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MINISTRY OF EDUCATION MINISTRY OF DEFENSE AND TRAINING VIET NAM MILIRATY MEDICAL UNIVERSITY NGUYEN THI THUY STUDY ON SEVERAL FEATURES OF CARDIOVASCULAR RISK FACTORS AND PLASMA ASYMMETRIC DIMETHYLARGININE CONCENTRATIONS IN KIDNEY TRANSPLANT PATIENTS Specilize: Internal medicine Indentification number: 9720107 SUMMARY OF MEDICAL THESIS Hanoi – 2023 The research was performed at: Viet Nam Military Medical University Scientific instructors: Assoc Prof Ph.D Le Viet Thang Judge 1: PGS.TS Lê Thu Hà Bệnh viện TƯQĐ 108 Judge 2: GS.TS Phạm Văn Thức Trường Đại học Y Dược Hải Phòng Judge Ư3: PGS.TS Nguyễn Oanh Oanh Học viện Quân y The thesis will be defended before the Thesis Assessment Concil at Institute level on the of ., 2023 Be able to search the thesis at: National library Viet Nam Military Medical University library Central Medical Information Library LIST OF PUBLICATIONS Nguyen Thi Thuy, Le Viet Thang (2022) Asymmetric dimethylarginine serum levels are associated with patient characteristics after renal transplant Tạp chí Y dược học Quân sự, Vol 47, N05 – 2022: 180-189 Nguyễn Thị Thúy, Lê Việt Thắng (2022) Liên quan nồng độ asymmetric dimethylarginine huyết tương với số yếu tố nguy tim mạch bệnh nhân bệnh thận mạn giai đoạn cuối trước ghép thận, Tạp chí Y dược lâm sàng 108, Tập 17- Số 5/2022: 153-158 Evaluating several clinical and subclinical characteristics of patients pre- and post- kidney transplant at 103 military hospital Tập 17 số Tiếng Anh 12/2022:112-117 RATIONALE End-stage renal disease (ESRD) is an increasing global health problem and burden on the health sector in many countries, especially in low-resource countries In 2017, 9.1% (697.6 million people) of the global population had ESRD, with roughly one-third (132.3 million people) from China and India (115 milion people) Individuals with ESRD have a higher chance of dying, primarily from cardiovascular disease According to recent studies, patients with ESRD are 10-100 times more likely than the general population to die from cardiovascular disease Diabetes, hypertension, dyslipidemia, being overweight or obese, anemia, inflammation, and advanced age were all identified as independent predictors of cardiovascular disease in ESRD patients Among the therapies for ESRD, kidney transplantation is the best option since patients may live a near-normal life, although pretransplant cardiovascular complications continue, and it is also the major cause of mortality in patients following kidney transplantation Cardiovascular risk factors existed in the patient before to transplantation and were influenced by immunosuppressive medication usage CRP, homocysteine, and asymmetric dimethylarginine (ADMA) have recently been linked to cardiovascular events in renal transplant patients According to the previous studies, the plasma ADMA concentrations in CKD patients was 1.13-1.36 times greater than in normal healthy persons and increased to the greatest level in the ERSD stage ADMA inhibits the formation of nitric oxide (NO) This substance's content is inversely related to glomerular filtration rate and has been linked to cardiovascular events in individuals both before and after kidney transplantation High ADMA levels have been associated with cardiovascular events and increased mortality risk in ESRD patients both before and after renal transplantation As a result, ADMA may be a predictor of cardiovascular events in patients with post-renal disaese Unfortunately, there are relatively few studies in Vietnam on ADMA and cardiovascular disease in kidney transplant patients, and no study on the relationship between cardiovascular risk factors and ADMA Hence, we conducted the study “Study on several features of cardiac risk factors and plasma asymmetric dimethylarginine concentrations in kidney transplant patients” The objectives 1.1 Survey of several cardiovascular risk factors, atherogenic indices, plasma asymmetric dimethylarginine concentrations, and their association to clinical and subclinical outcomes in persons with end-stage chronic renal disease prior to kidney transplantation 1.2 Assessment of changes in several cardiovascular risk factors, atherosclerotic indices and plasma asymmetric dimethylarginine levels in patients months after kidney transplantation New contributions of the thesis - This is the first study on the novel cardiovascular risk factor Asymmetric dimethylarginine (ADMA) in kidney transplant patients in Vietnam The study's findings first reveal an unique predictor of cardiovascular events in individuals with renal failure - The study's findings revealed that the ADMA index in patients after kidney transplant decreased significantly when compared to the time before kidney transplant, implying that after the patient received kidney replacement surgery, it may help reduce the risk of kidney failure-related cardiovascular events - The enzyme immunoassay was employed in the study to evaluate patients' plasma ADMA levels This approach is less expensive than previous procedures, has higher accuracy, and is simple to apply, thus it may be used on all patients - The findings of this study will be used as a foundation for future research on ADMA in chronic renal disease and kidney transplant patients to better understand the function of ADMA in cardiovascular disease in these individuals 3 The layout of the thesis The thesis consists of 139 pages, with chapters: Rationale 02 pages, Chapter - Introduction: 38 pages, Chapter - Subjects and methods 23 pages, Chapter - Results 33 pages, Chapter - Discussion 40 pages, Conclusion and recommendations 03 pages The thesis has 41 tables, 11 chart 05 figures, 01 diagram, 169 references including 13 Vietnamese documents and 156 English documents CHAPTER OVERVIEW 1.1 End stage chronic kidney disease According to the NKF-KDOQI (Kiney Disease Outcomes Quality Initiative) of the American Society of Nephrology - 2012, kidney disease is considered chronic when one of the following two criteria is met: - Renal damage in renal structure and function, with or without decreased glomerular filtration rate (GFR) > months - Decreased GFR < 60 ml/min/1.73 m2 continuously for more than months, with or without associated structural renal damage Chronic kidney disease (CKD) is divided into five stages based on the decline in glomerular filtration rate: stage (GFR ≥ 90 ml/min/1.73 m2), stage (60-89 ml) /min/1.73 m2), stage 3a (45-59 ml/min/1.73 m2), stage 3b (30-44 ml/min/1.73 m2), stage (15-29 ml/min/1.73 m2), stage ( 0,05 12 Dyslipidemia Yes (n=94) 0,64 (0,52 – 0,76) No (n=18) 0,54 (0,39 – 0,64) p < 0,01 Overweight and Yes (n=23) 0,68 (0,49 – 0,87) obesity No (n=89) 0,62 (0,51 – 0,69) p > 0,05 Anemia Yes (n=104) 0,62 (0,51 – 0,74) No (n=7) 0,61 (0,41 – 0,88) p > 0,05 Increase blood Yes (n=50) 0,63 (0,55 – 0,81) CRP No (n=62) 0,61 (0,46 – 0,70) p > 0,05 AIP index < 0,11 (n=39) 0,53 (0,42 – 0,63) 0,11-0,21 (n=21) 0,66 (0,55 – 0,74) > 0,21 (n=52) 0,68 (0,60 – 0,84) p < 0,001 CRI – I > 4,0 (n= 58) 0,65 (0,53- 0,77) ≤ 4,0 (n= 54) 0,58 (0,44- 0,71) p > 0,05b CRI- II > 3,0 (n= 40) 0,65 (0,57- 0,79) ≤ 3,0 (n= 72) 0,61 (0,47- 0,70) p > 0,05 AC > 2,0 (n= 92) 0,63 (0,53- 0,74) ≤ 2,0 (n= 20) 0,54 (0,42- 0,69) p < 0,001 Comment: There is a relationship between plasma ADMA concentration and risk factors such as: dyslipidemia and atherogenic index AIP, atherosclerotic coefficient AC with p < 0.01 and 0.001 There was no relationship between plasma ADMA concentration and risk factors such as: hypertension, left ventricular hypertrophy, overweight and obesity, anemia, increased CRP and smoking, p > 0.05 3.3 Changes in several cardiovascular risk factors, atherogenic index and plasma ADMA levels in patients after months of kidney transplantation 13 Table 3.28 Characteristics of blood urea, creatinine, GFR and proteinuria of patients after months of kidney transplantation Characteristics Patient Ratio % Increase 13 17,3 Ure (mmol/L) X̅± SD 5,72 ± 1,62 Increase 31 41,3 Creatinine(µmol/L) X̅± SD 102,50 ± 23,05 < 60 ml/phút 9,3 GFE (ml/min) Median 72 (65 – 86) (quartile) Positive 5,3 Negative 71 94,7 Comments: 17.3% of patients still had increased urea and 41.3% of creatinine after months of kidney transplant The rate of patients with MLCT < 60 ml/min was only 9.3% The number of patients with proteinuria after months of transplantation was 5.3% Table 3.29 Comparison of cardiovascular risk factors before and months after kidney transplantation (n=75) Factors (n,%) Prior-trans Afterp trans 67 (89,3) 45 (60,0) < Hypertension 0,001 Diabetes (0) (4) N/A Overweight, obesity 15 (20) 15 (20) > 0,05 Dyslipidemia 59 (78,7) 65 (86,7) > 0,05 CRP > mg/l 31 (41,3) 15 (20) < 0,01 68 (90,7) 22 (29,3) < Anemia 0,001 44 (58,7) 18 (24,0) < LV hypertrophy 0,001 AIP > 0,11 45 (60) 53 (70,7) > 0,05 CRI - I > 4,0 39 (52) 40 (53,3) > 0,05 CRI - II > 3,0 25 (33,3) 33 (44,0) > 0,05 AC > 2,0 61 (81,3) 67 (89,3) > 0,05 Comments: The indices of hypertension, CRP increase, anemia and left ventricular hypertrophy were significantly reduced after Proteinuria 14 months of kidney transplantation compared with the time before transplantation, the difference was statistically significant with p < 0.005 After months of transplantation, patients (4%) had new diabetes There was no difference in the proportion of overweight and obese patients, dyslipidemia and atherogenic index before and months after kidney transplantation, p > 0.05 Table 3.31 Comparison of plasma ADMA concentrations before and months after kidney transplantation (n=75) ADMA (µmol/ L) ADMA Median (quartile ) Min Max Pior-trans (1) Aftertrans (2) Control (3) p 0,62 (0,49-0,74) 0,57 (0,47-0,65) 0,17 (0,130,23) < 0,001 (1)(2) < 0,05 (1)(3) < 0,001 (2)(3) < 0,001 0,27 1,16 0,12 1,00 0,09 0,37 Comment: The average plasma ADMA concentration months after kidney transplant was significantly lower than before, p < 0.001 Although there was a reduction, the plasma ADMA concentration after months of transplantation was still significantly higher than that of healthy subjects, p < 0.001 Table 3.34 Correlation of plasma ADMA levels with several hematological and biochemical indices at the 6th month after kidney transplantation Index ADMA (µmol/ Correlation equation L) R p Hemoglobin (g/ > 0,05 0,157 L) Ure (mmol/L) 0,141 > 0,05 ADMA = 0,773 MLCT (ml/phút) -0,261 < 0,05 0,003*MLCT Acid uric (µmol/ ADMA = 0,001*Acid 0,287 < 0,05 L) uric + 0,379 15 < 0,001 ADMA = 0,275*AIP + 0,482 ADMA = 0,046*CRICRI – I 0,319 < 0,01 I + 0,358 ADMA = 0,056*CRICRI – II 0,311 < 0,01 II + 0,394 ADMA = 0,046*AC AC 0,319 < 0,01 + 0,404 CRP (mg/L) 0,099 > 0,05 Comment: At the 6th month after kidney transplant, ADMA concentration was negatively correlated with MLCT and positively correlated with uric acid concentration as well as atherogenesis index, p < 0.05 There was no correlation between ADMA levels with hemoglobin, urea, and blood CRP in patients months after kidney transplantation, p > 0.05 AIP 0,468 CHAPTER DISCUSSION 4.1 Characteristics of the study participants The male was 2.73 times larger than that of women, with men accounting for 73.2% and women was 26.8% Hoang Trong Ai Quoc indicated that the male-female ratio was 52.8% and 47.2%, Nguyen Hoang Thanh Van was 55.93% and 44.07%, Abelling (59% and 41%), and Goncalves (59.5% and 40.5%) The discrepancy in the male/female ratio across the research might be attributable to the fact that our study used a full, random sample, therefore the male/female ratio is different from the studies that used the sampling method on purpose The mean age of men/women, the patient and the control groups are nearly same (36.67 - 36.60 years old), younger than the studies of Hoang Trong Ai Quoc (54.47 years old), Seoane-Pillado (46.97 years old), and Goncalves (46.97 years old) (49.6 years old) The age discrepancy between this study and others might be attributed to a variety of factors such as study subjects, treatment procedures, sample size, and so on 16 Most patients got treatments, with hemodialysis accounting for 83.0%, peritoneal dialysis accounting for 7.2%, and internal therapy conservation department accounting for 9.8% Progressive CKD causes a progressive loss of kidney function and eventually leads to end-stage renal failure; the progression period can be quick or slow depending on the origin, location of damage, and influencing variables, and can lead to kidney failure in the ultimate stage Renal replacement treatment with extrarenal dialysis, peritoneal dialysis, or kidney transplantation is necessary for patients with GFR 15 ml/min The instances have been identified as ESRD, but the patient's urine output is normal and responds to medical therapy, therefore the patient will be monitored while waiting for a kidney transplant 4.2 Characteristics of several cardiovascular risk factors, atherogenic indices, plasma ADMA levels and their clinical and subclinical relationships in patients with chronic kidney disease before kidney transplantation Characteristics of biochemical and hematological indicators Biochemical and hematological indices such as urea, creatinine, uric acid, and triglyceride (TG) were substantially greater in the disease group than in the control group, whereas hemoglobin, cholesterol, LDL-C, and HDL-C were lower in the disease group than in the control group Dyslipidemia is a risk factor for cardiovascular disease, and studies on chronic renal disease have revealed the existence of dyslipidemia The study by Hoang Trong Ai Quoc, Tae, and Mikolasevic all found that the patient group had greater levels of cholesterol, serum TG, LDL-C, and HDL-C than the control group However, there is a discrepancy in the pace of rise across ages, which might be attributed to the time of testing, age, and gender ratio of the participants The aforementioned studies all choose a fairly even ratio of males to women, and the age is also rather high (60 years old), however in our study, the patient group is quite young (37 years old), therefore the difference is significant Age can cause variations in biochemical and hematological parameters Furthermore, the discrepancy might be connected to the patient's nutrition; nutritional limitation frequently produces imbalance and alterations in blood components 17 Characteristics of cardiovascular risk factors BMI: 19.7% of patients were malnourished (BMI < 18.5), 20.5% were overweight and obese (BMI > 23.0), 59.8% had just normal BMI, and the group's mean BMI was 20.79 - 2.61 The BMI is comparable to that found in the studies of Ngo Thi Khanh Trang (20.27 - 2.81), Nguyen Thi Huong (20.50 - 2.62), and Nguyen Hoang Thanh (18.76 2.83), but lower than those found in Claes K J (25.36 - 4.9), Kanbay M (26.0 2.7), and Said M Y (26.0 - 3.1) The difference is due to the physical condition and characteristics of the Vietnamese people, as well as the fact that chronic kidney failure in our country is primarily caused by chronic glomerulonephritis and chronic pyelonephritis, whereas chronic kidney failure in developed countries is primarily caused by chronic kidney failure due to diabetes Hypertension: more than 90% of patients have hypertension, with only 9.8% having no hypertension Almost half of the patients with hypertension had blood pressure management that was not on target Similar rates were found in the studies of Ngo Thi Khanh Trang, Nguyen Hoang Thanh Van, Nguyen Thi Huong, Agarwal R., and Vaios Hence, the data have shown that the rate of hypertension in chronic kidney failure patients is greater than in healthy persons, implying that hypertension is the cause of kidney failure progression; the higher the blood pressure, the faster the danger of kidney failure Individuals with uncontrolled blood pressure frequently have a very bad prognosis Anemia: 93.7% of patients had anemia (6.7% had severe anemia), with just 6.3% not anemic, similar to the study of Ngo Thi Khanh Trang, Nguyen Thi Huong, and Nguyen Hoang Thanh Van There are several causes of anemia in people with CKF: first, the kidneys not produce enough Erythropoietin to stimulate the bone marrow to produce red blood cells or iron deficiency, metabolic disorders, malnutrition, inflammation ; second, blood loss during hemodialysis; third, poor nutrition; fourth, a high rate of destruction of red blood cells due to toxic substances in the blood; and fifth, leakage through the gastrointestinal tract As a result, anemia is frequent in people with renal failure; this long-term disease will lead
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