Академический Документы
Профессиональный Документы
Культура Документы
Blackwell Munksgaard
doi: 10.1111/j.1600-6143.2004.00332.x
Herwig-Ulf Meier-Kriesche∗ , Jesse D. Schold, ter kidney transplantation (1–5). These studies implied that
Titte R. Srinivas and Bruce Kaplan a reduction in early acute rejection rates would lead to im-
provements in long-term graft survival (5). This led investi-
University of Florida, College of Medicine, Division of gators to postulate that early acute rejection could predict
Nephrology, Gainesville, FL long-term graft survival (1,4). From the era of 1988 until
∗ 1996, both acute rejection rates and graft survival rates
Corresponding author: Herwig-Ulf Meier-Kriesche,
Meierhu@medicine.ufl.edu were improving (6), lending support for this postulate.
Acute rejection is known to have a strong impact on On the other hand, new therapeutic regimens, while reduc-
graft survival. Many studies suggest that very low ing the incidence of acute rejection, have often times failed
acute rejection rates can be achieved with current im- to show a significant beneficial effect on long-term graft
munosuppressive protocols. We wanted to investigate survival. In some cases this may be owing to trials pow-
how acute rejection rates have evolved on a national ered to show a statistically significant difference in acute
level in the U.S. and how this has impacted graft sur- rejection rates but not adequately powered for the rarer
vival in the most recent era of kidney transplantation. and later end point of graft survival.
For this purpose, we analyzed data provided by the
Scientific Registry of Transplant Recipients regarding
all adult first renal transplants between 1995 and 2000. Numerous groups have attempted to develop clinical and
histopathological criteria to further characterize the relation
We noted a significant decrease in overall acute rejec- between acute rejection and graft survival (7–9). In most
tion rates during the first 6 months, during the first clinical trials, acute rejection rates, histological grades and
year, and also in late rejections during the second year steroid responsiveness are reported, while response to
after transplantation. Despite this decrease in the rate therapy in terms of functional recovery is usually not re-
of acute rejection, there was no significant improve- ported. In 1972, Silcott et al. reported that of those renal
ment in overall graft survival; furthermore, we noted
allografts ‘which were unable to return the serum creati-
a statistically significant trend towards worse death-
censored graft survival. There was also a trend for a nine value to within 20% of the pre rejection levels, 93%
greater proportion of rejection episodes to fail to re- ultimately failed and 47% of the patients died’, compared
cover to previous baseline function after treatment. with a failure rate of 27% in patients with acute rejection
but no loss of function within 20%. More recent studies
Our data suggest that decreasing acute rejection rates reemphasize the concept that acute rejection might not
between 1995 and 2000 have not led to an increase in have any deleterious effect on long-term graft survival pro-
long-term graft survival. Part of this discordance might vided complete functional recovery is achieved (10,11).
be related to a higher proportion of acute rejections
which have not resolved with full functional recovery
in more recent years. However, the etiology of this con- With the present study, we first determined trends in
cerning trend for worse death censored graft survival acute rejection rates and long-term graft survival and sub-
in recent years will warrant further investigation. sequently proceeded to investigate whether continued im-
provements in acute rejection rates have translated into
Key words: Acute rejection, era effect, graft survival, improved graft survival.
kidney transplantation
378
Lack of Improvement in Renal Allograft Survival
test (p < 0.001). The acute rejection rates for the entire ilar fashion, during the third year post transplant the rejec-
follow-up periods that we investigated indicated later acute tion rates were 3.5% for the no acute rejection group, 6.4%
rejection rates were consistently higher in the group that for the return to baseline group, and 11.3% for the fail to
had initially displayed acute rejection in the second 6-month return to baseline. Rates in the fourth year post-transplant
post-transplant follow-up period. The rate of rejection in followed the same pattern; for the no acute rejection group
the second year post-transplant for the no acute rejection the rate of acute rejection was 3.0%, for the return to base-
group was 5.7%, for the return to baseline group 16.3%, line group 5.0%, and for the failure to return to baseline
and for the fail to return to baseline group 27.7%. In a sim- group 8.1%.
Table 2: Two-tier univariate overall graft survival rates for recip- 1.2 1.1 4
ients with and without indications of acute rejection within 6 1.10 1. 09 1.09
1.1
months post-transplant by donation type 1.2
Relative 1 1.00
Risk 1.00 1.03
No indication of acute rejection Acute rejection 0.9 1.1
0.9 7
0.8 0.9 6 0.9 4 1
Year of Deceased Deceased 0.89
0.7
transplant donor Living donor Living 0.88 0.9
1.2
Return to baseline function estimated by 1/Scr.
1.1 4
1.1 1
1.1 2 Significant linear trend (p < 0.001) towards no return to baseline
1.1
1.04
Relative 1.2 as tested by the Cochran-Armitage trend test.
Risk 1 1.00 0.99
0.9 1.1
0.8 1
0.7 0.8 5 0.8 4
0.79 0.9 unadjusted rates were 74.4%, 72.7%, and 50.4%, with
0.8 3 0.8 1
Deceased Donor
Transplants
0.8 2
0.8
an overall test for equality of strata being highly signifi-
cant also (p < 0.0001), when testing the model with the
0.7
1999
2000 first two strata only, there was no significant difference be-
Living
Transplants 1997
1998
tween the groups with no acute rejection and with acute
1996
1995 Year of Transplant
rejection and return to baseline (p = 0.5289). Subsequently,
we examined the results using the MDRD estimate of GFR
Figure 2: Relative risk for overall graft loss by donor type. and (serum creatinine)−1 and found very similar results. We
Model corrected for induction, antiproliferative, and inhibitor med- also analyzed the overall graft survival by use of five acute
ication regiments at baseline, cold ischemia time, PRA level, HLA- rejection/renal function levels (no acute rejection, acute re-
A, -B, and -DR mismatches, recipient and donor gender, ethnicity, jection and return to baseline, acute rejection and a return
and age, presence of delayed graft function, primary diagnosis, to 85–95% renal function, acute rejection and return to 75–
and waiting time on dialysis. 85% renal function, and acute rejection and a return to less
than 75% renal function). The 6-year overall unadjusted
We analyzed the impact of the acute rejection/renal func- graft survival rates by functional status after rejection as
tion groupings on overall graft survival. Examining the out- measured by Cockcroft-Gault as an estimate for GFR were
comes for the three group designations (no acute rejection, 74.4%, 72.7%, 67.0%, 50.2%, 38.0% (see Figure 4), re-
rejection with return to baseline, and rejection without re- spectively.
turn to baseline) utilizing Cockcroft-Gault as an estimate
of GFR yield 3-year-unadjusted survival rates of 91.5%, We were also interested in measuring the death-censored
91.1%, and 72.1%, respectively, (see Table 4). The 6-year graft survival for the same grouping levels. Utilizing the
Table 4: Unadjusted overall graft survival by acute rejection/renal censored graft survival shows a significant decrease in
function group the same time period. This lack of improvement has been
3-year overall 6-year overall shown in the setting of an almost halving of early and late
Group graft survival graft survival acute rejection rates during the same time period. This po-
No acute rejection 91.5 74.4 tential discordance between trends in acute rejection rates
Acute rejection and return 91.1 72.7 and trends in long-term graft survival has been observed
to baseline in several recent clinical trials.
Acute rejection and fail to 72.1 50.4
return to baseline Acute rejection has been used in many studies as the pri-
mary endpoint, under the assumption that reduced acute
rejection rates would ultimately lead to better graft survival.
The data analyzed here would question this assumption
and furthermore would imply that the achievement of ever
lower rejection rates does not necessarily lead to improved
graft survival.
Table 5: Multivariate risk estimates for death-censored graft survival by acute rejection status and functional return to baseline
Reference group
Acute rejection and return to functional baseline group
No acute rejection Hazard Confidence interval
Acute rejection and return to within 95% of baseline 1.067 (0.882, 1.291)
Acute rejection and return to within 85–95% of baseline 1.223 (0.874, 1.713)
Acute rejection and return to within 75–85% of baseline 2.739 (2.024, 3.705)
Acute rejection and return to within < 75% of baseline 5.130 (4.332, 6.076)
Return to baseline function estimated by calculated creatinine clearance (Cockroft-Gault).
is likely that maintenance immunosuppression has also 2. Pirsch JD, Ploeg RJ, Gange S et al. Determinants of graft survival
changed during this time period, particularly given the re- after renal transplantation. Transplantation 1996; 61: 1581–1586.
cent emphasis on immunosuppression minimization and 3. Almond PS, Matas A, Gillingham K et al. Risk factors for chronic
rejection in renal allograft recipients. Transplantation 1993; 55:
withdrawal trials.
752–756.
4. Ferguson RM. Acute rejection episodes – Best predictor of long-
In summary, despite impressive reductions in acute rejec- term primary cadaveric renal transplant survival. Clin Transplant
tion rates since 1995, the favorable trend in graft survival 1994; 8: 328–331.
observed in previous years has not continued during the 5. Flechner SM, Modlin CS, Serrano DP et al. Determinants of
same time period. Changes in acute rejection rates do not chronic renal allograft rejection in cyclosporine-treated recipients.
seem to reliably correlate with the later end point of graft Transplantation 1996; 62: 1235–1241.
loss. However, as the risk for graft loss is different be- 6. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh
tween acute rejections that lead to functional deterioration MJ, Stablein D. Improved graft survival after renal transplantation
as opposed to those that do not, this distinction should in the United States, 1988–96. N Engl J Med 2000; 342: 605–612.
7. McKenna R, Stern E, Jeffery J, Ru DN. Computerized image anal-
be reported when novel therapeutic regimens are studied.
ysis of Sirius Red-stained renal allograft biopsies as a surrogate
The reason for the lack of graft survival improvements in
marker to predict long-term allograft function.J Am Soc Nephrol
more recent era needs to be investigated in more detail. 2003; 14: 1662–1668.
In this era of more novel therapies, some caution may be 8. Haas M, Kraus ES, Samaniego-Picota M, Racusen LC, Ni W, Eu-
needed in extrapolating improvements in intermediate end stace JA. Acute renal allograft rejection with intimal arteritis: his-
points and improvements in long-term outcomes. tologic predictors of response to therapy and graft survival. Kidney
Int 2002; 61: 1516–1526.
9. Takeuchi K, Tei K, Mannami M, Toshino A, Oka A, Ohoka H, Ito
Acknowledgments H. Histopathology of a human allografted kidney with clinically
sufficient function. Clin Transplant 2000; 14: 25–29.
The data reported here were supplied by the U.S. Scientific Renal Trans- 10. Vereerstraeten P, Abramowicz D, de Pauw L, Kinnaert P. Absence
plant Registry (SRTR). The interpretation and reporting of these data are of deleterious effect on long-term kidney graft survival of rejec-
the responsibility of the authors and in no way represent an official policy tion episodes with complete functional recovery. Transplantation
or interpretation of the U.S. Government. 1997; 63: 1739–1743.
11. Madden RL, Mulhern JG, Benedetto BJ et al. Completely re-
Part of this data was presented at the annual meeting of the American versed acute rejection is not a significant risk factor for the devel-
Society of Transplantation in Washington 2003. opment of chronic rejection in renal allograft recipients. Transpl
Int 2000; 13: 344–350.
We would like to express our appreciation to Suzanne C. Johnson who has 12. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
helped with the editing and reviewing of the paper. serum creatinine. Nephron 1976; 16: 31–41.
13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A
more accurate method to estimate glomerular filtration rate from
References serum creatinine: a new prediction equation. Modification of Diet
in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–
1. Tesi RJ, Elkhammas EA, Henry ML, Davies EA, Salazar A, Fer- 470.
guson RM. Acute rejection episodes. best predictor of long-term 14. Meier-Kriesche HU, Ojo AO, Hanson JA et al. Increased impact
primary cadaveric renal transplant survival. Transplant Proc 1993; of acute rejection on chronic allograft failure in recent era. Trans-
25: 901–902. plantation 2000; 70: 1098–1100.