Study the relationship of erythropoietin and interleukin 1 beta with some biochemical variables in chronic kidney disease patients

Introduction

Chronic kidney disease is a global general medical issue which causes of morbidity and mortality worldwide and increasingly recognized as a global public healthcare challenge, especially in developing countries [1] . (CKD) represents a condition with reduced renal function, which is defined by glomerular filtration rate (GFR) < 60 mL/min per 1.73 m 2 or with present markers of kidney damage or both for more than 3 months and with implications for health. Markers of kidney damage are defined by Kidney Disease Improving Global Outcomes (KDIGO) guidelines from 2012 as albuminuria, urine sediment abnormalities, electrolyte, and other abnormalities due to tubular disorders, abnormalities detected by histology, structural abnormalities detected by imaging, and history of kidney transplantation. CKD should be categorized into categories according to GFR ranging from G1-G5 (GFR in G1 ≥ 90, G2 60-89, G3a 45-59, G3b 30-44, G4 15-29, and G5 ≤ 15 mL/min/1.73 m 2 ), and albuminuria should be accounted for in categories from A1-A3 (albumin excretion rate in A1 < 30, A2 30-300, and A3 > 300 mg/24 h) [2] . Erythropoietin, often abbreviated as EPO, is a glycoprotein hormone primarily produced by the kidneys in response to hypoxia (low oxygen levels in the blood) and an endogenous glycoprotein which stimulates red blood cell production. kidney is responsible to produce Erythropoietin and stimulates the diversion and differentiation of committed erythroid progenitors in the bone marrow [3,4] . Its main function is to stimulate the production of red blood cells (erythrocytes) in the bone marrow, thus playing a crucial role in erythropoiesis (the formation of red blood cells).

Erythropoietin has important clinical applications, particularly in the treatment of anemia, especially in chronic kidney disease patients, cancer patients undergoing chemotherapy, and those with certain other medical conditions [5,6] . This study's findings contribute significant insights into the prevalence and characteristics of Erythropoietin Resistance in patients with (CKD). The etiology of erythropoietin resistance is multifactorial, involving factors such as iron deficiency, inflammation, malnutrition, and the accumulation of uremic toxins [7] . Interleukin-1 (IL-1) is a pro-inflammatory cytokine that plays a significant role in the immune response and has been implicated in various diseases, including chronic kidney disease (CKD), which may causing kidney damage when elevated levels of IL-1 contribute to the inflammatory environment [8] . Pathophysiology of CKD in CKD, persistent inflammation leads to fibrosis and progressive loss of kidney function. IL-1 promotes the activation of other inflammatory pathways, including the recruitment of immune cells to the kidneys, which can worsen renal injury. Studies have shown that IL-1 inhibitors can reduce inflammation and improve kidney function in experimental models of CKD. Clinical Implications elevated IL-1 levels have been associated with worse outcomes in CKD patients. Monitoring IL-1 levels may provide insights into disease progression and response to therapy [9,10,11] . In this observational study, we focused on patients diagnosed with chronic kidney disease (CKD) accompanied by Inflammatory cytokine, who were visiting Fallujah Teaching Hospital in Anbar Governorate.

Materials and Methods

The study spanned 8 months, from December 2023 to April 2024, and employed purposive sampling to select patients. Supervisor clearance was duly obtained prior to the commencement of the study. Sixty men with CKD who were present at the Unit of CKD at the Al-Fullwja Teaching Hospital between December 2023 and April 2024 were enrolled on the study, using the American CKD Association's 1981 revised principles for the classification of CKD [12] . thirty age and sex matched healthy control subjects with no history of any CKD or autoimmune disease were also enrolled in the study, which was given ethical clearance by the ethics board of the University of Tikrit. Written informed consent was provided by all of the contributors.

Statistical Analysis

Analysis of data was carried out using the Graph Pad prism version 7. Data were presented in simple measures of mean and standard deviation (SD) values. The significance of difference of different means (quantitative data) was tested using analysis of variance (ANOVA) test for difference among more than two independent means. Statistical significance was considered whenever the P value was equal or less than 0.05. Pearson correlation was calculated for the correlation between two quantitative variables. Receiver operator curve (ROC) analysis was also employed. The area under the ROC curve gives an idea about the usefulness of a tested parameter in differentiating between three groups (one of which is a control group). A cut-off value was calculated for each variable, well as sensitivity (Sen %), specificity (spec%) and likelihood ratio (LHR).

Results

According to the (Table 1). The mean SD and SEM are used to express the results for the patients and the control group. In this study, the mean of men with CKD were (35.43) and (56.47) (p=0.001) respectively. The levels of EOP were significantly higher in men with CKD than in healthy (21.75) (p=.0.001). The results indicate that CKD had considerably higher serum IL-1 levels (140.71) and (199.63) (ng/ml) respectively compare than control healthy (86.45) (P=0.001). 6-3B we do observe significant and insignificant association between IL-1β ng/L and other studied parameters. insignificant negative correlations were detected of IL-1 ng/L with Zn, Fe, K, and Na (r=-0.464, P=0.0001), (r=-0.477, P=0.0001), (r=-0.462, p=0.0001), (r=-0.440, p=0.0001) respectively, while Significant posative correlations were detected of IL-1 ng/L with IL-1 ng/L, EOP mIU/mL, GFR ml/min , Mg mg/dL, (r=1, P<0.0000) , (r=0.823, P=0.0001), (r=-0.927, p=0.0001), (r=-0.527, p=0.0001) respectively.

Discussion

The present study investigated Erythropoietin Resistance in patients with Chronic Kidney Disease (CKD) and found that 11.4% of the participants exhibited resistance. This prevalence is somewhat consistent with previous studies, although there is variability depending on the CKD stage and patient demographics. For example, a study by Singh et al. reported a slightly higher prevalence of Erythropoietin Resistance in a similar cohort [13][14][15][16] . Erythropoietin (EPO) production and function can be influenced by various trace elements e.g. Iron, Zinc, etc. The diagnostic performance of various predictors, such as serum iron, Magnesium, Zinc, Potassium, and Sodium, was evaluated in our study. The area under the ROC curve for serum variables was 0.666, 0.7733, 0.7529, 0.5019, 0.5714, 0.7130, respectively suggesting good diagnostic accuracy. This is consistent with the findings of Weiss and Goodnough, who reported a similar AUROC for serum varibles in predicting Erythropoietin Resistance [17,18,20] . The results from this study definitely show that the studies of serum erythropoietin in patients with renal failure should continue and expand [19] . Interleukin-1 (IL-1) is a pro-inflammatory cytokine that plays a significant role in the pathophysiology of chronic kidney disease (CKD). Here are some of its role in Inflammation as it IL-1 is a key mediator of the inflammatory response. In CKD, elevated levels of IL-1 contribute to chronic inflammation, which can exacerbate kidney damage and progression of the disease. as that mechanism IL-1 promotes the activation of immune cells, leading to the release of additional inflammatory cytokines and chemokines, perpetuating the inflammatory cycle. while in role IL-1 is involved in the development of renal fibrosis, a common consequence of CKD. It stimulates the proliferation of fibroblasts and the production of extracellular matrix components, leading to scarring and loss of kidney function. while in erythropoiesis Inhibition IL-1 can inhibit erythropoiesis, contributing to anemia commonly seen in CKD patients. Mechanism by promoting inflammation, IL-1 can interfere with erythropoietin production and the responsiveness of bone marrow to erythropoietin, leading to reduced red blood cell production. Cardiovascular Risk it role large Chronic inflammation mediated by IL-1 is associated with increased cardiovascular risk in CKD patients. IL-1 contributes to atherosclerosis and cardiovascular complications, which are prevalent in individuals with CKD. Potential therapeutic target role given its involvement in CKD progression, IL-1 has been considered a potential therapeutic target. Inhibiting IL-1 signaling may reduce inflammation and fibrosis, potentially slowing the progression of CKD [21,22,23] .

References

1. Yang CW, Harris DCH, Luyckx VA, Nangaku M, Hou FF, Garcia G, et al. Global case studies for chronic kidney disease/end-stage kidney disease care. Kidney Int Suppl (2011). 2020;10(1). DOI: 10.1016/j.kisu.2019.11.010.
2. Anders HJ, Muruve DA. The inflammasomes in kidney disease. J Am Soc Nephrol. 2011;22:1007-1018.
3. Cappellini MD, Motta I. Anemia in clinical practice - definition and classification: Does it make a difference? J Intern Med. 2015;277(2):170-190.
4. Daga MK, Jain P. Erythropoietin: Physiology and clinical use. J Clin Med Res. 2012;4(1):1-6.
5. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011-1023.
6. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519-550.
7. Khan SR, Kahn A. Interleukin-1 and chronic kidney disease: A review. Clin Kidney J. 2018;11(4):487-493.
8. Ruggenenti P, Remuzzi G. The role of inflammation in the progression of chronic kidney disease. Nat Rev Nephrol. 2012;8(12):703-711.
9. Miyamoto Y, Kato Y. Interleukin-1 blockade in chronic kidney disease: A new therapeutic approach. Kidney Int Suppl. 2016;6(1):1-5.
10. Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014;63(5):713-735.
11. Jelkmann W. Erythropoietin: Structure, control of production, and function. Physiol Rev. 2011;91(4):1127-1164. DOI: 10.1152/physrev.00041.2010.
12. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-1634.
13. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098.
14. Zhao Y, Zhao K, Fang J, Wang W. Hemoglobin level and erythropoietin response in hemodialysis patients. Ren Fail. 2024;46(1):2353338.
15. Todorova GV, Akisheva AM, Pendicheva-Duhlenska DI. Serum erythropoietin in patients with chronic renal failure in the predialysis stage. J Biomed Clin Res. 2023;16(2).
16. Kumar A, Sharma R. Role of trace elements in the regulation of erythropoiesis. Int J Res Med Sci. 2015;3(8):1985-1990. DOI: 10.18203/2320-6012.ijrms20150505.
17. Khan SR, Kahn A. Role of interleukin-1 in chronic kidney disease. Clin J Am Soc Nephrol. 2018;13(5):785-792. DOI: 10.2215/CJN.08600817.
18. Miyamoto Y, Kato Y. Interleukin-1 and chronic kidney disease: A review. Kidney Int Suppl. 2019;9(1):1-8. DOI: 10.1016/j.kisu.2018.10.001.
19. Ruggenenti P, Remuzzi G. Inflammation and fibrosis in chronic kidney disease: The role of interleukin-1. Nat Rev Nephrol. 2018;14(4):217-229. DOI: 10.1038/nrneph.2018.1