Methods

• Study design: parallel quasi‐RCT

• Recruitment period: March 2002 to February 2003

• Duration of follow‐up: 9 to 12 months

Participants

• Country: Iran

• Setting: Single centre

• Inclusion criteria: men and women kidney transplant recipients ≥ 18 years with a diagnosis of asymptomatic bacteriuria (defined as the as the joint presence of pyuria and bacteriuria in urine analysis, with a positive culture with colony count > 100,000 of one organism and the absence of irritative voiding symptoms, fever and chills); at least one year post‐transplantation

  • Main causes of underlying disease: hypertension (43.1%), diabetes mellitus (14.8%), glomerulonephritis (12.5%), urolithiasis (10.2%)

• Number (randomised/analysed): 100/88 (12 excluded after randomisation)

  • Treatment group (43); control group (45)

• Sex (M/F): treatment group (20/23); control group (20/25)

• Mean age ± SD (years): treatment group (44.2 ± 12.7); control group (40.9 ± 13.2)

• Exclusion criteria: urethral catheter; ureteral stent; Proteus infection

Interventions

Treatment group

• Antibiotic: choice of antibiotics was according to the antimicrobial susceptibility testing results

  • Duration of therapy: 10 days

  • Doses: not provided

• In case of recurrence of asymptomatic bacteriuria during the follow‐up period, treatment was repeated in the intervention arm

Control group

• No treatment

Outcomes

• Incidence of symptomatic UTI

• Graft function as measured by SCr during the follow‐up period

• Incidence of relapse or persistent asymptomatic bacteriuria

Notes

• No specific strategy mentioned to obtain good quality urine samples

• Primary outcome not defined

• Funding source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "According to the order of patients' transplant code, they were divided into two groups of case and control, in every other one manner"

Comment: high‐risk of selection bias is associated with quasi‐RCTs

Allocation concealment (selection bias)

High risk

Quote: "According to the order of patients' transplant code, they were divided into two groups of case and control, in every other one manner"

Comment: high‐risk of selection bias is associated with quasi‐RCTs

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "In case group, a 10‐day oral antibiotic therapy was administered (...). The patients in control group were left untreated"

Comment: as symptoms of UTIs are in part subjective, the absence of blinding may impact the number of symptomatic infections observed

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "In case group, a 10‐day oral antibiotic therapy was administered (...). The patients in control group were left untreated"

Comment: as symptoms of urinary tract infections are in part subjective, the absence of blinding may impact the number of symptomatic infections observed

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "The patients with lost follow‐up visits, acute rejection, and pyelonephritis leading to hospitalization during the study were excluded. (...) Twelve patients were excluded of the study, 11 because of lost follow‐up visits and 1 because of acute pyelonephritis, and eventually, data from 88 patients were analyzed"

Comment: Twelve enrolled patients (12%) were excluded from the analysis (11 subjects lost to follow‐up and 1 patient due to occurrence of acute graft pyelonephritis). A high‐risk of attrition bias was suspected.

Selective reporting (reporting bias)

High risk

Comment: no published protocol. Authors did not divided outcomes into primary and secondary outcomes. Some expected outcomes such as incidences of antimicrobial resistance, pyelonephritis, graft rejection and graft loss, all‐cause mortality, incidence of hospitalisation for UTI and incidence of adverse reactions to antimicrobial agents were not reported

Other bias

High risk

Comment: Moradi 2005 did not provide a specific definition of the term "symptomatic UTI" and there were no details on the episodes of symptomatic UTI. Attempts to contact the corresponding author were unsuccessful.

Methods

• Design: parallel RCT

• Recruitment period: April 2011 to February 2014

• Duration of follow‐up : the follow‐up period was theoretically extended to the first 2 years after transplantation unless acute pyelonephritis (9 patients), graft loss (2 patients) or death (3 patients) occurred during the study period. Median follow‐up time was 16.9 months (range 0.4 to 22), with 61/112 (54.5%) patients completing the follow‐up until two years after transplantation

Participants

• Country: Spain

• Setting: single centre

• Inclusion criteria: men and women kidney transplant recipients ≥ 18 years with a diagnosis of asymptomatic bacteriuria according to IDSA guidelines; at least two months post‐transplantation; both inpatients and outpatients were potentially eligible

  • Main causes of underlying disease: diabetes mellitus (23.2%), glomerulonephritis (21.4%), polycystic kidney disease (14.3%), hypertension (9.8%)

• Number: treatment group (53); control group (59) patients

• Mean age ± SD (years): treatment group (55.4 ± 14.5); control group (53.04 ± 15.8)

• Sex (M/F): treatment group (28/25); control group (31/28)

• Exclusion criteria: kidney‐pancreas transplant recipients; double J ureteral stents or indwelling urethral catheter; pregnancy; graft loss within the first two months after transplantation; occurrence of at least one episode of asymptomatic bacteriuria between the end of the second month after transplantation and the study screening

Interventions

Treatment group

• Antibiotics: choice of antibiotics: according to the antimicrobial susceptibility testing results

  • Duration of therapy: 3 to 7 days for the first episode of asymptomatic bacteriuria. The first relapse was theoretically treated for 14 days. In presence of two or more relapses, a urinary tract ultrasound examination was ordered to rule out obstruction, and a 6‐week antibiotic course was prescribed. If a further relapse was detected, a long‐term suppressive therapy with low doses of antibiotic was set up for 6 months

  • Doses: more than 10 different antimicrobial agents were used during this study, with choice and dosing selected according to parameters such as antimicrobial susceptibility testing results

• In case of recurrence of asymptomatic bacteriuria during the follow‐up period, treatment was repeated in the intervention arm

Control group

• No treatment

Outcomes

Primary outcome

• Cumulative incidence of a first episode of acute pyelonephritis, as defined by the simultaneous presence of fever and bacteriuria and/or bloodstream infection along with at least one of the following symptoms: lumbar pain, graft pain, chills and/or irritative voiding symptoms

Secondary outcomes

• Incidence of lower UTI

• Incidence of overall symptomatic UTI

• Incidence of colonization or infection due to multi‐drug resistant bacteria, with multi‐drug resistance being defined as acquired non‐susceptibility to at least one agent in three or more antimicrobial categories

• Graft function as measured by eGFR at 12 and 24 months after transplant (MDRD equation)

• Incidence of graft loss, including permanent return to dialysis or retransplant (does not include death with a functioning graft)

• Incidence of acute graft rejection (biopsy‐proven or not)

• Incidence of adverse events

• Incidence of persistent asymptomatic bacteriuria

• Incidence of Clostridium difficile, defined as the passage of 3 or more unformed stools in 24 hours in the presence of a positive stool test for toxigenic C. difficile

• Incidence of hospital admission for UTI

• Incidence of all‐cause mortality

Notes

• Specific strategies to obtain good quality urine samples: dedicated nurses instructed the patients in the proper collection of urinary samples to minimize the risk of contamination. In case of contamination of the culture, urine collection was repeated

• Funding source: "This work was partially supported by the Fundacion Mutua Madrile˜na de Investigacion Medica (FMM Grant 2010/0015), by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias [FIS] 12/02269 and Proyecto Integrado de Excelencia [PIE] 13/00045), and by the European Development Regional Fund (EDRF) “A way to achieve Europe”."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "participants were randomised (1:1 ratio) using a predetermined computer‐generated sequence and consecutively numbered sealed envelopes"

Allocation concealment (selection bias)

Low risk

Quote: "participants were randomised (1:1 ratio) using a predetermined computer‐generated sequence and consecutively numbered sealed envelopes"

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "open‐label, parallel‐group, randomised trial"

Comment: as symptoms of UTIs are in part subjective, the absence of blinding may impact the number of symptomatic infections observed

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "open‐label, parallel‐group, randomised trial"

Comment: as symptoms of UTIs are in part subjective, the absence of blinding may impact the number of symptomatic infections observed

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "the 12‐ and 24‐month follow‐up periods were completed in 98 (86.6%) and 61 patients (54.4%), respectively"

Comment: all the 112 participants were included into the intention‐to‐treat analysis. However, little more than half reached the end of the two year study period. Participants were withdrawn after they developed acute pyelonephritis, which could have biased results for the other outcomes.

Selective reporting (reporting bias)

Low risk

Comment: all the expected outcomes were reported.

Other bias

Low risk

Quote: 'this work was partially supported by the Fundación Mutua Madrileña de Investigación Médica (FMM Grant 2010/0015), by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias [FIS] 12/02269 and Proyecto Integrado de Excelencia [PIE] 13/00045), and by the European Development Regional Fund (EDRF) "A way to achieve Europe". J.O. holds a research‐training contract "Rio Hortega" (CM13/00180) from the Spanish Ministry of Economy and Competitiveness (Instituto de Salud Carlos III). M.F.R. holds a clinical research contract “Juan Rodés” (JR14/00036) from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III"

Comment: a low‐risk of sponsorship bias is expected due to the nature of the study.