The purpose of this study is to compare frequency of UTI, urine leak and need for reoperation in patients after renal transplant with early or delayed Foley catheter removal. The hypothesis of the ELUCATR trial is that there is no need to keep Foley catheter longer than 24 hours after kidney transplant due to lack of significant effect on urological complications (urine leak, ureter strictures). Early removal can also reduce urinary tract infections.

Main advantage of urinary catheter placement is continual diuresis monitoring and lower bladder pressure. Some hypothesize that increased pressure can disrupt ureteroneocystostomy with resultant urinary fistula. Clinical practice is to remove the catheter between 1-10 post-transplant day. Only few studies described removal of Foley catheter in the first 48 hours. There is no level 1 evidence for timing of urinary catheter removal after kidney transplantation.

Urinary tract infection is a common complication after KTx occurring in about 7-80% patients. Studies suggest direct negative effect of UTI on long-term renal allograft function. There are several independent risk factors for developing UTI: female sex, diabetes and obesity. Duration of catheterization is a modifiable risk factor.

Urine leak and ureter stenosis are relatively frequent surgical complications of kidney transplantation. Urine leaks occur in 2-9% of all kidney transplants. Most of them happen within 3 months after surgery. Urinary fistula contributes to mortality and graft loss. Majority of them need intervention with nephrostomy, pigtail ureteral stent or surgery. Anastomotic or ureter stenosis occurs in 3.1% of all kidney transplants and is usually resolved with open ureteroneocystostomy. Diagnosed and treated early, it does not affect patient and graft survival. There are no solid data documenting influence of the urinary bladder catheterization on fistulas, urinomas, ureter strictures and need for reoperation in this set of patients.

European Best Renal Practice Guidelines recommend removal of the catheter as early as possible, however a randomized trial on timing and adverse event rates (urinary tract infection, urinary leakage) is needed.

1. Objectives of the study

   1. Main aim of the study:

      Early urinary catheter removal is safe and does not increase urinary complications rate. Zero hypothesis is that early and delayed Foley catheter removal have similar urinary complications rate (urinary fistula, urinary tract infections). Alternative hypothesis is that early catheter removal decreases urinary tract infections.

   2. Primary endpoints:

      • Urinary fistula or stenosis requiring intervention,
      • 30 day graft function measured as serum creatinine,
      • 1 year graft survival and function.

   3. Secondary endpoints:

      • Urinary tract infections,
      • BK virus infection,
      • length of hospital stay.

2. Patients and Methods

2.1 Study organisation

The study has been designed as a randomized, controlled, open label, multicenter trial to compare urinary complications rate between early and delayed Foley catheter removal groups in kidney transplant recipients. Computer list of random numbers will be generated, even numbers will be assigned to early and odd numbers to late catheter removal, 1:1 randomisation ratio is expected. At least 3 large-volume renal transplant centers will participate in the study. Randomisation will be supervised centrally by the leader center. Generated numbers will be closed in non-transparent envelopes numbered sequentially and shipped to each participating center. A center is supposed to use the envelopes for group assignment consecutively with increasing numbers. A record of computer-generated number and envelope number will be stored at the leader center. An institutional review board of the Medical University of Warsaw accepted the study design and patient information leaflet. MS Access-based electronic case report file will be used. CRFs will be checked for completeness and concordance with source documents and adherence to the study protocol by the study leader.

2.2 Study design

Donor and pre-transplant recipient data will be noted in a database. Donor blood, urine and preservation solution will be cultured, 10^5 colonies in the former is considered significant. Important transplant anatomical features, like multiple renal arteries will be noted. After screening and informed consent of the patient for participation in the study, kidney transplantation will be performed. Single dose of cefazolin adjusted for patient weight will be administered 30 minutes prior to skin incision. Other options of antibiotic prophylaxis or preemptive treatment are acceptable, however agent and duration must be noted in an electronic Case Report File (CRF). At the beginning of surgical procedure in the operating room, sterile catheterization of the urinary bladder and microbiology sampling will be performed. After uneventful vascular anastomosis, neoureterocystostomy will be done with Lich-Gregoire or a variation of U-stitch technique (McKinnon, other typical). Ureteral stent will be placed at surgeon's discretion. Suction drainage will be positioned in graft proximity. After wound closure and completion of the surgery, inclusion and exclusion criteria will be evaluated. Intraoperative data (blood loss, surgery duration, cold ischemia time, details of the anastomosis, utilization of magnifying loupes, pigtail placement) will be noted.

2.3 Eligibility and exclusion criteria.

2.3.1 Inclusion criteria

• Age>18
• Kidney transplant recipient
• Informed consent signed

2.3.2 Exclusion criteria BMI<18 or >40 kg/m2 Significant anatomical abnormalities of lower urinary tract Previous surgery on bladder or urinary tract Unusual urinary anastomosis (Leadbetter-Politano, Boari, conduit, psoas hitch, pyelo-ureteral or uretero-ureteral, double ureter) Severe vascular complications during surgery with blood loss >1000 ml Haemodynamic shock or profund instability after surgery

Participants will be randomised to a group early urinary catheter removal (EG) or delayed removal group (DG). Early catheter removal will be done 24±6 hours after surgery. In a delayed group catheter will be removed 72±6 hours after completion of surgery. Shorter or longer catheterization will be considered protocol violation and reasons for ought to be explained in source documents and CRF.

Suction drain will be removed when discharge volume falls below 50 ml/day. If clear discharge (>100 ml/day) continues for 2 consecutive days, discharge fluid and serum creatinine ought to be measured. If fluid creatinine exceeds its serum concentration by at least 30%, urine leakage will be diagnosed and appropriate intervention applied according to surgeon's clinical judgement. Only fistulas requiring medical intervention: reintroduction of the catheter, endoscopic stenting, nephrostomy or surgery will be considered significant and fulfill criteria for primary endpoint of the study.

The course of study will consist of screen visit, hospitalization (with the transplantation procedure, catheter removal, follow up after 48h after catheter removal), follow up visit at 15 days after procedure and follow up visit at 30 days after procedure (see table 2). Patients with urinary complications (fistula, stenosis, infection) will have additional visits every 30 days until complete resolution of complication. Patients with stented anastomosis who will not have a pigtail removed until day 30 will be followed till 7 days after stent removal or resolution of complications would any occur. A final visit 1 year after transplantation will assess patient and graft survival, kidney function, late urinary complications beyond one month from transplantation.

2.4 Sample size and statistics

The investigators assumed early catheter removal reduces the risk of UTI by 10% (RR=0.9) and risk of urinary anastomosis complications is comparable. To achieve a power of 80% at p=0,05 an expected sample size is 450 patients divided fairly into 2 groups. An intent-to-treat analysis will be performed. Graft survival analysis and length of hospital stay will be calculated with log-rank test. Renal function will be analysed with Student t test, provided normal distribution of serum creatinine is observed. Chi2 will be used for analysis of urinary complications. Post hoc analysis of donor and recipient entry data will confirm groups being comparable fo UTI and urinary fistula risk factors.

Subgroup analysis in groups with and without urinary stent will be performed.

Inclusion Criteria:

• Kidney transplant recipient
• Informed consent signed

Exclusion Criteria:

• BMI under 18kg/m2
• BMI over 40 kg/m2
• Significant anatomical abnormalities of lower urinary tract
• Previous surgery on bladder or urinary tract
• Unusual urinary anastomosis (Leadbetter-Politano, Boari, conduit, psoas hitch, pyelo-ureteral or uretero-ureteral, double ureter)
• Severe vascular complications during surgery with blood loss >1000 ml
• Underwent haemodynamic shock or profund instability after surgery

Randomisation will be supervised centrally by the leader center. Generated numbers will be closed in non-transparent envelopes numbered sequentially and shipped to each participating center. A center is supposed to use the envelopes for group assignment consecutively with increasing numbers.