Renal outcome after kidney-transplantation in Korean patients with lupus nephritis

Abstract

We investigated renal outcome of kidney-transplantation in 19 Korean recipients with biopsy-proven lupus nephritis and compared it with 18 Korean age- and gender-matched recipients without lupus nephritis who were diagnosed with end-stage renal disease caused by renal diseases other than lupus nephritis in a single centre. We reviewed histological findings of kidneys and calculated cumulative dose of immunosuppressive agents. We assessed renal flare of systemic lupus erythematosus, recurrence of lupus nephritis and graft failure as prognosis. The mean age of recipients with lupus nephritis was 43.5 years and all patients were female. Six patients had class III, 10 had class IV and three had class V. There were no meaningful differences in demographic data, renal replacement modality, cumulative doses of immunosuppressants and prognosis between recipients with and without lupus nephritis. Eight patients experienced renal flare of systemic lupus erythematosus, but there were no cases of recurrence of lupus nephritis or graft failure in recipients with lupus nephritis. Kidney-recipients with class IV lupus nephritis exhibited a lower cumulative renal flare of systemic lupus erythematosus free survival rate than those with class III lupus nephritis. In conclusion, renal outcome of kidney-transplantation in patients with lupus nephritis is similar to that in those without lupus nephritis, and class IV was associated with renal flare of systemic lupus erythematosus.

Keywords

Systemic lupus erythematosus lupus nephritis kidney-transplantation prognosis

Introduction

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of autoimmune aetiology. Because SLE can affect almost all the systemic organs, SLE can exhibit diverse clinical manifestations such as cardiomyopathy, pneumonitis and nephritis.¹ Lupus nephritis (LN), one of the serious complications of SLE, is initiated by the deposition of immune-complexes in the glomeruli of kidneys, resulting in glomerular capillary damage along with membranous nephropathy and mesangial proliferation.^2,3 LN is categorized as six classes according to histopathological patterns: proliferative LN (class III and IV) has the worst prognosis and generally requires intravenous cyclophosphamide or oral mycophenolate mofetil as an induction therapeutic regimen.^4,5 Although many efforts have been made to find new drugs for LN, end-stage renal disease (ESRD) develops in 5–22% of patients with SLE,^5,6 and particularly, ESRD might be observed in up to 30% of patients with proliferative LN.⁷ In the past, with concerns over increased morbidity and the high probability of recurrence, kidney-transplantation was not recommended in patients with LN. However, so far, many studies within the last decade have reported a low incidence or absence of renal flare of SLE and recurrence of LN in kidney-recipients with LN.^8–10 Moreover, renal outcome of kidney-transplantation in LN patients was reported to be similar to that in those with renal diseases other than LN (non-LN).¹¹ Thus, kidney-transplantation is currently recommended as one of the therapeutic modalities in SLE patients with ESRD. Considering ethnic differences, investigating renal outcome of kidney-transplantation in Korean patients with LN may be valuable. There was a report on patient-survival in 59 Korean patients with LN,¹² but till now, there was no report regarding renal outcome of transplanted kidneys in Korean recipients with LN. Hence, in this study, we investigated renal outcome of kidney-transplantation in 19 Korean recipients with biopsy-proven LN and compared it with 18 Korean age- and gender-matched recipients without LN who had been diagnosed with ESRD caused by renal diseases other than LN and undergone renal biopsy in a single centre.

Methods

Patients

We retrospectively reviewed the electronic medical records of 19 Korean kidney-recipients with LN according to the inclusion criteria: (i) those who had been first classified as SLE at the Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Severance hospital; (ii) those who had fulfilled the American College of Rheumatology revised criteria for the classification of SLE;¹³ (iii) those who had biopsy-proven LN and in whom the classification of LN was done based on the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN;^14,15 (iv) those who had ESRD due to LN and underwent kidney-transplantation at Severance hospital between January 2005 and December 2016; (v) those who had received prednisolone, mycophenolate mofetil and/or tacrolimus based on the same protocol suggested by the Department of Transplantation Surgery; (vi) those who had no significant medical history or who had never received medications for diseases other than LN. We also inquired into the electronic medical records of 18 Korean age- and gender-matched kidney-recipients, who had been diagnosed with ESRD caused by renal disease other than LN, undergone kidney-transplantation at Severance hospital and received immunosuppressive agents during the same period. This study was approved by the Institutional Review Board of Severance Hospital (4-2017-0444).

Clinical and laboratory data and prognosis

For the 19 recipients with LN, we collected age, gender, age at onset of diseases and time-gap from disease to kidney-transplantation. The follow-up duration after kidney-transplantation was defined as either the period from kidney-transplantation to the last visit for subjects without renal flare of SLE or the period from kidney-transplantation to the time of renal flare of SLE for those experiencing flare. We also reviewed the histological classification of LN and immunological results measured within three days before or on the same day as kidney-transplantation.¹⁴ For the 18 recipients without LN, we examined the causes of ESRD. In terms of comparison variables between recipients with and without LN, we collected age, gender and age at kidney-transplantation as demographic data and obtained dialysis duration, renal replacement modality and concurrent viral infections such as human immunodeficiency virus, hepatitis B and C viruses. Donor sources were categorized as three items, and cumulative dose of immunosuppressive agents was defined as the accumulated area under the curve of the dose from kidney-transplantation to the present study. Prognosis of kidney-transplantation included renal flare of SLE, recurrence of LN and graft failure.

Definition of prognosis and pathological findings on renal biopsy after kidney-transplantation

Renal flare of SLE was defined as nephritic flare, which means an increase or recurrence of active urinary sediment and/or proteinuria with an increase >25% in serum creatinine, and as proteinuric flare, which means a persistent increase in proteinuria (>0.5–1.0 g/day) after achieving complete remission or a doubling of proteinuria (>1 g/day) after achieving partial remission.^2,16 Recurrent LN of a grafted kidney was defined by histological findings compatible with LN.^14,17,18 Graft failure was defined as a status which needed dialysis therapy to be restarted or re-transplantation and death due to renal and non-renal causes.^8,17,18 Patients with unexplained elevated serum creatinine (greater than 30% increase over baseline), increased proteinuria (greater than 0.5 g/day) and persistent hematuria (>5 RBC/HPF) were subjected to renal biopsy.^8,19,20 We investigated acute T cell mediated rejection, acute antibody mediated rejection, chronic active antibody mediated rejection, acute calcineurin inhibitor toxicity and others as pathological findings of renal biopsy.

Statistical analysis

All statistical analyses were conducted using SPSS software (version 23 for windows; IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation, and categorical variables were done as number and the percentage. We used the chi-square test and Fisher’s exact test to compare significant differences of categorical data between the two groups and used Student’s t test or the Mann–Whitney U test to compare continuous variables between the two groups. The optimal cut-offs of C3 and C4 at kidney-transplantation to predict renal flare of SLE during the follow-up duration were extrapolated by calculating the area under the receiver operator characteristic curve (AUROC). Cumulative renal flare of SLE free survival was analysed by the Kaplan–Meier survival analysis. p values less than 0.05 were considered statistically significant.

Results

Characteristics of kidney-recipients with LN

The characteristics of the 19 kidney-recipients with LN are described in Table 1. The mean age of recipients with LN was 43.5 years and all patients were female. The mean age at onset of SLE was 26.2 years and that of LN was 27.2 years. Six patients had class III LN, 10 had class IV LN and three had class V LN. The mean time-gaps from SLE to LN and LN to ESRD were 12.5 and 80.9 months. Kidney-transplantation was, on average, performed 136.8 months after SLE diagnosis and 124.3 months after LN diagnosis. The mean follow-up duration after kidney-transplantation was 70.1 months. Antinuclear antibody was detected in 14 patients (73.3%), anti-ds DNA antibody was observed in three patients and antibodies related to anti-phospholipid syndrome were found in six patients. The mean C3 and C4 were 69.0 and 22.3 mg/dL.

Table 1

Characteristics of kidney-recipients with lupus nephritis (N = 19)

Variables	Values
Demographic data
Age (years)	43.5 ± 10.5
Female gender (N, (%))	19 (100)
Age at onset of diseases (years)
Age at onset of SLE	26.2 ± 13.6
Age at onset of LN	27.2 ± 13.1
Histological classification of LN (N, (%))
LN III	6 (31.6)
LN IV	10 (52.6)
LN V	3 (15.8)
Time-gap (months)
From SLE to LN	12.5 ± 33.4
From LN to ESRD	80.9 ± 79.5
From SLE to kidney-transplantation	136.8 ± 95.9
From LN to kidney-transplantation	124.3 ± 99.7
Follow-up duration after kidney-transplantation	70.1 ± 32.8
Immunological results at kidney transplantation
Antinuclear antibody (N, (%))	14 (73.7)
Anti-dsDNA antibody (N, (%))	3 (15.8)
Antibodies related to anti-phospholipid syndrome (N, (%))	6 (31.6)
C3 titres (mg/dL) (reference value 90–180)	69.0 ± 17.4
C4 titres (mg/dL) (reference value 10–40)	22.3 ± 10.5

Values are expressed as the mean ± standard deviation or N (%).

LN: lupus nephritis; SLE: systemic lupus erythematosus; ESRD: end-stage renal disease; dsDNA: double-stranded deoxyribonucleic acid; C: complement.

Aetiology of ESRD in kidney-recipients without LN

The causes of ESRD in patients without LN are summarized in Table 2. Among the known causes, the most common aetiology of ESRD in kidney-recipients without LN was IgA nephropathy (33.3%), followed by chronic GN, DM nephropathy and tubulointerstitial nephritis (11.1% for all). The causes of ESRD were not identified in four kidney-recipients (22.2%).

Table 2

Aetiology of end-stage renal diseases in kidney-recipients without lupus nephritis (N = 18)

Variables (N, (%))	Values
IgA nephropathy	6 (33.3)
Chronic GN	2 (11.1)
DM nephropathy	2 (11.1)
Tubulointerstitial nephritis	2 (11.1)
Alport syndrome	1 (5.6)
Polycystic kidney	1 (5.6)
Unknown causes	4 (22.2)

Values are expressed as N (%).

LN: lupus nephritis; IgA: immunoglobulin A; GN: glomerulonephritis; DM: diabetes mellitus.

Comparison of variables between kidney-recipients with and without LN

The mean age (43.5 vs 43.6 years) and age at the time of kidney-transplantation (37.6 vs 37.9 years), and the rate of female gender (100% for all) did not differ between the two groups. Both recipients with LN and those without LN exhibited similar dialysis duration (43.3 vs 50.3 months) and renal replacement modalities. Because ESRD was defined as the status requiring dialysis or transplantation, one recipient with LN and three without LN, who had a GFR < 15 mL/min/1.73 m², were classified as ESRD at the time of kidney-transplantation. One recipient in each group was infected with hepatitis B virus (Table 3). Patients with LN received a kidney from a living related donor more frequently than those without LN (78.9% vs 38.9%, p = 0.013), while those with LN received a kidney from a deceased donor less often than those without LN (15.8% vs 55.5%, p = 0.011). One recipient in each group received a kidney from a living unrelated donor. There were no meaningful differences in cumulative doses of prednisolone, tacrolimus and mycophenolate mofetil (Table 3).

Table 3

Comparison of variables between kidney-recipients with and without lupus nephritis

Variables	Recipients with LN (N = 19)	Recipients without LN (N = 18)	p value
Demographic data
Age (years)	43.5 ± 10.2	43.6 ± 10.5	0.968
Female gender (N, (%))	19 (100)	18 (100)
Age at kidney-transplantation (years)	37.6 ± 10.5	37.9 ± 10.9	0.942
Renal replacement therapy before kidney-transplantation
Dialysis duration (months)	43.3 ± 47.9	50.3 ± 43.8	0.663
Renal replacement modality (N, (%))
Hemodialysis	14 (73.7%)	11 (61.1%)	0.414
Peritoneal dialysis	4 (21.0%)	4 (22.2%)	0.999
None	1 (5.3%)	3 (16.7%)	0.340
Concurrent viral infections before kidney-transplantation
Human immunodeficiency virus	0 (0%)	0 (0%)	1.000
Hepatitis B virus	1 (5.3%)	1 (5.6%)	0.999
Hepatitis C virus	0 (0%)	0 (0%)	1.000
Kidney-transplantation
Donor sources
Living related donor	15 (78.9%)	7 (38.9%)	0.013
Deceased donor	3 (15.8%)	10(55.5%)	0.011
Living unrelated donor	1 (5.3%)	1 (5.6%)	0.999
Cumulative dose of immunosuppressive agents after kidney-transplantation
Prednisolone (mg)	12970.8 ± 15876.1	7378.8 ± 6855.5	0.177
Tacrolimus (mg)	5590.0 ± 5170.3	3798.1 ± 5382.2	0.309
Mycophenolate (g)	503.1 ± 530.9	456.2 ± 464.9	0.777
Prognosis of transplanted kidneys
Renal flare of SLE	8 (42.1%)	NA	NA
Recurrence of LN	0 (0%)	NA	NA
Graft failure	0 (0%)	1 (5.6%)	0.486

Values are expressed as the mean ± standard deviation or N (%).

LN: lupus nephritis; SLE: systemic lupus erythematosus; NA: not applicable

Prognosis of transplanted kidneys

Among 19 kidney-recipients with LN, eight recipients with LN (42.1%) experienced renal flare of SLE during follow-up after kidney-transplantation. Among the eight kidney-recipients with LN having renal flare, a total of 12 renal biopies were performed in six: two patients underwent renal biopsy three-times, two patients two-times, and two patients once, respectively. Two patients with LN having renal flare of SLE did not undergo renal biopsy because their renal function and the amount of proteinuria were normalized within one month (one had class III LN and the other had class IV LN). On the other hand, among the 18 kidney-recipients without LN, a total of 15 renal biopsies were done in seven kidney-recipients, who exhibited unexplained creatinine elevation, increased proteinuria and hematuria: one patient underwent renal biopsy four-times, two patients three-times, one patient two-times, and three patients once, respectively. One recipient, who had suffered from diabetes mellitus nephropathy, had presented with graft failure and recently undergone a second kidney-transplantation. Meanwhile, no graft failure was documented in kidney-recipients with LN (Table 3). Nine of 12 cases in kidney-recipients with LN and nine of 15 cases in those without LN exhibited histological features related to rejection without significant differences.One recipient in each group showed acute calcineurin inhibitor toxicity. Non-specific histological findings were observed in two kidney-recipients with LN and five without LN (Table 4).

Table 4

Pathologic findings on renal biopsy in kidney-recipients with and without lupus nephritis

Variables (N, (%))	Recipients with LN (12 cases)	Recipients without LN (15 cases)	p value
Acute T cell mediated rejection	4 (33.3)	4 (26.7)	0.706
Acute antibody mediated rejection	2 (16.7)	4 (26.7)	0.535
Chronic active antibody mediated rejection	3 (25.0)	1 (6.7)	0.183
Acute calcineurin inhibitor toxicity	1 (8.3)	1 (6.7)	0.869
Others	2 (16.7)	5 (33.2)	0.326

SLE: systemic lupus erythematosus; LN: lupus nephritis.

Cumulative renal flare of SLE free survival rates

The cumulative renal flare of SLE free survival rates with respect to class of LN and the presence of antibodies related to anti-phospholipid syndrome at kidney-transplantation are depicted in Figure 1. Kidney-recipients with class IV LN exhibited a lower cumulative renal flare of SLE free survival rate than those with class III LN (p = 0.011). Kidney-recipients with antibodies related to anti-phospholipid syndrome tended to show a lower cumulative renal flare of SLE free survival rate than those without, but there was no statistical significance (p = 0.114). ANA, anti-dsDNA, C3 and C4 at kidney transplantation exhibited no association with renal flare of SLE during follow-up.

Discussion

Despite the development of new therapeutic modalities, LN stills exhibits poor renal outcomes with progression to ESRD in up to 30% of patients with proliferative LN.⁷ Thus, therapeutic modalities such as kidney-transplantation along with haemodialysis or peritoneal dialysis should be early and positively considered and prepared in LN patients with a glomerular filtration rate (GFR) <15 mL/min/1.73 m². However, in a clinical setting, many physicians hesitate over recommending kidney-transplantation to LN patients with ESRD because of concerns over recurrence of SLE after kidney-transplantation and the toxicities of immunosuppressive agents at stronger than usual doses for many years. So far, many studies have fortunately proposed positive results regarding renal outcome of transplanted kidneys in kidney-recipients with LN, which is similar to that in those without LN.^{8–10,17,20,21} Among 50 renal transplantations in 40 Spanish kidney-recipients with LN, only one patient experienced recurrence of LN in renal allograft,⁸ and among 14 Brazilian kidney-recipients with LN and 33 Italian kidney-recipients with LN, none exhibited clinical or histological evidence of LN recurrence.^10,20 Similar to previous studies, in this study, although eight recipients with LN experienced renal flare of SLE after kidney-transplantation, there was no case of recurrence of LN or graft failure in kidney-recipients with LN. Moreover, there were no remarkably different pathological findings between kidney-recipients with and without LN who underwent the follow-up renal biopsy. From these results, we could conclude that kidney-transplantation is a safe and effective therapeutic modality in LN patients with ESRD and renal outcome of transplanted kidneys in patients with LN is similar to that in those without.

The main issue in kidney transplantation is preventing and delaying allograft rejection. Antigens of allograft-kidney are processed in antigen presenting cells and presented to CD4+ T cells. Both antigen-T cell receptor and co-stimulations switch on three signal transduction pathways, calcineurin, mitogen-activated protein and nuclear factor kappa B, and enhance the expression of down-stream proteins, including interleukin-2 and CD25. Interleukin-2 and CD25 subsequently bind CD122 and CD133 and turn on signal 3, the mammalian target of rapamycin (mTOR), leading to a breakdown of immune homeostasis and tolerance, and provoking allograft rejection.^22,23 Therefore, a number of drugs have been developed to cut this vicious cycle from T cell receptor to cell cycle and are in clinical trials. Among many immunosuppressive drugs, calcineurin inhibitors and mycophenolate mofetil along with prednisolone are currently recommended as conventional maintenance treatment after kidney-transplantation.²⁴ Tacrolimus, one of the calcineurin inhibitors, binds to FKBP12, the 12-kDa FK506-binding protein, and inhibits calcineurin phosphatase, discouraging activated T cells from inducing allograft rejection.²⁵ Mycophenolate mofetil reduces purine synthesis by inhibiting the biosynthesis of guanosine monophosphate nucleotides, preventing T and B cell proliferation.²⁶ Prednisolone, mycophenolate mofetil and calcineurin inhibitors are therefore maintenance therapeutic regimens for preventing not only allograft rejection but also recurrence of LN.^27–29 This theoretical background may alleviate concerns over LN recurrence after kidney transplantation

We also investigated LN-related factors at kidney transplantation to predict flare of LN during the follow-up, and Class IV LN was associated with renal flare of SLE, compared with class III LN, during the follow-up. However, the presence of antibodies related to APS exhibited no association with renal flare of SLE (Figure 1). Because all recipients with class V LN experienced no renal flare of SLE, there were no meaningful differences among those with class III, IV and V LN. The presence of antinuclear antibody or anti-ds DNA had no influence on cumulative renal flare of SLE free survival rates in patients with LN. In addition, we calculated the optimal cut-offs of C3 and C4 to predict renal flare of SLE during the follow-up. However, we found no optimal cut-offs of C3 (AUROC 0.513, p = 0.929) and C4 (AUROC 0.450, p = 0.722).It was often proposed to postpone kidney-transplantation until the quiescence of SLE activity. However, delayed transplantation turned out not to be associated with recurrent LN.^30,31 African ancestry, younger age and female gender rather than SLE activity were known to be risk factors for recurrence of LN.³⁰ From these results, we could conclude that physicians should not avoid or delay kidney-transplantation in LN patients with ESRD due to covert concerns over recurrent LN. Furthermore, physicians may provide protocol-based renal biopsies for post-transplantation surveillance in recipients with class IV LN.³²

Our study has the strong advantage that we first reported renal outcome of patients with LN after kidney-transplantation under the controlled therapeutic protocol in a single centre. Furthermore, we clarified that class IV LN rather than immunological burden of SLE was the only predictor of renal flare of SLE, but not recurrence of SLE. However, our study has several limitations. First, the lack of serial and protocol-based histological data is the main limitation, particularly in recipients experiencing renal flare of SLE. Second, the number of subjects was not large enough to represent Korean patients with LN and ESRD. Third, because this study was retrospectively designed, the regularly recorded assessment of SLE activity during follow-up was not available. If future studies can prospectively and serially perform protocol-based renal biopsy and assess SLE activity after kidney-transplantation, they could reveal dynamic information on renal flare of SLE and recurrence of LN during follow-up.

In conclusion, renal outcome of kidney-transplantation in patients with LN is similar to that in those without LN, and class IV was associated with renal flare of SLE after kidney-transplantation.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1D1A1B03029050) and a faculty research grant of Yonsei University College of Medicine (6-2016-0159).

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