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Keywords:

  • Cadaveric kidney transplantation, complications of immunosuppression, delayed graft function, rapamycin, sirolimus

Abstract

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

Sirolimus, lacking known nephrotoxicity, appeared to be an ideal immunosuppressive agent in the setting of delayed graft function (DGF) after renal transplantation. Coincident with our use of sirolimus however, we noticed prolongation of DGF. To investigate possible causes of prolonged DGF, extensive donor, recipient, transplant, and post-transplant data were collected on 132 consecutive cases of DGF at the University of California, San Francisco between 1/1/97 and 6/30/01. Cox proportional hazards analysis of time to graft function was used in univariate and multivariate models to identify factors that prolong DGF. Sirolimus had a large and highly significant effect on time to graft function (hazard ratio 0.48, p = 0.0007). The hazard ratio indicates that a recipient on sirolimus is half as likely to resolve DGF or twice as likely to remain on dialysis as a recipient without sirolimus. Two other factors had less potent but still significant association with DGF duration: recipient sensitization (hazard ratio 0.66, p = 0.037), and Novartis score (hazard ratio 0.93 per 1.0 increase; p = 0.034). Sirolimus retained its profound negative association with time to graft function in all multivariate models. Because sirolimus appears to prolong DGF, it may not be the optimal immunosuppressive choice in the DGF setting.


Introduction

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

Delayed graft function (DGF) continues to plague cadaveric renal transplantation. Most frequently defined as the requirement for dialysis during the first week after transplantation, it has been associated with short- and long-term adverse outcomes including decreased graft function and decreased graft and patient survival (1–10). Absence of immediate function complicates the recipient's peri-transplant management including the choice of an immunosuppression strategy. Since calcineurin inhibitors have nephrotoxicity which prolongs recovery from DGF (11–13), many transplant centers do not initiate them until the graft is functioning. Centers committed to a calcineurin-sparing strategy in the DGF setting, however, differ in their choice of an alternative strategy. Historically, depleting antilymphocyte preparations have been the only possible choices. Although these agents provided excellent protection against rejection, they were concomitantly associated with increased incidence of both infection and malignancy. Particularly for recipients of low immunologic risk, the disadvantages of such potent up-front immunosuppression may outweigh the advantages. More recently, humanized monoclonal antibodies against the interleukin-2 receptor (IL-2R) have become available as another alternative. Although extremely well tolerated without known long-term sequelae, their use without calcineurin inhibitors has been associated with a high incidence of rejection (45%), with the majority of episodes (84.1%) occurring within 90 days of transplantation (14). Therefore, the optimal immunosuppression strategy for the DGF setting remained elusive when sirolimus became generally available.

Sirolimus, a macrocyclic lactone with potent immunosuppressive effects and without known nephrotoxicity, appeared to fit the profile of an ideal immunosuppressive agent for DGF. At the University of California, San Francisco (UCSF), beginning in December 1999, sirolimus was added to the basic immunosuppression protocol of steroids, mycophenolate mofetil, and anti-IL-2R antibody for cadaveric renal transplant recipients with DGF (15,16). Calcineurin inhibitors were withheld until there was evidence of renal function. Coincident with our routine use of sirolimus in the DGF setting was an apparent lengthening of the duration of DGF. Although there is substantial knowledge regarding risk factors for DGF, risk factors associated with the duration of DGF are poorly elucidated. Therefore, we decided to undertake an analysis of our adult cadaveric renal transplant recipients to identify factors associated with prolongation of DGF.

Materials and Methods

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

Patients and data collection

Recipients.  Between January 1, 1997 and June 30, 2001, 563 adults underwent single organ cadaver kidney transplantation at UCSF. Our study group comprised 132 recipients (23.4%) who experienced DGF, defined as the need for dialysis within 1 week after transplantation. Two patients with mechanical complications accounting for the lack of allograft function were excluded. Retrospective chart review was performed using inpatient and outpatient medical records.

Donors.  Information regarding the cadaver donors and kidneys corresponding to the recipients of our study was collected with particular attention to verifying the presence or absence of hypertension and diabetes, both defined as requiring medical therapy. Duration of hypertension corresponded to the duration of medication usage.

Transplant parameters

The degree of HLA matching was determined by mismatches in the A, B, and Dr loci. Cold ischemia time was defined as the interval from donor cross-clamp to removal from cold storage for anastomosis; warm ischemia time represents anastomotic time, defined as the interval from removal from cold storage to reperfusion.

Post-transplant parameters

Information regarding post-transplant events such as duration of post-transplant dialysis, immunosuppression regimen, and allograft biopsies was collected. Details regarding immunosuppression including administration of anti-IL-2R antibody and lymphocyte-depleting antibody preparations (equine or rabbit anti-thymocyte globulin and OKT3) along with the indication (induction or rejection) were noted. The date of sirolimus initiation, the specific calcineurin inhibitor (cyclosporine or tacrolimus) and its date of initiation were all collected. The final pathology report for each allograft biopsy was reviewed and, for all cases where the findings and/or the diagnosis were unusual or inconclusive, slides were reviewed with our kidney transplant pathologist.

Transplant procedure

Briefly, kidneys were procured according to standard techniques and cold preserved in University of Wisconsin solution without pulsatile perfusion. All kidneys except one were from heart-beating donors.

Typically, central venous pressure monitoring was used to optimize volume status for recipients during the operative procedure. All but two grafts were placed in the iliac fossa through an extraperitoneal approach. Two recipients who had undergone multiple previous renal transplants had grafts placed in an intraperitoneal position. Extravesicular ureteroneocystostomy was performed, usually without a stent. Intravenous mannitol and furosemide were infused prior to graft reperfusion. Additional diuretics and dopamine were administered at the surgeon's discretion.

Immunosuppression and rejection

The UCSF Kidney Transplant Service uses a calcineurin-sparing approach for immunosuppression in the DGF setting. Therefore, with few exceptions (<5%), transplant recipients did not start daily cyclosporine or tacrolimus until resolution of DGF. All recipients during the study period received steroids (methyl-prednisolone intravenously or prednisone orally) and mycophenolate mofetil (2–3 g orally per day adjusted for hematologic parameters and/or clinical symptoms). Additional immunosuppression was dictated by the recipient's immunologic status and the availability of various agents as outlined below.

‘High immunologic risk’ recipients, defined as those with a peak PRA of >30% and/or a history of previous renal transplantation, were generally induced with a lymphocyte depleting antibody preparation, either OKT3 or anti-thymocyte globulin (equine prior to April, 1998 and rabbit subsequently). The immunosuppression protocol for recipients of ‘low immunologic risk’ with DGF evolved during the study period. From January through October 1997, recipients received equine anti-thymocyte globulin. Beginning November 1997, recipients typically received anti-IL-2R antibody either intraoperatively if DGF was anticipated or in the immediate post-transplant period when DGF was strongly suspected. In December 1999, sirolimus became available and was thus added to the protocol. Patients typically received a loading dose of 5–20 mg, followed by maintenance doses of 2–10 mg/day, targeting for trough blood levels of 10–15 ng/mL.

Transplant recipients with DGF typically underwent allograft biopsies at regular intervals until clinical evidence of improving renal function. Two cores were obtained for histologic assessment.

Scoring systems to assess kidney and/or transplant quality

Four different scoring systems were applied to the transplants in our study to more quantitatively assess the donor kidney and/or transplant quality. Each index combines different donor, recipient, and/or transplant factors with varying weights to stratify the ‘quality’ of either the kidney or the transplant. The Expanded Criteria Donor (ECD) index uses four donor criteria to determine the relative risk of graft failure (17) and forms the basis for a new allocation strategy designed to expedite placement of suboptimal kidneys. Two of the indices, Sangstat (18) and Novartis (19), were derived to identify transplant recipients at high risk of DGF. Finally, the Nyberg (20) scoring system was derived to identify transplant recipients at high risk for early graft dysfunction. All four indices were retrospectively derived; two of the indices (Novartis and Nyberg) have been prospectively validated.

Statistical analysis

Cox proportional hazards analysis of time to graft function was used in univariate and multivariate models to identify factors that correlate with the duration of DGF. Hazard ratios below 1.0 indicate variables associated with longer DGF. Individual factors as well as composite scores from the four risk indices were used for the analysis. Sirolimus exposure was modeled as a time-dependent covariate to account for variability in timing and duration of drug administration. Based upon its pharmacokinetic profile and our typical dosing practice, full exposure was considered achieved after five successive doses; discontinuation was assumed to result in a linear decline in exposure over 7 days. Similarly, rejection was also modeled as a time-dependent covariate, with its effect beginning 2 days prior to diagnosis and lasting for 5 days after diagnosis. The proportional hazards assumption for all covariates in all models was also tested by including an interaction of each covariate with log time. All analyses were performed using SAS, version 8.2 (SAS Institute, Cary, NC, USA).

Results

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

Baseline characteristics

Our study group comprised of 132 of 563 adult cadaver kidney transplant recipients between January 1, 1997 and June 30, 2001 who experienced DGF, defined as dialysis during the first week after transplantation. Our overall rate of DGF was 23.4%. One patient in the study group expired prior to resolution of DGF. Two allografts never functioned: one recipient developed refractory rejection unresponsive to both thymoglobulin and OKT3 and underwent transplant nephrectomy 61 days after transplantation; the etiology of nonfunction for the second allograft was never determined in spite of multiple biopsies, and the recipient underwent transplant nephrectomy 116 days after transplantation.

Tables 1 and 2 display the recipient and donor demographics and Tables 3 and 4 display transplant and post-transplant parameters for our study group. The mean duration of DGF, defined by the last dialysis treatment day, was 11.5 days with a median of 8 days. Most patients in our study group (117 of 132 recipients or 88.6%) were induced with either a lymphocyte depleting antibody preparation (42 recipients; 31.8%) or an IL-2R antibody (78 recipients; 59.1%); three patients were initiated on anti-IL-2R antibody and switched over to a depleting agent shortly after transplantation. In December 1999, sirolimus was added to our standard anti-IL-2R antibody induction protocol for DGF. From then until the end of our study, 55 of 64 patients (85.9%) received sirolimus, which was initiated, on average, 2.1 days after transplantation. More than half of these patients started sirolimus on or before the first post-transplant day.

Table 1. : Baseline characteristics of cadaveric renal transplant recipients with DGF: UCSF; 1/1/1997–6/30/2001
Total # recipients132
Age
 Mean50.2±10.8years
 Median49.9years
 Range22.4–72.8years
Sex
 Male91 recipients (68.9%)
 Female41 recipients (31.1%)
Race
 Caucasian39 recipients (29.5%)
 African American35 recipients (26.5%)
 Hispanic24 recipients (18.2%)
 Asian34 recipients (25.8%)
BMI
 Mean25.9±4.7
 Median25.1
 Range17.0–41.8
Etiology of renal failure
 Glomerulonephritis52 recipients (39.4%)
 Diabetes mellitus27 recipients (20.5%)
 Hypertension26 recipients (19.7%)
 Polycystic kidney disease12 recipients (9.1%)
 Congenital/urologic5 recipients (3.8%)
 Other/Unknown10 recipients (7.6%)
Dialysis
 Hemodialysis107 recipients (81.1%)
 Peritoneal dialysis24 recipients (18.2%)
 None1 recipients (0.76%)
Sensitization
 Non-sensitized91 recipients (68.9%)
 Sensitized = Peak PRA>30% OR Prev Txp41 recipients (31.1%)
 Peak PRA>30%20 recipients (15.2%)
 Previous transplant25 recipients (18.9%)
Table 2. : Baseline characteristics of cadaveric donors of renal transplants with DGF: UCSF; 1/1/1997–6/30/2001
Age
 Mean38.6±13.9years
 Median39.0years
 Range8.1–69.9years
 >60years old4 kidneys (3.0%)
Sex
 Male74 kidneys (56.1%)
 Female58 kidneys (43.9%)
Race
 Caucasian88 kidneys (66.7%)
 African American8 kidneys (6.1%)
 Hispanic23 kidneys (17.4%)
 Asian9 kidneys (6.8%)
 Other4 kidneys (3.0%)
BMI
 Mean27.8±6.8
 Median26.0
 Range13.5–51.4
Type
 Heart-beating131 kidneys(99.2%)
 Non-heart-beating1 kidney (0.8%)
Cause of death
 Trauma69 kidneys (52.3%)
 Non-trauma (CVA, ischemia, anoxia)62 kidneys (47.0%)
 Unknown1 kidney (0.8%)
Hypertension
 Yes17 kidneys (12.9%)
 No115 kidneys (87.1%)
Diabetes mellitus
 Oral hypoglycemic agent4 kidneys (3.0%)
 InsulinNone
Procurement creatinine
 Mean1.0±0.4mg/dL
 Median1.0
 Range0.4–1.9mg/dL
 >1.5mg/dL8 kidneys (6.1%)
Procurement creatinine clearance
 Mean113.5±44.0mL/min
 Median105.6mL/min
 Range37.2–248.8mL/min
Table 3.  Transplant characteristics for cadaveric renal transplants with DGF: UCSF; 1/1/1997–6/30/2001
Number of HLA mismatches 
 Mean4.1±1.7
 # 0 Mismatches14 transplants (10.6%)
Cold ischemia time
 Mean20.3±7.7h
 Median21.1h
 Range5.3–37.2h
 <12h22 transplants (16.7%)
 23–24h71 transplants (53.8%)
 >24h39 transplants (29.5%)
  >24–30h24 transplants (18.2%)
  >30–36h12 transplants (9.1%)
  >36h3 transplants (2.3%)
Warm ischemia time
 Mean39.0 ± 12.0min
 Median37min
 Range17–92min
 <30min19 transplants (14.4%)
 30–45min88 transplants (66.7%)
 46–60min17 transplants (12.9%)
 >60min8 transplants (6.1%)
Table 4.  Post-transplant characteristics for cadaveric renal transplants with DGF: UCSF; 1/1/1997–6/30/2001
Last day of dialysis 
 Mean11.5±11.0days
 Median8days
 Range0–60days
Thymoglobulin
 Induction26 recipients (19.7%)
 Rejection17 recipients (12.9%)
OKT3
 Induction18 recipients (13.6%)
 Rejection13 recipients (9.9%)
Anti-IL2 Receptor Ab
 Yes78 recipients (59.1%)
 No Sirolimus54 recipients (40.9%) 54 of 63 recipients (85.7%)
  between 12/1/99 and 6/30/01
 Date of initiation: Mean2.1±3.2days
 Date of initiation: Median1day
 Date of initiation: Range−1–19days
Calcineurin inhibitors
 Prograf89 recipients (67.4%)
 Cyclosporine36 recipients (27.3%)
 None7 recipients (5.3%)
Date of calcineurin initiation
 Mean20.9±32.3days
 Median13days
 Range0–218days
 Unknown3 recipients (2.3%)
Rejection
 Within 3months of transplantation39 episodes 39 recipients (29.5%)
 Date of first rejection episode
 Mean14.9±17.9days
 Median7.5days
 Range4–86days

Calcineurin inhibitors, which were also started in most patients (125 of 132 recipients; 94.7%) were, however, initiated much later, once good graft function was established. The median day of calcineurin inhibitor initiation was day 13. Our overall incidence of rejection within the first 90 days of transplantation was 29.5%.

The collected primary data were used to calculate composite scores for each transplant in our study group according to four scoring systems (Table 5) in an attempt to estimate the ‘quality’ of the transplant. The ECD kidney values represent the relative risk of graft loss compared to an ideal donor kidney (17). The mean and median ECD relative risk of the kidneys in our group was modest at 1.24 ± 0.29 and 1.14 (Table 6); only nine kidneys (6.8%) met the definition of an ECD kidney. Similarly, the mean and median Novartis, Sangstat, and Nyberg scores for the transplants in our study are all quite modest (Table 6), since 100% of the transplants in our study group experienced DGF. Our mean Novartis score (3.6) predicts a 61% risk of DGF (19); our mean Sangstat score (138) predicts approximately a 41% risk of DGF (18); and our mean Nyberg score (5.7) predicts approximately a 20% risk of DGF (20), which they defined as the need for more than one hemodialysis treatment within 30 days of transplantation.

Table 5. : Factors included in extended criteria donor (ECD), Novartis, Sangstat, and Nyberg scoring systems for assessment of cadaveric renal transplants
 ECDNovartisSangstatNyberg
Donor factors
 AgeXXXX
 Cause of deathXXXX
 History of hypertensionX XX
 History of diabetes   X
 Final creatinineX X 
 Final creatinine clearance   X
  (Cockcroft-Gault equation)
 Heart-beating vs. non-heart-beating  X 
 Renal artery plaque   X
Recipient factors
 Race: African American vs. Other XX 
 Sex  X 
 Previous transplant XX 
 Peak PRA  X 
 Pre-transplant dialysis: Yes vs. No  X 
 History of transfusion  X 
 Etiology of renal disease: Diabetes vs. Other  X 
Transplant factors
 Cold ischemia time XXX
 Number of HLA mismatches  X 
 Single organ transplant: Yes vs. No  X 
Table 6. : Extended criteria donor (ECD), Novartis, Sangstat, and Nyberg scores for cadaveric renal transplants with DGF: UCSF; 1/1/1997–6/30/2001
ECD score
 Mean1.2±0.3
 Median1.1
 Range1.0–2.2
 Relative risk >1.7=ECD kidney9 kidneys (6.8%)
Novartis score
 Mean3.6±2.6
 Median3
 Range0–12
Sangstat score
 Mean138.0±15.2
 Median138.7
 Range69.7–173.2
Nyberg score
 Mean5.7±4.6
 Median4.0
 Range0–18

Univariate models

Table 7 shows the outcome of Cox proportional hazards analysis of time to graft function using univariate models. Only three variables: sirolimus exposure (hazard ratio 0.48 for full exposure vs. no exposure, p = 0.0007), recipient sensitization (hazard ratio 0.66, p = 0.037), and Novartis score (hazard ratio 0.93 per unit increase; p = 0.034), were significantly associated with time to graft function. Neither of the two parameters which determine sensitization achieved statistical significance alone. Since a hazard ratio of less than 1 indicates a negative association with time to graft function, sirolimus exposure, recipient sensitization, and higher Novartis score are all associated with prolongation of DGF. The hazard ratio of 0.48 for sirolimus exposure indicates that a recipient with full sirolimus exposure is less than half as likely to resolve DGF at any given time (or more than twice as likely to remain on dialysis) as a recipient without sirolimus exposure.

Table 7. : Cox univariate models of time to graft function for cadaveric renal transplants with DGF: UCSF; 1/1/1997–6/30/2001
VariableHazard ratioConfidence intervalp-value
  • *

    Both variables included in one model relative to donor age<40years.

  • #

    Both variables included in one model relative to CIT<12h.

Sirolimus (full exposure vs. none)0.490.32–0.750.0009
Recipient sensitization0.660.45–0.980.037
 Peak PRA>30%0.910.56–1.490.71
 History of previous Tx0.720.46–1.130.15
Novartis score (per 1.0 increase)0.930.87–1.000.034
Recipient sex: Female vs. Male0.760.52–1.110.16
Recipient race: AA vs. Others0.860.58–1.280.45
Recipient mode of dialysis: Hemo vs. peritoneal dialysis0.890.57–1.390.60
Recipient etiology of renal disease: Diabetes vs. others0.960.62–1.470.84
Donor age 40–50years*0.950.60–1.490.81
Donor age>50years*0.840.55–1.280.42
Donor hypertension0.950.58–1.570.85
Donor mode of death Trauma vs. all others1.080.76–1.540.67
Donor final creatinine1.130.72–1.780.59
Donor final creatinine >1.5mg/dL1.070.52–2.190.86
Donor final creatinine clearance1.001.00–1.000.54
Donor final creatinine clearance: >100mL/min vs.<100mL/min0.850.56–1.310.47
HLA mismatch0.940.85–1.040.23
HLA mismatch >00.730.41–1.270.26
CIT 12–24h#0.860.52–1.410.54
CIT>24h#0.750.44–1.280.29
WIT>30min1.070.65–1.770.78
Induction with lymphocyte depleting antibody1.320.91–1.910.15
Induction with IL-2R antibody0.910.65–1.290.60
Rejection (any vs. none)1.280.80–2.040.31
ECD score (per 0.1 increase)0.970.92–1.030.32
Sangstat score (per 10.0 increase)1.020.99–1.050.16
Nyberg score (per 1.0 increase)1.000.96–1.040.92

Univariate models did not identify any other donor, recipient, or transplant factors that were statistically significantly associated with time to graft function (Table 7). Specifically, factors strongly associated with the likelihood or probability of DGF, such as donor age, cause of death, medical history, renal function, cold ischemia time, and warm ischemia time, were not strongly predictive of the duration of DGF. Furthermore, none of the other three composite scoring systems reached statistical significance. Induction immunosuppression strategy – the use of a lymphocyte depleting antibody or an anti-IL-2R antibody – did not affect the duration of DGF. Finally, the occurrence of rejection also did not demonstrate a significant association with duration of DGF.

Multivariate models

Table 8 shows the outcome of Cox proportional hazards analysis of time to graft function using multivariate models that include sirolimus. In every model, sirolimus retains its profound negative association with time to graft function (hazard ratio 0.40–0.49; p ≤ 0.0001–0.008). From 85 tests of the proportional hazards assumption for all covariates in all models presented in Tables 7 and 8, the smallest p-value was 0.06, a value not unexpected for this large number of tests. For sirolimus in particular in Table 8, the smallest p-value was 0.12. We therefore did not include any modeling of potential nonproportional effects in the results shown.

Table 8. : Cox multivariate models of time to graft function for cadaveric renal transplants with DGF: UCSF; 1/1/1997–6/30/2001
VariablesHazard ratiosp-values
  • #

    per 0.1 increase.

  • *

    per 1.0 increase.

  • &per 10.0 increase.

Sirolimus/Year0.47/1.020.008/0.82
Sirolimus/Donor age0.48/1.000.0007/0.39
Sirolimus/Donor final creatinine >1.5mg/dL0.49/1.110.001/0.78
Sirolimus/Donor hypertension0.49/0.990.001/0.96
Sirolimus/Donor mode of death0.49/1.020.001/0.94
Sirolimus/Recipient sex: Female vs. Male0.49/0.750.0008/0.14
Sirolimus/CIT 12–24h/CIT>24h0.48/0.75/0.700.0007/0.25/0.20
Sirolimus/WIT>30min0.47/0.820.0007/0.46
Sirolimus/Rejection0.50/1.140.001/0.60
Sirolimus/Mismatch >00.48/0.690.0007/0.20
Sirolimus/ECD score#0.49/0.970.0008/0.29
Sirolimus/Nyberg score*0.49/1.000.0009/0.91
Sirolimus/Sangstat score&0.45/0.990.002/0.54
Sirolimus/Induction with lymphocyte depleting antibody0.50/1.040.002/0.86
Sirolimus/IL-2R antibody induction0.46/1.170.0006/0.39
Sirolimus/Recipient sensitization0.43/0.570.0001/0.006
Sirolimus/History of previous transplant0.43/0.580.0001/0.022
Sirolimus/Peak PRA>30%0.42/0.630.0002/0.086
Sirolimus/Recipient sensitization/Induction with lymphocyte depleting antibody0.46/0.53/1.250.0006/0.003/0.30
Sirolimus/Recipient sensitization/Induction with IL-2R antibody0.44/0.56/0.960.0003/0.008/0.83
Sirolimus/Novartis score*0.46/0.910.0003/0.012
Sirolimus/Novartis score*/Recipient sensitization0.42/0.93/0.710.0001/0.040/0.15
Sirolimus/Novartis score*/Peak PRA>30%0.40/0.92/0.65<0.0001/0.016/0.11
Sirolimus/Novartis score*/History of previous transplant0.42/0.93/0.64<0.0001/0.040/0.07

Discussion

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

Our study demonstrates a profound and highly statistically significant association between sirolimus and prolongation of DGF. This effect was surprising since lack of nephrotoxicity is a well-known characteristic of sirolimus (21–24). Sirolimus exerts its immunosuppressive effect by inhibiting the mammalian target of rapamycin, an enzyme required for T- and B-cell proliferation and differentiation. Sirolimus exposure results in G1 cell cycle arrest of T and B cells (22,25). The anti-proliferative effect of sirolimus has also been observed in smooth muscle cells, resulting in potent inhibition of neointimal proliferation after balloon-induced vascular injury in animal models (26,27). Interestingly, a recent report strongly suggests that sirolimus may exert a similar anti-proliferative effect in renal tubular cells (28). The authors suggest that ‘the combined effects of increased tubular cell loss (via apoptosis) and profound inhibition of the regenerative response of tubular cells’ together delayed recovery from ischemia-induced acute renal failure. Together, the data from animal models and our results in human patients suggest that sirolimus, while non-nephrotoxic to an uninjured kidney, may hinder the recovery of an injured kidney.

Recipient sensitization also had a statistically significant association with time to graft function. Recipient sensitization, although variously defined, is a well-known risk factor for the occurrence of DGF (5,7,9,29–32). Furthermore, two studies have correlated high PRA and history of previous transplant with prolonged DGF (33,34). A possible mechanism accounting for these associations is humoral rejection or the development of an antibody response against the graft. Recently, the contribution of humoral mechanisms to acute allograft rejection has become increasingly recognized (35–38). Standard immunosuppression regimens which target T-cell function are ineffective against antibody-mediated rejection, a B-cell mediated process. Therefore, humoral rejection may well explain, at least in part, the association between recipient sensitization and prolonged time to graft function.

In general, our analysis did not demonstrate a consistent association between factors that predispose to the occurrence of DGF and those that prolong DGF. Using four scoring systems developed by others to assess transplant quality or the risk of DGF, only the Novartis score, calculated from five parameters (donor age, donor cause of death, recipient race, recipient history of previous transplant, and cold ischemia time) emerged with a statistically significant association with time to graft function. Interestingly, none of these five factors individually demonstrated a statistically significant association with DGF duration. Furthermore, none of the other three scoring systems (ECD, Sangstat and Nyberg), which were calculated using different but overlapping parameters, appeared to correlate substantially with the duration of DGF.

To our knowledge, no previous study directly addresses risk factors for DGF duration, although some limited data are provided by a few studies that examine the impact of DGF duration on long-term graft outcomes (33,34,39–42). The factors identified by these studies as correlating with the duration of DGF were those classically associated with the risk of DGF, such as donor age, asystolic arrest, hemodynamic instability, cause of death, cold and warm ischemia times, and recipient history of previous transplant or PRA > 30% (33,34,39–41). The logical inference is that the duration of DGF reflects the severity of injury producing DGF (3). We, however, did not identify similar correlations. Our data suggest that prolonged DGF reflects impaired recovery from injury as a result of sirolimus exposure rather than worse transplant quality or more severe injury. The different conclusions may not be surprising since our study involved sirolimus use, which was not a factor in any of the previous studies. We believe that the substantial proportion of suboptimal donors and/or suboptimal transplant parameters in the previous studies resulted in their finding that factors associated with the probability of DGF also correlated with the duration of DGF. In contrast, the narrower range of donor kidney quality and transplant parameters in our study likely accounts for our findings. We therefore conclude that the duration of DGF in our study does not reflect the degree of injury but rather the speed of recovery from injury, and that sirolimus retards recovery from injury. We would postulate that there should be no significant decrement in short- or long-term graft function or graft survival associated with sirolimus usage in the DGF setting and are in the process of gathering data to make this determination.

Thus, in summary, we have discovered a strong association between sirolimus exposure and time to graft function for cadaveric kidney transplants which experience DGF. Our data indicate that sirolimus impairs the kidney's ability to recovery from injury. Therefore, we would suggest that sirolimus may not be the ideal immunosuppressive agent in the context of DGF.

Acknowledgments

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

We thank Alan Bostrom for his diligence and dedication to this project.

References

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