IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. IgAN progresses to end-stage kidney disease in 20–40% of patients within 20 years of diagnosis. Kidney transplantation is the most effective option for patients with end-stage kidney disease caused by IgAN, but recurrence can occur in the transplanted kidney. The IgAN recurrence rate varies from 1% to 10% per year and varies according to the follow-up period, diagnostic modality, and biopsy criteria. Of note, studies based on protocol biopsies have reported a higher incidence of recurrence, which also occurred earlier after transplantation. In addition, recent data show that recurrence of IgAN is a more significant cause of allograft failure than previously believed. Little is known about the pathophysiology of IgAN recurrence, but several potential biomarkers have been investigated. Among them, galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, and soluble CD89 could play a pivotal role in disease activity. This review aims to describe the current status of recurrent IgAN, including the incidence, clinical characteristics, risk factors, and future perspectives, with a focus on the available therapeutic approaches.
IgA nephropathy (IgAN) is one of the most common causes of primary glomerulonephritis worldwide. The natural course of IgAN leads to end-stage kidney disease (ESKD) in 15–20% of patients after 10 years and in 20–40% of patients within 20 years [1, 2]. Kidney transplantation is the most effective treatment for patients with ESKD, offering improved longevity and quality of life, but long-term allograft survival has improved little in recent decades . Recurrent glomerulonephritis is the frequent cause of allograft failure at 10 years, next to chronic rejection and death with a functioning allograft, but the overall 10-year incidence of allograft loss was similar among transplant recipients with biopsy-proved glomerulonephritis and among those with other causes of kidney failure . However, subsequent recent studies revealed that recurrent IgAN after kidney transplantation is associated with allograft failure and special attention should be paid to this issue [5‒8]. Understanding the pathogenesis and clinical implications of recurrent IgAN will facilitate identification of candidates at high risk of recurrence and allow earlier diagnosis, thus significantly improving prevention and therapeutic outcomes.
Recurrence of IgAN and Its Impact on Allograft Survival
A representative analysis of the 2002 Australia and New Zealand Dialysis and Transplant (ANZDATA) registry data showed that the 10-year incidence of allograft failure due to recurrence of any type of glomerulonephritis was 8.4% (95% confidence interval [CI], 5.9–12.0), which increased subsequently . The 10-year incidence of allograft failure due to IgAN recurrence was 9.7% (95% CI, 4.7–19.5), but it was concluded that recurrence of IgAN was not a risk factor for allograft loss because the rate of graft loss due to recurrence was the same as for recipients without recurrence . Similarly, analysis of data from the US Renal Data System (USRDS) 2017 report revealed that patients with IgAN had the lowest mortality and allograft failure rates among 6 selected glomerulonephritis such as focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, or vasculitis, and the proportion of allograft failure due to IgAN recurrence was only 1.6% . Most physicians believe that the clinical manifestations of recurrent IgAN are inconspicuous, and often include asymptomatic microscopic hematuria without kidney dysfunction . However, this perception may be due to a lack of understanding of the true natural history of IgAN recurrence during long-term follow-up among physicians .
The rate of allograft failure caused by recurrent IgAN increases after 12–15 years . A recent long-term observational study reported recurrence rates based on analysis of 2017 ANZDATA registry data of 5.1%, 10.1%, and 15% at 5, 10, and 15 years after transplantation, respectively. Transplant recipients with recurrent disease were twice as likely to lose their allografts compared to those without recurrence (adjusted hazard ratio [HR], 2.04; 95% CI, 1.81–2.31) . Of note, the 5-year allograft failure rate was 42% for recipients with recurrent IgAN . Similarly, the Post-Transplant Glomerular Disease (TANGO) project, conducted in 16 centers located on three continents, revealed that the incidence of IgAN recurrence was 19% at 10 years (95% CI, 12–26) and 23% at 15 years (95% CI, 14–34) after kidney transplantation; the allograft failure rate was higher among patients with IgAN recurrence compared to those without (HR, 3.69; 95% CI, 2.04–6.66), and the allograft failure rate was 32% (95% CI 50–82) 8 years after recurrence had been diagnosed . Moreover, studies based on clinical or protocol biopsies have reported a higher incidence of allograft glomerulonephritis than other previous studies. For example, according to Mayo Clinic reports, histological recurrence of IgAN was seen in 12.5%, 42.0%, and 51.0% of patients 1, 3, and 5 years post-transplantation, respectively, and the HR of death-censored allograft failure associated with IgAN recurrence was 3.44 (95% CI, 1.22–9.71) . The clinical diagnosis of IgAN recurrence is often made late, so an early diagnosis by protocol biopsies is important earlier after kidney transplantation.
Risk Factors for Recurrence and Progression of IgAN
Several risk factors for IgAN recurrence have been described. Recurrence appears to be more common in young recipients; for every year increase in age at transplantation, there was a 2% reduction in the risk of disease recurrence (adjusted HR, 0.96; 95% CI, 0.94–0.97) . Other risk factors, including early steroid withdrawal, no induction therapy with anti-thymocyte globulin (ATG), zero-HLA mismatched live-related donor kidney, and a shorter ischemic time have been described, but these were identified in population cohort studies and results have not been consistent [11, 14‒16]. The TANGO project reported that a preemptive transplant, the presence of donor-specific antibodies at the time of transplantation, and the development of de novo donor-specific antibodies after transplantation were associated with IgAN recurrence . The reason why the risk of recurrence was higher in association with preemptive transplanted patients and humoral immunity was not clear. It could be that active and/or aggressive IgAN disease may “burn out” on dialysis, but the author reported no effect of length of dialysis on recurrence .
Pathological risk factors for recurrence and progression of IgAN have not been fully identified. The complement-activation pathway in IgAN is mainly alternative and lectin pathways rather than classical pathway. Of note, several recent studies have emphasized mesangial C1q deposition, which is rare in native IgAN but relatively frequent in recurrent IgAN, and may predict a poor outcome of kidney transplantation in native and recurrent IgAN cases [17‒19]. Future research is needed to determine the effects of mesangial C1q deposition on recurrence and progression of IgAN.
Biomarkers for IgAN Recurrence
A multi-hit hypothesis regarding the pathogenesis of IgAN involves four sequential steps in disease development, including elevated circulatory IgA1 with a degree of O-glycan deficiency in galactose (galactose-deficient IgA1, Gd-IgA1), produce IgG autoantibodies that recognize Gd-IgA1, and subsequent immune complex formation and glomerular deposition following activation of complement . In addition, B-cell-activating factor inhibitor (BAFF) and a proliferation-inducing ligand (APRIL) are important factors for B-cell hemostasis and were involved in the IgAN pathogenesis . Higher levels of circulating Gd-IgA1 and IgA-IgG complexes, and lower levels of circulating IgA-soluble CD89 complexes, at pre-transplantation are associated with recurrence of IgAN [22, 23]. On the other hand, the level of normalized serum Gd-IgA1-specific IgG autoantibodies at transplant has been associated with the risk of IgAN recurrence . The monoclonal antibody KM55, which specifically recognizes Gd-IgA1 in a nonlectin-based enzyme-linked immunoassay, has been developed . Several reports using this enzyme-linked immunoassay kit have shown that plasma Gd-IgA1 levels increase in IgAN patients compared to healthy controls . The mean serum Gd-IgA1 level was 13.9 ± 9.3 μg/mL in IgAN patients and 7.0 ± 4.1 μg/mL in healthy controls . The serum Gd-IgA1 cut-off value for distinguishing IgAN patients from healthy controls was 7.98 μg/mL and the sensitivity and specificity were 74.3% and 72.0%, respectively . The average serum Gd-IgA1 level at the time of kidney transplantation was 5.7 μg/mL . Based on these data, serum Gd-IgA1 levels may be suppressed by the immunosuppression occurring during kidney transplantation. Another study reported that the higher level of serum Gd-IgA1 was associated with recurrent IgAN in patients undergoing kidney transplantation, and the cut-off value in receiver operating characteristic curve analysis was 4.3 μg/mL (area under the curve, 0.76; 95% CI, 0.57–0.95) . In addition, recent studies on native kidneys reported that the plasma Gd-IgA1/C3 ratio and level of recombinant CD89-bound poly-IgA immune complex were associated with the progression of chronic kidney disease and IgAN severity [30, 31]. Next-generation sequencing technologies, such as the NanoString nCounter® platform, have been applied to clarify the molecular mechanism of allograft rejection and lupus nephritis using paraffin-embedded allograft tissue sections [32, 33]. Further research using this technology is needed to confirm the biomarkers of IgAN recurrence and prognosis in a large independent cohort.
Perspectives on Preventive and Therapeutic Strategies for IgAN Recurrence
There are no universally accepted guidelines for treating recurrence in IgAN patients undergoing kidney transplantation. The goal of therapy should be to prevent the recurrence of IgAN. Many observational studies have suggested that early steroid withdrawal is associated with an increased risk of recurrent IgAN and graft loss [14, 34]. Induction therapy with ATG may reduce the likelihood of IgAN recurrence, although no evidence for an effect of ATG was reported by the TANGO project [12, 15]. Transplant patients receive three immunosuppressive therapies, so to prevent severe infections, a treatment with no immunosuppressive effects should be selected. Studies from Asia have reported favorable outcomes after tonsillectomy in patients with IgAN. A recent study suggested that elective tonsillectomy 1 year after kidney transplantation may be associated with a reduced likelihood of histological IgAN recurrence, in association with lower serum Gd-IgA1 levels and mesangial Gd-IgA1 immunoreactivity . It hypothesized that tonsillectomy before recurrent IgAN after transplantation might prevent or slow the progression of the disease, but this needs to be verified in a prospective randomized controlled trial.
Tonsillectomy is a therapeutic option for recurrent IgAN. In native IgAN, a multicenter randomized controlled trial conducted in Japan showed that tonsillectomy combined with steroid-pulse therapy had a greater anti-proteinuric effect than steroid pulse alone during a 12-month follow-up . In addition, a meta-analysis reported that tonsillectomy may induce clinical remission and reduce the likelihood of ESKD in patients with IgAN . Patients with higher TLR9 expression in the tonsils had a lower serum Gd-IgA1 level, and hematuria improved immediately after tonsillectomy . Similarly, for IgAN patients undergoing kidney transplantation, tonsillectomy has also been reported to decrease proteinuria and induce clinical remission in recurrent IgAN or IgA vasculitis [38‒41]. However, tonsillectomy did not improve the outcomes of kidney transplantation in European IgAN, suggesting that the underlying mechanisms of Gd-IgA1 production may differ among ethnic groups. Thus, different approaches are needed to treat IgAN recurrence after kidney transplantation [42, 43].
The data accumulated by clinical trials of treatments for native IgAN could inform the prevention and treatment of recurrent IgAN in the future. According to a randomized, double-blind, placebo-controlled phase 3 trial (NeflgArd trial), budesonide reduced proteinuria and stabilized kidney function in patients with IgAN . This finding suggests a possible role for this drug in patients exhibiting IgAN recurrence after kidney transplantation. Rituximab showed no anti-proteinuric effect in patients with IgAN, whereas bortezomib had an anti-proteinuric effect [45, 46]. Other evidence demonstrates that BAFF, APRIL, spleen tyrosine kinase, and C5 activation have crucial roles in IgAN pathogenesis and disease progression; clinical trials are being conducted, including phase 2 trials on atacicept (a BAFF and APRIL dual inhibitor; NCT 02808429), fostamatinib (a spleen tyrosine kinase inhibitor; NCT02112838), and avacopan (a C5a receptor blocker; NCT02384317) .
Despite the high recurrence rate and effect on graft survival, kidney transplantation is the best treatment option for patients with ESKD due to IgAN. Further research is needed to investigate the pathogenesis of IgAN and improve recurrence and graft failure rates when using new technology, such as NanoString nCounter®, and biorepositories of human blood, cell, and tissue samples. A better understanding of the pathogenesis of this disease will enable targeted therapeutic strategies. A large prospective multicenter randomized controlled trial with a long follow-up to evaluate interventions for recurrent IgAN after kidney transplantation would help clinicians and patients.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
This work was not supported by any funding sources.
Mayuko Kawabe and Izumi Yamamoto contributed to the preparation of the manuscript and approved the final version.