Glomerular Disease Recurrence After Transplantation

Glomerular Disease Recurrence After Transplantation

John Manllo Dieck

Nada Alachkar


  • Glomerulonephritis (GN) recurrence varies widely in terms of incidence and impact on allograft survival.

    • Incidence of recurrence

      • May be underestimated for various reasons including lack of diagnoses in native kidneys, lack of biopsies performed in allograft kidney, discrepancies in recognizing histologic versus clinical recurrences, short follow-up duration, and/or misdiagnoses of GN due to lack of immunofluorescence/electron microscopy (IF/EM) techniques

      • Varying reports of incidence of recurrence may reflect specific immunosuppression regimen.

        • image Retrospective observation studies have shown a reduction in the incidence of recurrence in patient who received thymoglobulin induction.1

        • image Using steroid-free or rapid discontinuation of steroid protocols for maintenance immunosuppression may be associated with increase rate of recurrent GN.2

      • In general, incidence of recurrence is GN specific3,4:

        • image Highest recurrence rates are associated with primary focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (MPGN) (dense deposit disease [DDD], C3 glomerulonephropathy, immune complex-medicated MPGN associated with monoclonal gammopathy).

        • image Rare recurrence for anti-glomerular basement membrane nephritis

        • image No recurrence for primary Alport disease (see chapter 4)

    • Impact of GN recurrence on allograft survival3,4

      • Recurrent GN can adversely affect allograft survival.

      • Allograft GN (both recurrent and de novo) has been reported to account for 18% to 22% of death-censored kidney allograft failures.

      • Type 1 MPGN and FSGS have been reported to have the highest rate of recurrence with subsequent graft loss, followed by immunoglobulin A (IgA) nephropathy (IgAN) (American Transplant Congress, 2015).

    • Clinical presentation

      • The diagnosis of recurrent disease requires histologic diagnosis of the same disease in native kidneys.

      • Early diagnosis with close monitoring and prompt intervention is key to slowing disease progression and allograft lost.

      • Kidney allograft loss due to recurrent glomerular disease is not a contraindication for retransplantation. The decision for retransplantation must be individualized.


Pathophysiology of immunoglobulin A nephropathy in native kidneys

  • IgAN is a GN thought to predominantly arise from the presence of galactose-deficient IgA1 (Gd-IgA1), subsequent auto-antibody production against the undergalactosylated IgA1, formation and deposition of the Gd-IgA1 immune complex in renal mesangium, followed by activation of the (C3) complement system leading to renal injury.

  • IgAN may be classified as primary or secondary:

    • Primary IgAN may present as renal involvement only or as a systemic disease (Henoch-Schönlein purpura).

    • Secondary IgAN may be associated with pathologies that involve organs that produce (gastrointestinal [GI] tract, skin, lungs) or clear (liver) IgA, inflammatory conditions that stimulate IgA production, or autoimmune diseases.

Recurrence of Immunoglobulin A nephropathy

  • The incidence of recurrent histologic IgAN has been reported to range from 10% to 65% with associated risk of graft loss at 2% to 16%.5 This wide variation is attributed to studies having different indications for allograft biopsies (protocol biopsy vs clinical indication) and duration of follow-up.

  • Clinical evidence of recurrence (ie, persistent microscopic hematuria, new or worsening proteinuria, and/or worsening serum creatinine) is rare during the first 3 to 5 years and may be present in 30% of patients at long-term follow-up.4,6 Histologic recurrent IgAN (with or without clinical evidence) is more common and presents earlier in the posttransplant period. Histopathologic findings of recurrent IgAN are discussed in chapter 9.

  • The use of triple immunosuppressant therapy has reduced the incidence of recurrent IgAN.7

  • Risk factors for IgAN recurrence4,6,8,9,10,11

    • Younger age

    • Aggressive course of disease in native kidneys

    • Loss of prior allograft to IgAN recurrence

    • Living versus deceased donation (Existing data are inconsistent. It is not recommended to avoid living donor transplant in IgAN.)

    • Steroid-free regimen

    • Others: Polymorphisms in interleukin (IL)-10; human leukocyte antigen (HLA)-B8-DR3 haplotype; HLA antigens HLA-B8, HLA-B35, HLA-DR3, and HLA-DR4 may be associated with recurrence; HLA antigens HLA-A2 and HLA-B46 may be protective against developing recurrence.

  • Factors associated with progression and poor outcome in recurrent IgAN

    • Proteinuria of >1 g/d

    • Glomerular sclerosis >30% on a kidney biopsy

  • Allograft survival for recurrent primary IgAN4,7,9,10,12

    • Generally better compared with that of other glomerulopathies

    • Graft survival in patients with IgA recurrent disease is similar within the first 10 years compared to patients without IgA recurrence.

    • Allograft loss within the first 3 years after transplant is rare.

    • The natural course of IgAN is altered due to the use of immunosuppression.


Pathophysiology of focal segmental glomerulosclerosis in native kidneys

  • FSGS refers to a morphologic pattern of glomerular injury that may arise from a primary podocytopathy or secondary process including adaptive FSGS (nephron mass reduction), genetic FSGS (apolipoprotein L1 [APOL1] susceptibility gene vs high-penetrance mutations), and infection/inflammation-associated and medication-associated FSGS.

  • Primary FSGS refers to primary podocytopathy thought to be due to the presence of circulating permeability factors (proposed factors include cardiotrophin-like cytokine-1 circulating factor, apolipoprotein A-1b [apoA1b], anti-CD40, soluble urokinase-type plasminogen activator receptor [suPAR]).4,14,15

Recurrence of focal segmental glomerulosclerosis

  • Primary FSGS commonly recurs after kidney transplant. It has been reported to be as high as 30% to 50% despite the use of immunosuppressive therapy.

  • Recurrence is thought to be primarily due to the presence of circulating permeability factors in the recipient.

  • Primary FSGS may recur immediately or months to years following transplant.

  • Risk factors for recurrence include4,14,15,16

    • Younger age at time of diagnoses.

    • Patients with rapid progression to end-stage kidney disease (ESKD) especially if <3 years.

    • White race.

    • High level of proteinuria (associated with 60% of recurrence).

    • First graft lost due to recurrence (associated with 80% of recurrence).

  • With the exception of podocin mutations (NPHS2), genetic forms of FSGS including those with the high-risk APOL1 genotype have a very low risk of recurrence.4

  • Secondary FSGS does not recur in the renal allograft if the underlying etiology leading to FSGS has been modified.

Clinical presentation

  • It is recommended to have a baseline urine protein to creatinine ratio prior to transplant so that FSGS recurrence may be promptly diagnosed when there is a posttransplant rise in proteinuria.

  • Posttransplant urine protein to creatinine ratio should be monitored closely, particularly in high-risk patients, in order to detect early recurrence.

  • Diagnosis of recurrent FSGS is challenging because histologic characteristics of FSGS take time to develop.

    • Light microscopy may be normal.

    • EM may reveal diffuse podocyte effacement within hours following transplant (see chapter 9).


Pathophysiology of membranous nephropathy in native kidneys

May 8, 2019 | Posted by in NEPHROLOGY | Comments Off on Glomerular Disease Recurrence After Transplantation

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