Nghiên cứu nồng độ sắt, ferritin và khả năng gắn sắt toàn phần trong huyết tương ở bệnh nhân bệnh thận mạn tính chưa điều trị thay thế thận tt tiếng anh

In patients with chronic kidney disease, it is necessary to determine the status of serum iron storage and itsclassification: iron deficiency, enough iron and iron overload.. Objectives

Chronic kidney disease (CKD) is increasing rapidly in the world aswell as in Vietnam due to the rapid increase of kidney damage causessuch as diabetes and hypertension Based on the changing of glomerularfiltration rate, chronic kidney diseases are divided into five sequentialand successive stages From stage 3 to stage 5 of chronic kidney disease(glomerular filtration rate < 60 ml/min) is considered as chronic renalfailure When glomerular filtration rate < 15 ml / min, patients needkidney replacement therapy such as hemodialysis or kidneytransplantation

Anemia is common in patients with chronic kidney disease Anemia

is often caused by a combination of three causes: dysfunction ofhematopoietic organs, lack of hematopoietic materials and bleeding, inwhich lack of erythropoietin and iron deficiency are two importantfactors Iron deficiency oftens occurs in patients with renal failure(glomerular filtration rate < 60 ml/min) Patients with end stage chronickidney disease often have high proportion of iron deficiency, but inhemodialysis patients, iron overload often occurs Both situationsaffects to the quality of anemia treatment in this group of patients

As the recommendation of the National Kidney Foundation DiseaseOutcomes Quality Initiative (NKF-K/DOQI), to treat anemia effectively

in patients with chronic kidney disease, besides providingerythropoietin, patients should be supplemented with amino acids, traceelements and iron in particular In patients with chronic kidney disease,

it is necessary to determine the status of serum iron storage and itsclassification: iron deficiency, enough iron and iron overload Thisrecommendation also mention that sufficient iron compensation should

be based on ferritin and transferin saturation Transferrin saturation iscalculated through serum iron and Total Iron Binding Capacity (TIBC).Thus, there are three most necessary quantities to assess iron deficiencystatus: iron, ferritin and TIBC

In Vietnam, there have been many studies on the status of serum iron,ferritin and transferrin in patients with chronic renal failure, but there havenot been many studies that mention to TIBC and the status of iron storagewhich is recommended by the K/DOQI in patients with chronic kidneydisease who have not undergoing renal replacement therapy For the above

reasons, we conducted the study "Study on the concentration of

plasma iron, ferritin, and total iron binding capacity in chronic

kidney disease patients without renal replacement"

1 Objectives of the study

The study was conducted in patients who were diagnosed with chronickidney disease (glomerular filtration rate < 60 ml/min) and had not beentreated with kidney replacement therapy in the Department of Nephrologyand Hemodialysis, Military Hospital 103, with the following twoobjectives:

- Describe the characteristics of anemia, the concentration of plasma iron, ferritin, TIBC and assess the status of iron storage according to the KDIGO in stage 3 to 5 chronic kidney disease patients without renal replacement.

- Determine the relationship between concentrations of plasma iron, ferritin, TIBC, the iron storage status with some characteristics of chronic kidney disease patients without renal replacement.

2 The urgency of the study

Anemia is a common manifestation in CKD patients, especially inpatients with GFR < 60 ml/min (renal failure) The mechanism ofanemia in CKD patients involves Erythropoietin deficiency and lack ofhematopoietic materials including iron Iron supplementation foranemia treatment in CKD patients requires a scientific basis and is adifficult problem for clinicians

As the recommendation of the World and Vietnam KidneyAssociation, it is necessary to determine the status of iron storage beforeiron compensation Assessment of iron status should be based on serumferritin concentration and transferin saturation, in which transferinsaturation is calculated by serum iron and TIBC concentrations Thus,the study on the concentration of iron, ferritin and TIBC, therebydetermining the status of iron storage in CKD patients who have notbeen treated by kidney replacement therapy, is a necessary study forclinical practice

3 New contributions of the thesis

This is the first study in Vietnam that quantifies serum TIBCconcentration, that recommended by the Kidney Associations to usealong with serum iron and ferritin concentrations to assess the ironstorage status of CKD patients who have not been treated by kidneyreplacement therapy The results of the study confirmed that mean value

of serum TIBC concentration in CKD patients was lower than that of

normal control group The results also showed high proportion ofpatients with lack of iron storage There are some factors related toTIBC and iron storage reduction Based on this results, clinicians willhave a strategy to compensate for iron, improve the effectiveness ofanemia treatment for patients with chronic kidney disease.

4 Thesis structure: The thesis includes 116 pages Introduction: 2

pages, literature review: 34 pages, subjects and methods: 16 pages,results: 30 pages, discussions: 31 pages, conclusions andrecommendations: 3 pages In the thesis, there are 43 tables, 14 charts, 1diagram, 2 pictures The thesis has 136 references, including 21Vietnamese and 115 English references

Chapter 1: LITERATURE REVIEW 1.1 Anemia in patients with chronic kidney disease

According to the World Health Organization, anemia is acondition that reduces circulating hemoglobin in peripheral blood belownormal levels of people with the same sex, age and in the same livingenvironment According to International Society of Nephrology, inpatients with chronic kidney disease, anemia was diagnosed when Hb <130g/l for men, Hb < 120g/l for women and Hb < 110g/l for pregnantwomen

1.2 Assessing the status of iron storages in patients with chronic kidney disease

Clinically, there are many indicators assessing iron function ofhealthy people, CKD and kidney failure patients KDOQI and KDIGOrecommend some commonly used indicators such as serum iron,ferritin, transferin, TIBC concentration and transferrin saturation(TSAT)

To assess the status of iron storage, International Society ofNephrology recommends that we mostly based on ferritin and TSAT.Calculation of TSAT according to the following formula:

Plasma iron (µmol/l) x 100

TSAT (%) =

Plasma TIBC (µmol/l)

+ Absolute iron deficiency:

- CKD patients who have not been treated by kidney replacementtherapy: Plasma ferritin concentration < 100ng/ml and/or serumtransferrin saturation level < 20%

- Patients with hemodialysis: Plasma ferritin concentration < 200

ng/ml and/or serum transferrin saturation level < 20%.

+ Functional iron deficiency: plasma ferritin concentration ≥200ng/ml and/or serum transferrin saturation level < 20%

+ Iron overload in CKD patients who have not been treated bykidney replacement therapy: serum ferritin concentration ≥ 500ng/mland/or TSAT ≥ 50%

1.3 Studies on concentrations of serum iron, ferritin and TIBC in CKD patients.

+ In the world, there had been many studies on the use of serumTIBC, iron and ferritin concentrations to assess iron storage status inpatients with and without dialysis Numerous studies had evaluated theresults of iron compensation in anemia treatment in patients withchronic kidney disease

+ In Vietnam: there were some studies on serum iron and ferritinlevels, however, there had been no studies on TIBC and iron storagestatus in chronic renal failure patients who have not been treated bykidney replacement therapy

Chapter 2: SUBJECTS AND METHODS 2.1 Subjects

The study was conducted on 190 subjects who was divided into 2groups:

- Study group: 124 patients with stage 3 to 5 chronic kidney disease,who have not been treated by kidney replacement therapy (GFR < 60ml/min), at the Department of Nephrology and Hemodialysis, MilitaryHospital 103

- Normal control group: 66 healthy people

+ Exclusion criteria

- Control group: Acute blood loss within the previous 3 months orbleeding People who are pregnant or have just given birth within the last 6months

- Study group: Blood transfusion during the previous 3 months

Acute blood loss within the previous 3 months or bleeding during thestudy period Patients have been taking iron or iron preparations.Patients have an indication for emergency dialysis

2.2 Methods

- A descriptive, cross-sectional, comparative case-control study

- Sample size calculation:

Percentage of patients with chronic renal disease with irondeficiency from 54.4% to 63.5% in previous studies Calculation of thesample size according to the following formula:

(Z1-α/2)2 x p (1-p)

n = -

D2

In which: Z = 1,96, with a reliability of 95%

p = 0,544 (lowest value in previous studies)

D = 0,1, the desired accuracy

According to the calculation, the study must have at least 96 patients

In the study, n = 124 patients were used

2.2.1 Study targets

Patients admitted to hospital, were asked for medical conditionsand were taken medical examination according to the research form.The following criteria were collected:

- Age, gender, history of disease

- Measuring for blood pressure, height, weight and BMI calculation

- Laboratory tests include: hematology, biochemistry (glucose, urea,creatinine, albumin, uric acid, four blood lipid indices, electrolytes, hs-CRP )

- Quantitative determination of plasma iron, ferritin, and TIBC levels:venous blood was taken when patients were hungry in the earlymorning Plasma iron and ferritin concentration were quantified onCobas 6000 system, which using the kit of Roche company, inDepartment of Biochemistry, Military Hospital 103 Serum TIBCconcentration were quantified by ELISA method at Department ofPathophysiology, Vietnam Military Medical University for both studyand control groups

- Calculating glomerular filtration rate under the guidance of K/DOQI using the MDRD formula which was based on creatinine, age,gender and race

NKF Calculation of transferrin saturation by plasma iron and TIBC

by Chi-square test, comparing mean values by Anova test, calculatingthe correlation coefficient (r).

2.2.3 Ethics in research

- The study did not violate ethics in medicine, serving for screening forchronic kidney disease patients

- The study was approved by the Department of Heart - Kidney - Joints

- Endocrinology, Vietnam Military Medical University beforeimplementation

- TIBC test fee was payed by myself

Chapter 3: RESULTS 3.1 General characteristics of subjects

- Age and gender characteristics:

+ Control group included 66 people with average age of 41.86 ± 5.68years, men accounted for 69.7% and women accounted for 30.3%.+ The research group included 124 patients whose average age was52.65 ± 17.95 years, men accounted for 72.6% and women accounted27.4%

- The cause of CKD: Chronic glomerulonephritis accounted for 49.2%,chronic renal pyelonephritis accounted for 16.9%, hypertensionaccounted for 15.3%, diabetes accounted for 12.9 %, the lowest due topolycystic kidneys and Gout which accounted for only 3.2% and 2.4%respectively

- The proportion of stage 5 CKD patients accounted for 79.8%, stage 3and 4 accounted for 20.2% The average glomerular filtration rate was8.3 ml/min

- Up to 89.5% of patients had hypertension in the study, only 10.5% ofpatients did not have hypertension.

- The group of patients with normal BMI accounted for the highest rate(70.2%), the proportion of overweight and obesity accounted for only15.3% and underweight accounted for 14.5% The average value ofBMI was 20.05

3.2 Characteristics of anemia, concentrations of plasma iron, ferritin, TIBC and iron storage status following to KDIGO in patients with chronic kidney disease

3.2.1 Characteristic of anemia in study group

Table 3.1 The percentage of patients on the severity of anemia (n = 124) Severity of anemia Number Percentage

Table 3.3 Percentage of patients according to the amount of

hemoglobin in each cell (n=119) Anemia classification Number Percentage

- The highest proportion was normochromic anemia with 62.2%

3.2.2 The concentrations of plasma iron, ferritin and TIBC in the study subjects

Table 3.4 Comparison of concentrations of plasma iron, ferritin and TIBC between study group and control group

Indices Control group

10.7 (6.62 – 15.25) < 0.001

403.73 (211.36 -548.42)

375.16 ng/ml; TIBC: Mean ± 1.96xSD: 44.89 90.27 µmol/l

- Plasma iron and TIBC concentrations in study group were significantlower than in control group, p < 0.001

- In contrast, plasma ferritin concentration in study group wassighnificant higher than in control group, p < 0.001

Table 3.5 The proportion of patients with increasing or decreasing concentrations of plasma iron, ferritin and TIBC compared to

Increase 2 1.6

- The proportion of patients with normal concentration of plasma ironwas 67.7% Up to 29% of patients had decreasing and 3.2% of patientsincreasing plasma iron concentration compared to control group

- Meanwhile, 54.8% of patients increased plasma ferritin concentrationcompared to control group

- The proportion of patients with decreasing TIBC concentration was 47.6%.There was only 1.6% of patients who had increasing TIBC concentration

3.2.3 Assessment of serum iron storage status according to KDIGO guideline in the study group

Table 3.6 Characteristics of transferin saturation in study group

(n=124) Characteristics

Both gender(n=124) Male (n=90)

22.3 (18.5 –34.47)

22.02 (13.29 –26.68)

> 0.05

- The proportion of patients with low TSAT (< 20%) was 30.6% Therewas 8.1% of patients with high TSAT (> 50%), while normal TSATaccounted for a major proportion (61.3%)

- There was no difference of TSAT characteristics between men andwomen

- The median value of TSAT was 22.31%

Table 3.7 Characteristics of iron storage status in study group

according to KDIGO guideline (n=124) Iron storage status * Number Percentage

non-deficiency in the study was 37.1%, however, there were also 38.7% ofpatients with iron overload.

3.3 The relationship between concentrations of plasma iron, ferritin, TIBC, iron storage status and some characteristics of patients with chronic kidney disease

3.3.1 The relation to the stage of chronic kidney disease

Bảng 3.8 Comparison of mean values of plasma iron, ferritin and TIBC concentrations between stages of chronic kidney disease

(n=124) Stages of

CKD

Iron (µmol/L) Median

Ferritin (ng/mL) Median

TIBC (µmol/L)

X ± SD

3+4 (n = 25) 10.16 (7 –

14.58)

252.6 (177.89– 437) 68.44 ± 16.36

Table 3.9 The proportion of patients with increasing or decreasing concentration of plasma iron, ferritin and TIBC between stages of

chronic kidney disease (n=124) Indices Stage 3 + 4 (n = 25) Stage 5 (n = 99) p

- In contrast, the proportion of increasing plasma ferritin concentration

in stage 5 chronic kidney disease patients was significant higher thanthat of patients in stage 3 and 4, p < 0.05

- The proportion of decreasing TIBC concentration in patients withstage 5 chronic renal disease was significant higher than that of patients

in stage 3 and 4, p < 0.001

Table 3.10 The relationship between iron storage status and stages

of chronic kidney disease in study group (n=124)

Stages of

CKD

Iron deficiency (n, %)

Enough iron (n, %)

Iron overload (n, %)

3.3.2 The relation to anemia

Table 3.11 The correlation between plasma iron, ferritin, TIBC and

hemoglobin concentration (n=124) Indices Hemoglobin (g/l) Correlation equation

-TIBC (µmol/L) 0.208 < 0.05 TIBC= 0.168*Hemoglobin +32.474

- Plasma iron and TIBC concentration had a weak positive correlationwhile plasma ferritin concentration had a weak negative correlationwith hemoglobin concentration (p <0.05)

3.3.3 The relation to plasma CRP and albumin

Table 3.12 The relationship between concentrations of plasma iron, ferritin, TIBC and albumin concentration in study group

(n=120)

concentration

Iron (µmol/L) (Median)

Ferritin (ng/mL) (Median)

TIBC (µmol/L) ( X ± SD)

Decrease (<35g/l)

(n=57)

8.1 (4.85 –11.9)

428.23 (187.5 –563.09)

47.05 ± 20.63

Normal (n=63) 11.9 (9.1 –

17.7)

380.39 (236.76 –488.28)

54.12 ± 18.88

- Plasma iron concentration in patients with decreasing albuminconcentration was significantly lower than that of patients with normalalbumin concentration (p <0.01)

- There was no difference between plasma ferritin and TIBCconcentrations and albumin concentration status with p > 0.05

Table 3.13 The relationship between concentrations of plasma iron, ferritin, TIBC and CRP concentration in study group (n=112) CRP

concentration

Iron (µmol/L) (Median)

Ferritin (ng/mL) (Median)

TIBC (µmol/L) ( X ± SD)

Increase > 5 mg/l

(n=48)

6.87 (4.35 – 12.34)

431.25 (231.5 –567.73)

46.52 ± 19.73

No increase

(n=64)

11.9 (8.8 – 18.6)

385.2 (193.1 –544.61)

54.89 ± 19.45

- In the group of patients with increasing hs-CRP concentration, plasmairon and TIBC concentrations were significant lower than that of non-increasing group (p < 0.05)

- In contrast, plasma ferritin concentration in patients with increasinghs-CRP were not significant difference with non-increasing hs-CRPgroup (p > 0.05)

3.3.4 The plasma TIBC in evaluating iron storage in study group