Abstract
Anti-glomerular basement membrane (GBM) disease causes rapidly progressive glomerulonephritis and end-stage kidney disease (ESKD). Studies of post-transplant outcomes in patients with ESKD due to anti-GBM disease in the United States are lacking. To better characterize outcomes of transplant recipients with a history of anti-GBM disease, we examined patient survival and graft survival among recipients with anti-GBM disease compared with IgA nephropathy at a single center in the United States. We analyzed patient survival, graft survival, disease recurrence, and malignancy rates for kidney transplant recipients with ESKD due to biopsy-proven anti-GBM disease who underwent kidney transplantation at our center between 1994 and 2015. 26 patients with biopsy-proven anti-GBM disease and 314 patients with IgAN underwent kidney transplantation from 1994 to 2015. The incidence of graft loss was 6.2 per 100 person-years for anti-GBM disease, which was similar to IgAN (4.08 per 100 person-years, p = .09). Patient mortality for anti-GBM was 0.03 per 100 person-years, similar to IgAN (0.02 per 100 person-years, p = .12). Disease recurrence occurred in one of the 26 anti-GBM patients. Four out of 26 patients (15%) developed malignancy, most commonly skin cancer. Long-term graft and patient survival for patients with ESKD due to anti-GBM was similar to IgAN after kidney transplantation.
Keywords: anti-GBM disease, disease recurrence, kidney transplant, long-term patient and graft outcomes, post-transplant malignancy
1 |. INTRODUCTION
Anti-glomerular basement membrane (GBM) disease accounts for 20% of rapidly progressive glomerulonephritis (RPGN) cases due to crescentic glomerulonephritis.1,2 Despite advances in immunosuppression, nearly 30%−50% of patients with RPGN develop end-stage kidney disease (ESKD).1,3 Kidney transplant is the best available renal replacement therapy. However, long-term patient survival and graft survival in kidney transplant recipients with ESKD due to anti-GBM disease have not been well characterized due to the very low incidence, with estimates varying from 0.1 to 1 per million population.4–6 The majority of studies of anti-GBM disease in transplant are from the previous immunosuppression era in the 1970s and 1980s when newer immunosuppression agents were not available.7–9 Recent literature about outcomes and recurrence of anti-GBM disease post-transplant is primarily in the form of case studies, except for two major national registries from Australia and New Zealand (ANZDATA registry) and the ERA-EDTA registry from Europe.10–17 The ANZDATA registry included long-term outcomes for transplant recipients with a history of anti-GBM disease, but included patients over a long duration between the years 1963 and 2010. Guidelines and practices have evolved over these several decades. The ERA-EDTA registry examined outcomes of transplant recipients with ESKD due to anti-GBM disease between 1982 and 1990; however, follow-up was limited to a maximum 5 years. Due to the lack of data for the anti-GBM transplant population in the United States, lack of contemporary disease cohorts, and limited duration of follow-up in previous studies, we sought to characterize factors that impact patient and graft survival for this population.
In this retrospective, single-center, cohort study, we report the long-term graft and patient survival for transplant recipients with ESKD due to anti-GBM disease and compare these findings with transplant recipients with ESKD due to IgA nephropathy (IgAN). We hypothesize that long-term graft survival and patient survival for transplant recipients with anti-GBM disease have improved and are comparable to IgAN.
2 |. PATIENTS AND METHODS
2.1 |. Patient population
The University of Wisconsin-Madison Institutional Review Board and Human Subjects Committee approved this study. Data were obtained from the Wisconsin Allograft Recipient Database (WisARD). Patients included in this study were all consecutive adult (>18 years) kidney transplant recipients with RPGN due to biopsy-proven native kidney anti-GBM disease who underwent kidney transplantation at the University of Wisconsin Hospital and Clinics between January 1, 1994, and September 30, 2015. Patients with a presumptive diagnosis without biopsy confirmation were excluded. The study included primary transplant and re-transplant patients. Kidney transplant recipients during the same time period with IgAN as cause of ESKD were used for the comparison group.
2.2 |. Primary and secondary outcomes
Primary outcome was patient and allograft survival. Graft failure was defined as return to dialysis or requirement of new transplant. Allograft survival was death-censored. Secondary outcomes included incidence of acute rejection, disease recurrence, and malignancy. Acute rejection was diagnosed using graft biopsy based on a clinical renal pathologist’s final diagnosis. An episode of acute rejection was defined as either acute cellular rejection or acute antibody-mediated rejection, as defined by the Banff 2013 criteria.18 Disease recurrence in patients with anti-GBM disease was defined by graft biopsy with pathologic diagnosis of crescentic glomerulonephritis. Disease recurrence in the patients with IgAN was defined by graft biopsy with pathologic diagnosis of recurrence by the renal pathologist. Allograft biopsies were performed for rise in serum creatinine or proteinuria at the discretion of the providers. Pre-transplant malignancies were excluded. Patients were followed until graft loss, death, or last available follow-up.
2.3 |. Statistical analysis
Continuous variables were compared between groups with t tests and Kruskal-Wallis tests. Categorical variables were compared between groups with chi-square tests. Time-to-event data were analyzed with the Kaplan-Meier curves and log-rank tests. All analyses were performed using Stata statistical software version 9.1 (SAS Institute, Inc).
3 |. RESULTS
3.1 |. Patient characteristics
A total of 26 patients with ESKD due to RPGN secondary to anti-GBM disease received kidney transplants during the study period. The majority of transplant recipients in both groups were Caucasian (Table 1). There were 50% females, and 46% had repeat transplant in the anti-GBM disease cohort. Patients with anti-GBM disease had a significantly longer duration of pre-transplant dialysis compared with patients with a history of IgAN. Pre-transplant anti-GBM titers were available for 14 of the 26 patients at a median of 0.7 months prior to transplant (range 25th–75th, −19 months [after transplant] to + 14 months [before transplant]). 13 patients had negative anti-GBM titers prior to transplant. Only one patient had a positive anti-GBM titer, which occurred 15 months prior to transplant. No anti-GBM titer was available for the remaining 12 patients. Immunosuppression was comparable between both groups, except for a lower proportion of patients with anti-GBM disease who received alemtuzumab for induction. Patients were followed for a median of 6.4 years. 46% (12/26) of patient had prior transplant in the anti-GBM group. 4% (1/26) lost first allograft due to disease recurrence, 27% (7/26) had chronic rejection, and 15% (4/26) had acute rejection. 4 patients among those with rejection as cause of their first graft failure had documented non-compliance with immunosuppression.
TABLE 1.
Baseline characteristics of patients at time of kidney transplantation
| Anti-GBM (n = 26) |
IgAN (n = 314) |
|
|---|---|---|
| Age (years), mean | 42.9 | 43.1 |
| Female (%) | 50 | 30 |
| Caucasian (%) | 88 | 85 |
| BMI (kg/m2), mean | 27.1 | 27.4 |
| Dialysis prior to transplant (%) | 88.5 | 71.3 |
| Duration of dialysis prior to transplant (months) | 21.8 | 14.4 |
| Donor type | ||
| Deceased (%) | 53 | 41 |
| Female (%) | 50 | 51 |
| Caucasian (%) | 100 | 95 |
| Age (years) | 39.5 | 41.5 |
| Cold ischemia (hours) | 17.1 | 15.9 |
| Prior transplant (%) | 46.2 | 17.5 |
| Peak PRA (%) | 30.9 | 6.4 |
| HLA mismatch > 2 (%) | 57.7 | 67.8 |
| Delayed graft function (%) | 19.2 | 10.2 |
| Induction | ||
| Alemtuzumab (%) | 7.7 | 11.8 |
| Basiliximab (%) | 38.5 | 52.9 |
| Thymoglobulin (%) | 34.6 | 17.2 |
| None (%) | 19.2 | 18.2 |
| Maintenance immunosuppression | ||
| Cyclosporine (%) | 40.9 | 42.7 |
| Tacrolimus (%) | 59.1 | 57.3 |
Abbreviations: BMI, body mass index; GBM, glomerular basement membrane; HLA, human leukocyte antigen; IgAN, IgA nephropathy; PRA, panel-reactive antibody.
3.2 |. Primary outcome: Allograft survival and patient Survival
Incidence of graft loss was 6.2 per 100 person-years in anti-GBM disease compared with 4.1 per 100 person-years in IgAN (p = .09) (Table 2). Graft loss occurred in a total of 12 of 26 patients with anti-GBM disease compared with 96 of 314 patients with IgAN during the study period. Median time to graft loss was 6.2 years with anti-GBM disease and 7.2 years with IgAN. Allograft survival was similar in both groups (Figure 1A). There was a trend toward worse survival with anti-GBM disease, but this was not statistically significant. The mortality rate was 0.03 per 100 person-years in anti-GBM disease compared with 0.02 per 100 person-years in IgAN (p = .12) (Figure 1B).
TABLE 2.
Incidence of graft failure, patient death, and acute rejection in kidney transplant recipients
| Anti-GBM (n = 26) |
IgAN (n = 314) |
p-Value | |
|---|---|---|---|
| Incidence rate of graft failure (per 100 person-years) | 6.2 | 4.1 | .09 |
| Incidence rate of patient death (per 100 person-years) | 0.03 | 0.02 | .12 |
| Incidence rate of acute rejection (per 100 person-years) | 7.8 | 7.4 | .43 |
FIGURE 1.
Kaplan-Meier curve of 10-year death-censored graft survival (A) and patient survival (B) for kidney transplant patients with ESRD. anti-GBM disease (dashed black), IgAN (solid black). (A) Death-censored graft survival was similar in patients with anti-GBM disease and IgAN. (B) Patient survival after kidney transplant in patients with ESRD due to anti-GBM disease was similar to IgAN
3.3 |. Secondary outcomes: Incidence of acute rejection, disease recurrence, and malignancy
Incidence of acute rejection was similar in both groups, 7.8 per 100 person-years in anti-GBM disease and 7.4 per 100 person-years in IgAN (p = .43) (Figure 2). Disease recurrence was seen in 3.85% of patients with anti-GBM disease (1 of 26 patients) following transplant compared with 9.2% in IgAN. The recurrence of anti-GBM disease occurred 1 year post-transplant. Unfortunately, we do not have an anti-GBM titer for the patient with disease recurrence. The patient lost the allograft 3 months after recurrence of disease.
FIGURE 2.
Incidence of acute rejection was similar in patients with ESRD due anti-GBM disease and IgAN. anti-GBM disease (dashed black), IgAN (solid black)
Four of 26 patients with anti-GBM disease (15.4%) developed at least one malignancy during the follow-up period (Table 3). Skin cancer was the most common malignancy in patients with anti-GBM disease, accounting for two-thirds of cancer diagnoses. Notably, two patients developed more than one malignancy following transplant. Half of post-transplant malignancies were detected within 1–2 years following transplant, which were limited to skin cancers. Three malignancies occurred late in follow-up, namely prostatic adenocarcinoma, hepatocellular carcinoma, and squamous cell carcinoma.
TABLE 3.
Malignancy in renal transplant patients with ESRD due to anti-glomerular basement membrane disease, n = 4
| Malignancy | Time since transplant (years) | Sex | Donor type | Immunosuppression |
|---|---|---|---|---|
| Squamous cell | 15 | F | Deceased donor | Cyclosporine |
| skin | 26 | Living donor | Mycophenolate | |
| Hepatocellular | Prednisone | |||
| Prostate | 32 | M | Deceased donor | Alemtuzumab |
| Living donor | Cyclosporine | |||
| Mycophenolate | ||||
| Prednisone | ||||
| Squamous cell | 1 | M | Deceased donor | Cyclosporine |
| skin | 2 | Mycophenolate | ||
| Melanoma | Prednisone | |||
| Squamous cell | 0.05 | M | Deceased donor | Cyclophosphamide |
| skin | Tacrolimus | |||
| Mycophenolate | ||||
| Prednisone |
4 |. DISCUSSION
In our study, we found that the incidence of graft loss was 6.2 per 100 person-years and incidence of patient mortality was 0.03 per 100 person-years for patients with kidney transplantation for ESKD due to anti-glomerular basement membrane disease. Long-term patient survival and graft survival for patients with anti-GBM were similar to IgAN as cause of ESKD.
The ANZDATA registry is the only other study presenting long-term outcomes of patients with anti-GBM disease.17 The graft survival and patient survival of patients with anti-GBM disease were similar to patients with other causes of ESKD in the ANZDATA registry and was comparable to IgAN in our cohort. We found a recurrence rate of 3.9% for anti-GBM disease, which was similar to the 2.7% recurrence rate of anti-GBM disease observed in the ANZDATA registry. This is in contrast to older studies, which report recurrence rates as high as 50%.19,20 Likewise, the ERA-EDTA study observed a recurrence rate of 14% for anti-GBM disease, which was greater than the rate of recurrent disease in the ANZDATA registry and in our current study. However, the ERA-EDTA study was conducted during the 1980s and 1990s, while the ANZDATA registry and our study included more recent patient populations. It is possible that the lower recurrent rate of anti-GBM disease in the more contemporary studies, such as the ANZDATA study and in our current study, compared with previous studies could be related to changes in immunosuppressive regimens over time. The patients with anti-GBM disease were longer on dialysis prior to transplant when compared to other ESKD patients in ANZDATA registry and IgAN patients in our cohort and more likely to receive re-transplants as well. The longer duration on dialysis could be due to transplant centers asking patients to wait before offering transplant to avoid recurrence of anti-GBM disease.
We also found that incidence of acute rejection was similar in patients with anti-GBM disease and IgAN. Acute rejection is one of the major factors along with recurrent disease, which determines graft survival. The similar incidence of acute rejection in both groups rein-forces the findings of similar long-term graft survival in both groups.
Prior studies demonstrated a 50% risk of recurrent anti-GBM disease in patients with positive circulating anti-GBM antibodies at the time of recurrent disease. A study published in 1982 suggested post-transplant recurrence of anti-GBM disease could be reduced by 6 to 12 months of dialysis prior to transplant.21 The high risk of recurrent disease in the setting of positive anti-GBM antibodies has led to the guideline of a 6- to 12-month wait time of seronegativity prior to transplant. It is unclear whether modern treatments can achieve serologic remission at an earlier time point in patients who require kidney transplant. Future studies are needed to examine the outcomes of delaying transplant after the diagnosis of anti-GBM disease compared with the risks due to increased time on dialysis, in particular how this may influence cardiovascular disease risk for this population. The paucity of data in the literature examining long-term patient and graft outcomes for patients with anti-GBM disease post-transplant continues the trend of postponing kidney transplant for patients with anti-GBM disease for at least six months to 1 year after ESKD. There is a possibility that even though the disease could recur, it is treatable with current immunosuppression without adversely affecting long-term graft outcomes.
Four of 26 (15.4%) kidney transplant recipients with anti-GBM disease developed post-transplant malignancy. As previously described in the literature, skin cancer is the most common observed post-transplant malignancy and it did account for two-thirds of all malignancies in our anti-GBM cohort. Reports of the incidence of malignancy in the adult kidney transplant population vary in the literature, ranging from 4% to 9.4%.22 The incidence of malignancy was higher in our study population (15.4% compared to 9.4%), which may indicate a greater preponderance for malignancy in patients with rapidly progressive glomerulonephritis as we have previously shown.23 This could be due to exposure to cyclophosphamide or other immunosuppression medications prior to transplant. Other studies have also suggested that glomerulonephritis as cause for kidney transplant confers higher risk of malignancy compared with other causes, such as ADPKD.24 Our results suggest the need for further investigation in this area and the importance of comprehensive cancer screening among transplant recipients with ESKD due to anti-GBM disease.
We acknowledge there are limitations in our study. This is a single-center study, which may be influenced by clinical practice and patient demographics at our institution. However, we were able to provide updated outcomes for a population of transplant recipients with a history of anti-GBM disease in the United States. Another limitation is that we do not have antibody titers at the time of transplant for a portion of our cohort. However, the standard practice at our institution is to wait 12 months after diagnosis of anti-GBM disease prior to consideration for kidney transplantation. In the case of the single anti-GBM patient who developed recurrent disease, antibody titers prior to transplant were not recorded, but anti-GBM titer was negative at the time of recurrent disease.
This is the first study to report long-term outcomes of patients with anti-GBM disease post-transplant in United States. One of the strengths of our study is that we present the long-term outcomes of a rare disease, that is, anti-GBM disease. Long-term graft survival and patient survival after kidney transplantation for anti-GBM patients are comparable to IgAN as cause of ESKD. Kidney transplantation should therefore be offered to patients with ESKD due to anti-GBM disease with appropriate caution given to comprehensive malignancy surveillance. Future studies are needed to determine whether the reduced incidence of recurrent anti-GBM disease seen in recent studies has implications for the practice of delaying transplant and the corresponding increase in dialysis duration for this patient population.
Footnotes
CONFLICT OF INTEREST
None.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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