IgA nephropathy: Recurrence after transplantation

INTRODUCTION — Transplantation is the treatment of choice for individuals with progressive kidney failure due to IgA nephropathy (IgAN), which is caused by the deposition of IgA in the kidney parenchyma. Recurrent IgA deposition in the allograft is common and may cause hematuria, proteinuria, or progressive kidney dysfunction. Among some patients, however, IgA deposits are observed on biopsy but do not appear to cause clinically significant disease [1]. IgA deposition may occur alone or be concurrent with other significant pathology, including chronic rejection.

Issues related to recurrence after transplantation in patients with IgAN or IgA vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) are reviewed here. Other aspects of IgAN and IgAV in the native kidney are discussed separately:

●(See "IgA nephropathy: Pathogenesis".)

●(See "IgA nephropathy: Clinical features and diagnosis".)

●(See "IgA nephropathy: Treatment and prognosis".)

●(See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

EPIDEMIOLOGY — The reported frequency of histologic or clinically significant recurrence of IgAN varies in the reported literature, with the incidence probably increasing as a function of time from transplantation [2-4]. In the multicenter Post-Transplant Glomerular Disease (TANGO) cohort study of 504 transplant recipients with biopsy-proven IgAN as the cause of end-stage kidney disease (ESKD) in the native kidneys, the cumulative incidence of recurrence was 19 percent at 10 years and 23 percent at 15 years [5]. Among patients with recurrent IgAN, the median time to recurrence was 3.4 years.

Histologic recurrence, with or without evidence of clinical disease, is common. As an example, in a combined retrospective and prospective study that reviewed biopsies from 29 allografts, histologic recurrence of IgA deposition was found in 17 patients (58 percent) [6]. Three of these patients had a normal urinalysis and normal glomeruli on light microscopy, while five had hematuria, heavy proteinuria, hypertension, and progressive kidney failure due to IgAN alone. The only predictor for recurrence was a longer time after transplantation (46 versus 15 months in those without recurrence).

In retrospective analyses of allograft biopsies obtained due to clinical concern for graft dysfunction, the recurrence of IgAN has ranged from 21 to 58 percent [6-11].

The prognosis of patients who develop recurrent IgAN is discussed below. (See 'Prognosis' below.)

RISK FACTORS — Possible risk factors for recurrence include the following:

●Use of living-related-donor kidney

●Specific human leukocyte antigen (HLA) alleles in recipient including HLA-B35, HLA-DR4, HLA-B8, HLA-DR3

●Good HLA match between donor and recipient

●Glucocorticoid withdrawal

●High serum IgA concentration

●Elevated galactose-deficient (Gd)-IgA1-specific immunoglobulin G (IgG) autoantibodies

●Rare genetic variants in complement factor H-related protein 5 (CFHR5)

●Recipient age

Donor effect — The risk of recurrence may be higher among recipients of living-related-donor kidneys, compared with deceased-donor kidneys. Therefore, the expected advantage in allograft survival with a living-related- compared with deceased-donor source may be negated. However, there is no basis for avoiding a living-related-donor source, largely due to the reported equivalence of graft survival independent of IgAN recurrence, but also given the expected deceased-donor waiting-list time and a reported decrease in patient mortality and increase in graft survival with earlier transplantation in relation to time on dialysis [12-14].

Conflicting data exist concerning a possible increased risk for recurrent IgAN in recipients of living, related allografts, compared with that with unrelated (living- or deceased-donor) allografts:

●Several retrospective analyses have found no increased risk of recurrence based upon living- versus deceased-donor status [9,10,15]. Another report found no difference in risk among recipients of living, related versus living, unrelated donors [7].

●By comparison, other studies have reported an increased risk of recurrence in recipients of living, related allografts [16-19]. There was no significant difference in graft survival based upon donor status in some reports [16,17], while others reported a survival advantage for living, related donors [20].

Human leukocyte antigen effect — HLA specificity may affect the likelihood of recurrent IgAN, with the presence of either HLA-B35 or HLA-DR4 increasing the risk in some series [21,22]. Other studies noted a higher representation of HLA-B35 and HLA-DR4 in the IgAN population, but their presence had no effect on the incidence of recurrence [7,10,16,19,23,24]. An analysis of the Eurotransplant registry revealed that the 10-year graft survival was significantly lower among patients with IgAN and HLA-B8, DR3 than those with IgAN without HLA-B8, DR3 (52.5 percent versus 69.1 percent, respectively) [25]. Graft survival was worse even among those with zero-mismatched kidneys, suggesting that graft loss may be due to factors other than rejection, although no definite association with IgAN recurrence was demonstrated. Conversely, the presence of HLA-B8, DR3 did not influence graft outcomes among control patients with pyelonephritis/interstitial nephritis and polycystic kidney disease (PKD).

A separate issue is the importance of HLA matching:

●In a series of 54 patients with 61 kidney transplants for end-stage kidney disease (ESKD) due to IgAN, there was a statistically significant decrease in graft survival with better HLA-DR matching [9,26]. There were insufficient numbers to separately calculate the effect in living-related- versus deceased-donor recipients.

●In a study of 86 kidney transplant recipients with a history of IgAN, the risk of IgAN recurrence was decreased among those who had an HLA-B full mismatch with their donor, compared with those who had at least a one HLA-B match [27].

●A registry study of 1354 patients with end-stage disease due to IgAN from Australia and New Zealand showed that zero-HLA-mismatched living-donor recipients were more likely to develop recurrence (17 percent) than the whole cohort of living and deceased donors (7 percent) [19]. In addition, although graft survival did not differ among those with recurrence and zero HLA mismatches compared with one or more HLA mismatches, the survival advantage of zero-antigen HLA mismatches compared with one or more HLA mismatches was lost.

●Conversely, a Korean study found no association with full HLA match and the risk of recurrent IgAN among patients with IgAN [20].

Glucocorticoid withdrawal — Early withdrawal of glucocorticoids from the maintenance immunosuppression regimen after kidney transplantation may be associated with an increased risk of recurrent IgAN. In a retrospective study of 9690 transplant recipients (2831 with early glucocorticoid withdrawal and 6859 with continued glucocorticoid use), 1238 patients experienced graft loss; 15.4 percent of these cases were due to IgAN recurrence [28]. A multivariate analysis found that continued glucocorticoid use was associated with a decreased risk of recurrence (hazard ratio [HR] 0.67, 95% CI 0.48 to 0.92). Patient survival and death-censored graft survival did not differ between the two groups. Similar findings were shown in another study that evaluated the impact of immunosuppressive therapy on the risk of recurrent IgAN among 120 transplant recipients with IgAN of the native kidney [29]. IgAN recurrence occurred in 28 of 51 allografts (55 percent) that were biopsied posttransplant. Although the use of maintenance immunosuppressive medications was not associated with an increased risk for IgAN recurrence, there was a nearly eightfold higher risk of IgAN recurrence among patients who experienced glucocorticoid withdrawal at any time posttransplant.

Serum IgA concentration — An increased serum IgA concentration may be a risk factor for recurrence [18,30]. This was suggested by a retrospective analysis of 48 transplant recipients who had biopsy-proven IgAN as a cause of ESKD of the native kidney [18]. The mean IgA value was higher among 14 patients with recurrence, compared with 34 patients without recurrence (4 versus 3.25 g/L, respectively).

Galactose-deficient IgA1-specific IgG autoantibodies — Elevated serum levels of Gd-IgA1-specific IgG autoantibody at the time of transplant may be associated with a higher risk of recurrence. In one study of 96 kidney transplant recipients with native kidney IgAN, an elevated level of normalized serum Gd-IgA1-specific IgG autoantibodies at the time of transplant was an independent risk factor for recurrent IgAN (relative risk 2.96, 95% CI 1.31-6.70) [31]. However, the same autoantibody level was not predictive of allograft failure. Further studies to validate these findings are needed.

Rare genetic variants in CFHR5 — There is increasing evidence supporting a role for complement dysregulation in the pathogenesis of IgAN (see "IgA nephropathy: Pathogenesis", section on 'Complement activation'). Genome-wide association studies (GWAS) have identified abnormalities in the complement factor H (CFH) and the CFH-related (CFHR) genes in patients with IgAN [32,33]. In particular, rare genetic variants in the CFHR protein 5 (CFHR5) gene have been associated with an increased genetic susceptibility to IgAN [34]. However, it is unclear if any of these CFHR5 variants increase the risk of IgAN recurrence posttransplant.

Recipient age — Age may be a risk factor for IgAN recurrence posttransplantation. In a study of 86 transplant recipients with a history of IgAN, younger age at the time of transplantation was a risk factor for disease recurrence and eventual development of allograft dysfunction [27]. The risk of IgAN recurrence decreased as a function of age at the time of transplant.

PREVENTION — There is no known preventive therapy for IgAN recurrence. Among transplant recipients, there are no conclusive data that the selection of immunosuppressive therapy alters the risk of recurrence (other than glucocorticoid withdrawal). No significant difference, for example, has been observed in the incidence or severity of IgAN in studies comparing the pre- and post-cyclosporine eras [8,9]. There is some evidence that the use of mycophenolate mofetil may decrease the risk of IgAN recurrence in the short term [7,35,36]. However, other studies have found no association with mycophenolate and recurrent IgAN [37-39]. Furthermore, in an analysis of the United States Renal Data System, the use of mycophenolate was associated with a nonsignificant trend towards an increased risk of graft loss due to recurrent IgAN (hazard ratio [HR] 1.79, 95% CI 0.49-6.49) [40]. In this same study, a nonsignificant trend for a decreased risk of graft loss due to recurrent IgAN was associated with the use of steroids (HR 0.57, 95% CI 0.12-2.71). However, neither association reached statistical significance. In an analysis of the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) of 1521 first-time kidney transplant recipients with end-stage kidney disease (ESKD) from IgA, maintenance steroid use was strongly associated with a reduced risk of recurrence (subhazard ratio 0.50, 95% CI 0.30–0.84) after adjusting for age, sex, human leukocyte antigen (HLA) mismatch, dialysis duration, and transplant era [41]. Limited data showed that kidney transplant patients who used cyclosporine had less recurrence [26].

Whether the choice of induction agent has any beneficial clinical effect on the incidence of recurrent IgAN is unclear. A retrospective analysis reported that the prevalence of recurrent IgA following transplantation was significantly reduced in patients receiving antithymocyte globulin, compared with either interleukin-2 (IL-2) induction or no induction treatment [42]. In this report, the 10-year cumulative recurrence rate, as defined by clinically directed biopsy, was 36 percent overall, 9 percent with antithymocyte induction, 41 percent with no induction, and 41 percent at a shorter five-year follow-up with IL-2 induction. Maintenance immunosuppression varied with the era. Graft loss from recurrent IgAN was 6 percent overall, and there was no difference in overall graft or patient survival based on choice of induction agent. Another study found a reduced risk of recurrent glomerulonephritis with antithymocyte globulin induction, compared with either IL-2 or alemtuzumab induction (HR 0.13, 95% CI 0.02-0.98) [43]. Among persons with IgAN, recurrent disease occurred in 0, 7.3, and 3.7 percent with antithymocyte globulin, IL-2, and alemtuzumab induction, respectively.

CLINICAL MANIFESTATIONS — Patients with recurrent IgA generally present with persistent microscopic hematuria. New or worsening proteinuria or, occasionally, an increase in the serum creatinine may also be seen. In one study that included 42 patients with recurrent IgAN, the following clinical presentations were observed [11]:

●Isolated microscopic hematuria (5 patients)

●Isolated proteinuria (8 patients)

●Microscopic hematuria plus proteinuria (12 patients)

●Isolated increase in serum creatinine (4 patients)

●Increased creatinine with either hematuria or proteinuria (13 patients)

If IgAN recurs, the time to onset of clinical manifestations due to kidney IgA deposition varies. In one study of 61 transplant recipients with initial kidney loss due to IgAN (of whom 18 had recurrent disease), the mean time to clinical recurrence and allograft failure was 31 and 63 months, respectively [9]. Occasionally, patients may develop early graft failure associated with crescentic IgAN [21,44,45].

Patients who had a rapidly progressive course to end-stage kidney disease (ESKD) in the native kidney tend to present early after transplantation with clinically significant recurrence [9,10,16,46]. Thus, patients with a rapidly progressive course of IgAN in their native kidneys should be informed that recurrent disease in the transplanted kidney may manifest early.

Similarly, patients with early graft loss from recurrent IgAN may have rapid recurrence of clinically significant disease following repeat transplantation; however, this is not certain, and good long-term outcomes have been described among such patients. (See 'Epidemiology' above.)

While persistent microscopic hematuria in a patient with IgAN is likely secondary to recurrent disease, this should not be assumed, and other potential etiologies should be investigated.

DIAGNOSIS — Recurrent IgAN should be suspected among patients who have a history of IgAN and who present with hematuria, new or worsening proteinuria, or an increased creatinine. The diagnosis is made by biopsy. The indications for biopsy vary among clinicians. All agree that, among transplant recipients with a history of IgAN, the following are indications for a transplant biopsy:

●An elevated creatinine above baseline, and/or

●Significant proteinuria (defined as >500 mg/day) despite an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and/or

●Persistent hematuria in the setting of a negative urologic evaluation

Some clinicians would also biopsy patients who present with isolated, persistent, low-grade proteinuria (defined as <500 mg/day), regardless of the absence or presence of an ACEI or ARB, whereas others would not perform a biopsy for such patients, providing the creatinine remained stable.

TREATMENT — We suggest that all patients with recurrent IgAN be treated with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Treatment with an ACEI or ARB may delay progression of recurrent disease in allografts [47,48].

We suggest that patients who had IgAN of the native kidneys, but who have no evidence of recurrence and do not have hypertension, not be treated with ACEI or ARB. It is not known whether early posttransplant initiation of these agents to all recipients with native IgAN, independent of disease recurrence, is beneficial.

Most studies that examined the benefit of ACEI therapy among patients with IgAN have included only nontransplant patients. These studies are discussed elsewhere. (See "IgA nephropathy: Treatment and prognosis", section on 'Angiotensin inhibition'.)

There are limited data on the benefit of ACEIs or ARBs among transplant recipients [47,48]. The best data are from a retrospective review of 75 transplant recipients with known IgAN of the native kidney, which demonstrated a higher 5- and 10-year graft survival associated with the use of ACEIs or ARBs, but this was not statistically significant [48]. Among patients with biopsy-proven recurrence, of those on an ACEI or ARB, three of nine progressed to end-stage kidney disease (ESKD). Among four patients with biopsy-proven IgAN who were not being treated with an ACEI or ARB, all progressed to ESKD.

It is not clear that graft survival is actually improved by initiating either an ACEI or an ARB following the detection of recurrent IgAN [38].

There have also been case reports of fish oil having a favorable effect in recurrent IgAN, but no studies have been performed to support its routine use [49]. (See "IgA nephropathy: Treatment and prognosis" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Immunosuppressive therapy specifically directed toward treatment of recurrent IgAN may be indicated in selected patients, such as those with biopsy-proven recurrence and rapidly rising serum creatinine or nephrotic-range proteinuria despite the use of ACEIs or ARBs. The optimal immunosuppressive therapy for recurrent IgAN is not known, and the approach is derived from studies of IgAN in the native kidney. (See "IgA nephropathy: Treatment and prognosis", section on 'Immunosuppressive therapy in high-risk patients'.)

Among such patients, high-dose glucocorticoids (such as prednisone 1 mg/kg/day) may be given for two months, followed by a slow taper back to low doses commonly used to prevent rejection.

An oral targeted-release formulation of the glucocorticoid budesonide (TRF-budesonide), which is designed to provide controlled release of budesonide in areas of the gut that have a high density of Peyer patches, has been shown to reduce proteinuria in nontransplant patients with IgAN of the native kidneys [50]. However, a similar benefit was not observed in a small series of transplant recipients who received a different formulation of targeted-release budesonide (which provided controlled release of budesonide throughout the colon) for recurrent IgAN [51]. (See "IgA nephropathy: Treatment and prognosis", section on 'Other regimens'.)

Patients who have a rapidly increasing serum creatinine despite high-dose glucocorticoids may benefit from oral or intravenous cyclophosphamide, based upon studies of patients with IgAN in the native kidney. There are no studies of these agents among patients with recurrent IgAN. (See "IgA nephropathy: Treatment and prognosis", section on 'Angiotensin inhibition'.)

If cyclophosphamide is used, the current antimetabolite used to prevent rejection (usually mycophenolate mofetil or azathioprine) should be discontinued for the duration that the patient is on cyclophosphamide to mitigate the risk of severe myelosuppression.

The use of rituximab in the treatment or prevention of recurrent IgAN has not been studied. However, a randomized controlled trial of nontransplant patients with IgAN that compared rituximab plus supportive therapy with supportive therapy alone found no benefit [52]. (See "IgA nephropathy: Treatment and prognosis", section on 'Other regimens'.)

Some data suggest that tonsillectomy may improve histologic and clinical findings of recurrent IgAN [53,54]. However, pretransplant tonsillectomy in patients with IgAN does not appear to prevent disease recurrence [55].

PROGNOSIS — Given the lack of a prospective study involving protocol biopsies, the true risk of significant graft dysfunction and/or graft loss from recurrent disease is unclear [6-11,16,56].

Historically, it was thought that, despite the risk of recurrent disease, among patients with a history of IgAN, the overall graft survival was similar to that of patients with a history of non-IgA glomerular or nonglomerular disease. As an example, in a large retrospective analysis (532 allograft recipients with primary IgAN) from Australia, the estimated 10-year incidence of graft loss due to recurrent disease was 9.7 percent [56]. Allografts in IgAN recipients exhibited a similar 10-year survival as allografts in recipients with either non-IgA glomerular or nonglomerular disease. In this series, recurrent IgAN was a less frequent cause of graft loss than either chronic rejection or death with a functioning graft. The risk of graft loss in relation to donor source was not evaluated.

However, other data provide further information on the long-term allograft survival of patients with IgAN. One study found that in patients with IgAN as the etiology for end-stage kidney disease (ESKD), IgAN recurrence posttransplantation was associated with allograft failure; the median time from diagnosis of recurrent IgAN to allograft loss was 3.1 years [57]. Another group reported that allograft survival beyond 12 years was lower for patients with IgAN compared with non-IgAN patients [58]. A third study that examined 15-year outcomes reported that death-censored graft survival was lower among patients with recurrent IgAN compared with controls (62.6 versus 72.4 percent, respectively) [11]. In the Post-Transplant Glomerular Disease (TANGO) study, the risk of graft loss was higher among patients with recurrence of IgAN than among those who did not have recurrence (hazard ratio 3.69, 95% CI 2.04-6.66) [5].

Recurrent IgAN in combination with chronic rejection has a worse prognosis, compared with recurrent IgAN alone [59].

There are only a few studies that have examined outcomes of a second transplant after the first was lost to recurrent IgAN. However, good long-term function has been described, despite evidence of IgA deposition in the second allograft [9,46].

Markers for progression — As with all glomerulopathies, increased urinary protein excretion and increased sclerosis and fibrosis on kidney biopsy with IgAN are associated with an enhanced risk of progressive disease. In one study of recurrent IgAN, for example, urine protein excretion >1 g/day and biopsy findings of prominent glomerulosclerosis (involving >30 percent of glomeruli) were associated with universal graft loss by six years after transplantation [60]. By comparison, urinary excretion <1 g/day and a kidney biopsy in which <10 percent of glomeruli show glomerulosclerosis forecast stable allograft function at nine years posttransplantation. In another study, the presence of glomerular crescents correlated with worse allograft survival [57]. (See "Secondary factors and progression of chronic kidney disease".)

The Oxford classification of IgAN, which is used to score kidney biopsies on the basis of five histologic variables (mesangial hypercellularity [M], endocapillary hypercellularity [E], segmental glomerulosclerosis [S], tubular atrophy/interstitial fibrosis [T], and crescents [C]), has been shown to predict kidney outcomes in nontransplant patients with IgAN. Studies suggest that the Oxford classification also has prognostic value in transplant recipients with recurrent IgAN, with higher MEST-C scores being associated with graft failure [61-63]. The Oxford classification is discussed in greater detail elsewhere. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Oxford classification of IgAN' and "IgA nephropathy: Treatment and prognosis", section on 'Risk factors for disease progression'.)

Although persistent microscopic hematuria may be an early marker of recurrent IgAN, its onset does not necessarily predict a poor outcome. A review of 41 kidney transplant recipients with primary IgAN found a higher prevalence of persistent microscopic hematuria, compared with recipients with other native kidney disease (32 versus 12 percent, respectively) [64]. Hematuria in the IgAN patients was not associated with donor status, kidney function, or time since transplantation.

IgA VASCULITIS (HENOCH-SCHÖNLEIN PURPURA) — IgA vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), which has kidney manifestations indistinguishable from IgAN, usually occurs in children, but has also been reported in adults. (See "IgA vasculitis (Henoch-Schönlein purpura): Kidney manifestations".)

The risk of recurrence of IgAV (HSP) appears to be the same as for IgAN, although data are limited. One analysis found overall a recurrence rate of 15 percent and graft survival rates of nearly 90 percent at 10 years, while another pooled analysis demonstrated clinically significant disease in 35 percent and graft loss in 11 percent at five years posttransplantation [65,66]. Also similar to IgAN, patients with a rapid pretransplant course culminating in kidney failure tended to develop prompt recurrence in the allograft.

Another study evaluated 13 patients who collectively received 18 kidney transplants and underwent protocol biopsies at the time of implantation, 3 months, and 12 months posttransplant, as well as biopsies for allograft dysfunction and proteinuria [67]. Histologic recurrence of IgAV (HSP) occurred in 11 of 18 (61 percent) allografts at a mean follow-up of 83 months. Only one patient presented with evidence of clinical disease. No patient in this study experienced allograft loss due to IgAV (HSP) recurrence [67].

OTHER CAUSES OF GLOMERULAR IgA DEPOSITION — IgA deposition that is unrelated to recurrent disease in a kidney allograft is not uncommon [68]. Kidney allograft recipients without native IgAN but with cirrhosis or celiac disease (gluten enteropathy) may develop mesangial IgA deposits [69,70]. Impaired removal of IgA complexes in liver disease [71,72] and the formation of IgA anti-gluten antibodies in celiac disease [73] are thought to underlie this process. (See "IgA nephropathy: Clinical features and diagnosis" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

Despite the IgA deposition, it is unusual for clinical evidence of kidney disease related to IgAN to be apparent in a native (or transplant) kidney in this setting [69,70]. The absence of clinically significant disease is postulated to result from a lack of complement activation and resultant inflammatory response [70]. The degree of concurrent IgG and complement deposition on immunofluorescence may help clarify whether the mesangial IgA deposition is solely a histologic finding or relevant to graft dysfunction.

Among patients with liver disease and progressive IgAN, the nephropathy may resolve after liver transplantation [74]. Similarly, in a native kidney with celiac disease-induced IgAN, the nephropathy may resolve with a gluten-free diet [75,76].

There are no published data looking at the potential recurrence of IgAN in kidney transplant recipients in association with celiac disease. Although it would be rare for a patient to have graft dysfunction as a result of IgA deposition in this setting, given the incidence of celiac disease in the general population, particularly in diabetics, it is reasonable to screen patients with recurrent IgAN for celiac disease, especially those with otherwise unexplained diarrhea, malabsorption, or iron deficiency. (See "Diagnosis of celiac disease in adults".)

TRANSPLANTATION OF A KIDNEY WITH IgA DEPOSITS — Both deceased- and living-donor kidneys with IgA deposition have been transplanted into non-IgAN recipients. In one study of 70 living-donor kidney biopsies obtained just prior to transplantation, 13 percent had glomerular IgA deposits [77]. Another report described the presence of latent mesangial IgA deposits in approximately 16 percent of biopsies obtained at the time of transplantation from both living and deceased donors otherwise considered healthy [78]. Graft outcomes were not reported in either of these analyses.

A prospective analysis of 83 recipients of deceased-donor allografts with IgA deposition reported an increased incidence of early acute rejection (31 versus 19 percent), delayed graft function, proteinuria, and hematuria, compared with 259 recipients of a deceased-donor allograft without evidence of IgA deposition [79]. Serial protocol biopsies tended to demonstrate gradual resolution of IgA deposition within 45 days following transplantation, as well as resolution of the proteinuria and hematuria. Despite the increased incidence of acute rejection and clinical signs of allograft dysfunction, graft survival at one and three years was similar in both groups.

Two other series with a total of 12 patients noted rapid resolution of IgA deposits after transplantation in most patients [80,81]. At present, our practice is not to use kidneys with known IgA deposits for donation. However, we have unknowingly transplanted deceased-donor allografts with evidence of IgA deposition evident on an early posttransplant biopsy that has resolved on follow-up biopsy with no evidence for adverse outcome on graft function or survival.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – IgA nephropathy (IgAN) is caused by the deposition of IgA in the kidney parenchyma. IgAN may cause progressive kidney dysfunction. Transplantation is the treatment of choice for individuals with progressive kidney failure. Recurrent IgA deposition in the allograft is common and may cause hematuria, proteinuria, or progressive kidney dysfunction. Among some patients, however, IgA deposits are observed on biopsy, but do not appear to cause clinically significant disease. (See 'Introduction' above and 'Clinical manifestations' above.)

●Risk factors – The risk of recurrence may be higher among recipients of living-related-donor kidneys, compared with deceased-donor kidneys. However, there is no basis for avoiding a living-related-donor source, largely due to the reported equivalence of graft survival independent of IgAN recurrence, but also given the expected deceased-donor waiting-list time and a reported decrease in patient mortality and increase in graft survival with earlier transplantation in relation to time on dialysis.

Other possible risk factors for recurrence include glucocorticoid withdrawal, specific human leukocyte antigen (HLA) alleles among recipients, a close HLA match between donor and recipient, increased serum IgA concentrations among recipients, serum levels of galactose-deficient IgA1-specific IgG autoantibodies, and rare genetic variants in complement factor H-related protein 5. However, none of these risk factors have been validated. (See 'Risk factors' above.)

●Diagnosis – The diagnosis of recurrent IgAN is made by biopsy. Indications for a transplant biopsy include an elevated creatinine above baseline and/or significant proteinuria (defined as >500 mg/day) despite an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and/or persistent hematuria in the setting of a negative urologic evaluation. Some clinicians would also biopsy patients who present with isolated, persistent, low-grade proteinuria (defined as <500 mg/day), regardless of the absence or presence of an ACEI or ARB, whereas others would not perform a biopsy for such patients, providing the creatinine remained stable. (See 'Diagnosis' above.)

●Prevention – There is no known preventive therapy for IgAN recurrence. There are no conclusive data that the selection of immunosuppressive therapy alters the risk of recurrence. (See 'Prevention' above.)

●Treatment

•Generally, all patients with recurrent IgAN are treated with ACEIs or ARBs, which may delay progression of recurrent disease in allografts. Patients with IgAN of the native kidney and hypertension are treated with an ACEI or ARB, even in the absence of any evidence of recurrent disease, although patients who had IgAN of the native kidney, but who have no evidence of recurrence and do not have hypertension, are generally not treated with ACEIs or ARBs. It is not known whether early posttransplant initiation of these agents to all recipients with native IgAN, independent of disease recurrence, is beneficial.

•Immunosuppressive therapy specifically directed toward treatment of recurrent IgA may be used in selected patients, such as those with biopsy-proven recurrence and rapidly rising serum creatinine or nephrotic-range proteinuria despite the use of ACEIs or ARBs. Among such patients, high-dose glucocorticoids may be given for two months, followed by a slow taper back to low doses commonly used to prevent rejection. Patients who have a rapidly increasing serum creatinine despite high-dose glucocorticoids may benefit from oral or intravenous cyclophosphamide, based upon studies of patients with IgAN in the native kidney. If cyclophosphamide is used, the current antimetabolite used to prevent rejection (usually mycophenolate mofetil or azathioprine) should be discontinued for the duration that the patient is on cyclophosphamide. (See 'Treatment' above.)

●Prognosis – Overall, the reported risk of graft loss due to recurrent disease is approximately 7 to 10 percent at 10 years, but the risk is probably higher than this as time from transplant increases. Among patients with graft dysfunction attributed to recurrent IgAN, the risk of graft loss is much higher. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Georges Saab, MD, who contributed to an earlier version of this topic review.