Association Between Neuropathic Pain and Serum Interleukin-6 and C-Reactive Protein Levels in Patients with Stage 3 to 5 Chronic KidneyDisease

Year 2026, Volume: 53 Issue: 1, 47 - 57, 10.03.2026

Mehmet Kiracı , Taha Enes Cetin , Veysel Baran Tomar , Saliha Yildirim , Özant Helvacı , Ülver Derici Galip Guz

https://doi.org/10.5798/dicletip.1906414

https://izlik.org/JA95UF84ZS

Abstract

Background: Chronic kidney disease (CKD) is commonly associated with peripheral neuropathy, yet its pathophysiology remains incompletely understood. Inflammatory markers, particularly interleukin-6 (IL-6) and C-reactive protein (CRP), are thought to play a role in the development and persistence of neuropathic pain. This study aimed to evaluate the relationship between neuropathic pain and serum IL-6 and CRP levels in patients with stage 3–5 CKD.
Methods: This prospective single-center study included 80 patients: 40 with stage 3–4 CKD and 40 with stage 5 CKD on dialysis (5D). Neuropathic pain was assessed using the PainDETECT questionnaire. Serum IL-6 and CRP levels were measured, and their associations with neuropathic pain were analyzed using correlation analysis, ROC curves, and multivariate logistic regression.
Results: Neuropathic pain was present in 44% of stage 3–4 and 73% of stage 5D patients. PainDETECT scores were significantly higher in stage 5D (p=0.009) and showed moderate positive correlations with IL-6 (r=0.642, p<0.001) and CRP (r=0.354, p=0.001). ROC analysis identified IL-6 as a strong predictor of neuropathic pain (AUC: 0.808, cut-off: 8.5 pg/mL), while CRP showed lower predictive ability (AUC: 0.658). IL-6 was the only independent predictor in multivariate analysis (OR: 1.155, p=0.005). Although HbA1c was not associated with neuropathic pain, diabetes duration showed a strong correlation with PainDETECT scores in diabetic patients.
Conclusion: Elevated IL-6 is significantly associated with neuropathic pain in CKD, particularly in pre-dialysis patients. IL-6 may be a more reliable biomarker than CRP, highlighting the role of systemic inflammation in CKD-related neuropathy.

Keywords

Neuropathic pain , Chronic kidney disease , interleukin-6 , C-reactive protein , PainDETECT questionnaire

Ethical Statement

The study was approved by the Gazi University Ethics Committee (Decision No: 1041, Date: 25.12.2023).

Evre 3-4 ve Evre 5 Kronik Böbrek Hastalığı Olan Hastalarda Nöropatik Ağrı ile Serum İnterlökin-6 ve C-Reaktif Protein Düzeyleri Arasındaki İlişki

https://izlik.org/JA95UF84ZS

Abstract

Giriş: Kronik böbrek hastalığı (KBH), sıklıkla periferik nöropati ile ilişkilidir; ancak altta yatan patofizyolojik mekanizmalar tam olarak açıklığa kavuşmamıştır. İnflamatuvar belirteçler, özellikle interlökin-6 (IL-6) ve C-reaktif protein (CRP), nöropatik ağrının gelişimi ve devamında rol oynayabilir. Bu çalışmanın amacı, evre 3–5 KBH hastalarında nöropatik ağrı ile serum IL-6 ve CRP düzeyleri arasındaki ilişkiyi değerlendirmektir.
Yöntemler: Bu prospektif, tek merkezli çalışmaya evre 3–4 KBH’li 40 hasta ile diyalize giren evre 5 (5D) KBH’li 40 hasta olmak üzere toplam 80 hasta dahil edildi. Nöropatik ağrı değerlendirmesi PainDETECT anketi ile yapıldı. Serum IL-6 ve CRP düzeyleri ölçüldü; bu biyobelirteçlerin nöropatik ağrı ile ilişkileri korelasyon analizi, ROC eğrisi ve çok değişkenli lojistik regresyon yöntemleriyle analiz edildi.
Bulgular: Nöropatik ağrı, evre 3–4 hastalarda %44, evre 5D hastalarda ise %73 oranında saptandı. PainDETECT skorları evre 5D hastalarda anlamlı olarak daha yüksekti (p=0,009) ve IL-6 (r=0,642, p<0,001) ile CRP (r=0,354, p=0,001) düzeyleriyle orta düzeyde pozitif korelasyon gösterdi. ROC analizinde IL-6, nöropatik ağrıyı öngörmede güçlü bir belirteç olarak tanımlandı (AUC: 0,808; cut-off: 8,5 pg/mL). CRP'nin öngörü gücü daha düşüktü (AUC: 0,658). Çok değişkenli analizde yalnızca IL-6 bağımsız bir prediktör olarak saptandı (OR: 1,155; p=0,005). HbA1c ile nöropatik ağrı arasında anlamlı ilişki bulunmazken, diyabet süresi ile PainDETECT skorları arasında güçlü bir korelasyon mevcuttu.
Sonuç: Serum IL-6 düzeyindeki artış, özellikle diyaliz öncesi KBH hastalarında nöropatik ağrı ile anlamlı şekilde ilişkilidir. IL-6, CRP'ye kıyasla daha duyarlı ve özgül bir biyobelirteç olabilir. Bu bulgular, KBH’ye bağlı nöropatide sistemik inflamasyonun önemli rolünü ve IL-6'nın klinik bir belirteç olarak potansiyel değerini ortaya koymaktadır.

Keywords

Nöropatik Ağrı , Kronik Böbrek Hastalığı , İnterlökin-6 , C-Reaktif Protein , PainDETECT anketi

References

• 1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-266.
• 2. Aggarwal HK, Sood S, Jain D, et al. Evaluation of spectrum of peripheral neuropathy in predialysis patients with chronic kidney disease. Ren Fail. 2013;35(10):1323-9.
• 3. Arnold R, Pianta TJ, Pussell BA, et al. Randomized, Controlled Trial of the Effect of Dietary Potassium Restriction on Nerve Function in CKD. Clin J Am Soc Nephrol. 2017;12(10):1569-77.
• 4. Yosipovitch G, Yarnitsky D, Mermelstein V, et al. Paradoxical heat sensation in uremic polyneuropathy. Muscle Nerve. 1995;18(7):768-71.
• 5. Davies AJ, Rinaldi S, Costigan M, et al. Cytotoxic Immunity in Peripheral Nerve Injury and Pain. Frontiers in Neuroscience. 2020;Volume 14-2020.
• 6. Laumet G, Ma J, Robison AJ, et al. T Cells as an Emerging Target for Chronic Pain Therapy. Frontiers in Molecular Neuroscience. 2019;Volume 12-2019.
• 7. Sandy-Hindmarch O, Bennett DL, Wiberg A, et al. Systemic inflammatory markers in neuropathic pain, nerve injury, and recovery. Pain. 2022;163(3):526-37.
• 8. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448-457.
• 9. Takeshita Y , F ujikawa S , S erizawa K , e t a l. N ew BBB Model Reveals That IL-6 Blockade Suppressed the BBB Disorder, Preventing Onset of NMOSD. Neurol Neuroimmunol Neuroinflamm. 2021;8(6).
• 10. Cavalcanti MRM, Passos FRS, Monteiro BS, et al. HPLC-DAD-UV analysis, anti-inflammatory and antineuropathic effects of methanolic extract of Sideritis bilgeriana (lamiaceae) by NF-κB, TNF-α, IL-1β and IL-6 involvement. J Ethnopharmacol. 2021;265:113338.
• 11. Bennett MI, Attal N, Backonja MM, et al. Using screening tools to identify neuropathic pain. Pain. 2007;127(3):199-203.
• 12. Cappelleri JC, Bienen EJ, Koduru V, et al. Measurement properties of painDETECT by average pain severity. Clinicoecon Outcomes Res. 2014;6:497-504.
• 13. Alkan H, Ardic F, Erdogan C, et al. Turkish version of the painDETECT questionnaire in the assessment of neuropathic pain: a validity and reliability study. Pain Med. 2013;14(12):1933-43.
• 14. Hill NR, Fatoba ST, Oke JL, et al. Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. PLoS One. 2016;11(7):e0158765.
• 15. Bikbov B, Purcell CA, Levey AS, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2020;395(10225):709-33.
• 16. Jasti DB, Mallipeddi S, Apparao A, et al. A Clinical and Electrophysiological Study of Peripheral Neuropathies in Predialysis Chronic Kidney Disease Patients and Relation of Severity of Peripheral Neuropathy with Degree of Renal Failure. J Neurosci Rural Pract. 2017;8(4):516-24.
• 17. Arnold R, Issar T, Krishnan AV, et al. Neurological complications in chronic kidney disease. JRSM Cardiovasc Dis. 2016;5:2048004016677687.
• 18. Attal N, Fermanian C, Fermanian J, et al. Neuropathic pain: are there distinct subtypes depending on the aetiology or anatomical lesion? Pain. 2008;138(2):343-53.
• 19. Matsubayashi Y, Takeshita K, Sumitani M, et al. Validity and reliability of the Japanese version of the painDETECT questionnaire: a multicenter observational study. PLoS One. 2013;8(9):e68013.
• 20. Hiyama A, Katoh H, Sakai D, et al. Clinical impact of JOABPEQ mental health scores in patients with low back pain: Analysis using the neuropathic pain screening tool painDETECT. J Orthop Sci. 2017;22(6):1009-14.
• 21. Pasaylo R. MO853: The Incidence of Peripheral Neuropathy Using Paindetect Questionnaire in Chronic Kidney Disease Patients on Hemodialysis in a Dialysis Center in Davao City. Nephrology Dialysis Transplantation. 2022;37.
• 22. Chiu L-T, Lin Y-L, Wang C-H, et al. Electrochemical Skin Conductance by Sudoscan in Non-Dialysis Chronic Kidney Disease Patients. Journal of Clinical Medicine. 2024;13(1):187.
• 23. Chanda D, Ray S, Chakraborti D, et al. Interleukin-6 Levels in Patients With Diabetic Polyneuropathy. Cureus. 2022;14(2):e21952.
• 24. Herder C, Bongaerts BWC, Rathmann W, et al. Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study. Diabetes Care. 2014;38(1):91-6.
• 25. Panichi V, Migliori M, De Pietro S, et al. C reactive protein in patients with chronic renal diseases. Ren Fail. 2001;23(3-4):551-62.
• 26. Doupis J, Lyons TE, Wu S, et al. Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab. 2009;94(6):2157-63.
• 27. Baxi H, Habib A, Hussain MS, et al. Prevalence of peripheral neuropathy and associated pain in patients with diabetes mellitus: Evidence from a cross-sectional study. J Diabetes Metab Disord. 2020;19(2):1011-7.
• 28. Naranjo C, Ortega-Jiménez P, Del Reguero L, et al. Relationship between diabetic neuropathic pain and comorbidity. Their impact on pain intensity, diabetes complications and quality of life in patients with type-2 diabetes mellitus. Diabetes Res Clin Pract. 2020;165:108236.
• 29. Nisar MU, Asad A, Waqas A, et al. Association of Diabetic Neuropathy with Duration of Type 2 Diabetes and Glycemic Control. Cureus. 2015;7(8):e302.
• 30. Gerdle B, Ghafouri B, Ernberg M, et al. Chronic musculoskeletal pain: review of mechanisms and biochemical biomarkers as assessed by the microdialysis technique. J Pain Res. 2014;7:313-26.