IgA nephropathy (IgAN) is the most prevalent form of glomerulonephritis in the world and a common cause of end-stage kidney disease (ESKD). Patients with IgA are typically younger, less afflicted by comorbid disease and consequently more frequently suitable for transplantation compared with those with other causes of ESKD, such as diabetes and vascular disease.1,2 Observational studies of patients transplanted due to IgAN have shown that IgA recurs in up to 60% of patient's grafts, and that IgA recurrence leads to graft failure in a growing portion of patients as time from transplant lengthens3,4 (Table 1). Why only some patients are affected, what mechanisms drive recurrence and progression to graft failure, and what can be done therapeutically to modify risk remain key questions for researchers, clinicians, and patients.
IgAN is the most common form of glomerulonephritis globally.5 The heterogeneity of clinical presentations ranges from macroscopic hematuria and acute kidney dysfunction during an upper respiratory tract or gastrointestinal infection in children and young adults, to proteinuria, microscopic hematuria, or hypertension in older adults. IgAN is twice as common in men than in women in Australia and in the United States, though the absence of sex bias has been reported among Asians.1,6-8 A significant proportion of patients' progress to ESKD over time, approximating 10% at 10 years and 20% at 20 years follow-up.9,10 IgAN is a common cause of ESKD and was responsible for 6% of all incident ESKD in Australia in the period 2010 to 2013.11 Clinical risk factors for progression to ESKD include proteinuria of 1 g or greater per day and uncontrolled hypertension.10,12 Whether the same risk factors for progression hold true for recurrent disease after transplantation remains to be seen.
Patients with IgAN enjoy greater access to kidney transplantation as compared with those with many other forms of kidney disease. As an example, diabetes is a far more frequent cause of ESKD; however, patients with ESKD caused by IgAN are typically younger, exhibit a lower burden of comorbidities, and have greater access to transplantation. Australian registry data for 2000 to 2012 shows that those with IgAN have transplants an average of 9 years younger than those with diabetic nephropathy (mean age of 47 years and 56 years, respectively), with significantly fewer comorbidities, almost double the rate of live donor kidneys and have a mean wait time that is 10 months shorter (Table 2). Similarly, United States Renal Data System data for 2007 to 2011 show that those with IgAN reach ESKD at a younger age than those with diabetic nephropathy (median age of 45 years and 63 years, respectively), and the proportion of dialysed patients who received a kidney transplant within 1 year was 30.2% for IgAN compared with just 2.4% for those with diabetes.2
IgA deposition frequently recurs in the graft, with published recurrence rates of 8% to 53% (15-78% of those biopsied)3,4,13-31 (Table 1). Rates of recurrence in the literature vary widely, primarily due to study differences in the indication for biopsy and length of posttransplant follow-up. Published recurrence rates are highest for centers that do protocol biopsies in addition to those that are clinically indicated. This is likely because in the early stages of IgAN recurrence, positive biopsy findings are frequently not accompanied by clinical changes, such as proteinuria, hematuria, or graft dysfunction.3 Recurrence of IgAN after transplantation appears to be a time-dependent phenomenon, with rates of recurrence increasing as time from transplant lengthens.4
We do not yet have a sufficient understanding of why some patients experience recurrence and others do not. Although heterogeneity in immunosuppressive protocols and disease pathogenesis across the spectrum of IgA disease is thought to be responsible, there have been no large, detailed, prospective, multicenter cohort studies to delineate risk factors for histological and/or clinical recurrence. From single-center studies and registry analyses, a number of possible associations have been identified, and these tend to mirror the risk factors for progression in native IgAN. Younger age at transplantation,16,25 rapid progression of the native IgAN,32 degree of proteinuria,25 and donor factors have all been identified as suspects.
Two donor factors have emerged as possible contributors to IgAN recurrence, donor source and donor IgA deposits. A number of studies have found an increased rate of recurrence in patients with a living related donor compared with a deceased donor; however, this finding is inconsistent and in the opinion of the authors should not preclude consideration of living donor transplantation for patients with IgAN.16,18,24-26,28,29,33,34 Two Australian registry studies have found that those with 1 or more HLA mismatches have a reduced rate of recurrence compared with those with zero mismatch kidneys.7,18 Similarly, ABO incompatible transplants have been found to have lower rates of recurrence, possibly due to differences in immunosuppression regimens.14 The other donor factor that has been considered is the presence of IgA deposits in the donor kidney. One single-center Japanese study found that IgA deposits in the donor, presumably subclinical, increased the risk of IgA recurrence in the recipient.20 Interestingly, when grafts with IgA deposits have been transplanted into non-IgA patients, the IgA has been rapidly cleared by the recipient with follow-up biopsies indicating complete resolution.35
Mechanism of Disease
The pathogenesis of IgA is complex and remains incompletely understood.5 There is marked variation in the clinical and pathological elements of IgA, suggesting it is not one, but rather many different diseases. As such, it is unlikely that a single mechanism is either driving IgA deposition in the mesangium or generating inflammation and kidney injury from this misplaced IgA.
There appears to be a genetic predisposition in at least a portion of those with IgAN, although how this manifests remains unclear and is an area of ongoing research interest.5 Areas of interest include specific HLA types, which have been found to be associated with IgAN in genetic association studies, and high serum IgA concentrations, which have been found both in patients as well as their nonaffected family members.36,37 It is possible that differences in the underlying genetic defects may be partly responsible for some of the demographic and clinical variability seen in IgAN.
Genetics though will only ever be a part of the story. Evidence to date is most supportive of a multihit hypothesis. That is, that IgAN occurs in an individual who is genetically predisposed to form atypical, poorly glycosylated IgA1 (the first hit), who then experiences a triggering respiratory or gastrointestinal illness (the second hit), which in the setting of immune dysregulation (the third hit) leads to production of antiglycan antibodies of either IgG or IgA isotypes.38 Antiglycan antibodies bind poorly glycosylated IgA1 to form complexes which circulate in serum and are then deposited within the mesangium, leading to kidney injury.38Figure 1 provides a schematic representation of this process as it is currently understood. There may be a relationship between specific features of the multihit hypothesis and the likelihood of disease recurrence. For example, recent work by Berthelot and others suggest that high pretransplant serum levels of poorly glycosylated IgA1 and antiglycan antibodies, as well as low levels of CD89 (a leukocyte cell surface receptor for IgA which has been shed), may be associated with more aggressive primary disease and a consequent increased risk of recurrence posttransplant.39
IgAN then, is a systemic disease mediated by circulating IgA-containing immune complexes. Despite kidney transplantation, the propensity to produce immune complex formation continues. Whether circulating immune complexes deposit in the mesangium and how immunosuppression modifies this and the subsequent responses of mesangial cells and recruited inflammatory cells likely determines whether IgAN recurs and the outcome of any recurrence.
Diagnosis of Recurrent IgAN
The diagnosis of IgAN recurrence requires histological evidence of IgA in the transplant kidney in a patient with biopsy-proven IgA disease in their native kidneys. Although clinical criteria are occasionally used for diagnosis in clinical practice, we do not recommend this practice for recurrence due to the potential for underdiagnosis and misclassification. Hematuria is not a reliable sign, being absent in 64% of patients with disease recurrence found on protocol biopsy.3 Given this, the absence of hematuria posttransplant should not deter biopsy nor count against the diagnosis of recurrence. As recurrent IgAN is only one in a number of pathologies that can cause transplant kidney dysfunction and proteinuria, with or without hematuria and hypertension, a biopsy is essential to ensure the correct diagnosis. A biopsy should also be performed in cases of declining graft function. One large registry study found that graft failure was more commonly attributed to chronic allograft nephropathy in patients with ESKD caused by glomerulonephritis than for those with other causes of ESKD, the implication being that when a biopsy is not performed, some cases of recurrence are likely attributed to chronic allograft nephropathy.23
The clinical implications of specific histological features seen on biopsy have recently been clarified through use of the Oxford Classification.40-42 The presence of 4 histological features, namely, the degree of mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity, and tubular atrophy (MSET) and interstitial fibrosis in the cortical area, were found to predict disease progression independent of clinical findings.42 Each of the 4 features are scored independently, giving an MSET score, with higher scores associated with worse outcomes.42 Although developed for IgAN in native kidneys, Oxford Classification criteria have been successfully applied to IgAN recurrence in transplant kidneys and clearly provide useful prognostic information for the transplant nephrologist.15
Up to 60% of patients with protocol biopsies are found to have histological recurrence, most of whom do not show clinical signs of recurrence.4 Despite this, protocol biopsies exclusively performed to assess histological recurrence cannot be recommended because histological diagnosis has not been proven to alter management, unless steroid freedom is present or steroid withdrawal is being considered, in which case observational data suggest maintenance steroids may be desirable to reduce risk of graft failure caused by recurrence.7 As yet, no treatments have been shown to halt, or even to slow, the development of clinical IgAN recurrence.
Longer-Term Outcomes From IgA Recurrence
Observational studies of 2 types have revealed important information on the natural history of IgAN after transplantation. Single-center, cohort studies have yielded information on patient and graft outcomes over long-term follow-up. The earliest reports of IgAN recurrence were made by Berger who reported a high rate of recurrence on histology and noted that this appeared to have little to no impact on graft function or patient outcomes over short-medium–term follow-up.31,43 Odum and others4 confirmed these observations, but were appropriately concerned about potential long-term impact. Such concerns have recently been validated by the publication of a cohort of 190 Italian patients followed up for 15 years.15 Recurrence was found in 22% of patients, although this is likely an underestimate because patients were biopsied only after developing persistent proteinuria of 0.5 g or greater per day, persistent microscopic hematuria, and/or acute renal dysfunction.15 Of those with recurrence, 29% lost their graft due to IgAN recurrence during follow-up.15 Death-censored graft survival at 15 years was approximately 10% lower in patients who had IgAN than in controls, largely attributable to IgAN recurrence.15
Registry analyses typically provide less granular data but superior numbers to single-center cohort studies. The majority of such studies demonstrate that overall graft survival in those with IgAN is no worse than those with other causes of ESKD.25 One European registry study showed that although graft survival was initially better in those with IgAN compared with other transplant recipients, after 3 years, they experienced increased graft loss.21 Two larger studies of the Australian and New Zealand Dialysis and Transplant Registry confirmed that although IgAN recurrence was a significant cause of graft loss for those with glomerulonephritis, third only to chronic allograft nephropathy and death with function, overall outcomes at 10 years were similar for those with IgAN as compared with those with other forms of glomerulonephritis and to those with other causes of ESKD.7,23 Outcomes past 10 years have been insufficiently studied to draw firm conclusions but long-term cohort studies suggest progressive graft loss due to recurrence will continue to accrue beyond 10 years.15
There are no proven, specific therapies for recurrent IgAN. Treatment aims to reduce proteinuria, optimize blood pressure, and reduce the inflammatory state. Kidney Disease Improving Global Outcomes (KDIGO) recently provided clinical practice guidelines for native kidney IgAN which have clarified recommended treatments and may reduce the variability seen in the management of these patients.44 The mainstays of care for those with IgAN have been angiotensin converting enzyme inhibitors or angiotensin II receptor blockers in those with proteinuria greater than 0.5 g per day, tight blood pressure control to less than 130/80 mm Hg in patients with protein less than 1 g per day and less than 125/75 in patients with protein greater than 1 g per day, and steroids and/or fish oil for those with persistent proteinuria greater than 1 g per day with estimated glomerular filtration rate greater than 50 mL/min per 1.73 m2.45 Although the role of mycophenolate, other immunosuppressive agents, and tonsillectomy remain controversial, current KDIGO guidelines do not recommend their use in native IgAN.
The KDIGO Transplant Guidelines recommend management aimed at reducing proteinuria and controlling blood pressure.46 Two small single-center studies have supported this practice and found that the use of angiotensin converting enzyme inhibitors in recurrent IgAN may increase graft survival, though more definitive studies are needed to confirm this finding.19,47
Our ultimate aim should be prevention of recurrence, rather than symptom management once it has occurred. To this end, there is some evidence that immunosuppression matters. Steroid withdrawal, in particular, has been associated with increased rates of recurrence.7 Retrospective data from a single center suggests there may be a role for induction therapy, most notably the use of antithymocyte globulin, in prevention.17 Furthermore, a reduction in frequency of graft loss attributed to recurrence over successive eras in Italy and Australia suggests that the combination of mycophenolate and tacrolimus may also be protective.7,15Figure 1 schematically represents mechanistic targets through which current immunosuppressive agents used in transplantation may act to retard IgAN recurrence in the allograft.
It is less clear what, if any, treatment should be instituted if there is recurrence on biopsy in a patient who has not developed any clinical signs or symptoms of recurrence.
Understanding the cause of the clinical and histological variation in IgAN is key to progressing our prevention and management of this disease for the individual. Better molecular characterization of IgAN may enable type-specific therapies. For instance, steroids may be important in some types but not others. There are hints at this in the variation of effectiveness of tonsillectomy reported in Asian versus western centers, which may be attributable to different genetic underpinnings of the disease.48-51
There have been no sizable, prospective randomized controlled trials on interventions for recurrent IgAN. This is in part a reflection of the low frequency of patients experiencing recurrence within any single center. This makes single-center studies unfeasible, and large multicenter studies with either protracted follow-up and/or use of appropriate surrogate markers may be required.
Recurrence of IgAN is common and leads to graft loss in a significant proportion of cases. It is therefore crucially important to patients with ESKD caused by IgAN who envisage transplantation as their mode of renal replacement therapy. Our limited understanding of the pathogenesis of IgAN, both native and recurrent, significantly hampers our ability to both inform patients and manage them. This should not dissuade us from pursuing transplantation, but rather should unite us in our efforts to accumulate the knowledge required to both advise and optimally manage our patients.
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