Anti-Glomerular Basement Membrane Nephritis Post-Renal Transplant in Alport Syndrome Patients

Alport syndrome (AS) is characterised by progressive chronic kidney disease (CKD) leading to kidney failure, sensorineural hearing loss and eye abnormalities. AS patients have reduced or no expression of the α3α4α5 triple helix, a major component of the kidney glomerular basement membrane (GBM), due to pathogenic variants in COL4A3 , COL4A4 and COL4A5 . Post-transplant anti-GBM nephritis continues to be seen in AS patients and is immunological distinct from ‘traditional’ anti-GBM (Goodpasture’s) disease. Post-transplant anti-GBM nephritis is reported to affect 5% of AS patients. There is also an isolated immunological anti-GBM disease counterpart, where despite the production of anti-GBM antibodies, the AS patient does not ever develop clinical nephritis post-transplant. The pathophysiology of anti-GBM nephritis post-transplant relates to the presentation of non-tolerised antigen to the immune system. The intact donor GBM is immunogenic, specifically the α3α4α5(IV) triple helix, which leads to the production of anti-GBM antibodies that can initiate a crescentic glomerulonephritis in the allograft. The target alloantigen most often implicated in X-linked dominant AS patients with post-transplant anti-GBM nephritis is α5(IV), whereas for autosomal recessive AS patients it is α3(IV). There is no agreed protocol for the treatment or prophylaxis of post-transplant anti-GBM nephritis in AS patients. Immunosuppressive strategies vary including steroids in combination with tacrolimus, azathioprine and ciclosporin. Plasmapheresis can be used to remove pathogenic anti-GBM antibodies. On initial transplantation, allograft failure due to anti-GBM nephritis may occur within weeks-to-months, and not usually beyond the first year post-renal transplant. Progression to graft loss secondary to diagnosed anti-GBM nephritis is often rapid. The recurrence of anti-GBM nephritis and accelerated allograft rejection (occurring within days-to-weeks) is reported in multiple AS patients who underwent retransplantation, having lost their first renal transplant to the same immune phenomenon. Improved diagnostics and disease registries are needed to document these immune phenomena and optimise personalised patient management.