SEARCH

SEARCH BY CITATION

Keywords:

  • Kidney transplantation;
  • rapid discontinuation of prednisone;
  • steroid-free immunosuppression

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n = 440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n = 151); high-level tacrolimus (TAC, 8–12 μg/L) and low-level sirolimus (SIR, 3–7 μg/L) (TACH/SIRL, n = 149) or low-level TAC (3–7 μg/L) and high-level SIR (8–12 μg/L) (TACL/SIRH, n = 140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p = 0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p = 0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.


Abbreviations
ANOVA

analysis of variance

AR

acute rejection

BID

twice daily

CAN

chronic allograft nephropathy

CR

chronic rejection

CSA

cyclosporine A

DCGS

death-censored graft survival

DGF

delayed graft function

ESRD

end-stage renal disease

FSGS

focal segmental glomerulosclerosis

F/U

follow-up

GS

graft survival

HPLC

high performance liquid chromatography

IF/TA

interstitial fibrosis and tubular atrophy

IQR

interquartile range

IRB

Institutional Review Board

KT

kidney transplant

MMF

mycophenolate mofetil

NODM

new-onset diabetes mellitus

OR

operating room; POD, post-operative day

PRA

panel reactive antibody

PS

patient survival

PTLD

posttransplant lymphoproliferative disorder

QD

once daily

RDP

rapid discontinuation of prednisone

SE

stand ard error

SIR

sirolimus

TAC

tacrolimus

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Since the earliest renal allotransplants, corticosteroids have been the mainstay of immunosuppression [1-4], but their long-term use has been associated with well-described complications, including hypertension, hyperlipidemia, glucose intolerance (and new-onset diabetes [NODM]), loss of bone mineral density (and fracture), avascular necrosis, cataracts, skin and appearance changes and in children—growth retardation [5-10]. These side effects make long-term prednisone use unpopular among kidney transplant (KT) recipients, resulting in noncompliance [11, 12], and increasing the risk of allograft rejection, dysfunction and loss [13]. Consequently, strategies to minimize or eliminate long-term steroid use have been developed over decades.

Early trials of prednisone reduction involved late steroid withdrawal (≥3 months) and were performed in KT recipients on maintenance regimens consisting of cyclosporine (CSA), prednisone and either azathioprine [14, 15] or mycophenolate mofetil (MMF) [16-19]. These studies found increased rates of acute rejection (AR) and late graft loss. More recent trials have involved rapid discontinuation of prednisone (RDP) within the first week post-KT [20-24]. Individual studies, meta-analyses and registry reports have indicated that RDP increases the risk of mild AR and minimizes steroid-related complications but has no impact on patient survival (PS) or graft survival (GS) [25-34]. Maintenance immunosuppression following RDP has not yet been optimized, with different centers trying combinations of induction agents (thymoglobulin, alemtuzumab, IL-2R inhibitors, none), calcineurin inhibitors (CSA, tacrolimus [TAC]), anti-metabolites (MMF, azathioprine), mammalian target of rapamycin inhibitors (sirolimus [SIR], everolimus) and even a costimulation blocker (belatacept) [25-36]. We started using RDP in 1999 and have recently reported our 10-year actuarial outcomes [37]. In 2001, we began a prospective, randomized trial to determine if one of three maintenance immunosuppressive protocols provided better outcomes. Recipients were randomized into one of three study arms: CSA and MMF (CSA/MMF), high-level TAC and low-level SIR (TACH/SIRL) or low-level TAC and high-level SIR (TACL/SIRH). The rationale for SIR-based maintenance immunosuppression was data suggesting it may minimize fibrosis [38, 39]. Interim (2-year) results from this trial have been reported [40]. Herein, we report the actuarial 10-year results.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Study design

From March 2001 through April 2006, all recipients of either a first or second (including both living donor and deceased donor) KT were invited to participate in this randomized trial; the protocol was approved by the Institutional Review Board (IRB) for human subjects’ research at the University of Minnesota (#0011M74301). Exclusion criteria for study entry included the use of maintenance prednisone within 3 months before KT or requiring prednisone to treat an underlying systemic or primary kidney disease. Anyone that was eligible but elected not to participate in the study was treated with our standard RDP protocol of maintenance CSA/MMF. The primary endpoint in our study included the composite of a return to dialysis, death with function, retransplant of biopsy-proven chronic allograft nephropathy (CAN), which was considered synonymous with chronic rejection (CR). To ensure detection of a 15% difference in the primary endpoints (power = 0.8), we determined we would need approximately 150 recipients per arm.

We enrolled a total of 440 recipients, and randomized them by nonblinded card pull into one of three maintenance therapy arms: CSA/MMF (n = 151); TACH/SIRL (n = 149); and TACL/SIRH (n = 140) (Figure 1). For TAC or SIR, the low blood levels corresponded to 3–7 μg/L and the high blood levels corresponded to 8–12 μg/L.

image

Figure 1. Diagram depicting study design, including the scheme for stratification of recipients as well as provisions for immunosuppression and participant status (alive, deceased, lost to follow-up) at most recent follow-up. BID = twice daily; CSA = cyclosporine; F/U = follow-up; OR = operating room; POD = post-operative day; QD = once daily; SIR = sirolimus; TAC = tacrolimus.

Download figure to PowerPoint

Immunosuppression

Our protocols have been described previously in detail [40]. Briefly, all recipients received Thymoglobulin (Genzyme Corp., Boston, MA, USA) induction at 1.25–1.5 mg/kg/dose intravenously for 5 doses. For delayed graft function (DGF, defined as need for dialysis within first post-KT week), we extended the course of Thymoglobulin (to a maximum of 10 doses). All recipients received methylprednisolone (500 mg) intraoperatively, and prednisone was administered and tapered over 5 post-KT days: 1 mg/kg on post-KT day 1, 0.5 mg/kg on post-KT days 2 and 3 and 0.25 mg/kg on post-KT days 4 and 5. Prednisone was discontinued on post-KT day 6 in all recipients, except in those experiencing DGF, who were given 5 mg/day prednisone concurrently with the extended course of Thymoglobulin, and whose prednisone was discontinued at the time of Thymoglobulin discontinuation. The remaining maintenance immunosuppression varied with respect to the study arm.

CSA/MMF

Recipients of CSA/MMF were given MMF at 1 g intraoperatively. Oral MMF (either 1 g twice daily for non-African Americans or 1.5 g twice daily for African Americans) was started on post-KT day 1, and the dosing was adjusted as needed in the presence of gastrointestinal side effects (nausea, vomiting or diarrhea) or myelosuppression. CSA (8 mg/kg/day, given in two divided doses) was started post-KT, and the dosing was adjusted to achieve blood levels of 150–200 μg/L (via high-performance liquid chromatography [HPLC]) for the first 3 post-KT months. In recipients with poor early graft function or clinical DGF, the CSA dosing was delayed or slowly titrated upwards.

TACH/SIRL

Recipients of TACH/SIRL were given SIR at 1 mg preoperatively. SIR (2 mg/day) was given postoperatively, and the dosing was adjusted to achieve blood levels of 3–7 μg/L (via HPLC). TAC (0.03 mg/kg twice daily) was started postoperatively, and the dosing was adjusted to achieve blood levels of 8–12 μg/L (via microparticle enzyme immunoassay).

TACL/SIRH

Recipients of TACL/SIRH were given SIR at 1 mg preoperatively. SIR (5 mg/day) was given postoperatively, and the dosing was adjusted to achieve blood levels of 8–12 μg/L (via HPLC). TAC (0.015 mg/kg twice daily) was started postoperatively, and the dosing was adjusted to achieve blood levels of 3–7 μg/L (via microparticle enzyme immunoassay).

Recipients with ≥25% increase in serum creatinine levels underwent percutaneous allograft biopsy. AR episodes were treated with steroids or with primary antibody therapy. Steroid-resistant AR was treated with lymphocyte-depleting antibody. The majority of recipients having experienced an AR episode remained on maintenance prednisone (5 mg/day) indefinitely, with a few insisting to discontinue steroid therapy again [41].

Statistical analysis

We studied actuarial PS, GS and death-censored GS (DCGS) rates, and rates of biopsy-proven AR and chronic rejection (CR) for each group. CR was characterized as a clinical diagnosis confirmed by presence of interstitial fibrosis and tubular atrophy (IF/TA) on histological analysis of biopsy. Graft failure was defined by retransplant, return to dialysis or death with functioning graft.

We tracked renal function, weight and lipid profiles, and also the rates of selected medication use (corticosteroids, lipid-lowering and antihypertensive agents). We also analyzed the rates of immunosuppression-related complications.

Categorical variables were analyzed via the chi-square test. Continuous variables were analyzed via 1-way analysis of variance (ANOVA) (for data that are normally distributed) or the Kruskal–Wallis test (for data that are not normally distributed), and survival, rejection and complication rates were analyzed via Kaplan–Meier methods and compared via the log-rank test. Adjustment for multiple comparisons was also performed via the log-rank test. Our statistical analyses were performed on an intention-to-treat basis.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

There were no differences between study arms in follow-up (∼7 [5.5–8.5] years, median [interquartile range, IQR]), or in recipient age (∼49 [40–59] years, median [IQR]). Similarly, there were no differences between study arms in other donor or recipient characteristics (Table 1).

Table 1. Recipient and donor characteristics
 Study arm
 Arm 1 (CSA/MMF)Arm 2 (TACH/SIRL)Arm 3 (TACL/SIRH)
  1. CSA = cyclosporine; ESRD = end-stage renal disease; FSGS = focal segmental glomerular sclerosis; IQR = interquartile range; MMF = mycophenolate mofetil; PRA = panel reactive antibody; SIR = sirolimus; TAC = tacrolimus.

  2. Superscripts: H = high blood level (8–12 μg/L); L = low blood level (3–7 μg/L).

  3. No overall differences between arms for any of the demographic characteristics.

Number [n (% of total)]151 (34.3)149 (33.9)140 (31.8)
Recipient [median (IQR) or n (% of Arm)] 
Patient f/u (months)85.1 (69.5–105.6)84.2 (67.7–107.6)88.4 (68.9–104.9)
Kidney f/u (months)82.4 (58.6–102.4)83.7 (63.1–103.7)86.7 (64.5–103.2)
Age (years)50.4 (39.9–58.7)48.1 (36.7–59.4)48.6 (41.4–58.1)
Gender [n (% of total)]   
Male [268 (60.9)]97 (64.2)88 (59.1)83 (59.3)
Female [172 (39.1)]54 (35.8)61 (40.9)57 (40.7)
Race [n (% of total)]   
Caucasian [400 (90.9)]141 (93.4)130 (87.3)129 (92.1)
African American [18 (4.1)]5 (3.3)8 (5.4)5 (3.6)
Asian American [15 (3.4)]3 (2.0)7 (4.7)5 (3.6)
Native American [7 (1.6)]2 (1.3)4 (2.7)1 (0.7)
Primary cause of ESRD [n (% of total)]   
Type 1 diabetes [103 (23.4)]32 (21.2)36 (24.2)35 (25.0)
Type 2 diabetes [56 (12.7)]16 (10.6)17 (11.4)23 (16.4)
Polycystic disease [55 (12.5)]20 (13.3)20 (13.4)15 (10.7)
Hypertension [33 (7.5)]17 (11.3)9 (6.0)7 (5.0)
IgA nephropathy [29 (6.6)]5 (3.3)10 (6.7)14 (10.0)
FSGS [25 (5.7)]7 (4.6)8 (5.4)10 (7.1)
Unknown [21 (4.8)]7 (4.6)7 (4.7)7 (5.0)
Pretransplant diabetes [n (% of total)]   
Overall [175 (39.8)]51 (33.8)61 (40.9)63 (45.0)
Type 1 [105 (23.9)]32 (21.2)37 (24.8)36 (25.7)
Type 2 [70 (15.9)]19 (12.6)24 (16.1)27 (19.3)
Transplant type [n (% of total)]   
Kidney alone [426 (96.8)]147 (97.4)145 (97.3)134 (95.7)
Simultaneous pancreas–kidney [11 (2.5%)]4 (2.7)3 (2.0)4 (2.9)
Kidney after pancreas [1 (0.3)]0 (0)0 (0)1 (0.7)
Kidney and other organ [2 (0.5)]0 (0)1 (0.7)1 (0.7)
Transplant # [n (% of total)]   
First [409 (93.0)]139 (34.0)140 (34.3)130 (31.8)
Second [31 (7.0)]12 (38.7)9 (29.0)10 (32.3)
HLA mismatch (number)3 (2–5)3 (2–5)3 (2–5)
Peak PRA > 10% [88/434 (20.3)]33/149 (22.2)28/147 (19.0)27/138 (19.6)
Transplant PRA > 10% [53/399 (13.3)]23/138 (16.7)15/138 (10.9)15/123 (12.2)
Donor
Age (years)39.6 (29.7–50.0)42.3 (33.1–48.9)43.9 (35.4–49.8)
Gender [n (% of total)]   
Male [180/425 (42.4)]66/146 (45.2)57/145 (39.3)57/134 (42.5)
Female [245/425 (57.7)]80/146 (54.8)88/145 (60.7)77/134 (57.5)
Race [n (% of total)]   
Caucasian [398/424 (93.9)]140/146 (95.9)132/144 (91.7)126/134 (94.0)
African American [13/424 (3.1)]4/146 (2.7)5/144 (3.5)4/134 (3.0)
Native American [5/424 (1.2)]2/146 (1.4)1/144 (0.7)2/134 (1.5)
Asian American [6/424 (1.4)]0 (0)5/144 (3.5)1/134 (0.8)
Type [n (% of total)]   
Deceased [118 (26.8)]43 (28.5)36 (24.2)39 (27.9)
Living-related [194 (44.1)]66 (43.7)68 (45.6)60 (42.9)
Living-unrelated [128 (29.1)]42 (27.8)45 (30.2)41 (29.3)

Of the 440 recipients, 139 (31.6%) experienced loss of their transplanted kidney, including 48 (31.8%) with CSA/MMF, 48 (32.2%) with TACH/SIRL and 43 (30.7%) with TACL/SIRH. The main causes of graft loss were death with functioning graft (48.2%) and CR (25.2%). There were no differences in the cause of kidney loss between study arms (p = 0.3). Loss due to CR (or IF/TA) occurred in 17 (35.4%) with CSA/MMF, in 10 (20.8%) with TACH/SIRL and in 8 (18.6%) with TACL/SIRH (p = 0.1). Death with a functioning graft occurred in 20 (41.7%) with CSA/MMF, 23 (47.9%) with TACH/SIRL and 24 (55.8%) with TACL/SIRH (Table 2). Ninety-one (20.7%) recipients died over the course of study follow-up, including 30 (19.9%) with CSA/MMF, 28 (18.8%) with TACH/SIRL and 32 (22.9%) with TACL/SIRH. Main causes of death included sudden death (8.8%), malignant metastasis (8.8%), congestive heart failure (7.7%), skin cancer (6.6%), kidney failure (5.5%), posttransplant lymphoproliferative disorder ([PTLD] 5.5%), cerebrovascular accident (4.4%) and infection (4.4%). There were no overall differences in the cause of recipient death between study arms (p = 0.5). Furthermore, 8.9% of recipients were lost to follow-up over the course of the study.

Table 2. Summary of prevalent causes of kidney loss in each randomized study arm
 Study arm
 Arm 1Arm 2Arm 3
 (CSA/MMF)(TACH/SIRL)(TACL/SIRH)
  1. CAN = chronic allograft nephropathy; CR = chronic rejection; CSA = cyclosporine; MMF = mycophenolate mofetil; SIR = sirolimus; TAC = tacrolimus

  2. Superscripts: H  =  high blood level (8–12 μg/L); L = low blood level (3–7 μg/L).

  3. No overall differences between arms in cause of kidney loss (p = 0.3 via chi-square test).

  4. No overall differences between arms in actuarial graft loss due to CR/CAN (p = 0.1 via log-rank test). However, direct comparison reveals difference approaching statistical significance between Arms 1 and 3 (1p = 0.07 via log-rank test).

  5. CR/CAN and recurrent disease were confirmed through biopsy.

  [n (% of arm)] 
Total [139 (31.6% of all kidneys)]48 (31.8)48 (32.2)43 (30.7)
Cause of kidney loss [n (% of all losses)][n (% of losses in arm)]
Death with functioning graft [67 (48.2)]20 (41.7)23 (47.9)24 (55.8)
CR/CAN [35 (25.2)]17 (35.4)110 (20.8)8 (18.6)1
Recurrent disease [6 (4.3)]1 (2.1)2 (4.2)3 (7.0)
Recipient noncompliance [5 (3.6)]2 (4.2)3 (6.3)0 (0)
Calcineurin inhibitor toxicity [4 (2.9)]0 (0)3 (6.3)1 (2.3)

There were no differences between study arms in actuarial PS (p = 0.7), GS (p = 0.96) and DCGS (p = 0.5). The 10-year PS was 73.0% with CSA/MMF, 72.9% with TACH/SIRL and 67.0% with TACL/SIRH. The 10-year GS was 63.5% with CSA/MMF, 59.9% with TACH/SIRL and 59.0% with TACL/SIRH. The 10-year DCGS was 77.5% with CSA/MMF, 80.4% with TACH/SIRL and 82.1% with TACL/SIRH (Table 3, Figure 2). The overall calculated graft half-lives (for recipients with DCGS >1 year) were 24.7 years with CSA/MMF, 27.5 years with TACH/SIRL and 38.7 years with TACL/SIRH (p = 0.5). For recipients of living donor kidneys, the graft half-lives were 23.9 years for CSA/MMF, 27.1 years with TACH/SIRL and 43.4 years with TACL/SIRH (p = 0.5). For recipients of deceased donor kidneys, the graft half-lives were 26.9 years with CSA/MMF, 28.8 years with TACH/SIRL and 30.4 years with TACL/SIRH (p = 0.98).

Table 3. Overall patient, graft and death-censored graft survival
 Study arm
 Arm 1Arm 2Arm 3
 (CSA/MMF)(TACH/SIRL)(TACL/SIRH)
  1. CSA = cyclosporine; MMF = mycophenolate mofetil; SIR = sirolimus; TAC = tacrolimus.

  2. Superscripts: H = high blood level (8–12 μg/L); L = low blood level (3–7 μg/L).

Outcome (% of total)(% of arm)
Patient survival
1-year (97.3)97.398.096.4
5-year (89.2)91.190.286.1
10-year (71.1)73.072.967.0
Graft survival
1-year (94.5)94.096.093.6
5-year (78.9)77.679.679.7
10-year (60.8)63.559.959.0
Death-censored graft survival
1-year (97.0)96.698.096.4
5-year (86.3)84.286.588.5
10-year (79.9)77.580.482.1

There were no differences between study arms in 10-year actuarial AR (p = 0.2) and CR (p = 0.4) rates. The 1-year overall AR rate was 18.5% with CSA/MMF, 10.1% with TACH/SIRL and 10.7% with TACL/SIRH. When comparing individual study arms, there was a difference in the 1-year AR rate between CSA/MMF and TACH/SIRL (p = 0.03), and a near difference when comparing CSA/MMF and TACL/SIRH (p = 0.054). The 1-year CR rate was 11.3% with CSA/MMF, 4.0% with TACH/SIRL and 4.3% with TACL/SIRH. When comparing individual study arms, there was a difference in the 1-year CR rates between CSA/MMF and TACH/SIRL (p = 0.01), and between CSA/MMF and TACL/SIRH (p = 0.02). Also, renal function was found to be stable over time and similar when comparing study arms throughout the 10-year follow-up period (Table 4, Figure 3).

Table 4. Allograft rejection and renal function
 Study arm
 Arm 1Arm 2Arm 3
 (CSA/MMF)(TACH/SIRL)(TACL/SIRH)
  1. CSA = cyclosporine; MMF = mycophenolate mofetil; SE = standard error; SIR = sirolimus; TAC = tacrolimus.

  2. Superscripts: H = high blood level (8–12 μg/L); L = low blood level (3–7 μg/L).

  3. Multiple comparisons via log-rank test: *p < 0.05.

  4. Direct comparisons via log-rank test: 1p = 0.03; 2p = 0.05; 3p = 0.01; 4p = 0.02.

Outcome [n (% of total)][n (% of arm)]
Rejection
Acute rejection   
1-year [58 (13.2)]28 (18.5)1215 (10.1)115 (10.7)2
5-year [90 (20.5)]36 (25.0)30 (21.6)24 (18.0)
10-year [98 (22.3)]40 (29.6)33 (26.2)25 (19.6)
Chronic rejection   
1-year [29 (6.6]*17 (11.3)346 (4.0)36 (4.3)4
5-year [99 (22.5)]37 (26.8)38 (28.0)24 (19.2)
10-year [122 (27.7)]44 (38.2)45 (35.3)33 (30.7)
Renal function[mean (±SE), in units of mg/dL or mL/min]
Serum creatinine   
1-year1.6 (±0.06)1.5 (±0.04)1.5 (±0.04)
5-year1.8 (±0.16)1.7 (±0.10)1.5 (±0.07)
10-year1.5 (±0.08)1.5 (±0.15)1.7 (±0.15)
Creatinine clearance   
1-year62.9 (±2.7)64.1 (±2.3)64.6 (±2.4)
5-year65.8 (±3.2)63.1 (±2.8)66.6 (±3.0)
10-year61.1 (±6.0)59.7 (±5.2)65.2 (±6.3)

For all recipients, 89.8% remained prednisone-free at 1 year, 90.4% at 5 years and 79.4% at 10 years post-KT (actuarial rates). The 5- and 10-year prednisone use did not differ significantly between study arms. The 1-, 3- and 5-year median (IQR) CSA levels were 112.0 (95.0–145), 89.0 (72.0–112) and 90.5 (68.5–117.0) with CSA/MMF. The 1-, 3- and 5-year median (IQR) TAC levels were 7.1 (5.4–8.8), 6.15 (4.9–7.9) and 6.1 (5.2–7.5) with TACH/SIRL, and 6.0 (4.4–7.4), 6.0 (4.6–7.4) and 5.4 (4.2–6.9) with TACL/SIRH. There were significant differences between study arms in TAC levels at 1 year (p = 0.0008) and 5 years (p = 0.048) but not at 3 years (p = 0.4). The 1-, 3- and 5-year median (IQR) SIR levels were 5.2 (4.1–6.7), 5.5 (3.6–7.8) and 6.9 (4.9–8.8) with TACH/SIRL, and 7.2 (5.5–9.2), 7.2 (5.5–8.7) and 6.3 (5.1–8.4) with TACL/SIRH. There were significant differences between study arms in SIR levels at 1 year (p = 0.0003) and 3 years (p = 0.002) but not at 5 years (p = 0.97). Of all recipients, 53.9% underwent a drug switch from their original maintenance immunosuppressive regimen sometime during the 10-year follow-up, including 42.4% with CSA/MMF, 63.1% with TACH/SIRL and 56.4% with TACL/SIRH. Most switches were due to drug side effects. For each study arm, weight and lipid profiles remained stable over time. In addition, there were no differences between arms in mean total cholesterol and triglyceride levels (data not shown). Rates of lipid-lowering medication use were different between study arms only at 6 months (p = 0.04), and at 1 (p = 0.001) and 3 years (p = 0.007) but not different at other time points post-KT. However, rates of lipid-lowering medication use were higher in recipients taking SIR, which may indicate an increased need for lipid control in these recipients. Rates of antihypertensive medication use were not different between study arms at any of the post-KT time points (Table 5).

Table 5. Summary for use of selected medications
 Study arm
 Arm 1 (CSA/MMF)Arm 2 (TACH/SIRL)Arm 3 (TACL/SIRH)
  1. CSA = cyclosporine; MMF = mycophenolate mofetil; SIR = sirolimus; TAC = tacrolimus.

  2. Superscripts: H = high blood level (8–12 μg/L); L = low blood level (3–7 μg/L).

  3. Multiple comparisons via chi-square test: *p < 0.05; **p < 0.01.

Type of medication [n (% of total)][n (% of arm)]
Corticosteroids   
Last kidney f/u [73/425 (17.2)]28/146 (19.2)21/145 (14.5)24/134 (17.9)
1-year rates [41/401 (10.2)]**22/137 (16.1)5/139 (3.6)14/125 (11.2)
5-year rates [32/332 (9.6)]16/112 (14.3)8/114 (7.0)8/106 (7.6)
10-year rates [7/34 (20.6)]3/14 (21.4)1/8 (12.5)3/12 (25.0)
Lipid-lowering   
Pretransplant [173/287 (60.3)]53/95 (55.8)62/106 (58.5)58/86 (67.4)
6-month rates [171/326 (52.5)]*46/110 (41.8)64/113 (56.6)61/103 (59.2)
1-year rates [190/328 (57.9)]**43/100 (43.0)76/120 (63.3)71/108 (65.7)
3-year rates [197/313 (62.9)]**54/105 (51.4)74/108 (68.5)69/100 (69.0)
5-year rates [102/167 (61.1)]31/55 (56.4)37/56 (66.1)34/56 (60.7)
Antihypertensive   
Pretransplant [357/386 (92.5)]116/129 (89.9)122/130 (93.8)119/127 (93.7)
6-month rates [358/418 (85.7)]123/143 (86.0)123/144 (85.4)112/131 (85.5)
1-year rates [345/411 (83.9)]122/140 (87.1)116/141 (82.3)107/130 (82.3)
3-year rates [296/351 (84.3)]107/118 (90.7)100/123 (81.3)89/110 (80.9)
5-year rates [152/184 (82.8)]53/60 (88.3)54/64 (84.4)45/60 (75.0)

Immunosuppression-related complications occurred in each study arm, but complications traditionally associated with prednisone therapy (avascular necrosis, cataracts, fractures) were rare. Only two of our studied complications, NODM (p = 0.04) and anemia (p = 0.04), exhibited differences in their incidence rates between study arms. The 10-year rates of NODM were 6.3% with CSA/MMF, 19.3% with TACH/SIRL and 5.5% with TACL/SIRH. When comparing individual study arms, there were differences in the overall rates of NODM between CSA/MMF and TACH/SIRL (p = 0.03), and between TACH/SIRL and TACL/SIRH (p = 0.03). The 10-year rates of anemia were 55.2% with CSA/MMF, 70.1% with TACH/SIRL and 67.2% with TACL/SIRH. When comparing individual study arms, there were differences in the overall rates of anemia between CSA/MMF and TACL/SIRH (p = 0.02), and a near difference when comparing CSA/MMF and TACH/SIRL (p = 0.055) (Figure 4). Other notable but not significant differences between individual study arms included rates of neutropenia, PTLD and skin cancer at 10 years post-KT (Table 6).

Table 6. Selected complications
 Study arm
 Arm 1 (CSA/MMF)Arm 2 (TACH/SIRL)Arm 3 (TACL/SIRH)
  1. CSA = cyclosporine; MMF = mycophenolate mofetil; SIR = sirolimus; TAC = tacrolimus.

  2. Superscripts: H = high blood level (8–12 μg/L); L = low blood level (3–7 μg/L).

  3. Multiple comparisons via log-rank test: *p < 0.05.

  4. Direct comparisons via log-rank test: 1p = 0.06; 2p = 0.02; 3p = 0.03; 4p = 0.03; 5p = 0.08; 6p = 0.04; 7p = 0.04; 8p = 0.04; 9p = 0.07.

 (% of arm)
Posttransplant year151015101510
Complication         
 Anemia*44.253.255.2 1,253.063.070.1 159.263.867.2 2
 BK Polyomavirus disease0.72.32.30.72.33.402.53.5
 Calcineurin inhibitor toxicity2.73.53.51.43.73.75.26.16.1
 Cerebrovascular accident0.73.27.61.42.913.23.73.712.9
 Deep vein thrombosis000000000
 Cytomegalovirus disease8.418.219.16.911.416.24.510.113.4
 Fascial dehiscence2.02.02.02.02.05.24.44.44.4
 Kidney infarction/thrombosis0.70.70.71.31.31.30.70.70.7
 Lymphocele12.112.112.114.314.314.310.410.410.4
 Myocardial infarction4.07.19.01.35.210.05.26.18.1
 New onset diabetes mellitus*1.03.46.3 37.113.919.3 342.75.55.5 4
 Neutropenia23.330.330.3 516.520.421.3 517.123.723.7
 Oral ulceration000 61.41.43.3 6,7000 7
 Pneumonia5.520.034.110.321.231.98.923.141.8
 Posttransplant lymphoproliferative disorder000 801.61.61.52.33.7 8
 Pulmonary embolus00.90.90.70.72.21.51.51.5
 Recurrent disease1.43.15.902.55.02.23.85.7
 Skin cancer3.521.739.2 90.712.832.0 91.515.224.4
 Thrombocytopenia2.75.25.21.44.49.03.76.17.4
image

Figure 2. Actuarial patient (top row), graft (middle row) and death-censored graft (bottom row) survival outcomes for each of the study arms for 10 years of posttransplant follow-up. There were no overall differences between study arms for any of the survival metrics (patient survival, p = 0.7; graft survival, p = 1.0; death-censored graft survival, p = 0.5 [left column]). Similarly, there were no differences when stratifying recipients based on type of donor kidney (living [middle column] vs. deceased [right column]).

Download figure to PowerPoint

image

Figure 3. Creatinine clearance as stratified for each study arm, up to 10 years of posttransplant follow-up. Error bars represent the standard errors of the mean. There were no differences in creatinine clearance between study arms, except at 9 years posttransplant (**p = 0.003).

Download figure to PowerPoint

image

Figure 4. Actuarial rates of new-onset diabetes mellitus ([NODM] left) and anemia (right) as stratified for each study arm. There are differences between arms in the rates of NODM for 10 years of posttransplant follow-up (p = 0.04). When comparing individual study arms, the rates of NODM were different between Arms 1 and 2 (p = 0.03), and Arms 2 and 3 (p = 0.03), but not different between Arms 1 and 3 (p = 0.9). There are differences between arms in the rates of anemia for 10 years of posttransplant follow-up (p = 0.04). When comparing individual study arms, the rates of anemia were different between Arms 1 and 2 (p = 0.02), were approaching a near difference between Arms 1 and 3 (p = 0.06) and were not different between Arms 2 and 3 (p = 0.7).

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

We found no long-term differences in actuarial survival outcomes (PS, GS and DCGS) when comparing CSA/MMF, TACH/SIRL and TACL/SIRH maintenance protocols. We and others have shown that RDP is associated with similar PS and GS but fewer prednisone-related side effects than chronic corticosteroid maintenance therapy [42, 43]. Our current analysis also shows no differences between study arms in actuarial AR and CR rates, or long-term allograft function. Approximately 80% of all recipients remained prednisone-free at 10 years post-KT. There were differences between study arms in the overall rates of only two (of 18) complications that were studied (NODM and anemia); NODM was significantly more prevalent with TACH/SIRL, and anemia with TACH/SIRL and TACL/SIRH.

This trial has a longer median follow-up period (∼7 years) than comparable trials of RDP [34, 42-46]. Data with long-term follow-up are important when comparing maintenance protocols. A consideration in the design of this study was the suggestion that SIR may be a better long-term agent due to its established antiproliferative and antifibrotic properties [38, 39]. Our data do not show differences in survival outcomes. Furthermore, the impact of SIR on preventing long-term IF/TA may not be as strong as initially hypothesized; 10-year CR rates were 38% with CSA/MMF versus 35% with TACH/SIRL and 31% with TACL/SIRH. It may be that our sensitivity to detect the effect of SIR in minimizing intrarenal fibrosis was limited because we did not incorporate protocol biopsies. Kumar et al. recently published 5-year results from a prospective randomized trial comparing four different maintenance protocols following induction with basiliximab and RDP on day 2 (n = 200). The study incorporated surveillance biopsies at seven different time points from 1 to 60 months post-KT [34]. The four protocols involved CSA/MMF, CSA/SIR, TAC/MMF and TAC/SIR (n = 50 recipients per protocol), using doses and blood levels that were similar when compared with our study. Recipient demographics differed from our study; Kumar et al. had more African Americans (∼50% vs. ∼5% in our study) and deceased donor KTs (∼80% vs. ∼27% in our study). The authors reported that the 5-year incidence of CR (or IF/TA) was 54% with CSA/MMF, 16% with CSA/SIR, 38% with TAC/MMF and 14% with TAC/SIR. When comparing individual study arms, there were differences in the incidence of IF/TA between CSA/MMF and CSA/SIR (p = 0.04), and between CSA/MMF and TAC/SIR (p = 0.04), suggesting that the incorporation of SIR into the maintenance regimen may decrease renal allograft fibrosis. However, there were no differences between study arms in PS or GS, or in serum creatinine levels and creatinine clearances. Interestingly, they reported that the highest tolerance of original immunosuppressive therapy was with TAC/SIR (90%) and was higher than in the other study arms (82% with CSA/MMF, 84% with CSA/SIR and 82% with TAC/MMF). Gallon et al. reported 3-year results of a prospective randomized single-center pilot study comparing TAC/MMF (n = 45) and TAC/SIR (n = 37) following basiliximab induction and RDP on day 2 (44); they reported GS that was significantly lower with TAC/SIR (84%) than with TAC/MMF (98%) (p = 0.04).

It is unclear what accounts for the differences in outcomes between Gallon et al., Anil Kumar et al. and our study. Although demographics were different, none of the differences suggest that the study populations were distinct enough to explain the disparity in outcomes. Furthermore, their immunosuppressive protocols indicated the use of similar TAC and SIR blood levels as in our study. Of note, both studies in Gallon et al. and Kumar et al. had smaller numbers of recipients in each study arm and our follow-up has been longer.

We found that the rates of studied drug-related complications were generally low, regardless of protocol. However, there were differences between study arms. First, NODM was more prevalent in those receiving TACH/SIRL. This finding can be explained in part by the known diabetogenicity of TAC, which is believed to be more pronounced than CSA [47], and which would be accentuated with higher blood levels of TAC. Second, anemia was more prevalent in those receiving SIR. This may be explained in part by a known interaction between CSA and MMF, which has been shown to reduce the therapeutic mycophenolic acid blood levels [48-50], which would in turn reduce the risk of myelosuppression. Interestingly, incidence of skin cancer was progressively lower with increasing maintenance blood levels of SIR. This finding may highlight the emerging data on the antineoplastic properties of SIR, particularly as it relates to nonmelonoma skin cancer [51-53].

Our study had several limitations. First, we did not include a steroid maintenance group in this study. This was primarily because we had shown excellent outcomes, including a markedly improved side-effect profile, with RDP during our earliest pilot trial [22]. Second, as mentioned earlier, there were no protocol biopsies. Consequently, subclinical AR or chronic fibrotic changes that did not manifest clinically may not have been detected.

In summary, outcomes at 10 years post-KT remain acceptable following RDP with most recipients remaining steroid-free. Recipients in one of three different maintenance protocol arms (CSA/MMF, TACH/SIRL or TACL/SIRH) had similar long-term PS and GS, rejection rates and renal function. However, cause of graft loss and complications appeared to vary depending on the type of immunosuppression, but this needs to be studied further and will be as more recipients reach ≥10 years post-KT. These results help establish the long-term efficacy of several maintenance immunosuppressive protocols used following RDP with KT. Future studies are necessary to continue to monitor for differences in late graft loss and for changes in side-effect profiles attributable to the immunosuppressive regimen being used.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors would like to thank Stephanie Daily and Hang McLaughlin for their assistance in the preparation of this manuscript.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References