Glomerular Disease Recurrence After Transplantation
John Manllo Dieck
Nada Alachkar
BACKGROUND
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.
Retrospective observation studies have shown a reduction in the incidence of recurrence in patient who received thymoglobulin induction.1
Using steroid-free or rapid discontinuation of steroid protocols for maintenance immunosuppression may be associated with increase rate of recurrent GN.2
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).
Rare recurrence for anti-glomerular basement membrane nephritis
No recurrence for primary Alport disease (see chapter 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.
IMMUNOGLOBULIN A NEPHROPATHY
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
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
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.
Treatment
There are limited options for the treatment of recurrent IgA.
Immunosuppressive induction with antithymocyte globulin has been shown to decrease the rate of recurrence.1,13
The use of angiotensin-converting enzyme inhibitors (ACEi) has been shown to reduce proteinuria.
The use of fish oil has not been studied in details in transplant patients.
If patient is on a steroid-free protocol, add prednisone back to immunosuppressive regimen. Pulse dose steroid can be used if recurrent disease does not respond to optimization of maintenance immunosuppression, tight blood pressure control, and ACEi.
In patients with aggressive disease (crescentic IgA) or rapidly progressive disease, cyclophosphamide may be used. If cyclophosphamide is used, discontinue antimetabolite (eg, mycophenolate, azathioprine) from the maintenance immunosuppressive regimen to avoid excessive bone marrow suppression.
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
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.
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).
Treatment
Optimize immunosuppression and ensure patient is on triple immunosuppressive regimen.
Typical plasmapheresis regimen: 1 plasma volume exchange daily × 3 consecutive days, followed by every other day to complete a total of 9 to 10 treatments
IVIG infusion (100 mg/kg) after each session of plasmapheresis
Rituximab (375 mg/m2/dose for 2-6 doses, at 1-2 week apart): In a retrospective study involving 22 patients with recurrent FSGS, combined plasmapheresis and rituximab therapy was shown to result in greater reduction in proteinuria compared to that of plasmapheresis alone.14,15,17,19,20
Prophylactic plasmapheresis: conflicting data
Other suggested therapies that require further studies: galactose infusion therapy to bind and clear FSGS permeability factor from circulation, cyclophosphamide, abatacept
Adrenocorticotropic hormone (ACTH) analogue gel has been proposed as a potential therapy for patients who fail to respond to conventional therapy with plasmapheresis and rituximab. A small retrospective study consisting of 20 patients with de novo or recurrent refractory FSGS demonstrated that ACTH gel 80 units sub-q two times a week for 6 months resulted in significant improvement in proteinuria. Fifty percent of patients achieved complete or partial remission.21
MEMBRANOUS NEPHROPATHY
Pathophysiology of membranous nephropathy in native kidneys
Membranous nephropathy (MN) is a glomerular disease caused by the deposition of antibody-antigen (Ab-Ag) complexes at podocytes leading to complement activation, formation of C5b-9, podocyte release of oxidants and proteases, and glomerular injury.Related posts:
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