luan an tom tat eng nghiên cứu căn nguyên nhiễm trùng tiết niệu sau ghép thận và một số yếu tố liên quan đến rối loạn chức năng thận ghép

Renal graft dysfunction is a progressive loss of kidney function that develops over one or more years after kidney transplantation, formerly known as chronic allograft nephropathy and no

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE

108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

THE THESIS WAS DONE IN: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

Supervisor:

1 Bui Tien Sy MD, Ph.D 2 Assoc Prof Tran Hong Nghi MD,Ph.D

Reviewer:

1 2 3

This thesis will be presented at Institute Council at: 108 Institute of Clinical Medical and Pharmaceutical Sciences

Day Month Year 2024

The thesis can be found at:

1 National Library of Vietnam 2 Library of 108 Institute of Clinical Medical and

Pharmaceutical Sciences 3 Central Institute for Medical Science Infomation and

Tecnology

QUESTION

Infection is one of the common causes of illness in people using immunosuppressive drugs and one of the causes of death in patients after kidney transplantation [5] According to estimates by the American Society of Nephrology (ASN), the infection rate in the first 3 years after kidney transplantation is 45% [6] At the same time, infection is one of the causes that affects kidney transplant function, rejection and even death [7]

Urinary tract infections, including asymptomatic urinary tract infections and symptomatic urinary tract infections, are the most common forms of infection after kidney transplantation [8]

Renal graft dysfunction is a progressive loss of kidney function that develops over one or more years after kidney transplantation, formerly known as chronic allograft nephropathy and now as interstitial fibrosis and tubular atrophy in the Banff classification [10], [11] Clinically, the disease is usually diagnosed by slowly increasing serum creatinine levels, increased proteinuria, and worsening hypertension

To evaluate the urinary infection status of patients after kidney transplant, determine the cause of urinary infection, as well as better understand the impact of factors related to kidney transplant

dysfunction, we conducted a study Current project: "Research on the

causes of urinary tract infection after kidney transplant and some factors related to kidney transplant dysfunction" with the following

Chapter 1: OVERVIEW 1.1 Overview of kidney transplantation 1.1.1 Anesthesia and resuscitation in kidney transplantation

You can choose one of two anesthetic methods during kidney transplant surgery: endotracheal anesthesia, or spinal anesthesia combined with epidural anesthesia, or epidural anesthesia combined with internal anesthesia trachea [5]

1.1.4.1 Early complications after kidney transplant 1.1.4.2 Late complications after kidney transplant

* Surgical complications Renal graft ureteral stenosis; Vesicoureteral reflux - ureteral kidney transplant and acute pyelonephritis; Kidney stones; Transplant renal artery stenosis;

* Internal medical complications Complications related to the use of immunosuppressive drugs, recurrence of old diseases, new kidney diseases, infections, cardiovascular complications, malignant diseases, gastrointestinal complications, liver and pancreatic complications, skin complications, musculoskeletal complications, neurological complications, blood complications [5]; Infection after kidney transplant; Delayed kidney graft function (DGF - delayed graft function); Hyperacute rejection; Acute rejection; Chronic rejection; New onset diabetes after organ transplant (NODAT - New onset diabetes after transplantation): Cardiovascular complications after kidney transplant; Complications of hyperuricemia (Gout)

1.1.5 Monitoring and treatment after kidney transplant 1.1.5.1 Induction treatment

Use IL-2 receptor antagonist (IL2-RA) as an induction treatment agent [5]

1.1.5.2 Maintenance immunosuppressive treatment

+ Tacrolimus + Mycophenolate mofetil + Prednisone + Cyclosporin A + Mycophenolate mofetil + Prednisone + Cyclosporin A + Azathioprine + Prednisone

+ Tacrolimus + Azathioprine + Prednisone

1.1.5.3 Treatment of transplant rejection

* Fulminant graft rejection Treatment: the only solution is to remove the transplanted kidney * Acute graft rejection

Treatment with Corticoid loading dose (250mg - 500mg/day × 3 consecutive days)

* Chronic graft rejection Treat chronic rejection by using the following methods: reduce dose, stop CNI or suggest replacing CNI with mTORi

1.2 Urinary tract infection after kidney transplant 1.2.1 Concept

Urinary tract infection when urine culture is positive ≥ 105

CFU/mL (CFU - colony forming units) with no more than 2 species of pathogenic microorganisms [47]

1.2.2 Classify

Asymptomatic urinary tract infections, symptomatic urinary tract infections, and complicated urinary tract infections

1.2.3 Causes of urinary tract infections

Bacteria, viruses, and fungi, but urinary tract infections caused by bacteria and viruses still predominate [49] The predominant bacterial

isolates were Escherichia coli (31.5%), Enterococcus (10.5%) [52]

One study showed that urinary infections were mainly caused by

Escherichia coli (28.4%), Pseudomonas aeruginosa (14.9%), and Enterobacter cloacae in kidney transplant recipients [49]

Candida glabrata/albicans, Adenovirus, tuberculosis must also be included in the differential diagnosis, Pseudomonas and Staphylococcus infections most commonly appear in the first month, Enterococcus and E coli are detected later [53]

1.2.4 Factors related to post-transplant urinary tract infection

* Risk originates from the donor * Anthropological factors

Female organ transplant patients have been reported in many studies to have a higher risk of urinary tract infections than men after kidney transplantation [8], [66], [67]

1.3 Kidney graft dysfunction 1.3.1 Concept

Kidney graft dysfunction is the gradual loss of kidney graft function one or more years after kidney transplantation [12] Clinically, renal graft dysfunction is defined as an increase in serum creatinine of 15% from baseline (baseline value) [68]

1.3.2 Classify

* Acute and chronic kidney transplant dysfunction * Early and late kidney transplant dysfunction * Kidney transplant dysfunction according to cause

1.3.3 Methods for assessing kidney transplant function

Kidney graft function is commonly measured by serum creatinine concentration and associated glomerular filtration rate (GFR) [81]

1.3.4 Factors related to kidney transplant dysfunction 1.3.4.1 Related factors before transplantation

* Factors from the donor * Recipient factor

1.3.4.2 Related factors after kidney transplant

* Transplant rejection * Calcineurin inhibitors (CNI) are nephrotoxic * Post-transplant hypertension

* The rate of comorbidities is higher in obese patients * Relationship between infection and kidney transplant function

1.4 Some international and domestic studies on urinary tract infections and kidney graft dysfunction in patients after kidney transplant

1.4.1 Research around the world

* Research on urinary tract infections after kidney transplant Research by Praveen Kumar Etta (2019) [21], shows that gram-negative bacteria contribute up to 60%–90% of the causes of urinary tract infections in patients after kidney transplant; Important pathogens include E coli (most common), Pseudomonas, Enterobacter, Klebsiella, and Proteus

According to research by P Meena and colleagues (2021) [110], after kidney transplantation, urinary infections are most common in the first month due to association with urinary stents and catheters, draining the graft kidney pit

* Research on kidney transplant dysfunction

Research by M Boratyńska et al (2014), during 10 years of up, kidney graft dysfunction developed in 43.1% of patients Proteinuria, serum creatinine levels >1.5 mg/dL at months 12 and 24, and CMV infection were identified as factors in the development of chronic allograft dysfunction (CAD) this is the most common cause of kidney graft dysfunction and graft loss [111]

follow-Research by Jeffery T Fletcher et al (2009) on chronic kidney graft dysfunction is the leading cause of kidney graft loss, there are both donor and recipient reasons for this, and it is likely that it reflects the combination of both immune and non-immune damage that occurs cumulatively over time [112]

1.4.2 Research in Vietnam

Research by Tran Van Hinh and Bui Van Manh (2012), at Military Hospital 103 from 1992 to 2012 with 98 kidney transplant patients showed that urinary infections accounted for 14.28%, of which 9/14 cases were infected infections within the first 3 months after transplantation [114]

Research by Thai Minh Sam and colleagues (2021) [115], studied 208 cases of kidney transplantation from living kidney donors from January 1, 2016 to May 31, 2018, analyzing the results of kidney transplantation in 1 year year after transplant, the most common infectious complication in the first year is urinary tract infection with 5.77%

Research by Nguyen Anh Thu and colleagues (2022), at Bach Mai hospital, out of 81 patients studied, 31 patients were infected with BK virus (38.3%) Among them, there were 20 patients with pure BK viruria (24.7%) and 11 patients with BK viremia (14.6%) There were 4 (out of 28) patients whose kidney biopsy results were BK viral kidney disease BK virus infection is related to the use of Tacrolimus at doses above 7 ng/ml, low glomerular filtration rate and loss of kidney graft function in study patients.[75]

Chapter 2: RESEARCH SUBJECTS AND METHODS 2.1 Research subjects

The study subjects included 94 first-time kidney transplant patients and outpatient follow-up at Central Military Hospital 108 (BVTWQD108) from December 2019 to December 2022

2.1.1 Criteria for selecting patients into the study group

- First-time kidney transplant patient then followed up as an outpatient at Hospital 108

- Patients ≥ 18 years old

2.1.2 Criteria for excluding patients from the study group

- The patient does not have enough follow-up records at Central Hospital 108

- Patients or family members refuse to participate in the study

2.1.3 Criteria taken out of the study

- Patients died from causes clearly unrelated to the transplanted kidney during the study period

- Patients transferred for outpatient follow-up to other hospitals

2.2 Research Methods 2.2.1 research design

Descriptive study with longitudinal follow-up

2.2.2 Sampling method: convenient 2.2.3 Research facilities

2.2.4 Research content and evaluation criteria 2.2.4.1 General characteristics of research subjects 2.2.4.2 Objective 1: Causes of post-transplant urinary infection

* Content 1: Determine the status of bacterial urinary infection in patients after kidney transplant at monthly follow-up visits, obtain urine culture results at intervals: from the Recovery period to 1 month (Resuscitation-T1); from 1 month to 3 months (T1-T3); from 3 months to 6 months (Tuesday-June); from 6 months to 9 months (June-September); from 9 months to 12 months (T12) after kidney transplant

- Determine the microbiological cause of urinary infection according to urine culture results at stages (Resuscitation-T1; T1-T12)

- Antibiotic treatment according to the instructions of the antibiogram for each specific case Adjust immunosuppressive dose accordingly * Content 2: Determine the status of viral urinary infection in patients after kidney transplant, obtain molecular biology test results (Real-time PCR) when the patient has symptoms of urinary infection that have been diagnosed Other causes can be ruled out and Real-time PCR tests are performed to routinely screen blood and urine samples

every 3 months according to the following timelines: at the time of Resuscitation; 1 month after transplant (T1), at 3 months after transplant (T3), at 6 months after transplant (T6), at 9 months after transplant (T9), at 12 months after kidney transplant ( T12)

- Determine the type of virus contracted according to Real-time PCR test results at time points (Resuscitation, T1, T3, T6, T9, T12)

2.2.4.3 Objective 2: Some factors related to kidney transplant dysfunction

* Content 1: Evaluate relevant factors before and after transplantation - Analyze factors related to kidney function

- Analyze pre-transplant treatment methods for kidney function - Analyze the relationship between age and kidney transplant function - Analyze the relationship between HLA compatibility and kidney function

- Analyze characteristics during surgery and treatment time * Content 2: Evaluate related factors after transplantation - Analyze accompanying diseases related to kidney function - Analyze factors related to immunosuppressive drugs on kidney transplant function

- Analyze factors related to infection and kidney function - Analyze factors related to viral infection

2.2.4.4 Evaluation criteria

* General information: * Evaluation criteria

2.2.5 How to conduct research

* Procedures - Routine treatment regimens after kidney transplant: • Resuscitation treatment after kidney transplant * Circulatory resuscitation:

* Kidney transplant resuscitation • Immunosuppressive treatment * Introductory treatment - Basilizimab (Simulect) + IL-2 receptor inhibitors * Maintenance immunosuppression regimen used: + Tacrolimus + Mycophenolate mofetil + Prednisone

+ Cyclosporin A + Mycophenolate mofetil + Prednisone + Cyclosporin A + Azathioprine + Prednisone

+ Tacrolimus + Azathioprine + Prednisone • Treatment of transplant rejection

* Microbiological testing * Molecular biology tests:

2.2.6 Definition of variables and standards used in research 2.2.6.1 Definition of variables

2.2.6.2 Standards used in research 2.2.7 Analyze and process data

Analyzed on SPSS 26.0 software (SPSS Inc., Chicago, IL, USA) Urinary tract infection etiology is expressed as frequency and percentage The association with kidney transplant dysfunction was analyzed using logistic regression divided into 2 univariate and multivariate steps p < 0.05 was considered significant

Chapter 3: RESEARCH RESULTS 3.1 General characteristics of research subjects 3.1 1 Age, gender, height, weight, BMI

Table 3.1 Distribution by age at the time of kidney transplantation

Age (years) n Study subjects (n = 94)) %

Chart 3.1 Distribution of patients by gender (n=94)

Men account for 74.5%; Women account for 25.5% of the research group, male/female ratio: 70/24 = 2.92

Table 3.2 Characteristics of height, weight, body mass index

Characteristic Research subjects (n=94)

𝑋𝑋� ± SD

BMI (kg/m2) 21.0 ± 2.80 Study subjects had an average body mass index (BMI) of 21 ± 2.80 kg/m2

3.1.2 Causes of chronic kidney failure, pre-transplant treatment methods

Chart 3.2 Causes of chronic kidney failure (n=94)

The main cause of chronic kidney failure is glomerulonephritis 74.5% Hypertension is the second cause of chronic kidney failure with 9.6%

Male (n=70), 74.5%Female (n=24), 25.5%

74.5 %5.3 %9.6 % 4.3 %

2.1 % 1.1 %3.2 % Glomerulonephritis (n=70)

Hypertension (n=9)Interstitial nephritis (n=4)Lupus (n=2)

IgA nephropathy (n=1)Other (n=3)

Chart 3.3 Pre-transplant treatment (n=94)

The main pre-transplant treatment method is pre-transplant dialysis, accounting for 88.3% (83/94 patients), the proportion of conservative medical patients accounting for 9.6% (9/94 patients)

Chart 3.4 Matching blood types between donor and recipient

Chart 3.5 Level of HLA compatibility by class (n=94)

For antigen matching, low HLA compatibility level of 0/6 occurs: 1.1% The level of HLA 3/6 compatibility accounts for the highest rate of 54.3%

3.1.6 Characteristics during kidney transplant surgery

88.3 %

Peritoneal filtration (n=2)Nội khoa bảo tồn (n=9)

0102030405060708090

12.8 %3.2 %83 %

1.1 %

Class I compatibly (n=12)Class II compatibl (n=3)Class I, class II compatibly (n=78)Not compatible (n=1)

3.1.7 Characteristics of the intensive care unit (ICU) period after kidney transplant

Table 3.10 Postoperative developments during the recovery period

antihypertensive medication, frequency

Using Loxen, frequency (percentage %) 15 (15.9) Using Amlor, frequency (percentage %) 60 (63.8) Time to appearance of increased BP (hours),

Time to increase in BP (hours), median (IQR) 4.0 (1.2 - 7.0) Hypertension grade I, frequency (percentage %) 20 (21.2) Hypertension grade II, frequency (percentage %) 55 (58.5) Blood transfusion after surgery, frequency

HC block, frequency (percentage %) 5 (5.3) HC and TC blocks, frequency (percentage %) 3 (3.2)

Table 3.11 Use immunosuppressants

Using Prednisolone after surgery, frequency

Using Tacrolimus after surgery, frequency