Why would one congenital twin experience kidney failure after a transplant while the other does not?

Why One Congenital Twin May Experience Kidney Failure After Transplant While the Other Does Not

The difference in kidney transplant outcomes between identical twins can be attributed to genetic mutations, antibody development against nephrin, or recurrence of the original kidney disease, particularly in those with specific genetic variants like NPHS1 or NPHS2 mutations. 1

Genetic Factors Contributing to Post-Transplant Kidney Failure

• Almost all children with congenital nephrotic syndrome (CNS) who experience recurrence of nephrotic-range proteinuria after kidney transplantation have a homozygous NPHS1 p.Leu41Aspfs variant (known as Fin-major) that leads to total absence of nephrin in the native kidney 1
• Post-transplant de novo glomerulopathy occurs in 25-35% of these patients, with at least 70% having detectable anti-nephrin antibodies caused by allo-immunization against the nephrin molecule in the kidney graft 1
• Recurrence can occur at any time after transplantation, with initially normal kidney function despite heavy proteinuria 1
• Early or late recurrence of nephrotic range proteinuria has also been reported in 1-2% of patients with homozygous or compound heterozygous pathogenic variants in the podocin gene (NPHS2, especially p.Arg138Ter and p.Arg138Gln variants) 1

Immune-Mediated Mechanisms

• Despite being identical twins, one twin may develop antibodies against proteins that were absent in their native kidneys but present in the transplanted kidney 1
• The pathophysiology of post-transplant de novo glomerulopathy in patients with NPHS2 pathogenic variants is unclear (causative antibodies have not been identified) and might be multifactorial 1
• Recent evidence from a case study of monozygotic twins with CRB2 mutation showed that one twin developed complications linked to immune dysregulation post-transplant, including post-transplant lymphoproliferative disease, immune thrombocytopenic purpura, multiple viremias, and de novo donor-specific antibodies 2

Original Disease Recurrence

• If the original kidney disease was immune-mediated, it may recur in the transplanted kidney 3
• A case report of identical twins with IgA nephropathy showed that one recipient experienced biopsy-proven IgA nephropathy recurrence 10 months post-transplantation, requiring treatment with mycophenolate mofetil, angiotensin receptor blockers, and steroids 3
• Another case showed a recipient who had hematuria and proteinuria 3 months post-transplantation, with crescent glomerulonephritis confirmed by biopsy, who did not respond to treatment and resumed hemodialysis 15 months post-transplantation 3

Medication-Related Factors

• Cyclosporine nephrotoxicity can be difficult to distinguish from rejection, as up to 20% of patients may have simultaneous nephrotoxicity and rejection 4
• Nephrotoxicity associated with cyclosporine has been noted in 25% of cases of renal transplantation 4
• Mild nephrotoxicity generally occurs 2-3 months after renal transplant and may be responsive to cyclosporine dosage reduction 4

Management Considerations

• In children with post-transplant proteinuria, antibody-mediated disease should be considered and antibody reduction strategies (plasmapheresis and immunosuppressive drugs) should be implemented 1
• Successful treatment outcomes have been reported after treatment with daily plasma exchanges, methylprednisolone pulses, and oral cyclophosphamide or rituximab 1
• Immunosuppressive therapy should be maintained in kidney transplant recipients who are identical twins with end-stage renal disease caused by initial nephropathy 3

Monitoring and Prevention

• Regular monitoring of kidney function is essential, as recurrence can occur at any time after transplantation 1
• Kidney biopsy is crucial for differentiating between rejection, recurrence of original disease, and medication toxicity 4
• For twins with genetic forms of nephrotic syndrome, genetic testing prior to transplantation can help identify those at higher risk of recurrence 1

Despite identical genetic makeup, differences in post-transplant outcomes between twins can occur due to variable expression of genes, development of antibodies against previously absent proteins, and differences in environmental exposures that may trigger immune responses.