N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury

Am J Transplant. 2021 Jan;21(1):148-160. doi: 10.1111/ajt.16140. Epub 2020 Jul 6.


Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.

Keywords: antibody biology; basic (laboratory) research/science; cellular biology; glomerular biology and disease; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; molecular biology; translational research/science.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Humans
  • Immunoglobulin G
  • Infant, Newborn
  • Kidney Transplantation* / adverse effects
  • Podocytes*


  • Immunoglobulin G
  • glycosylated IgG
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcium