PRURITUS IN HEMODIALYSIS PATIENTS

PRURITUS IN HAEMODIALYSIS PATIENTS

Dr. Giovambattista Virga

Nephrology and Dialysis Unit, Camposampiero (Padova), Italy

virgolino14@libero.it

THE SYMPTOM

Pruritus is an unpleasant cutaneous sensation prompting a desire to scratch. It is a common and disturbing symptom among patients (pts) receiving hemodialysis (HD). The percentage of HD pts suffering from pruritus varies reportedly from 50% to 90% ^{[1,2,3,4,5,6,7]}. Interestingly, pruritus is typically not seen in acute renal failure ^[8].

PATHOPHYSIOLOGY

Itch is transmitted by dedicated C neurons and the proximity of dermal mast cells to afferent C neurons has suggested a functional relation between these two cell types: mast cell activation releases tryptase, which activates a receptor localised on C fibre nerve terminals that transmit the itching sensation to the central nervous system. Additionally, receptor activation will lead to a local release of substance P that activates dermal mast cells, resulting in an increased release of TNF- which in turn sensitises nociceptor nerve terminals and enhances their responsiveness ^[9]. Substance P, a neurotransmitter widely distributed in the afferent sensory neurons, can communicate pain and some itching sensations from the periphery to the central nervous system and is considered potentially responsible for itching ^[10,11]. It is a potent vasodilator and may serve as a mediator for axon reflex vasodilatation ^[12].

EVALUATION

The degree of itching is scored according to severity, frequency and distribution. The system proposed by Duo ^[13], modified by Mettang ^[14] and again by Hiroshige ^[3] is as follows:

scores for severity:

score 1: itching prompting no scratching
score 2: itching requiring scratching but without excoriations
score 3: itching demanding interminable scratching or accompanied by excoriations
score 4: itching causing total restlessness;

scores for distribution:

score 1: itching at a single location
score 2: scattered itching
score 3: generalised itching;

scores for frequency:

score: for every four short episodes (<10 minutes each) or one long episode (>10 minutes) of itching receives 1 point, up to a maximum of 4 points.

Other subjective evaluation methods are reported, based on intensity (absent, moderate, severe) and frequency (absent, occasionally, every day) ^[7]. Many studies have simply divided patients according to the presence or absence of itching ^[3,15,16,17].

COMPLICATIONS

In the uraemic population pruritus is often benign but serious complications have been described, such as greater irritability, skin excoriations (Fig. 1), sleep deprivation, depression, lower quality of life, and even suicide ^[18].

ASSOCIATIONS WITH URAEMIC PRURITUS IN HAEMODIALYSIS PATIENTS

Many different metabolic disorders frequently associated with uraemia have been thought to be involved in the onset of pruritus in HD, but its aetiology still remains obscure.

Parathormone was initially accused of causing pruritus ^[19,20], but was subsequently found not guilty ^{[3,4,5,15,21,22,23,24]}. The theory of an altered bivalent ion metabolism, i.e. hypercalcaemia and hyperphosphoraemia ^[19,20,21], was not confirmed ^{[3,4,5,7,15,22,23,24]}. Hypermagnesaemia was also suggested as a potential culprit ^[25] without any subsequent confirmation ^[22].

A relationship between dialysis adequacy and pruritus has been suggested in some studies ^[3,5,26] and rejected in others ^[4,7,23,27].

Patients who are dialysed with less permeable and less biocompatible membranes are more likely to have pruritus than those using more permeable polysulfone types ^[28]. Dermatological studies have demonstrated that an intradermal injection of complement activation products or cytokines induces local itching ^[29,30,31] and complement activation and cytokine release are related to blood-membrane contact ^[32,33,34].

Numerous other agents have been considered responsible for uraemic pruritus, e.g. aluminium ^[15], vitamin A ^[35] (not confirmed ^[36]), histamine ^[16,37] (not confirmed ^[38]), serum bile acids ^[23] and clinical conditions, as well as xerosis of the skin ^[1,39] (not confirmed ^[40,41]), peripheral neuropathy ^[42] and iron-deficiency anaemia ^[43] (not confirmed ^[7]).

A role of opioid peptides has been suggested ^[44], but these findings have not been confirmed ^[45].

Interleukin-2 (IL-2), which is secreted by activated T helper cells type 1 (Th1), may be involved in the genesis of uraemic itch ^{[46,47,48,49]}.

Inflammatory status has recently been found associated with pruritus in HD pts ^[7,17].

Inflammation markers such as transferrin and albumin were found significantly lower in HD pts affected by pruritus, while ferritin proved to be higher ^[7]. Additionally, serum C-reactive protein and interleukin-6 (IL-6) levels were significantly higher in HD pts with than in those without pruritus ^[17].

Potential culprits for pruritus in HD
Parathormone	not confirmed
Hypercalcaemia	not confirmed
Hyperphosphoraemia	not confirmed
Hypermagnesaemia	not confirmed
Iron-deficiency anaemia	not confirmed
Dialysis inadequacy	not confirmed
Xerosis of the skin	not confirmed
Vitamin A	not confirmed
Histamine	not confirmed
Opioid peptides	not confirmed
Aluminium overload
Skin mast cells
Peripheral neuropathy
Substance P
Bile acids
Inflammation
Interleukin-2
Interleukin-6

CAUSES OF NON-URAEMIC PRURITUS IN HAEMODIALYSIS PATIENTS

The differential diagnosis of pruritus in HD patients includes neuropathic itches, such as occurs in postherpes neuralgia (simultaneously with pain) and the central neuropathic itch related to multiple sclerosis ^[9]. Cholestasis can induce severe pruritus and atopic eczema associated with psoriasis is a common dermatological cause of itching ^[9]. Many other conditions, e.g. diabetes, thyrotoxicosis, and malignant tumours, can also cause pruritus ^[50].

THERAPY

Just as the aetiology of uraemic pruritus is not fully understood, several therapies are used, none of which is entirely satisfactory. Antihistamines are often ineffective in uraemic pruritus.

Capsaicin, a natural alkaloid, used topically (0.025% cream), has proved effective in the treatment of HD-related pruritus ^[11,12,51]. It depletes and prevents the re-accumulation of substance P from local type C sensory nerve terminals ^[11,52].

Naltrexone, an opioid antagonist, has been found useful for a short-term amelioration of pruritus in HD patients, but it carries mild gastrointestinal side effects ^[44] so it should only be considered for severe pruritus.

By suppressing IL-2 production ^[46,48], drugs such as tacrolimus and thalidomide are quite effective in the treatment of itching in dialysis patients ^[47,49].

Non-pharmacological therapies include ultraviolet B phototherapy (which attenuates Th1 expression ^[53] and thereby relieves uraemic pruritus ^[54,55]) and electrical needle stimulation, that has been associated with encouraging results in uraemic patients ^[13].

Therapy	References
Naltrexone	[44]
Capsaicin	[11,12,51]
Tacrolimus	[49]
Thalidomide	[47]
Ultraviolet B	[54,55]
Electrical needle	[13]

REFERENCES

1. Young AW, Sweeney EW, David DS, Cheing J, Hochgelerent EL, Sakai S, Stenzel KH, Rubin AL. Dermatologic evaluation of pruritus in patients on hemodialysis. NY St J Med 1973; 73:2670-4.

2. Matsumoto M, Ichimaru K, Horie A. Pruritus and mast cell proliferation of the skin in end stage renal failure. Clin Nephrol 1985; 6:285-8.

3. Hiroshige K, Kabashima N, Takasugi M, Kuroiwa A. Optimal dialysis improves uremic pruritus. Am J Kidney Dis 1995; 25(3):413-9.

4. Virga G, Mastrosimone S, AmiciG, Munaretto G, Gastaldon F, BonadonnaA. Symptoms in hemodialysis patients and their relationship with biochemical and demographic parameters. Int J Artif Organs 1998; 21(12):788-93.

5. Goicoechea M, de Sequera P, Ochando A, Andrea C, Caramelo C. Uremic pruritus: an unresolved problem in hemodialysis patients. Nephron 1999; 82: 73-4.

6. Merkus MP, Jager KJ, Dekker FW, de Haan RJ, Boeschoten EW, Krediet RT. Physical symptoms and quality of life in patients on chronic dialysis: results of The Netherlands Cooperative Study on Adequacy of Dialysis (NECOSAD). Nephrol Dial Transplant 1999; 14(5):1163-70.

7. Virga G, Visentin I, La Milia V, BonadonnaA. Inflammation and pruritus in hemodialysis patients. Nephrol Dial Transplant 2002; 17:2164-9.

8. Stahle-Backdahl M. Uremic pruritus. Semin Dermatol 995; 14:297-301.

9. Yosipovitch G, Greaves MW, Schmelz M. Itch. Lancet 2003; 361:690-4.

10. Bernstein JE. Capsaicin in dermatologic disease. Semin Dermatol 1988; 7:304-309.

11. Tarng DC, Cho YL, Liu NH, Huang TP. Hemodialysis-related pruritus: a double-blind placebo-controlled, crossover study of capsaicin 0.025% cream. Nephron 1996; 72:617-22.

12. Breneman DL, Cardone JS, Blumsack RF, Lather RM, Seaile EA, Pollack VE. Topical capsaicin for the treatment of hemodialysis-related pruritus. J Am Acad Dermatol 1992; 26:91-4.

13. Duo LJ. Electrical needle therapy of uremic pruritus. Nephron 1987; 47:179-83.

14. Mettang T, Fritz P, Weber J, Machleidt C, Hubel E, Kuhlmann U. Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis: the role of plasma histamine and skin mast cells. Clin Nephrol 1990; 34136-141.

15. Friga V, Linos A, Linos DA. Is aluminum toxicity responsible for uremic pruritus in chronic hemodialysis patients? Nephron 1997; 75:48-53.

16. De Marchi S, Cecchin E, Villalta D, Sepiacci G, Santini G Bartoli E. Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 1992; 326:969-74.

17. Kimmel M, Alscher D, Dunst R, Kuhlmann U, Mettang T. The role of inflammation in uremic pruritus (abstract). M647. World Congress of Nephrology, 2003.

18. Shoop KL. Pruritus in end stage renal disease. ANNA J 1994; 21:147-153.

19. Massry SG, Popovtzer MM, Coburn JW, Makoff DL, Maxwell MH, Kleeman CR. Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia: disappearance of itching after subtotal parathyroidectomy. N Engl J Med 1968; 279:697-700.

20. Hampers CL, Katz AI, Wilson RE, Merrill JP. Disappearance of "uremic" itching after subtotal parathyroidectomy. N Engl J Med 1968; 279:695-7.

21. Carmichael AJ, McHugh MM, Martin AM, Farrow M. Serological markers of renal itch in patients receiving long term hemodialysis. Br Med J 1988; 296: 1575.

22. Ostlere LS, Taylor C, Baillod R, Wright S. Relationship between pruritus, transepidermal water loss, and biochemical markers of renal itch in haemodialysis patients. Nephrol Dial Transplant 1994; 9:1302-4.

23. Mamianetti A, Tripodi V, Vescina C, Garrido D, Vizioli N, Carducci C, Agost Carreno C. Serum bile acids and pruritus in hemodialysis patients. Clin Nephrol 2000; 53(3):194-8.

24. Saatçi Ü, Basin E, Özdemir FN, Turan M, Micozkadioglu H, Haberal M. Pruritus and HLA in hemodialysis patients (abstract). Tissue Antigens 2002; 60:559.

25. Graf H, Kovarik J, Stummvoll HK, Wolf A. Disappearance of uraemic pruritus after lowering dialysate magnesium concentration. Br Med J 1979; 279:1478-1479.

26. Masi CM, Cohen EP. Dialysis efficacy and itching in renal failure. Nephron 1992; 62:257-61.

27. Carmichael AJ, McHugh MI, Martin AM. Itch unrelated to adequacy of haemodialysis (letter). Br Med J 1989; 297:95.

28. Murphy M, Carmichael AJ. Renal itch. Clin Exp Dermatol 2000; 25:103-6.

29. Yancey KB, Hammer CH, Harvath L, Renfer L, Frank MM, Lawley TJ. Studies of human C5a as a mediator of inflammation in normal human skin. J Clin Invest 1985; 75:486-95.

30. Wahlgren CF, Tengvall Linder M, Hagermark O, Scheynius A. Itch and inflammation induced by intradermally injected interleukin-2 in atopic dermatitis patients and healthy subjects. Arch Dermatol Res 1995; 287:572-80.

31. Darsow U, Scharein E, Bromm B, Ring J. Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumour necrosis factor-alpha) at the dermal-epidermal junction. Br J Dermatol 1997; 137:415-7.

32. Rousseau Y, Haeffner-Cavaillon N, Poignet JL, Meyrier A, Carreno MP. In vivo intracellular cytokine production by leukocytes during haemodialysis. Cytokine 2000; 12:506-17.

33. Schouten WE, Grooteman MP, van Houte AJ, Schoorl M, van Limbeek J, Nube MJ. Effects of dialyser and dialysate on the acute phase reaction in clinical bicarbonate dialysis. Nephrol Dial Transplant 2000; 15:379-84.

34. Deppisch RM, Beck W, Goehl H, Ritz E. Complement components as uremic toxins and their potential role as mediators of microinflammation. Kidney Int 2001; 59 (Suppl 78):S271-7.

35. Berne B, Vahlquist A, Fischer T, Danielsson B, Berne C. UV treatment of uremic pruritus reduces the vitamin A content of the skin. Eur J Clin Invest 1984; 14:203-6.

36. De Kroes S, Smeerk G. Serum vitamin A levels and pruritus in patients on hemodialysis. Dermatologica 1983; 166:192-202.

37. Stockenhuber F, Kurz RW, Sertl K, Grimm G, Balcke P. Increased plasma histamine levels in uraemic pruritus. Clin Sci 1990; 79:477-82.

38. De Filippo C, Ragazzini R, Piazza V, Galli F, Pisati P, Sacchi S, Salvadeo A. Uraemic pruritus is not related to plasma histamine concentrations. Clin Exp Dermatol 1995; 20:294-6.

39. Morton CA, Lafferty M, Hau C, Henderson I, Jones M, Lowe JG. Pruritus and skin hydration during dialysis. Nephrol Dial Transplant 1996; 11:2031-6.

40. Yosipovitch G, Tur E, Morduchowitz G, Boner G. Skin surface pH, moisture and pruritus in haemodialysis patients. Nephrol Dial Transplant 1993; 8:1129-1132.

41. Stahle-Backdahl M. Stratum corneum hydration in patients undergoing maintenance hemodialysis. Acta Derm-Venereol 1988; 68:531-544.

42. Weismann K, Graham RM. Systemic disease and the skin; in Champion RH, Burton JL, Ebling FJG (eds): Textbook of Dermatology, ed 5. Oxford, Blackwell, 1992, pp 2407-2453.

43. Robertson KE, Mueller BA. Uremic pruritus. Am J Health Syst Pharm 1996; 53:2159-70.

44. Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M, laina A. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348:1552-54.

45. Mettang T, Fischer F-P, Dollenbacher U, Kuhlman U. Uraemic pruritus is not elated to -endorphin serum levels in haemodialysis patients. Nephrol Dial Transplant 1998:13:231-2.

46. Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med 1994; 331:365-76.

47. Silva SR, Viana PC, Lugon NV, Hoette M, Ruzany F, Lugon JR. Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial. Nephron 1994; 67:270-3.

48. McHugh SM, Rifkin IR, Deighton J, Wilson AB, Lachmann PJ, Lockwood CM, Ewan PW. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 1995;99:160-7.

49. Pauli-Magnus C, Klumpp S, Alscher DM, Kuhlmann U, Mettang T. Short-term efficacy of tacrolimus ointment in severe uremic pruritus. Perit Dial Int. 2000; 20:802-3.

50. Abel EA, Farber EM: Malignant cutaneous tumors. In: Rubenstein E, Federman DD, eds.: Scientific American. Medicine. New York: Scientific American, Inc, Chapter 2: Dermatology, Section XII, 1-20, 1992.

51. Weisshaar E, Dunker N, Gollnick H. Topical capsaicin therapy in humans with hemodialysis-related pruritus. Neurosci Lett 2003; 24:192-4.

52. Lynn B. Capsaicin: action on C fibre afferents that may involved in itch. Skin Pharmacol 1992; 5:9-13.

53. Garssen J, Vandebriel RJ, De Gruijl FR, Wolvers DA, Van Dijk M, Fluitman A, Van Loveren H. UVB exposure-induced systemic modulation of Th1- and Th2-mediated immune responses. Immunology 1999; 97:506-14.

54. Tan JKL, Haberman HF, Coldman AJ. Identifying effective treatment for uremic pruritus. J Am Acad Dermatol 1991; 25:811-818.

55. Gilchrest BA, Rowe JW, Brown RS, Steinman TI, Arndt KA. Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanism of action. Ann Intern Med 1979; 91:17-21.