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Keywords:

  • African American recipients;
  • early steroid withdrawal;
  • kidney transplantation

Abstract

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

Generally chronic steroid therapy is standard care for African American (AA) kidney recipients because of their higher incidence of rejections and lower long-term graft survival. This prospective study evaluated the long-term safety and efficacy of early steroid withdrawal (ESW) in AA recipients. A total of 206 recipients were studied; 103 AA and 103 non-AA recipients monitored by serial surveillance biopsies from 1 to 60 months posttransplantation to evaluate subclinical acute rejections (SCAR) and chronic allograft injury (CAI). Biopsy-proven clinical acute rejections (BPAR) and SCAR were treated. Primary end point was BPAR and secondary end points were 5-year SCAR, CAI and survival. Incidences of BPAR was 16% versus 14% (p = 1.0), prevalence of CAI due to hypertension was 48% versus 30% (p = 0.05) and interstitial fibrosis/tubular atrophy was 47% versus 32% (p = 0.05) and the mean serum creatinine levels were 2.1 versus 1.8 mg/dL (p = 0.05) at 5-years in AA versus non-AA recipients. The incidence of SCAR was 23% versus 11% at 1 month (p = 0.04), 12% versus 3% at 3 years (p = 0.04) and 10% versus 1% at 5 years (p = 0.04) in AA and non-AA recipients, respectively. Five-year patient survivals were 81% and 88% (p = 0.09) and graft survivals were 71% and 73%(p = 0.19) in AA and non-AA groups, respectively. After early steroid withdrawal AA kidney recipients have significantly lower renal function and higher SCAR and CAI but 5-year graft survival are comparable to non-AA recipients.


Introduction

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

Since the inception of kidney transplantation, chronic steroid therapy has been an integral part of maintenance immunosuppression (1,2). Despite chronic steroid therapy and higher doses of immunosuppression AA kidney recipients suffer from increased rejection and lower long-term graft survival compared to non-AA group (3,4). Even with modern immunosuppression that includes a calcineurin inhibitor and mycophenolate mofetil, long-term graft survival of African Americans kidney recipients has not improved (5). Therefore, it is generally believed that removing chronic steroid therapy will further increase acute rejections and decrease survival in AA recipients, and chronic steroid therapy continues to be employed despite the high susceptibility to steroid side effects.

On the other hand, the incidence and cost of diabetes and other steroid-induced side effects remain high in kidney transplant recipients (6,7). Plus, the removal of chronic steroids in low or normal risk non-AA recipients has shown no adverse effect on outcomes (8). Short-term steroid withdrawal does appear safe and beneficial for AA recipients. (9–12). There is one previous long-term study that compares steroid avoidance in AA recipients to a historical cohort of AA recipients with chronic steroid therapy (13). A prospective trial of long-term safety efficacy of early steroid withdrawal (ESW) in AA recipients is yet to be reported. Therefore, we thought it reasonable, using a carefully monitored protocol, to evaluate long-term safety and efficacy of ESW after kidney transplantation in AA kidney recipients. We prospectively measured clinical acute rejection, renal function and long-term patient/graft survivals of AA recipients and compared these data to non-AA recipients monitored the same way during the same time period. The aim of this study was to test the long-term outcome of ESW in high-risk AA recipients compared to low to medium risk non-AA recipients. The primary end point was BPAR and secondary end points were 5-year patient and graft survival, SCAR, CAI and adverse events.

Patients and Methods

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

This prospective study of ESW after kidney transplantation was approved by the institutional review board (IRB) of Drexel University and Hahnemann University Hospital. All patients in the study signed approved consent forms, and the IRB protocol was initiated in June 2000. Previously we have reported a series of 77 patients enrolled in IRB approved ESW protocol (14). After completing and reporting IRB approved randomization protocol ESW after kidney transplantation became standard of care in our institution in December 2002. This report includes a total of 206 patients with 77 patients enrolled in randomized IRB protocol between June 2000 and December 2002 and 129 patients enrolled per standard of care treatment between January 2003 and March 2004. A total of 206 consecutive consenting adult kidney recipients were analyzed in this study; 103 recipients were AA and 103 were non-AA. A portion of the same cohort of patients was also included in a controlled trial-evaluating outcome of ESW in general and not ethnicity (15). The primary end point of this study was biopsy-proven clinical acute rejection (BPAR). Secondary end points were 5-year patient and graft survivals, renal function, complications and surveillance biopsy findings: sub clinical acute rejection (SCAR) and chronic allograft injury (CAI). In the present report we have eliminated chronic allograft nephropathy and updated the biopsy report to CAI according to Banff 2005 classification (16,17). We concluded in our previous 1-year report that longer-term outcomes have to be evaluated in AA recipients with ESW after kidney transplantation (10). Here we report longer-term outcome of the same exact cohort of patients that were reported earlier for 1-year outcomes (10).

Selection criteria

All eligible AA or non-AA adult recipients aged 20 years or older of living or deceased donor kidneys, able to sign an informed consent, HIV negative and with a current panel reactive antibody of less than 10% transplanted between June 2000 and March 2004 were included in this study. The study was to include 100 recipients with functioning kidney for at least 1 month posttransplant. Our consultant statistician recommended 100 patients in each group to power this study to answer the differences in primary and secondary end points between AA and non-AA recipients in this study. During patient enrollment, three patients in each group developed primary nonfunction secondary to preservation injury and technical problems and thus the enrollment was extended to 103 patients to attain 100 recipients in each group without primary nonfunction. The three primary nonfunction kidneys in each of the groups are included in the final survival analysis.

Immunosuppression protocol

Immunosuppression was induced with basiliximab and methylprednisolone. All patients received i.v. infusion of basiliximab 20 mg on days 0 and 4 plus methylprednisolone 250 mg on the day of transplantation, followed by 125 mg on day 1. After the second dose of methylprednisolone, steroid therapy was completely discontinued (9).

Immunosuppression was maintained using a calcineurin inhibitor (CNI) cyclosporine or tacrolimus plus either mycophenolate mofetil (MMF) or sirolimus (SRL). Tacrolimus was initiated on day 1 at 0.02 mg/kg orally twice daily, and the dosage was adjusted to maintain trough levels of 15–18 ng/mL. Cyclosporine was initiated on day 1 at 2 mg/kg orally twice daily with the dosage adjusted to maintain C2 levels (blood level 2 h postadministration) of 1000–1200 ng/mL. The doses of CNIs were gradually reduced over the next months to maintain levels of 600–700 ng/mL for cyclosporine and 6–9 ng/mL for tacrolimus at 1 year. In the long term C2 levels were maintained between 500 and 700 ng/mL and these levels were lowered in the presence of nephrotoxicity diagnosed by either indicated or surveillance biopsies. MMF was initiated on day 1 and continued at 2 g/day in divided doses. SRL was initiated on day 4 at 2 mg/day and the dose adjusted to maintain trough blood levels of 5–10 ng/mL. Maintenance steroid therapy was avoided in all patients (10,15).

Infection prophylaxis

All recipients were given Pneumocystis carinii prophylaxis with trimethoprim-sulfamethoxazole for at least 100 days. Recipients susceptible to cytomegalovirus (CMV) infection also received valganciclovir as prophylaxis for 100 days.

Percutaneous biopsy of transplant kidney

The biopsies were performed at 1, 6, 12, 24, 36, 48 and 60 months after transplantation in each patient in transplant outpatient office using 18-gauge needle of Easy Core Biopsy Systems™. Usually one core of biopsy was obtained but in many cases two cores were obtained for detailed examination of renal tissue with hematoxylin and eosin, Masson trichrome, periodic Schiff, Jones metanamine silver and C4D stains. After biopsy patients were kept under observation and absolute bed rest for 4 h and were discharged home on the same day.

Surveillance biopsy: subclinical acute rejection and chronic allograft injury

Surveillance biopsies were performed at 1, 6, 12, 24, 36 and 60 months to determine subclinical acute rejection (SCAR) and CAI. For this study SCAR of Banff grades 1A or higher were reported. Borderline or suspicious SCAR was not considered valid for the purposes of this study. In our previous 1-year report we evaluated renal biopsy tissue according to Banff criteria 97 and reported it as chronic allograft nephropathy. In this report the biopsy was reevaluated according to 2005 Banff protocols and chronic changes are reported as CAI (16,17).

Defining BPAR and SCAR

We are reporting BPAR and SCAR separately according to previously established practice (18–21). Few centers perform surveillance or protocol biopsies at predetermined time intervals and report SCAR. Clinical acute rejection or acute graft dysfunction was diagnosed with a persistent elevation of serum creatinine by 15% or more from the baseline. Biopsy was indicated and performed in all recipients with acute graft dysfunction. BPAR was defined as both a clinical and pathological event. In other words, BPAR required both graft dysfunction and confirmatory biopsy. We are reporting all borderline or higher BPAR in this study. SCAR was defined as pathological findings of acute rejection in surveillance biopsy without graft dysfunction. Only grade 1A or higher SCAR is considered valid according to our established protocol in this study. Both BPAR and SCAR were graded per Banff schema (16,17). We are reporting BPAR and SCAR separately to avoid confusion and according to previous reports by other investigators (18–22).

Treatment of BPAR and SCAR

All borderline or higher BPAR and grade 1A or higher SCAR were treated. Both BPAR and SCAR were treated by pulse doses of i.v. methylprednisolone 500 mg for 4 days plus concomitant increase of CNIs so that trough blood levels of tacrolimus increased by 3 to 5 ng/mL and C2 levels of cyclosporine increased by 25–50 ng/mL over prerejection baselines. These new levels were maintained for 3 months (10,15). The diagnosis of steroid-resistant BPAR was made only by repeat biopsy in which case it was treated with anti-thymocyte globulin (Thymoglobulin®, Genzyme Corporation, Cambridge, MA). In no cases was Thymoglobulin used as treatment for SCAR. All recipients including those with BPAR and SCAR have remained without chronic steroid therapy.

Posttransplantation renal function

Kidney function was monitored by serial serum creatinine measurements with creatinine clearance estimated using the Cockroft–Gault method.

Surveillance of proteinuria

All recipients were monitored for proteinuria at every surveillance biopsy point and every time there was clinical indication for biopsy. Random urine samples were collected prior to biopsy and protein/creatinine ratio was measured. Urine creatinine was determined by Jaffe reaction and urine protein was measured by pyrogallol red method (23,24). The definition of proteinuria for this study is protein excretion of >300 mg/day (25).

Adverse events

In this study, we defined four types of adverse events: (i) new onset diabetes mellitus (NODM), (ii) severe infections, (iii) increase in body mass index (BMI) and (iv) complications of percutaneous biopsy of transplant kidneys. NODM was defined according to the American Diabetes Association by ‘de novo elevation of fasting blood sugar of >125 mg/dL and/or requirement for oral hypoglycemic agents or insulin after transplantation’ (26). Severe infections were defined as those that required hospitalization. BMI was measured at the time of transplantation and then annually for 5 years.

Early steroid withdrawal

ESW was defined for this study as discontinuation of steroid therapy 2 days posttransplant without any subsequent maintenance steroid therapy (10,15).

Statistical analysis

Statistical tests were performed using SPSS® (Statistical Package for the Social Services, SPSS, Inc., Chicago, IL, version 6.14) software. Pearson chi-square test and Fisher's exact test were used to compare continuous variables, categorical demographic variables or outcome differences between patient groups. A difference of 5% or more was considered statistically significant.

Survival analysis utilized Kaplan–Meier methodology. The Poisson regression model and paired t-test were used to analyze patient and graft loss between the groups. Graft loss was defined by patient death, transplant nephrectomy or return to maintenance dialysis. Patient death was not censored in analyzing graft survival.

Results

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

All recipients have completed 3 years after transplantation with a range of 3.5–7.2 years (1277–2628 days). The mean posttransplant period was 4.6 ± 1.0 years (1692 ± 388 days) and median was 4.4 years (1609 days). Three recipients each in AA and non-AA groups lost the grafts within 1 month due to primary nonfunction of transplant kidneys and these are included in survival analysis. AA recipients had significantly lower living donor transplants compared to non-AA recipients (Table 1). The duration of pretransplant dialysis was 865 ± 66 days in AA group and 629 ± 84 days in non-AA group (p = 0.03). All recipients, including those with BPAR and SCAR, have remained free of chronic steroid therapy. Table 1 shows the donor and recipient demography and characteristics of AA and non-AA groups.

Table 1.  Demographics and clinical characteristics of recipients and donors
Donor and recipient characteristicsAfrican American recipientsNon-African American recipientsp-Value
  1. *Only for deceased donor kidneys.

  2. **No immunosuppression for three recipients in each group with primary nonfunction.

  3. Mycophenolate mofetil.

Recipient demographics
 Number of recipients103 103 1.0
Ethnicity
 African American93 0 0.01
 Caribbean10 0 0.05
 Caucasian 092 0.01
 Hispanic 0 7 0.06
 Asian 0 40.2
Male gender67710.9
Age in years (mean ± SD)52.9 ± 12.053.0 ± 15.60.9
Recipient body mass index (mean ± SD)28.9 ± 7.1 27.3 ± 6.0  
HLA antigen mismatch (mean ± SD)4.6 ± 1.44.4 ± 3.40.7
Pretransplant diabetes mellitus3021 0.09
Recipients with chronic hypertension88851.0
Hepatitis C virus positive14 90.8
Donor characteristics
 Deceased donors9383 0.05
 Donor age (mean ± SD)42.0 ± 16.542.3 ± 19.21.0
 Donor body mass index (mean ± SD)26.2 ± 6.228.7 ± 15.8 0.06
 Donor male gender5170 0.05
 Donor age >56 years26230.9
 Donors with chronic hypertension10121.0
Recipient characteristics
 Duration of pretransplant dialysis (days)865 ± 66629 ± 84  0.03
 Cold ischemia time in hours* (mean ± SD)15.5 ± 6.815.9 ± 12.10.8
Maintenance therapy**
 Tacrolimus/MMF32260.6
 Tacrolimus/sirolimus28240.8
 Cyclosporine/MMF25251.0
 Cyclosporine/sirolimus15250.4

Biopsy-proven acute rejection

We performed diagnostic biopsies for clinical indications in 25 AA versus 28 non-AA recipients in the first year. Subsequently we performed biopsies in 12 versus12 recipients at 2 years, 9 versus 4 recipients at 3 years, 6 versus 6 recipients at 4 years and 5 versus 4 recipients at 5 years in AA versus non-AA recipients, respectively. Table 2 shows the number of recipients completing indicated biopsies at 1 month, 1, 2, 3, 4 and 5 years and the pathology of the renal tissue. In the first year clinical BPAR was diagnosed in 16% of AA recipients and in 14% of non-AA recipients (p = 0.9). In the subsequent years the incidence of BPAR was small and is shown in Figure 1. All rejections were treated by pulse doses of methylprednisolone. In the first year Banff grade 1A or 1B rejections were most common in both groups; 11/16 (68%) in the AA group and 11/14 (78%) in the non-AA group. Steroid resistant rejections occurred in 50% of AA recipients and in 29% of non-AA recipients (p = 0.08). All resistant rejections were treated by Thymoglobulin infusion.

Table 2.  Number of recipients with clinical indication for biopsies and the pathology of renal tissue in AA and non-AA recipients
Posttransplant period1 month1 year*2 years3 years4 years5 years
AANon-AAAANon-AAAANon-AAAANon-AAAANon-AAAANon-AA
  1. *One-year number includes 1-month number.

Number of recipients with clinical indication for biopsies2528121294665445
Pathology in the biopsy
 1. BPAR clinical acute rejection (%)1096522212121
40%32%50%42%22%50%33%16%40%25%50%20%
 2. Acute pyelonephritis (%)001021232211
0%0%8%0%22%25%33%50%40%50%25%20%
 3. Acute tubular necrosis (%)12141220000001
48%50%8%16%22% 0% 0% 0% 0% 0% 0%20%
 4. Acute calcineurin toxicity (%)354531221112
12%18%34%42%34%25%34%34%20%25%25%40%
image

Figure 1. BPAR from 1 to 5 years in AA and non-AA recipients.

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Patient and graft survival

Patient and graft survival in both groups were actual at 3 years and actuarial at 5 years. Patient survivals at 1, 3 and 5 years were: 94%, 88% and 81% in AA and 96%, 90% and 88% in non-AA recipients (p = 0.09). Sixteen patients died in AA group; cardiac in eight, infections in four, cerebro-vascular in three and gastro intestinal bleeding in one. Among non-AA recipients 10 patients died; cardiac in 5, malignancy in 2 and severe infection in 3. Most of the patient deaths in both groups occurred in diabetic patients; 11 of the 16 dead recipients (69%) in AA group and 6 (60%) of the 10 dead recipients in non-AA group had pretransplant diabetes. Additionally six (37%) of the dead recipients in AA group and three (30%) in non-AA group had pretransplant HCV infection.

Using the observation that 16 deaths occurred per 139 050 person-days follow-up in AA recipients and 10 deaths occurred per 133 900 person-days follow-up in non-AA recipients, the Poisson regression program returned an estimated relative risk of 1.6 and odds ratio of 1.7 around 95% confidence interval from −0.186 to 0.012.

Graft survivals at 1-, 3- and 5-years posttransplant were: 91%, 81% and 71% in AA and 92%, 82% and 73% in non-AA recipients (p = 0.19). At 5 years 29 grafts had been lost in the AA group: primary nonfunction in 3, patient deaths in 16, irreversible BPAR in 2 and severe CAI in 8 recipients. In the non-AA group 23 grafts were lost: primary nonfunction in 3, patient deaths in 10, irreversible BPAR in 2 and CAI in 8 recipients. Based on the fact that 29 graft were lost per 138 060 person-days follow-up in AA group versus 23 graft loss per 132 285 person-days in the non-AA group the Poisson regression returned an estimated relative risk of 1.26 and odds ratio of 1.40 around 95% confidence interval from −0.223 to 0.009. Patient death was analyzed as graft loss. Figure 2 shows the patient and graft survivals in both groups from 1 to 5 years after transplantation.

image

Figure 2. Five-year patient and graft survival in African American and non-African American kidney recipients with early steroid withdrawal.

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Renal function in recipients

Serum creatinine and estimated creatinine clearances were measured in both groups at 1, 3, 6 12, 24, 36 and 60 months. At 5 years the mean serum creatinine was 2.1 ± 0.8 and 1.8 ± 0.8 mg/dL and creatinine clearances were 57.1 ± 22.2 and 66.7 ± 25.1 in AA and non-AA groups, respectively (p = 0.05). Figure 3 shows the serum creatinine levels and creatinine clearances in both groups from 1 year to 5 years.

image

Figure 3. Kidney function: Serum creatinine and estimated creatinine clearance.

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Surveillance biopsy: Subclinical acute rejection and chronic allograft injury

Surveillance biopsies were completed in 93% of recipients. In 7% of recipients surveillance biopsies were not performed due to associated comorbid conditions such as anti-coagulation therapy, extreme obesity and patients' reluctance for biopsy.

The incidence of SCAR was 23% versus 11% at 1 month (p = 0.04), 10% versus 6% at 1 year (p = 1.0), 16% versus 6% at 2 years (p = 0.04), 12% versus 3% at 3 years (p = 0.04), 11% versus 2% at 4 years (p = 0.04) and 10% versus 1% at 5 years (p = 0.04) in AA and non-AA recipients, respectively. Figure 4 shows the incidence of SCAR from 1 month to 5 years in AA and non-AA recipients. The Table in Figure 4 shows the number of recipients with functioning grafts and number of recipients completing surveillance biopsies at each time point.

image

Figure 4. Surveillance biopsy: Number of recipients with functioning grafts completing surveillance biopsies from 1 month to 5 years posttransplant and incidence of treated subclinical acute rejections in African American and non-African American kidney recipients.

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Treated BPAR and SCAR

We treated all BPAR in indicated biopsies and Banff grade 1A or higher SCAR in surveillance biopsies. The combined total of treated BPAR and SCAR in AA versus non-AA recipients was 39% versus 25% at 1 year (p = 0.06), 18% versus 8% at 2 years (p = 0.04), 13% versus 5% at 3 years (p = 0.05), 13% versus 3% at 4 years (p = 0.05) and 12% versus 2% at 5 years (p = 0.03). The increased treated rejections in AA recipients were due to increased SCAR in surveillance biopsies.

Subgroup analysis of living donor transplants in AA versus non-AA recipients

Ten recipients in AA and 20 in non-AA group were living donor transplants (p = 0.05). The incidences of BPAR, SCAR and CAI were not statistically significant between this small group of living donor transplants in AA versus non-AA groups.

Chronic allograft injury

CAI increased from the time of transplantation to 5 years in both groups. Figures 5–7 show the immunological and nonimmunological CAI from 1 year to 5 years in AA and non-AA groups. Severity of interstitial fibrosis and tubular atrophy of uncertain etiology was graded per Banff schema 2005 and is shown in Table 3.

image

Figure 5. Chronic nonimmunological allograft injury in AA and non-AA recipients.

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image

Figure 6. Chronic immunological allograft injury in AA and non-AA recipients.

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image

Figure 7. Interstitial fibrosis and tubular atrophy; no specific etiology.

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Table 3.  Grading of interstitial fibrosis and tubular atrophy at 1, 2, 3, 4 and 5 years in AA and non-AA recipients
Years posttransplantAA recipientsnon-AA recipients
1234512345
Recipients with interstitial fibrosis and tubular atrophy
 Mild <25% of cortex region4910151459121315
 Moderate 26–50% of cortex region46 6182137 4 7 7
 Severe >50% cortex region25 5 81024 6 9 9

In addition to CAI, surveillance biopsy also showed recurrent disease in transplant kidney and HCV-related kidney disease in HCV positive patients. Table 4 shows the incidence of these findings in AA and non-AA recipients.

Table 4.  Other incidental pathological findings in surveillance biopsy
PathologyAA recipientsNon-AA recipients
Recurrent kidney disease33
HCV-related nephropathy31

Change in immunosuppression

Surveillance biopsy showed acute CNI toxicity in 8 AA recipients and 10 non-AA recipients despite blood levels within the therapeutic range and baseline renal function. The daily dose of CNI was reduced by 25% in all these patients. Chronic CNI toxicity was seen in both AA and non-AA recipients. At 1 year, Chronic CNI toxicity was observed in 4% in AA and 3% in non-AA and this gradually increased to 12% and 11% in AA and non-AA recipients at 5 years. Chronic CNI toxicity was treated by either dose reduction or complete withdrawal of CNI to prevent further progression of chronic toxicity. In five AA and six non-AA recipients the dose was reduced and the blood levels were maintained at 25% lower from the baseline. CNI was completely discontinued in six AA and six non-AA recipients. Recipients with complete withdrawal of CNI were maintained on SRL and enteric-coated mycophenolic acid sodium (myfortic®, Novartis pharmaceuticals Inc, East Hanover, NJ). All these patients remain free of chronic steroid therapy after dose reduction or withdrawal of CNI. All recipients with either dose reduction or complete withdrawal of CNI are included in survival analysis. Table 5 shows the initial Immunosuppression and final Immunosuppression in AA and non-AA recipients.

Table 5.  Initial and final immunosuppression in AA and non-AA recipients: Final immunosuppression was with and without a calcineurin inhibitor
Recipient groupInitial immunosuppression (N)Final immunosuppression (N) with calcineurin inhibitorFinal immunosuppression (N) without calcineurin inhibitor
  1. *Two recipients with initial cyclosporine/MMF were converted to Tacrolimus/sirolimus.

AA recipientsTacrolimus/MMF 32Tacrolimus/MMF 30Sirolimus/MPA-EC 2
Tacrolimus/sirolimus 28Tacrolimus/sirolimus 30*Sirolimus/MPA-EC 0
Cyclosporine/MMF 25Cyclosporine/MMF 20Sirolimus/MPA-EC 3
Cyclosporine/sirolimus 15Cyclosporine/sirolimus 14Sirolimus/MPA-EC 1
Non-AA recipientsTacrolimus/MMF 26Tacrolimus/MMF 25Sirolimus/MPA-EC 1
Tacrolimus/sirolimus 24Tacrolimus/sirolimus 22Sirolimus/MPA-EC 2
Cyclosporine/MMF 25Cyclosporine/MMF 23Sirolimus/MPA-EC 2
Cyclosporine/sirolimus 25Cyclosporine/sirolimus 24Sirolimus/MPA-EC 1

Incidence of proteinuria

Surveillance of proteinuria showed that 15 AA recipients and 13 non-AA recipients had proteinuria >300 mg/day. Nine recipients in AA group and eight in non-AA group had proteinuria greater than 1 g/day. Figure 8 shows the overall cumulative proteinuria and Table 6 shows the severity of proteinuria in 15 AA and 13 non-AA recipients.

image

Figure 8. Proteinuria in African American and non-African American kidney recipients at 5 years.

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Table 6.  Severity of protienuria in AA and non-AA recipients at 5 years posttransplant
Proteinuria per 24 h300–1000 mg1000–2000 mg2000–3500 mgNephrotic range protienuria (>3500 mg)
Number of AA recipients3435
Number of Non-AA recipients5332

Adverse events

The mean BMI increased by 2% in AA recipients and 1.8% in non-AA recipients (p = 0.09). Seventy-three recipients in the AA group and 82 recipients in the non-AA group without pretransplant diabetes mellitus were at risk for new onset diabetes mellitus. At 5 years six patients in the AA group (8.2%) and fie patients in the non-AA group (6.0%) developed new onset diabetes mellitus (p = NS). New onset diabetes mellitus was diagnosed within the first year in three AA and four non-AA recipients. The remaining three AA and one non-AA recipients developed diabetes in the second year after transplantation. Serious infections requiring hospitalization were seen in 14 patients in the AA group and 15 patients in the non-AA group. Serious infections in the AA group included septicemia or pulmonary infections in three, Candidae and pyelonephritis of the transplanted kidney in nine and clostridium difficale infections in two. In the non-AA group, serious infections included two patients with CMV, five pulmonary infections, four with severe urinary infections and four with clostridium difficale.

The other adverse events included complications of biopsy. In this study we performed 1365 biopsies for clinical indication and for surveillance. The complications of biopsies were mild and severe. Mild complications included transient hematuria in 21(1.5%) versus 25 (1.8%) and insufficient or no renal tissue requiring a repeat biopsy 10 (0.7%) versus 11 (0.9%) in AA and non-AA groups, respectively. Severe complications included massive hematuria requiring blood transfusion in two (0.2%) versus two (0.2%) and transient arterio-venous fistula within the kidney three (0.3%) versus two (0.2%) in AA and non-AA groups, respectively.

Discussion

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

This is a single center experience with sample size of 200 patients and the only prospective study reporting long-term outcome of ESW in AA kidney recipients. This report is preliminary and a larger multi-center trial is required to confirm the outcomes reported in this study before ESW is routinely recommended in AA recipients.

Despite advances in immunosuppression and the use of triple or quadruple therapy consisting of antibody induction, chronic steroid therapy, CNI and MMF, AA recipients continue to suffer increased rejection episodes, inferior renal function and lower graft survival compared to non-AA recipients (4,27–30). To prevent further erosion of long-term graft survival in AA kidney recipients, chronic steroid therapy and increased maintenance immunosuppression became standard of care for these patients. Some of the side effects of chronic steroid therapy such as diabetes mellitus may actually lower the survival and increase the health care costs of transplant recipients (6,7,31). Chronic steroid therapy has not improved long-term graft survival or deterioration of renal function in AA kidney recipients, and the differences in survival between AA and non-AA recipients is significant (27,29,30,32).

This prospective study of predominantly deceased donor kidney transplants compares long-term outcomes of ESW in AA recipients and non-AA recipients monitored by surveillance biopsy. AA recipients had significantly longer duration of pretransplant dialysis and lower living donor transplants compared to non-AA recipients. Both these factors are known to affect the outcome of kidney transplantation (32). Subclinical pathological events such as SCAR and CAI affect both short-term and long-term graft survival and function after kidney transplantation. Surveillance biopsy detects these changes and it is possible to improve the outcome by preemptive actions that include treatment of SCAR and alteration of immunosuppression. At present there is no long-term data on SCAR or CAI in AA recipients with or without chronic steroid therapy.

In our study, patient survival at 5 years was lower in AA recipients compared to non-AA recipients (p = 0.08). Most of the deaths in both AA and non-AA groups occurred in diabetic recipients. Patients with diabetes mellitus are known to have higher incidence of cardiac and cerebro-vascular diseases and lower patient survival after kidney transplantation (33,34). Increased death rates in AA recipients may be explained by higher incidence of pretransplant diabetes mellitus and longer person-days follow-up for AA recipients. The incidence of BPAR was comparable between AA and non-AA recipients. Serial surveillance biopsies showed a significantly higher proportion of AA recipients had Banff grade 1A or higher SCAR compared to non-AA recipients, and all Banff grade 1A or higher SCAR episodes were treated just like BPAR. Recent study in 2007 shows that subclinical infiltrates of all types may be significant (35). Our decision not to treat borderline or suspicious SCAR was based on the protocol written in 2000 and the study was completed before this new data on subclinical infiltration became available. Hence we did not treat borderline SCAR.

We are reporting BPAR and SCAR separately. SCAR is a hidden pathological event that is uncovered only by surveillance biopsy at predetermined intervals. SCAR is reported by few centers that perform surveillance or protocol biopsies and there are clinical differences between BPAR and SCAR. Most of the transplant centers do not report SCAR and we believe that combined reporting will cause confusion (22).

Immuno-histochemical and transcriptional studies show that SCAR and BPAR are essentially different stages of similar alloimmune responses (36,37). SCAR with stable graft function is milder and earlier alloimmune response, while BPAR with graft dysfunction likely represents more advanced and severe response. The differences between BPAR and SCAR may be explained by real quantitative and qualitative differences or increased ability of the allograft to withstand immune injury (36,37). The differences in severity of immune responses may explain improved long-term graft survival with treatment of SCAR compared to BPAR. Untreated SCAR in kidney recipients has a limited number of avenues: spontaneous regression without any adverse outcome, progression to BPAR with chronic graft dysfunction leading to early onset of CAI and graft loss. Nevertheless, our conclusions related to the outcome of treatment of SCAR in this study remain conjectural in the absence of follow-up biopsies. It seems likely, since we did not do any other intervention, that early detection and preemptive treatment aborted some of the SCAR progressing to BPAR and this may have mitigated early graft loss. A high incidence of BPAR is associated with decreased graft survival (38). In recipients with BPAR who fail to recover renal function within 5% from the baseline the relative risk of early graft failure was significantly higher compared to recipients without BPAR (39). In this series all BPAR including borderline or suspicious grade were treated because of significant association of graft dysfunction. Additionally reports from other investigators show the beneficial effects of treatment of SCAR by improvement in histological and functional outcomes in kidney recipients compared to those without treatment (21,40–42). During treatment of both BPAR and SCAR, we increased the baseline maintenance immunosuppression and maintained at these higher levels for 3 months. This strategy of increasing baseline immunosuppression was used because of two reasons; first was to avoid the use of chronic steroid therapy, second was that baseline immunosuppression was inadequate to prevent BPAR or SCAR. Previous report indicates that for treatment of SCAR, pulse steroid therapy by itself may be inadequate (42).

We have used basiliximab induction to reduce BPAR and prolong survival in both AA and non-AA recipients in this study. Basiliximab induction has been used in AA recipients by other investigators to reduce acute rejections in the first few months and prolong graft survival after kidney transplantation (43–45).

The graft survival in AA recipients is comparable to non-AA recipients. Patient deaths contributed to 55% and 44% graft loss in AA and non-AA recipients at 5 years. Despite increased patient deaths, 5-year graft survival in AA recipients is comparable to non-AA recipients may be attributed to early detection and preemptive treatment of SCAR that may have decreased BPAR and CAI.

There was progressive increase in frequency and severity of CAI in both AA and non-AA recipients from 1 to 5 years. The progression of CAI is due to many factors such as chronic CNI toxicity or unresponsive SCAR or incompletely treated BPAR or other comorbid conditions such as hypertension or a combination of all of the above (19,46). AA recipients had significantly higher incidence of nonimmune injury from hypertension and interstitial fibrosis/tubular atrophy compared to non-AA recipients at 5 years posttransplant.

Surveillance biopsy showed acute CNI toxicity in several patients in both groups despite normal renal function and therapeutic blood levels of CNIs. Combining SRL with a CNI may potentiate the nephrotoxicity as previously reported by other investigators (47,48). To avoid the increased nephrotoxicity in recipients treated with CNI and SRL combination the blood levels of both cyclosporine and tacrolimus were maintained at significantly lower levels compared to recipients maintained on CNI and MMF combination. Additionally both indicated and surveillance biopsies were studied for both acute and chronic nephrotoxicity. Chronic CNI toxicity in surveillance biopsy was addressed by reduction of the dose or complete withdrawal of CNIs preemptively prior to affliction of renal function. All these patients continue to be free of chronic steroid therapy and have stable or improved graft function.

The mean serum creatinine levels were higher and creatinine clearances lower in AA recipients at 5 years. The higher incidence of SCAR and higher prevalence of CAI due to hypertensive changes and Interstitial Fibrosis/Tubular Atrophy may explain lower renal function in AA recipients at 5 years. Previous reports show that AA recipients experience long-term decrease in renal function occurs with or without chronic steroid therapy (4,5,12). There is only one previous study with long-term outcome that reports high rate of noncompliance in AA recipients that resulted in significantly increased overt clinical acute rejections and significant late deterioration of renal function that was more pronounced after steroid withdrawal compared to steroid-treated group (13). In our series we feel noncompliance was low because we were following patients with surveillance biopsies. It is also possible that noncompliance and late onset clinical acute rejections may have been reduced in our series by surveillance biopsies and preemptive treatment of SCAR.

Proteinuria in both groups was seen mainly in recipients with recurrent disease such as focal segmental glomerulosclerosis, HCV-related nephropathy and severe immunological CAI.

New onset diabetes mellitus was observed in 7% of recipients in this study, which is significantly lower than in previously reported series with recipients maintained on chronic steroid therapy (49).

There are limitations to this study. We mentioned one, that the outcome of treatment of SCAR is conjectural since there were no posttreatment biopsies. We discussed this with the IRB and believed that a second biopsy few days after surveillance biopsy increased risks without benefits to the patients. The second limitation was that our only control arm were non-AA recipients treated without chronic steroids. We lacked two randomized control arms: (i) AA recipients who remained with standard chronic steroid treatment plus (ii) AA recipients on the steroid withdrawal protocol but without preemptive treatment of SCAR. At the initiation of the study, we realized that many AA patients insisted on being withdrawn from chronic steroids as described in our previous report and therefore we thought that the randomized former control arm would be difficult to achieve and to interpret (15). We eliminated the second control arm because we feared the risk of imperiling patient safety. Due to these limitations this study is unable to show if chronic steroid therapy in AA recipients would have prevented higher incidence of SCAR and a more rapid deterioration of renal function.

There are no prospective studies comparing long-term outcome of steroid treatment versus steroid withdrawal in AA recipients. Prospective studies comparing ESW in AA recipients compared to non-AA recipients is also lacking. This study prospectively evaluated the long-term safety and efficacy of ESW after kidney transplantation between AA and non-AA recipients. We selected non-AA kidney recipients as a control group, because these are considered lower immunological risk group and this group has been tested for the effects of ESW on long-term survival. Previous reports show that long-term outcome of ESW had no deleterious effect in non-AA recipients (8). AA recipients have been considered higher risk group. We thought it is reasonable to test and compare ESW on the long-term survival and outcomes in higher risk AA recipients versus low to medium risk non-AA recipients.

In summary, early detection and preemptive treatment of SCAR in surveillance biopsies may have decreased BPAR in this series. Preemptive changes in immunosuppression regimen may have decreased both acute and chronic CNI nephrotoxicity. Chronic active antibody and T-cell rejections were comparable between the groups. Our initial data show that at 5 years, AA recipients have significantly higher incidence of Banff grade 1A subclinical acute rejections, CAI due to hypertension and interstitial fibrosis/tubular atrophy and significantly lower renal function, but 5-year graft survival are comparable to non-AA recipients after ESW.

Acknowledgments

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

A portion of these data was presented at the American Transplant Congress in San Francisco in May, 2007. This study was in part funded by NIH grant U01AI052748–04 and by an unrestricted educational grant from Novartis Pharmacueticals Inc.

References

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