Uremic Pruritus (Basic Science → Evidence → Practice) - Dr. Gawad

Uremic Pruritus
Basic Science → Evidence → Practice
Mohammed Abdel Gawad
Nephrology Specialist
Kidney & Urology Center (KUC)
Alexandria – EGY
drgawad@gmail.com
17th Annual Conference
Damanhour Nephrology Department
10 / Nov / 2017

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
• Different scoring systems for the intensity of pruritus
19

Risk-of-bias assessment for all
included studies
19
Am J Kidney Dis. 2017;70(5):638-655

Hugh C. Rayner et al. CJASN doi:10.2215/CJN.03280317
©2017 by American Society of Nephrology

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?

Hiroshige K. Am J Kidney Dis. 1995 Mar;25(3):413-9.
3 months of
observation
n=59
18

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

Saudi J Kidney Dis Transpl 2015;26(5):890-895
Significantly higher Kt/V in the patients with pruritus.
17

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.
17

It is suggested to use generally accepted Kt/V
targets because of overall benefit conferred
rather than a specific demonstrated effect on
pruritus
16

Ko MJ et al. PLoS One. 2013 Aug 6;8(8):e71404.
16

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
P < 0.001
16

Pathogenesis
Xerosis
Decrease in
sweat volume Atrophy
Dehydration
Pornanong Aramwit. Updates in Hemodialysis. Chapter 2. September 9, 2015.
15

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.
15

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

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
14

Pathogenesis – Microinflamation (2)
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
13

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

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

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)
12

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

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.
Extract from capsicum or common pepper plant
12

C fibers
12
vanilloid
receptor
subtype 1

C fibers
12
vanilloid
receptor
subtype 1
May not be a practical solution for
large areas or generalized pruritus

Pathogenesis – Nervous Conduction (2)
Ca Channel
11

Gabapentin / Pregabalin
11

11
J Dermatolog Treat. 2016 Nov;27(6):515-519
n = 54 placebo-
controlled study
100 mg after each HD session, titrated
up to 300 mg, if necessary

10
Nephrology (Carlton).
2012 Nov;17(8):710-7

10
Nephrology (Carlton).
2012 Nov;17(8):710-7
Both improved pruritus significantly, and there
was no difference between the study drugs in
terms of efficacy

Nephron Clin Pract. 2012;122(3-4):75-9
16 started Pregabalin
21
n = 13
(81%)
09

Pathogenesis
Opioid Hypothesis
Keiichi Niikura et al. Trends in Pharm Science. Volume 31, Issue 7. July 2010, Pages 299–305
09
↑ Pain
↓ Pain
Ƙ opioid receptor
mµ opioid receptor

Pathogenesis
Opioid Hypothesis
Kumagai H et al. In: Itch, Basic Mechanisms and Therapy, New York 2004. p.286.
09
↑ Pain
↓ Pain
Ratio of the µ-
receptor agonist
(beta-endorphin)
to
Ƙ-receptor agonist
(dynorphin-A)
is increased in
hemodialysis
patients
Ƙ opioid receptor
mµ opioid receptor

Naltrexone / Nalfurafine /
Nalbuphine, Butorphanol
Kumagai H et al. In: Itch, Basic Mechanisms and Therapy, New York 2004. p.286.
09
↑ Pain
↓ Pain
Ƙ opioid receptor
Naltrexone
mµ-antagonist
Nalfurafine
Ƙ-agonist
mµ opioid receptor

Naltrexone (mµ-antagonist)
Peer G et al. Lancet 1996; 348: 1552–1554.14.
n = 15
08

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
08

Naltrexone / Nalfurafine /
Nalbuphine, Butorphanol
J Am Acad Dermatol. 2006;54(3):527
BMC Nephrol. 2015;16:47
08
↑ Pain
↓ Pain
Ƙ opioid receptor
Naltrexone
mµ-antagonist
Nalfurafine
Ƙ-agonist
mµ opioid receptor Nalbuphine,
Butorphanol
mµ-antagonist
Ƙ-agonist

Felix Stockenhuber et al. Clinical Science (1990) 79,477-482
07

Weisshaar E et al. Exp Dermatol 2004; 13: 298–304.
07

Weisshaar E et al. Exp Dermatol 2004; 13: 298–304.
Beneficial effect of anti-
histamincs probably results
from their sleep-inducing side
effect
07

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?

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.
06

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.
06

Chou FF et al. J Am Coll Surg 2000; 190:65.
06

Chou FF et al. J Am Coll Surg 2000; 190:65.
05

• 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.
05

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.
04

PHOTOTHERAPY
High risk for skin malignancies
following UVB irradiation
Other Physical Therapies
• Acupuncture
• Thermal Therapy
• Sauna
04

OTHERS
• Sertraline
• Activated charcoal
• Erythropoietin
• Omega-3 fatty acid
• Turmeric
• Zinc
• Cholestyramine
• Avena sativa
• Vinegar
• Oral nicotinamide
• Pramoxine ointement
• IV Lidocaine
04

03

03
More accurately to be termed
‘chronic kidney disease-associated
pruritus’
(CKD-aP)

Control Ca, Phosphrous, PTH
03

Modification: M.Gawad www.NephroTubeCNE.com
Pregabalin
(25mg after HD
to 75 mg daily)
if not well
tolerated or
no response
(50 mg daily) !!! Skin cancer
02
After each
HD session

Is it uremic pruritus?
• Site: most commonly localized to the back, followed by the
forearm with an AVF, abdomen, or head.
• Symptoms tend to be worse at night
• increased pruritus with heat (especially with excessive
perspiration) and stress
• Decreased pruritus with physical activity, cooler
temperatures, and with either hot or cold showers
• Most cases presents dry and scaly.
Am J Kidney Dis. 2007;50(1):11
01

Is it uremic pruritus?
• Suspect other etiology if:
–More generalized.
–Primary specific skin lesions.
–Resistant pruritus.
Acta Derm Venereol 2012; 92: 563–581
01

Modification: M.Gawad www.NephroTubeCNE.com
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

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