Glomerulonephritis Recurrence in the Renal Graft

Renal transplantation is a treatment, not a cure. Although transplantation may return renal function to the recipient, it does not necessarily remove the cause of the recipient's original renal disease. Glomerulonephritis is the cause of renal failure for 20 to 40% of those who receive a transplant; for these recipients, the threat of recurrent disease is real. The transplant setting of immunosuppression, different antigenic characteristics of the graft versus the native kidney, and different chronology may attenuate or prevent recurrence of some forms of glomerulonephritis. Others will, despite these barriers, recur and may result in allograft failure. Allograft survival rates have steadily improved over the past 20 yr, largely as a result of our increasing ability to prevent and treat rejection (1). Recurrent glomerulonephritis is at present a minor contributor to allograft failure, responsible for 3% of all grafts lost in Australia and New Zealand from 1979 to 1998 (E. Briganti and S. Chadban, unpublished data) and a similar number in the United Kingdom (2). However, the propensity for glomerulonephritis to recur seems to be time dependent (3). Thus, as graft survival increases, so, too, does the likelihood of disease recurrence. As the average cadaveric graft is now projected to function for more than 13 yr and the average live-donor graft for more than 21 yr (1), we can expect to see an increased incidence of recurrent glomerulonephritis and a greater number of grafts failing as a result of recurrence. By implication, the diagnosis of recurrent glomerulonephritis requires an accurate diagnosis of both the primary renal disease and subsequent disease in the transplant kidney. In most cases, these criteria will be fulfilled only by obtaining renal biopsy material from both organs for diagnostic assessment, which may need to include electron microscopy and immunohistology (4,5). Although biopsy of native and transplant kidneys is simple, safe, and widely practiced, it is not performed in all cases of suspected glomerulonephritis in native or transplanted kidneys (6). Electron microscopy and immunohistology also are not routinely performed on transplant biopsies. Thus, the true incidence and impact of recurrent glomerulonephritis is not accurately known and is probably underestimated. This article discusses recurrent glomerulonephritis in the current era. The strength and quality of data reported in the literature are variable; where evidence is cited, its strength is considered. The epidemiology of recurrence is reviewed in a general sense, and recurrence of specific forms of glomerulonephritis is addressed individually. The incidence of recurrence and recurrence leading to graft failure is examined, and risk factors for disease recurrence are assessed. Where available, data on the pathogenesis and management of recurrent glomerulonephritis also is presented. Controversies in the area are discussed, including the diagnosis of recurrent glomerulonephritis and the implications of recurrence for retransplantation. The issues of de novo glomerulonephritis posttransplantation and recurrent metabolic diseases have been reviewed elsewhere (6,7,8) and are not directly addressed here. Epidemiology of Recurrent Glomerulonephritis Diagnosis and Definitions By implication, the diagnosis of recurrent glomerulonephritis requires an accurate identification and characterization of glomerulonephritis in the native kidney and subsequent identification of the same disease affecting the transplant kidney. These criteria mandate a renal biopsy of both native and transplant kidneys. Such criteria are not fulfilled in many cases of recurrent glomerulonephritis cited in the literature (6). Patients who are presumed to have glomerulonephritis (no biopsy) as the primary cause of renal failure and who go on to develop biopsy-proven glomerulonephritis after transplantation are frequently labeled as having recurrent glomerulonephritis (9). Such patients may have either recurrent or de novo glomerulonephritis (7,8). Given this difficulty, many studies group de novo glomerulonephritis with recurrent glomerulonephritis. Conversely, underdiagnosis of recurrent glomerulonephritis is also likely to be a major flaw in the literature, as many patients with the clinical features of deteriorating renal function and proteinuria posttransplantation are misclassified as having “chronic rejection” and are not biopsied or assessed adequately (see the section Clinical Features and Differential Diagnosis of Recurrent Glomerulonephritis). Thus, the true incidence and impact of recurrent glomerulonephritis are not accurately known and are probably underestimated in the published literature (6). Reports on recurrent glomerulonephritis vary in terms of diagnostic criteria and definition. Recurrent glomerulonephritis is categorized in the present article in three ways: Recurrent glomerulonephritis—confirmed (biopsy proven) or presumed (clinical criteria alone) Recurrent glomerulonephritis causing graft loss—clinical and biopsy features demonstrating recurrence as the sole or dominant pathology resulting in loss of graft function that requires renal replacement therapy or causes death as a result of uremia Recurrent glomerulonephritis contributing to graft loss—recurrent glomerulonephritis as one of two or more pathologies, such as chronic rejection or chronic cyclosporin nephrotoxicity, identified as contributing to graft failure that requires renal replacement therapy or causes death as a result of uremia. Frequency and Significance of Recurrence Virtually all recognized forms of glomerulonephritis may recur posttransplantation. Published data suggest that recurrent glomerulonephritis occurs in 6 to 19.4% of all renal transplant recipients, largely dependent on the time of assessment after transplantation (2,3,10,11), and causes the loss of 1.1 to 4.4% of all renal allografts (2,3,9,11). The rate of recurrence and recurrence causing graft loss is obviously higher in patients with end-stage renal failure as a result of glomerulonephritis but varies enormously depending on the type of glomerulonephritis. For example, lupus nephritis recurs in fewer than 10% of cases and graft losses are uncommon, whereas recurrence is almost universal in cases of type II mesangiocapillary glomerulonephritis and graft losses are frequent. Although the impact of recurrent glomerulonephritis on graft survival depends on the type of glomerulonephritis, at a population level, the presence of recurrent glomerulonephritis clearly incurs an increased risk of graft failure (12). Data from the Renal Allograft Disease Registry in the United States demonstrate the negative impact of disease recurrence on graft survival, documenting a relative risk of 1.9 (95% confidence interval [CI], 1.57 to 2.40) for graft loss at 5 yr as compared with those without recurrence (12). Factors in addition to the underlying type of glomerulonephritis may influence the risk of recurrence. Time of follow-up clearly is important and may be related to the duration of exposure of the graft to the nephritogenic factors that are responsible for causing glomerulonephritis (3). In general, grafts that are lost early as a result of rejection are exposed relatively briefly and rarely develop recurrence. In contrast, grafts that survive long term are exposed to nephritogenic factors for longer and are more likely to develop recurrent glomerulonephritis. This concept is borne out by registry data from the United States and ANZDATA. Renal Allograft Disease Registry data show that the incidence of recurrent disease (glomerulonephritis and metabolic diseases) increases with duration of follow-up, from 2.8% at 2 yr to 9.8% at 5 yr and 18.5% at 8 yr of follow-up (12). As the overall duration of graft survival has improved (1), largely because of a decline in graft loss caused by rejection, the incidence of graft loss caused by recurrent disease paradoxically has increased. In Australia, from the period 1979 to 1988 to the period 1989 to 1998, the incidence of all-cause graft loss fell by 45.5 per 1000 transplants (95% CI, 40.9 to 50.2), largely because of a fall in the incidence of graft loss caused by acute rejection, which fell by 28.5 per 1000 transplants. In contrast, the incidence of recurrent disease rose by 1.3 per 1000 (95% CI, 0.6 to 2.1; Figure 1; E. Briganti and S. Chadban, unpublished data). Consistent with these observations, the recipients of human leukocyte antigen (HLA)-identical transplants rarely experience rejection, they enjoy prolonged graft survival, but they have a high rate of recurrent glomerulonephritis (13). In one report, recurrent glomerulonephritis was present in 36 to 42% of those biopsied and resulted in 24% of graft losses, thereby being the second most frequent cause of graft loss after death in this group (13).Figure 1.: Incidence of graft loss: Australia 1979 to 1998, all causes versus recurrent disease. The incidence of graft loss has fallen progressively over the past 20 yr, largely as a result of reductions in loss from acute and chronic rejection. In contrast, graft loss caused by recurrent disease has increased over the same period (P < 0.05), particularly in the 14- to 55-yr recipient age group (E. Briganti and S. Chadban, unpublished data).Other groups of recipients may experience higher rates of recurrent glomerulonephritis. Higher rates of recurrence have been reported in pediatric transplant recipients, in whom recurrent glomerulonephritis has been the cause of 6% of first allograft losses and 12% of subsequent graft losses (14). Patients who experience first allograft loss from recurrent glomerulonephritis are also at higher risk of recurrence in a subsequent graft, documented at up to 48% (9). Several measures aimed at reducing the risk of recurrence have been reported. Bilateral native kidney nephrectomy, as a means of eliminating antigenic stimulation, has been examined in a large, single-center, retrospective study (10). Of 361 patients with end-stage renal failure caused by glomerulonephritis, 61 received bilateral native nephrectomy pretransplantation (nonrandomized). After 10 yr of follow-up, a higher rate of recurrence was recorded in nephrectomized patients (42% versus 19.4% for non-nephrectomized patients), demonstrating a clear lack of benefit. Other strategies have included induction of disease remission before transplantation, prolonged time on dialysis pretransplantation, avoidance of living related donation, and variations in posttransplantation maintenance immunosuppression. These issues are discussed within specific disease categories (see below). Thus, recurrent glomerulonephritis seems to be a significant problem. It is important, however, to view these general data with several reservations: Many of the reported data include patients with de novo glomerulonephritis and recurrent metabolic diseases pooled into a single group labeled recurrent disease (12). Where possible in this article, these conditions are separated from recurrent glomerulonephritis. Most data are retrospective and are therefore subject to limitations of documentation, recall, variations in local practice, and changes in practice over time. Many data, particularly reports on specific disease entities and their treatment, have been obtained from single-center studies that generally include relatively small patient numbers. Patient demographics and the clinical approach may differ from the global transplantation population. The broadest data have been collected by registries: UNOS (United Network for Organ Sharing), Renal Allograft Disease Registry (USA), ANZDATA (Australia and New Zealand), ERA-EDTA, Eurotransplant, and the UK data on of however, and type of data and of by and the of data vary the which may to the For example, recurrent glomerulonephritis was reported to cause graft loss in 3% of first transplants reported to the registry (9). However, because of the in the of renal biopsy to glomerulonephritis, of patients included as having native kidney glomerulonephritis without biopsy Thus, it is not possible to recurrent from de novo disease in these registry these the and of recurrent glomerulonephritis are over time. The of this article discusses current and management of recurrent glomerulonephritis. Data specific to of glomerulonephritis are in and are discussed in the Differential diagnosis of recurrent Features and Differential Diagnosis of Recurrent Glomerulonephritis The features of recurrent glomerulonephritis are those of nephritis the native kidney, including and in renal Renal function may be or at the time of and the rate of is Most important, recurrent glomerulonephritis may be one of several conditions that an with chronic allograft or with glomerulonephritis. The presence of some forms of recurrent glomerulonephritis may the graft to rejection, and and For most of recurrent glomerulonephritis, clinical features of the recurrence are similar to those of the primary disease. features of the primary may recur with recurrence in the such as and in and in recurrent may be in some cases, such as in in but may be in such as in recurrent lupus of or is important recurrent or glomerulonephritis. Renal biopsy is the diagnosis of recurrence is of the biopsy by and electron microscopy is and in many cases (4,5). microscopy and immunohistology are to recurrent from de novo glomerulonephritis, rejection, and The presence of or changes suggest acute rejection rejection may chronic and including and which may be to from mesangiocapillary glomerulonephritis by microscopy The of immunohistology of and electron microscopy and of and may the diagnosis (4,5). The major of recurrent glomerulonephritis are in and and may the same disease with the more and of the both have been of as causes of graft because of its and because of its despite a high rate of recurrence. However, data suggest that we expect to an increasing of disease from recurrent as its more with longer follow-up is the most of glomerulonephritis that to end-stage renal failure, and patients who have this frequently receive transplants. recurrence is posttransplantation Most have reported a recurrence rate of to however, the only study in which all patients biopsied recurrence in The clinical of disease is and time Reports on graft survival in patients with have an graft survival rate for those who experience recurrence The not as reported in single-center reports of the clinical recurrence rate of and its impact on graft follow-up in all was 5 yr, with renal performed as for of graft or Recurrence was in to of cases, resulting in or contributing to significant graft or loss in to of loss the first yr posttransplantation was however, and graft losses increased in number with longer follow-up, with recurrence progressively greater as a cause of graft failure over time. In one with an average follow-up of 61 the time to clinical recurrence was and to graft failure was it is clear that with follow-up, may be and the time to will Recurrence is to Patient and been to have posttransplantation or and posttransplantation have impact of biopsy is are more likely to related transplantation has been with an increased risk of recurrence and graft loss in some but not in The in risk and the in graft survival seems to be however, and does not the avoidance of living related transplantation in patients with Recurrence of is two pooled of patients from and recurrence in and graft loss in at 5 yr of follow-up however, a higher risk of recurrence in patients with a disease failure within yr of was transplantation yr after the of was not to prevent Thus, the of recurrence seems to be similar to that of of recurrent and has not been The of measures to renal survival, such as and avoidance of is and Glomerulonephritis pooled of all reported of recurrent has largely the of the group of after transplantation and glomerulonephritis reported and the from and the United States included in the a of reports from the to however, as all the risk of of recurrence was recurrence was in of cases after to of follow-up Renal and with graft losses reported in a of was reported at all of follow-up, with an average time to of but both early and reported Clinical not in patients who likely to experience a posttransplantation. disease duration of at time of transplantation and follow-up, or disease or and type of transplant or cadaveric impact on recurrence rate The and management of have not been In most patients not receive a transplant in clinical remission from being and the of clinical remission before transplantation has not been Although the addition of cyclosporin to and was not to influence the rate of the of from the time of transplantation has not been In reported literature, patients with renal most with immunosuppression, and this was in a remission in of cases The of patients who receive transplants with seems to be at as as that of the general population The rate is in the transplant population as compared with the general because of the and duration of after transplantation the two be in this such as the impact of renal failure the of may patients from and age in the transplant Patient and graft survival posttransplantation to be in the as compared with the general transplant population the for and the lack of characteristics that this transplantation seems to be an of therapy for patients with renal failure caused by The for at be recognized and frequent for clinical evidence of such as renal and and of is of in or In the of data, therapy seems to be in the of Disease recurrence is in of patients who receive transplants but in only 5 to of patients who receive transplants 6 or more after the of transplantation, the rate of clinical recurrence is have been Recurrent disease be with and Recurrent disease is from de novo disease in some patients with who develop in to exposure of type the transplant Recurrence of posttransplantation has been the subject of a that examined 10 reports grafts in patients Recurrence in of cases and was with a graft survival was for those with recurrence versus in those of recurrence (P < Recurrence was with an age of of the original transplantation, transplantation, and the of also documented a rate of recurrence in those with as compared with a high rate in those with including Recurrence be from de novo which may be related to or rejection. Recurrence is generally within the first 6 however, have been reported The clinical may be or with and renal Although de novo disease may to of the management of recurrent disease is of and of is a In cases of or may be by transplant The of recurrent disease is than of grafts are lost within the first and graft survival 5 yr is and has been the recurrence of because of the of as a cause of end-stage renal failure and its widely recognized to recur early and after As to most forms of glomerulonephritis, significant into the pathogenesis of recurrence of have been and and have Patients with renal failure cause by a risk of recurrence of 20 to for first transplants Recurrence is at a time of posttransplantation in and is by and graft Patients with recurrent disease are more to acute rejection and acute renal failure as as graft which occurs in to of cases The rate of recurrence is more than in subsequent grafts the first graft was lost recurrence but is the first graft was lost causes Patients who are at risk of recurrence are those with an failure within yr of age than yr, on or recurrence in a transplant reports on an in recurrence after living related however, subsequent reports have the of this approach seems to over and in terms of Recurrent seems to be by a which is to This can be by or either a or an and can proteinuria to identification of the is to the presence of the as a to the risk of recurrence have some but have not a of the does to be the responsible for the of in the therapy of recurrent Although not assessed by a several have reported the of in remission in the of patients within 2 of after of has been but may be or by either chronic or with reports have of with increased of and however, these be as to therapy with or Recurrent is a but not transplantation in this group of transplantation probably be for those without features that suggest a high risk of recurrence or be performed in cases only after of the with all for the of proteinuria be for the first after transplantation in all cases, and recurrence be early with and Glomerulonephritis Data on recurrent glomerulonephritis is by two of reports significant of patients and the of de novo posttransplantation. novo has been reported to in 2 to of transplant recipients and to present more and than recurrent time to versus 10 The from in and reported a recurrence rate of in patients at yr posttransplantation and graft survival of at 5 yr and at 10 yr of This recurrence rate is higher than but with study from This for factors to the risk of recurrence but was to pretransplantation disease duration of dialysis before transplantation, graft or of cyclosporin to recurrence risk of recurrent is on reports and of data on the management of native kidney and with all have been reported As a of of three follow-up of patients with recurrent related to of the primary transplantation seems to be for first grafts but probably be for second grafts graft loss was the result of because the risk of recurrence in subsequent grafts is probably Glomerulonephritis Given the chronic allograft rejection and assessment of transplant as as accurate diagnosis of the native kidney disease is in from the more of chronic rejection. is by the presence of on for and for on immunohistology and by the presence of on electron microscopy (4,5). This is important to in the literature on recurrent for of and in the implications for patients risk of recurrence and graft loss in subsequent grafts after graft loss caused by recurrent type seems to be by of by exposure to native in lupus or or As the are not by transplantation, recurrence of disease is and is in 20 to of graft recipients loss has been reported in up to 40% of those with and the risk of recurrence in subsequent grafts Patients who receive grafts to be at risk of recurrence of is and the underlying cause of recurrent type be in related to may a of data are transplantation has been reported with Other forms of type have been with and with in single II type II has been to recur in to of grafts The clinical and proteinuria the first after transplantation, with renal function losses have been reported in 10 to of recurrent cases, with on and proteinuria a higher risk of graft loss therapy is and have been in reports (2). of type recurrence 13 posttransplantation has been in graft loss after yr The reported recurrence rate of lupus nephritis has from to Recurrence has been reported early and after transplantation, with a time to recurrence of yr in the reported of dialysis before transplantation and have not been to recurrence and have been to be of disease recurrence posttransplantation The clinical and of recurrence is variable; and and and all have been reported In to pooled data suggest that overall graft and patient survival may be in the lupus despite the age of lupus patients Recurrent may result in graft and graft loss may also as a result of in with the presence of a lupus Of reported transplant in lupus and recipients, three studies reported but studies reported for those with survival seems to be after live-donor transplantation than transplantation of recurrent has not been however, the of and all have been with a remission in one patient by from to with and maintenance data). the and early posttransplantation be for patients with and a of or lupus have been performed after graft loss caused by disease however, the small number of cases reported does not to be on the of Recurrent lupus does more frequently than was and graft in to be than for the general transplant population. However, the of patients who receive transplants for can expect a of recurrence and a in general of their for these transplantation a retrospective of patients reported to the UNOS registry after a kidney transplant for has been performed patients reported and survival was at yr and at 5 yr and 24% of patients the period The recurrence rate not be however, recurrence was responsible for graft loss in of cases in which the cause was which is with a reported recurrence rate of (2). factors for recurrence not and cyclosporin not to the recurrence rate The of transplantation on the of has not been The management of recurrent is The of posttransplantation to treat in this group of patients seems the posttransplantation of seems to be similar to that of lupus and renal transplantation seems to be a for those with end-stage renal failure. Glomerulonephritis and Glomerulonephritis Although only a small number of transplant recipients have been reported to have glomerulonephritis and glomerulonephritis, the recurrence rate of this disease seems to be more than of as with the primary requires electron microscopy The of the reported a rate of decline in renal function in three patients with recurrent as compared with those with native kidney that transplantation is an in patients with end-stage renal disease caused by glomerulonephritis or glomerulonephritis As a of one of early recurrence that to graft failure has been reported data have on of risk factors for and the implications for patient and graft after recurrence of the most Such data to receive a many and from These data to patients and their with to to and to to In contrast, data on recurrence of the are and our practice is therefore by small and local It is that this will be addressed in the the of and some of which are data on specific studies of of recurrent glomerulonephritis are As grafts longer and recurrent glomerulonephritis a more significant affecting greater of the to study management will This likely will a approach and clearly is the The the of ANZDATA and is to and E. for the