This document outlines the pathogenesis and management of uremic pruritus. It begins with an outline of the topics to be discussed, including dialysis adequacy and modification, xerosis, microinflammation, nervous conduction, the opioid hypothesis, various drug therapies, physical therapy using UV light, and other treatments. It then discusses various studies that have examined the relationship between increased dialysis adequacy as measured by Kt/V and the severity of pruritus. The document also reviews the role of xerosis, microinflammation mediated by cytokines like TNF-α and IL-1β, the nervous system through substances like substance P, and the opioid hypothesis in the pathogenesis of uremic pruritus.

1. Uremic Pruritus
Pathogenesis & Management
Mohammed Abdel Gawad
Nephrology Specialist
Kidney & Urology Center (KUC)
Alexandria – EGY
drgawad@gmail.com
7th NephroShams / 15-17 Oct 2015

2. Weak Soft Evidence
• Small number of patients were tested by
different studies.
• Conflicting and contradictory results
• Short time of follow up
• Lack of head-to-head comparisons among
different agents
19

3. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
19

4. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
19

5. Hiroshige K. Am J Kidney Dis. 1995 Mar;25(3):413-9.
3 months of
observation
n=59
19

6. n=111
Ko MJ et al. PLoS One. 2013 Aug 6;8(8):e71404.
p = 0.002
18

7. Saudi J Kidney Dis Transpl 2015;26(5):890-895
Significantly higher Kt/V in the patients with pruritus.
18

8. n=105
Duque MI et al. Clin Nephrol 2006; 66:184.
18

9. n=105
• Higher Kt/V = prolonged contact with dialyzer membranes or
silicone tubing.
• If no residual renal function or worse metabolic parameters =
need higher Kt/V
Accounted for the pruritus
Duque MI et al. Clin Nephrol 2006; 66:184.
18

10. It is suggested to use generally accepted Kt/V
targets because of overall benefit conferred
rather than a specific demonstrated effect on
pruritus
17

11. Ko MJ et al. PLoS One. 2013 Aug 6;8(8):e71404.
17

12. Lin HH et al. Artif Organs. 2008 Jun;32(6):468-72.
Started using PMMA
P < 0.001
Back to previously
used high flux filter
17

13. Lin HH et al. Artif Organs. 2008 Jun;32(6):468-72.
Started using PMMA
Back to previously
used high flux filter
P < 0.001
17

14. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
16

15. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
16

16. Pathogenesis
Xerosis
Decrease in
sweat volume Atrophy
Dehydration
Pornanong Aramwit. Updates in Hemodialysis. Chapter 2. September 9, 2015.
16

17. Topical Moisturing & Emollients
Thomas Mettang. Kidney International (2015) 87, 685–691.
Manenti et al. Kidney Int, 2008. 73(4): p. 512.
It has been suggested by several researchers
that the use of emollients with high water
content should be the first-line treatment
• Dexpanthenol
• Glycerol and Paraffin
• If simple emollients fail:
–Evening Primrose oil rich in essential fatty
acids (γ-linolenic acid)
–Bath oil that contains polidocanol
–Cream that contains natural lipids and
endocannabinoids
Pornanong Aramwit. Updates in Hemodialysis. Chapter 2. September 9, 2015.
16

18. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
15

19. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
15

20. Pathogenesis – Microinflamation (1)
Interleukin 2
Th1 lymphocytes
Interleukin 2
Kurban et al. Clin Dermatol, 2008. 26(3): p. 255-264.
15

21. Th1 lymphocytes
Interleukin 2
Gianni LM et al. Ann Pharmacother 2001; 35: 943–946.
Pauli-Magnus C et al. Perit Dial Int 2000; 6: 802–803.
Kuypers DR et al. Nephrol Dial Transplant 2004; 19: 1895–1901.
Tacrolimus Ointment
2 times/day for 1-6 weeks
15

22. Th1 lymphocytes
Interleukin 2
Gianni LM et al. Ann Pharmacother 2001; 35: 943–946.
Pauli-Magnus C et al. Perit Dial Int 2000; 6: 802–803.
Kuypers DR et al. Nephrol Dial Transplant 2004; 19: 1895–1901.
Tacrolimus Ointment
2 times/day for 1-6 weeks
15

23. Pathogenesis – Microinflamation (2)
TNF-α and IL-1β
Aramwit et al. J Biosci Bioeng, 2009. 107(5): p. 556-561.
14

24. Sericin Cream (concentration 8%)
Water-soluble protein that is obtained from
the silkworm (Bombyx mori)
Characterized by the presence of
32% serine, which is the main
amino acid of the natural moisture
factor (NMF) in human skin
Pornanong Aramwit. Updates in Hemodialysis. Chapter 2. September 9, 2015.
O. Keongamaroon. et al. BMC Nephrol, 2012. 13: p. 119.
Twice daily for 6 weeks
14

25. Sericin Cream (concentration 8%)
Water-soluble protein that is obtained from
the silkworm (Bombyx mori)
Pornanong Aramwit. Updates in Hemodialysis. Chapter 2. September 9, 2015.
O. Keongamaroon. et al. BMC Nephrol, 2012. 13: p. 119.
Twice daily for 6 weeks
14

26. Pathogenesis – Microinflamation (3)
TNF-α
Zhang R et al. J Immunother 2007; 30: 89–95
Silva SR et al. Nephron 1994; 67: 270–273.
TNF α
Thalidomide
Pentoxifylline
14

27. Pentoxifylline - Pathogenesis
The American Journal of Gastroenterology 109, 1424-1426 (September 2014)
Anti-inflammatory
13

28. Mettang T et al. Nephrol Dial Transplant 2007; 22: 2727–2728.
Pentoxifylline: 600mg IV,
3X/week (at the end of each
dialysis session), for 4 weeks
n = 7 on HD (didn’t respond to
gabapentin or UVB-phototherapy)
3 patients
stopped
treatment
n = 1 Insomnia
n = 2 Nausea
n = 1 Jaundice
Itch score (median; range)
13

29. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
10

30. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
13

31. Pathogenesis – Nervous Conduction (1)
Substance P
C fibers
Tarikci N et al. Scientific World Journal. 2015;2015:803752
Kuypers DR. Nat Clin Pract Nephrol 2009; 5:157.
12

32. Capsaicin 0.025% Cream
C fibers
Tarng, D.C. et al. Nephron, 1996. 72(4): p. 617-622.
Breneman et al. J Am Acad Dermatol, 1992. 26(1): p. 91-94.
Cho YL et al. J Am Acad Dermatol 1997; 36:538.
Kuypers DR. Nat Clin Pract Nephrol 2009; 5:157.
Extract from capsicum or common pepper plant
12

33. Capsaicin 0.025% Cream
C fibers
Tarng, D.C. et al. Nephron, 1996. 72(4): p. 617-622.
Breneman et al. J Am Acad Dermatol, 1992. 26(1): p. 91-94.
Cho YL et al. J Am Acad Dermatol 1997; 36:538.
Kuypers DR. Nat Clin Pract Nephrol 2009; 5:157.
Extract from capsicum or common pepper plant
12
vanilloid
receptor
subtype 1

34. Capsaicin 0.025% Cream
C fibers
Tarng, D.C. et al. Nephron, 1996. 72(4): p. 617-622.
Breneman et al. J Am Acad Dermatol, 1992. 26(1): p. 91-94.
Cho YL et al. J Am Acad Dermatol 1997; 36:538.
Kuypers DR. Nat Clin Pract Nephrol 2009; 5:157.
Extract from capsicum or common pepper plant
12
vanilloid
receptor
subtype 1
May not be a practical solution for
large areas or generalized pruritus

35. Pathogenesis – Nervous Conduction (2)
Ca Channel
Thomas Mettang. Kidney International (2015) 87, 685–691.
12

36. Gabapentin / Pregabalin
Thomas Mettang. Kidney International (2015) 87, 685–691.
11

37. Razeghi E et al. Ren Fail 2009; 31: 85–90.
Gabapentin
n = 34 on HD
Double-blind,
Crossover study
100 mg of oral
gabapentin
3X/week
Gabapentin
therapy
phase
Washout &
Placebo
phase
11

38. Gunal AI et al. Nephrol Dial Transplant 2004; 19: 3137–3139.
n = 25 on HD
300 mg of oral
gabapentin
3X/week
for 4 weeks
8.4
1.2
4 weeks
Gabapentin 11

39. Gunal AI et al. Nephrol Dial Transplant 2004; 19: 3137–3139.
Pregabalin
21
10

40. Gunal AI et al. Nephrol Dial Transplant 2004; 19: 3137–3139.
Pregabalin
16 started Pregabalin
21
n = 13
(81%)
10

41. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
10

42. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
10

43. Pathogenesis
Opioid Hypothesis
Keiichi Niikura et al. Trends in Pharm Science. Volume 31, Issue 7. July 2010, Pages 299–305
10
Pain
↓ Pain
Ƙ opioid receptor
µ opioid receptor

44. Pathogenesis
Opioid Hypothesis
Kumagai H et al. In: Itch, Basic Mechanisms and Therapy, New York 2004. p.286.
9
Pain
↓ Pain
Ratio of the µ-
receptor agonist
(beta-endorphin)
to
Ƙ-receptor agonist
(dynorphin-A)
is increased in
hemodialysis
patients
µ opioid receptor
Ƙ opioid receptor

45. Naltrexone / Nalfurafine
Kumagai H et al. In: Itch, Basic Mechanisms and Therapy, New York 2004. p.286.
9
Pain
↓ Pain
µ opioid receptor
Ƙ opioid receptor
Naltrexone
µ-antagonist
Nalfurafine
Ƙ-agonist

46. Naltrexone (µ-antagonist)
Peer G et al. Lancet 1996; 348: 1552–1554.14.
n = 15
9

47. Kumagai H et al. Nephrol Dial Transplant 2010; 25: 1251–1257.
Nalfurafine (Ƙ-agonist)
Placebo (n=111)
5 µg (n=144), P = 0.0002
2.5 µg (n=112), P = 0.0001
8

48. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
8

49. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
8

50. Felix Stockenhuber et al. Clinical Science (1990) 79,477-482
8

51. Weisshaar E et al. Exp Dermatol 2004; 13: 298–304.
7

52. Weisshaar E et al. Exp Dermatol 2004; 13: 298–304.
Beneficial effect of anti-
histamincs probably results
from their sleep-inducing side
effect
7

53. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-recptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
7

54. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-recptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
7

55. PTH
• Persistent uremic pruritus of patients with
secondary hyperparathyroidism decreased after
parathyroidectomy
• Intradermal application of parathormone did not
cause a significant skin reaction in humans.
• Itching can occur in patients with accepted PTH
serum level.
Kleeman CR et al. Trans Assoc Am Physicians. 1968;81:203–212.
Massry SG et al. N Engl J Med. 1968;279(13):697–700.
Ståhle-Bäckdahl M et al. J Intern Med. 1989;225(6):411–415.
7

56. Calcium & Phosphorous
• Hypercalcemia and hyperphosphatemia with
secondary deposition of calcium phosphate crystals
in the skin may contribute to itch.
• Calcium × phosphate < 55 can play a role in
improving the pruritus.
• Pruritus may recur when serum calcium is restored
to normal, or persist despite low serum calcium
levels.
Kurban et al. . Clin Dermatol, 2008. 26(3): p. 255-264.
Schwartz, I.F. and A. Iaina, Semin Dial, 2000. 13(3): p. 177-180.
6

57. Chou FF et al. J Am Coll Surg 2000; 190:65.
6

58. Chou FF et al. J Am Coll Surg 2000; 190:65.
6

59. Chou FF et al. J Am Coll Surg 2000; 190:65.
5

60. • Parathyroidectomy should not be considered
as a routine therapy for uremic pruritus.
• Target the commonly accepted calcium,
phosphate and PTH concentrations that have
been developed for the overall benefit of
such patients.
5

61. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
5

62. PHOTOTHERAPY
UVB vs. UVA
• Broad band UVB phototherapy reported a
marked reduction in pruritus.
• Long-wave UVA radiation treatment did not
improve itch intensity.
• Saltzer et al. Cutis, 1975. 16: p.298-299.
• Gilchrest et al. N Engl J Med, 1977. 297(3): p. 136-138
• Gilchrest et al. Ann Intern Med 1979; 91: 17–21.
• Gilchrest. Int J Dermatol, 1979. 18(9): p. 741-748.
• Blachley et al. Am J Kidney Dis, 1985. 5(5): p.237-241.
• Tan JKL et al. J Amer Acad Dermatol 1991; 25: 811–818.
• Kurban et al. Clin Dermatol, 2008. 26(3): p. 255-264.
4

63. International Journal of Dermatology. 2007, 46, 367–370
n = 15
5.5  2.7
12  4.1
4

64. M-J. Ko et al. Briish Association of Dermatologists 2011 165, pp633–639
The treatment group received NB-UVB phototherapy
three times per week for 6 weeks.
The control group received time-matched exposures to
long-wave UVA radiation.
4

65. PHOTOTHERAPY
High risk for skin malignancies
following UVB irradiation
Thomas Mettang. Kidney International (2015) 87, 685–691.
Other Physical Therapies
• Acupuncture
• Thermal Therapy
• Sauna
3

66. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
3

67. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
3

68. OTHERS
• Sertraline
• Activated charcoal
• Erythropoietin
• Omega-3 fatty acid
• Turmeric
• Zinc
• Cholestyramine
• Avena sativa
• Vinegar
• Oral nicotinamide
• Pramoxine ointement
• IV Lidocaine
3

69. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
2

70. Thomas Mettang. Kidney International (2015) 87, 685–691.
2

71. Thomas Mettang. Kidney International (2015) 87, 685–691.
2
More accurately to be termed
‘chronic kidney disease-associated
pruritus’
(CKD-aP)

72. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
2

73. 1
Thomas Mettang. Kidney International (2015) 87, 685–691.

74. Thomas Mettang. Kidney International (2015) 87, 685–691.
Modification: M.Gawad www.NephroTubeCNE.com
Control Ca, Phosphrous, PTH
Pregabalin
(25mg after HD
to 75 mg daily)
if not well
tolerated or
no response
(50 mg daily) !!! Skin cancer
1
Modified approach
according to available
drugs in Egypt and
adding of another
drugs with re-
arrangement of the
drugs sequence

75. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
1

76. Talk Outline
• Dialysis adequacy & modification
• Xerosis
• Microinflamation
• Nervous conduction
• Opioid hypothesis
• Anti-histamine / 5HT3-receptor antagonist
• PTH / Calcium / Phosphorus
• Physical therapy (UV)
• Other therapies
• Terminology
• Suggested step wise management approach
• Is it uremic pruritus?
1

77. Is it uremic pruritus?
• Site: most commonly localized to the back,
followed by the forearm with an AVF,
abdomen, or head.
• Most cases presents dry and scaly.
• In contrast to dermatological pruritus, primary
skin lesions are not observed in patients with
CKD-aP.
Thomas Mettang. Kidney International (2015) 87, 685–691.
0

78. Is it uremic pruritus?
• Site: most commonly localized to the back,
followed by the forearm with an AVF,
abdomen, or head.
• Most cases presents dry and scaly.
• In contrast to dermatological pruritus, primary
skin lesions are not observed in patients with
CKD-aP.
Thomas Mettang. Kidney International (2015) 87, 685–691.
Scratch marks with
excoriations
Hyperkeratotic partly
excoriated nodules
(prurigo nodularis)
Deep scars and prurigo
nodules
0

79. Is it uremic pruritus?
Thomas Mettang. Kidney International (2015) 87, 685–691.
• Suspect other etiology if:
–More generalized.
–Primary specific skin lesions.
–Resistant pruritus.
Acta Derm Venereol 2012; 92: 563–581
0

80. Thomas Mettang. Kidney International (2015) 87, 685–691.
Modification: M.Gawad www.NephroTubeCNE.com
Control Ca, Phosphrous, PTH
Pregabalin
(25mg after HD
to 75 mg daily)
if not well
tolerated or
no response
(50 mg daily) !!! Skin cancer
Exclusion of
other
causes
including
drugs if
resistant
0
Modified approach
according to available
drugs in Egypt and
adding of another
drugs with re-
arrangement of the
drugs sequence

81. Thomas Mettang. Kidney International (2015) 87, 685–691.
Modification: M.Gawad www.NephroTubeCNE.com
Control Ca, Phosphrous, PTH
Pregabalin
(25mg after HD
to 75 mg daily)
if not well
tolerated or
no response
(50 mg daily) !!! Skin cancer
Exclusion of
other
causes
including
drugs if
resistant
0
Modified approach
according to available
drugs in Egypt and
adding of another
drugs with re-
arrangement of the
drugs sequence

82. Gawad
Thank You