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Uremic Pruritis - Pathogenesis & Management - Dr. Gawad

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Uremic Pruritis - Pathogenesis & Management - Dr. Gawad

  1. 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. 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. 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. 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. 5. Hiroshige K. Am J Kidney Dis. 1995 Mar;25(3):413-9. 3 months of observation n=59 19
  6. 6. n=111 Ko MJ et al. PLoS One. 2013 Aug 6;8(8):e71404. p = 0.002 18
  7. 7. Saudi J Kidney Dis Transpl 2015;26(5):890-895 Significantly higher Kt/V in the patients with pruritus. 18
  8. 8. n=105 Duque MI et al. Clin Nephrol 2006; 66:184. 18
  9. 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. 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. 11. Ko MJ et al. PLoS One. 2013 Aug 6;8(8):e71404. 17
  12. 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. 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. 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. 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. 16. Pathogenesis Xerosis Decrease in sweat volume Atrophy Dehydration Pornanong Aramwit. Updates in Hemodialysis. Chapter 2. September 9, 2015. 16
  17. 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. 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. 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. 20. Pathogenesis – Microinflamation (1) Interleukin 2 Th1 lymphocytes Interleukin 2 Kurban et al. Clin Dermatol, 2008. 26(3): p. 255-264. 15
  21. 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. 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. 23. Pathogenesis – Microinflamation (2) TNF-α and IL-1β Aramwit et al. J Biosci Bioeng, 2009. 107(5): p. 556-561. 14
  24. 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. 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. 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. 27. Pentoxifylline - Pathogenesis The American Journal of Gastroenterology 109, 1424-1426 (September 2014) Anti-inflammatory 13
  28. 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. 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. 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. 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. 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. 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. 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. 35. Pathogenesis – Nervous Conduction (2) Ca Channel Thomas Mettang. Kidney International (2015) 87, 685–691. 12
  36. 36. Gabapentin / Pregabalin Thomas Mettang. Kidney International (2015) 87, 685–691. 11
  37. 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. 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. 39. Gunal AI et al. Nephrol Dial Transplant 2004; 19: 3137–3139. Pregabalin 21 10
  40. 40. Gunal AI et al. Nephrol Dial Transplant 2004; 19: 3137–3139. Pregabalin 16 started Pregabalin 21 n = 13 (81%) 10
  41. 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. 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. 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. 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. 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. 46. Naltrexone (µ-antagonist) Peer G et al. Lancet 1996; 348: 1552–1554.14. n = 15 9
  47. 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. 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. 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. 50. Felix Stockenhuber et al. Clinical Science (1990) 79,477-482 8
  51. 51. Weisshaar E et al. Exp Dermatol 2004; 13: 298–304. 7
  52. 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. 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. 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. 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. 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. 57. Chou FF et al. J Am Coll Surg 2000; 190:65. 6
  58. 58. Chou FF et al. J Am Coll Surg 2000; 190:65. 6
  59. 59. Chou FF et al. J Am Coll Surg 2000; 190:65. 5
  60. 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. 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. 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. 63. International Journal of Dermatology. 2007, 46, 367–370 n = 15 5.5  2.7 12  4.1 4
  64. 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. 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. 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. 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. 68. OTHERS • Sertraline • Activated charcoal • Erythropoietin • Omega-3 fatty acid • Turmeric • Zinc • Cholestyramine • Avena sativa • Vinegar • Oral nicotinamide • Pramoxine ointement • IV Lidocaine 3
  69. 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. 70. Thomas Mettang. Kidney International (2015) 87, 685–691. 2
  71. 71. Thomas Mettang. Kidney International (2015) 87, 685–691. 2 More accurately to be termed ‘chronic kidney disease-associated pruritus’ (CKD-aP)
  72. 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. 73. 1 Thomas Mettang. Kidney International (2015) 87, 685–691.
  74. 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. 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. 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. 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. 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. 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. 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. 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. 82. Gawad Thank You
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