Effect of chronically increased erythrocyte complement receptors on immune complex nephritis

Lee A. Hebert, Daniel J. Birmingham, John D. Mahan, Xiao Ping Shen, Cynthia Mcallister, Fernando G. Cosio, John J. Dillon

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Abstract

Experimental studies in humans and other primates have shown that the erythrocyte (E) complement receptor Type 1 (CR1), which is unique to the primate, plays an important role in clearing immune complexes (IC) from the circulation by binding C3b/C4b opsonized immune complexes and carrying the IC to liver and spleen for disposal. The results of these acute experiments suggest that increasing E-CR1 levels chronically should protect against IC- mediated glomerulonephritis (IC-GN) induced by chronic formation of IC in the circulation. In the present study this hypothesis was tested in the cynomolgus monkey (CYN). IC-GN was induced by daily bolus intravenous infusion of BGG into immunized CYN for 8, 10, or 14 weeks. Prior to and during the daily bolus infusions of BGG, sustained differences in E-CR1 levels were achieved between the experimental group (increased E-CR1 levels) and the control group (maintained or decreased E-CR1 levels), by one of two methods: (1) Twice weekly exchange transfusion. The CYN donors were blood type compatible with the recipients and had either constitutive high E-CR1 expression (3,000 to 5,000 CR1/E) or constitutive low E-CR1 expression (< 100 CR/E). The recipients of the exchange transfusions (N = 2) had constitutive mid-level E-CR1 expression. (2) Weekly phlebotomy (PL) or sham PL. CYN with mid-level E-CR1 expression were randomly assigned to receive weekly either PL (causing increased E-CR1 expression by stimulating erythropoiesis) (N = 8) or sham PL (which has no effect on E-CR1 expression (N = 9). We found that the exchange transfusion model produced large differences between the CYN in CR1/E (mean 910 in the CYN exchanged with high E-CR1 donors vs. 210 in the CYN exchanged with the low E-CR1 donors) but was labor intensive. The PL/sham PL model also induced large and sustained differences in CR1/E between the PL group (1150 ± 160 CR1/E) and the sham PL group (530 ± 80 CR1/E), and was relatively easy to perform. Deaths due to respiratory failure during BGG infusion occurred in the first week of daily BGG infusion in three CYN randomized to the Sham PL. These CYN are not included in the final analysis. The primary outcome variable was a blinded morphometric evaluation of glomerular electron dense deposits, expressed as the percent of a given glomerular component occupied by deposit, in the biopsy performed at the termination of the GN-induction protocol. The renal biopsies done prior to administration of BGG show no glomerular electron dense deposits. The terminal renal biopsy results are as follows: in the experimental group (raised E-CR1 levels) versus the control group (decreased or maintained E- CR1 levels) the glomerular capillary wall electron deposits were 3.2 ± 1.5% versus 9.8 ± 3.8% (P = 0.15), and the mesangial deposits were 14.3 ± 2.2 versus 21.5 ± 5.2%, (P = 0.34). Urine protein/urine creatinine ratio measured in the terminal urine samples was 0.7 ± 0.2 in the experimental group and 2.3 ± 1.1 in the control group (P = 0.22). Antibody levels, total BGG dose, and serum creatinine levels were not significantly different between the control and experimental groups. We conclude that increasing E- CR1 levels chronically does not provide statistically significant protection against glomerular accumulation of immune deposits or proteinuria in this bolus model of IC-GN.

Original languageEnglish (US)
Pages (from-to)493-499
Number of pages7
JournalKidney international
Volume45
Issue number2
DOIs
StatePublished - Feb 1994

ASJC Scopus subject areas

  • Nephrology

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    Hebert, L. A., Birmingham, D. J., Mahan, J. D., Shen, X. P., Mcallister, C., Cosio, F. G., & Dillon, J. J. (1994). Effect of chronically increased erythrocyte complement receptors on immune complex nephritis. Kidney international, 45(2), 493-499. https://doi.org/10.1038/ki.1994.64