Features of Etiology and Pathogenesis of Skin Itching in Patients with Chronic Kidney Disease Receiving Hemodialysis. Literature Review

Litvinov A. S.
¹²

Gasanov M. Z.
³

Kukhtina A. A.
⁴

1 - Limited liability Company «Baltic Medical Company», Russia, Vladikavkaz
2 - Limited liability Partnership «Metaco LLP», London, United Kingdom
3 - Federal state budgetary educational institution of higher education «Rostov state medical University» of the Ministry of health of the Russian Federation, Internal Medicine Department № 1, Rostov-on-Don, Russia
4 - ]Federal state budgetary educational institution of higher education «Moscow state medical and dental University named after A. I. Evdokimov» of the Ministry of health of the Russian Federation, Department of polyclinic therapy, Moscow, Russia

Alexander S. Litvinov; e-mail: dirge@yandex.ru

The study had no sponsorship.

None declared.

Pruritus associated with chronic kidney disease, also known as uremic pruritus, is a common and underestimated clinical condition that occurs in over 60% of patients treated with programmed hemodialysis. Moderate to severe itching develops in 20-40% of patients. It often leads to a decrease in the quality of life, sleep disturbances, depression, and an increased risk of infection and death. The pathogenesis of pruritus remains unclear. It is believed to be a multifactorial process in which metabolic disturbances, immune dysregulations, hormonal imbalances, systemic inflammation, and increased levels of parathyroid hormone, histamine, calcium and magnesium salts play an important role. However, there are currently no unified approaches to the treatment of uremic pruritus, and off-label treatment is not effective enough and is associated with side effects, which requires further search for new pharmaceutical possibilities.

pruritus, uremia, hemodialysis, etiology and pathogenesis of pruritus, T-helpers, μ-receptor agonists, substance P, neurotransmitters, cytokines, neurotransmitters, chronic kidney disease, capsaicin, histamine, bradykinin, pruriceptors, pruritogens

10.29234/2308-9113-2020-8-4-25-40

1. Akhyani M., Ganji M.R., Samadi N., Khamesan B., Daneshpazhooh M. Pruritus in hemodialysis patients. BMC Dermatol. 2005; 5(1): 1. doi: 10.1186/1471-5945-5-7.

2. Aramwit P., Supasyndh O. Uremic pruritus; its prevalence, pathophysiology and management. In: Suzuki H, editor. Updates in hemodialysis. 2015; London: InTechOpen.

3. Aucella F., Gesuete A., Vigilante M., Prencipe M. Adsorption dialysis: From physical principles to clinical applications. Blood Purification 2013; 35(2): 42-47.

4. Bautista D.M., Wilson S.R., Hoon M.A. Why we scratch an itch: The molecules, cells and circuits of itch. Nat. Neurosci. 2014; (17): 175-182. doi: 10.1038/nn.3619.

5. Berger T.G., Steinhoff M. Pruritus and renal failure. Semin Cutan Med Surg. 2011; (30): 99-100. doi: 10.1016/j.sder.2011.04.005

6. Chen H.Y., Chiu Y.L., Hsu S.P. Elevated C-reactive protein level in hemodialysis patients with moderate/severe uremic pruritus: a potential mediator of high overall mortality. QJM 2010; (103): 837-846.

7. Chen Y., Jiang S., Liu Y., Xiong J., Liang J., Ji W. Role of ERK1/2 activation on itch sensation induced by bradykinin B1 activation in inflamed skin. Exp. Med. 2016; (12): 627-632. doi: 10.3892/etm.2016.3426

8. Chiu Y.L., Chen H.Y., Chuang Y.F. Association of uraemic pruritus with inflammation and hepatitis infection in haemodialysis patients. Nephrol. Dial. Transplant. 2008; (23): 3685-3689.

9. Combs S.A., Teixeira J.P., Germain M.J. Pruritus in Kidney Disease. Semin. Nephrol. 2015; (35): 383-391.

10. De Welter E.Q., Frainer R.H., Maldotti A., Losekann A., Weber M.B. Evaluating the association between alterations in mineral metabolism and pruritus in hemodialysis patients. An. Bras. Dermatol. 2011; (86): 31-66.

11. Dyachenko P., Shustak A., Rozenman D. Hemodialysis-related pruritus and associated cutaneous manifestations. Int. J. Dermatol. 2006; 45(6): 664-667.

12. Fallahzadeh M.K., Roozbeh J., Geramizadeh B., Namazi M.R. Interleukin-2 serum levels are elevated in patients with uremic pruritus: a novel finding with practical implications. Nephrol. Dial. Transplant. 2011; 26(10): 3338-3344.

13. Furue M., Yamamura K., Kido-Nakahara M., Nakahara T., Fukui Y. Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis. Allergy 2018; (73): 29-36. doi: 10.1111/all.13239

14. Gibbs B.F., Patsinakidis N., Raap U. Role of the Pruritic Cytokine IL-31 in Autoimmune Skin Diseases. Front. Immunol. 2019; (10): doi: 10.3389/fimmu.2019.01383

15. Göksütün D. The relationship between uremic pruritus and 25-hdyroxy vitamin D in hemodialysis patients. 2014; Department of Internal Medicine. Başkent University: Ankara: Master Thesis.

16. Gonçalves I., Edsfeldt A., Ko N.Y. Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology 2012; 32(6): 1505-1512.

17. Han L., Dong X. Itch mechanisms and circuits. Annu. Rev. Biophys. 2014; (43): 331-355

18. Hon K.L., Lam M.C., Wong K.Y. Pathophysiology of nocturnal scratching in childhood atopic dermatitis: the role of brain-derived neurotrophic factor and substance P. Br. J. Dermatol. 2007; (157): 922-925.

19. Ibrahim M.K., Elshahid A.R., El B.T. Impact of uraemic pruritus on quality of life among end stage renal disease patients on dialysis. J. Clin. Diagn. Res. 2016; (10): 1-5.

20. Kardon A.P., Polgar E., Hachisuka J., Snyder L.M., Cameron D., Savage S., Cai X., Karnup S., Fan C.R., Hemenway G.M. Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron. 2014; (82): 573-586.

21. Keith-Reddy S.R., Patel T.V., Armstrong A.W., Singh A.K. Uremic pruritus. Kidney Int. 2007; (72): 373-377.

22. Kılıç Akça N., Taşçı S. Using nonpharmacological methods for controlled itch. TAF. Prev. Med. Bull. 2013; 12 (3): (article in Turkish with an abstract in English). doi: 10.5455/pmb.1-1338788781

23. Kimata N., Fuller D.S., Saito A., Akizawa T., Fukuhara S., Pisoni R.L., Robinson B.M., Akiba T. Pruritus in hemodialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS). Hemodial Int. 2014; 18(3): 657-667

24. Kimmel M., Alscher D.M., Dunst R. The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients. Nephrol. Dial. Transplant. 2006; (21): 749-755. doi: 10.1093/ndt/gfi204

25. Ko M.J., Wu H.Y., Chen H.Y., Chiu Y.L., Hsu S.P., Pai M.F., Ju Y., Lai C.F., Lu H.M., Huang S.C. Uremic pruritus, dialysis adequacy, and metabolic profiles in hemodialysis patients: A prospective 5-year cohort study. PLoS ONE 2013. 8:e71404 doi: 10.1371/annotation/43d10c8d-5a10-41c4-ad44-605dfee7f630

26. Lai J.W., Chen H.C., Chou C.Y., Yen H.R., Li T.C., Sun M.F., Chang H.H., Huang C.C., Tsai F.J., Tschen J., & Chang C.T. Transformation of 5-D itch scale and numerical rating scale in chronic hemodialysis patients. BMC Nephrology, 2017; 18(1): 56. doi: 10.1186/s12882-017-0475-z

27. Liu X.Y., Wan L., Huo F.Q., Barry D.M., Li H., Zhao Z.Q., Chen Z.F. B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway. Mol. Pain. 2014; (10): 4.

28. Manns B., Hemmelgarn B., Lillie E. Setting research priorities for patients on or nearing dialysis. Clin. J. Am. Soc. Nephrol. 2014; (9): 1813-1821.

29. Mathur V.S., Lindberg J., Germain M. A longitudinal study of uremic pruritus in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 2010 (5): 1410-1419.

30. Mehrpooya M., Gholyaf M., Yasrebifar F., Mohammadi Y., Sheikh V. Evaluation of Efficacy of Mirtazapine on Pruritus and Serum Histamine and Serotonin Levels in Patients Undergoing Hemodialysis: A Before-After Pilot Clinical Trial. Int. J. Nephrol. Renovasc. Dis. 2020; (13): 129-138. doi: 10.2147/IJNRD.S246393

31. Mettang T. Chronic kidney disease-associated pruritus. In: Misery L, Ständer S, editors. Hypertension 2010; London: Springer-Verlag. 166-175.

32. Mettang T., Kremer A.E. Uremic pruritus. Kidney Int. 2015; 87(4): 685-691.

33. Minato S., Hirai K., Morino J. Factors Associated with Uremic Pruritus in Patients Undergoing Peritoneal Dialysis. Int J Nephrol Renovasc Dis. 2020; (13): 1-9. doi: 10.2147/IJNRD.S224871

34. Mishra S.K., Hoon M.A. The cells and circuitry for itch responses in mice. Science 2013; (340): 968-971.

35. Mistik S., Utas S., Ferahbaş A., Tokgöz B., Ünsal G., Sahan H., Özturk A., Utas C. An epidemiology study of patients with uremic pruritus. J. Eur. Acad. Dermatol. Venereol. 2006; (20): 672-678. doi: 10.1111/j.1468-3083.2006.01570.x.

36. Moon S.J., Kim H.J., Cho S.B. Epidermal proteinase-activated receptor-2 expression is increased in end-stage renal disease patients with pruritus: a pilot study. Electrolyte & Blood Pressure 2014; (12): 74-79.

37. Morton C.A., Lafferty M., Hau C. Pruritus and skin hydration during dialysis. Nephrol. Dial. Transplant. 1996; (11): 2031-2036.

38. Narita I., Iguchi S., Omori K., Geivo F. Uremic pruritus in chronic hemodialysis patients. J. Nephrol. 2008; (21): 161-165.

39. Pisoni R.L., Wikström B., Elder S.J. Pruritus in haemodialysis patients: International results from the Dialysis Outcomes and Practice Patterns Study (DOPPS) Nephrol. Dial. Transplant. 2006; (21): 3495-3505. doi: 10.1093/ndt/gfl461

40. Prasad P.V.S., Kaviarasan P.K., Nethra T., Kannambal Uremic pruritus – a review. Glob. Dermatol. 2015; (2): 218-224.

41. Wu Q., Zhang H., Ding J.-R., Hong Z.-Y., Wu H., Zhu Z.-Y., Guo Z.-Y., Chai Y.-F. UPLC-QTOF MS-Based Serum Metabolomic Profiling Analysis Reveals the Molecular Perturbations Underlying Uremic Pruritus. BioMed Research International 2018; 4351674. doi: 10.1155/2018/4351674

42. Razeghi E., Tavakolizadeh S., Ahmadi F. Inflammation and pruritus in hemodialysis patients. Saudi J. Kidney Dis. Transpl. 2008; (19): 62-66.

43. Ross S.E., Mardinly A.R., McCord A.E., Zurawski J., Cohen S., Jung C., Hu L., Mok S.I., Shah A., Savner E.M. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron. 2010; (65): 886-898.

44. Ryborg A.K., Deleuran B., Thestrup-Pedersen K., Kragballe K. Lysophosphatidylcholine: a chemoattractant to human T lymphocytes. Archives of Dermatological Research 1994; 286(8): 462-465.

45. Sasagawa T., Suzuki K., Shiota T., Kondo T., Okita M. The significance of plasma lysophospholipids in patients with renal failure on hemodialysis. Journal of Nutritional Science and Vitaminology 1998; 44(6): 809-818.

46. Senturk N., Ozkaya O., Aytekin S. Characteristics of pruritus in children on peritoneal dialysis. Nephron. Clin. Pract. 2008; (109): 168-172.

47. Shakiba M., Sanadgol H., Azmoude H. R., Mashhadi M. A., Sharifi H. Effect of sertraline on uremic pruritus improvement in ESRD patients. International Journal of Nephrology 2012; (5): 5.

48. Shavit L. Use of pregabalin in the management of chronic uremic pruritus. J. Pain. Symptom. Manag. 2013; 45(4): 776-781.

49. Sun Y.G., Chen Z.F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007; (448): 700-703.

50. Tajbakhsh R., Joshaghani H., Bayzayi F., Haddad M., Qorbani M. Association between pruritus and serum concentrations of parathormone, calcium and phosphorus in hemodialysis patients. Saudi J. Kidney Dis. Transpl. 2013; (24): 702-706. doi: 10.4103/1319-2442.113858

51. Takahashi T., Kubota M., Nakamura T. Interleukin-6 gene expression in peripheral blood mononuclear cells from patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Ren Fail. 2000; (22): 345-354.

52. Tentori F., Blayney M.J., Albert J.M., Gillespie B.W., Kerr P.G., Bommer J., Young E.W., Akizawa T., Akiba T., Pisoni R.L. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am. J. Kidney Dis. 2008; (52): 519-530. doi: 10.1053/j.ajkd.2008.03.020

53. Weiss M., Mettang T., Tschulena U. Health-related quality of life in haemodialysis patients suffering from chronic itch: results from GEHIS (German Epidemiology Haemodialysis Itch Study). Qual. Life. Res. 2016; (25): 3097-3106.

54. Wikstrom B., Gellert R., Ladefoged S.D., et al. Kappa-opioid System in Uremic Pruritus: Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Studies. J. Am. Soc. Nephrol. 2005; (16): 3742-3747.

55. Wojtowicz-Prus E., Kiliś-Pstrusińska K., Reich A. Chronic kidney disease-associated pruritus in children. Acta. Derm. Venereol. 2016; (96): 938-942.

56. Wu H.Y., Hung K.Y., Huang T.M. Safety issues of long-term glucose load in patients on peritoneal dialysis – a 7-year cohort study. PLoS One 2012; (7): е30337.

57. Fishbane S., Jamal A., Munera C. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. N Engl J Med. 2020 Jan 16; 382 (3): 222-232. doi: 10.1056/NEJMoa1912770

58. Min J.W., Kim S.H., Kim Y.O., et al. Comparison of uremic pruritus between patients undergoing hemodialysis and peritoneal dialysis. Kidney Res Clin Pract. 2016; 35(2):107-13. doi: 10.1016/j.krcp.2016.02.002

59. Tessari G., Dalle Vedove C., Loschiavo C., et al. The impact of pruritus on the quality of life of patients undergoing dialysis: a single centre cohort study. J Nephrol. 2009; 22(2): 241-8.