Overcoming Barriers to Long-Term Graft Survival

Overcoming Barriers to Long-Term Graft Survival Bruce Kaplan, MD ● Although short-term kidney graft survival has improved in recent years, the focus has shifted to the challenge of improving long-term graft survival. Acute rejection, chronic allograft nephropathy, and cardiovascular disease are associated with graft loss and patient death. Reducing the potential for such posttransplantation complications may improve long-term graft survival. In addition, gaining a better understanding of the role that various immunosuppressive therapies have in decreasing the risk for graft injury will help clinicians make better-informed decisions about appropriate treatment regimens for individual kidney transplant recipients. Am J Kidney Dis 47(S2):S52-S64. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Kidney transplant; acute rejection; chronic allograft nephropathy (CAN); renal function; graft survival; immunosuppression; tacrolimus (TAC); cyclosporine (CsA); mycophenolate mofetil (MMF); sirolimus (SRL).

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HE INCIDENCE OF acute rejection has decreased progressively during the last decade with the advent of more efficacious immunosuppressive therapies. One might expect that decreased episodes of acute rejection ultimately would lead to better graft survival. However, in the same period, there has been little improvement in long-term graft survival.1 Therefore, the current focus is on reducing late graft dysfunction while also minimizing immunosuppressive adverse events. Understanding and defining the process of longterm injury to the transplanted kidney is essential for improving graft and patient survival. It is hoped that this better understanding will lead to a positive impact on graft and patient survival over time. In addition, new immunosuppression regimens are being investigated. As transplant physicians and nephrologists progressively gain a better understanding of the many differences between current treatment protocols, it is hoped that posttrans-

From the Department of Medicine, University of Illinois College of Medicine, Chicago, IL. Received November 1, 2005; accepted in revised form December 9, 2005. This article was published as part of a supplement supported by an educational grant from Astellas Pharma US, Inc. Acknowledgment of research support: Dr Kaplan: Grants from Novartis Pharmaceuticals, Roche Pharmaceuticals, Astellas Pharma US, Inc. Consultant: Roche Pharmaceuticals, Bristol-Myers Squibb Company. Address reprint requests to Bruce Kaplan, MD, University of Illinois College of Medicine, Department of Medicine, 820 South Wood St, Room W-417 CSN, MC 793, Chicago, IL 60612-7315. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4704-0105$32.00/0 doi:10.1053/j.ajkd.2005.12.044 S52

plantation renal function and long-term graft survival will improve. TRENDS IN LONG-TERM GRAFT SURVIVAL

The frequency of late graft loss is approximately 7% per year in Canada and the United States.2 In a single-center study of 429 patients who underwent transplantation between 1990 and 2000, results indicated that the stability of renal function may be increasing, which is believed to correlate with an overall decrease in acute rejection episodes and treatment with new immunosuppressive agents.2 However, a more recent study1 found that renal function and graft survival have not improved despite advances in kidney transplantation. In a recent pooled analysis, rates of acute rejection and early graft failure improved considerably during the past 2 decades; however, the rate of late graft failure remained relatively constant.3 Likewise, analysis4 of actual (versus projected) half-lives for patients who underwent kidney transplantation between 1988 and 1995 showed no significant improvement in long-term graft survival (Table 1). The 2-year increase in overall half-lives during the 7-year time frame primarily was caused by improvements in retransplantation. However, improving long-term graft survival has been more difficult in recent years given that the age of donors and recipients has increased, waiting time to transplantation has increased, more transplantations are being performed on high-risk patients, and more extendedcriteria donor kidneys are being used. Therefore, the small improvement in graft half-lives still shows progress. Meier-Kriesche et al1 also analyzed data from more than 62,000 adult first-transplant recipients

American Journal of Kidney Diseases, Vol 47, No 4, Suppl 2 (April), 2006: pp S52-S64

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Table 1. Death-Censored Graft Survival by Year of Transplantation Transplantation Year

Half-Life Graft Survival (y)

1988 1989 1990 1991 1992 1993 1994 1995*

6.0 6.8 7.0 7.5 7.4 7.6 7.8 8.0

NOTE. Analysis by means of Kaplan-Meier method. *Kaplan-Meier half-life based on time to 51% survival. Data from Meier-Kriesche et al.4

and found that, from 1995 to 2000, acute rejection rates decreased from 35.7% to 14.6% in the 0- to 6-month posttransplantation period, from 21.4% to 6.0% in the 6- to 12-month posttransplantation period, and from 22.5% to 2.9% in the 12- to 24-month posttransplantation period. Overall, 6-year graft survival rates were similar for patients without acute rejection versus those who experienced acute rejection with near-complete recovery of baseline renal function (74.4% versus 72.7%, respectively). However, in patients who experienced acute rejection and less than complete recovery of baseline renal function, graft survival rates were associated with lower graft survival, and they declined in proportion to the degree of impairment in renal function (Table 2). Because the overall rate of graft loss remains unacceptably high, reducing the risk for late graft loss has become a current challenge in kidney transplantation. RISK FACTORS FOR KIDNEY GRAFT DYSFUNCTION AND LOSS

The duration of graft survival after transplantation is dependent on the quality of the donor kidney, as well as severity and frequency of various insults. Such insults can occur early after transplantation or they may occur either discretely at later times or reflect cumulative lowgrade injury, which may lead to a decline in renal function and, ultimately, graft failure. Histological and clinical associative factors related to graft failure include early acute rejection, late rejection, nonadherence, and chronic allograft nephropathy (CAN).5 The development of proteinuria after kidney transplantation also is

associated with increased renal failure.6 Patient survival also was lower in patients with proteinuria, and relative risk for death increased with increased severity.6 It was concluded that proteinuria is an independent predictor of both graft failure and patient death. Opelz et al7 analyzed data from 29,751 deceased-donor kidney transplantations and found a significant association between elevated systolic blood values posttransplantation and poorer kidney graft survival (P ⬍ 0.0001). Elevated diastolic blood pressure also was a significant predictor of subsequent graft failure. Elevated blood pressure was associated with poorer longterm outcomes even when rejection was not present. In addition, increased systolic blood pressure resulted in decreased graft survival regardless of diastolic blood pressure. Reports suggested a relationship between the length of time a patient is on dialysis therapy before transplantation and graft survival after transplantation. In a retrospective cohort study8 of 81,130 kidney transplant recipients from the US Renal Data System (USRDS) registry, patients who were on dialysis therapy for 181 days or longer had a significantly greater rate of graft failure after transplantation, whereas patients who had a shorter duration of dialysis therapy (⬍6 months) experienced no detrimental effect on graft or patient survival after transplantation. Delayed graft function also was associated with significantly lower 3-year graft survival rates compared with those who did not experience DGF (84% versus 68%, respectively; P ⬍ 0.001) according to the United Network for Organ Sharing Renal Transplant Registry, including 165,151 Table 2. Overall 6-Year Graft Survival Rates by Acute Rejection and Recovery of Baseline Renal Function

Acute Rejection During Posttransplantation Months 6-12

No acute rejection Acute rejection Acute rejection Acute rejection Acute rejection

Baseline Renal Function Recovered at 1 Year Posttransplantation (%)

6-Year Allograft Survival (%)

— 95-100 85-95 75-85 ⬍75

74.4 72.7 67.0 50.2 38.0

NOTE. Cockcroft-Gault formula was used to estimate GFR. Data from Meier-Kriesche et al.1

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kidney transplantations performed between 1987 and 2001.9 In addition, kidney transplant recipients of an extended-criteria donor organ had 3-year graft survival rates that were 14% to 15% lower compared with those who received normal donor kidneys. Impact of Acute Rejection on Long-Term Graft Function and Graft Survival Acute rejection is a major risk factor for the development of chronic graft failure.10 Although there are no definitive prospective studies that show a correlation between decreased acute rejection episodes and better long-term graft survival, acute rejection is deleterious to the graft. Therefore, taking measures to reduce the risk for acute rejection and aggressively treating all acute rejection episodes are important clinical objectives. The association between acute rejection and long-term graft survival was investigated in a single-center study at the University of Minnesota. Matas et al11 divided 653 kidney transplant recipients according to the number and timing of rejection episodes to determine whether these variables had an impact on graft half-life (the time it takes for one half of the graft’s functioning to fail at 1 year). The investigators found that patients who experienced more than 1 rejection episode within the first year after transplantation or 1 or more episodes after the first year were at high risk for late graft loss (Fig 1). Severity and timing of acute rejection episodes also were associated with progression to chronic rejection. Humar et al12 found that kidney transplant recipients who experienced mul-

Fig 1. The impact of acute rejection on half-life (t½). All patients had received primary kidney transplants and had at least 1 year of graft function. (Data from Matas et al.11)

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tiple acute rejection episodes had a greater risk for developing chronic rejection. Likewise, a single late acute rejection episode (occurring ⬎6 months after transplantation) also was associated with increased risk for chronic rejection. In addition, 5-year graft survival was significantly less for kidney transplant recipients who experienced more than 1 episode of acute rejection versus patients who experienced only 1 acute rejection episode (52.5% versus 85.1%, respectively; P ⫽ 0.0001).13 CAN, a major cause of graft loss, was significantly more common in patients who experienced more than 1 acute rejection episode versus those who experienced only 1 episode (34.8% versus 8.9%, respectively; P ⫽ 0.001).13 In another study, relative risk for graft failure was 3.06 when acute rejection occurred early (within the first 3 months posttransplantation) and 5.27 when acute rejection occurred later.14 A study by Wissing et al15 identified posttransplantation hypercholesterolemia as an independent risk factor for graft loss. The researchers applied an actuarial method to retrospectively analyze the long-term loss of a deceased-donor kidney graft in patients who had a functioning graft at 1 year. Patients who had experienced acute rejection and had elevated cholesterol levels (ⱖ250 mg/dL [ⱖ6.47 mmol/L]) were significantly more likely to lose their grafts at 10 years posttransplantation than recipients who had cholesterol levels less than 250 mg/dL (50% versus 25.3%, respectively; P ⬍ 0.01). As listed in Table 3, in a study conducted by Foster et al,16 5-year graft survival rates were lower for African-American recipients of livingdonor or deceased-donor kidneys (82.9% and 68.9%, respectively) compared with graft survival rates for non–African-American kidney transplant recipients (89.1% and 73.7%, respectively). In addition, the incidence of acute rejection as a cause of graft loss was greater for African-American recipients of living-donor kidneys than for non–African-American recipients of living-donor kidneys (20.4% versus 4.8%, respectively; P not reported). Furthermore, for recipients of deceased-donor kidneys, the incidence of acute rejection as a cause of graft loss was similar for both ethnic groups (4.7% for African-American recipients versus 4.0% for non–African-American recipients; P not reported).

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Table 3. Acute Rejection as a Cause of Graft Loss and 5-Year Graft Survival in African-American and Non–African-American Kidney Transplant Recipients Living-Donor Transplant

Outcomes

African American

Non–African American

Acute rejection (%) 5-Year graft survival (%)

20.4 82.9

4.8 89.1

Deceased-Donor Transplant

P

African American

Non–African American

P

Not reported 0.032

4.7 68.9

4.0 73.7

Not reported 0.008

Data from Foster et al.16

Living-related grafts usually progress from acute to chronic rejection at a slower rate than a deceased-donor kidney.17 However, a deceaseddonor graft that is free of acute rejection at 3 months after transplantation has the same likelihood of graft functioning at 5 years as a livingrelated graft. Strategies for Preventing and Treating Acute Rejection The goals of immunosuppression therapy are to decrease rejection episodes and increase patient and graft survival. Therefore, immunosuppressive agents that have the greatest likelihood of preventing acute rejection should be considered. Compared with azathioprine (AZA), mycophenolate mofetil (MMF) has been shown to decrease the risk for acute rejection. Ojo et al18 evaluated 66,774 kidney transplant recipients from the US Renal Transplant Scientific Registry. The incidence of acute rejection in the first 6 months posttransplantation was 24.7% for patients treated with AZA-based therapy versus 15.5% for patients treated with MMF-based therapy (P ⬍ 0.001).18 Although MMF has been shown to decrease the occurrence of acute rejec-

tion, there have been mixed results regarding the long-term benefits.19 As listed in Table 4, acute rejection rates ranged from 4% to 17% with tacrolimus (TAC)based regimens and from 14% to 20% with current cyclosporine (CsA)-based regimens.20-22 In a 2-year follow-up study,23 the percentage of patients requiring antilymphocyte antibody treatment for rejection was 5.6% with TAC/ MMF treatment, 13.2% with TAC/AZA, and 12% with CsA/MMF. Similar results were found for the subset of African-American kidney transplant recipients. These findings may provide clinically relevant information for the design of immunosuppressive regimens for certain patient populations. Posttransplantation hypertension was associated with acute rejection in kidney transplant recipients. In a study of 1,641 adult kidney transplant recipients, Cosio et al24 found that elevated systolic blood pressure was associated with an increasing incidence of acute rejection. For each 20-mm Hg increase in systolic blood pressure, there was a 4-fold increase in risk for an acute rejection episode.24 Therefore, preventing hypertension or aggressively treating elevated blood pressure may

Table 4. Acute Rejection Rates and Common Immunosuppression Protocols Publication Year

200020

Study Duration

1y

200521

6 mo

200422

1y

Protocol

No. of Patients

Acute Rejection (%)

TAC/AZA TAC/MMF CsA/MMF TAC/SRL TAC/MMF TAC/MMF TAC/SRL CsA/SRL

76 72 75 185 176 50 50 50

17.1 15.3 20 13.0 11.4 4.0 4.0 14.0

NOTE. All studies were randomized open-label trials; all protocols included corticosteroids.

P

Not reported

0.64 0.03

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help decrease the risk for acute rejection. Likewise, the development of posttransplantation diabetes mellitus was associated with decreased graft survival.25 Adherence to a medication regimen also is essential for maintaining graft function and decreasing the risk for acute rejection. Failure to maintain adherence also can result in return to dialysis therapy, decreased quality of life, increased health care costs, and increased morbidity and mortality. Chisolm et al26 developed the immunosuppressant therapy barrier scale to assess transplant recipient barriers to adherence. The immunosuppressant therapy barrier scale is a 13-item scale with 2 subscales that measure “uncontrollable barriers” and “controllable barriers.” Their study showed a correlation between patient-reported barriers to adherence and rejection. Identifying barriers can help clinicians design intervention strategies that may enhance adherence and potentially improve patient outcomes. CAN and Graft Failure CAN is another leading cause of graft loss after the first posttransplantation year.27 Formerly called chronic rejection, CAN is a nonspecific diagnosis applied when graft function deteriorates progressively over time. It is a composite term that refers to various types of damage to the transplanted kidney. More recently, because of changes to Banff classifications for kidney graft biopsies, CAN is being referred to more specifically as chronic/sclerosing allograft nephropathy. Clinically, CAN is associated with progressive renal dysfunction and frequently is associated

with late rejection, proteinuria, early tubular injury, chronic interstitial fibrosis, and chronic intimal thickening.5 The pathogenesis of CAN includes both immunologic and nonimmunologic factors, as identified by Pascual et al27 (Fig 2). Various factors that may have a role include poorly controlled hypertension, dyslipidemia, and long-term effects of immunosuppressive drugs. Conversely, inadequate immunosuppression resulting from insufficient doses of calcineurin inhibitors (CNIs) can trigger immunologic mechanisms that increase the risk for CAN. CAN occurs in 2 distinct phases, as shown by Nankivell et al28 in a longitudinal histological study of kidney graft biopsy specimens. In the first year posttransplantation, CAN was characterized by early tubulointerstitial damage caused by ischemic injury, prior severe rejection, and subclinical rejection. Importantly, the prevalence of subclinical rejection was less for patients treated with TAC and/or MMF compared with CsA therapy. After the first year posttransplantation, CAN was characterized by additional tubulointerstitial damage, increasing glomerulosclerosis, and progressive high-grade arteriolar hyalinosis with luminal narrowing. These changes were attributed to CNI-related nephrotoxicity. Because histological diagnosis of CAN may be difficult in routine clinical practice, evaluation of renal function has been used as a surrogate marker. During the pre-CsA era of 1978 to 1982, Kasiske et al29 calculated monthly estimates of glomerular filtration rates (GFRs) for 200 kidney transplant recipients who survived at

Immunologic Factors Poor HLA matching and previous sensitization

Nonimmunologic Factors

Delayed graft function

Older donor age or poor graft quality

Episodes of acute rejection Subacute and chronic alloimmune response

Chronic Allograft Nephropathy

Brain death injury, preservation injury, or ischemic injury

Acute perioperative injuries or delayed graft function Hypertension Hyperlipidemia

Suboptimal immunosuppression

Nonadherence

Toxic effects of chronic CNI therapy

Fig 2. Pathogenesis of CAN. (Copyright © 2002 Massachusetts Medical Society. All rights reserved. Adapted with permission from Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB: N Engl J Med 346:580-590, 2002.27)

LONG-TERM GRAFT SURVIVAL

least 12 months with a functional graft. Creatinine clearance and serum creatinine (SCr) levels were used to calculate estimated GFRs of these patients. Of the patients studied, 12.5% had an irreversible decline in renal function caused by acute rejection, 25% had a gradual and chronic decline in renal function, and 62.5% had stable renal function. Decline in renal function typically occurred early in the posttransplantation period; however, for 26% of patients, it occurred after 2 years posttransplantation. In addition, the decline in kidney function was rapid in some cases, slowly progressive in others, and erratic in still others, which indicates that chronic decreases in renal function can have an unpredictable onset and are associated with a variable clinical course. Given the difficulty of identifying CAN and the variability of its clinical course, prevention is the best interventional strategy. Selection of immunosuppressive therapy that may reduce the risk for CAN may help improve graft survival. Strategies for Preventing and Treating CAN Treatment approaches to prevent or treat CAN include blood pressure control and modification of CNI-based immunosuppression regimens. However, interventions involving modification of CNI-based regimens should be undertaken with care so that adequate immunosuppression can be maintained. Treatment with TAC versus CsA may be beneficial for kidney transplant recipients at risk for chronic allograft failure. Waid30 studied the substitution of TAC for CsA in posttransplantation immunosuppression therapy of such patients. After receiving CsA therapy for at least 3 months posttransplantation, patients with either elevated SCr levels (ⱖ2.0 mg/dL [ⱖ177 ␮mol/L] for males or ⱖ1.7 mg/dL [ⱖ150 ␮mol/L] for females) or a greater than 30% increase in posttransplantation SCr nadir were randomly assigned to continue treatment with CsA therapy or convert to TAC therapy. At 24 months posttransplantation, patients who were converted to TAC therapy had significantly lower SCr levels and a significant decrease from baseline SCr levels (Fig 3). In addition, significantly fewer patients who were treated with TAC had SCr levels greater than 2.0 mg/dL (⬎177 ␮mol/L) at 24 months posttransplantation (56.8% versus 87.5%, respectively;

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P ⫽ 0.002). The incidence of acute rejection was not significantly different between the 2 groups. The efficacy of TAC versus CsA was evaluated in a paired-kidney analysis that involved 3,070 pairs of deceased-donor kidneys transplanted from 1995 to 2002.31 One of each kidney pair was allocated to a transplant recipient treated with TAC, and the other was allocated to a transplant recipient treated with CsA. SCr levels of patients treated with TAC were significantly lower throughout the study, indicating that TAC therapy had a less detrimental effect on SCr levels than CsA therapy (Fig 4). However, it must be emphasized that this study showed no difference in graft or patient survival between TAC-treated versus CsA-treated patients. Additionally, blood pressure control may slow the progression of CAN, much as it slows the progression of chronic kidney disease. Pharmacological intervention with angiotensin-converting enzyme inhibitors and/or angiotensin-receptor blockers may have additional benefits. Although observational studies suggested the potential benefit of statin therapy for kidney transplant recipients, prospective studies have not confirmed these findings. For example, Holdaas et al32 conducted a multicenter, randomized, placebo-controlled, double-blind trial of 2,102 kidney transplant recipients with high cholesterol levels (156 to 351 mg/dL [4.03 to 9.08 mmol/L]). Patients were randomly assigned to treatment with fluvastatin or placebo and were followed up for 5 to 6 years. At a mean of 5.1 years, mean low-density lipoprotein cholesterol level decreased by 32% with

Fig 3. Renal function after conversion from CsA to TAC therapy in patients at risk for chronic renal allograft failure. To convert SCr in mg/dL to ␮mol/L, multiply by 88.4. (Data from Waid.30)

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1.85

1.82

1.78

SCr Levels, mg/dL

1.80 1.73

1.75 1.70

1.79

1.67

1.69 1.65 1.63

1.65 1.60 1.55

1.64

1.57

1.54

1.55 1.50

TAC (n=3070) CsA (n=3070)

1.45 1.40 6 Months

1 Year

2 Years

3 Years

4 Years

5 Years

Time Posttransplant

Fig 4. SCr levels after kidney transplantation: TAC versus CsA. To convert SCr in mg/dL to ␮mol/L, multiply by 88.4. (Data from Kaplan et al.31)

fluvastatin and total cholesterol level decreased significantly with fluvastatin compared with placebo. However, the number of cardiac events in patients treated with fluvastatin versus placebo was not significantly different, although a subsequent post hoc analysis of this study showed a statistically significant decrease in cardiovascular events in a number of subgroups.33 SCr LEVEL AS A PREDICTIVE MEASUREMENT

Because long-term survival rates are similar among the various maintenance immunosuppression regimens, surrogate markers of immunosuppression medication efficacy are required. Until new surrogate markers for late graft failure are defined, kidney function remains the best means of predicting outcomes.3 Kaplan et al34 retrospectively analyzed USRDS data for adult first-transplant recipients. Using 1-year posttransplantation SCr level as the baseline value, the investigators found that a 1-mg/dL (0.03-mmol/L) increase in SCr level was associated with increased risk for graft loss in subsequent years (Table 5). However, analysis of areas under the curve indicated that a 1-mg increase in SCr level correctly predicted graft outcome in approximately 62% of cases, which is only slightly better than the 50% of cases that would have been classified correctly on the basis of chance alone. Therefore, it was concluded that although renal function is a strong risk factor for and correlates highly with graft failure, the utility of renal function as a predictive tool for graft loss was limited. SCr levels also vary by patient age, sex, race, and body weight.35 Although increases in SCr

levels may correlate with long-term graft failure, they do not have adequate predictive value.35 Measuring change in GFR is another way of monitoring decreases in kidney function.36 Annualized change in GFR is the preferred method by which to monitor the progression of kidney function decline in patients with chronic kidney disease, including transplant recipients.36 IMMUNOSUPPRESSIVE STRATEGIES FOR IMPROVING LONG-TERM RENAL FUNCTION AND GRAFT SURVIVAL

Short-term and long-term strategies are needed to prevent late kidney graft dysfunction, as well as graft loss and/or patient death. As discussed, pharmacological prevention and intervention may decrease the frequency of acute rejection and improve renal function among kidney transplant recipients. Preventing cardiovascular complications and their progression to CAN also was discussed as a strategy for preventing late graft loss. Other strategies that are being pursued in an effort to improve long-term outcomes include the addition of induction therapy, corticosteroid avoidance, and, possibly, CNI minimization. Induction Therapy There has been renewed interest in adding induction therapy to immunosuppression regimens as a means of decreasing acute rejection after kidney transplantation. A study by Ciancio et al37 evaluated the effect of daclizumab (DAC) induction therapy when added to a TAC/MMF/ corticosteroid immunosuppressive protocol. This regimen was compared retrospectively with a control group of 225 kidney transplant recipients administered muromonab-CD3 induction therapy and a similar TAC/MMF/corticosteroid maintenance regimen. At 12 months, patient and graft survival were similar between the 2 groups. The incidence of Table 5. Increase in SCr Level* and Risk for Kidney Graft Loss

Follow-Up (y)

Odds Ratio (95% Confidence Interval)

Area Under the Curve

2 7

2.22 (2.13-2.31) 2.40 (2.31-2.50)

0.627 0.624

*1 mg/dL increase relative to 1-year posttransplant baseline level. Data from Kaplan et al.34

LONG-TERM GRAFT SURVIVAL

acute rejection was significantly less in the DAC group versus the muromonab-CD3 group, especially during the first 6 months posttransplantation (2.1% versus 7.1%, respectively; P ⫽ 0.011). In addition, significantly fewer patients in the DAC treatment group required hospitalization as a result of infectious complications versus the muromonab-CD3 control group (7.3% versus 16%, respectively; P ⬍ 0.0036). Therefore, the addition of DAC induction therapy to TAC/ MMF therapy may be more effective in preventing graft rejection than regimens that include muromonab-CD3. Studies also showed that induction therapies may facilitate rapid (or early) elimination of corticosteroid therapy (ie, within 7 days posttransplantation). An open-label multicenter study38 of 538 kidney transplant recipients compared a regimen of DAC/TAC/MMF with TAC/MMF/corticosteroid. At 6 months, the incidence of acute rejection was 16.5% in both groups and renal function was similar. However, compared with the TAC/MMF/corticosteroid regimen, the incidence of new-onset diabetes mellitus (NODM) was significantly less in patients treated with corticosteroid-free immunosuppression that consisted of DAC/TAC/MMF (5.4% versus 0.4%, respectively; P ⫽ 0.003). The first prospective multicenter study of early (day-4) corticosteroid withdrawal with induction therapy included 77 low-risk kidney transplant recipients.39 Basiliximab was used as induction therapy, and maintenance immunosuppression included TAC and sirolimus (SRL). At 1 year of follow-up, results indicated that early corticosteroid therapy withdrawal with basiliximab/TAC/ SRL provided excellent graft and patient survival, good renal function, decreased hyperlipidemia, and low acute rejection rates. Woodle et al40 also conducted the first randomized double-blind trial designed to compare early corticosteroid withdrawal (ie, by day 7) with continued corticosteroid therapy with antibody induction therapy (either an interleukin 2 receptor antagonist or thymoglobulin) for all patients. Patients were randomly assigned to either discontinue corticosteroid therapy on posttransplantation day 7 or remain on continued corticosteroid therapy. All patients received immunosuppressive maintenance therapy with TAC and MMF. At the 1-year follow-up of this 5-year study,

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combined overall patient mortality and graft loss was 4.1%, acute rejection rate was 15.3%, and biopsy-proven acute rejection rate was 10.4%. Overall, patient and graft survival remained excellent, and acute rejection rates and NODM rates were low. However, the study design did not allow for comparisons between treatment groups at 1 year of follow-up. Corticosteroid Withdrawal Because long-term corticosteroid therapy is associated with serious adverse events, corticosteroid-sparing and corticosteroid-withdrawal protocols have been investigated. Early corticosteroid withdrawal has the potential to safely minimize adverse events, such as NODM, as concluded in a prospective study by Boots et al.41 In that study, 62 kidney transplant recipients treated with TAC were randomly assigned to discontinue corticosteroid therapy 7 days after transplantation or gradually be weaned off corticosteroid therapy during 3 to 6 months after transplantation. After a median of 2.7 years, overall patient survival rate was 97%, and graft survival rate was 90%. These survival rates were similar between the 2 groups. The incidence of acute rejection was less for patients who stopped prednisolone therapy at 7 days posttransplantation versus patients who were weaned off prednisolone therapy (29% versus 33%, respectively; P ⫽ 0.30). Creatinine clearance and proteinuria were not statistically significantly different at 3, 6, 9, and 12 months. However, the incidence of NODM was significantly less for patients who discontinued prednisolone therapy versus those who were weaned off prednisolone (8% versus 30%, respectively; P ⫽ 0.04). Therefore, it would seem that withdrawing corticosteroid therapy early after transplantation is safe for the majority of kidney transplant recipients. Wlodarczyk et al42 investigated whether early corticosteroid therapy withdrawal had an effect on SCr level. Results showed that patients who continued treatment with TAC/MMF/corticosteroid or TAC/AZA/corticosteroid had greater median SCr concentrations than corticosteroid-free patients at 6 months. Thus, there was no evidence of a decrease in renal function for patients who had corticosteroid therapy withdrawn early in the posttransplantation period.

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P=0.04 P=0.04

1.8

1.57

1.6

Median SCr, mg/dL

1.4

1.3

1.35

TAC/MMF (n=56) TAC/AZA (n=60) CsA/MMF (n=54)

1.2 1.0 0.8 0.6 0.4 0.2 0

Fig 5. Renal function 2 years after kidney transplantation. Kruskal-Wallis test. To convert SCr in mg/dL to ␮mol/L, multiply by 88.4. (Data from Ahsan et al.23)

P=0.02 P=0.02

60

51.9 Patients With SCr >1.5 mg/dL, %

CNI Therapy and Minimization Strategies The development of new immunosuppressive agents during the last decade has precipitated the need for clinical trials to investigate the efficacy and safety of various combinations of agents. The design of maintenance immunosuppressive protocols should be based on short-term outcomes, as well as long-term survival and safety.10,12 Long-term immunosuppressive therapy has been known to affect renal function and graft survival. Although nephrotoxicity sometimes is considered a drug-related class effect of CNIs, there is some evidence that TAC may have a slight advantage over CsA in terms of renal function.2,23,43 A 2-year follow-up study by Ahsan et al23 investigated the efficacy and safety of 3 immunosuppression regimens: TAC/MMF, CsA/MMF, and TAC/AZA. A total of 223 kidney transplant recipients were randomly assigned to treatment with 1 of the 3 regimens plus corticosteroids. Results at 2 years were similar to those at 1 year. Overall patient and graft survival were similar among the 3 treatment groups. Median SCr level was significantly better for TAC-treated patients (Fig 5), and there were significantly fewer patients with an SCr level greater than 1.5 mg/dL in both TAC-treated arms versus the CsA treatment arm (Fig 6). Gourishankar et al2 examined changes in creatinine clearance across 3 immunosuppressant eras: CsA/AZA (1990 to 1993), CsA/MMF (1994 to 1997), and TAC/MMF (1998 to 2000). Creatinine clearance rates after kidney transplantation decreased significantly during the CsA/AZA (⫺0.34 mL/min/mo; P ⬍ 0.001) and CsA/MMF

50

TAC/MMF (n=56) TAC/AZA (n=60) CsA/MMF (n=54)

38.3

40 28.6 30 20 10 0

Fig 6. Patients with an SCr greater than 1.5 mg/dL at 2 years. Pearson chi-square test. To convert SCr in mg/dL to ␮mol/L, multiply by 88.4. (Data from Ahsan et al.23)

eras (⫺0.20 mL/min/mo; P ⬍ 0.001), but increased during the TAC/MMF era (⫹0.29 mL/ min/mo; P ⫽ 0.009). More recently, to decrease the incidence of graft nephropathy, some researchers suggested that SRL replace CNIs in posttransplantation immunosuppression therapy. In 1 study, Kahan44 reported on the treatment of kidney transplant recipients with CsA and prednisone in combination with either AZA (2 to 3 mg/kg/d) or SRL (2 or 5 mg/d). The incidence of biopsy-confirmed acute rejection was not significantly different in the AZA and 2-mg SRL groups, but it was significantly less for the 5-mg SRL group (17.5% versus 32.3% in the AZA group; P ⬍ 0.001). However, compared with the AZA group, the 2and 5-mg SRL groups had significantly elevated mean SCr levels at 6, 12, and 24 months posttransplantation (Fig 7). In a study by Gonwa et al,45 246 kidney transplant recipients were randomly assigned to treatment with either full-dose CsA plus fixeddose SRL (2 mg/d; n ⫽ 97) or reduced-dose CsA plus concentration-controlled SRL (troughs, 10 to 20 ng/mL; n ⫽ 100). In the latter group, CsA dosage was tapered during the subsequent 4 to 6 weeks until eliminated. At 1 year, renal function was significantly better in the CsA-elimination group. SCr levels at 12 months were significantly less in the CsA-elimination versus CsA-based treatment arm (1.38 mg/dL [122 ␮mol/L] versus 1.82 mg/dL [161 ␮mol/L], respectively; P ⬍ 0.001), and GFRs (Nankivell method) were significantly greater (73.5 mL/min/1.73 m2/y [1.23 mL/s] versus 57.2 mL/min/1.73 m2/y [0.95 mL/s]; P ⬍

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S61 AZA SRL 2 mg/d SRL 5 mg/d

Mean SCr, mg/dL

2.0

1.5

1.0

0.5

P<0.01 SRL 2 mg vs AZA; P<0.001 SRL 5 mg vs AZA

P<.001 SRL 2 mg and SRL 5 mg vs AZA

P<0.05 SRL 2 mg; P<.001 SRL 5 mg vs AZA

0 6

12

24

Time Posttransplant, mo

Fig 7. Mean SCr levels in patients treated with CsA in combination with SRL or AZA. All patients also were treated with CsA and prednisone as baseline immunosuppression therapy. To convert SCr in mg/dL to ␮mol/L, multiply by 88.4. (Data from Kahan.44)

0.001). Biopsy-confirmed acute rejection was not significantly different between the 2 treatment groups. However, in an observational study by Kaplan et al46 of 17 kidney transplant recipients who developed deterioration of renal function while being treated with SRL plus a CNI, 15 patients responded well to withdrawal of SRL therapy and the addition of MMF. Mean SCr level improved significantly, from 2.75 mg/dL (243 ␮mol/L) before SRL therapy withdrawal to 2.24 mg/dL (198 ␮mol/L) after SRL therapy withdrawal (P ⫽ 0.0002). Johnson et al47 evaluated whether CsA could be eliminated from an SRL/CsA/corticosteroid immunosuppression regimen. At 3 months posttransplantation, kidney transplant recipients were randomly assigned to continue the original SRL/ CsA/corticosteroid regimen or discontinue treatment with CsA. At 1 year posttransplantation, the CsA-withdrawal group had a significantly lower SCr level (1.61 mg/dL [142 ␮mol/L] versus 1.79 mg/dL [158 ␮mol/L], respectively; P ⬍ 0.001), but also had an acute rejection rate that was more than twice that observed for the CsAcontinuation group (9.8% versus 4.2%, respectively; P ⫽ 0.035; Fig 8). This is clinically relevant because more than 50% of kidneys do not return to baseline function after an acute rejection episode.1 The difference in 4-year acute rejection rates was not statistically significant between the CsAwithdrawal versus the CsA-continuation group (10.2% versus 6.5%, respectively; P ⫽ 0.223).48

The study showed some evidence of excellent long-term outcomes among certain patients after careful withdrawal of a CNI. Although these results are promising, additional studies are needed to clarify the long-range implications of posttransplantation immunosuppression treatment regimens that do not include CNIs. In the interim, these protocols should be implemented with extreme caution.49 Similarly, in a study of kidney transplant recipients initially treated with CsA, MMF, and prednisone, patients who continued on the triple-drug regimen and patients who had prednisone therapy withdrawn had significantly lower 2-year acute rejection rates than those who had CsA therapy withdrawn (Fig 9).50 It was speculated that SRL has less ability to exacerbate CNI-related nephrotoxicity when administered in combination with TAC instead of CsA. In a randomized 3-arm study with 1-year follow-up, Ciancio et al51 compared CsA/SRL (n ⫽ 50), TAC/SRL (n ⫽ 50), and TAC/MMF (n ⫽ 50). When mean SCr levels of the 2 SRL treatment groups were averaged and compared with mean SCr levels of the TAC/MMF treatment group, SCr level was significantly less in the TAC/MMF group (1.20 mg/dL [106 ␮mol/L] versus 1.45 mg/dL [128 ␮mol/L], respectively; P ⫽ 0.02). These results might suggest that the combination of TAC/MMF is less nephrotoxic than CsA/SRL or TAC/SRL. To compare the efficacy of SRL versus MMF in combination with TAC-based immunosuppression, Mendez et al21 conducted a multicenter study that included 361 kidney trans12

P=0.035

P=NS 10.2

9.8

CsA Continuation CsA Withdrawal

10 Acute Rejection, %

2.5

8 6.5 6 4.2 4 2 0 4 Years

1 Year Time Posttransplant, Years

Fig 8. Effect of CsA therapy withdrawal on acute rejection rate. Both immunosuppression treatment regimens included SRL and corticosteroids. Abbreviation: NS, not significant. (Data from Johnson et al47 and Oberbauer et al.48)

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Fig 9. Acute rejection after CsA or steroid withdrawal. All patients were treated with a triple-drug immunosuppression regimen of MMF, CsA, and prednisone before either CsA or prednisone therapy was withdrawn. (Data from Smak Gregoor et al.50)

plant recipients who were randomly assigned to treatment with either TAC/SRL (n ⫽ 185) or TAC/MMF (n ⫽ 176). At 1 year, there were no significant differences in incidences of biopsyconfirmed acute rejection, patient survival, or graft survival. However, renal function was significantly better in the TAC/MMF arm versus the TAC/SRL arm (median SCr, 1.3 mg/dL [115 ␮mol/L] versus 1.5 mg/dL [133 ␮mol/L], respectively; P ⫽ 0.03). Likewise, 45.4% of patients in the TAC/SRL arm had an SCr level greater than 1.5 mg/dL (⬎133 ␮mol/L) versus 35.7% of patients in the TAC/MMF arm. There were significantly fewer patients with an SCr level greater than 2.0 mg/dL (⬎177 ␮mol/L) in the TAC/ MMF group (11%) versus the TAC/SRL group (20.4%; P ⫽ 0.02). Therefore, the effect of SRL on renal function should be a consideration when choosing an immunosuppressive regimen. CONCLUSION

During the last decade, acute rejection rates have improved dramatically for kidney transplant recipients. However, 5-year graft survival rates have not improved at the same rate, which underscores the need for more effective strategies that will reduce the risk for late graft loss. Reducing the risk for acute rejection, cardiovascular disease, and CAN after transplantation potentially may increase long-term graft survival. Strategies for preventing these complications are essential to decreasing the severity and frequency of injury to the kidney graft. Furthermore, better understanding of the progression of graft injury and a clear definition of

the pathogenesis of impaired renal function and graft failure are needed to help solve the problem of graft loss. In addition, as transplant physicians and nephrologists progressively gain a better understanding of the many differences among current immunosuppressive treatment protocols, it is anticipated that renal function and long-term graft survival should continue to improve because clinicians will be able to make betterinformed treatment decisions for individual kidney transplant recipients. REFERENCES 1. Meier-Kriesche H-U, Schold JD, Srinivas TR, Kaplan B: Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 4:378-383, 2004 2. Gourishankar S, Hunsicker LG, Jhangri GS, Cockfield SM, Halloran PF: The stability of the glomerular filtration rate after renal transplantation is improving. J Am Soc Nephrol 14:2387-2394, 2003 3. Kasiske BL, Gaston RS, Gourishankar S, et al: Longterm deterioration of kidney allograft function. Am J Transplant 5:1405-1414, 2005 4. Meier-Kriesche H-U, Schold JD, Kaplan B: Long-term renal allograft survival: Have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 4:1289-1295, 2004 5. Nankivell BJ, Fenton-Lee CA, Kuypers DRJ, et al: Effect of histological damage on long-term kidney transplant outcome. Transplantation 71:515-523, 2001 6. Fernandez-Fresnedo G, Plaza JJ, Sanchez-Plumed J, Sanz-Guajardo A, Palomar-Fontanet R, Arias M: Proteinuria: A new marker of long-term graft and patient survival in kidney transplantation. Nephrol Dial Transplant 19:Siii47Siii51, 2004 (suppl 3) 7. Opelz G, Wujciak T, Ritz E, for the Collaborative Transplant Study: Association of chronic kidney graft failure with recipient blood pressure. Kidney Int 53:217-222, 1998

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8. Goldfarb-Rumyantzev A, Hurdle JF, Scandling J, et al: Duration of end-stage renal disease and kidney transplant outcome. Nephrol Dial Transplant 20:167-175, 2005 9. Cecka JM: The UNOS Renal Transplant Registry, in Cecka JM, Terasaki PI (eds): Clinical Transplants 2002. Los Angeles, CA, UCLA Immunogenetics Center, 2002, pp 1-20 10. Meier-Kriesche H-U, Ojo AO, Hanson JA, et al: Increased impact of acute rejection on chronic allograft failure in recent era. Transplantation 70:1098-1100, 2000 11. Matas AJ, Gillingham KJ, Payne WD, Najarian JS: The impact of an acute rejection episode on long-term renal allograft survival (t1/2). Transplantation 57:857-859, 1994 12. Humar A, Kerr S, Gillingham KJ, Matas AJ: Features of acute rejection that increase risk for chronic rejection. Transplantation 68:1200-1203, 1999 13. Humar A, Payne WD, Sutherland DE, Matas AJ: Clinical determinants of multiple acute rejection episodes in kidney transplant recipients. Transplantation 69:2357-2360, 2000 14. Joseph JT, Kingsmore DB, Junor BJR: The impact of late acute rejection after cadaveric kidney transplantation. Clin Transplant 15:221-227, 2001 15. Wissing KM, Abramowicz D, Broeders N, Vereerstraeten P: Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection. Transplantation 70: 464-472, 2000 16. Foster CE III, Philosophe B, Schweitzer EJ, et al: A decade of experience with renal transplantation in AfricanAmericans. Ann Surg 236:794-805, 2002 17. Knight RJ, Burrows L, Bodian C: The influence of acute rejection on long-term cadaveric donor transplantation. Transplantation 72:69-76, 2001 18. Ojo AO, Meier-Kriesche H-U, Hanson JA, et al: Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 69:24052409, 2000 19. European Mycophenolate Mofetil Cooperative Study Group: Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 345:1321-1325, 1995 20. Johnson C, Ahsan N, Gonwa T, et al: Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 69:834-841, 2000 21. Mendez R, Gonwa T, Yang HC, Weinstein S, Jensik S, Steinberg S, for the Prograf Study Group: A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: Results at 1 year. Transplantation 80:303-309, 2005 22. Ciancio G, Burke GW, Gaynor JJ, et al: A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (Neoral) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year. Transplantation 77:244-251, 2004 23. Ahsan N, Johnson C, Gonwa T, et al: Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus my-

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39. Woodle ES, Vincenti F, Lorber MI, et al: A multicenter pilot study of early (4-day) steroid cessation in renal transplant recipients under simulect, tacrolimus, and sirolimus. Am J Transplant 5:157-166, 2005 40. Woodle ES, for the Fujisawa Corticosteroid Withdrawal Study Group: A prospective, randomized, multicenter, double-blind study of early corticosteroid cessation versus long-term maintenance of corticosteroid therapy with tacrolimus and mycophenolate mofetil in primary renal transplant recipients: One year report. Transplant Proc 37: 804-808, 2005 41. Boots JMM, Christiaans MHL, van Duijnhoven EM: Early steroid withdrawal in renal transplantation with tacrolimus dual therapy: A pilot study. Transplantation 74:17031709, 2002 42. Wlodarczyk Z, Walaszewski J, Perner F, et al: Freedom from rejection and stable kidney function are excellent criteria for steroid withdrawal in tacrolimus-treated kidney transplant recipients. Ann Transplant 7:28-31, 2002 43. Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J: A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: Evidence for improved allograft survival at five years. Transplantation 73:775-782, 2002 44. Kahan BD: Two-year results of multicenter phase III trials on the effect of the addition of sirolimus to cyclosporinebased immunosuppressive regimens in renal transplantation. Transplant Proc 35:S37-S51, 2003 (suppl 3A) 45. Gonwa TA, Hricik DE, Brinker K, Grinyo JM, Schena FP, for the Sirolimus Renal Function Study Group: Improved renal function in sirolimus-treated renal transplant

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patients after early cyclosporine elimination. Transplantation 74:1560-1567, 2002 46. Kaplan B, Schold J, Srinivas T, et al: Effect of sirolimus withdrawal in patients with deteriorating renal function. Am J Transplant 4:1709-1712, 2004 47. Johnson RWG, Kreis H, Oberbauer R, Brattström C, Claesson K, Eris J: Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 72:777-786, 2001 48. Oberbauer R, Segoloni G, Campistol JM, et al, for the Rapamune Maintenance Regimen Study Group: Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int 18:22-28, 2005 49. Lo A: Strategies to prevent chronic allograft nephropathy in kidney transplantation: Focus on calcineurin inhibitors. Prog Transplant 14:157-164, 2004 50. Smak Gregoor PJ, de Sevaux RG, Ligtenberg G, et al: Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: A randomized, prospective, multicenter study. J Am Soc Nephrol 13:1365-1373, 2002 51. Ciancio G, Burke GW, Gaynor JJ, et al: A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (Neoral) and sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation 77:252-258, 2004