Angiotensin 1 receptor antibody

1. ANGIOTENSIN 1 RECEPTOR
ANTIBODY
SKJ
08-11-2017

2. Introduction
• AT1R is a seven transmembrane spanning G-protein coupled receptor
found on endothelial, mononuclear and other immune cells
• It mediates most of the physiologic functions of AT II, including
arterial blood pressure, and water-salt balance
• The binding of antibodies to AT1R appears to cause
– Hypertension
– vasoconstriction
– vascular smooth muscle migration and proliferation

3. Secondary structure and consensus sequence of the mammalian angiotensin AT1 receptor.
M. de Gasparo et al. Pharmacol Rev 2000;52:415-472
The American Society for Pharmacology and Experimental Therapeutics

4. Associations
• Autoantibodies that activate the major AT II R have been associated
with
– Preeclampsia
– malignant hypertension
– renal allograft rejection
– Systemic Sclerosis

5. Pre Ecclampsia
• Circulating auto-antibodies to AT-1 have been shown to increase after
20 weeks of gestation in Pre ecclampsia
• AT1-AAs isolated from sera of preeclampsia women cause
upregulation of ROS and the NADPH oxidase components
• This results in increased soluble Fms-like tyrosine kinase-1 (sFlt-1)
and soluble endoglin (sEng) production from human trophoblasts and
placental explants
• contributes to the anti-angiogenic state that is characteristic of PE

6. Pre Ecclampsia
• AT1-AAs directed are prevalent in over 95% of patients with
pregnancy-associated hypertension
• Antibody titres correlate positively with disease severity
• Administration of AT1-AAs isolated from preeclamptic humans to
pregnant mice was shown to induce hypertension in those animals

7. In renal transplantation
• Elevated levels of AT1R antibodies were first reported in renal
transplant recipients with severe steroid-refractory vascular rejection
and malignant hypertension in the absence of HLA-DSAs
• Subsequently many studies showed that AT1R antibodies correlated
with an increased incidence of AMR and inferior graft survival
• only complement-fixing subclasses IgG1 and IgG3 exert an agonistic
effect on the AT1R

9. Rat models
• The same authors have also demonstrated that infusion of anti-AT1R
Abs into rats one week post kidney transplantation resulted in biopsy-
proven vascular rejection confirmed by endarteritis and intravascular
infiltrates, while rats infused with control IgG showed only
endothelial activation
• Conversely, pharmacological blocking of the AT1R with ARBs reduces
cytokine production and abolishes the agonistic effects of anti-AT1R
Abs

14. Treatment
• Treatment of AT1R antibody positive patients with a combination of
plasmapheresis, intravenous immunoglobulin (IVIG), and losartan
resulted in significantly improved allograft survival compared to
outcomes for patients who received standard anti-rejection therapy

15. • a case of new-onset collapsing FSGS and AMR that occurred 1 month
after kidney transplantation in a Lupus Nephritis patient in
association with AT1-receptor antibodies
• In this patient, depletion of AT1-receptor antibody with
plasmapheresis and losartan therapy were associated with the
resolution of antibody-mediated rejection and collapsing focal
segmental glomerulosclerosis and a marked decrease in podocyte
injury

16. Systemic Sclerosis
• Anti-AT1R antibodies are also found in about 85% of SSc patients
• Higher levels of anti-AT1R and anti-ETAR antibodies were associated
with severe SSc vascular manifestations such as digital ulcers and PAH

17. Essential Hypertension
• The prevalence of AT1-AA among refractory hypertension was studied
in more recent studies
• an overall percentage of 59% of refractory hypertensive patients
harbored AT1-AA & the prevalence of AT1-AA increased with
increasing blood pressure
• In a study involving 512 patients with roughly half on candesartan (an
ARB) and half on imidapril (an ACE inhibitor), the results clearly
showed that the ARB-based regimen is more effective in lowering
blood pressure than an ACE inhibitor-based regimen in AT1-AA–
positive patients

18. Conclusions
• The importance of anti-AT1R Abs has received increased recognition
recently
• Anti-AT1R Abs are associated with preeclampsia, malignant
hypertension, and renal allograft failure
• Anti-AT1R Abs could be considered as a supplementary test where
atypical pathology or graft dysfunction exists in the absence of DSA or
in the presence of malignant hypertension
• Addition of losartan to standard therapy resulted in significantly
improved allograft survival