Short-term Outcome of Renal Transplantation in the Modern Era：
Experience of a Single-center in Taiwan
Ying-Chih Lo*, Hao-Chung Ho**, Ming-Ju Wu*,***, Cheng-Hsu Chen*,****,
Chi-Hung Cheng*,***, Tung-Min Yu*, Ya-Wen Chuang*, Shih-Ting Huang*,
Cheng-Kuang Yang**, and Kuo-Hsiung Shu*,***
Correspondence author:
Kuo-Hsiung Shu, MD
Chief, Division of Nephrology,
Department of Internal Medicine,
Taichung Veterans General Hospital,
160, Section 3, Taichung-Kang Rd,
Taichung, 407, Taiwan
E-mail: khshu@vghtc.gov.tw
Tel : +886-4-23592525 ext. 3040
Fax : +886-4-23594980
Running title: Renal transplantation in Taiwan
___________________________
Division of Nephrology*, Department of Internal Medicine, Division of Urology**,
Department of Surgery, Taichung Veterans General Hospital, School of Medicine,
Chung-Shan Medical University***, Institute of Clinical Medicine, China Medical
University****, Taichung, Taiwan
1
中文摘要
背景：腎臟移植相較於透析治療，能提供更好之病患存活率與生活品質，然而，
因為器官來源缺乏，在台灣只有少數末期腎病變的病患有機會接受腎臟移植，這
個回溯性的研究希望透過分析台中榮民總醫院的腎臟移植病人以進一步釐清腎
臟移植的好處與潛在之風險。
方法： 我們回溯性地分析 248 位在 2004 年 1 月到 2008 年 12 月之間接受腎臟移
植且在台中榮民總醫院追蹤的病人，我們所分析的臨床結果包括切片證實之急性
排斥率、移植腎存活率、病人存活率、移植後糖尿病與腫瘤發生率。我們並將移
植後腫瘤與急性排斥的結果做進一步之分類與分析。
結果： 一年無急性排斥(acute rejection-free)存活率，五年移植腎存活率與
病患存活率分別為 88.3%, 92.7%和 96.4%。而移植後糖尿病與腫瘤發生率則為
12.9%和 6.7%，生殖泌尿系統腫瘤是最常見之移植後腫瘤，而急性細胞排斥則是
有急性排斥的病人的腎臟切片檢體最常看到的病理診斷。
結論： 台灣腎臟移植的成績與已開發國家相當，例行性的腫瘤篩檢與對移植後
糖尿病的適當處理可望進一步提升我們對腎移植患者之照護品質。
關鍵字：急性排斥，移植腎存活率，病人存活率，腎臟移植
2
ABSTRACT
Background: Renal transplantation provided better patient survival and quality of
life than dialysis therapy. However, due to organ shortage, there are only few patients
with end-stage renal disease in Taiwan had the opportunity to receive transplantation.
This retrospective study aimed to analysis the outcomes of renal transplantation at
Taichung Veterans General Hospital and to elucidate the benefit and potential risk of
renal transplantation.
Methods: Two hundred and forty-eight (248) renal transplant recipients at the
Taichung Veterans General Hospital from January 2004 and December 2008 were
retrospectively studies. The clinical outcomes include biopsy-proven acute rejection,
graft survival, patient survival, post-transplant diabetes mellitus and malignancy. The
type of the post-transplant malignancy and acute rejection were further analyzed.
Results: The one year acute rejection-free survival, five years graft survival and
patient survival were 88.3%, 92.7% and 96.4%, respectively. The incidence of
post-transplant diabetes mellitus and malignancy were 12.9% and 6.7%, respectively.
Tumor of the genitourinary tract is the most common type of the malignancy. Acute
cellular rejection is the most common pathological diagnosis in patients with
biopsy-proven acute rejection.
Conclusions: The outcome of renal transplantation in Taiwan is comparable with that
3
in the developed countries. Routine malignancy surveillance and medical control for
post-transplant diabetes mellitus is crucial to further improve the care quality of renal
transplant recipients.
Key words: acute rejection, graft survival, patient survival, renal transplantation
4
INTRODUCTION
According to the data of the Taiwan Society of Nephrology, there are more than
fifty thousand end-stage renal disease patients receiving dialysis therapy in Taiwan.
However, only about one-tenth of them have the opportunity to receive renal
transplantation. In a previous study, patients receiving renal transplant had higher risk
of mortality within 106 days after the operation when compared with the uremic
control group. However, the survival benefit of transplantation appears since the 244
days post-operation.1 Besides, the long-term transplant patient survival is also better
than the dialysis patient. Increasing evidence had also showed that renal
transplantation can provide better quality of life with less medical cost. However, due
to the universal situation of organ shortage, most of the uremic patients had no choice
but to receive the dialysis therapy. In Taiwan, due to the high incidence of end-stage
renal disease and lower rate of patient mortality, there are more and more patients
requiring renal replacement therapy. However, due to hemodialysis is still the
modality mostly adapted, the financial burden of the care system in Taiwan is
increasing. Promotion of renal transplantation is one of the practical measurements to
reduce the medical cost of the uremic patients. This retrospective study aimed to
analysis the various outcomes of renal transplant patients who follow up at Taichung
Veterans General Hospital and to elucidate the benefit and potential risk of renal
5
transplantation.
6
MATERIALS AND METHODS
Patients
All patients underwent renal transplantation between January 2004 and
December 2008 and followed up at Taichung Veterans General Hospital were
retrospectively reviewed. The pre-transplant evaluations included complete blood
count with differential count, biochemistry studies, coagulation profiles, viral hepatitis
marker (hepatitis B and hepatitis C), antibody titer of Epstein-Barr virus (EBV) and
cytomegalovirus (CMV), rapid plasma reagin (RPR), panel reactive antibody (PRA),
cross-match test, chest X-ray, abdominal sonography and electrocardiography.
Echocardiography was selectively performed in those with high risk for
cardiovascular disease.
After the operation, all patients received oral trimethoprim-sulfamethoxazole for
Pneumocystis jiroveci prophylaxis for 6 months and oral valganciclovir for
cytomegalovirus (CMV) prophylaxis for 3 months.
Immunosuppressive agents
Immediately before the surgery, all patients received steroid pulse therapy with
500mg intravenous methylprednisolone. Oral 0.2 mg/kg tacrolimus or 8 mg/kg
cyclosporine was also prescribed. Totally, 118 (47.6%) patients received induction
therapy with interleukin-2 receptor antagonist (IL2RA) in the peri-operative period.
7
Whether induction therapy with IL2RA was use or not is according to the preference
of the attending physician and the economic affordability of the patients. After the
operation, 500mg intravenous methylprednisolone were also used and gradually
tapered to 30mg/day oral prednisolone on day 4 post-transplant, 15 mg/day by the end
of first month, and to 5 mg/day by the end of the third month. Steroid use was kept to
the minimum required dosage during subsequent outpatient visits. The initial
immunosuppressive regimens include calcineurin inhibitor (CNI, either cyclosporine
in a dose of 8mg/kg/d or tacrolimus in a dose of 0.2mg/kg/d), mycophenolate mofetil
(1.5-2.0 g/day) and prednisolone. The selection of CNI was based on the clinical
judgment of the attending physicians. The target whole blood level of tacrolimus were
8-12 ng/ml in the first year post-transplant, 5-8 ng/ml in the following years, and
decreased to 3-5 ng/ml in the patients with stable long-term graft function. The whole
blood trough level of cyclosporin was kept around 100-150 ng/ml in the first three
months after transplantation and decreased to 50-100 ng/ml later. In some patients,
sirolimus was added in the immunosuppressive regimen during follow-up, regardless
of withdrawal one of the other immunosuppressive agents.
Definitions
Delayed graft function was defined as the requirement of dialysis within the first
week post-transplant. All acute rejection episodes in our study were proven via renal
8
biopsy, which was performed before or within 48 hrs after the initiation of
anti-rejection therapy. Acute rejections were classified according to the 1997 Banff
criteria and updated 2005.2,3 Borderline change followed by a favorable response to
anti-rejection therapy was classified as acute rejection. Cockcroft-Gault equation was
used for the calculation of estimated glomerular filtration rate (eGFR). Post-transplant
diabetes mellitus (PTDM) was defined as newly developed hyperglycemia requiring
treatment with oral anti-diabetic drugs (OAD) or insulin after renal transplantation.
Graft loss was recorded if the patients returned to dialysis, received another renal
transplantation or died.
Outcomes
The measured outcomes were incidence of delayed graft function, biopsy-proven
acute rejection, serum creatinine, eGFR, post-transplant diabetes mellitus, newly
developed malignancy, one year rejection-free survival, five years graft and patient
survival.
Statistical analysis
The continuous data were expressed as mean ± SD or median (range).
Categorical data were expressed as number of patients (percent). Kaplan-Meier
survival curves were drawn for one year acute rejection-free survival, five years graft
and patient survival. Independent t test were used for the comparison of the mean time
9
of acute rejection between those with acute antibody-mediated rejection and those
with acute cellular rejection. Data was collected manually and inputted into an Excel
spreadsheet (Microsoft, Seattle, WA, USA). All analyses were performed using the
SPSS statistical software (version 15.0, SPSS Inc., Chicago, IL). A p<0.05 was
considered statistically significant.
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RESULTS
A total of 248 patients were included for analysis. Table 1 summarized the
baseline recipients and donors characteristics. As for the recipients, male gender (56%)
was slightly more than the female in our series. The most common primary disease
was chronic glomerulonephritis (31.5%). However, due to the cause of the end-stage
kidney disease was unknown in most of the patients (39.5%), the proportion of
chronic glomerulonephritis may be underestimated. The HCV infection rate was
13.3%, which is higher than the general population.4 Majority of the patients (62.5%)
had ever received hemodialysis before the transplantation. However, there is also
some patients (14.5%) received preemptive transplantation. There is also a few (8.1%)
patients received repeated renal transplantation. Tacrolimus is the most commonly
adopted CNI in the current practice, which was used in 81.9% of our patients.
Nearly twenty percent of our patients had delayed graft function. The incidence
of post-transplant malignancy and diabetes mellitus during the study period were
6.7% and 12.9%, respectively (Table 2). In our study, three patients developed
malignancy within 3 months after renal transplantation. Whether these events were
due to effect of renal transplantation or progression of previously undiagnosed
malignancy was uncertain. Incidence of post-transplant malignancy would be 5.6% if
these patients were excluded.
11
Twenty-nine patients (11.7%) experienced at least one episode of acute rejection
during the first year post-transplant. Isolated acute cellular rejection (ACR) is the
most common finding (79.3%) among patients with acute rejection. When compared
with acute antibody-mediated rejection (AAMR), ACR tend to occur at relatively later
period (p<0.001, Table 3, Fig. 3). Transitional cell carcinoma is the leading cause of
post-transplant malignancy, followed by renal cell carcinoma, prostate cancer and
hepatocellular carcinoma (Table 4). Among these, 4 (24%) patients died of advanced
malignancy during the follow-up period. The first year rejection-free survival, graft
and patient survival were 88.3%, 98.4% and 99.6%, respectively. The five year graft
and patient survival were 92.7% and 96.4%, respectively. (Fig. 1, Fig. 2) The mean
follow-up duration after renal transplant was 41.1 ± 18.1 months (range, 0.5-75
months).
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DISCUSSION
In a previous epidemiological study in southern Taiwan, the seroprevalence of
hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among general
population were 15.1% and 8.6%, respectively.4 However, our patients had an obvious
higher rate of HCV infection (13.3%) than the general population. The results may be
due to the majority (62.5%) of our transplant recipients had ever received
hemodialysis, which had been known to increase the risk of HCV infection.5 Whether
HBV and HCV infection will affect the transplant outcome had been widely studied.
In a previous study conducted at our hospital, HBV infection had been shown to be an
independent risk factor of long-term patient survival but not graft survival. No
obvious correlation was found between HCV infection and the outcomes of renal
transplant recipients.6 In spite of that, there is still some studies revealed poor
outcomes with those had HCV infection.7,8 What about the influence of pre-transplant
dialysis duration on the patient outcomes? Remport and colleagues found that longer
duration of previous dialysis history had a negative impact on the patient and graft
survival due to premature mortality and graft loss may appear before the appearance
of survival benefit of transplantation. Patients had dialysis history more than 3 years
had higher risk than those with less than 3 years.9 The mean dialysis duration of our
patients was 44.7 months and this may hint that promotion of early transplantation
13
may improve our patient outcomes further.
IL2RA is a monoclonal antibody targeting on the IL2 receptor of activated
T-lymphocyte to inhibit it’s proliferation and differentiation.10 Previous studies had
showed reduced early acute rejection rate with it’s use in the peri-operative period
among White and Black people.11 However, due to this drug was not reimbursed by
the National Health Insurance system in Taiwan and the efficacy had not been well
established among Chinese population, we did not use it routinely in our transplant
patients. However, due to the drug was relative safe for the patients, we still
recommend this premedication for patients as long as he or she is economically
affordable.
Tacrolimus was the most commonly (81.9%) used calcineurin inhibitor in our
current practice due to the higher drug potency and better clinical outcomes.12,13
Cyclosoprine was used for those had intolerance to tacrolimus and those had HCV
infection; based on the finding that cyclosporine may have a beneficial effect on
chronic HCV infection.14 About one-tenth of the patients had ever experienced
biopsy-proven acute rejection within the first years post-transplant. The result is
comparable with the data of USRDS 2010 annual report. According to the data of The
Transplantation Society of Taiwan, the overall graft survival and patient survival in
Taiwan is similar or even better than that of the United States. This represents that the
14
quality of surgery and medical care for renal transplant patients in Taiwan is
comparable with those in developed countries.
Among patients who had acute rejection within the first year post-transplant,
most (79.3%) had ACR (Table 3). We also found that AAMR tent to appear earlier
than the ACR (p<0.001, Fig. 3). The early humoral rejection may be due to some
memory B cell, which were already exist before transplantation. Upon transplant,
these cells might be activated and secret anti-donor antibodies, thus induced early
humoral rejection. IL2RA has been shown to be effective in preventing acute T cell
mediated rejection. The biological half-life may be as long as 3 months following
injection. This may partly explain why ACR tends to occur later.
As for the analysis of post-transplant malignancy (Table 4), we found that de
novo transitional cell carcinoma of the urinary tract is the most common, which
composed 50% of all patients with post-transplant malignancy. Renal cell carcinoma
ranked the second, followed by prostate cancer and hepatocellular carcinoma. In brief,
majority of malignancy were originated from the urinary tract, which is a unique
feature in Taiwan.15 In the Western countries, skin cancer is the most common
malignancy after transplant. Whether this difference is due to racial disparity remains
uncertain.16,17 Previous reports confirmed that aristolochic acid in certain Chinese
herb is responsible for urothelial carcinoma.18 Given the high prevalence of herb
15
usage among Taiwanese, the causal relationship of high incidence of transitional cell
carcinoma and herb consumption can not be ignored. We suggest routine surveillance
of genitourinary tract tumor is essential to prevent transplant recipients from the
morbidity and mortality of malignancy in Taiwan. The median time to malignancy
was 23.8 months in our study. However, due to the risk of malignancy increases after
the use of immunosuppressive agents, we suggest malignancy surveillance program
should be started early after the operation due to the immunosuppressive agents may
speed up the development of malignancy that may be subclinical before the
transplantation.
In conclusion, this retrospective study elucidated the outcomes of renal
transplantation patients in a medical center of central Taiwan. The results were
comparable with that of the developed countries. However, there are still some
potential adverse events that should be kept in mind, such as post-transplant
malignancy, post-transplant diabetes mellitus and acute graft rejection. Routine
surveillance for malignancy and appropriate management for the post-transplant
diabetes mellitus is crucial to further improve the care quality of renal transplant
recipients.
16
ACKNOWLEDGEMENTS
The authors would like to thank the biostatistics task force of Taichung Veterans
General Hospital for their assistance in statistical analysis.
17
REFERENCES
1
2
3
4
5
6
7
8
9
10
11
12
13
Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all
patients on dialysis, patients on dialysis awaiting transplantation, and
recipients of a first cadaveric transplant. N Engl J Med 1999; 341: 1725-30
Racusen LC, Solez K, Colvin RB, et al: The Banff 97 working classification
of renal allograft pathology. Kidney Int 1999; 55: 713-23
Solez K, Colvin RB, Racusen LC, et al: Banff 07 classification of renal
allograft pathology: updates and future directions. Am J Transplant 2008; 8:
753-60
Yang JF, Lin CI, Huang JF, et al: Viral hepatitis infections in southern Taiwan:
a multicenter community-based study. Kaohsiung J Med Sci 2010; 26: 461-9
Patel PR, Thompson ND, Kallen AJ, Arduino MJ: Epidemiology, surveillance,
and prevention of hepatitis C virus infections in hemodialysis patients. Am J
Kidney Dis 2010; 56: 371-8
Lee WC, Shu KH, Cheng CH, Wu MJ, Chen CH, Lian JC: Long-term impact
of hepatitis B, C virus infection on renal transplantation. Am J Nephrol 2001;
21: 300-6
Ridruejo E, Diaz C, Michel MD, et al: Short and long term outcome of kidney
transplanted patients with chronic viral hepatitis B and C. Ann Hepatol 2010;
9: 271-7
Dominguez-Gil B, Morales JM: Transplantation in the patient with hepatitis C.
Transpl Int 2009; 22: 1117-31
Remport A, Keszei A, Vamos EP, et al: Association of pre-transplant dialysis
duration with outcome in kidney transplant recipients: a prevalent cohort study.
Int Urol Nephrol 2010:
Kahan BD, Rajagopalan PR, Hall M: Reduction of the occurrence of acute
cellular rejection among renal allograft recipients treated with basiliximab, a
chimeric anti-interleukin-2-receptor monoclonal antibody. United States
Simulect Renal Study Group. Transplantation 1999; 67: 276-84
Webster AC, Ruster LP, McGee R, et al: Interleukin 2 receptor antagonists for
kidney transplant recipients. Cochrane Database Syst Rev 2010: CD003897
Cheung CY, Chan HW, Liu YL, Chau KF, Li CS: Long-term graft function
with tacrolimus and cyclosporine in renal transplantation: paired kidney
analysis. Nephrology (Carlton) 2009; 14: 758-63
Dallos G, Hidvegi M, Kosa G, et al: Results and complications after living
related kidney transplantation in Hungary: 30 years' experience. Transplant
Proc 2010; 42: 2312-4
18
14
15
16
17
18
Kamar N, Selves J, Sandres-Saune K, Durand D, Izopet J, Rostaing L: Does
cyclosporine have a beneficial effect on the course of chronic hepatitis C
infection after renal transplantation? Transplant Proc 2006; 38: 1329-32
Wu MJ, Lian JD, Yang CR, et al: High cumulative incidence of urinary tract
transitional cell carcinoma after kidney transplantation in Taiwan. Am J
Kidney Dis 2004; 43: 1091-7
Harzallah K, Abderrahim E, Chareffedine K, et al: Cancers after renal
transplantation: multicenter experience. Saudi J Kidney Dis Transpl 2008; 19:
825-30
Stratta P, Morellini V, Musetti C, et al: Malignancy after kidney transplantation:
results of 400 patients from a single center. Clin Transplant 2008; 22: 424-7
Nortier JL, Martinez MC, Schmeiser HH, et al: Urothelial carcinoma
associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J
Med 2000; 342: 1686-92
19
TABLE
Table 1. Baseline demographic data (n=248)
Recipient age (yrs)
45.5 ± 12.6
Recipient gender, male
139 (56%)
2
Body mass index (kg/m )
23.0 ± 4.0
Primary disease
Diabetes mellitus
Chronic glomerulonephritis
Drug induced nephropathy (include herb)
Unknown etiology
24 (9.7%)
78 (31.5%)
15 (6.0%)
98 (39.5%)
Others
Viral hepatitis history
HBV
HCV
Previous dialysis modality
Hemodialysis
Peritoneal dialysis
No dialysis
Dialysis duration (mos)
Previous renal transplantation
33 (13.3%)
Donor age (yrs)
Donor gender, male
HLA mismatch number
Recipient PRA ≧20%
35.6 ± 15.0
119 (48.0%)
2.56 ± 1.27
26 (10.5%)
118 (47.6%)
29 (11.7%)
33 (13.3%)
155 (62.5%)
56 (22.6%)
36 (14.5%)
44.7 ± 45.5
20 (8.1%)
Interluekin-2 receptor antagonist use
Baseline calcineurin inhibitor
Cyclosporine
Tacrolimus
43 (17.3%)
203 (81.9%)
Abbreviation: PRA, panel reactive antibody
Values are expressed as mean ± SD or number of patients (percent)
20
Table 2. Short-term clinical outcome (n=248)
Delayed graft function
Biopsy-proven acute rejection at 1yr
Serum Cr at 1yr (mg/dl)
46 (18.5%)
29 (11.7%)
1.39 ± 0.42
Estimated GFR at 1yr (ml/min)*
56.6 ± 16.5
Post-transplant malignancy
Post-transplant diabetes mellitus
17 (6.7%)
32 (12.9%)
Abbreviation: GFR, glomerular filtration rate
*
Calculated via Cockcroft-Gault equation
Values are expressed as mean ± SD or number of patients (percent)
21
Table 3. Summary of biopsy-proven acute rejection at first year
AAMR
Borderline change
ACR
AAMR + ACR
Total
Total patient
Time to rejection
Outcome
(n=29)
(days)
Resolved Graft loss
3 (10.3%)
2 (6.9%)
23 (79.3%)
1 (3.4%)
29 (100%)
10 ± 7
56 ± 68
102 ± 108
83
89 ± 101
3 (100%) 0 (0%)
2 (100%) 0 (0%)
20 (87%) 3 (13%)
1 (100%) 0 (0%)
26 (90%) 3 (10%)
Abbreviation: AAMR, acute antibody-mediated rejection; ACR, acute cellular rejection
Values are expressed as number of patients (percent) or mean ± SD
22
Table 4. Summary of post-transplant malignancy
Hepatocellular carcinoma
Transitional cell carcinoma
Renal cell carcinoma
Prostate cancer
Nasopharyngeal carcinoma
Total
Total patient (n=17)
Time to malignancy (months)
2 (11.8%)
9 (52.9%)
3 (17.6%)
2 (11.8%)
1 (5.9%)
17 (100%)
5.5 (1.9 - 9.1)
23.7 (1.4 - 55.0)
25.6 (1.7 - 52.4)
39.7 (6.2 - 73.2)
65.2
23.8 (1.4 - 73.2)
Values are expressed as number of patients (percent) or median (range)
23
FIGURE LEGENDS
Figure 1. Kaplan-Meier curves for one year rejection-free survival
Figure 2. Kaplan-Meier curves for five years graft and patient survival
Figure 3. Comparison of time to acute rejection. Abbreviation: AAMR, acute
antibody-mediated rejection; ACR, acute cellular rejection
24