inhibition8,10
Goal: to reduce sodium, protein, and fats in the diet to control symptoms such as edema, hypertension, and proteinuria and to reduce the waste load on the kidneys6,8
None of these are indicated for the treatment of C3G or primary IC-MPGN.

By the numbers: burdens of C3G and primary IC-MPGN

Current management approaches are unable to effectively address complement overactivation underlying both diseases. Therefore, many patients ultimately progress to ESKD and require dialysis and/or kidney transplantation.1,5-7

Kidney transplantation is not curative since it does not address the complement overactivation. Patients are at a substantial risk for disease recurrence and graft loss, potentially leading to11:

  • The need for multiple transplants12,13
  • Vulnerability to the risks of immunosuppressants used to help prevent rejection with each transplant14

In a retrospective analysis of 18 adult patients with C3G who underwent transplantation15

Of the 10 patients who underwent transplantation and had disease recurrence in a retrospective analysis of 80 adults and adolescents with C3G16

Beyond the kidney damage

For patients and caregivers, chronic dialysis, transplantation, and potential graft loss result in a range of hardships3,17,18:

Physically
Financially
Mentally and emotionally

The National Kidney Foundation 2018 report highlights the C3G patient experience3:

  • Uncertainty of their future health, described as “crippling” or “paralyzing,” leading to anxiety and depression
  • 57% reported C3G having a moderate or significant impact on their daily lives
  • Resistance from insurers in paying for certain medications, resulting in treatment interruptions
  • Frustration with current standard of care was reported due to debilitating side effects and ineffectiveness in slowing disease progression or preserving transplanted kidney function

The burdens of the disease, current management approaches, and demanding appointment schedules leave patients and caregivers to endure significant challenges and disruptions in3:

School
Work
Social lives

The progressive, debilitating nature of C3G and primary IC-MPGN and lack of treatments spotlight an unmet need in these diseases1-3,19

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ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; C3=complement component 3; C5=complement component 5; C3G=C3 glomerulopathy; eGFR=estimated glomerular filtration rate; ESKD=end-stage kidney disease; IC-MPGN=immune complex membranoproliferative glomerulonephritis.

References: 1. Smith RJH, Appel GB, Blom AM, et al. C3 glomerulopathy — understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019;15(3):129-143. 2. Caravaca-Fontán F, Lucientes L, Cavero T, Praga M. Update on C3 glomerulopathy: a complement-mediated disease. Nephron. 2020;144(6):272-280. 3. National Kidney Foundation. Voice of the patient. Accessed November 6, 2024. https://www.kidney.org/sites/default/files/C3G_EL-PFDD_VoP-Report_3-29-18.pdf 4. Cook HT, Pickering MC. Clusters not classifications: making sense of complement-mediated kidney injury. J Am Soc Nephrol. 2018;29(1):9-12. 5. Nester C, Decker DA, Meier M, et al. Developing therapies for C3 glomerulopathy: report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group. Clin J Am Soc Nephrol. Published online June 3, 2024. doi:10.2215/CJN.0000000000000505 
6. National Kidney Foundation. Complement 3 glomerulopathy (C3G). Accessed November 6, 2024. https://www.kidney.org/kidney-topics/complement-3-glomerulopathy-c3g 7. Servais A, Noël LH, Roumenina LT, et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012;82(4):454-464. 8. Noris M, Remuzzi G. C3G and Ig-MPGN—treatment standard. Nephrol Dial Transplant. 2024;39(2):202-214. 9. Schena FP, Esposito P, Rossini M. A narrative review on C3 glomerulopathy: a rare renal disease. Int J Mol Sci. 2020;21(2):525. 10. Le Quintrec M, Lapeyraque AL, Lionet A, et al. Patterns of clinical response to eculizumab in patients with C3 glomerulopathy. Am J Kidney Dis. 2018;72(1):84-92. 11. Bartoli G, Dello Strologo A, Grandaliano G, Pesce F. Updates on C3 glomerulopathy in kidney transplantation: pathogenesis and treatment options. Int J Mol Sci. 2024;25(12):6508. 12. Clark S, Kadatz M, Gill J, Gill JS. Access to kidney transplantation after a failed first kidney transplant and associations with patient and allograft survival: an analysis of national data to inform allocation policy. Clin J Am Soc Nephrol. 2019;14(8):1228-1237. 13. Benkö T, Halfmann P, Gäckler A, et al. Long-term outcome of third, fourth and fifth kidney transplantation: technical aspects and immunological challenges. Clin Kidney J. 2019;12(6):895-900. 14. Fiorentino M, Gallo P, Giliberti M, et al. Management of patients with a failed kidney transplant: what should we do? Clin Kidney J. 2020;14(1):98-106. 15. Tarragón B, Peleg Y, Jagannathan G, et al. C3 glomerulopathy recurs early after kidney transplantation in serial biopsies performed within the first 2 years after transplantation. Clin J Am Soc Nephrol. 2024;19(8):1005-1015. 16. Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. 2014;9(1):46-53. 17. American Kidney Fund. Mental health and kidney disease. Accessed November 6, 2024. https://www.kidneyfund.org/living-kidney-disease/mental-health-and-kidney-disease 18. Golestaneh L, Alvarez PJ, Reaven NL, et al. All-cause costs increase exponentially with increased chronic kidney disease stage. Am J Manag Care. 2017;23(10 Suppl):S163-S172. 19. Noris M, Daina E, Remuzzi G. Membranoproliferative glomerulonephritis: no longer the same disease and may need very different treatment. Nephrol Dial Transplant. 2023;38(2):283-290.