Cigarette smoking, kidney function, and mortality after live donor kidney transplant.
ABSTRACT The role of smoking as a risk factor for adverse renal outcomes after kidney transplant has not been well studied. We therefore undertook this investigation to assess the association of smoking with transplant outcomes.
Retrospective cohort study.
997 consecutive laparoscopic live donor kidney transplant recipients at a tertiary-care transplant center.
Smoking at the time of the transplant evaluation.
Primary outcome is transplant survival.
At the time of pretransplant evaluation, 329 participants had ever smoked and 668 participants had never smoked. Transplant survival was worse in ever smokers compared with never smokers (adjusted HR, 1.47; 95% CI, 1.08-1.99; P = 0.01), as was patient survival (adjusted HR, 1.60; 95% CI, 1.06-2.41; P = 0.02). First-year rejection-free survival was substantially worse (adjusted HR, 1.46; 95% CI, 1.05-2.03; P = 0.03) and risk of rejection on or before posttransplant day 10 was much higher (adjusted HR, 1.8; 95% CI, 1.10-2.94; P = 0.02) in ever smokers compared with never smokers. Glomerular filtration rate (estimated using the Modification of Diet in Renal Disease Study equation) at 1 year posttransplant was lower and poor early transplant function was more common in ever smokers on univariate, but not multivariate, analysis.
Lack of quantitation of smoking exposure and uncertainty about whether patients were still smoking at the time of transplant.
Our results suggest that any history of smoking before transplant is associated with impaired transplant and patient survival and increases the risk of early rejection after live donor kidney transplant. Further study is needed to determine whether smoking may impart immunomodulatory and perhaps nephrotoxic effects.
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ABSTRACT: To systematically review and summarize the evidence of an association between preoperative smoking status and postoperative complications elaborated on complication type. The conclusions of studies examining the association between preoperative smoking and postoperative complications are inconsistent, thus there is a need for a review and meta-analysis to summarize the existing evidence. A systematic review and meta-analysis based on a search in MEDLINE, EMBASE, CINAHL, and PsycINFO. Included were original studies of the association between smoking status and postoperative complications occurring within 30 days of operation. In total, 9354 studies were identified and reviewed for eligibility and data were extracted. Forest plots and summarized relative risks (RR) including 95% confidence intervals (CIs) were estimated for various complication types. Of the 9354 identified studies, 107 studies were included in the meta-analyses and based on these, 157 data sets were extracted. Preoperative smoking was associated with an increased risk of various postoperative complications including general morbidity (RR = 1.52, 95% CI: 1.33-1.74), wound complications (RR = 2.15, 95% CI: 1.87-2.49), general infections (RR = 1.54, 95% CI: 1.32-1.79), pulmonary complications (RR = 1.73, 95% CI: 1.35-2.23), neurological complications (RR = 1.38, 95% CI: 1.01-1.88), and admission to intensive care unit (RR = 1.60, 95% CI: 1.14-2.25). Preoperative smoking status was not observed to be associated with postoperative mortality, cardiovascular complications, bleedings, anastomotic leakage, or allograft rejection. Preoperative smoking was found to be associated with an increased risk of the following postoperative complications: general morbidity, wound complications, general infections, pulmonary complications, neurological complications, and admission to the intensive care unit.Annals of surgery 06/2013; · 7.90 Impact Factor
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ABSTRACT: Baseline co-morbidities influence patient outcomes in renal transplantation. Identification of high risk recipients for patient death and early allograft loss might lead to superior stratification. In this retrospective study risk stratification models were developed in a cohort of 392 kidney transplant recipients and validated in an independent cohort to predict short term (2 year) outcomes. Peripheral arterial disease [OR 7.7 (95% confidence interval (CI): 2.45-24.60); P<0.001], use of oral anticoagulation [OR 18.68 (95% CI: 3.77-92.46); P<0.0001], smoking [OR 5.15 (95% CI: 1.67-15.84); P=0.004], recipient age >60years [OR 7.28 (95% CI: 2.33-22.69; P=0.001)], serum-albumin <40g/l [OR 5.08 (95% CI: 1.82-14.19); P=0.002], serum-calcium >2.42 mmol/l [OR 6.47 (95% CI: 1.37-30.58); P=0.02] living donation [OR 2.95, (95% CI: 0.31-28.29); P=0.34)] and previous hemodialysis [OR 3.33, (95% CI: 0.39- 28.11); P=0.27) ] were included in the model. The validated model discriminated between low (<3 points) and high risk recipients (>8.5 points) with mortality rates of 0% vs. 54%. The comparison of the model with the Charlson comorbidity index (CCI) yielded significantly better receiver operating characteristic (ROC) areas (Novel Score ROC: 0.87 vs. CCI: 0.72, P=0.0012). Early allograft loss was associated with pre-sensitization [OR 3.02 (95% CI: 1.29-7.09); P=0.011] and presence of hepatitis C antibodies [OR 2.42 (95% CI: 1.09-5.34); P=0.029]. A risk model (ROC: 0.62) for allograft loss could not be developed. Risk stratification based on the novel score might identify high risk recipients with disproportional risk of early patient death and lead to optimised strategies. This article is protected by copyright. All rights reserved.European Journal of Clinical Investigation 11/2013; · 3.37 Impact Factor
- Nursing 01/2013; 43(1):58-62.
Cigarette Smoking, Kidney Function, and Mortality After Live Donor
Joseph M. Nogueira, MD,1Abdolreza Haririan, MD,1Stephen C. Jacobs, MD,2
Matthew Cooper, MD,3and Matthew R. Weir, MD1
Background: The role of smoking as a risk factor for adverse renal outcomes after kidney transplant
has not been well studied. We therefore undertook this investigation to assess the association of
smoking with transplant outcomes.
Study Design: Retrospective cohort study.
Setting & Participants: 997 consecutive laparoscopic live donor kidney transplant recipients at a
tertiary-care transplant center.
Predictor: Smoking at the time of the transplant evaluation.
Outcomes & Measurements: Primary outcome is transplant survival.
Results: At the time of pretransplant evaluation, 329 participants had ever smoked and 668
participants had never smoked. Transplant survival was worse in ever smokers compared with never
smokers (adjusted HR, 1.47; 95% CI, 1.08-1.99; P ? 0.01), as was patient survival (adjusted HR, 1.60;
95% CI, 1.06-2.41; P ? 0.02). First-year rejection-free survival was substantially worse (adjusted HR,
1.46; 95% CI, 1.05-2.03; P ? 0.03) and risk of rejection on or before posttransplant day 10 was much
higher (adjusted HR, 1.8; 95% CI, 1.10-2.94; P ? 0.02) in ever smokers compared with never smokers.
Glomerular filtration rate (estimated using the Modification of Diet in Renal Disease Study equation) at 1
year posttransplant was lower and poor early transplant function was more common in ever smokers on
univariate, but not multivariate, analysis.
Limitations: Lack of quantitation of smoking exposure and uncertainty about whether patients were
still smoking at the time of transplant.
Conclusions: Our results suggest that any history of smoking before transplant is associated with
impaired transplant and patient survival and increases the risk of early rejection after live donor kidney
transplant. Further study is needed to determine whether smoking may impart immunomodulatory and
perhaps nephrotoxic effects.
Am J Kidney Dis 55:907-915. © 2010 by the National Kidney Foundation, Inc.
INDEX WORDS: Kidney transplantation; smoking; acute rejection.
Editorial, p. 817
opment of chronic kidney disease.1-3Several
studies have suggested an association between
smoking and risk of microalbuminuria and mac-
roalbuminuria/proteinuria.4-7Some studies also
suggest that smoking may promote a decrease in
kidney function, particularly in those with hyper-
tension,8diabetes mellitus,9and primary renal
gested that the overall evidence for cigarette
smoking as a remediable risk factor for incident
chronic kidney disease is strong.3
The mechanisms of smoking-related kidney
injury are not entirely clear, and the pathophysi-
hypothesized direct vascular effects that could
lead to both small- and large-vessel disease.14-18
n the general population, smoking may be an
Others have suggested that activation of the
sympathetic nervous system may aggravate hy-
pertension, increase oxidative stress, and result in
endothelial dysfunction.19,20Smoking-induced al-
terations in intrarenal hemodynamics also may be
at play.13,21,22Cigarette smoking also may affect
From the1Division of Nephrology, Department of Medi-
3Department of Surgery, Section of Transplantation, Univer-
sity of Maryland School of Medicine, Baltimore, MD.
Received June 19, 2009. Accepted in revised form Octo-
ber 27, 2009. Originally published online as doi:10.1053/j.
ajkd.2009.10.058 on February 22, 2010.
Address correspondence to Joseph M. Nogueira, MD,
University of Maryland School of Medicine, Division of
Nephrology, N3W143, Department of Medicine, 22 S Greene
St, Baltimore, MD 21201. E-mail: jnogueir@medicine.
© 2010 by the National Kidney Foundation, Inc.
2Divison of Urology, Department of Surgery; and
American Journal of Kidney Diseases, Vol 55, No 5 (May), 2010: pp 907-915907
of progression of immune-mediated native kidney
tation suggest that active smoking may be an
important risk factor for transplant loss24-26and
mortality.25,27A retrospective review of 1,334
renal transplant recipients performed by Kasiske
and Klinger25at Hennepin County Medical Cen-
ter between 1963 and1997 found that a smoking
history of ? 25 pack-years was associated with a
whereas lesser magnitudes of smoking did not
show significant associations with transplant sur-
vival.Their data showed that stopping smoking 5
years before transplant abrogated some of the
risk of smoking. The study also suggested that
the higher rate of transplant loss in heavy smok-
ers was caused by an increase in deaths because
higher mortality was noted in smokers and return
to dialysis therapy and 1-year serum creatinine
levels were not different in smokers.25
of 645 kidney transplant recipients from 1958-
1995 and found that pretransplant smoking was a
strong and independent risk factor for transplant
loss during follow-up of ?10 years (adjusted rela-
tive risk, 2.3; P ? 0.005). In contrast to the study
by Kasiske and Klinger,25they did not show a
statistically significant difference in patient sur-
vival between smokers and nonsmokers. Similar to
the Kasiske and Klinger25study, they noted that
those who stopped smoking pretransplant were not
at higher risk of transplant loss compared with
those who never smoked. Additionally, they noted
no difference in risk of acute rejection between
able data suggest that current smoking at the time
of transplant appears to be associated with worse
transplant survival, but the mechanism for this
We undertook this study to examine whether
ever smoking is predictive of impaired patient and
transplant survival after kidney transplant. Impor-
tantly, we also evaluated acute rejection risk and
renal function parameters in hopes of providing
which smoking may impact on transplant survival.
Additionally, we limited our analysis to living do-
nor kidney recipients, for whom there would be
less variability in the quality of the transplant to
confound interpretation of short- and long-term
The study population included 997 consecutive recipients
of laparoscopically procured living donor renal transplants
at our major university hospital transplant center, and trans-
plants were performed between March 1996 and November
2005. The laparoscopic surgical technique was described
During the study period, our immunosuppression protocol
of choice evolved. Lymphocyte-depleting agents, including
lymphocyte immune globulin, antithymocyte globulin
(equine) sterile solution (Atgam; Pfizer, www.pfizer.com),
centocor.com), rabbit antithymocyte globulin (Thymoglobu-
lin; Genzyme Corporation, www.genzyme.com), were used
as induction in recipients who had a prior transplant or panel
reactive antibody level ? 40%. In others, basiliximab was
used routinely for induction since February 2002. The main-
tenance immunosuppression regimen initially consisted of
microemulsion cyclosporine, mycophenolate, and pred-
nisone. In October 1997, tacrolimus replaced cyclosporine.
In the absence of a prior transplant or panel reactive anti-
body level ? 40%, corticosteroid dosage was tapered off
within 3 weeks in non–African American recipients since
February 2002 and in African American recipients since
August 2005. Sirolimus was used sporadically since 2002.
Percutaneous renal transplant biopsies were performed in
recipients with poor transplant function every 7-14 days in
the early posttransplant period, and later biopsies were
performed as clinically indicated to evaluate transplant dys-
function.Acute rejection was treated with high-dose cortico-
steroids or a course of lymphocyte-depleting agents.
After approval from The University of Maryland Institu-
were retrieved for study participants. Patient demographic,
clinical, and laboratory data, as well as transplant and patient
survival status, were compiled primarily from our transplant
database, with review of transplant clinic and hospital records
plant evaluation. Ever smokers were defined as past or
current smokers. Never smokers were defined as those who
had negative responses to queries about prior and current
smoking. Current smokers were defined as those who admit-
ted to current smoking at the time of pretransplant evalua-
tion, and ex-smokers are defined as those who had quit
smoking by the time of the pretransplant evaluation. Quanti-
tation of either past or current smoking history was not
Nogueira et al908
Failure of the renal transplant was defined as return to
another form of renal replacement therapy (dialysis or re-
peated kidney transplant) or patient death with a functioning
transplant. Follow-up time and survival analyses were cen-
sored at the time of the most recent follow-up with our
center. Poor early transplant function was defined as the
need for hemodialysis on posttransplant day 1-7 or serum
creatinine level ? 3.0 mg/dL on posttransplant day 5. Need
for dialysis was determined by identifying which patients
generated an inpatient hemodialysis unit bill during the first
postoperative week. Estimated glomerular filtration rate
(eGFR) was calculated using the 4-variable Modification of
Diet in Renal Disease (MDRD) Study equation.29Identifica-
tion of acute rejection episodes during the first posttrans-
plant year was achieved using manual review of pathology
reports for all recipients by the first author. Acute rejection
was defined as biopsy-proven acute cellular or humoral
rejection according to prevailing Banff criteria.30,31Find-
ings similar to or more severe than Banff 1A rejection were
required to qualify as acute cellular rejection. Very early
rejection was defined as acute rejection diagnosed on or
before posttransplant day10.The primary outcome was renal
transplant survival, and our primary analysis of interest was
the comparison of ever smokers with never smokers.
Continuous variables were reported as mean ? standard
deviation and compared using analysis of variance and t
tests. Categorical variables were reported as absolute num-
ber of patients and/or percentage of the particular group and
compared using ?2tests. Adjustments for multiple covari-
ates, as detailed in the Results section, were made using
sion for categorical outcomes. Survival analyses were per-
formed using Kaplan-Meier techniques, compared using
log-rank tests, and adjusted for potential confounders using
tions were tested using Schoenfeld tests and log-minus-log
survival plots. The assumption of linearity of the relation-
ship was examined using component plus residual plotting
for continuous variables and comparing subgroup residuals
for binary covariates. P ? 0.05 is considered statistically
significant. Potential confounding variables were chosen a
priori for inclusion in the multivariate analysis from baseline
factors that were asymmetrically distributed between the
groups, for which data were available from a sufficient
number of participants (?95%), and for which an indepen-
dent effect on the outcomes was believed to be reasonably
expected, even if a statistically significant effect was not
shown in univariate analysis. SPSS version 8.0 (SPSS Inc,
www.spss.com) and Stata SE 9.1 (Stata Corp, www.stata.
com) software were used for statistical analyses.
At the time of transplant evaluation, there
were 668 participants who never smoked and
329 who had ever smoked, 96 of whom were
current smokers and 233 were ex-smokers. The
lapse of time from initial pretransplant evalua-
tion (at which time smoking history was rou-
tinely obtained) to transplant was 265 ? 273
days, with 79% ? 1 year and 94% ? 2 years.
Baseline demographic and clinical parameters of
participants and duration of follow-up are listed
in Table 1. Some important differences between
groups existed, including older recipient age and
higher proportion of male recipients, diabetes
mellitus, and steroid-free initial maintenance im-
on the a priori criteria discussed, the following
covariates were used in regression analyses: re-
cipient age, recipient sex, diagnosis of diabetes
mellitus, steroid-sparing initial maintenance im-
munosuppression regimen, and history of illegal
drug use. We found no evidence for interactions
among smoking and the predicting covariates
(analyses not shown).
Overall renal transplant survival was worse in
ever smokers compared with never smokers, as
shown in Fig 1A. Patient survival was worse in
ever smokers, as shown in Fig 1B. Table 2 lists
cumulative events and event rates for the ever- and
never-smoker groups. These differences persisted
on multivariate analysis, andTable 3 lists details of
Figure 2A and B show these survival analyses
the ever-smoker group separated into current
smokers and ex-smokers. On multivariate analy-
sis of transplant survival in the ex-smoker and
current-smoker subgroups of ever versus never
ally more likely (adjusted hazard ratio [HR],
1.37; 95% confidence interval [CI], 0.97-1.94;
P ? 0.07) and current smokers were significantly
more likely (adjusted HR, 1.76; 95% CI, 1.14-
2.7; P ? 0.01) to experience transplant loss
compared with never smokers. On multivariate
smoker cohorts of ever versus never smokers, we
found that ex-smokers were more likely (ad-
justed HR, 1.61; 95% CI, 1.02-2.53; P ? 0.04)
and current smokers were marginally more likely
(adjusted HR, 1.77; 95% CI, 0.99-3.17; P ?
0.06) to die compared with never smokers.
We had information about cause of death for 22
of 50 participants who died in the ever-smoker
group, and these included 8 cardiovascular, 11
Smoking and Kidney Transplant Outcomes 909
about cause of death in 23 of 58 participants who
There were no statistically significant differences
between groups in the proportion of any of these
Death-censored renal transplant survival was
similar in ever and never smokers, as shown in
Fig 1C, with cumulative events and event rates
listed in Table 2. There was a trend of worse
death-censored transplant survival (graphs not
shown) in current compared with never smokers
(P ? 0.08), but there was no apparent difference
in ex- compared with never smokers (P ? 0.5).
On multivariate analysis, a trend toward worse
death-censored transplant survival was noted in
the ever-smoker group (adjusted HR, 1.42; 95%
CI, 0.94-2.17; P ? 0.1).
To explore potential mechanisms that could
link smoking to decreased renal survival (in
addition to the effect of increased patient mortal-
ity), we assessed rejection rates, early kidney
function outcomes, and later renal outcomes in
the 2 groups. As shown in Fig 1D, rejection-free
kidney survival in ever smokers was worse dur-
ing the first posttransplant year, and this differ-
ence persisted on multivariate analysis (Table 3).
Figure 2C shows differences in rejection-free
survival among current, ex-, and never smokers.
Interestingly, Fig 1D shows that the curves
separate early, and very early acute rejection
(diagnosed on or before posttransplant day10)
Table 1. Baseline Factors of Groups
(N ? 997)
(n ? 329)
(n ? 668)
P (ever vs
Duration of follow-up (y)
Mean ? SD
3.49 ? 2.57
3.46 ? 2.55
3.51 ? 2.59
Age at transplant (y)
African American (%)
Body mass index (kg/m2)
Diabetes mellitus (%)
Prior transplant (%)
History of illegal drug use (%)
Zero HLA mismatch with donor (%)
HLA mismatch (no. of loci)
58.5 63.256.2 100
46.2 ? 13.9
26.7 ? 5.8
3.04 ? 1.59
50.6 ? 12.2
27.1 ? 6.6
2.99 ? 1.59
44.1 ? 14.2
26.5 ? 5.9
3.06 ? 1.59
Age at transplant (y)
African American (%)
Genetically unrelated to recipient (%)
40.2 ? 11.3
40.1 ? 11.2
40.0 ? 11.4
LDA induction (%)
Anti–interleukin 2 antibody induction (%)
Tacrolimus in initial maintenance IS
Sirolimus in initial maintenance IS
Steroid-free maintenance IS regimen (%)
Pretransplant desensitization (%)
Abbreviations: HLA, human leukocyte antigen; IS, immunosuppression; LDA, lymphocyte depletion antibody; NS, not
Nogueira et al910
was much more common in ever than never
smokers (12.5% and 6.6%, respectively; P ?
0.002), even on multivariate analysis (Table 3).
We also found that the incidence of very early
acute rejection was higher in the ex-smoker
subset of ever smokers compared with never
smokers (28 of 233 [12%] and 44 of 666 [6.6%],
respectively; P ? 0.009). We likewise found
significantly higher rates of very early rejection
in the current-smoking cohort compared with
never smokers (13 of 96 [13.5%] and 44 of 666
[6.6%], respectively; P ? 0.02). In the subgroup
that experienced very early rejection, there were
no statistically significant differences in baseline
factors listed in Table 1 for ever smokers com-
pared with never smokers (data not shown).
Additionally, we did not find differences in out-
comes based on smoking status in this group,
including eGFR at 1 year (48.7 ? 15.4 mL/min/
1.73 m2in ever smokers vs 53.1 ? 19.8 mL/min/
1.73 m2in never smokers; P ? 0.3), transplant
plant loss (log-rank P ? 0.9), and patient sur-
vival (log-rank P ? 0.7).
The ever-smoker group was more likely to
experience poor early transplant function than
never smokers (19.8% vs 14.5%, respectively;
P ? 0.04). One year posttransplant, the ever-
smoker group also had lower eGFRs than the
Table 2. Cumulative Event Rates for Various Survival
Event rate/100 person-years
Event rates/100 person-years
Death-censored graft loss
Event rates/100 person-years
Acute rejection in first year
(B) Patient survival for ever smokers. (C) Death-censored renal transplant survival. (D) Rejection-free renal survival.
Survival outcomes for ever versus never smokers. (A) Renal transplant survival (non–death censored).
Smoking and Kidney Transplant Outcomes911