J. Pharm. Pharmacogn. Res., vol. 11, no. 1, pp. 55-62, January-February 2023.
DOI: https://doi.org/10.56499/jppres22.1518_11.1.55
Original Article
The role of plasma angiotensin-converting enzyme and interleukin-6 levels on the prognosis of non-dialysis chronic kidney disease patients
[Papel de los niveles plasmáticos de la enzima convertidora de angiotensina e interleucina-6 en el pronóstico de los pacientes con enfermedad renal crónica no sometidos a diálisis]
Hendri Susilo1,2**, Mochammad Thaha3,4, Budi Susetyo Pikir1,2, Mochamad Yusuf Alsagaff1,2, Satriyo Dwi Suryantoro3,4, Ifan Ali Wafa5, Nando Reza Pratama5, David Setyo Budi5, Bayu Satria Wiratama6, Citrawati Dyah Kencono Wungu7,8*
1Department of Cardiology and Vascular Medicine, Universitas Airlangga Hospital, Surabaya, Indonesia.
2Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
3Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
4Department of Internal Medicine, Universitas Airlangga Hospital, Surabaya, Indonesia.
5Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
6Departement of Biostatistics and Epidemiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Indonesia.
7Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
8Institute of Tropical Disease, Universitas Airlangga, Surabaya.
E-mail: *citrawati.dyah@fk.unair.ac.id; **hendrisusilo@staf.unair.ac.id
Abstract
Context: Inflammatory factors and oxidative stress were discovered to play significant roles in the progression of chronic kidney disease (CKD). There is, however, no research on the direct impact of high plasma angiotensin converting enzyme (ACE) and interleukin (IL)-6 levels on CKD prognosis, particularly in non-hemodialysis patients.
Aims: To investigate the potential role of plasma ACE and IL-6 levels in CKD prognosis.
Methods: A total of 75 non-dialysis CKD patients participated in this cross-sectional study. The estimated glomerular filtration rate (e-GFR) and albuminuria were used to determine the prognosis of CKD. The plasma ACE and IL-6 levels were measured using an enzyme-linked immunoassay (ELISA). Spearman’s rank correlational analysis was used to examine the relationship between ACE and IL-6 plasma levels with the prognosis of CKD.
Results: The result showed a statistically significant correlation between age and plasma ACE (p = 0.038, r = 0.241), serum creatinine, and urine albumin-creatinine ratio with CKD prognosis (p<0.0001). A negative significant correlation was found between the e-GFR and CKD prognosis (p<0.0001). Additionally, there were also significant correlations between plasma ACE and IL-6 with CKD prognosis (p = 0.021, r = 0.266 and p = 0.04, r = 0.238, respectively). A significant positive correlation was also found between plasma ACE and IL-6 (p = 0.024, r = 0.260).
Conclusions: There was a significant correlation between plasma ACE and IL-6 levels with CKD prognosis. Further investigation revealed a statistically significant positive relationship between plasma ACE and IL-6 levels.
Keywords: angiotensin converting enzyme; chronic kidney disease; interleukin-6; non-hemodialysis; prognosis.

Resumen
Contexto: Se ha descubierto que los factores inflamatorios y el estrés oxidativo desempeñan un papel importante en la progresión de la enfermedad renal crónica (ERC). Sin embargo, no existen investigaciones sobre la repercusión directa de los niveles elevados de la enzima convertidora de angiotensina (ECA) e interleucina (IL)-6 en plasma sobre el pronóstico de la ERC, en particular en los pacientes que no están en hemodiálisis.
Objetivos: Investigar el papel potencial de los niveles plasmáticos de ECA e IL-6 en el pronóstico de la ERC.
Métodos: Un total de 75 pacientes con ERC no en diálisis participaron en este estudio transversal. Se utilizaron la tasa de filtración glomerular estimada (TFGe) y la albuminuria para determinar el pronóstico de la ERC. Los niveles plasmáticos de ECA e IL-6 se midieron mediante un inmunoensayo enzimático (ELISA). Se utilizó el análisis correlacional por rangos de Spearman para examinar la relación entre los niveles plasmáticos de ECA e IL-6 y el pronóstico de la ERC.
Resultados: El resultado mostró una correlación estadísticamente significativa entre la edad y la ECA plasmática (p = 0,038, r = 0,241), la creatinina sérica y el cociente albúmina-creatinina en orina con el pronóstico de la ERC (p<0,0001). Se encontró una correlación negativa significativa entre el e-GFR y el pronóstico de la ERC (p<0,0001). Además, también hubo correlaciones significativas entre la ECA y la IL-6 plasmáticas con el pronóstico de la ERC (p = 0,021, r = 0,266 y p = 0,04, r = 0,238, respectivamente). También se halló una correlación positiva significativa entre la ECA plasmática y la IL-6 (p = 0,024, r = 0,260).
Conclusiones: Existe una correlación significativa entre los niveles plasmáticos de ECA e IL-6 con el pronóstico de la ERC. Investigaciones posteriores revelaron una relación positiva estadísticamente significativa entre los niveles plasmáticos de ECA e IL-6.
Palabras Clave: enfermedad renal crónica; enzima convertidora de angiotensina; interleucina-6; no hemodiálisis; pronóstico.

Citation Format: Susilo H, Thaha M, Pikir BS, Alsagaff MY, Suryantoro SD, Wafa IA, Pratama NR, Budi DS, Wiratama BS, Wungu CDK (2023) The role of plasma angiotensin-converting enzyme and interleukin-6 levels on the prognosis of non-dialysis chronic kidney disease patients. J Pharm Pharmacogn Res 11(1): 55–62. https://doi.org/10.56499/jppres22.1518_11.1.55
References
Amador-Martínez I, Pérez-Villalva R, Uribe N, Cortés-González C, Bobadilla NA, Barrera-Chimal J (2019) Reduced endothelial nitric oxide synthase activation contributes to cardiovascular injury during chronic kidney disease progression. Am J Physiol Renal Physiol 317: F275–F285. https://doi.org/10.1152/AJPRENAL.00020.2019
Anguiano L, Riera M, Pascual J, Valdivielso JM, Barrios C, Betriu A, Mojal S, Fernández E, Soler MJ, Faura A, Castro E, María V, Molí T, Soria M, Aladrén RMJ, Almirall J, Ponz E, Arteaga CJ, Bajo RMA, Belart RM, Bielsa-García S, Bover SJ, Bronsoms AJ, Cabezuelo RJB, Muray CS, Calviño VJ, Caro AP, Carreras BJ, Cases AA, Massó JE, Castilla PJ, Cigarrán GS, López PS, Comas ML, Comerma I, Compte JMT, Cuberes IM, De ÁF, Hevia OC, De ADLFG, Del PPMD, Diaz-Tejeiro IR, Dotori M, Duarte V, Estupiñan TS, Fernández RMJ, Fernández RML, Fernández G, Galán SA, García CC, García HAL, García MM, Gil SL, Aguilar M, Górriz JL, Huarte LE, Lerma JL, Liebana CA, Marín ÁJP, Martín AN, Martín GJ, Martínez CA, Martínez VM, Martínez I, Moina EI, Moreno LHS, Mouzo MR, Munar VA, Muñoz DAB, Navarro GJF, Nieto J, Carreño A, Novoa FE, Ortiz A, Fernandez B, Paraíso V, Pérez FM, Peris DA, Piñera HC, Prados GMD, Prieto VM, Puig MC, Rivera GM, Rubio E, Ruiz P, Salgueira LM, Martínez PAI, Sánchez TJA, Sánchez JE, Sans LR, Saracho R, Sarrias M, Prat O, Sousa F, Toran D, Tornero MF, Usón CJJ, Valera CI, Vilaprinyo DPMM, Virto RRC (2015) Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease. Nephrol Dial Transplant 30: 1176–1185. https://doi.org/10.1093/NDT/GFV025
Bikbov B, Purcell C, Levey A, Smith M, Abdoli A, Abebe M, Adebayo O, Afarideh M, Agarwal S (2020) Global, regional, and national burden of chronic kidney disease, 1990 – 2017 : A systematic analysis for the Global Burden of Disease Study 2017. Lancet 395: 709–733. https://doi.org/10.1016/S0140-6736(20)30045-3
Carrero JJ, Stenvinkel P (2010) Inflammation in end-stage renal disease–what have we learned in 10 years? Semin Dial 23: 498–509. https://doi.org/10.1111/J.1525-139X.2010.00784.X
Chang HL, Wu CC, Lee SP, Chen YK, Su W, Su SL (2019) A predictive model for progression of CKD. Medicine (Baltimore) 98: e16186. https://doi.org/10.1097/MD.0000000000016186
Chen TK, Knicely DH, Grams ME (2019) Chronic kidney disease diagnosis and management. JAMA 322: 1294. https://doi.org/10.1001/jama.2019.14745
Christofides EA, Desai N (2021) Optimal early diagnosis and monitoring of diabetic kidney disease in type 2 diabetes mellitus: Addressing the barriers to albuminuria testing. J Prim Care Community Health 12. https://doi.org/10.1177/21501327211003683
Dai S, Ding M, Liang N, Li Z, Li D, Guan L, Liu H (2019) Associations of ACE I/D polymorphism with the levels of ACE, kallikrein, angiotensin II and interleukin-6 in STEMI patients. Sci Rep 9: 19719. https://doi.org/10.1038/s41598-019-56263-8
Duni A, Liakopoulos V, Roumeliotis S, Peschos D, Dounousi E (2019) Oxidative stress in the pathogenesis and evolution of chronic kidney disease: Untangling Ariadne’s thread. Int J Mol Sci 20: 3711. https://doi.org/10.3390/IJMS20153711
Imig JD, Ryan MJ (2013) Immune and inflammatory role in renal disease. Compr Physiol 3: 957–976. https://doi.org/10.1002/CPHY.C120028
International Society of Nephrology (2013) Summary of recommendation statements. Kidney Int Suppl 3: P5–14. https://doi.org/10.1038/kisup.2012.77
Kagami S (2012) Involvement of glomerular renin-angiotensin system (RAS) activation in the development and progression of glomerular injury. Clin Exp Nephrol 16: 214–220. https://doi.org/10.1007/S10157-011-0568-0
Kamińska J, Stopiński M, Mucha K, Jędrzejczak A, Gołębiowski M, Niewczas MA, Pączek L, Foroncewicz B (2019) IL 6 but not TNF is linked to coronary artery calcification in patients with chronic kidney disease. Cytokine 120: 9–14. https://doi.org/10.1016/J.CYTO.2019.04.002
Khosla N, Kalaitzidis R, Bakris GL (2009) The kidney, hypertension, and remaining challenges. Med Clin North Am 93: 697–715. https://doi.org/10.1016/J.MCNA.2009.02.001
Krata N, Zagożdżon R, Foroncewicz B, Mucha K (2018) Oxidative stress in kidney diseases: The cause or the consequence? Arch Immunol Ther Exp (Warsz). 66: 211–220. https://doi.org/10.1007/S00005-017-0496-0
Lambers HHJ, Gansevoort RT, Brenner BM, Cooper ME, Parving HH, Shahinfar S, De ZD (2010) Comparison of different measures of urinary protein excretion for prediction of renal events. J Am Soc Nephrol 21: 1355–1360. https://doi.org/10.1681/ASN.2010010063
Lee DE, Qamar M, Wilke RA (2021) Relative contribution of genetic and environmental factors in CKD. S D Med 74: 306–309.
Lee DL, Sturgis LC, Labazi H, Osborne JB, Fleming C, Pollock JS, Manhiani M, Imig JD, Brands MW (2006) Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Am J Physiol Heart Circ Physiol 290: H935–H940. https://doi.org/10.1152/AJPHEART.00708.2005
Levin A, Stevens PE, Bilous RW, Coresh J, De FALM, De JPE, Griffith KE, Hemmelgarn BR, Iseki K, Lamb, EJ, Levey AS, Riella MC, Shlipak MG, Wang H, White CT, Winearls CG (2013) Kidney disease: Improving global outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 3: P1–150. https://doi.org/10.1038/kisup.2012.73
Luther JM, Gainer JV, Murphey LJ, Yu C, Vaughan DE, Morrow JD, Brown NJ (2006) Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism. Hypertension 48: 1050–1057. https://doi.org/10.1161/01.HYP.0000248135.97380.76
Magno AL, Herat LY, Carnagarin R, Schlaich MP, Matthews VB (2019) Current knowledge of IL-6 cytokine family members in acute and chronic kidney disease. Biomedicines 7: 19. https://doi.org/10.3390/BIOMEDICINES7010019
Miller WG, Bruns DE, Hortin GL, Sandberg S, Aakre KM, McQueen MJ, Itoh Y, Lieske JC, Seccombe DW, Jones G, Bunk DM, Curhan GC, Narva AS (2009) Current issues in measurement and reporting of urinary albumin excretion. Clin Chem 55: 24–38. https://doi.org/10.1373/CLINCHEM.2008.106567
Miura H, Nakayama M, Sato T (1984) Serum angiotensin converting enzyme (S-ACE) activity in patients with chronic renal failure on regular hemodialysis. Jpn Heart J 25: 87–92. https://doi.org/10.1536/IHJ.25.87
Oberg BP, McMenamin E, Lucas FL, McMonagle E, Morrow J, Ikizler TA, Himmelfarb J (2004) Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int 65: 1009–1016. https://doi.org/10.1111/J.1523-1755.2004.00465.X
Perna A, Ruggenenti P, Testa A, Spoto B, Benini R, Misefari V, Remuzzi G, Zoccali C (2000) ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies1. Kidney Int 57: 274–281. https://doi.org/10.1046/J.1523-1755.2000.00818.X
Rodríguez-Ortiz ME, Pontillo C, Rodríguez M, Zürbig P, Mischak H, Ortiz A (2018) Novel urinary biomarkers for improved prediction of progressive EGFR loss in early chronic kidney disease stages and in high risk individuals without chronic kidney disease. Sci Rep 8: 15940. https://doi.org/10.1038/S41598-018-34386-8
Roy N, Rosas SE (2021) IL-6 is associated with progression of coronary artery calcification and mortality in incident dialysis patients. Am J Nephrol 52: 745–752. https://doi.org/10.1159/000518652
Shi C, Lu K, Xia H, Zhang P, Zhang B (2020) Alteration and association between serum ACE2/ angiotensin(1-7)/Mas axis and oxidative stress in chronic kidney disease: A pilot study. Medicine (Baltimore). 99: E21492. https://doi.org/10.1097/MD.0000000000021492
Soler MJ, Riera M, Crespo M, Mir M, Márquez E, Pascual MJ, Puig JM, Pascual J (2012) Circulating angiotensin-converting enzyme 2 activity in kidney transplantation: a longitudinal pilot study. Nephron Clin Pract 121: c144–c150. https://doi.org/10.1159/000345508
Su H, Lei CT, Zhang C (2017) Interleukin-6 signaling pathway and its role in kidney disease: An update. Front Immunol 8: 405. https://doi.org/10.3389/fimmu.2017.00405
Susilo H, Pikir BS, Thaha M, Alsagaff MY, Suryantoro SD, Wungu CDK, Wafa IA, Pakpahan C, Oceandy D (2022) The effect of angiotensin converting enzyme (ACE) I/D polymorphism on atherosclerotic cardiovascular disease and cardiovascular mortality risk in non-hemodialyzed chronic kidney disease: The mediating role of plasma ace level. Genes (Basel) 13: 1121. https://doi.org/10.3390/genes13071121
Tang WH, Hung WC, Wang CP, Wu CC, Hsuan CF, Yu TH, Hsu CC, Cheng YA, Chung FM, Lee YJ, Lu YC (2022) The lower limit of reference of urinary albumin/creatinine ratio and the risk of chronic kidney disease progression in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 13: 858267. https://doi.org/10.3389/FENDO.2022.858267
Vaidya SR, Aeddula NR (2022) Chronic Renal Failure. In: StatPearls. Treasure Island (FL): StatPearls Publishing.
Yan MT, Chao CT, Lin SH (2021) Chronic Kidney Disease: Strategies to Retard Progression. Int J Mol Sci 22. https://doi.org/10.3390/IJMS221810084
Yang CW, Lu LC, Chang CC, Cho CC, Hsieh WY, Tsai CH, Lin YC, Lin CS (2017) Imbalanced plasma ACE and ACE2 level in the uremic patients with cardiovascular diseases and its change during a single hemodialysis session. Ren Fail 39: 719–728. https://doi.org/10.1080/0886022X.2017.1398665
Zhang W, Wang W, Yu H, Zhang Y, Dai Y, Ning C, Tao L, Sun H, Kellems RE, Blackburn MR, Xia Y (2012) Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage. Hypertension 59: 136–144. https://doi.org/10.1161/HYPERTENSIONAHA.111.173328
Zhong J, Yang HC, Fogo AB (2017) A perspective on chronic kidney disease progression. Am J Physiol Renal Physiol 312: F375–F384. https://doi.org/10.1152/AJPRENAL.00266.2016
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