Abstract

Background.

Idiopathic focal segmental glomerulosclerosis (FSGS) occurring at young age is known to predispose to poor graft outcome, but the outcome of adulthood-onset FSGS (A-FSGS) has not been thoroughly investigated. Here, we compared the graft outcomes between kidney recipients with A-FSGS and childhood-onset FSGS (C-FSGS).

Methods.

We enrolled 47 A-FSGS recipients and 60 C-FSGS recipients with an onset age of ≤15, from four of the largest transplant centers in Korea.

Results.

The baseline characteristics were similar between two groups. The 1- and 3-year cumulative recurrence rates were 20.0 and 22.1%, respectively. FSGS was recurrent in 19 C-FSGS patients [median duration, 2 months (interquartile range, IQR, 1–35)], and 11 patients had recurrent disease in A-FSGS [5 months (IQR, 3–37)]. The recurrence rate was similar between two groups (P = 0.126). The 5- and 10-year graft survival rates were 90.0 and 78.5%, respectively. The overall graft survival rates were not different between two groups. After adjusting baseline characteristics, the development of major outcomes was similar between two groups except acute rejection that was more frequent in A-FSGS. The age of disease onset did not affect recurrence in both groups. While grafts with recurrence had poorer graft survival in the A-FSGS group (P = 0.005), the recurrence was not associated with graft loss in the C-FSGS group (P = 0.558).

Conclusions.

The onset age did not affect the graft outcome in patients with FSGS, and the recurrence significantly affected graft survival in A-FSGS. Therefore, the main focus should aim for the management of recurrence.

Introduction

Focal segmental glomerulosclerosis (FSGS) is an important glomerular disease that frequently leads to end-stage renal disease (ESRD) that requires dialysis therapy or transplantation. Furthermore, the incidence of FSGS and the proportion of ESRD attributed to FSGS have increased considerably [ 1 ]. Since recurrent FSGS after kidney transplantation was first described by Hoyer et al. [ 2 ], subsequent studies have revealed that recurrent FSGS develops in up to 30–50% of kidney transplant recipients [ 3 ] and that recurrence negatively affects the graft outcome. The risk factors for recurrence include a history of graft loss attributed to recurrence [ 4 ], white race [ 5 ] and younger age [ 6–9 ]. The effect of age has also been documented in other primary glomerular diseases [ 10–12 ]. However, the reasons that patients who are younger at the onset of the disease are more susceptible to recurrence are not well understood. Therefore, the effect of disease onset age on graft outcome may be an important issue, but interpretation of the results of previous studies has been limited because of the use of small sample sizes.

While several studies on the outcome of kidney allograft attributed to childhood-onset FSGS (C-FSGS) have been reported, there are few studies on adulthood-onset FSGS (A-FSGS) patients [ 9 , 13–15 ]. Furthermore, even in the studies that have included adult FSGS patients, C-FSGS and A-FSGS patients were not distinguished based on disease onset. Additionally, direct comparisons between kidney transplant outcome in A-FSGS patients and C-FSGS patients have rarely been conducted. In this study, we included FSGS transplant recipients recruited from the four large hospitals in Korea to achieve an adequate number of patients. We evaluated and compared the long-term outcomes in the two groups of FSGS.

Materials and methods

Patients

The institutional review board of Seoul National University Hospital approved this study (no. C-1104-117-360). One hundred seven kidney recipients, who suffered from ESRD due to biopsy-proven idiopathic FSGS, were recruited from four institutions (Seoul National University Hospital, Ulsan University College of Medicine Asan Medical Center, Sungkyunkwan University School of Medicine Samsung Medical Center and Yonsei University College of Medicine Severance Hospital, Seoul, Korea). All the patients were diagnosed as having idiopathic FSGS and not familial or secondary FSGS. We excluded the recipients who had previously received organ transplants or had multi-organ transplantation. Medical records were reviewed retrospectively. Clinical parameters such as age (at the onset of FSGS and at the time of transplantation), sex, time interval from biopsy-proven FSGS to the development of ESRD and the duration of dialysis before transplantation were collected. Donor factors such as age at transplantation, sex and donor source were evaluated. The degree of human leukocyte antigen (HLA) matching between recipient and donor was also assessed. The enzyme-linked immunosorbent assay method was applied for the detection of donor-specific antibody. We divided patients into two groups according to the age of FSGS onset: C-FSGS (age ≤ 15 years old) and A-FSGS (age > 15 years old).

Immunosuppression and outcome variables after transplantation

Steroids, calcineurin inhibitors (cyclosporine/tacrolimus) and inhibitors of purine synthesis were the basic immunosuppressive agents used for the majority of patients. When acute T-cell-mediated rejection developed, it was treated with intravenous methylprednisolone pulse therapy. If recurrent FSGS developed, the treatment included pulsed methylprednisolone and/or plasmapheresis therapies.

Major changes in status following transplantation [acute rejection (T-cell mediated and antibody mediated), chronic change and recurrence of FSGS] were evaluated by indication kidney biopsy. If unexplained hematuria, proteinuria and deteriorating renal function developed, kidney biopsies were performed. However, a protocol biopsy was not routinely performed. All the biopsy specimens were evaluated by nephropathologists. Recurrence of FSGS was histologically defined by both light microscopy (segmental glomerulosclerosis in focal distribution in the biopsy specimen) and electron microscopy (diffuse fusion of epithelial cell foot processes). The time of recurrence was classified according to Cameron’s classification: immediately (<48 h), early (<3 months) and late (≥3 months) [ 16 ]. Acute rejection was defined according to the Banff classification 2007 [ 17 ]. Chronic change was defined as cases of interstitial fibrosis and tubular atrophy, chronic active antibody-mediated rejection and chronic transplant glomerulopathy. Graft loss was defined as a requirement for maintenance dialysis and re-transplantation.

Statistical analysis

All analyses and calculations were performed using the SPSS software (SPSS version 16.0, Chicago, IL). Data were presented as the mean (±SD) for continuous variables and as the proportion for categorical variables. If the distribution of data was skewed, the median (interquartile range, IQR) was used. Continuous and categorical data were compared using Student’s t -test (or the Mann–Whitney U -test) and the chi-square test, respectively. Graft survival rates were calculated using the Kaplan–Meier method, and comparison between groups was performed using the log-rank test. The Cox regression model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI). A P-value < 0.05 was considered significant.

Results

Baseline characteristics of patients

The baseline characteristics of A-FSGS and C-FSGS groups are described in Table 1 . The mean ages at the onset of FSGS were 28.6 years in the A-FSGS group and 7.5 years in the C-FSGS group. Of the 60 patients in the C-FSGS group, 19 received grafts after age 15. The demographics between two groups were not statistically different, with the exception of the proportion of patients having dialysis and donor age. The duration of dialysis before transplantation was also similar. Most grafts were received from living donors. C-FSGS patients were followed longer than A-FSGS patients. Donor-specific antibody was not detected in this cohort. Tacrolimus and mycophenolate mofetil were used in 35.5 (30.0% in C-FSGS and 42.6% in A-FSGS) and 49.5% (41.7% in C-FSGS and 59.6% in A-FSGS) of patients, respectively. The frequencies of immunosuppressive agents were not statistically different between two groups.

Table 1.

Baseline characteristics of the study subjects a

  C-FSGS group ( n = 60)   A-FSGS group ( n = 47)   Total ( n = 107)  P-value 
Age at the onset of FSGS (year) 7.5 ± 3.70 28.6 ± 10.29 16.8 ± 12.83 <0.001 
Recipient’s sex (male:female) 35:25 24:23 59:48 n.s. 
From diagnosis to ESRD (month) b 23 (8–48) 35 (10–60) 26 (10–52) n.s. 
Dialysis before operation (%) 96.7 85.1 91.6 0.032 
Dialysis duration (month) b 18 (4–32) 6 (1–28) 12 (2–30) n.s. 
From diagnosis to operation (month) b 45 (27–77) 48 (19–90) 45 (24–84) n.s. 
Age at operation (year) 12.3 ± 6.19 34.0 ± 11.17 21.8 ± 13.88 <0.001 
Deceased donor (%) 29.3 14.9 22.9 n.s. 
Donor’s age (year) 34.3 ± 13.22 39.6 ± 11.22 36.6 ± 12.61 0.029 
Donor’s sex (male:female) 38:22 30:17 68:39 n.s. 
HLA mismatching 2.6 ± 0.88 2.7 ± 1.17 2.7 ± 1.04 n.s. 
Immunosuppressive agent     
    Cyclosporine (%) 70.0 57.4 64.5 n.s. 
    Mycophenolate mofetil (%) 41.7 59.6 49.5 n.s. 
Following duration (month) b 102 (54–166) 71 (26–122) 86 (39–153) 0.020 
  C-FSGS group ( n = 60)   A-FSGS group ( n = 47)   Total ( n = 107)  P-value 
Age at the onset of FSGS (year) 7.5 ± 3.70 28.6 ± 10.29 16.8 ± 12.83 <0.001 
Recipient’s sex (male:female) 35:25 24:23 59:48 n.s. 
From diagnosis to ESRD (month) b 23 (8–48) 35 (10–60) 26 (10–52) n.s. 
Dialysis before operation (%) 96.7 85.1 91.6 0.032 
Dialysis duration (month) b 18 (4–32) 6 (1–28) 12 (2–30) n.s. 
From diagnosis to operation (month) b 45 (27–77) 48 (19–90) 45 (24–84) n.s. 
Age at operation (year) 12.3 ± 6.19 34.0 ± 11.17 21.8 ± 13.88 <0.001 
Deceased donor (%) 29.3 14.9 22.9 n.s. 
Donor’s age (year) 34.3 ± 13.22 39.6 ± 11.22 36.6 ± 12.61 0.029 
Donor’s sex (male:female) 38:22 30:17 68:39 n.s. 
HLA mismatching 2.6 ± 0.88 2.7 ± 1.17 2.7 ± 1.04 n.s. 
Immunosuppressive agent     
    Cyclosporine (%) 70.0 57.4 64.5 n.s. 
    Mycophenolate mofetil (%) 41.7 59.6 49.5 n.s. 
Following duration (month) b 102 (54–166) 71 (26–122) 86 (39–153) 0.020 
a

The difference between the childhood-onset and the adulthood-onset groups was evaluated using Student’s t -test (or the Mann–Whitney U -test) for continuous variables and the chi-square test for categorical variables. n.s., not significant

b

Data are expressed as the median (IQR) when the distribution of data was skewed.

Clinical course and outcomes after transplantation

During the observation period, acute rejection developed in 25 C-FSGS [median duration, 5 months (IQR, 1–29)] and 23 A-FSGS patients [median duration, 1 month (IQR, 11.5 weeks)]. Twenty-one C-FSGS patients were submitted to graft biopsies resulting from chronic change [median duration, 52 months (IQR, 34–101)], while graft biopsies were performed in 13 A-FSGS patients [median duration, 37 months (IQR, 18–76)]. The HR for major outcomes in the A-FSGS group compared to C-FSGS group are shown in Table 2 . Of the 60 C-FSGS patients, FSGS recurrence was diagnosed in 19 cases (32%) [median duration, 2 months (IQR, 1–35)], while FSGS recurrence developed in 11 cases among 47 A-FSGS patients (23%) [median duration, 5 months (IQR, 3–37)]. The recurrence rate of original disease in A-FSGS was similar with that of C-FSGS group (P = 0.126 by the Mann–Whitney U -test). Table 3 shows the detailed data of recurrence and treatment in patients with FSGS recurrence. Immediate recurrence (<48 h) was observed in only one patient with C-FSGS. Early recurrence (<3 months) developed more frequently in the C-FSGS group (11 patients) than the A-FSGS group (2 patients) (P = 0.034). However, in the A-FSGS group, recurrence was observed later after transplantation compared to the C-FSGS patients (9 A-FSGS versus 7 C-FSGS patients, P = 0.017). Of 19 C-FSGS patients with recurrence, the response of treatment was as follows: complete response, 6 cases; partial response, 12 cases; no response, 1 case. Of 11 A-FSGS patients with recurrence, there were seven partial response cases and two no response cases but not any complete response cases. Two A-FSGS patients with recurrence did not receive necessary treatments due to medical status such as malignancy.

Table 2.

HR for major complications in the childhood-onset focal segmental glomerulosclerosis group compared to the adulthood-onset group a

 Unadjusted HR P-value  Adjusted HR b P-value 
ATMR + AAMR 0.64 (0.36–1.13) n.s. 0.32 (0.12–0.86) 0.024 
IFTA 0.82 (0.39–1.71) n.s. 0.42 (0.12–1.48) n.s. 
Chronic change 0.92 (0.46–1.84) n.s. 0.52 (0.16–1.68) n.s. 
FSGS recurrence 1.34 (0.64–2.83) n.s. 2.30 (0.66–7.99) n.s. 
Graft loss 0.78 (0.35–1.75) n.s. 0.29 (0.07–1.19) n.s. 
 Unadjusted HR P-value  Adjusted HR b P-value 
ATMR + AAMR 0.64 (0.36–1.13) n.s. 0.32 (0.12–0.86) 0.024 
IFTA 0.82 (0.39–1.71) n.s. 0.42 (0.12–1.48) n.s. 
Chronic change 0.92 (0.46–1.84) n.s. 0.52 (0.16–1.68) n.s. 
FSGS recurrence 1.34 (0.64–2.83) n.s. 2.30 (0.66–7.99) n.s. 
Graft loss 0.78 (0.35–1.75) n.s. 0.29 (0.07–1.19) n.s. 
a

HR (95% CI) are calculated using the Cox regression model.

b

Adjusted for dialysis proportion before operation, age at operation and the donor’s age. ATMR, acute T-cell-mediated rejection; AAMR, acute antibody-mediated rejection; n.s., not significant; IFTA, interstitial fibrosis and tubular atrophy.

Table 3.

Patients with recurrence of focal segmental glomerulosclerosis after kidney transplantation a

    FSGS recurrence Last follow-up 
Patients Onset group Op age (sex) Donor Time (months) Therapy Outcome Time (months) Status Cause of graft loss 
C-FSGS 13 (M) Deceased 37 Imm PR 116 Maintain  
C-FSGS 16 (M) Deceased mPD + PLX PR 73 Loss 
C-FSGS 15 (M) Living mPD + PLX CR 58 Maintain  
C-FSGS 12 (M) Living 1 week PLX CR 34 Maintain  
C-FSGS 16 (F) Deceased 2 days PLX CR 21 Maintain  
C-FSGS 18 (F) Deceased 2 weeks PLX CR 21 Maintain  
C-FSGS 19 (M) Living 35 Imm PR 171 Maintain  
C-FSGS 16 (M) Living 3 weeks Imm PR Maintain  
C-FSGS 3 (F) Living 82 Imm PR 184 Maintain  
10 C-FSGS 10 (F) Living PLX None 56 Loss CC 
11 C-FSGS 25 (F) Living 3 weeks PLX PR 36 Maintain  
12 C-FSGS 20 (M) Living Imm PR 180 Maintain  
13 C-FSGS 8 (F) Living mPD + PLX PR 86 Loss CC 
14 C-FSGS 12 (F) Living 77 Imm PR 167 Loss 
15 C-FSGS 14 (M) Living 1 week PLX CR 203 Maintain  
16 C-FSGS 7 (M) Living 150 mPD PR 219 Maintain  
17 C-FSGS 14 (F) Living 1 week mPD + PLX PR 11 Maintain  
18 C-FSGS 19 (M) Deceased 1 week mPD + PLX PR 164 Loss 
19 C-FSGS 9 (F) Deceased mPD + PLX CR 67 Loss CC 
20 A-FSGS 44 (M) Living 12 Imm PR 163 Maintain  
21 A-FSGS 37 (M) Living 37 None  56 Loss 
22 A-FSGS 19 (M) Living 86 Imm PR 120 Loss 
23 A-FSGS 37 (M) Living 21 Imm PR 160 Loss CC 
24 A-FSGS 18 (M) Living None  Loss 
25 A-FSGS 25 (M) Living PLX None 19 Loss 
26 A-FSGS 49 (M) Deceased PLX + CTX PR 23 Maintain  
27 A-FSGS 30 (F) Living PLX None 32 Loss 
28 A-FSGS 60 (M) Living 2 weeks PLX PR 14 Maintain  
29 A-FSGS 46 (F) Living 79 Imm PR 90 Maintain  
30 A-FSGS 19 (F) Living 1 week PLX PR 62 Maintain  
    FSGS recurrence Last follow-up 
Patients Onset group Op age (sex) Donor Time (months) Therapy Outcome Time (months) Status Cause of graft loss 
C-FSGS 13 (M) Deceased 37 Imm PR 116 Maintain  
C-FSGS 16 (M) Deceased mPD + PLX PR 73 Loss 
C-FSGS 15 (M) Living mPD + PLX CR 58 Maintain  
C-FSGS 12 (M) Living 1 week PLX CR 34 Maintain  
C-FSGS 16 (F) Deceased 2 days PLX CR 21 Maintain  
C-FSGS 18 (F) Deceased 2 weeks PLX CR 21 Maintain  
C-FSGS 19 (M) Living 35 Imm PR 171 Maintain  
C-FSGS 16 (M) Living 3 weeks Imm PR Maintain  
C-FSGS 3 (F) Living 82 Imm PR 184 Maintain  
10 C-FSGS 10 (F) Living PLX None 56 Loss CC 
11 C-FSGS 25 (F) Living 3 weeks PLX PR 36 Maintain  
12 C-FSGS 20 (M) Living Imm PR 180 Maintain  
13 C-FSGS 8 (F) Living mPD + PLX PR 86 Loss CC 
14 C-FSGS 12 (F) Living 77 Imm PR 167 Loss 
15 C-FSGS 14 (M) Living 1 week PLX CR 203 Maintain  
16 C-FSGS 7 (M) Living 150 mPD PR 219 Maintain  
17 C-FSGS 14 (F) Living 1 week mPD + PLX PR 11 Maintain  
18 C-FSGS 19 (M) Deceased 1 week mPD + PLX PR 164 Loss 
19 C-FSGS 9 (F) Deceased mPD + PLX CR 67 Loss CC 
20 A-FSGS 44 (M) Living 12 Imm PR 163 Maintain  
21 A-FSGS 37 (M) Living 37 None  56 Loss 
22 A-FSGS 19 (M) Living 86 Imm PR 120 Loss 
23 A-FSGS 37 (M) Living 21 Imm PR 160 Loss CC 
24 A-FSGS 18 (M) Living None  Loss 
25 A-FSGS 25 (M) Living PLX None 19 Loss 
26 A-FSGS 49 (M) Deceased PLX + CTX PR 23 Maintain  
27 A-FSGS 30 (F) Living PLX None 32 Loss 
28 A-FSGS 60 (M) Living 2 weeks PLX PR 14 Maintain  
29 A-FSGS 46 (F) Living 79 Imm PR 90 Maintain  
30 A-FSGS 19 (F) Living 1 week PLX PR 62 Maintain  
a

Op, operation; M, male; Imm, increasing dose of immunosuppressive agent; PR, partial response; mPD, methylprednisolone pulses; PLX, plasmapheresis; R, recurrence; CR, complete response; F, female; CC, chronic change; CTX, cyclophosphamide.

In total, 26 grafts failed. The causes of graft failure were as follows: chronic change, 10 cases (38.5%); acute rejection, 5 cases (19.2%); recurrence, 8 cases (30.8%); other causes, 3 cases (11.5%). The cumulative 5-year and 10-year graft survival rates were 90.0 and 78.5%, respectively. The overall graft survival rates were not different between A-FSGS and C-FSGS groups. After adjusting baseline characteristics that were different between the two groups, the development of major outcomes such as chronic change, recurrence, and graft loss was similar between the groups. However, episodes of acute rejection were more frequent in patients with A-FSGS.

Factors related to the recurrence of original disease

We evaluated factors associated with the recurrence of FSGS, but none of the baseline characteristics and donor-related factors were associated with recurrence ( Table 4 ). The interval from the diagnosis of FSGS to transplantation, donor age and the source of graft did not influence the recurrence of FSGS. The degree of HLA mismatching was similar between recurrent and non-recurrent groups. Furthermore, we evaluated the effect of onset age for the recurrence. The total patient number was divided into tertiles according to onset age, but each tertile showed similar risk of recurrence ( Table 5 ). The insignificant effect of onset age was consistent when we compared the risk separately as in A-FSGS and C-FSGS.

Table 4.

Baseline characteristics according to the recurrence of focal segmental glomerulosclerosis a

 C-FSGS A-FSGS 
  No recurrence ( n = 41)   Recurrence ( n = 19)  P-value  No recurrence ( n = 36)   Recurrence ( n = 11)  P-value 
Age at the onset of FSGS (year) 7.0 ± 3.54 8.5 ± 3.92 n.s. 27.9 ± 9.48 30.9 ± 12.86 n.s. 
Recipient’s sex (male:female) 25:16 10:9 n.s. 16:20 8:3 n.s. 
From diagnosis to ESRD (month) b 23 (5–46) 22 (15–54) n.s. 35 (12–65) 27 (2–55) n.s. 
Dialysis before operation (%) 95.1 100 n.s. 83.3 90.9 n.s. 
Dialysis duration (month) b 17 (1–30) 22 (8–50) n.s. 8 (1–33) 6 (3–24) n.s. 
From diagnosis to operation (month) b 39 (22–77) 56 (35–78) n.s. 51 (20–92) 45 (6–84) n.s. 
Age at operation (year) 11.5 ± 6.49 14.0 ± 5.23 n.s. 33.7 ± 10.37 34.9 ± 13.99 n.s. 
Deceased donor (%) 28.2 31.6 n.s. 16.7 9.1 n.s. 
Donor’s age (year) 33.2 ± 13.50 36.4 ± 12.65 n.s. 39.6 ± 11.43 39.5 ± 11.07 n.s. 
Donor’s sex (male:female) 27:14 11:8 n.s. 22:14 8:3 n.s. 
HLA mismatching 2.4 ± 0.87 2.9 ± 0.83 n.s. 2.8 ± 1.26 2.6 ± 0.82 n.s. 
Immunosuppressive agent       
    Cyclosporine (%) 65.9 78.9 n.s. 55.6 63.6 n.s. 
    Mycophenolate mofetil (%) 43.9 36.8 n.s. 63.9 45.5 n.s. 
Following duration (month) b 107 (60–162) 73 (34–171) n.s. 82 (27–127) 56 (19–120) n.s. 
 C-FSGS A-FSGS 
  No recurrence ( n = 41)   Recurrence ( n = 19)  P-value  No recurrence ( n = 36)   Recurrence ( n = 11)  P-value 
Age at the onset of FSGS (year) 7.0 ± 3.54 8.5 ± 3.92 n.s. 27.9 ± 9.48 30.9 ± 12.86 n.s. 
Recipient’s sex (male:female) 25:16 10:9 n.s. 16:20 8:3 n.s. 
From diagnosis to ESRD (month) b 23 (5–46) 22 (15–54) n.s. 35 (12–65) 27 (2–55) n.s. 
Dialysis before operation (%) 95.1 100 n.s. 83.3 90.9 n.s. 
Dialysis duration (month) b 17 (1–30) 22 (8–50) n.s. 8 (1–33) 6 (3–24) n.s. 
From diagnosis to operation (month) b 39 (22–77) 56 (35–78) n.s. 51 (20–92) 45 (6–84) n.s. 
Age at operation (year) 11.5 ± 6.49 14.0 ± 5.23 n.s. 33.7 ± 10.37 34.9 ± 13.99 n.s. 
Deceased donor (%) 28.2 31.6 n.s. 16.7 9.1 n.s. 
Donor’s age (year) 33.2 ± 13.50 36.4 ± 12.65 n.s. 39.6 ± 11.43 39.5 ± 11.07 n.s. 
Donor’s sex (male:female) 27:14 11:8 n.s. 22:14 8:3 n.s. 
HLA mismatching 2.4 ± 0.87 2.9 ± 0.83 n.s. 2.8 ± 1.26 2.6 ± 0.82 n.s. 
Immunosuppressive agent       
    Cyclosporine (%) 65.9 78.9 n.s. 55.6 63.6 n.s. 
    Mycophenolate mofetil (%) 43.9 36.8 n.s. 63.9 45.5 n.s. 
Following duration (month) b 107 (60–162) 73 (34–171) n.s. 82 (27–127) 56 (19–120) n.s. 
a

The difference between the non-recurrence and recurrence groups is evaluated using Student’s t -test (or the Mann–Whitney U -test) for continuous variables and the chi-square test for categorical variables. ns, not significant.

b

Data are expressed as the median (IQR) when the distribution of data was skewed.

Table 5.

HR for recurrence according to the tertiles of onset age in the childhood-onset and adulthood-onset focal segmental glomerulosclerosis groups a

Tertile (range of onset age) HR P-value 
Total 
    1st tertile (1–8) 1 (reference)  
    2nd tertile (9–20) 1.46 (0.63–3.40) n.s. 
    3rd tertile (21–60) 0.80 (0.32–2.04) n.s. 
C-FSGS 
    1st tertile (1–5) 1 (reference)  
    2nd tertile (6–9) 1.21 (0.38–3.80) n.s. 
    3rd tertile (10–15) 2.34 (0.74–7.40) n.s. 
A-FSGS 
    1st tertile (16–21) 1 (reference)  
    2nd tertile (22–30) 0.98 (0.20–4.89) n.s. 
    3rd tertile (31–60) 1.71 (0.41–7.19) n.s. 
Tertile (range of onset age) HR P-value 
Total 
    1st tertile (1–8) 1 (reference)  
    2nd tertile (9–20) 1.46 (0.63–3.40) n.s. 
    3rd tertile (21–60) 0.80 (0.32–2.04) n.s. 
C-FSGS 
    1st tertile (1–5) 1 (reference)  
    2nd tertile (6–9) 1.21 (0.38–3.80) n.s. 
    3rd tertile (10–15) 2.34 (0.74–7.40) n.s. 
A-FSGS 
    1st tertile (16–21) 1 (reference)  
    2nd tertile (22–30) 0.98 (0.20–4.89) n.s. 
    3rd tertile (31–60) 1.71 (0.41–7.19) n.s. 
a

HR (95% CI) are calculated using the Cox regression model. n.s., not significant.

Impact of recurrence on the graft survival

The 1- and 3-year cumulative recurrence rates were 20.0 and 22.1%, respectively. Of 30 recurrent cases, 77.3% were treated using methylprednisolone pulse therapy plus plasmapheresis and the others were treated using methods such as increasing doses of immunosuppressive agents or only methylprednisolone pulse therapy. Figure 1 shows the graft survival rates according to the development of recurrent FSGS. Transplants with recurrent FSGS were associated with a higher risk of graft loss than transplants without recurrence [HR, 2.23 (95% CI, 1.03–4.85); P = 0.037 by the log-rank test].

Fig. 1.

Kaplan–Meier curves of graft survival in recipients with and without recurrence of focal segmental glomerulosclerosis. The patients in the recurrence group have a poorer graft outcome than in the non-recurrence group (P = 0.037 by the log-rank test).

Fig. 1.

Kaplan–Meier curves of graft survival in recipients with and without recurrence of focal segmental glomerulosclerosis. The patients in the recurrence group have a poorer graft outcome than in the non-recurrence group (P = 0.037 by the log-rank test).

We evaluated the impact of recurrence on graft survival rates in the A-FSGS and C-FSGS groups. While grafts with recurrence had poorer graft survival than grafts without recurrence in the A-FSGS group (P = 0.005 by the log-rank test) ( Figure 2A ), the recurrence was not associated with graft loss in the C-FSGS group (P = 0.558 by the log-rank test) ( Figure 2B ). The cause of graft loss as FSGS recurrence was similarly distributed between the two groups (3 of 16 lost grafts in C-FSGS group and 5 of 10 lost grafts in A-FSGS group were directly associated with recurrence, P = 0.093 by the chi-square test).

Fig. 2.

The impact of recurrent focal segmental glomerulosclerosis on the overall graft outcome in A-FSGS group ( A ) and C-FSGS group ( B ). While recurrence affected the graft outcome in the adulthood-onset group (P = 0.005), recurrence was not associated with the graft outcome in the childhood-onset group (P = 0.558 by the log-rank test).

Fig. 2.

The impact of recurrent focal segmental glomerulosclerosis on the overall graft outcome in A-FSGS group ( A ) and C-FSGS group ( B ). While recurrence affected the graft outcome in the adulthood-onset group (P = 0.005), recurrence was not associated with the graft outcome in the childhood-onset group (P = 0.558 by the log-rank test).

Discussion

To date, there are several reports on the long-term outcomes of kidney transplant recipients with FSGS. However, the natural course of kidney graft of A-FSGS was not fully understood as the previous studies have only evaluated small-sized cohorts, which significantly limit interpretation of the results. In this study, we addressed the clinical outcomes of kidney allograft of A-FSGS, and furthermore, we compared it with that of C-FSGS. The rate of graft loss and the original disease recurrence was not affected by the onset age of the original disease.

A young age at the onset of FSGS has been considered a significant recurrence-related factor in most studies. If it was true, this might explain the differences in graft outcome between C-FSGS and A-FSGS patients. To test this notion, we divided our cohort of FSGS patients into two groups based on the age of onset (FSGS onset before or after age 15) and evaluated the recurrence-related factors and the graft outcome. Our findings revealed that the recurrence-related factors described in previous studies were not reproduced in our cohort. Prior to this study, only one report had directly addressed the relationship between the age of FSGS onset and the recurrence rate [ 6 ]. In the previous study, the cohort was identical to the cohort of another study [ 16 ], and in both studies, the patients were divided into C-FSGS (27 grafts) and A-FSGS (32 grafts). The results showed that a younger age of onset was associated with a higher rate of recurrence: 42% in C-FSGS group and 12% in A-FSGS group. However, in that study, the patients in the C-FSGS group had second or third grafts at a much higher frequency than patients in the A-FSGS group. Furthermore, three cases in the C-FSGS represented familial FSGS. This heterogeneity of baseline characteristics may affect the recurrence rate of FSGS [ 4 , 18 ]. But in this work, we enrolled only idiopathic FSGS cases that had undergone the first transplant. Patients with familial FSGS or repeated transplants were excluded. Although some factors were different between C-FSGS and A-FSGS groups, those factors did not affect recurrence rates. Furthermore, the recurrence rates were also similar between the two groups after adjusting those factors.

In addition to the age at disease onset, other factors have been listed as recurrence-related factors. It is known that patients with rapid progression to ESRD have a tendency of recurrence after kidney transplantation [ 19–21 ]. However, other studies have found no correlation [ 6 , 9 ]. Donor characteristics, such as age or type (living/deceased), have been reported as significant factors in some studies [ 15 , 20 ] but not in others [ 9 ]. Immunologic matching between recipient and donor has also been a subject of debate [ 21 , 22 ]. Recently, it was reported that the histologic variant of FSGS associated with recurrent allograft is similar to the variant that occurs in the native kidney [ 23 ]. However, the predictive ability of this factor has also been disputed [ 24 ]. Similarly, there are several debates surrounding the recurrence-related factors and other issues in transplant recipients with FSGS. The reason that many issues have yet to be resolved is that all previous studies have used small samples and a retrospective design. Furthermore, the unadjusted comparisons were not relevant because the baseline characteristics were not uniform between the groups. In our study, some variables (the proportion of patients having dialysis and donor age) were different between the C-FSGS and A-FSGS groups, but the recurrence rate was not different after adjusting those variables. Finally, we included a sufficient number of recipients, thus strengthening the reliability of our results.

The present study revealed that the overall graft outcomes were similar between A-FSGS and C-FSGS patients. However, the effect of recurrence on graft loss in the C-FSGS group was relatively small compared to that in A-FSGS group. This different effect of recurrence can be explained by the following reasons. Firstly, cases with complete response existed frequently in the C-FSGS group but not in the A-FSGS group. Secondly, the occurrence of acute tubular necrosis may be different between two groups. Patients with FSGS recurrence have been shown to have higher rates of acute tubular necrosis [ 25 ], but unfortunately we did not collect data on the acute tubular necrosis. When including the childhood-onset patients without evidence of chronic change, the effect of recurrence on the outcome was evident (data not shown). The reason for this is not fully understood, but this result is consistent with a previous report that found that recurrence had less effect on the outcome in the C-FSGS group [ 26 ]. However, most previous studies have a significant association between recurrence and overall graft outcome. This discrepancy was not surprising because chronic allograft dysfunction is the most common cause of graft loss [ 3 ].

Although our results are informative, our study has some limitations. Firstly, the study design was retrospective and did not involve routine kidney protocol biopsy. Furthermore, we did not classify the FSGS histology according to the Columbia classification [ 27 ]. Secondly, all the recipients in our data set were Korean. Inferences from our data may not be applicable to other ethnicities because racial differences in FSGS transplants have been shown to exist [ 28 ]; however, some data addressed the similar transplant outcomes among patients with different ethnicities [ 29 ]. Lastly, the treatment protocol for recurrence was not unified in the current study subjects. Recently, the new regimens for FSGS transplants have been introduced [ 30 ], and thus, the new regimens should be applied for the recurrent patients to evaluate the effectiveness.

Interest in recurrent disease after kidney transplantation is likely to increase because the long-term graft outcome has improved. The present study addresses the issues of recurrence and overall graft outcomes according to the age of disease onset. To the best of our knowledge, this paper provides the largest scale analysis of the correlation between the age at disease onset and graft outcome. The outcome of transplant in A-FSGS patients was not different from that in C-FSGS patients. Additionally, recurrence-related factors reported in previous studies with small sample sizes did not appear to be significant in the present study, which included an adequate sample size. Consequently, kidney transplantation in A-FSGS patients should be managed as in patients with C-FSGS.

This work was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A102065).

Conflict of interest statement . None declared.

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Author notes

*
Both authors contributed equally to this research.

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