Nghiên cứu tình trạng thăng bằng kiềm toan và điện giải máu ở bệnh nhân bệnh thận mạn tính giai đoạn 4, 5 chưa được can thiệp điều trị tt tiếng anh

MINISTRY OF EDUCATION MINISTRY OF DEFENSE AND TRAINING VIETNAM MILITARY MEDICAL UNIVERSITY -o0o - NGUYEN DUC PHAT INVESTIGATION OF ACID - BASE BALANCE AND BLOOD ELECTROLYTES IN PATIENTS WITH CHRONIC KIDNEY DISEASE STAGE 4, WITHOUT TREATMENT INTERVENTION Speciality: Internal Medicine Code: 9720107 SUMMARY OF MEDICAL DOCTORAL THESIS HA NOI – 2019 The work was completed in Vietnam Military Medical Academy Supervisors: Ass.Prof Ph.D.Hoang Trung Vinh Ass.Prof Ph.D.Pham Van Tran Reviewer 1: Ass.Prof Ph.D.Dinh Thi Kim Dung Reviewer 2: Ass.Prof Ph.D.Pham Thien Ngoc Reviewer 3: Ass.Prof Ph.D.Nguyen Linh Toan The dissertation will be defended before the council of doctoral dissertation in the Vietnam Military Medical university organised at: ………hour… day …… month… year 20… The thesis can be found at: - National Library - Vietnam Military Medical University’s Library INTRODUCTION THE URGENCY OF THE SUBJECT Kidneys play an important role in the functions of excretion, endocrine and metabolism to maintain homeostasis The kidneys excrete hydrogen and reabsorb bicarbonate (HCO3- ) from glomerular filtrate When kidney function is impaired, ability of hydrogen excretion and HCO3- reabsorption will reduce, leading to disorders of acid - base balance, which is mainly expressed by metabolic acidosis Most metabolic acidosis appear when glomerular filtration rate (GFR) < 25ml/min, corresponding to chronic kidney disease (CKD) stage 4, Along with acid - base disturbance, disorder of electrolytes is also common However, appearance of acid - base and electrolyte disorders in CKD patients depends on many factors and has individual characteristic Therefore, it is necessary to base on arterial blood gas test and venous blood electrolytes to adjust the disorders accordingly In fact, it may be inadequate between stage of CKD and acid - base and electrolyte disorders Metabolic acidosis and electrolyte disturbances in patients with CKD are not a new problem but never old in many respects Therefore, we conducted the thesis "Investigation of acid - base balance and blood electrolyte in patients with chronic kidney disease stage 4, without treatment intervention" with two purposes: To determine the indexes of artery blood gas and venous blood electrolyte in patients with chronic kidney disease stage 4, who have not been received treatment intervention (blood alkalization or renal replacement therapy) at Kien Giang General Hospital To analyse relation between the indexes of arterial blood gas and venous blood electrolytes with some clinical and subclinical parameters in patients with chronic kidney disease stage 4, who have not been treated (blood alkalization or renal replacement treatment) NEW CONTRIBUTIONS OF THE THESIS + The study showed that patients with CKD stage 4, without treatment had acid - base and electrolyte disorders met all types with different rates + Rates of metabolic acidosis, decreased Na + and increased K+ were higher than those of other disorders + Having applied and determined renal tubular acidosis - The content has not been mentioned in domestic studies All four types of renal tubular acidosis were seen, in which disorder of HCO3reabsorption in the proximal tubule (type 2) had the highest rate + Although there are many coordinating factors affecting acid base disorder and blood electrolytes, we have been identified some significantly relevant factors when analyzing univariate correlation Only GFR significantly correlated with HCO3- when analyzing multivariate regression with cut-off value less than 13.975 ml/min / 1.73m2 STRUCTURE OF THE THESIS The main content of the thesis is 109 pages, including: Introduction: 02 pages; Overview: 29 pages; Subjects and methods: 14 pages; Results: 26 pages; Discussion: 34 pages; Limitations of the thesis: 01 page; Conclusion: 02 pages; Recommendation: 01 page The thesis has 48 tables; charts; graphs; picture The appendix includes: 02 related articles (1 in English, in Vietnamese); 164 reference documents (34 Vietnamese documents; 130 English documents); Sample of research medical records; List of research patients CHAPTER 1: OVERVIEW 1.1 Acid - base disorder in patients with chronic kidney disease 1.1.1 Control acid - base balance by kidney The body maintains a stable acid-base balance based on three mechanisms including: buffer systems in intracellular and extracellular fluid, regulation of acid - base balance by lungs and regulation by kidneys The third path is also the last one to protect the body from acid-base disturbance is the kidney The kidney responds to changes in blood pH and PaCO2 by changing H+ and HCO3- excretion accordingly The kidney's response is often slow, it takes several days to complete, which reflects the time necessary for the kidney to increase synthesis and activation of enzymes associated with NH 4+ production, but this is the most effective and sustainable way to correct acid- base disturbance of the body In case of acidosis (reduced blood pH, increased H + level or PaCO2) will stimulate nephrons to reabsorb bicarbonate filtered by glomeruli, increase production and excretion of NH 4+, so kidney increases acid excretion New HCO 3- formed during the acid excretion process is reabsorbed back to the body, which results in increasing HCO3- level in the blood 1.1.2 Types of acid - base disturbances In disturbance of acid - base, the protective mechanism of the respiratory system and kidney is appropriate, whereby lungs compensate for metabolic disorders while kidneys compensate for respiratory disorders This mechanism can not completely regulate the disorder, it only partly regulates blood pH changes To completely recover the disorder of acid –base balance requires resolving causes Table 1.1 Characteristics of disturbance of acid - base balance Disorder Blood pH Metabolic acidosis Decrease Metabolic alkalosis Increase Primary change [HCO3-] [HCO3-] Respiratory Decrease acidosis [PaCO2] Respiratory Increase alkalosis [PaCO2] Protective mechanism Buffers in intracellular and extracellular fluid Increase respiratory frequency (to decreaseinPaCO Buffers intracellular and 2) extracellular fluid; Decrease respiratory frequency (to increaseinPaCO Buffers intracellular and 2) extracellular fluid; kidney increases excretion of acid and reabsorption of HCO3- and Buffers in intracellular extracellular fluid; kidney decreases excretion of acid and reabsorption of HCO3- 1.1.3 Mechanism of pathogenesis of metabolic acidosis due to kidney disease In CKD patients due to damage of the kidney structure, in which the most important is the injury of glomeruli and renal tubules that directly affect the process of elimination or reabsorption of ions related to homeostasis in the body, in which there are H + and HCO3involved Due to increased acidic substances such as urea, creatinine, uric acid in the blood and impaired renal function of H+ elimination, the body is stagnant by these substances The level of acidic substances gradually increases according to the degree and stage of the disease Moreover, because of the decrease in renal tubular HCO3reabsorption capacity, levels of the stagnant substances in the body increase more, leading to acid - base imbalance and metabolic acidosis appearance as a result of disorder of acid - base When the body's adaptive and compensatory mechanisms, especially buffer systems and lungs cannot control resulting in clinical metabolic acidosis appearance 1.1.4 Consequences of metabolic acidosis in chronic kidney disease Chronic metabolic acidosis in patients with CKD causes the following lesions: reduced bone mineral density and osteoporosis; Increased protein catabolism of muscle tissue; increased secondary hyperparathyroidism Reduced reservation and respiratory buffer system Reducing the activity of Na+ - K+ - ATPase in erythrocytes and cardiomyocytes, therefore ability of cardiac contraction decreased leading to heart failure Endocrine-related changes such as resistance to growth hormone and insulin, increased triglycerides, increased risk of inflammation, and decreased blood pressure Metabolic acidosis is associated with mortality of patients Numerous observational studies have recorded the association between metabolic acidosis and increased mortality in CKD patients without dialysis or end stage 1.2 Disorders of blood electrolytes in patients with chronic kidney disease 1.2.1 Disorders of Na+, Cl- in patients with chronic kidney disease Normally when GFR > 15ml/minute, patients still have ability to maintain Na+ level at normal or near normal level However, when GFR < 15 ml/min, the kidney will not be able to increase Na + excretion to maintain the normal concentration At this time, if intake of NaCl in the body < 120-170 mEq/day, increase in intracellular fluid volume will be avoided When GFR in the range of 15-50 ml/min, kidney is still capable of regulating NaCl except for nephrotic syndrome However, in fact, NaCl excretory ability of kidney to reach < 30 mEq/day is little If GFR still in that range but the amount of NaCl intake limited, the kidney is still able to eliminate NaCl through the urinary tract to maintain normal state 1.2.2 K+ disorder in patients with chronic kidney disease Hyperkalemia is common in CKD patients with reduced GFR or excessive infusion of hypertonic saline or using numerous contrast drugs Catecholamin can cause a transient increase in potassium in the extracellular fluid by moving potassium from the intracellular to the extracellular Therefore, hyperkalemia can use  sympathetic antagonist to reduce blood potassium level even in patients with CKD When using a lot of acidic solution such as HCl, NH4Cl will cause hyperkalemia 1.2.3 Calcium and phosphorus disorders in patients with chronic kidney disease Disorders of calcium, phosphorus and PTH are typical changes in patients with CKD The association among the three indexes is both positive and negative, in which increasing phosphorus level leading to reduced calcium and secondary hyperparathyroidism causing increased PTH Disorders of calcium, phosphorus and PTH levels occur early when GFR 18 + CKD due to different causes determined + Have not been treated by renal replacement therapy or alkalization yet 2.1.2 Exclusion criteria +Patients with acute diseases such as: acute heart failure, stroke, coma, acute bronchitis – pneumonia, acute respiratory failure +Concurrent chronic diseases: chronic heart failure grade 3,4; Cirrhosis, chronic obstructive pulmonary disease, bronchial asthma + Acute kidney failure + Tests requested by the study were insufficiently performed + Have been treated by hemodialysis or Nabica before taking tests of the study 2.2 Methods +Study design: prospective, descriptive, cross section +Place and time: Nephrology Department and Intensive care unit of Kien Giang General Hospital; 10/2013 – 11/2017 2.2.1 Study contents + Revealing medical history + Asking and examining clinical signs and symptoms + Hematological and biochemical tests Arterial blood gas tests were performed on GEM Premier 3000 selective electrode machine with indexes: pH, HCO3-, BE, PaCO2, PaO2, SaO2 Anion gap (AG) was determined by the formula: AG = [Na +] - ([Cl-] + [HCO3-]), then AG was adjusted based on serum albumin level, which was called albumin - corrected AG (AGc) + Urine test: Urine volume per day was collected and then urine biochemical tests were performed including pH 2.2.2 Criteria for diagnosis and classification used in the study + Hypertension, diabetes mellitus, chronic glomerulonephritis, chronic pyelo-nephritis and polycystic kidney disease were diagnosed according to guidelines of Vietnam National Heart Association, Vietnam Society of Diabetes and Endocrinology and educational materials + Classification of blood pressure levels according to JNC VI + Diagnosis and classification of anemia according to WHO Table 2.1 Normal range of arterial blood gas indexes Index Unit pH Normal range 7.38 - 7.42 PaCO2 mmHg 38 - 42 HCO3- mmol/l 22 - 26 PaO2 mmHg 85 - 100 BE mmol/l (-2) - (+2) SaO2 % 95 - 97 12 + Metabolic alkalosis was seen with the lowest rate 13 Table 3.5 Distribution of patients by HCO3- and AG value Index Level Quantity (n) Percentage (%) 15 - 20 60 33 (increased) + Mildly metabolic acidosis accounted for the highest rate + Severely metabolic acidosis was seen with the lowest rate + Increased AG (>20 mmol/l) was recorded in 1/3 of the patients (which was equal to half of the rate of patients with normal AG) Figure 3.1 Percentages of patients by types of renal tubular acidosis (n=152) 14 + Patients with renal tubular acidosis were distributed at all four types with different percentages + Type accounted for the highest rate, type was seen with the lowest rate 3.2.2 Venous blood electrolytes Table 3.6 Rates of patients by levels of blood electrolytes Decreased Normal Increased (n, %) (n, %) (n, %) + Na 68 ( 37.4%) 113 ( 62.1%) ( 0.5%) K+ 21 ( 11.5%) 106 ( 58.2%) 55 ( 30.2%) Cl60 ( 33.0%) 100 ( 54.9%) 22 ( 12.2%) Ca++ ( n = 64) 27 ( 42.2%) 36 ( 56.3%) ( 1.6%) + Electrolyte indexes were distributed at levels of reduction, normal and increasing with different rates + Patients with electrolyte indexes at normal level accounted for higher rates compared to those at decreased and increased level 3.3 Relation between arterial blood gas, venous blood electrolytes and some parameters Table 3.7 Relation between metabolic acidosis and stages of CKD Electrolytes Non - metabolic Metabolic p acidosis acidosis n % n % (n = 72) 38 52.8 34 47.2 < 0.01 (n = 110) 30 27.3 80 72.7 OR=12.096 Total 68 37.4 114 62.6 182 CKD stage had rate of metabolic acidosis significantly higher than CKD stage with p < 0.01; OR = 12.096 Stage of CKD 15 Table 3.8 Correlation between some ABG indexes and GFR ABG index r p Equation pH 0.231 < 0.05 pH = 0.0028 x GFR + 7.3038 HCO30.291 < 0.05 HCO3- = 0.2202 x GFR + 15.006 (mmol/l) BE (mmol/l) 0.325 < 0.05 BE = 0.229 x GFR – 10.448 AG (mmol/l) -0.221 < 0.05 AG = -0,1948 x GFR + 20.725 + pH had a significantly positive correlation with GFR (r=0.23; p < 0.05) + HCO3- was significantly positively correlated with GFR (r=0.29; P < 0.05) + BE had a significantly positive correlation with GFR (r=0.325; p < 0.05) + AG and GFR had a significantly negative correlation (r=-0.22, p < 0.05) Table 3.9 Multivariate regression analysis between metabolic acidosis and some parameters Parameter Age (year) Gender CKD causes Edema Hypertension Hb (g/l) GFR (ml/min/1.73m2) OR 0.72 0.8 1.00 0.79 0.15 1.26 9.75 p >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 0.05 Ca++ (n = 64) 0.25 < 0.05 Ca++ = 3.8962 x HCO3- + 10.624 ( mmol/l) + Na+ and Ca++ were significantly positively correlated with HCO3- + K+ was significantly negatively correlated with HCO3- + Cl- was not correlated with HCO3- CHAPTER 4: DISCUSSION 17 4.1 Arterial blood gas and venous blood electrolyte indexes in patients with chronic kidney disease Analysing indexes of arterial blood gas test, we found that most indexes such as pH, HCO3-, PaCO2, PaO2 and BE declined, met with high rates, except for SaO having normal rate highest Reduced BE accounted for the highest proportion up to 92.3%, followed by a decrease in HCO3- (83.5%) Reducing the absolute value of pH was seen in 70.3% of the cases Decreased indexes of AG accounted for the highest rates, which was followed by AG indexes at normal range Increased AG indexes were met with the lowest rates In general, 76.9% of patients showed acid - base disorders with different types, in which most (97.9%) were simple acid - base disorders, only cases (equivalent to 2.1%) had mixed disorders Among patients with acid - base imbalance, metabolic acidosis accounted for the highest rate, corresponding to 61% of the whole patient and 79.3% of the cases with acid - base disturbances Different types of acid - base balance disorders were met in the study patients, in which metabloc acidosis was found with the highest rate, followed by respiratory alkalosis (10.5%), and respiratory acidosis (2.8%) Mixed metabolic acidosis and respiratory acidosis was seen in 1.6% of the patients Unique metabolic alkalosis had the lowest rate To identify metabolic acidosis, many authors only based on HCO3- level to diagnose, whereby if HCO3- level < 22 mmol/l was determined as metabolic acidosis This condition require treatment by either oral or intravenous infusion alkalinizing agents NKF KDOQI (National Kidney Foundation Kidney Disease Outcomes Quality Initiative) also selected such standards Ortega LM - 2012 said that reduced plasma HCO3- level will appear when GFR < 20 ml/minute Table 4.1 Rate of metabolic acidosis in CKD patients by some authors 18 Author Participants CKD stage 4, without alkalization Our research - 2019 or renal replacement therapy All stages of CKD Vu Thi Thu Huong without renal 2014 replacement treatment Kraut JA - 2016 Harambat J - 2017 Kovesdy CP - 2012 Costa de 2015 Oliveira Sajgure AD - 2017 Liborio AB - 2013 Rate and feature of metabolic acidosis 79.3%, in which HCO3 of 15- 22 mmol/l accounted for 71.1% 42.1% met with criteria for metabolic acidosis 60.3% had HCO3- < 22 mmol/l stage 3: 2.3 - 13% CKD stage 3, Stage 4: 19 - 37% Stage 3: 43% CKD stage 3, 4, Stage 4: 60% Stage 5: 45% Stage 1: 1.1% Stage 2: 2.7% Stage 3a: 27.9% All stages of CKD Stage 3b: 19.2% Stage 4: 9.4% Stage 5: 1.4% 94.7%, in which End stage renal 10.3% with HCO3- disease with 20mmol/l) in 1/3 of the patients (33%) + All four types of renal tubular acidosis were seen with different rates, among them the rate of type was the highest (48.7%) whereas the figure for type was the lowest (2.6%) 1.2 Variation of venous blood electrolytes + Electrolytes including Na+, K+, Cl-, Ca++ distributed into all three states including decrease, normality and increase with different rates + Decrease of Na+, Cl-, Ca++ levels accounted for higher rates than increase while decrease of K + level accounted for a lower rate than increase 24 Relation between arterial blood gas, venous blood electrolyte indexes and some parameters 2.1 Relation between arterial blood gas indexes and some parameters + HCO3-, pH, BE were positively correlated with GFR Significantly negative correlation was found between anion gaps and GFR + Stage of CKD increased the rate of metabolic acidosis to 12,096 times as compared to stage + The cut-off value of GFR showing metabolic acidosis was 13.975ml/min/1.73 m2 The area under ROC curve = 0.663 with sensitivity of 61.76%, specificity of 68.42% + HCO3- level and metabolic acidosis were not significantly related to age, gender, cause of anemia, urine volume per day 2.2 Relation between venous blood electrolytes and some parameters + Na+ and Ca++ levels were positively correlated while K+ level was inversely correlated with HCO3- + Na+, K+, Cl-, Ca++ were not significantly related to urine volume per day and stages of CKD 25 RECOMMENDATIONS + In clinical practice, it should be noted that in patients with CKD stage 4, without blood alkalization or renal replacement treatment, in addition to metabolic acidosis which is the most common, other types of acid - base imbalance such as respiratory alkalosis, respiratory acidosis, metabolic alkalosis and mixed acid base disorders also occurs To identify acid - base disturbances is only based on arterial blood gas, in which the most important is HCO3- as the basis for the choices of appropriate treatment + Determine the types of renal tubular acidosis based on the concentration of HCO3- and urine pH + GFR < 13.975 ml/min/1.73m2 is the threshold at which metabolic acidosis may occurr LIST OF ARTICLES PUBLISHED STUDY RESULTS OF THE THESIS Nguyen Duc Phat, Hoang Trung Vinh, Pham Van Tran (2018) "Acid - Base distrurbances in patients with chronic kidney disease stage 4, 5" Journal of Military Pharmaco - Medicine, vol 43, No9, pp.121 - 127 Nguyen Duc Phat, Hoang Trung Vinh, Pham Van Tran (2018) "Relation between bicarbonate level in arterial blood gas test and blood electrolytes in patients with chronic kidney disease stage 4, 5" Vietnam Medical Journal, November, No2, volume 472, pp.94 - 98 ... Level 15 - 5. 5 Type ≤ 5. 5 Type > 5. 5 Type ≤ 5. 5 < 10 > 15 10 - 15 > 15 Normal... 1.00 0.79 0. 15 1.26 9. 75 p >0. 05 >0. 05 >0. 05 >0. 05 >0. 05 >0. 05