American Journal of Transplantation 2007; 7: 899–907
Blackwell Munksgaard
Acute Pyelonephritis Represents a Risk Factor
Impairing Long-Term Kidney Graft Function
G. Pelléa , S. Vimontb , P. P. Levyc , A. Hertiga ,
N. Oualia , C. Chassind , G. Arletb , E. Rondeaua, ∗
and A. Vandewallea, d, ∗
a
Service des Urgences Néphrologiques et Transplantation
Rénale, b Service de Bactériologie, c Département de
Biostatistiques, Hôpital Tenon, AP-HP, Paris F-75970;
Université Paris 6-Pierre et Marie Curie 6 and d INSERM,
U773, Centre de Recherche Biomédicale Bichat-Beaujon
CRB3, BP 416, F-75018, Paris France; Université Paris
7-Denis Diderot, site Bichat, Paris, F-75870, Paris, France
∗ Corresponding authors: Alain Vandewalle and Eric
Rondeau,
vandewal@bichat.inserm.fr
eric.rondeau@tnn.aphp.fr
Urinary tract infections (UTIs) and acute pyelonephri-
tis (APN) often occur after renal transplantation, but
their impact on graft outcome is unclear. One hun-
dred and seventy-seven consecutive renal transplan-
tations were investigated to evaluate the impact of
UTIs and APN on graft function. The cumulative inci-
dence of UTIs was 75.1% and that of APN was 18.7%.
UTIs occurred mainly during the first year after trans-
plantation and Escherichia coli, Pseudomonas aerug-
inosa and Enteroccocus sp. were the most frequent
pathogens identified. The risk of developing APN was
higher in female (64%) than in male recipients, and was
correlated with the frequency of recurrent UTIs (p <
0.0001) and rejection episodes (p = 0.0003). APN did
not alter graft or recipient survival, however, compared
to patients with uncomplicated UTIs, patients with
APN exhibited both a significant increase in serum cre-
atinine and a decrease in creatinine clearance, already
detected after 1 year (aMDRD-GFR: APN: 39.5 ± 12.5;
uncomplicated UTI: 54.6 ± 21.7 mL/min/1.73 m2 , p <
0.01) and still persistent (∼ − 50%) 4 years after trans-
plantation. Multivariate analysis revealed that APN
represents an independent risk factor associated with
the decline of renal function (p = 0.034). Therefore,
APN may be associated with an enduring decrease in
renal graft function.
Key words: Glomerular filtration rate, pyelonephritis,
risk factors, renal transplantation, urinary tract infec-
tion
Abbreviations: APN, acute pyelonephritis; aMDRD-
GFR, abbreviated modification of diet in renal disease-
glomerular filteration rate formula; CrCI, creatinine
clearance; DGF, delayed graft function; PRA, panel re-
active antibodies; UTI, urinary tract infection.
C 2007 The Authors
Journal compilation 
C 2007 The American Society of
Transplantation and the American Society of Transplant Surgeons
doi: 10.1111/j.1600-6143.2006.01700.x
Received 24 July 2006, revised 2 October 2006 and
accepted for publication 5 December 2006
Introduction
Urinary tract infection (UTI), including asymptomatic bac-
teriuria, cystitis and pyelonephritis, is the most common
form of bacterial infection in renal transplant recipients (1,
2). These infections are thought to be directly attributable
to exposure to pathogens during the early postoperative
period and to immunosuppressive therapy (3–5). The im-
provement of surgical procedures, rapid removal of the
urethral catheter, and antibiotic prophylaxis have reduced
the incidence of UTI during the immediate postoperative
period (6, 7), but it is still higher in transplanted patients
than in the normal population. Until recently UTI was con-
sidered to be relatively benign, but a recent major retro-
spective study has revealed that late UTIs occurring after
renal transplantation (i.e. more than 6 months following
surgery) are associated with a significantly increased risk
of subsequent death (8). However, this study did not es-
tablish whether UTIs were the primary cause of death or
were a consequence of serious underlying illness. In ad-
dition, most of the studies did not distinguish between
simple UTIs and pyelonephritic UTIs and the impact of
acute pyelonephritis (APN) on immediate and long-term
renal graft function is still debated (9–11). Also, the impact
of APN on chronic allograft nephropathy, which is the most
prevalent cause of renal transplant failure in the first decade
posttransplant, is not clear. Although the incidence of early
APN (i.e. during the 3 months following surgery) appears to
be significantly detrimental to graft outcome (11), the long-
term consequences of APN on graft survival have not been
clearly established (8, 11, 12). Therefore, the question re-
mains as to whether the occurrence of APN following renal
transplantation may significantly impair renal function and
thereby promote graft loss. The aim of the present study is
to characterize the frequency of causative microorganisms
responsible for simple or pyelonephritic UTI, to analyze the
factors associated with APN and to evaluate the impact of
APN on renal function in a group of adult patients who had
kidney transplant, with a follow-up time of 4 years.
Materials and Methods
Patients
This retrospective study was conducted on 172 consecutive patients who
had received a renal allograft (177 kidney transplants) from January 2000
899
Pellé et al.
to December 2005 at Tenon hospital (Paris, France). The median follow-up
period was 665 days and the percentage of graft loss was 16.9%. In all
patients, a de novo insertion of the ureter into the bladder was performed.
A ureteral stent catheter was inserted, and removed by cystoscopy 4 to 6
weeks later. A urethral catheter was also inserted, and then systematically
removed 5 days after surgery.
Immunosuppressive treatment
Several different protocols were used for the induction and maintenance of
immunosuppression. For induction therapy, the monoclonal anti-IL-2 recep-
tor antagonist basiliximab (Simulect® , Novartis Pharma, Rueil Malmaison,
France) was used in 138 renal grafts, and rabbit ATG (Thymoglobulin® ,
Imtix-Sangstat, Lyon, France) were used in 26 renal grafts. Thirteen pa-
tients did not receive any induction therapy. Corticosteroids were given to
all the patients. A single 500 mg dose of methylprednisolone (Solumedrol® ,
Pharmacia, St Quentin-en-Yvelines, France) was given intraoperatively, with
1 mg/kg/day prednisone thereafter (Cortancyl® , Novartis Pharma, Rueil Mal-
maison, France), and was progressively decreased to a dose of 5 mg/day.
Steroid treatment in 66% of the patients, was associated with a combina-
tion of mycophenolate mofetil (Cellcept® , Roche, Neuilly-sur-Seine, France)
followed by cyclosporin treatment (Neoral® , Novartis Pharma), which was
started when the serum creatinine fell below 2.5 mg/dL, at latest day 7 post-
transplantation. The dose of cyclosporin was adjusted to provide drug blood
level between 100 ng/mL and 200 ng/mL. Fourteen patients were treated
with a combination of prednisone, mycophenolate mofetil, and sirolimus
(Rapamune® , Wyeth-Lederlé, Paris, France). Thirty-four patients (19.2%) re-
ceived prednisone, mycophenolate mofetil, and tacrolimus (Prograf® , Astel-
las Pharma Inc., Levallois Perret, France). The dose of tacrolimus was ad-
justed to obtain trough blood levels of 5–15 ng/mL. Five patients received
only prednisone and mycophenolate mofetil.
Antibiotic prophylaxis
All the patients received antibiotic prophylaxis consisting of 2 g of
intravenous cefazolin intraoperatively. Postoperative antibiotic prophy-
laxis consisted of trimethoprim-cotrimoxazole (Bactrim® , Roche, Neuilly-
sur-Seine, France), administered during the first 3 months to pre-
vent bacterial infection and Pneumocystis carinii pneumoniae. Due to
intolerance to Bactrim® , three patients received inhalation of pen-
tamidine isethionate on a monthly basis (Pentacarinat® nebulizer so-
lution, Sanofi-Aventis, Paris, France). All subjects also received oral
fluconazole (Triflucan® , Pfizer, Orsay, France) daily and prophylactic treat-
ment against cytomegalovirus (CMV) consisting of ganciclovir (Cymevan® ,
Roche, France) or valganciclovir (Rovalcyte® , Roche, France) during the
first 3 months, except for the CMV-negative recipients who received a
CMV-negative kidney. None of the patients received prophylactic treat-
ments such as lactobacillus or cranberry products, thought to prevent fim-
briated E. coli from adhering to uroepithelial cells (13, 14). Eight patients
developed CMV disease. This was defined as the association of fever with
one or more of the following clinical symptoms or biological abnormali-
ties: leukopenia, gastrointestinal disease, pancreatitis, hepatitis, pneumoni-
tis, myalgia, arthralgia and/or nephritis. Virological proof of CMV infection
was obtained in all patients by antigenemia or rapid viremia tests. The pa-
tients who had developed CMV infection were treated with intravenous
ganciclovir.
Laboratory investigation
Blood samples and urinary midstream specimens were obtained twice
weekly during the first 3 months, weekly during the following three months,
and approximately monthly after over a period of 4 years. Creatinine clear-
ance (CrCl) was calculated using the Cockcroft and Gault formula (15)
and the abbreviated MDRD formula [aMDRD = 1.86 × (serum creati-
nine, mg/dL)−1.154 × (age)−0.203 × (0.742 for woman; × 1.21 for African
American)] (16).
900
Episodes of UTI and APN
The diagnosis of UTI was reached on the basis of a urinary bacteria count
of more than 104 colony forming units (cfu)/mL combined with a urinary
leukocyte count of more than 104 /mL, or of a single urinary bacteria count
of more than 105 cfu/mL. Urinalysis and urine culture were performed in
all patients irrespective of symptoms at the frequency described above.
Additional urine culture and urinalysis was performed when patients ex-
hibited symptoms suggesting of UTI. UTI was referred to as recurrent if
it followed the resolution of a previous UTI and/or involved a reinfection
or relapse. APN was defined as a combination of a positive diagnosis of
UTI and fever and with one or more of the following clinical or biological
symptoms: graft pain, chills, cystitis, dysuria. An association of two an-
timicrobial agents, based on the antimicrobial susceptibility of the infecting
organism, were used, first intravenously until apyrexia was achieved, and
then orally for at least 3 weeks. All patients exhibiting APN were hospital-
ized and monitored at least twice a week during approximately 1 month.
Urological evaluation was only carried out for patients who developed a
second episode of APN. Patients with uncomplicated UTIs were generally
orally treated using single antibiotherapy during 5–7 days. For all patients
with uncomplicated UTIs, plasma levels of drugs and laboratory investiga-
tions were generally performed the day of the diagnosis and the 2 weeks
following, until clinical symptoms and bacteriological abnormalities were
resolved.
Acute rejection episodes
Acute rejection episodes were suspected in the case of an elevation
of the serum creatinine and were confirmed by graft biopsy examina-
tion. Anti-donor HLA specific antibodies in the serum were not per-
formed systematically, except for patients with humoral rejection diag-
nosed by histological examination of graft biopsy sample. In most cases,
the patients with acute rejection were not tested for C4d staining. In a
few cases (eight patients), biopsy sampling was not technically possible,
and these ‘intention-to-treat’ episodes also were taken into account. The
treatment of acute rejection consisted of intravenous corticosteroid (Sol-
umedrol® ) boluses for five consecutive days, followed by ATG in the event
of corticosteroid resistance manifested as the persistence or exacerbation
of the elevated serum creatinine after the last bolus, and the absence of
histological improvement.
Parameters studied and statistical analyses
A number of factors listed in tables were analyzed. Body mass index (BMI)
and proteinuria were analyzed after 3 months and 1 year following trans-
plantation. CrCl was determined at 3 and 6 months, and 1, 2, 3 and 4 years
after renal transplantation. Analyses were performed on the entire cohort of
patients and in three groups of patients: Group 1, patients who did not de-
velop UTI (-UTI); Group 2, patients with uncomplicated UTI (+UTI, −APN);
Group 3, patients with pyelonephritic UTI (+APN). In patient Group 3, only
serum creatinine and CrCl values measured after the first episode of APN
were taken into account. For each of the continuous variables studied, we
compared the three groups using the Kruskall Wallis test, and when a p
value was <0.05, comparison between two groups was performed using
the Mann-Whitney U test. For categorical variables, v 2 was used. Serum
creatinine and glomerular filtration rate (GFR) values were compared be-
tween the three groups at various times following transplantation. Data are
reported as mean values ± SD, and a p value <0.01 was considered to
be significant. A backward stepwise logistic regression analysis was also
performed to determine the independent risk factors for APN. Variables
with a p value <0.2 in the univariate analysis were included in the multi-
variate model. Graft and patient survival analyses were performed using
the Kaplan-Meier method, and statistical differences between curves were
assessed using the log rank test. Backward stepwise logistic regression
was also performed to identify the potential independent risk factors asso-
ciated with the decline of GFR during the first year posttransplantation. For
American Journal of Transplantation 2007; 7: 899–907
 Long-Term Kidney Graft Function

Table 1: Differences in demographic factors linked to the presence or absence of APN

Total Group 1 Group 2 Group 3 p-value
Number of transplants 177 44 108 25
∗
Recipient age (year ) 46.5 43.9 47.9 44.8 NS
Ethnic group (Caucasian/African/Other) 90/45/42 22/10/12 55/31/22 13/4/8 NS
Male recipients 117 34 74 9 0.0017
Anti-PRA > 20 % 14 5 6 3 NS
Hepatitis C virus seropositivity 19 4 11 4 NS
BMI at 3 months post-T∗ 24.6 24.4 24.7 24.6 NS
BMI at 1 year post-T∗ 24.9 24.6 25.4 23.3 NS
Initial end-stage renal disease
Glomerulonephritis 66 2 33 10 NS
Nephroangiosclerosis and others 111 21 75 15 NS
∗
Donor age (year ) 51.7 52.2 50.8 55.3 NS
Male donors 104 25 66 13 NS
Living donor 24 7 14 3 NS
Primary transplantation 148 34 96 18 NS
∗
Cold-ischemia time (h ) 20.3 18.1 20.6 22.9 NS
Immunosuppressive treatment NS
Anti IL-2 receptor 138 33 86 19 NS
ATG 26 8 12 6 NS
Cyclosporine/MMF/prednisone 117 29 71 17 NS
Sirolimus/MMF/prednisone 14 1 9 4 NS
Tacrolimus/MMF/prednisone 34 10 21 3 NS
Number of patients with DGF 45 15 24 6 NS
Patients with acute rejection 55 13 27 15 0.0003
CMV disease 8 1 5 2 NS
Post-graft diabetes 17 4 10 3 NS
Proteinuria at month-3 post-T (g/24h∗ ) 0.54 0.59 0.57 0.29 NS
Proteinuria at year-1 post-T (g/24h∗ ) 0.73 0.73 0.61 1.26 NS
Total = whole population of transplanted patients; Group 1 = patients who never had UTI; Group 2 = patients who did have uncomplicated
UTI; Group 3 = patients who did experience APN. Diabetes, urological and polycystic kidney diseases are not included in the Table,
as they were only 1 to 4 of initial disease in each group. BMI = body mass index; Anti-PRA = panel reactive antibodies; MMF =
mycophenolate mofetil; DGF = delayed graft function; Post-T = posttransplantation.
∗
Values are given as means.

this purpose, we used a binary variable. The limit between the upper third
and fourth quartiles of serum creatinine variations (creat) between year
1 and month 3 posttransplantation was 19 lmol/L. Such creat increase
was considered as clinically representative of degradation of renal graft
function. Therefore, preoperative, operative and postoperative potential risk
factors were analyzed for their association using this criteria on 107 patients
for which data were available at month 3 and year 1 posttransplantation.
For univariate statistics, v 2 (for categorical variables) and Mann-Whitney’s
U-tests (for continuous variables) were used. Variables with a p value <0.2
in the univariate analysis were included in this backward stepwise logis-
tic regression. Differences were considered to be significant for p value
<0.05. Statistical analysis was performed with StatViewTM software. Mul-
tivariate analysis using the Cox proportional hazard model analysis was also
used to determine relevant risk factors for graft lost on the entire cohort of
transplant patients.
Results
Frequency of urinary tract infections and causative
microorganisms
The demographic characteristics of the three groups of
transplanted patients analyzed are shown in Table 1. Af-
ter transplantation, most of the patients (75.1%) had at
least one episode of UTI during the five years of follow-up.
UTIs occurred more often in female than in male recipi-
ents. Table 2 recapitulates the diversity and percentages
of causative microorganisms identified in urine cultures
during the first episode of UTI or during second and sub-
sequent UTIs. A wide range of other Gram-negative and
Gram-positive rods, which had not been detected during
the first episode of UTI, were also identified as the single
causative agent (Table 2). The proportion of polymicrobial
UTI (two germs in most cases, most probably the con-
sequence of contamination of the sample) was about 8%,
whether during the first or the subsequent episodes of UTI
(Table 2).
Figure 1 displays the timing of the occurrence of the first
episode of UTI following renal implantation. P. aeruginosa,
coagulase-negative Staphylococci or E. cloacae were fre-
quently detected in the urine within the first 3–5 weeks fol-
lowing surgery. Enterococcus sp and E. coli were also fre-
quently detected during the first six weeks and 12 weeks,
respectively, after transplantation (Figure 1). The microor-
ganisms responsible for the first episode of UTI during the
first three months following renal graft (excluding the natu-
ral resistance of P. aeruginosa to Bactrim® ) were frequently
found to be resistant to trimethoprim-cotrimoxazole (E.
coli , 84%; E. cloacae, 67%; noncoagulase Staphylococcus,

American Journal of Transplantation 2007; 7: 899–907 901

Pellé et al.

Table 2: Causative microorganisms identified in urine of renal transplant recipients during the first and recurrent episodes of UTI over
5 years
First episode of UTI Second and more episodes of UTI
Number of positive cultures (%) Number of positive cultures (%)
Causative microorganisms 148 499
Gram-negative rods
Escherichia coli 42 (28.4) 126 (25.1)
Pseudomonas aeruginosa 22 (14.9) 80 (16.0)
Enterobacter cloacae 9 (6.1) 20 (4.0)
Klebsiella pneumoniae 3 (2.0) 29 (5.8)
Klebsiella oxytoca 2 (1.3) 13 (2.6)
Serratia marcescens 2 (1.3) 10 (2.0)
Stenotrophomonas maltophilia 2 (1.3) 5 (1.0)
Citrobacter freundii 1 (<1.0) 16 (3.2)
Proteus mirabilis – – 10 (2.0)
Morganella morganii – – 6 (1.2)
Gram-positive cocci
Enterococcus sp 35 (23.6) 92 (18.4)
Staphylococcus nonaureus 17 (11.5) 48 (9.6)
Streptococcus sp 4 (2.7) 11 (2.2)
Others∗ 9 (6.1) 33 (6.6)
Total number of UTIs 136 459
Polymicrobial UTIs 12 (8.8) 37 (8.1)
∗ Others corresponded to rare pathogens (≤1%) detected during the first episode of UTI (such as Klebsiella planticola or Haemophilus
influenzae), and second or more UTI episodes (such as Comamonas sp, Staphylococcus aureus or Aeromonas hydrophila). Polymicrobial
UTIs corresponded to UTI with positive urine culture for two germs and in one case to three germs in the group of second and more
episodes of UTIs.

Trimethoprim-cotrimoxazole
3 episodes: 5 patients). The risk of developing APN was
50 closely correlated to the frequency of recurrent episodes
E. coli of UTI (p < 0.0001). Among patients with recurrent APN,
Number of patients

40
Enterococcus sp vesicoureteric reflux and dilatation of the upper urinary
30 tracts were detected in three cases. Figure 2A depicts
the cumulative incidence of APN as a function of time af-
20 Pseudomonas aeruginosa
Coagulase-negative Staphylococcus
ter renal engraftment. About half of APN (51%) occurred
within the first six months following transplantation. Where
10 Enterobacter cloacae E. coli represented the main uropathogen (51%) respon-
0
sible for about half of the APN, the percentages of the
0 20 40 60 80 100 120 140
other causative microorganisms were similar to those of
pathogens identified in urine cultures over the follow-up
Time (days)
period. At 30 months following renal graft, graft survival
was 85.1% in patients without APN and 76.5% with APN.
Figure 1: Time to occurrence of the first episode of UTI de-
Kaplan-Meier analysis of graft survival indicated that the
pending on the microorganism identified in the urine culture.
occurrence of single or recurrent episodes of APN did not
Time values are means ± SD from (n) positive urine culture.
significantly influence graft survival in patients with or with-
out APN (Figure 2B). However, Kaplan-Meier analysis strat-
86%; Enterococcus sp, 46%). Most of the UTIs (74%) ified by gender revealed larger differences in graft survival
occurred during the first year following transplantation, in female than in male transplant patients (Figure 2C and
mainly during the first three months (81.9%). Thereafter, D). Due to the relative limited number of transplanted pa-
the proportion of UTIs significantly decreased during the tients, it cannot be excluded that the differences might
second (35.7%) to fourth (21.5%) year following transplan- have been significant with a larger sample size. Despite
tation. this restriction, APN also did not significantly affect graft
survival in patients with APN compared to patients with-
Incidence of acute graft pyelonephritis in renal out APN (graft survival rates after 5 years: patients without
transplant recipients APN: 76%; patients with APN: 75.6%).
Among 133 renal transplant patients who experienced sin-
gle or recurrent episodes of UTI, 25 patients (18.7%; 9 Factors associated with acute pyelonephritis
men, 16 women) had 41 typical episodes of APN (one We then analyzed the various groups of transplant pa-
episode of APN: 14 patients; 2 APN episodes: 6 patients; tients to find out which factors were associated with the
902 American Journal of Transplantation 2007; 7: 899–907
 Long-Term Kidney Graft Function

A Influence of acute pyelonephritis on long-term graft

function
30
To find out whether uncomplicated UTIs and/or APN could
25 impair renal graft function, the variations in serum crea-
APN (%)

20 tinine and CrCl values were analyzed in transplanted pa-

tients over the posttransplant follow-up period (Figure 3).
15
The time of occurrence of APN and rejection episodes tem-
10 porally associated with APN on the evolution of serum cre-
0 atinine levels for individual patients are illustrated in Figure
0 1 2 3 4 5 3A. In two cases, APN with rejection was followed by a
B Years posttransplantation
po dramatic increase in serum creatinine. In all other patients,
100 - APN, + APN serum creatinine frequently tend to increase progressively
Graft survival (%)

Male + female after APN (Figure 3A). As a result, mean serum creatinine
values were significantly greater (p < 0.01) one year after
80 renal graft in patient Group 3 (2.01 ± 0.42 mg/dL) than in
p = 0.4796
patient Group 1 (1.59 ± 0.51 mg/dL) and patient Group 2
(1.60 ± 0.63 mg/dL). The levels of CrCl did not differ sig-
nificantly in the three groups of patients for the first three
60
months after surgery (Figure 3B). One year after transplan-
0 1 2 3 4 5
C Years posttransplantation
p tation, CrCl was significantly lower (p < 0.01) in patient
100 Group 3 with APN than in the other patient Groups 1 and 2
Male with or without uncomplicated UTIs, respectively (aMDRD;
Graft survival (%)

Group 1: 56.4 ± 20.5; Group 2: 54.6 ± 21.7; Group 3: 39.5

p = 0.5415 ± 15.5 mL/min/1.73 m2 ). No differences in the levels of
80
CrCl were observed in the six patients who experienced
rejection episodes less than 3 months before or after the
episode of APN as compared to those of patients from
60 Group 3 who did not (aMDRD; 41.9 ± 22.1 vs. 38.6 ± 13.4
D 0 1 2 3 4 5 mL/min/1.73 m2 ). Thereafter, CrCl values always remained
Years posttransplantation
post
100 significantly lower in patient Group 3 with APN than in the
Female other two groups (Figure 3B). Four years after renal trans-
Graft survival (%)

plantation, the mean CrCl value for the patient Group 3

80
p = 0.1819
60
0 1 2 3 4 5
Years posttransplantation
post
Figure 2: Frequency of APN and Kaplan-Meier analysis of
graft survival after transplantation. (A) Cumulative incidence
of APN (expressed in % of total renal grafts). (B–D) Kaplan-
Meier analysis was performed on the whole population of patients
(male + female) with (+APN) and without APN (-APN) (B) and the
same group of patients stratified by gender (C and D).
occurrence of APN (Table 1). Significant differences were
found between the three groups for the gender of the re-
cipient (p = 0.0017), acute rejection episodes (p = 0.0003)
and in patients who developed recurrent UTIs (p < 0.001).
The multivariate analysis also indicated that female recip-
ient (risk ratio: 5.143, 95%CI: 1.862–14.206, p = 0.0017),
acute rejection episodes (risk ratio: 3.84, 95%CI: 1.371–
10.790, p = 0.0105), and the number of UTIs (risk ratio:
1.177, 95%CI: 1.061–1.306, p = 0.0021) represented in-
dependent risk factors associated with APN.
was about 50% lower (p < 0.01) than that found for pa-
tient Group 1 who did not develop UTI or patient Group
2 who exhibited uncomplicated UTIs (Figure 3B). Similar
results were found using the C&C method (not shown). To
better assess the deleterious consequence of APN on re-
nal graft function, CrCl levels measured just before (time 0),
six months and one year after the occurrence of the first
episode of APN in patient Group 3 were compared with
corresponding CrCl values of patients with no or simpe
UTI (Groups 1 and 2). The time 0 chosen for Groups 1 and
2 corresponded to the mean time delay of occurrence of
the first APN episode in patients Group 3 (i.e. 6.5 months
posttransplantation). The results confirmed that the occur-
rence of APN was associated with significant delayed de-
crease in CrCl (Figure 3C). Table 3 outlines the risk factors
associated with the decline of renal graft function. Uni-
variate analysis identified the following risk factors: pro-
teinuria at 1 year posttransplantation, diabetes mellitus,
acute rejection episodes and APN. Multivariate analysis re-
vealed that APN represented the only independent risk fac-
tor (p = 0.0034) associated with the decline in renal func-
tion (Table 3). Although of borderline significance, acute
rejection did not appear to be a significant risk factor
(p = 0.0643), suggesting that APN represents a factor
associated with renal function degradation independently
of acute rejection. Furthermore, the risk of decline of

American Journal of Transplantation 2007; 7: 899–907 903

Pellé et al.

A
4 *
3
2
1
4 4 4 *
3 3 3
2 2 2 *
1 1 1
4 4 4
3 * 3 3
2 2 2
Serum creatinine (mg/dL) 1 1 1
4 4 4
3 * 3 3
2 2 2
1 1 1
4 4 4
3 3 3
2 2 2
1 1 1
4 * * 4 4
3 3 3
2 2 2
1 1 1
4 4 4 *
3 3 3
2 2 2
1 1 1
4 4 4
3 3 3
2 2 2
1 1 1
4 4 * 4
3 3 3
2 2 2
1 1 1 0 3 65 730 10 95 14 60

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
0 3657301095
1460 0 3657301095
1460
Years after transplantation
B C
- UTI, + UTI - APN, + APN - UTI, + UTI - APN, + APN
100
(mL/min/1.73 m2)
(mL/min/1.73 m2)

60 y = -0.21x + 56.6 (r = -0.99)

GFR - aMDRD
GFR - aMDRD

80
60 50 y = -0.25x + 54.2 (r = -0.98)
*
40 40
* * * * y = -0.65x + 44.7 (r = -0.95)
20
* 30
0
0 1 2 3 4 0 6 12
Years after transplantation Time (months)

Figure 3: Influence of APN on serum creatinine and creatinine clearance (CrCl) in renal grafts. (A) Individual variations of serum
creatinine levels in patient Group 3 with APN. Arrows indicate the time of occurrence of APN. Open circles correspond to serum creatinine
values measured during the APN episode. Stars indicate the rejection episodes temporally (before or after) associated with APN. (B)
Variations of CrCl values measured using the aMDRD formula in patient Group 1 (no UTI, –UTI); patient Group 2 (uncomplicated UTI, +UTI
–APN) and patient Group 3 (+APN). (C) Variations in mean CrCl values in patients Group 3 (+APN) before, and 6 months and 1 year after
the first episode of APN and compared to corresponding values from patients with no UTI (–UTI) or uncomplicated UTI (+UTI –APN).
∗ p < 0.01 Group 3 versus Groups 1 and 2.

the renal graft function increased by 3.4-fold in patient Discussion

Group 3 with APN. Multivariate analysis using the Cox
model on the whole cohort of transplanted patients in- Patients who have undergone renal transplantation are
dicated that the factors associated with increased graft highly susceptible to UTIs, and in the present study 18.7%
loss were: donor age (p = 0.035), graft origin (deceased of the patients with UTIs went on to develop APN, which is
or live donor) (p = 0.0173) and aMDRD at year 1 post- a potent risk factor for the deterioration of renal graft func-
transplantation (p = 0.037). Neither APN nor acute rejec- tion. Renal grafts are particularly susceptible to the direct
tion episodes appeared to be independent factors of graft and/or indirect consequences of UTI. There is greater risk
loss. of bacterial invasion of the transplanted kidney, because of

904 American Journal of Transplantation 2007; 7: 899–907

 Long-Term Kidney Graft Function

Table 3: Univariate and multivariate analysis of factors associated with a decline of renal graft function between 3 months and 1 year
after renal transplantation
Univariate analysis Patient groups p
creat ≤ 19lmol/L (n = 81) creat > 19 lmol/L (n = 26)
Male recipients∗ 59 17 NS
Ethnic groups (Africans vs. others∗ ) 18 7 NS
Recipient age at transplantation (year∗∗ ) 45.6 44.8 NS
Deceased donors∗ 69 23 NS
Donor age (year∗∗ ) 48.9 51.8 NS
Male donor∗ 52 17 NS
Anti-PRA >20%∗ 5 3 NS
Hepatitis C virus seropositivity∗ 6 4 NS
Duration of cold-ischemia (h∗∗ ) 20.1 20.6 NS
Patients with DGF∗ 11 6 NS
Hospitalization for CMV∗ 6 1 NS
BMI at month 3 post-T∗∗ 24.6 23.1 NS
Proteinuria at month 3 post-T (g/24 h∗∗ ) 0.29 0.69 NS
BMI at year 1 post-T∗∗ 25.1 24 NS
Proteinuria at year-1 post-T (g/24 h∗∗ ) 0.46 1.44 0.071
Antidyslipidemia treatment at month 3 post-T∗ 19 6 NS
Acute rejection∗ 26 13 0.192
Diabetes∗ 3 3 0.1404
Antihypertensive treatment at month 3 post-T∗ 58 16 NS
APN∗ 19 9 0.040
Multivariate analysis RR 95%CI p
APN 3.39 1.19–17.90 0.0035
APN = acute pyelonephritis; post-T = posttransplantation; creat = difference in serum creatinine between year 1 and month 3
posttransplantation.
∗ Number of patients in each group.
∗∗ Values are given as means.

the immunosuppression and vulnerability of the graft that
follow surgical manipulation (3–5). Intraoperative ureteral
stents and bladder catheter may also increase the risk of
UTIs in transplanted patients (5, 12).
The cumulative incidence of UTIs differs widely from one
study to another, ranging from 6% to 86% (11, 17–19). In
the present study, UTIs occurred in about 75.1% of the
renal recipients over a 5-year period. Such a high incidence
of UTI may be explained by the frequency of urine sam-
pling, and the criteria used to define UTI. Furthermore,
the relatively high percentage of uropathogens resistant
to the trimethoprim-cotrimoxazole may explain, at least
in part, the relative high incidence of UTI and APN dur-
ing the 3 months following transplantation and raised the
question of a more adapted antibiotic prophylactic treat-
ment.
The factors associated with an increased risk of UTI af-
ter renal transplantation are still controversial. We show
that among risk factors, female sex and acute rejection
episodes are associated with a higher incidence of APN.
Giral et al. (11) also reported that female recipients had a
higher risk than the male recipients of developing APN. UTI
is not uncommon in patients with renal failure secondary
to diabetic nephropathy, and the immunosuppressive ef-
fect of corticosteroid therapy and steroid-induced diabetes
are both thought to increase the susceptibility to infection.
However, in our study, underlying kidney disease, such as
diabetic nephropathy or polycystic kidney disease, did not
appear to influence the incidence of UTI and APN in re-
nal grafts (1). Likewise, the different immunosuppressive
regimens had no significant impact on the occurrence of
UTIs. The role of the immunosuppressive regimen as an
infection risk factor remains controversial. Recent random-
ized trials comparing combinations of two different doses
of sirolimus plus cyclosporin (20) or tacrolimus versus cy-
closporin for primary immunosuppression (21, 22) led to
the conclusion that these immunosuppressive treatments
have no direct influence on the occurrence of infections.
However, mycophenolate mofetil-based primary immuno-
suppression has been recently reported to be associated
with a greater incidence of APN (12).
There is also no consensus about the impact of UTIs
on graft rejection. It is generally agreed that the in-
creased incidence of infections is proportional to the inten-
sity of immunosuppressant therapy (23–25). Müller et al.
(23) reported that transplanted patients displaying chronic
rejection had more UTIs than those displaying no appar-
ent signs of rejection. In contrast, Giral et al. (11) reported
that rejection episodes do not constitute a risk factor for
APN. In the present study, we found a statistical significant
association between acute rejection episodes and APN.

American Journal of Transplantation 2007; 7: 899–907 905

Pellé et al.
The rapid onset of APN (six cases) following acute rejec-
tion episodes suggests that the pyelonephritis is a direct
consequence of more intensive immunosuppressant ther-
apy. On the other hand, the occurrence of three acute rejec-
tion episodes rapidly following APN could also suggest that
the renal infection may have triggered an immunostimula-
tory response, which in turn increased the risk of acute re-
jection. Other similar occurrences of acute rejection shortly
after APN have been reported recently (26). However, in
most cases the APN was not directly or chronologically
linked to acute rejection episodes. Since not all patients
with acute rejection develop UTI, we cannot rule out the
possibility that variations in the host’s immune function
may also determine susceptibility to UTIs (25,27). Further
studies are needed to investigate the immunological status
of the transplanted patients who are particularly suscepti-
ble to APN.
The consequences of UTI on long-term graft function
are poorly defined. Early APN occurring during the first
3 months following renal transplantation is detrimental to
graft outcome independently of acute rejection episodes
(11). Later onset UTI has been generally considered to be
relatively benign. However, a recent retrospective study on
a large cohort of primary renal transplant recipients reveals
that even UTIs occurring some considerable time after re-
nal transplantation, can contribute significantly to subse-
quent mortality and graft loss (8). Kaplan-Meier analysis
indicates that single or recurrent episodes of APN did not
significantly alter middle-term graft survival. However, the
occurrence of APN appears to be associated with a decline
of renal graft function. Whether APN represents an inde-
pendent risk factor for long-term renal graft dysfunction re-
main to be determined. The results from the multivariate
analysis also suggest that APN represent an independent
risk factor of the degradation of the renal graft function, in-
dependently of acute rejection episodes, which however
are more frequent in the group of pyelonephritic patients.
However, the present study has some limitations. This is
a single center study and the cohort of patients analyzed
remains limited. Although all transplanted patients were
screened, this is a retrospective study, and it cannot be
fully excluded that some data are missing. Moreover, our
data are associative by nature and one also cannot exclude
that some unidentified factor(s) associated to APN would
be the real culprit in the decline of renal graft function.
Although the statistical analyses revealed association be-
tween APN and the decline of CrCl, they also show, but do
not explain, the association between APN and acute rejec-
tion episodes. Further studies should therefore be required
to confirm on a larger scale, and also to better understand,
the links between APN, acute rejection episodes, and the
decline of renal graft function. Still, the present findings
suggest that APN has a delayed negative impact on re-
nal graft function. More specific attention to prevention
and monitoring of recurrent UTIs and/or APN can be ex-
pected to be of benefit for the long-term preservation of
renal grafts.
906
Acknowledgments
This work was supported in part by the INSERM and by an Interface
INSERM-Assistance Publique-Hôpitaux de Paris (AP-HP) grant (to AV). We
thank Mrs. M. Richard for her precious help in data collection.
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