Urinary Tract Infections in Kidney Transplant Recipients Hospitalized

at a Transplantation and Nephrology Ward: 1-Year Follow-up

skaa, Ł. Chabrosb, G. Młynarczykb, A. Kwiatkowskic, A. Chmurac,
J. Gozdowskaa,*, M. Czerwin
a
and M. Durlik
a
Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland; bChair
and Department of Medical Microbiology, Medical University of Warsaw, Warsaw, Poland; and cChair and Department of General and
Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland

ABSTRACT
Introduction. The aim of this study was to investigate risk factors for urinary tract in-
fections (UTI), the causative organisms of UTI and also their management and treatment.
In addition, we evaluated the effects of UTI on renal graft function.
Methods. This analysis included 107 kidney transplant recipients (64% women) with a
diagnosis of UTIs confirmed by positive results on urine culture. Type of pathogens,
sensitivity to drugs, risk factors for infection, incidence of urosepsis, hospitalization period,
treatment methods, and recurrence rates were analyzed. Statistical analysis was performed
by using Pearson’s c2 test, Yates’ c2 test, the Student t test, Welch’s t test, the Mann-
Whitney U test, Fisher’s exact test, and the Shapiro-Wilk normality test.
Results. The most common species isolated from urine samples included Escherichia coli
(42%), Klebsiella pneumoniae (15%), and Enterococcus faecalis (10%). The percentage of
multidrug-resistant strains was 31%, and urosepsis was diagnosed in 16% of patients.
Recurrences developed in 76% of infected patients. Bricker ureterointestinal
anastomosis was performed in 11% of patients. Risk factors for severe infections
included: pre-transplantation urinary tract surgery (P ¼ .02), double-J stent insertion
(more common in men) during KTx (N ¼ 34; 32%), (P ¼ .021), reoperations following
transplantation (P ¼ .36), elevated tacrolimus levels at the time of infection (P ¼ .024).
Severe infections were diagnosed in patients with lower eGFRs, were associated with a
need for longer hospitalization (P ¼ .04) and escalation of antibacterial treatment.
Carbapenems were used in 22 patients (20.5%).
Conclusions. UTIs were more common in women, in patients with impaired function of
the kidney transplant, and in those with a history of urinary tract interventions. Severe
infections were associated with a risk of urosepsis, longer hospitalization, and a need for
escalation of antibiotic treatment.

A HEALTHY person’s urinary tract is protected against

infections by several nonimmune and immune mech-
anisms that are not fully functional in kidney transplant
patients. Urinary tract infections (UTIs), mainly bacterial,
are a common infectious complication in kidney transplant
recipients. Studies conducted in a variety of transplantation
centers globally showed that the incidence of UTIs in these
patients may reach 80% of all infections, with most of them
developing in the first 6 months after transplantation [1,2].
The development of infection depends not only on micro-
bial virulence but also on the host’s susceptibility. Exposure
to microorganisms may be environmental or endogenous.
*Address correspondence to Jolanta Gozdowska, Department
of Transplantation Medicine, Nephrology and Internal Diseases,
Medical University of Warsaw, Nowogrodzka 59, 02-006 War-
saw, Poland. E-mail: jola-md@go2.pl

0041-1345/16 ª 2016 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.transproceed.2016.01.061 360 Park Avenue South, New York, NY 10010-1710

1580 Transplantation Proceedings, 48, 1580e1589 (2016)

UTI IN HOSPITALIZED KIDNEY TX RECIPIENTS
Impaired response of the immune system can be caused by
multiple factors, including: use of immunosuppressant
agents, disturbed integrity of the natural barrier formed by
the mucosa of the urinary tract, concomitant diseases,
neutropenia, lymphopenia, metabolic disorders (eg, dia-
betes mellitus), and nutrition disorders. Apart from
decreased immunity due to immunosuppressant agents,
additional problems may be posed by various preoperative
urologic disorders, vesicoureteral reflux to the transplanted
kidney as a result of ureteral implantation technique, or
instrumentation of the urinary tract (eg, Foley catheter,
double-J ureteral stent). These factors all contribute to the
high incidence of UTIs diagnosed in kidney transplant pa-
tients [3].
Infections in transplant recipients are characterized by
decreased inflammatory response, a clinically oligosympto-
matic course, rapid development in the kidney, disease
generalization, and frequent recurrences. Infections with a
mixed flora of 2 microorganisms are common. A clinical
course such as this requires prompt diagnosis and intensive
treatment. Because treatment of the infection should be
initiated as soon as possible, it is usually empirical; modifi-
cations are introduced after obtaining microbial test results.
In severe and moderate infections, immunosuppression
should be reduced. To decrease the risk of infections,
pharmacologic prophylaxis is commonly used in the first
months after transplantation, when immunosuppression is
intensive.
UTIs are generally divided into early infections, devel-
oping during the first 6 months after transplantation, and
late infections, occurring after 6 months. Epidemiology,
etiology, and clinical course of UTIs change over time from
surgery. In the early posttransplantation period, trans-
mission of infection from the donor with the transplanted
organ or the recipient’s flora may constitute the source of
infection. Donors hospitalized at intensive care units are
often infected with multidrug-resistant pathogens. In addi-
tion, antibiotic prophylaxis in the kidney transplant recipient
may foster the selection of resistant strains. In kidney
transplant patients, clinical symptoms specific to UTIs even
in severe infections may be unpronounced due to immu-
nosuppression; leukocyturia may be absent. Direct associa-
tion between these infections and organ loss or increased
mortality has not been clearly demonstrated [3,4].
UTIs may indirectly affect survival and transplant status,
resulting in bacteremia and episodes of acute rejection, or
they may create favorable conditions for viral infections,
including that with cytomegalovirus (CMV) [5]. The etiology
of UTIs is diverse, with the most common causative factor
being gram-negative bacilli (Escherichia coli and Klebsiella
pneumoniae), which are often resistant to many antibiotics
[2e4]. According to a Spanish register of infectious compli-
cations in organ transplant recipients (RESITRA [Network
for Research on Infection in Transplantation]), infections
are most frequent in the first 6 months after transplantation
[6]. Per the investigators, factors fostering the development
of infections are older age of the donor (risk increased by
1581
10% per decade), recipient’s female sex (a 75% increase in
the risk), and delayed graft function after the transplantation
requiring dialysis (63%). According to the register, the type
of immunosuppression, including induction therapy, was not
associated with an increased risk of infections.
PATIENTS AND METHODS
The present study included 107 kidney transplant recipients, hos-
pitalized at the Clinic of Transplantation Medicine, Nephrology and
Internal Diseases, Medical University of Warsaw (Warsaw, Poland),
in the 12-month period between October 2013 and October 2014;
the diagnosis of UTI was confirmed by using positive results on
urine culture. The study was retrospective. The time from trans-
plantation to infection development was analyzed, and 2 periods
were differentiated: early infection (ie, the period up to 6 months
after kidney transplant) and late infection (ie, after the 6-month
period). The nature of infection was analyzed (asymptomatic
bacteriuria, lower UTI, upper UTI [graft pyelonephritis (GPN)],
and urosepsis), and the investigators also assessed whether the UTI
developed for the first time (recurrences).
The analysis also covered other clinical data, including: fever at
admission (>38 C), presence of dysuria symptoms, and laboratory
findings (C-reactive protein level on admission day, urine sediment
changes, and normal or leukocyturia [pyuria]). In addition, the last
pre-UTI creatinine level was recorded, and the estimated glomer-
ular filtration rate was calculated by using the Modification of Diet
in Renal Disease equation.
In each case, before initiation of antibiotic therapy, a urine
sample was collected for culture; for those patients in moderate or
severe condition, a blood sample was also collected. The species of
pathogens obtained and their sensitivity to drugs were then
assessed. Drug-resistant strains were analyzed separately.
Another issue studied was the assessment of risk factors for
UTIs: pretransplantation urinary tract surgeries, insertion of a
double-J stent during the procedure, Bricker ureterointestinal
anastomosis, and early urinary tract reoperations with surgical
complications. Other assessed factors that may have an influence on
the incidence of infections were type 1 and 2 diabetes mellitus, as
well as new-onset diabetes after transplantation (NODAT) or viral
infections (CMV, hepatitis B virus, and hepatitis C virus). The type
of immunosuppressive treatment was also analyzed, including in-
duction and maintenance therapies, as well as the doses or con-
centrations of immunosuppressant agents used. The effect of acute
rejection episodes and the manner of their management (methyl-
prednisolone pulse therapy and polyclonal antibodies) on the
development of UTIs was evaluated.
Other studied criteria included hospitalization period and anti-
biotics prescribed. Two therapy categories were differentiated: (1)
empirical treatment on admission day; and (2) targeted therapy
after obtaining urine culture results and an antibiogram. Empirical
treatment was continued if it was clinically effective and if the
cultivated strains demonstrated in vitro sensitivity to the agent used.
In selected clinical cases, antibiotic therapy was modified (treat-
ment escalation or de-escalation). Some patients, after discharge,
continued antibiotic treatment with oral medications; the most
commonly used agents were assessed.
Definitions
UTI definitions were adopted according to the 2005 guidelines of
the Infectious Diseases Society of America [7].
1582 
GOZDOWSKA, CZERWINSKA, CHABROS ET AL

Asymptomatic bacteriuria is an increase (demonstrated in
microbiologic test results) in the count of a pathogen amounting
to 105 CFU/mL in a patient otherwise asymptomatic with respect
to UTI (including leukocyturia). In women, these values must be
recorded in 2 consecutive urine samples collected with at least a 24-
hour interval, <105 CFU/mL in patients undergoing antibiotic
therapy, or 102 CFU/mL in a single urine sample collected after
catheter insertion.
Lower UTI was diagnosed in the case of clinically significant
bacteriuria with dysuria symptoms and possible fever <38 C,
without tenderness or pain in the proximity of the transplanted
kidney, and/or without deterioration in the excretion function of the
graft.
Diagnosis of an upper UTI (GPN) was made in the case of
coexisting clinically significant bacteriuria, fever >38 C, and/or
tenderness or pain in the proximity of the transplanted kidney, and/
or deterioration in the excretion function of the graft.
Urosepsis was diagnosed if the same pathogen was detected in
urine and blood cultures.
Statistical Analysis
Statistical analysis was performed by using independent sample tests
(Pearson’s c2 test, Yates’ c2 test, the Student t test, Welch’s t test,
the Mann-Whitney U test, and Fisher’s exact test). The Shapiro-
Wilk normality test was also used, as was an F test of equality of
variances.
RESULTS
Recipients’ Baseline Characteristics
Baseline demographic, clinical, and biochemical character-
istics are included in Table 1. The study group of 107 kidney
transplant recipients included more women (n ¼ 69 [64%])
than men (n ¼ 38 [36%]); their age ranged from 21 to 71
years (mean age, 52.51 years). The majority of patients (n ¼
88 [82%]) were studied after their first kidney trans-
plantation, with 17 (16%) and 2 (2%) patients after their
second and third transplantations, respectively. One hun-
dred patients (93%) received kidneys from a deceased
donor, and the remaining 7 (7%) received a kidney from a
living donor. Twenty-five (23.5%) patients developed an
early UTI (within 6 months after KTx), and the remaining
subjects (n ¼ 82 [76.5%]) were affected after the 6-month
period. Infections in as many as 81 recipients (76%) were
recurrent (range, 2e13; mean, 3.7).

Table 1. Demographic and Clinical Characteristics of the 107 Kidney Transplant Recipients According to Gender
Variable All Female Male P

Mean age, y 52.51 53.41 50.89 NS

No. (%) of patients 107 (100) 69 (64) 38 (36) NS
No. (%) of KTx
1 88 (82) 55 (80) 33 (87) NS
2 17 (16) 13 (19) 4 (11) NS
3 2 (2) 1 (1) 1 (3) NS
Transplantation type, no. (%)
Living 7 (7) 5 (7) 2 (5) NS
Deceased 100 (93) 64 (93) 36 (95) NS
Mean time from KTx, wk 80.73 85.58 71.92 NS
Risk factors, no. (%)
Pre-KTx urinary tract surgeries 20 (19) 6 (9) 14 (37) .009
Post-KTx re-operations 21 (20) 9 (13) 12 (32) .039
Double-J stent 34 (32) 16 (23) 18 (47) .0212
Bricker anastomosis 11 (11) 5 (8) 6 (16) NS
Acute rejection, no. (%) 32 (30) 22 (34) 10 (17) NS
Thymoglobulin therapy, no. (%) 4 (4) 3 (5) 1 (3) NS
Diabetes mellitus, no. (%) 34 (34) 20 (29) 14 (37) NS
Type 1 5 (5) 2 (3) 3 (8) NS
Type 2 7 (7) 5 (7) 2 (5) NS
NODAT 22 (21) 13 (19) 9 (24) NS
Immunosuppressive regimen: induction (Simulect/Thymoglobulin) 34 (29/5) 24 (19/5) 10 (10/0) NS
Maintenance treatment
Steroids, no. (%); mean dose, mg 104 (97); 6.8 66 (96); 6.6 38 (100); 7.13 NS
Tacrolimus, no. (%); mean concentration, ng/mL 69 (65); 8.4 43 (62); 8.3 26 (68); 8.51 NS
Cyclosporine, no. (%); mean concentration, ng/mL 26 (25); 111.1 18 (26); 102.8 8 (21); 126.7 NS
Mycophenolate mofetil, no. (%); mean dose, mg 79 (74); 1183 49 (71); 1176 30 (79); 1207 NS
Mycophenolate sodium, no. (%); mean dose, mg 16 (15); 922.5 9 (13); 800 7 (18); 1080 NS
Azathioprine, no. (%); mean dose, mg 5 (5); 72.5 3 (4); 65.62 2 (5); 100 NS
mTOR, no. (%) 3 (3) 2 (3) 1 (3) NS
BMI, kg/m2 24.9 24.27 26.04 NS
Pre-UTI creatinine level, mg/dL 1.83 1.72 2.03 NS
eGFR (MDRD), mL/min/1.73 m2 44.38 42.03 48.66 NS
Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; KTx, kidney transplant; MDRD, Modification of Diet in Renal Disease; mTOR,
mammalian target of rapamycin; NODAT, new-onset diabetes mellitus after transplantation; NS, not significant; UTI, urinary tract infection.
UTI IN HOSPITALIZED KIDNEY TX RECIPIENTS 1583

Immunosuppression Table 2. Infection Characteristics

Induction treatment with polyclonal serum was adminis- Variable Value

tered to 5 (5%) recipients, and 29 (27%) patients received Early UTI 6 mo 25 (23)
antieinterleukin (IL)-2 monoclonal antibodies (basiliximab Late UTI >6 mo 82 (77)
or daclizumab). Acute rejection occurred in 32 (30%) kid- No. of recurrences 79 (74)
ney transplant recipients. Methylprednisolone pulse therapy Changes in urine
was administered to all patients, and 4 patients (12.5%) None 14 (13)
Pyuria 93 (87)
received polyclonal serum infusions. Basic immunosup-
Dysuria symptoms 52 (49)
pression in the majority of cases (n ¼ 103) was based on CRP, mean concentration, mg/dL 87.82
steroids (prednisone or methylprednisolone; mean dose, Pathogens count
6.8 mg), mycophenolic acid (mycophenolate mofetil, n ¼ 79 1 85 (79)
[mean dose, 1182 mg] or mycophenolate sodium, n ¼ 16 2 17 (16)
[mean dose, 922.5 mg]) or azathioprine (n ¼ 5; mean dose, 3 4 (4)
72.5 mg), as well as calcineurin inhibitors (tacrolimus, n ¼ 4 0
69 [mean concentration, 8.28 ng/mL] or cyclosporine, n ¼ 5 1 (1)
26 [mean concentration, 111.1 ng/mL]). Only 2 recipients Unmodified treatment 77 (72)
received mammalian target of rapamycin inhibitors (siroli- Escalation 20 (18)
De-escalation 10 (10)
mus or everolimus) (Table 1).
Mean treatment duration 10.55
(hospitalization), d
Potential Risk Factors Outpatient treatment n ¼ 64; mean, 14.62 d
The majority of recipients were women (n ¼ 69 [64%]). Data are expressed as no. (%) unless otherwise indicated.
Urinary tract surgeries in the pretransplantation period Abbreviations: CRP, C-reactive protein; UTI, urinary tract infection.
were performed in 20 patients (19%) and more often in men
(n ¼ 14; P ¼ .009). Double-J stents during kidney trans- Their hospitalization was longer (12.3 vs 9.8 days; P ¼ .04),
plantation were inserted in 34 kidney transplant recipients and they received posthospital treatment more often
(32%), also significantly more frequently in men (P ¼ .0212) (P ¼ .04). Severe infections were more frequent in patients
and in patients who had had surgeries before trans- after pre-kidney transplant surgeries (P ¼ .02) and in those
plantation (P ¼ .009) and who underwent reoperation (P ¼ who underwent reoperation after kidney transplantation
.0398). Eleven patients (11%) with a lower urinary tract (P ¼ .036). Recurrences developed in 76% of kidney
pathology had a Bricker ureterointestinal anastomosis per- transplant recipients (n ¼ 81) (Table 4).
formed. These patients were younger compared with the
Pathogens
remaining subjects (33.45 vs 47.25 years; P ¼ .00175).
Clinical symptoms of infection in these patients were rarer Early UTIs. Thirty-four isolates were obtained from
(P ¼ .069). Early complication-related reoperations on the samples of 25 kidney transplant recipients diagnosed with
urinary tract were performed in 21 kidney transplant re- early UTIs (23%). Predominant species included K pneu-
cipients (20%) and more often in men (P ¼ .0398). Diabetes moniae (n ¼ 11 [33%]), E coli (n ¼ 10 [30%]), Enterococcus
mellitus was diagnosed in 34 recipients, including type 1 faecalis (n ¼ 5 [15%]), Enterococcus faecium (n ¼ 2 [6%]),
(n ¼ 5 [5%]) and type 2 (n ¼ 7 [7%]); NODAT was most and Pseudomonas aeruginosa (n ¼ 2 [6%]). In addition,
prevalent (n ¼ 22 [21%]). Patients with diabetes were older individual cases of Staphylococcus warneri, Steno-
(51.26 vs 43.3 years; P ¼ .042), their C-reactive protein level trophomonas maltophila, and Candida albicans (Table 5)
on admission day was lower (70.79 vs 95.74 mg/L; P ¼ .054). were recorded. Resistant strains constituted as many as
Nineteen patients (18%) had a history of CMV infection, 17 44% of isolates (n ¼ 15), mainly K pneumoniae extended-
(16%) were diagnosed with chronic hepatitis B, and 15 spectrum beta-lactamaseeproducing Enterobacteriaceae
(14%) were diagnosed with hepatitis C. (ESBL)(þ) (n ¼ 8), E faecalis high-level aminoglycoside
resistant (HLAR) (n ¼ 4), E faecium HLAR (n ¼ 1), P
Urinary Tract Infections aeruginosa metallo-beta-lactamase(þ) (n ¼ 1), and E coli
metallo-beta-lactamase(þ) (n ¼ 1) (Table 6).
Asymptomatic bacteriuria was diagnosed in 13% of hospi-
Late UTIs. Late infections (ie, occurring >6 months after
talized patients (n ¼ 13). In most cases, pyuria was observed
kidney transplant) were diagnosed in a majority of patients
(n ¼ 93 [87%]); 52 (49%) patients reported clinical symp-
toms. Thirty-nine patients (37%) experienced a severe
Table 3. Bacterial Pathogens Isolated From Blood (N [ 17)
clinical course (eg, fever 38 C, pyuria, dysuria symptoms,
Bacterial Species No. (%) of Isolates
C-reactive protein level 100 mg/L on admission day); they
were diagnosed with GPN. Urosepsis was diagnosed in 17 Escherichia coli 7 (41)
patients (16% of all UTI cases, 44% of GPN cases) Klebsiella pneumoniae 4 (24)
(Tables 2 and 3). Tacrolimus levels on admission were Staphylococcus epidermidis 2 (12)
Other 4 (24)
higher in patients with GPN (11.05 vs 7.3 ng/mL; P ¼ .0245).
1584 
GOZDOWSKA, CZERWINSKA, CHABROS ET AL

Table 4. Recurrent Bacterial Pathogens Isolated From Urine
(N [ 40)
Bacterial Species
Escherichia coli
Klebsiella pneumoniae
Enterococcus faecalis
Enterobacter cloacae
(n ¼ 82 [77%]). A total of 102 isolates were obtained: E coli
(n ¼ 47 [46%]), E faecium (n ¼ 10 [10%]), K pneumoniae
(n ¼ 9 [9%]), E faecalis (n ¼ 8 [8%]), and P aeruginosa
(n ¼ 6 [6%]). Rarer species included Staphylococcus hae-
molyticus, Klebsiella oxytoca, Proteus mirabilis, Enterobacter
cloacae, Staphylococcus epidermidis, S warneri, and others
(Table 5); 25.5% of isolates (n ¼ 26) were resistant strains.
Predominant species included E faecium HLAR (n ¼ 5), K
pneumoniae ESBL(þ) (n ¼ 4), and E faecalis HLAR
(n ¼ 4); 2 of them were also vancomycin-resistant
enterococci (n ¼ 2). S haemolyticus (methicillin-resistant
coagulase-negative staphylococci, n ¼ 3) and macrolide-
lincosamide-streptogram B resistance (MLSb)(þ)
(methicillin-resistant coagulase-negative staphylococci,
n ¼ 1) were also recorded (Table 6). Recurrences mainly
involved E coli, K pneumoniae, and E faecalis.
Treatment
The average duration of all hospitalizations was 10.55 days.
For patients with milder infections, the average duration
was 7.07 days compared with 12.27 days in cases of severe
infections (GPN) (P ¼ .04). Depending on the nature of the
infection (first occurrence or recurrence, mild or severe
clinical course), a decision on antibiotic therapy was made.
After collecting urine samples for culture, antibiotic treat-
ment was initiated (empirical or based on previous culture
No. of Isolates results for recurrent infections). After obtaining culture
26 results, depending on drug sensitivity of a cultivated path-
9 ogen, the treatment was continued if clinical improvement
4 was obtained and sensitivity was confirmed (n ¼ 77 [72%]),
1 or it was escalated if the treatment was found to be inef-
fective and the pathogen was resistant (n ¼ 20 [19%]); more
rarely, it was de-escalated to a narrower spectrum antibiotic
to prevent drug resistance (n ¼ 10 [9%]). In empirical
treatment, the most commonly used agents included cipro-
floxacin (n ¼ 29), ceftriaxone (n ¼ 22), ciprofloxacin in
combination with ceftriaxone (n ¼ 13), ceftazidime (n ¼ 8),
amoxicillin/clavulanic acid (n ¼ 7), meropenem (n ¼ 7),
vancomycin (n ¼ 5), imipenem (n ¼ 4), and others. If
treatment was ineffective, it was usually escalated (n ¼ 20
[19%]) to carbapenems (meropenem, n ¼ 5; imipenem, n ¼
4), tazobactam/piperacillin (n ¼ 4), ceftazidime (n ¼ 2), or
colistin in combination with meropenem (n ¼ 2).
DISCUSSION
UTI is the most common cause of bacterial infections in
kidney transplant patients. This discussion was prepared
based on our own observations and literature review, and it
was divided into several categories.
Urinary Tract Infections
UTIs are generally categorized as asymptomatic bacteriuria,
lower or upper (GPN) UTI, and urosepsis.
In a study conducted by Fiorante et al [4] in a group of
189 recipients of kidneys from deceased donors, 52.9% of
patients were diagnosed with UTIs during a 3-year

Table 5. Bacterial Pathogens Isolated During UTI Episode

Early UTIs (n ¼ 25 patients); Late UTIs (n ¼ 82 patients);
Bacterial Species All Isolates (N ¼ 136) No. of Isolates (n ¼ 34) No. of Isolates (n ¼ 102)

Escherichia coli 57 (42%) 10 (30%) 47 (46%)

Klebsiella pneumoniae 20 (15%) 11 (32%) 9 (9%)
Enterococcus faecalis 13 (10%) 5 (15%) 8 (8%)
Enterococcus faecium 12 (9%) 2 (6%) 10 (10%)
Pseudomonas aeruginosa 8 (6%) 2 (6%) 6 (6%)
Staphylococcus haemolyticus 4 (3%) 0 4 (4%)
Klebsiella oxytoca 3 (2%) 0 3 (3%)
Proteus mirabilis 3 (2%) 0 3 (3%)
Enterobacter cloacae 2 (2%) 0 2 (2%)
Staphylococcus warneri 2 (2%) 1 (3%) 1 (1%)
Staphylococcus epidermidis 2 (2%) 0 2 (2%)
Serratia liquefaciens 1 (1%) 0 1 (1%)
Proteus vulgaris 1 (1%) 0 1 (1%)
Serratia marcescens 1 (1%) 0 1 (1%)
Raoultella planticola 1 (1%) 0 1 (1%)
Stenotrophomonas maltophilia 1 (1%) 1 (3%) 0
Morganella morganii 1 (1%) 0 1 (1%)
Candida albicans 1 (1%) 1 (3%) 0
Other 3 (2%) 1 (3%) 2 (2%)
Resistant strains, n ¼ 41 (no. of patients, 35) 41 (31%) 15 (11%) 26 (20%)
Abbreviation: UTI, urinary tract infection.
UTI IN HOSPITALIZED KIDNEY TX RECIPIENTS
Table 6. Resistant Strains Isolated in 35 Patients
All Resistant Pathogens
Bacterial Species (n ¼ 41) in 35 Patients
Klebsiella pneumoniae n ¼ 12
Enterococcus faecalis n¼9
Enterococcus faecium n¼5
Staphylococcus haemolyticus n¼4
Pseudomonas aeruginosa n ¼
Escherichia coli n ¼
Klebsiella oxytoca n ¼
Serratia marcescens n ¼
Enterobacter cloacae n ¼
Staphylococcus epidermidis n ¼
Morganella morganii n ¼
Abbreviations: ESBL, extended-spectrum beta-lactamaseeproducing Enterobacteriaceae; HLAR, high-level aminoglycoside resistant; MBL, metallo-beta-lactamase;
MRCNS, methicillin-resistant coagulase-negative staphylococci; VRE, vancomycin-resistant enterococci.
follow-up, with 85% of cases of asymptomatic bacteriuria.
The investigators demonstrated that the incidence of acute
GPN was significantly higher in the group of patients with
recurrent asymptomatic bacteriuria, despite administered
treatment. Asymptomatic bacteriuria may progress to acute
GPN, bacteremia, and symptomatic urosepsis. Yacoub and
Akl [8] analyzed reports published in the PubMed and
Cochrane databases for risk factors, diagnostics, and treat-
ment of UTIs in kidney transplant patients. According to
the investigators, significant risk factors for UTIs in renal
transplant recipients are pretransplant UTI, prolonged
period of hemodialysis before hospitalization, polycystic
kidney disease, diabetes mellitus, postoperative bladder
catheterization, immunosuppression, allograft trauma,
cadaveric donor, history of vesicoureteral reflux, and tech-
nical complications associated with ureteral anastomosis.
Risk Factors
Female Sex. Observations made by numerous in-
vestigators (including our own) agree that women are more
susceptible to UTIs, which results from anatomical features
[9,10]. Differences in the clinical course of UTIs in women
and men may be associated with different immune
responses to the presence of bacteria in the urinary tract,
depending on sex. In male kidney transplant patients,
bacteriuria is associated with strong inflammatory
response and stimulation in the urinary tract of cells
producing proinflammatory cytokines, such as IL-6, IL-8,
and soluble IL-1 receptors 1 and 6, whereas in women,
inflammatory response is inhibited. Elevated levels of anti-
inflammatory soluble IL-1 receptor antagonists are found
both in serum and in urine. This scenario is probably due
to the activity of female sex hormones and adaptation to
frequent stimulations with bacterial antigens [2]. In a
German study, asymptomatic bacteriuria was diagnosed in
57% of women and 21% of men from a group of 388
transplant patients treated in the outpatient setting. In a
1585
Early UTIs (n ¼ 13 patients); Late UTIs (n ¼ 22 patients);
No. of Isolates (n ¼ 15) No. of Isolates (n ¼ 26)
ESBL(þ); n ¼ 8 ESBL(þ); n ¼ 4
HLAR; n ¼ 4 HLAR; n ¼ 5
HLAR; n ¼ 1 HLAR; n ¼ 2
HLAR, VRE; n ¼ 2
n¼0 MRCNS; n ¼ 3
MLS(þ), MRCNS; n ¼ 1
3 MBL(þ); n¼1 MBL(þ); n ¼ 2
2 MBL(þ); n¼1 ESBL(þ); n ¼ 1
1 n¼ 0 ESBL(þ); n ¼ 1
1 n¼ 0 AmpC(þ), ESBL(þ); n ¼ 1
1 n¼ 0 AmpC(þ), KPC(), MBL(þ); n ¼ 1
1 n¼ 0 MRCNS; n ¼ 1
2 n¼ 0 ECSM; n ¼ 2
Spanish study, female transplant recipients reportedly had
twice the incidence of UTIs of male transplant recipients.
Other posttransplant risk factors of having a delayed UTI
(>6 months’ postprocedure) include patients with serum
creatinine levels >2 mg/dL, a daily prednisone dose >20
mg, multiple rejection therapy, or chronic viral infection
[11]. Wojciechowski et al [12] also found that female sex
was a UTI risk factor (P ¼ .0003). Similarly, in a study by
Lee et al [13], independent risk factors for the first
episode of UTI included female sex (P < .001). In our
study, UTIs were predominantly diagnosed in women
(n ¼ 69 [64%]).
Association With Acute Rejection. A number of publica-
tions have shown that patients are most susceptible to UTIs
after acute rejection [10]. Coexistence of UTIs and acute
rejection episodes may be explained by the use of
intensive immunosuppression. However, there are reports
that UTI itself is an initiation factor for the acute
rejection process. During infection, antigens from bacterial
wall fragments may bond with Toll-like receptors (TLRs)
in urethra cells, macrophages in the interstitium, and
dendritic cells. In addition, in the course of bacterial
infections, defensins are produced by urethral epithelial
cells. Beta-defensin 2 is an endogenous ligand for TLR-4
and also stimulates dendritic cells. Thus, exogenous and
endogenous ligands for TLRs may be a potent initiation
factor for stimulation of alloreactive T cells. Because
acute rejections do not develop after each UTI, additional
regulatory factors must exist, inhibiting T-cell responses in
some cases [14]. Alangaden et al [15] demonstrated a
relationship between UTI and a history of at least 1 acute
rejection episode. In a study conducted by Kamath et al
[16], acute rejection episodes in 41% of patients preceded
the development of acute GPN. Lee et al [13] concluded
that untreated UTIs were associated with an increased
risk of acute cellular rejection (P ¼ .01). In our study, no
relationship between UTIs and induction treatment with
polyclonal serum or acute rejection episodes was
1586
demonstrated. More severe infections (eg, GPN, urosepsis)
developed in patients with elevated blood levels of
tacrolimus (P ¼ .0245).
Relationship Between UTI and CMV Infection. Some in-
vestigators note that UTIs are reported more frequently in
recipients with a history of CMV infection. CMV intensifies
immunosuppression, affects the host’s defense mechanisms,
and, therefore, fosters the development of UTIs, among
other infections. Conversely, inflammation of the urinary
tract as a result of bacterial infection, with a simultaneous
release of proinflammatory cytokines (eg, tumor necrosis
factor), creates favorable conditions for CMV replication
[17,18]. In our study, although 18% of recipients had a
history of CMV infection, no relationship between virus
replication and the incidence or type of UTI was determined.
Ureteral Stenting
The effect of ureteral stenting using a double-J ureteral
stent on the risk of UTI raises some controversies [19]. It
has been emphasized that prophylactic ureteral stenting in
kidney transplant recipients prevents such complications as
ureteric leak and obstruction; conversely, it is associated
with other complications (eg, UTIs, hematuria, stent
migration, stent encrustation, forgotten stents). Giakousti-
dis et al [20] observed no increased morbidity of UTIs in
patients with double-J stents. In a prospective, randomized
study involving 201 kidney transplant recipients, Tavakoli
et al [21] recorded a significantly higher incidence of UTIs if
a double-J stent was kept for >30 days.
Shoab et al retrospectively analyzed 157 patients for the
occurrence of UTI in DJ-stented vs nonstented renal
transplant recipients. Sixty-one (38.85%) of the 157 patients
developed a UTI, including 30 (40.54%) of 74 stented pa-
tients and 31 (37.34%) of 83 nonstented renal transplant
recipients. Relative risk was calculated to be 1.08. The study
failed to demonstrate differences in the incidence of UTIs
between double-Jestented and nonstented renal transplant
recipients [19]. Lee et al [13] reported that double-J stents
constitute an independent risk factor for UTIs in the early
post-KTR period (P ¼ .01).
At the Institute of Transplantology in Warsaw, double-J
ureteral stents are removed between 4 and 6 weeks after
kidney transplantation. However, the use of double-J stents
was not shown to be a risk factor for UTI.
Dysfunction of the Lower Urinary Tract
Vesicoureteral reflux or narrowing of the ureterovesical
anastomosis is a risk factor for recurrent UTIs. UTIs,
including severe infections such as urosepsis, were signifi-
cantly more frequent in kidney transplant recipients with a
major dysfunction of the lower urinary tract that required
pretransplantation or peri-transplantation reconstruction
[22]. It is noteworthy that many investigators point out that
UTIs are more frequent in recipients of kidney transplants
from cadaveric donors [9]. As it follows from our observa-
tions, the incidence of severe UTIs (eg, GPN, urosepsis) was

GOZDOWSKA, CZERWINSKA, CHABROS ET AL
significantly higher in kidney transplant recipients with a
history of pretransplantation surgeries involving the urinary
tract (P ¼ .02), as well as in patients who underwent re-
operation due to complications (P ¼ .036). An atypical
urine diversion method in the form of Bricker ureter-
ointestinal anastomosis for urinary diversion (modified
Bricker techniques, ileal conduit) was not associated with an
increased risk of severe infections, perhaps because these
infections were diagnosed earlier. Patients who pay atten-
tion to changes in urine color, smell, or clarity report to the
physician earlier, before clinical symptoms in the form of
fever or malaise develop (P ¼ .069). Patients with Bricker
ureterointestinal anastomosis received prophylactic treat-
ment more often (80%).
Immunosuppressant Agents
Some reports indicate an increased UTI morbidity when
patients undergo a 4-drug immunosuppression regimen us-
ing induction with antithymocyte globulin or basiliximab. In
individual publications, higher susceptibility to UTI was
reported in which 3-drug regimens were used, including
antimetabolites (azathioprine or mycophenolate sodium or
mycophenolate mofetil). Other investigators showed that in
the calcineurin inhibitor group, tacrolimus increased the
risk of UTIs compared with cyclosporine [10]. Similarly, in
our study, more severe forms of UTI (eg, GPN, urosepsis)
developed in patients with elevated tacrolimus levels in the
blood (P ¼ .0245).
Concomitant Diseases
A patient’s susceptibility to UTIs may result from the fact
that transplant recipients are increasingly prone to comor-
bidities. Abbott et al [23] analyzed 28,942 kidney transplant
recipients and reported an association between recurrent
infections and the presence of congestive heart failure and
pretransplantation nutrition status. The development of late
UTI (after >6 months) was associated with an increased risk
of death and loss of renal graft. Silva et al [24] conducted a
study in which comorbidity was considered to be a risk
factor for bacteremia (including urosepsis), as assessed by
using the Charlson Comorbidity Index. In our study, no
relationship between the incidence of UTIs and comorbid-
ities such as all-type diabetes mellitus (types 1 and 2 or
NODAT), history of CMV, and chronic hepatitis B virus or
hepatitis C virus infection was demonstrated. Associations
with other conditions were not studied.
Pathogens
Etiologic Factors. Etiologic factors for UTIs in kidney
transplant patients are similar to those in the case of
complicated UTIs in the general population. E coli is the
most common pathogen identified in urine cultures and in
blood cultures in the cases of urosepsis [5,10]. Often,
Pseudomonas species and Klebsiella species are also found.
The growing role of Enterococcus species as an etiologic
factor for UTIs in kidney transplant patients is also
UTI IN HOSPITALIZED KIDNEY TX RECIPIENTS
emphasized [9]. In a study conducted by Alangaden et al
[15], >1 uropathogen was isolated in 10% of cases. In the
present study, >1 pathogen was identified in 22 transplant
recipients (21%). In early UTIs, most common species
included K pneumoniae, E coli, E faecalis, and E faecium;
in late UTIs, the most common species were E coli and,
less commonly, E faecium, K pneumoniae, E faecalis, and
P aeruginosa. Resistant strains were mainly K pneumoniae
and enterococci, and, to a lesser extent, E coli. In another
Polish center, the incidence of infections with enterococci
strains in the early posttransplantation period reached
40%, which, according to the investigators, resulted from
routine use of ceftriaxone as part of perioperative
prophylaxis. The antibiotic’s spectrum covers gram-
negative bacilli, thus fostering the selection of enterococci
[8]. Fungal infections are not a significant issue, with an
incidence of no more than 4% in a majority of centers.
Candida species are the most commonly isolated.
Pathogens and Urosepsis. Gram-negative bacteremias are
20-fold more frequent in vascularized organ transplant
receivers than in the general population, and the most
common form of bacteremia in kidney transplant recipients
is the most severe UTI (ie, urosepsis) [5]. In a retrospective
study, Silva et al [24] analyzed cases of bacteremia in
>3300 kidney transplant recipients. The overall incidence
of blood infections was slightly higher than 4%, with the
urinary tract as the source of infection in nearly 40% of
cases. E coli was the predominant etiologic factor [26]. In
the present study, bacteremia (urosepsis) developed in
16% of patients. The clinical course in the case of
urosepsis was significantly more severe, with patients
requiring longer hospitalization (P < .001) and posthospital
treatment. In this group, carbapenems (59%) and
combination treatment with 2 antibiotics (ceftriaxone and
ciprofloxacin) were administered more frequently.
Multidrug-Resistant Strains
The etiology of UTIs changes over time from the trans-
plantation. In many reports, the growing incidence of in-
fections with multidrug-resistant strains is indicated,
especially with ESBLs. The risk of infection with an ESBL
bacillus increases with each UTI episode. In these times of
growing antibiotic resistance, primary colonization of the
recipient’s kidney and factors fostering infection re-
currences seem to play a key role.
Pilmis et al [25] assessed the incidence of ESBL-producing
Enterobacteriaceae, risk factors associated with infection with
the strain, and risk factors for recurrence. Bacteriuria was
diagnosed in as many as 10.9% of kidney transplant recipients
(72 of 659), and in 47.2% of those (34 of 72), ESBL-PE-
related UTIs were found. In 41.2% of patients (14 of 34)
with recurrent infection, a correlation was identified between
2 factors: (1) advanced age (P ¼ .032); and (2) bacteriuria
found 48 hours after initiation of targeted antibiotic therapy
(P ¼ .04). No correlation between potential recurrence risk
factors (eg, the presence and management of a ureteral stent
1587
during the first UTI, causative microorganisms, diabetes
mellitus) was identified [27].
In a Spanish study, as many as 20% of 867 kidney trans-
plant recipients (N ¼ 174) were diagnosed with at least 1
episode of UTI, and recurrent UTIs were found in 55 pa-
tients (32%). The most common causative factors of recur-
rent UTIs were ESBL-producing K pneumoniae (31%),
followed by noneESBL-producing E coli (15%), multidrug-
resistant P aeruginosa (14%), and ESBL-producing E coli
(13%). Factors associated with an increased risk of recurrent
UTIs were first or consecutive episode of infection with a
multidrug-resistant bacteria, age >60 years, and reopera-
tions. No effect of UTIs on acute rejection, graft function,
graft loss, or 1-year survival was demonstrated. Classic risk
factors such as female sex and diabetes mellitus were not
associated with UTIs in this study group [28].
Prophylaxis and Treatment
Prophylaxis. Most transplantation centers use periopera-
tive antibiotic prophylaxis in the form of several antibiotic
doses on a routine basis. Three to 12 months of trimethoprim
or sulfamethoxazole therapy constitutes common practice in
preventing opportunistic infections with Pneumocystis jiroveci,
Listeria monocytogenes, Nocardia asteroides, Toxoplasma gon-
dii, and, to a lesser extent, UTIs. In each case of symptomatic
UTI, it is indicated to perform urine culture with antibiogram
and administer targeted therapy. While administering empir-
ical treatment, one needs to take into account the fact that in
kidney transplant patients, strains resistant to commonly used
antibiotics/chemotherapeutic agents, such as ciprofloxacin
or trimethoprim/sulfamethoxazole, are much more frequent.
In a study by Pelle et al, 84% of E coli strains, 67% of
E cloacae strains, 86% of coagulase-negative staphylococci,
and 46% of Enterococcus species isolates were resistant to
trimethoprim/sulfamethoxazole. In some centers, resistance
to trimethoprim or sulfamethoxazole reached 100%, and
resistance to ciprofloxacin reached 75% [27]. Wojciechowski
et al [12] retrospectively compared 2 groups of kidney
transplant patients. One group received sulfamethoxazole/
trimethoprim at a dosage of 800/160 mg daily for 30 days,
followed by 3 times a week for 3 months (group 1, n ¼ 106).
The second group received sulfamethoxazole/trimethoprim 3
times a week for 6 months plus ciprofloxacin 250 mg twice
daily for 30 days (group 2, n ¼ 130). The groups were
compared for UTI incidence after kidney transplantation. In
group 1, UTIs developed more frequently (23.6% vs 10.8%;
P ¼ .01) and within a shorter period of time from
transplantation (96.6  79.5 vs 168  89.7 days; P ¼ .01).
The incidence of UTIs caused by Enterococcus species was
higher in group 2 (28.6% vs 4%; P ¼ .047), with enteric
gram-negative bacilli accounting for the remaining
infections. Ciprofloxacin administration for 30 days lowered
the incidence of UTI.
In the Institute of Transplantology, kidney transplant
recipients receive antibiotic prophylaxis in the peri-
transplantation period on a routine basis. It consists of a
1588
single dose of third-generation cephalosporin (ceftriaxone)
before induction of anesthesia. In terms of postoperative
prophylaxis, a 480-mg daily dose of trimethoprim/sulfa-
methoxazole for a period of 3 months is recommended.
Also, before each double-J stent insertion or removal, a
single dose of a third-generation cephalosporin or quino-
lone is administered. In the case of suspected UTI (clinical
symptoms and/or leukocyturia), urine and blood samples
are collected for aerobic and anaerobic cultures, and
empirical antibiotic therapy is initiated. It usually includes
second- or third-generation cephalosporins or quinolone. If
treatment is clinically effective, and the pathogen obtained
is sensitive to the agent used, the therapy is continued. If the
treatment is ineffective, it is modified based on an antibio-
gram. In the case of a recurrent infection, the antibiotic is
selected while taking into account previous culture findings,
especially with respect to multidrug-resistant pathogens. In
such situations, carbapenems and tazobactam/piperacillin
are frequently used. In the case of resistant, prolonged in-
fections, treatment is escalated; however, antibiotic therapy
is occasionally de-escalated if a pathogen identified in urine
culture is sensitive to lower generation drugs. The proce-
dure is aimed at preventing the emergence of multidrug-
resistant strains.
Treatment. There are no unambiguous recommendations
on performing surveillance microbiologic tests and treating
asymptomatic bacteriuria in kidney transplant patients. Some
investigators recommend performing surveillance urine cul-
tures in the early posttransplantation period because even in
severe infections, clinical symptoms specific to UTIs may be
unpronounced. In addition, it is worth recommending
attempted treatment of asymptomatic bacteriuria because it
may be an indicator of increased susceptibility to infections.
Clear guidelines are also lacking on the recommended
duration of treatment for infection. However, it seems that
treatment in the early posttransplantation period should be
no shorter than 10 to 14 days, and if a double-J stent has been
inserted, it should be removed and a culture performed. In
the late posttransplantation period (>6 months after
procedure), lower UTIs should be treated for 5 to 7 days,
upper UTIs should be treated for 10 to 14 days, and
urosepsis should be treated for at least 14 to 21 days. In
recurrent infections, diagnostic imaging and functional tests
with urologic evaluation are recommended.
The history of pretransplantation UTIs also needs to be
reviewed. The patient’s own kidneys or a nonfunctional
kidney transplanted during a subsequent surgery may
constitute the source of infection; this scenario is especially
probable in polycystic kidneys, particularly in those cases
with a history of multiple episodes of cyst infections, renal
calculus, or vesicoureteral reflux to the patient’s own
kidneys. Pretransplantation and posttransplantation re-
infections with the same etiologic factor suggest such a
source of recurrent UTIs. In addition, in men, prostatitis
needs to be considered as the source of recurrent infections.
In the case of recurrent UTIs with E coli etiology, nitro-
furantoin (100 g) and trimethoprim/sulfamethoxazole

GOZDOWSKA, CZERWINSKA, CHABROS ET AL
(480 mg) therapy for several weeks may be considered, if
resistance is retained.
UTI and Renal Transplant Function
Mild UTIs, such as asymptomatic bacteriuria or lower UTIs,
do not affect the glomerular filtration rate; however, IL-8
levels in the urine of kidney transplant recipients diag-
nosed with asymptomatic bacteriuria are significantly higher
than in sterile urine, with comparable IL-6 levels. IL-8 is
excreted by urethral cells, among other sources, and is co-
responsible, with IL-6, for the development of local
inflammation, pyuria, and symptoms of UTI [28]. Ariza-
Heredia et al assessed the effect of UTI on graft function
by evaluating several measures such as iothalamate
glomerular filtration rate, estimated glomerular filtration
rate, and creatinine value. In 34% of transplant recipients
(101 of 301), at least 1 UTI episode was diagnosed, with
25% during the first posttransplantation year. Estimated
glomerular filtration rate and creatinine level did not differ
significantly between the UTI and non-UTI groups. When
nuclear imaging was used to assess kidney function, a ten-
dency toward deterioration of allograft function was
observed in patients who developed at least 1 UTI episode
after transplantation (P ¼ .044) [29].
GPN is associated with acute renal injury and scarring. GPN
effects on the graft and kidney transplant recipient remain
controversial. In a study conducted by Shin et al, 265 kidney
transplant recipients were assessed for the effect of early-onset
GPN (during the first 6 months’ posttransplantation) on
allograft function during 10-year follow-up. Thirty recipients
(11.3%) were diagnosed with early-onset GPN. Poorer prog-
nosis applied to kidney transplant recipients in the early-onset
GPN group (13 patients; 43.3%) than in those without early-
onset GPN (43 patients; 18.3%) (P ¼ .002). Multivariate
Cox regression analyses demonstrated that early-onset GPN
was an independent factor for poor prognosis for kidney
transplant (P ¼ .04) [30].
CONCLUSIONS
Female patients are more susceptible to the development of
UTIs due to anatomical and physiological conditions. How-
ever, men hospitalized due to UTIs had the urinary tract
operated on before transplantation, underwent re-operation
after kidney transplantation due to surgical complications,
and had a double-J stent inserted more often than women.
Due to immunosuppressant agents, clinical symptoms specific
to UTIs even in serious infections may be unpronounced;
leukocyturia can be absent in some kidney transplant re-
cipients. Advanced age of recipients, elevated tacrolimus
levels, and impaired allograft function are all risk factors for
severe UTIs (eg, GPN, urosepsis). Patients diagnosed with
upper UTIs require longer hospitalization and prophylactic
treatment in outpatient setting, and a high recurrence rate is
observed. The most common etiologic factors of UTIs in the
early posttransplantation period are K pneumoniae and, later,
E coli. Some pathogens are resistant to antibiotics.
UTI IN HOSPITALIZED KIDNEY TX RECIPIENTS
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