Tuesday May 02, 2023 - 16:15 to 17:20
Beneficial Effects of C1q in Resolving Ischemia Reperfusion in Kidney Transplants
Hirotsugu Noguchi1, Raneem Khedraki1, Ran Fan1, Karen S Keslar1, Nina Dvorina1, William M Baldwin III1.
1Inflammation & Immunity, Lerner Research Institute Cleveland Clinic, Cleveland, OH, United States
Introduction: Complement has been implicated as a proinflammatory mediator in ischemia- reperfusion injury (IRI) and various complement inhibitors have been employed to decrease IRI. However, some complement components have anti-inflammatory functions. For example, C1q, a subcomponent of C1, functions as a pattern recognition receptor (PRR) that removes apoptotic and necrotic cells (1,2). The pattern recognition function of C1q does not require the enzymatic components, C1s and C1r, of the C1 complex. Moreover, unlike C1r and C1s, the principal source of C1q is local myeloid cells. These experiments were designed to define the role of C1q in IRI of kidney transplants.
Methods: We examined the effects of C1q in a clinically relevant model of life-supporting kidney allografts. A/J kidneys were transplanted to bilaterally nephrectomized wild type B6 or C1q deficient recipients. The kidneys were subjected to either 4 hours of cold ischemia storage before transplantation or prolonged warm ischemia (additional 20 minutes before removing vascular clamps) during the surgical anastomotic procedure.
Results: Under both conditions, all A/J kidneys transplanted to wild type B6 recipients survived more than 14 days. In contrast, 30% (5 out of 17) and 78% (7 out of 9) of A/J kidneys subjected to increased cold or warm ischemia, respectively, failed between 3 and 12 days after transplantation in C1q deficient recipients. Graft failure was accompanied by evidence of unresolved IRI including elevated serum BUN levels and increased myeloid infiltrates surrounding injured tubules at the corticomedullary junction. Expression of C1q transcripts increased progressively in allografts from about 2-fold at 1 day to 30-fold at 7 days after transplantation. NanoString analysis on flow sorted infiltrating (H-2Kb) versus resident (H-2Kk) myeloid cells isolated from the transplanted kidney indicated that resident macrophages expressed 4-fold greater amounts of C1q transcripts compared to infiltrating macrophages.
Conclusions: Together, these data indicate that C1q functions as a PRR to resolve IRI incurred as the result of cold and warm ischemia at the time of transplantation. Resolution of IRI is facilitated through local C1q production by resident donor and infiltrating recipient cells that increases early after transplantation. These data support the use of therapeutic interventions that block the enzymatic activity of C1 such as C1 esterase inhibitor or anti-C1s, but preserve the function of C1q.
All authors are supported by NIH R01 AI165513.
 Khedraki R, Noguchi H, Baldwin WM, 3rd. Balancing the View of C1q in Transplantation: Consideration of the Beneficial and Detrimental Aspects. Front Immunol 2022;13:873479.
 Baldwin WM, 3rd, Valujskikh A, Fairchild RL. C1q as a potential tolerogenic therapeutic in transplantation. Am J Transplant 2021;21(11):3519-3523.