INTRODUCTION

prevalence and incidence, poor prognosis, and high costs. The prevalence of CKD increases with

the increase in the number of elderly people, the incidence of diabetes mellitus, hypertension,

obesity, and primary kidney disorders. The global prevalence of CKD based on the results of

systematic review and meta-analysis was 13.4%. The Global Burden of Disease in 2010 stated that

Sumatra as much as 1.8%. Based on data obtained from medical records at RSUP Dr. M. Djamil

Padang in 2016 there were 2,937 CKD patients with outpatient and 586 CKD patients with

hospitalization. This number continued to increase until September 2017, namely there were 7,801

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

CKD patients with outpatients and 911 CKD patients with hospitalization. CKD based on KDIGO

2012 is classified by cause, glomerular filtration rate (GFR) category (G1-G5) and albuminuria

category (A1-A3). CKD which is at very high risk (G5) with GFR <15 ml/min/1.73 m2 or stage 5

CKD which is ESRD in the 2002 classification, requires kidney replacement therapy in the form

of peritoneal dialysis, kidney transplantation or hemodialysis (HD) (Eknoyan et al., 2013;

physiological parameters or genetic changes that identify the presence, severity, or course of a

disease. Identification of optimal biomarkers and/or combinations of biomarkers can be helpful in

identifying vulnerabilities to CKD and the development of its incidence. Several studies have

shown that galectin-3 plasma biomarkers in chronic heart failure (CHF) show a relationship with

renal dysfunction. It is a new biomarker of heart failure, signaling inflammation and fibrosis and

linking cardiovascular disease to kidney disease. This galectin plasma was first isolated in 1976,

now there are 15 different galectins that have been characterized and numbered according to the

order of discovery (galectin-1 to galectin-15). Galectin-3 plasma is a β-galactoside-binding lectin

expressed in monocytes, which plays an important role in the processes of inflammation,

immunity, cancer, and is involved in the pathogenesis of atherosclerosis, diabetes, renal fibrosis

such as lethargy, itching, or loss of appetite. The diagnosis is usually made after a chance finding

from a screening test (urine dipstics or blood test), or when the symptoms become more severe.

Chronic kidney disease can be prevented and treated, the chances of getting effective therapy will

be greater if it can be detected earlier in at-risk populations. Based on the background above, this

journal was written to improve understanding of galectin-3 plasma as one of the biomarkers in

CKD.

METHOD

various literatures, mainly relevant reports and scientific journals. The data were obtained by

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

RESULT AND DISCUSSION

Plasma Galectin-3

more reliable diagnostic tools in establishing diagnoses. In some medical disciplines, including

nephrology, there are many delays in diagnosis and administration as well as referrals to

indicators (Alam et al., 2019; Chan et al., 2020; Zhang et al., 2019).

galactoside-binding lectin expressed in monocytes, which plays an important role in the processes

of inflammation, immunity, cancer, and is involved in the pathogenesis of atherosclerosis,

diabetes, renal fibrosis and asthma. Galectin-3 has been shown to promote TGF-β-mediated

fibroblast activation into myofibroblasts that secrete the matrix in the liver and kidney tissue.

Higher galectin-3 levels were associated with decreased eGFR in cross-sectional studies. Because

the liver is an organ that mainly excretes galectin-3, before kidney disease appears, galectin-3 has

the potential to be a biomarker that is useful for identifying people who are at risk of CKD, such

as patients suffering from diabetes or hypertension. O'Seaghdha et al, hypothesized that galectin-

(Alam et al., 2019; Chen & Kuo, 2016; Desmedt et al., 2016; Suwitra, 2015).

glycoproteins and cell glycolipids also known as 35-kDa lectin, IgE-binding protein, laminin

binding protein and Mac-2 antigen, is a multifunctional protein with various biological functions

such as intercellular adhesion, proliferation, malignant transformation and metastasis. Excessive

levels of galectin-3 in the body play a role in promoting inflammatory and fibrosis responses that

cause progressive heart failure, cirrhosis of the liver and kidney failure according to the research

of Liu et al, in 2014. Drechsler C et al. in 2015 stated that the concentration of galectin-3 increases

with progressive kidney damage. The research of Szu C et al, 2016 states that galectin-3 may

increase in patients with decreased GFR, but there have not been many studies that state galectin-

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

monocytes, dendritic cells, eosinophils, mast cells, natural killer cells, and activated T and B cells),

epithelial cells, endothelial cells and sensory cells. The expression of Galectin-3 in tissues is

regulated its development, more during embryogenesis compared to adults. During the early stages

of embryogenesis, the expression patterns are more specific, mainly located in the epithelium,

and active guanosine-5'-triphosphate (GTP)-bound K-Ras. Galectin-3 in the nucleus promotes pre-

mRNA splicing and regulates gene transcription, whereas extracellular galectin-3 modulates the

interaction of cells, including epithelial cells and extracellular matrices. Therefore, galectin-3 is

essential in a variety of biological activities including cell growth, cell proliferation,

differentiation, apoptosis, pre-mRNA splicing, transformation, angiogenesis, inflammation,

fibrosis, fibrogenesis and host defense. The action of galectin on this cell is shown in Figure 2.

Previous evidence suggests that galectin-3 is involved in the pathogenesis of remodeling,

cardiovascular fibrosis and ventricular dysfunction, as well as in various autoimmune and

inflammatory processes (Alam et al., 2019; Chen & Kuo, 2016; de Oliveira et al., 2015; Desmedt

et al., 2016; Dong et al., 2018; Drechsler et al., 2015; Hara et al., 2020; Rebholz et al., 2018;

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

diseases including heart, kidney, liver, cancer, autoimmune diseases, tumors and infections.

Galectin-3 is a stable biomarker and is not related to age, body mass index or gender. Galectin-3

is also useful for detecting the early stages of some diseases. Galectin-3 has also currently been

used as a new biomarker for early detection of myocardial dysfunction and heart failure. Galectin-

Galectin-3 Measurements

measured in serum samples taken at the beginning and stored at - 80°C until the analysis process.

Galectin-3 concentrations were determined using the ELISA method developed by BG Medicine

(Waltham, MA). This quantitative 23 test measures the concentration of human galectin-3 in

ethylenediaminetetraacetic acid stabilized in plasma or serum. The test had high sensitivity (lowest

detection limit of 1.13 ng/ml; intraassay variability 3.2%; interassay variability 5.6%) and showed

no cross-reactivity with collagen or other galectin protein families. Commonly used cardiovascular

drugs such as angiotensin-converting enzyme inhibitors, b-blockers, spironolactone, furosemide,

intra-assay and interassay variability of 3.2% and 0.8%, respectively. These tests produce identical

results to serum or plasma, when used manually or automated procedures (Drechsler et al., 2015).

Role of Galectin-3 Plasma in Nephrogenesis

the renal collecting duct. During metanefros, with adult renal precursors, Galectin-3 can be

detected in the apical domain of ureteric bud branches. Galectin-3 is also expressed intensely in

the medullary and papillaries of the fetal collectivus ducts in both the cytoplasm and plasma

membranes. Low levels of galectin-3 are also found in adult cytoplasmic collecting duct cells.

Galectin-3 can modulate branching morphogenesis from ureteric bud/collecting duct lineage, but

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

to collecting primary tubules and cilia, in addition to being temporarily expressed by proximal

tubules during regeneration (Chen & Kuo, 2016).

Role of Galectin-3 Plasma in CKD

Conall et al, assessed kidney function in 2,450 participants of the Framingham Offspring Study.

In the Framingham Offspring Study, among 2,450 participants without CKD, higher galectin-3

was associated with a 50% increased risk of CKD events and a rapid decrease in kidney function,

but not with an incidence of albuminuria. The study was followed for 10 years taking into account

age, gender, diabetes, hypertension, proteinuria and a preliminary assessment of eGFR, suggesting

that galectin-3 predicts tubulointerstitial fibrosis, but not glomerular injury. eGFR declined rapidly

(≥3 ml/min/1.73 m 2/year) in 241 (9.2%) participants, while the incidence of CKD (eGFR <60

ml/min/1.73 m

developed in 277 (11.3%) and in 194 (10.1%). They also found an association between higher

plasma levels of galectin-3 and decreased eGFR as a higher risk factor of the incidence of CKD

but has a weak relationship with albuminuria that contradicts the hypothesis that glomerular injury

is an early mechanism. Higher levels of galectin-3 in the circulation have been associated with a

higher risk of CKD incidence and decreased kidney function, thus suggesting that galectin-3 levels

can be used to predict kidney injury years before CKD is clinically detected, thus allowing for

early treatment targeting and progressive prevention of the disease (Chen & Kuo, 2016).

nondiabetic nephropathy. Drechsler et al, analyzed two groups of patients with variation in renal

function from the Germany Diabetes Mellitus Dialysis (4D) study (1,168 patients with type 2 DM

undergoing dialysis) and the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2,579

patients undergoing coronary angiography). Galectin-3 concentrations were measured at the

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

cause mortality, cardiovascular mortality, death from infection, and sudden cardiac death in

patients with eGFR 60-89 ml/min per 1.73 m

galectin-3 levels were also associated with myocardial infarction and death from chronic heart

failure. In 4D studies, galectin-3 levels were used to predict all-cause death, cardiovascular events,

stroke, and death from infections. So from 4D and LURIC studies, it was found that the

extended this relationship to patients with kidney disease. The study used post hoc analysis in two

selected german patient groups. Therefore, the general association between increased galectin-3

levels and adverse outcomes has limited yields. In addition, proteinuria is not measured, which is

an important variable that affects the kidneys and cardiovascular (Chen & Kuo, 2016; Drechsler

et al., 2015).

identify patients who have a risk for suffering from CKD years before clinical onset appears. In

addition, lectin plays an important role in the process of renal fibrosis, which proceeds earlier in

the pathogenesis of CKD. However, in a multicenter cohort-based community study of 2,763

elderly adults who had no clinical symptoms of heart failure (median age 72 ± 5 years, 63%

(incidence of albuminuria), and predict kidney function in the general population. Patients with

CKD showed a decrease in eGFR (<15 ml/min/1.73 m

galectin-3. This serum showed an area below the recipient's operating characteristic curve of 0.89,

indicating a potential role in the diagnosis of CKD. Six-year renal survival rates with galectin-3

groups were low (≤6 ng/ml) and high (>6 ng/ml) of 47.3 and 22.8%, respectively (Alam et al.,

2019; Ji et al., 2017; McPherson & Pincus, 2021).

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

(left) describes eGFR, and the red line represents the trajectory of eGFR with respect to time during

the course of the disease. The y-axis (right) describes the number of remaining nephrons, and the

purple line describes the nephron numbers during the course of the disease. The delay in diagnosis

(labeled as the distance between the dotted green vertical lines) can be reduced by the use of renal

tubular health biomarkers, which begin to increase as the number of nephrons begins to fall. In the

early stages of CKD, the number of nephrons begins to decrease before a clinically meaningful

decrease in eGFR is obtained, because the kidneys are able to compensate for the loss of nephrons

through the phenomenon of renal filtration reserves. Trapezium A is labeled as renal reserve and

covers the initial course of the disease when nephron counts begin to fall, however eGFR is stable

number of nephrons is commensurate with a decrease in eGFR due to a loss of renal reserves. At

this stage biomarkers have less use in the development of CKD. Triangle C is an advanced stage

of CKD, located the therapeutic window for intervention. The use of tubular injury biomarkers can

identify therapeutic targets and shift to the starting point of the disease. This is spelled out in Figure

3 (Zhang et al., 2019).

patients with kidney disease across the spectrum of renal impairment severity. However, it is

difficult to assess whether galectin-3 is the best option for assessing risk stratification in kidney

patients due to the lack of a "gold standard" for risk stratification in kidney disease. Framingham's

study showed that elevated levels of galectin-3 preceded the development of CKD and several

Plasma Galectin-3 Biomarkers in Chronic Kidney Disease

correlated with initial speed/initial diastolic mitral annular velocity (E') and left atrial volume

index. Further analysis showed that galectin-3 can be used in the diagnosis of LV diastolic function

with sensitivity and specificity of 67.6% and 84.6%, respectively. A multi-center, prospective,

observational study identified that an increase in galectin-3 levels is a prognostic determinant of

all-cause mortality and mortality in hemodialysis patients. Another study confirmed this finding,

end-stage kidney disease wherein a small cross-sectional study of 101 heart failure patients, 105

hemodialysis patients and 20 healthy participants, plasma concentrations of galectin-3 were

obtained. very high detected in patients with terminal renal insufficiency in compared to control.

Similar results were obtained in a study of 100 hemodialysis patients, 50 predialysis patients and

94 healthy people. In the third study of 88 hemodialysis patients with a follow-up of 22.2±4.7

months, a multivariable cox proportional hazards model showed that the plasma cut-off of

galectin-3 of 23.73 ng/ml was an independent predictor of all-cause mortality in patients

undergoing hemodialysis (Bansal et al., 2016; Desmedt et al., 2016; Drechsler et al., 2015; Gurel

et al., 2015; Hogas et al., 2016; Ozkan et al., 2015).

suggesting the potential for new mechanisms associated with galectin-3 expression that could

contribute to the development of CKD. Galectin-3 is also reported to play an important role in

renal interstitial fibrosis. Thus, inhibition of galectin-3 may be a promising therapeutic strategy to

prevent the progression of kidney disease (Hara et al., 2020).

Relationship of CKD, Chronic Heart Failure with Plasma Levels of Galectin-3

galectin-3 are associated with renal insufficiency. Galectin-3 plasma is a new prognostic marker

of death in chronic heart failure patients and its prognostic value is independent of the severity of

heart failure. The relationship between renal insufficiency, heart failure and galectin-3 is not fully