Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease

clinical investigation

http://www.kidney-international.org & 2012 International Society of Nephrology

Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease Wen Tang1,2,3, Stephen P. McDonald1,4, Carmel M. Hawley1,3, Sunil V. Badve1,3, Neil C. Boudville1,5, Fiona G. Brown1,6, Philip A. Clayton1,7, Scott B. Campbell1,3, Janak R. de Zoysa1,8 and David W. Johnson1,3 1

ANZDATA Registry, Adelaide, South Australia, Australia; 2Division of Nephrology, Peking University Third Hospital, Beijing, China; Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia; 4Department of Nephrology and Transplantation Services, University of Adelaide at Central Northern Adelaide Renal and Transplantation Services, Adelaide, South Australia, Australia; 5School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, The University of Western Australia, Perth, Western Australia, Australia; 6Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia; 7Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia and 8Department of Renal Medicine, North Shore Hospital, Auckland, New Zealand 3

There are few reports regarding outcomes of anti-glomerular basement membrane (GBM) disease in patients who underwent renal replacement therapy. To help define this we studied all patients with anti-GBM disease who started renal replacement therapy for end-stage renal disease (ESRD) in Australia and New Zealand (ANZDATA Registry) between 1963 and 2010 encompassing 449 individuals (0.8 percent of all ESRD patients). The median survival on dialysis was 5.93 years with death predicted by older age and a history of pulmonary hemorrhage. Thirteen patients recovered renal function, although 10 subsequently experienced renal death after a median period of 1.05 years. Of the 224 patients who received their first renal allograft, the 10-year median patient and renal allograft survival rates were 86% and 63%, respectively. Six patients experienced anti-GBM disease recurrence in their allograft, which led to graft failure in two. Using multivariable Cox regression analysis, patients with anti-GBM disease had comparable survival on dialysis or following renal transplantation (hazard ratios of 0.86 and 1.03, respectively) compared to those with ESRD due to other causes. Also, renal allograft survival (hazard ratio of 1.03) was not altered compared to other diseases requiring a renal transplant. Thus, anti-GBM disease was an uncommon cause of ESRD, and not associated with altered risks of dialysis, transplant or first renal allograft survival. Death on dialysis was predicted by older age and a history of pulmonary hemorrhage. Kidney International (2013) 83, 503–510; doi:10.1038/ki.2012.375; published online 19 December 2012

KEYWORDS: anti-GBM disease; anti-glomerular basement membrane antibody disease; end-stage renal disease; kidney failure; renal function recovery; renal transplantation

Anti-glomerular basement membrane (anti-GBM) disease is generally a fulminant and rapidly progressive disease that is caused by autoantibodies to the noncollagenous domain of the a3 chain of type IV collagen. It can present as an isolated glomerulonephritis, or as a pulmonary–renal syndrome with severe lung hemorrhage (Goodpasture’s disease).1–3 The incidence of anti-GBM disease is estimated to be 0.5–1.8 cases per million per year in both European Caucasoid4–6 and Asian populations.7–9 It is responsible for 1–5% of all types of glomerulonephritis and is the cause in 10–20% of patients with crescentic glomerulonephritis.4 Even with intensive treatment with immunosuppression and/or plasma exchange, many patients will develop end-stage renal disease (ESRD) necessitating life-long renal replacement therapy (RRT).10,11 One-year patient and renal survival rates following a diagnosis of anti-GBM disease have been reported to be 73% and 25%, respectively.7 Although the course, treatment, and outcomes from the onset of anti-GBM disease have been well described,4,12–15 there are few reports regarding the predictors and outcomes of anti-GBM disease once long-term RRT (dialysis or kidney transplantation) has been commenced. The aim of this study was to investigate the characteristics, treatments, and outcomes of all cases of ESRD due to antiGBM disease in the Australian and New Zealand dialysis populations, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry.

Correspondence: David W. Johnson, Department of Renal Medicine, Level 2, Ambulatory Renal and Transplant Services Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia. E-mail: [email protected]

RESULTS Patient characteristics

Received 1 June 2012; revised 16 August 2012; accepted 31 August 2012; published online 19 December 2012

Between 15 May 1963 and 31 December 2010, 58,422 individuals started RRT for ESRD. Of these, 449 individuals

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503

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W Tang et al.: Anti-GBM disease ESRD

Table 1 | Characteristics of all patients with ESRD secondary to anti-GBM disease or other causes in Australia and New Zealand (1963–2010) Characteristics Age (years)

Anti-GBM disease ESRD (n ¼ 449)

Other ESRD (n ¼ 57,973)

P-value

45.8±20.8

54.1±17.4

o0.001 o0.001

Age category (years) 0–9 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80 +

0 39 117 32 48 65 77 56 15

Gender: male

257 (57%)

Racial origin European ATSI MPI Asian Other

(0%) (9%) (26%) (7%) (11%) (15%) (15%) (13%) (3%)

572 1596 3807 5772 9105 12,299 12,810 9698 2314

(1%) (3%) (7%) (10%) (16%) (21%) (22%) (17%) (4%)

33,746 (58%)

o0.001 405 (90%) 4 (1%) 31 (7%) 7 (2%) 2 (0%)

45,180 3484 5083 2477 1749

(78%) (6%) (9%) (4%) (3%) o0.001

RRT era 1963–1975 1976–1985 1986–1995 1996–2000 2001–2005 2006–2010

34 89 109 54 70 93

(8%) (20%) (24%) (12%) (16%) (21%)

2800 6452 12,054 9807 12,331 14,529

(5%) (11%) (21%) (17%) (21%) (25%)

Ever smoked Current Former Never Missing

61 122 120 146

(14%) (27%) (27%) (33%)

6105 17,633 22,408 11,827

(11%) (30%) (39%) (20%)

Hypertension Yes No Missing

115 (26%) 80 (18%) 254 (57%)

24,438 (42%) 4476 (8%) 29,059 (50%)

Diabetes mellitus Yes No Missing

16 (4%) 336 (75%) 97 (22%)

17,886 (31%) 31,616 (55%) 8446 (15%)

Chronic lung disease Yes No Missing Coronary artery disease Yes No Missing Peripheral vascular disease Yes No Missing

504

0.68

o0.001

o0.001

o0.001

o0.001 43 (10%) 298 (66%) 108 (24%)

17,594 (30%) 30,657 (53%) 9722 (17%) o0.001

19 (4%) 320 (71%) 110 (25%)

11,436 (20%) 36,694 (63%) 9843 (17%)

Characteristics Cerebrovascular disease Yes No Missing

Anti-GBM disease ESRD (n ¼ 449)

Other ESRD (n ¼ 57,973)

P-value o0.001

16 (4%) 328 (73%) 105 (23%)

6538 (11%) 41,606 (72%) 9829 (17%)

BMI (kg/m2)

26.4±6.0

Late referral Yes No Missing

173 (39%) 99 (22%) 177 (39%)

9219 (16%) 33,760 (58%) 14,995 (26%)

First RRT Hemodialysis Peritoneal dialysis Renal transplant

388 (86.4%) 59 (13.1%) 2 (0.45%)

38,910 (67%) 17,580 (30%) 1483 (3%)

26.6±6.3

0.54 o0.001

o0.001

Abbreviations: ATSI, Aboriginal and Torres Strait Islander; BMI, body mass index; ESRD, end-stage renal disease; GBM, glomerular basement membrane; MPI, Maori and Pacific Islander; RRT, renal replacement therapy.

(0.8%) had ESRD secondary to anti-GBM disease. The baseline characteristics of ESRD patients with and without anti-GBM disease are displayed in Table 1. Using multivariable logistic regression analysis, anti-GBM disease was significantly associated with younger age and Caucasian racial origin compared with other forms of ESRD (Table 2). In a supplementary analysis using a more contemporary cohort (1996–2010) in which complete data were available on comorbidities (n ¼ 36,884 including 217 patients with antiGBM disease), anti-GBM disease was independently associated with smoking, late referral to a renal unit, and lower probabilities of hypertension, diabetes mellitus, cerebral vascular disease, coronary artery disease, and Aboriginal and Torres Strait Islander racial origin (Table 2). Patients with pulmonary hemorrhage in the setting of ESRD secondary to anti-GBM disease (n ¼ 300) were independently predicted by younger age (odds ratio per decade 0.75, 95% confidence interval (CI) 0.67–0.84, Po0.001). No associations were observed with cigarette smoking or the presence of chronic lung disease. Patient survival on dialysis

7112 (12%) 41,017 (71%) 9844 (17%) o0.001

41 (9%) 295 (66%) 113 (25%)

Table 1 | Continued

Death occurred in 147 (33%) anti-GBM disease ESRD patients and 26,166 (46%) patients with ESRD due to other causes (Po0.001). The causes of death were cardiac (29% vs. 41%, respectively), dialysis withdrawal (29% vs. 24%), infections (16% vs. 13%), vascular (13% vs. 10%), malignancy (6% vs. 6%), and other (8% vs. 6%). Median survival of patients with anti-GBM disease on dialysis (5.93 years, 95% CI 4.35–7.51 years) was superior to that of patients with other causes of ESRD (4.41 years, 95% CI 4.35–4.47 years) (log-rank score 13.5, Po0.001) (Figure 1). Respective survival rates in the two groups were 88.4% vs. 88.1% at 1 year, 78.3% vs. 76.5% at 2 years, and 56.7% vs. 44.9% at 5 years. Kidney International (2013) 83, 503–510

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W Tang et al.: Anti-GBM disease ESRD

Table 2 | Multivariable binary logistic regression analysis of predictors of ESRD due to anti-GBM disease, as opposed to an alternative cause of ESRD Contemporary cohort (1996–2010) (n ¼ 36,884)

b

Odds ratio (95% CI)

b

Odds ratio (95% CI)

 0.24

0.79 (0.75–0.83)

NS

NS

NS

NS

NS

NS

 2.12  0.41  1.16  0.29

Reference 0.12 (0.05–0.32) 0.66 (0.46–0.96) 0.31 (0.15–0.66) 0.12 (0.03–0.50)

 1.47 NS NS NS

Reference 0.23 (0.06–0.96) NS NS NS

RRT era

NS

NS

NS

NS

Ever smoked Current Former Never

NA

NA

Hypertension Diabetes mellitus Chronic lung disease Coronary artery disease Peripheral vascular disease Cerebrovascular disease BMI (kg/m2) Late referral

NA NA NA NA

NA NA NA NA

 0.90  2.33 NS  0.82

0.41 (0.28–0.61) 0.10 (0.04–0.27) NS 0.44 (0.24–0.82)

NA

NA

NS

NS

NA

NA

 1.26

0.28 (0.09–0.93)

NA NA

NA NA

NS 2.04

NS 7.67 (5.04–11.7)

Characteristics Age (per decade, years) Gender: male Racial origin European ATSI MPI Asian Other

0.8 Cumulative survival

Entire cohort (1963–2010) (n ¼ 58,442)

ESRD cause Others Anti-GBM Others-censored Anti-GBM-censored

1.0

0.6

0.4

0.2

0.0 0.80 0.38

2.23 (1.33–3.74) 1.48 (0.94–2.33) Reference

Abbreviations: ATSI, Aboriginal and Torres Strait Islander; BMI, body mass index; CI, confidence interval; ESRD, end-stage renal disease; GBM, glomerular basement membrane; MPI, Maori and Pacific Islander; NA, not analyzed due to incomplete data prior to 1996; NS, not statistically significant; RRT, renal replacement therapy. Dependent factor, 1 ¼ ESRD patients due to anti-GBM disease, 0 ¼ ESRD patients with other causes.

Anti-GBM disease was independently associated with lower mortality on dialysis in the entire cohort after adjustment for age, gender, racial origin, and dialysis era (adjusted hazard ratio (HR) 0.85, 95% CI 0.72–1.00, P ¼ 0.049), and was associated with a lower mortality hazard in the supplementary analysis of the contemporary (1996–2010) cohort after adjustment for age, gender, racial origin, dialysis era, body mass index, smoking status, history of hypertension, chronic lung disease, cerebrovascular disease, ischemic heart disease, diabetes mellitus, peripheral vascular disease, and late referral (HR 0.65, 95% CI 0.48–0.88, P ¼ 0.005). In light of the possibility of informative censoring due to a higher rate of renal transplantation in the anti-GBM group, a competing risks approach was used in the entire cohort, which showed that anti-GBM disease was not significantly associated with mortality on dialysis (HR 0.86, 95% CI 0.72–1.02, P ¼ 0.08). When only patients with anti-GBM disease were considered, death on dialysis was predicted by older age (HR per decade 1.54, 95% CI 1.38–1.73, Po0.001), dialysis era (HR per period 0.73, 95% CI 0.63–0.83, Po0.001), and a history of pulmonary hemorrhage (HR 1.49, 95% CI 1.05–2.12, P ¼ 0.024). In the contemporary cohort (1996–2010), death was predicted by age (HR 1.79 per decade, 95% CI 1.31–2.47, Po0.001), diabetes mellitus (HR 5.59, 95% CI 1.35–23.1, P ¼ 0.017), and a history Kidney International (2013) 83, 503–510

0

2

4

6

8

10

34 3478

19 1652

Time (years) At risk Anti-GBM 447 Other 56,490

199 29,129

101 14,703

52 7265

Figure 1 | Kaplan–Meier survival curves for anti-glomerular basement membrane (anti-GBM) disease end-stage renal disease (ESRD) and other causes of ESRD in Australian and New Zealand dialysis patients between 1963 and 2010. The difference between the groups was statistically significant (log-rank score 13.5, Po0.001). Outcomes were censored for renal function recovery, loss to followup, renal transplantation, and end of study.

of pulmonary hemorrhage (HR 2.52, 95% CI 1.14–5.57, P ¼ 0.022). None of the other parameters included in the multivariable models was associated with death on dialysis in patients with anti-GBM disease. Recovery of renal function

Recovery of dialysis-independent renal function occurred in 13 (3%) anti-GBM disease patients and 879 (1.5%) ESRD patients with other forms of renal disease (P ¼ 0.02). AntiGBM disease was associated with a significantly shorter time to renal recovery (log-rank score 6.49, P ¼ 0.011) and independently predicted renal function recovery in the entire cohort (HR 1.93, 95% CI 1.11–3.34, P ¼ 0.02). However, of the 13 anti-GBM disease patients who recovered renal function, 10 (77%) experienced renal death (1 died and 9 returned to dialysis) within a median period of 1.05 years (minimum 0.1 years, maximum 7.92 years). Renal transplant graft survival

A total of 224 (50%) patients with anti-GBM disease received 286 renal allografts during the study period (Table 3). Compared with other renal transplant recipients, patients with anti-GBM disease were significantly more likely to be younger, Caucasian, current smoker, referred late to a renal unit, and to have re-transplants. They were less likely to have diabetes mellitus, hypertension, and coronary artery disease. The median time from dialysis commencement to first renal transplant was longer for anti-GBM disease patients (1.63 years, interquartile range 0.96–2.91) than non-anti-GBM 505

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Table 3 | Characteristics of all patients with ESRD secondary to anti-GBM disease or other causes in Australia and New Zealand who underwent renal transplantation during the period 1963–2010 Characteristics

Anti-GBM disease ESRD (n ¼ 224)

Other ESRD (n ¼ 19,455)

Age (years) Gender: male

35.6±15.5 134 (60%)

41.9±14.9 11,622 (60%)

Racial origin European ATSI MPI Asian Other

203 1 14 5 1

16,653 489 802 921 590

(86%) (3%) (4%) (5%) (3%)

18 (8%) 55 (25%) 55 (25%) 30 (13%) 28 (13%) 38 (17%)

1925 (10%) 3416 (18%) 4562 (23%) 2663 (14%) 3146 (16%) 2743 (19%)

Ever smoked Current Former Never Missing

38 45 50 91

(17%) (20%) (22%) (41%)

1532 (8%) 3637 (19%) 7809 (40%) 6477 (33%)

Hypertension Yes No Missing

66 (29%) 46 (21%) 112 (50%)

8550 (44%) 1875 (10%) 9030 (46%)

Diabetes mellitus Yes No Missing

1 (0%) 178 (80%) 45 (20%)

2098 (11%) 13,367 (69%) 3988 (21%)

Coronary artery disease Yes No Missing Peripheral vascular disease Yes No Missing

0.09

o0.001

o0.001

o0.001

0.79 5 (2%) 164 (73%) 55 (25%)

577 (3%) 14,278 (73%) 4600 (24%) 0.002

1 (0%) 163 (73%) 60 (27%)

1203 (6.2%) 13,428 (69%) 4824 (25%) 0.09

2 (1%) 165 (74%) 57 (25%)

702 (4%) 14,082 (72%) 4671 (24%)

Cerebrovascular disease Yes No Missing

1 (0%) 169 (75%) 54 (24%)

393 (7%) 14,464 (58%) 4598 (23%)

BMI (kg/m2)

25.7±5.5

24.7±5.1

Late referral Yes No

64 (29%) 58 (26%)

1713 (9%) 10,292 (53%)

506

o0.001 0.98 0.005

(91%) (0.4%) (6%) (2.2%) (0.4%)

Transplant era 1963–1975 1976–1985 1986–1995 1996–2000 2001–2005 2006–2010

Chronic lung disease Yes No Missing

P-value

0.25

0.053 o0.001

Table 3 | Continued Anti-GBM disease ESRD (n ¼ 224)

Other ESRD (n ¼ 19,455)

Missing

102 (46%)

7450 (38%)

Donor type Deceased Living

164 (73%) 60 (27%)

14,448 (74%) 5007 (26%)

Characteristics

Subsequent grafts 2nd 3rd 4th 5th

P-value

0.72

0.001 47 13 2 0

(16%) (5%) (1%) (0%)

2703 430 60 5

(12%) (2%) (0%) (0%)

Abbreviations: ATSI, Aboriginal and Torres Strait Islander; BMI, body mass index; ESRD, end-stage renal disease; GBM, glomerular basement membrane; MPI, Maori and Pacific Islander.

disease patients (1.43 years, interquartile range 0.64–2.92, P ¼ 0.02). Death-censored renal allograft survival rates were generally comparable between patients with anti-GBM disease ESRD and those with ESRD due to other causes, regardless of donor type (living or deceased) and transplant era. Median death-censored, first graft survival rates were 21.2 years (95% CI 14.4–28.0 years) in the anti-GBM group and 18.9 years (95% CI 18.2–19.6 years) in the other group (log-rank score 1.23, P ¼ 0.27) (Figure 2). The respective 10-year graft survival rates were 63% vs. 67%. Using multivariable Cox proportional hazards model analysis of first grafts, anti-GBM disease was not associated with renal allograft survival in the entire cohort (HR 1.03, 95% CI 0.83–1.27). For subsequent grafts, median graft survival in patients with anti-GBM disease (8.1 years, 95% CI 0.5–15.7 years) was nonsignificantly lower than that in patients with other causes of ESRD (11.5 years, 95% CI 10.3–12.7; log-rank score 3.01, P ¼ 0.083). The respective 10-year graft survival rates were 45 and 53%. Using multivariable Cox proportional hazards model analysis, it was found that anti-GBM disease was not associated with subsequent renal allograft survival (HR 1.29, 95% CI 0.93–1.80, P ¼ 0.13). When only anti-GBM disease patients with first renal allografts were considered, mean death-censored first renal allograft survival in anti-GBM patients with a history of pulmonary hemorrhage (16.3 years, 95% CI 13.7–19.0 years) tended to be inferior to that in non-anti-GBM ESRD patients (20.9 years, 95% CI 17.4–24.5 years) (log-rank score 3.83; P ¼ 0.050). The respective graft survival rates in the two groups were 72% vs. 80% at 5 years and 59% vs. 70% at 10 years. Using multivariable Cox proportional hazards model analysis of first grafts in anti-GBM patients, older age at transplant (HR 0.98, 95% CI 0.96–1.00, P ¼ 0.034) was an independent predictor of renal allograft survival after adjusting for gender, a history of pulmonary hemorrhage, race, donor type, and time from first dialysis to transplant. For subsequent transplants, no independent predictors of renal allograft failure were identified. When anti-GBM disease patients were analyzed according to whether they Kidney International (2013) 83, 503–510

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1.0

Others Anti-GBM Others-censored Anti-GBM-censored

0.6

0.4

0.2

Time to transplant <1 Year .1 Year <1 Year-censored .1 Year-censored

0.8

Cumulative survival

0.8

Cumulative survival

1.0

ESRD cause

0.6

0.4

0.2

0.0 0.0 0 At risk Anti-GBM 224 Other 19,455

5

10

15

20

Time (years) 122 10,333

77 5743

42 2863

26 1337

Figure 2 | Kaplan–Meier death-censored first graft survival curves for anti-glomerular basement membrane (anti-GBM) disease end-stage renal disease (ESRD) and other causes of ESRD undergoing renal transplantation in Australia and New Zealand between 1963 and 2010. The difference between the groups was not statistically significant (log-rank score 1.23, P ¼ 0.27).

At risk <1 Year .1 Year

Renal transplant patient survival

When first renal allografts were considered, the median survival of anti-GBM disease patients was comparable to that of patients with other causes of ESRD (log-rank score 3.09, P ¼ 0.08) (Figure 4). The 10-year patient survival rates were 86 and 78%, respectively. Ten-year survival rates were also comparable between the two groups for deceased donor transplants (83% vs. 75%, P ¼ 0.21) and living donor transplants (94% vs. 90%, P ¼ 0.21). The causes of death in Kidney International (2013) 83, 503–510

10 Time (years)

15

20

59 162

35 86

23 54

15 27

9 17

1.0

0.8 Cumulative survival

Six (2.7%) patients with anti-GBM disease experienced renal biopsy–confirmed disease recurrence in their allografts, which led to graft failure in 2 (0.9%) cases after 0.08 and 0.48 years. In contrast, 1 (0.013%) patient with non-anti-GBM disease ESRD (Alport’s disease) experienced de novo anti-GBM disease causing renal allograft failure. The remaining causes of renal allograft failure in the anti-GBM disease and nonanti-GBM disease ESRD groups were chronic allograft nephropathy (54% vs. 48%, respectively), acute rejection (15% vs.19%), hyperacute rejection (2% vs. 3%), renal artery thrombosis (2% vs. 3%), renal vein thrombosis (5% vs. 3%), glomerulonephritis other than anti-GBM disease (3% vs. 4%), non-compliance (5% vs. 2%), and others (14% vs. 18%).

5

Figure 3 | Kaplan–Meier death-censored first graft survival curves for patients with anti-glomerular basement membrane (anti-GBM) disease end-stage renal disease (ESRD) who received a transplant o1 year or X1 year after starting dialysis. The difference between the groups was not statistically significant (log-rank score 0.73, P ¼ 0.39).

received a transplant o1 year or X1 year after starting dialysis, the median renal allograft survival rates were 19.0 years (95% CI 5.21–32.9) and 21.2 years (95% CI 12.3–30.1), respectively (log-rank score 0.73, P ¼ 0.39; Figure 3). Anti-GBM disease recurrence in renal transplants

0

0.6

0.4

ESRD cause Others Anti-GBM Others-censored Anti-GBMcensored

0.2

0.0 0 At risk Anti-GBM 224 Other 19,455

5

10 Time (years)

15

20

122 10,333

77 5743

42 2863

26 1337

Figure 4 | Kaplan–Meier patient survival curves for antiglomerular basement membrane (anti-GBM) disease end-stage renal disease (ESRD) and other causes of ESRD undergoing first renal transplantation in Australia and New Zealand between 1963 and 2010. The difference between the groups was not statistically significant (log-rank score 3.09, P ¼ 0.08).

the anti-GBM disease (n ¼ 41) and non-anti-GBM disease groups (n ¼ 4137) were cardiac (24% vs. 30%), vascular (20% vs. 13%), malignancy (24% vs. 25%), infection (20% 507

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vs. 19%), therapy withdrawal (2% vs. 4% ), and others (10% vs. 9%). Using multivariable Cox proportional hazards model analysis in the entire cohort, anti-GBM disease was not associated with patient mortality following renal transplantation (HR 1.03, 95% CI 0.75–1.40, P ¼ 0.87). When only anti-GBM disease patients were analyzed, the mean survival of anti-GBM patients with a history of pulmonary hemorrhage (n ¼ 160) (18.4 years, 95% CI 15.0–21.9 years) was lower than those without pulmonary hemorrhage (n ¼ 64) (26.2 years, 95% CI 22.9–29.5 years), although it did not reach statistical significance (log-rank score 3.54, P ¼ 0.06). The respective transplant patients’ survival rates in the two groups were 93% vs. 92% at 5 years and 86% vs. 86% at 10 years. Using multivariable Cox proportional hazards model analysis of first transplant survival, age at transplant (HR 1.07, 95% CI 1.04–1.10, Po0.001) was a significant predictor of mortality after adjusting other factors, including a prior history of pulmonary hemorrhage. DISCUSSION

This retrospective, multicenter, multicountry registry analysis examined the outcomes of 449 ESRD patients with anti-GBM disease compared with 57,973 patients with ESRD due to other causes. Our study found that anti-GBM disease was not associated with altered dialysis survival, renal transplant patient survival, or renal allograft survival, although it was associated with an increased probability of renal recovery (albeit short-lived). In addition, in patients with anti-GBM disease, a history of pulmonary hemorrhage was associated with an increased risk of mortality on dialysis. Until now, the rarity of anti-GBM disease as a cause of ESRD has impeded the study of outcomes of this condition once RRT has commenced. Limited outcome data from observational cohort studies of anti-GBM disease populations that included patients without ESRD reported 1-year patient survival rates in the range of 65–93%.3,9,12,16 A longterm outcome study over a 25-year period (1975–2000) of 39 patients with anti-GBM disease and dialysis-dependent endstage renal failure reported 1- and 5-year dialysis survival rates of 65 and 44%, respectively.12 The results of this study, which covered a somewhat longer time period (1963–2010), demonstrated slightly higher 1- and 5-year dialysis survival rates of 88 and 57%, respectively. A novel finding of the current investigation was that the survival rates of patients with anti-GBM disease on dialysis or following renal transplantation were comparable to those of patients with ESRD due to other causes. In contrast to previous studies, which found that age was not associated with anti-GBM patient survival,2,12 the present study observed that age was a significant, independent predictor of mortality on dialysis, such that each additional decade was associated with a 54% increase in mortality in the entire cohort and a 79% increase in mortality in the contemporary cohort. The apparent disparity in findings may relate to the fact that previous smaller studies lacked statistical power to identify an association of age with survival. 508

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In addition to age, our study also observed that the presence of pulmonary hemorrhage in anti-GBM patients predicted a greatly increased risk of death on dialysis in both the entire cohort (49% increase) and the contemporary cohort (152% increase) despite these patients being younger. Although there have been no prior reports examining the outcomes of Goodpasture’s disease in ESRD populations per se, Levy et al.12 found that the median time to death was 2 months in patients with pulmonary hemorrhage compared with 18 months in those without. These findings may relate to pulmonary hemorrhage connoting the presence of more serious disease or necessitating more intense immunosuppression. The proportion of patients experiencing pulmonary hemorrhage in our study (67%) was higher than that reported from centers in New Zealand (40%),6 Hong Kong (40%),9 France (48%),17 and China (26 to 46%),2 but similar to that reported in the United Kingdom (62%)12 and the United States (61%).18 A possible reason for the more frequent occurrence of pulmonary hemorrhage in the present population is that, unlike the aforementioned studies, our study only included ESRD patients, thereby representing the more severe end of the disease spectrum. Moreover, the ethnic composition of patients in the present study differed from those in Asian centers. In keeping with the findings of other series,2,12 pulmonary hemorrhage was associated with younger age. Similar to the report by Taylor et al,6 smoking was independently associated with anti-GBM disease, raising the possibility that smoking may induce an autoimmune response either directly or indirectly by uncovering epitopes. In our series, recovery of dialysis-independent renal function in anti-GBM disease ESRD patients was uncommon (3%) and toward the lower end of the range reported by other studies (3–18%).12,19–21 This finding may be related to the fact that patients were registered with ANZDATA, if they were considered to have ESRD requiring long-term RRT. Thus, patients not requiring dialysis or those requiring shortterm dialysis for reversible acute kidney injury may not have been registered and therefore not included in this analysis. Importantly, in those patients in the present study who did experience renal recovery, the duration of this recovery was found to be short-lived, such that approximately threequarters of patients returned to dialysis around a median period of 1 year. This suggests that patients experiencing renal recovery on dialysis should have their renal function monitored closely. Another important finding of this study was that transplant patient survival and renal allograft survival rates in individuals with ESRD secondary to anti-GBM disease were comparable to those of patients with ESRD due to other causes following multivariable adjustment for potentially confounding factors. These results differ from those previously reported by the European Renal AssociationEuropean Dialysis and Transplant Association (ERA-EDTA) Registry for 190 patients with Goodpasture’s disease receiving first transplants between 1982 and 1990.22 In that study, the Kidney International (2013) 83, 503–510

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overall survival of Goodpasture’s disease patients following renal transplantation was significantly higher at 5 years than in patients with other causes of ESRD (92% vs. 86%, Po0.05), whereas renal allograft survival rates were lower (44% vs. 58%, p not significant). Multivariable analysis was not performed in the latter paper. Although 5-year patient survival rates in the ERA-EDTA registry study were similar to those of the present investigation (92% vs. 93%, respectively), 5-year renal allograft survival rates were considerably lower (44% vs. 72%). It should be noted that the definition of graft failure in the present study (censored for patient death) and the ERA-EDTA registry study (death with a functioning graft counted as a graft failure) may account for the apparent difference in survival outcomes. In addition, an appreciably higher rate of Goodpasture’s disease recurrence in the ERA-EDTA study, which led to 14% of renal allograft failures (compared with only two allograft failures in the present study), may have accounted for the differences seen. This may reflect different immunosuppressive treatment strategies between Europe and Oceania and/or different approaches to the timing of renal transplantation following the onset of anti-GBM disease. Although early case series showed frequent biopsy-demonstrated recurrence in the allograft (up to 50%),23 reports of recurrent disease leading to renal allograft failure with modern therapeutic approaches are rare.11,24,25 In 1982, Cameron suggested that recurrence could be reduced to less than 5% if the patient was dialysed for 6–12 months before renal transplantation.26 However, in the present study, renal allograft survival was comparable between patients with anti-GBM disease ESRD transplanted o1 year vs. X1 year after commencing dialysis. This analysis was limited by the absence of information regarding anti-GBM antibody titers and duration of remission before renal transplantation. It is also possible that a number of patients transplanted within 1 year of dialysis commencement had experienced anti-GBM disease some time before they started on dialysis. In this respect, it should be noted that at least 22% of patients with anti-GBM disease had been referred to a renal unit at least 3 months before the commencement of RRT. The main weakness of this study was the limited depth of data collection. ANZDATA does not collect important information, such as severity of comorbidities, concomitant medications, patient compliance, individual unit management protocols (including plasma exchange and immunosuppression), laboratory values (such as anti-GBM antibody measurements), and detailed renal histopathology. Even though we adjusted for a large number of patient characteristics, the possibility of residual confounding could not be excluded. In common with other Registries, ANZDATA is a voluntary Registry and there is no external audit of data accuracy, including the diagnosis of anti-GBM disease. In conclusion, anti-GBM disease is an uncommon cause of ESRD, which was not associated with altered risks of dialysis survival or renal transplant patient or allograft survival, although it was associated with an increased Kidney International (2013) 83, 503–510

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probability of renal recovery (albeit short-lived). Death on dialysis in anti-GBM disease patients was predicted by older age and a history of pulmonary hemorrhage. MATERIALS AND METHODS Patient population All patients with ESRD enrolled in the ANZDATA registry, who commenced RRT between 15 May 1963 and 31 December 2010, were included in the study. Demographic and clinical data were collected throughout the calendar year by medical and nursing staff in each renal unit and submitted every 6 months to the ANZDATA Registry until 2005 and then annually thereafter. Patients with a primary renal diagnosis of anti-GBM disease (defined as proliferative glomerulonephritis with linear immunoglobulin G with or without lung hemorrhage) were compared with the remainder of the cohort with an alternative primary renal diagnosis. Patients with anti-GBM disease were subcategorized according to whether they had a history of pulmonary hemorrhage. Dialysis and transplant eras were determined by the dialysis and transplant commencement dates, respectively: 15 May 1963 to 31 December 1975, 1 January 1976 to 31 December 1985, 1 January 1986 to 31 December 1995, 1 January 1996 to 31 December 2000, 1 January 2001 to 31 December 2005, and 1 January 2006 to 31 December 2010. The primary outcomes were patient survival on dialysis (censored for renal function recovery, loss to follow-up, renal transplantation and end of study), time from dialysis commencement to recovery of dialysis-independent renal function (censored for death, loss to follow-up, renal transplantation, and end of study), renal transplant patient survival (censored for allograft failure, loss to follow-up, and end of study), and renal allograft survival (censored for death, loss to follow-up, and end of study). Recovery of dialysisindependent renal function was considered to have occurred if the treating renal unit had recorded that the patient had recovered renal function and completed dialysis therapy. The onset of recovery was defined as the date of the last dialysis treatment. Statistical analysis Results were expressed as frequencies and percentages for categorical variables, mean±s.d. for continuous normally distributed variables, and median (interquartile range) for continuous variables that were not normally distributed. ESRD patients with or without anti-GBM disease were compared using w2 tests, two-tailed unpaired t-tests, or Mann–Whitney tests, depending on data distribution. The independent predictors of anti-GBM disease ESRD were assessed by multivariable logistic regression analysis. Time to event analyses were evaluated by Kaplan–Meier and multivariable Cox proportional hazards survival analyses. The covariates included in the model for the entire cohort were age, gender, racial origin, ESRD cause, and dialysis era or transplant era (as well as donor type, renal allograft number, and time from dialysis commencement to renal transplantation for renal transplant analyses). In light of the possibility of informative censoring due to differential transplantation rates between patients with and without anti-GBM disease ESRD, multivariable Cox proportional hazards survival analysis using a competing risks approach was also performed for dialysis patient survival analyses.27 A supplementary, fully adjusted analysis was also conducted using a contemporary cohort (1996–2010), in which data were available on body mass index, smoking status, history of hypertension, chronic lung disease, cerebrovascular disease, ischemic heart disease, diabetes mellitus, peripheral vascular 509

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disease, and late referral. Statistical analysis was performed using the SPSS software, version 13.0 (SPSS., Chicago, IL) and Stata/SE version 11.2 (StataCorp. CollegeStation, TX). P-values o0.05 were considered statistically significant.

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DISCLOSURE

DWJ is a consultant for Baxter Healthcare Pty and has previously received research funds from this company. He has also received speakers’ honoraria and research grants from Fresenius Medical Care and is a current recipient of a Queensland Government Health Research Fellowship. FGB is a consultant for Baxter and Fresenius and has received travel grants from Amgen and Roche. SPMcD has received speaking honoraria from AMGEN Australia, Fresenius Australia, and Solvay Pharmaceuticals, and travel grants from AMGEN Australia, Genzyme Australia, and Jansen-Cilag. CMH has received research funds from Amgen, Roche, Shire, and Abbott, travel grants from Amgen, speaking honoraria from Amgen, Roche, Shire, Genzyme, and Fresenius. NCB has previously received research funds from Roche, travel grants from Roche, Amgen, and Jansen Cilag, and speaking honoraria from Roche. All the other authors declared no competing interests. ACKNOWLEDGMENTS

We acknowledge the substantial contributions of the entire Australian and New Zealand nephrology community (physicians, surgeons, database managers, nurses, renal operators, and patients) in providing information for and maintaining the ANZDATA Registry database. WT was supported by grants from National Natural Science Foundation of China (Project 30900681), Beijing Municipal Science & Technology Commission (D09050704310905) and Fund of Peking University Third Hospital (76496-02).

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