mini review
http://www.kidney-international.org & 2013 International Society of Nephrology
Uremic pruritus Thomas Mettang1 and Andreas E. Kremer2 1
Department of Nephrology, Deutsche Klinik fu¨r Diagnostik, Wiesbaden, Germany and 2Department of Medicine 1, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient’s quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) l-opioid receptor antagonists and j-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as l-opioid-receptor—antagonists (i.e., naltrexone) or j-opioidreceptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on ‘high urgency’-status, as successful kidney transplantation will relieve patients from CKD-aP. Kidney International advance online publication, 8 January 2014; doi:10.1038/ki.2013.454 KEYWORDS: chronic kidney disease; hemodialysis; itch; peritoneal dialysis; uremic pruritus
Correspondence: Thomas Mettang, Department of Nephrology, Deutsche Klinik fu¨r Diagnostik, Aukammallee 33, Wiesbaden 65191, Germany. E-mail: [email protected] Received 3 March 2013; revised 14 August 2013; accepted 22 August 2013 Kidney International
Uremic pruritus or more accurately termed ‘chronic kidney disease-associated pruritus’ (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease.1 The prevalence and the burden of this symptom are often underestimated by nephrologists.2 Effective treatment options are limited because of a low number of randomized, placebo-controlled trials with most of them reporting only limited therapeutic success. In addition, several times in the past, reports on putative effective novel treatment options were followed by studies with contradictory results.3–6 The lack of effective treatment modalities also results from a still incomplete knowledge of the underlying pathophysiological mechanisms. This review highlights the recent clinical and experimental findings focusing on the pathogenesis and current treatment options of CKD-aP. CLINICAL FEATURES OF CKD-aP
Intensity and spatial distribution of pruritus in patients with chronic renal insufficiency may vary significantly over time. The degree of CKD-aP may range from sporadic discomfort to complete restlessness during day- and nighttime strongly reducing the patient’s quality of life. The skin of affected patients is often unchanged, resembling that of patients without pruritus, which in most cases presents dry and scaly. In contrast to dermatological pruritus, primary skin lesions are not observed in patients with CKD-aP. However, excoriations with and without impetigo, linear crusts, papules, ulcerations, and less commonly prurigo nodularis may be seen as secondary skin changes due to intense scratching activity (Figure 1a–c). Up to 50% of patients with CKD-aP complain about generalized pruritus.7,8 In the remaining patients, CKD-aP seems to affect predominantly back, face, and shunt arm, respectively.9 Interestingly, in about 25% of patients pruritus is reported most severe during or immediately after dialysis. Once patients have developed CKD-aP, this symptom will in most cases last for month or years.10 In patients with generalized pruritus, other causes such as dermatological, hepatobiliary, hematological, endocrinological, neurological and psychiatric disorders, drug intake as well as solid tumors need to be ruled out. The diagnosis of CKD-aP may be challenging. Many patients with CKD in advanced stages (IV–V) are suffering from other diseases, such as cardiovascular diseases, diabetes mellitus, chronic liver or hematological diseases, which by itself or by medication given to treat these entities may provoke itch. 1
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In some cases, the clinical appearance (localization, pattern, quality of itch, and so on) may be helpful to categorize the itch in these patients. Quite often, however, a definitive diagnosis cannot be established and treatment has to be initiated according to considerations of likelihood. Epidemiology
Although in the early days of dialysis treatment, CKD-aP was a very common problem afflicting up to 85% of patients11 its incidence declined to 50–60% in the late eighties.12 However, numbers are difficult to compare as chronic itch has rarely
T Mettang and AE Kremer: Uremic pruritus
been analyzed and instruments used to assess the intensity of itch diverge. A recent large-scale investigation on several thousand patients reported that 440% of patients undergoing hemodialysis suffer from chronic pruritus1 (Figure 2). This study uncovered a higher mortality of patients suffering from pruritus. However, when controlled for sleep disturbance this correlation did not remain statistically significant. Severe pruritus is, however, very rare in pediatric patients on dialysis (Figure 3).13 Data on the prevalence of CKD-aP in patients undergoing peritoneal dialysis are rather scarce. The few reports available, however, permit the conclusion that patients undergoing peritoneal dialysis are similarly affected by pruritus as patients on hemodialysis.12,14 Although prevalence of pruritus has declined during the last decades potentially by improved hemodialysis techniques, this symptom remains a major clinical symptom and in severe cases often a medical challenge. Etiopathology
The pathogenesis of CKD-aP remains obscure.15 Various substances have been discussed as potential pruritogens in
DOPPSI / DOPPSII 30
26
29
29
29
Patients (%)
45% / 42% 20
18
18 15
14
12
10 I
II
I
II
I
II
I
II
10
I
II
0 Somewhat Not n=1555/2135 1768/2105
Moderately 1066/1339
Very much 925/994
Extremely 715/698
Degree of being bothered by itchiness
Figure 2 | Prevalence and intensity of uremic pruritus according to DOPPS-data from 1996 to 1999 (I) and 2002 to 2003 (II) (after Pisoni et al.1). DOPPS, Dialysis Outcome and Practice Patterns Study.
P = 0.0013 600 18.8% Number of patients
500 400 300
505 9.1%
200 100
199 18
0
Figure 1 | Typical skin changes observed in patients suffering from chronic kidney disease-associated pruritus (CKD-aP). (a) Scratch marks with excoriations at the lower leg. (b) Typical hyperkeratotic partly excoriated nodules (prurigo nodularis) located on the forearm. (c) Deep scars and prurigo nodules at the shoulders and back of a female patient. 2
Patients ≤ 18 years Patients on dialysis
95 Patients > 18 years Patients with uremic pruritus
Figure 3 | Prevalence of uremic pruritus in children on dialysis (18 years or younger) and in adult dialysis patients (older than 18 years). Prevalence of uremic pruritus in children is significantly lower than in adult patients (w2 test according to Schwab et al.13). Kidney International
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T Mettang and AE Kremer: Uremic pruritus
CNS • Opioid disbalance • Psychological factors Supplemental influences Stimuli • Parathormone • Histamine • Tryptase • Xenobiotica • Uremic toxins • Cytokines • Inflammation
– Scaly skin, dry skin – Serological factors
Neuropathy Nerve-proliferation
Figure 4 | Schematic synopsis of potential pathogenic factors in chronic kidney disease-associated pruritus (CKD-aP). CNS, central nervous system.
chronic renal diseases; however, a causal relation could never be established. Among others, parathormone and histamine were investigated more closely as presumable pruritogenic factors. Parathormone is believed to be a possible pathogenetic factor based on the observation that persistent pruritus in patients with secondary hyperparathyroidism improved after parathyroidectomy.16,17 In contrast, parathormone did not elicit any cutaneous reaction upon intradermal application in humans and could not be detected in skin biopsies of affected patients.18 Stockenhuber et al.19 observed increased levels of histamine in patients with CKD-aP and suggested that accumulation of this classical pruritogen would have a key role. Nevertheless, contradictory data on the impact of histamine have been reported.12 The absence of typical skin changes such as wheals and the regularly observed therapeutic failure of antihistamines in patients with CKD-aP challenge the concept of histamine as a major pruritogen.20 Interestingly, increased levels of tryptase, another substance released by mast cells were observed in patients with CKD-aP.21 The impact of xenobiotic agents and uremia toxins has not yet been established. There is also some controversy about the influence of other factors, that is, increased tissue concentrations of vitamin A and metastatic microcalcifications caused by calcium and magnesium salts.22 Xerosis of the skin is described in a large number of patients with renal failure and was suspected as a significant pathogenetic factor in CKD-aP. However, many patients with marked xerosis do not necessarily suffer from itch but those who do often do better by moisturizing and rehydrating the skin. Thus, it is likely that xerosis adds to the intensity of itch if CKD-aP is present.23 Special attention has been focused on neuropathic changes, nerve proliferations of the pruritus-mediating cells, and central nervous alterations. Similar to cholestatic pruritus, enhanced stimulation of the central m-opioid receptors by cumulated endorphins or cumulated endogenic morphines has been suggested as a cause for CKD-aP. This hypothesis was underlined by the observation in a single study showing a substantial amelioration of itching in uremic patients after the Kidney International
oral application of the m-opioid receptor antagonist naltrexone.5 This positive anti-pruritic effect could, however, not be confirmed in a large-scale study of our group on hemodialysis patients presenting with pruritus. A more recent hypothesis on CKD-aP reported on an imbalance between the activities of the mostly antagonistic acting m- and k-opioid receptors in favor of m-receptor activation. For this reason, application of a k-agonist was recommended for the treatment. More recent research points to microinflammation on skin and probably systemic level as an etiopathologically relevant factor in CKD-aP. In this regard, elevated levels of c-reactive protein were observed in serum of hemodialysis patients with chronic pruritus;24,25 furthermore, relatively increased proinflammatory relevant TH1-cells and raised interleukin-6 concentrations could be detected in these patients by our study group.25 Figure 4 summarizes the potential pathogenic factors in CKD-aP. Treatment options
Pruritus may be extremely vexing at times and difficult to control. Therapeutic options in CKD-aP are, however, limited. Most studies on this symptom are not reliable because of inadequate documentation of patient’s characteristics, concomitant diseases, therapeutic measures taken, and often very low case numbers. Moreover, effects that might be statistically significant may not necessarily be clinically relevant and vice versa. To give an example, a reduction of itch intensity from 8 to 6 on a visual analog scale (VAS), even though not statistically significant, might mean a great improvement in the torture of itch, whereas a reduction from 3.5 to 2.5 may be statistically significant without a subjective improvement for the patient. Owing to a meticulous study by Staender et al. done in 192 patients with pruritus, the minimal clinical important difference is 1.40 for the improvement of pruritus on a VAS ranging from 0 to 10 (personal communication). For future studies, improved strategies for the assessment of itch are required that do better reflect the burden of suffering of our patients. In the following, the most consequential approaches to treatment are presented: Topical treatment Gabapentin Systemic treatment with m-opioid receptor antagonists and k-agonists Drugs with an anti-inflammatory action Phototherapy Acupuncture Others Table 1 summarizes most of the randomized controlled trials on the above-mentioned treatment options. TOPICAL TREATMENT
Daily topical treatment using rehydrating emollients should be regarded as baseline therapy. Addition of cooling 3
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T Mettang and AE Kremer: Uremic pruritus
Table 1 | Selection of most important randomized, placebo-controlled trials in patients with CKD-aP Number of Duration of patients treated treatment Results
Author
Intervention/medication
Design
Gunal et al.31 Razeghi et al.32 Wikstro¨m et al.34 Kumagai et al.35 Peer et al.5 Pauli-Magnus et al.6
Gabapentin 300 mg p.o. three times a week RCT crossover Gabapentin 100 mg p.o. three times a week RCT crossover Nalfurafine 5 mg i.v. three times a week Meta-analysis of two RCTs Nalfurafine 2.5 vs. 5 mg p.o. daily RCT Naltrexone 50 mg p.o. daily RCT crossover Naltrexone 50 mg p.o. daily RCT crossover
Silva et al.37
Thalidomide100 mg p.o. daily
RCT
Duo41
Electro-acupuncture 3 weekly
Che-Yi et al.42
Acupuncture 3 weekly
Ko et al.40 Duque et al.29
Photo therapy (UVB-narrow band) Tacrolimus 0.01%-ointment daily 2 daily
Controlled (sham acupuncture) Controlled (sham acupuncture) Single blinded Vehicle controlled
Chen et al.30
2.2% Gamma linolenic acid–containing ointment 3daily
RCT crossover
25 34 144
4 Weeks 4 Weeks 2–4 Weeks
Highly significant effect Highly significant effect Significant effect
337 15 23
2 Weeks 7 Days 28 Days
29
7 Days
6
2 Weeks
Significant effect Highly significant effect No effect (no difference between placebo and verum) Moderate but significant effect (Po0.05) Significant effect
40
1 Month
Significant effect
21 22
6 Weeks 4 Weeks
17
2 Weeks
No significant effect No significant difference between vehicle and verum Significant effect (Po0.0001)
Abbreviations: CKD-aP, chronic kidney disease-associated pruritus; i.v., intravenous; RCT, randomized controlled trial; UVB, ultraviolet light B.
substances such as menthol to emollients may further improve its antipruritic effect. However, properly controlled studies are lacking. Tacrolimus ointments
Topical treatment with tacrolimus has been shown to completely or partially resolve eczema and pruritus in atopic dermatitis.26 As microinflammatory processes may be involved in the pathogenesis of CKD-aP, we tested this drug in a preliminary study of three patients on peritoneal dialysis with severe CKD-aP. Patients applied tacrolimus 0.03% ointment twice daily to the most affected areas for a period of 7 days and scored itch intensity on a VAS before, during, and after treatment. Tacrolimus ointment strongly improved pruritus during treatment period; however, pruritus rose back to baseline values within days after end of treatment.27 Our observation was confirmed in a proof of concept study by Kuypers et al.28 reporting about 25 patients treated with tacrolimus ointment for a period of 6 weeks with a reduction of itch intensity by 43%. A more recent doubleblind, vehicle-controlled study conducted on 22 hemodialysis patients with pruritus29 showed a strong reduction of itch intensity in both the verum and vehicle group of about 80%. A difference between tacrolimus and vehicle could not be demonstrated. However, the highly unexpected improvement on the basic cream (vehicle) could not be explained by the authors. One should note that no serious adverse reactions were seen in this study using either tacrolimus or the carrier. Gamma linolenic acid ointment
In a study conducted by Chen et al.30, a cream containing high concentrations of gamma linolenic acid (GLA), an essential fatty acid derived from certain plant seed oils, was tested on 17 patients with CKD-aP. In this randomized 4
double-blind, placebo-controlled, crossover study patients were treated for 6 weeks, with a washout period of 2 weeks in between the two treatment phases. Paired analysis showed that the intensity of pruritus was significantly reduced following GLA treatment whereas pruritus scores after placebo treatment revealed a nonsignificant reduction. This investigation suggests that GLA can exert an improved antipruritic effect over vehicle and may serve as a useful adjunct in providing symptomatic relief. It was speculated that the mechanism of action of this therapeutic agent may be the formation of anti-inflammatory acting prostaglandins, which are derived from the ‘prodrug’ GLA. SYSTEMIC TREATMENT Gabapentin and pregabalin.
Gabapentin, an anticonvulsant and centrally acting calcium-channel-blocker, has been shown to exert a pain-modulating effect in patients with neuropathic pain. In a study by Gunal et al.31 involving 25 patients on hemodialysis with CKD-aP, 300 mg of oral gabapentin administered three times weekly for 4 weeks was safe and highly effective in reducing pruritus. Itch intensity as determined by a VAS dropped from 8.4 before treatment to 1.2 after 4 weeks of treatment. Similar results could be obtained in another double-blind, controlled, crossover study treating 34 patients with 100 mg gabapentin orally three times a week.32 Our group has seen comparable beneficial effects in the use of gabapentin. As this drug is largely well tolerated, it should be considered as a promising treatment option in the management of CKD-aP if topical treatment is ineffective. There are a couple of reports that pregabalin is reducing CKD-aP. One recent trial suggests that patients on dialysis not responding to or not tolerating gabapentin might be switched to pregabalin with good success and tolerability.33 Kidney International
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T Mettang and AE Kremer: Uremic pruritus
l-Opioid receptor antagonists Naltrexone. A placebo-controlled, double-blind, cross-
over trial by Peer et al.5 showed that administration of oral naltrexone for 1 week led to an almost complete resolution of pruritus in 15 patients with severe CKD-aP. However, when trying to confirm these results by a 4-week lasting placebocontrolled, double-blind, crossover study in 23 patients with severe CKD-aP, we failed to demonstrate a significant effect of treatment with a daily dose of 50 mg naltrexone compared with placebo. Itch intensity decreased by 29.2% during naltrexone and by 16.9% during placebo treatment as determined by VAS without being statistically significant.6 The findings of Peer et al.5 are in sharp contrast to the results of our study and cannot be explained by differences in patients compliance, naltrexone dose, or study design, as both studies were randomized, placebo-controlled, double-blind, and crossover trials. The studies merely differed as to the intensity of pruritus in the evaluated groups. Although the trial by Peer et al. exclusively concentrated on patients most seriously afflicted with pruritus (mean VAS 10), the mean intensity of pruritus in our patients was found to be VAS 6. This and other differences, for instance, regarding hemodialysis treatment, the material used, divergent lifestyle, eating habits, and environmental circumstances in different parts of the world may well have been involved in causing these contradicting results.
Pentoxifylline
Suggesting that CKD-aP is mediated by systemic microinflammation, we investigated the use of pentoxifylline in seven hemodialysis patients with CKD-aP who did not respond to treatment with gabapentin or ultraviolet light B (UVB)-phototherapy. Pentoxifylline, a weak tumor necrosis factor-alpha inhibitor, was administered at 600 mg intravenously three times a week (at the end of each dialysis session) for 4 weeks. Those patients tolerating the drug experienced an almost complete resolution of pruritus, which continued for at least 4 weeks after cessation of therapy. However, four patients discontinued therapy due to treatment-related or -unrelated health problems.36 Considering the rather modest tolerance of the agent at least with the dose chosen, this approach may only be recommended in severe refractory cases. Thalidomide
Thalidomide, which is currently used as an immunomodulator to treat graft-versus-host reactions and myeloma, suppresses production of tumor necrosis factor-alpha and may therefore be effective in the treatment of CKD-aP.37 A placebo-controlled, crossover, randomized double-blind study of thalidomide for the treatment of refractory uremic pruritus demonstrated improvements in itch scores in approximately 55% of patients in both phases of the trial. Aside from the suppression of tumor necrosis factor-alpha, a centrally abating effect might be responsible for beneficial antipruritic effects.
j-Opioid receptor agonists
As k-opioid receptors primarily mediate m-opioid receptorantagonistic effects, and as k-agonistic drugs are known to suppress morphine-induced itch, it was assumed that these substances might be capable of alleviating pruritus. These substances are likely to act on spinal cord level by inhibiting the itch impulse transmitted by the first neuron. Nalfurafine. Nalfurafine is a highly selective k-opioidreceptor agonist. A meta-analysis of two randomized doubleblind and placebo-controlled studies on a total of 144 hemodialysis patients with CKD-aP corroborated an antipruritic effect of nalfurafine. In these studies, the substance was administered as a short infusion following hemodialysis three times weekly for a total period of 4 weeks. A moderate, but significant effect of nalfurafine could be demonstrated.34 In another randomized, prospective, placebo-controlled phase-III-study a total of 337 hemodialysis patients with pruritus were treated orally with nalfurafine hydrochloride at doses of 2.5 or 5 mg daily for 2 weeks.35 On treatment with the test substance, the itch intensity, measured by VAS (0–100 mm), significantly decreased by 22 (5 mg) and 23 mm (2.5 mg), respectively, after 7 days of application, while it merely dropped by 13 mm in the placebo group. However, the incidence of undesired drug actions (insomnia in particular) was substantially higher in both verum groups (35.1% on 5 mg and 25% on 2.5 mg) compared with the placebo group (16.2%). Moreover, the effect of medication was wearing off fast once treatment was stopped. Kidney International
PHOTOTHERAPY
In the late 1970s, Gilchrest et al.38 reported on the effectiveness of sunburn-spectrum UVB-phototherapy on patients with CKD-aP. Although long-wave UVA radiation treatment did not improve itch intensity, 9 of 10 subjects treated with UVB phototherapy reported a marked reduction in pruritus. Subsequently, a series of studies explored the effectiveness of phototherapy in CKD-aP, particularly using radiation with broadband UVB. According to a meta-analysis by Tan et al.39, the most promising phototherapy for uremic itch is UVB radiation, whereas UVA does not appear to be effective. More recent research suggested that side effects of narrow-band UVB-radiation were less frequent and treatment is just as effective as treatment using broadband UVB. However, in newer studies the effectiveness of narrow-band UVB-radiation could not be verified.40 The risk for skin malignancies following UVB irradiation and long-term systemic immunosuppression remains a matter of debate, especially in immunocompromised patients suffering from advanced disease or in those scheduled to receive immunosuppressive treatment after renal transplantation. Thus, patients should be carefully evaluated before considering UVB therapy. ACUPUNCTURE
An interesting approach to treat CKD-aP is acupuncture. Electro-acupuncture or sham-electro-stimulation was applied 5
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T Mettang and AE Kremer: Uremic pruritus
to six patients on hemodialysis in a blinded manner in a study by Duo41. Patients on acupuncture showed a significantly higher reduction in pruritus determined by a score than the sham-treated patients. In another study, 40 patients with CKD-aP were treated with acupuncture either at the Quchi (LI11) acupoint or at a non-acupoint 2 cm lateral thrice weekly for 1 month. Patients treated using the correct acupoint revealed a substantial reduction in pruritus using a score regarding severity, distribution, and sleep disturbance ending up with maximum 45 points (38.3±4.3, 17.3±5.5, and 16.5±4.9 start vs. 4 weeks vs. 12 weeks later), whereas pruritus in patients with sham-acupuncture did not change substantially (38.3±4.3, 37.5±3.2 and 37.1±5 start vs. 4 weeks vs. 12 weeks later).42 Given these results, acupuncture at least in experienced hands might be a useful tool in the treatment of CKD-aP. OTHERS
Many other substances such as orally applied activated charcoal, erythropoietin, and ondansentron have been reported to be effective in case reports or case series, however, their beneficial effects could not be proven in randomizedcontrolled trials.43 Treatment of CKD-aP remains a frustrating endeavor and continues to present a significant therapeutic challenge. Besides topical treatment, gabapentin, immunomodulatory
Exclusion of other causes for pruritus
Assessment of severity of pruritus
Moisturing ointment oil bath
Weak
drugs, and kappa-receptor agonists may be helpful in severe cases. A stepwise approach is suggested in choosing a therapeutic modality, and whenever possible, treatment should be initiated with the drug exhibiting the most favorable safety and efficacy profiles (Figure 5). In desperate cases patients principally eligible for a kidney transplant may be switched to ‘high urgency’ status, which will decrease their waiting time. In most cases, successful kidney transplantation will relieve patients from CKD-aP.44 Figure 5 shows a potential therapeutic algorithm of CKD-aP. PERSPECTIVES
During the last decade basic research on pruritus has considerably emerged. Besides novel insights into central itch processing, peripheral itch-signaling neurons, receptors, and intracellular signaling pathways could be identified. It became apparent that different forms of itch are conveyed by distinct pathways and that various mechanisms and factors are involved in the pathogenesis of pruritus.45 Beside mast cells, eosinophilic granulocytes may contribute on skin level to itch by release of neurotrophins, neuropeptides, and their cytotoxic granule proteins. Another interesting approach would be to study the role of novel receptors being involved in itch induction such as the mas-related G-protein coupled receptors being activated by histamine and the anti-malaria drug chloroquine, the protease-activated receptors 2 and 4, which can be altered by exogenous and endogenous proteases and the recently described histamine-4-receptor. Which of those cells and receptors may have a role in CKD-aP warrant further investigations. Thus, development of a causal pharmacological treatment for those patients remains on the distant horizon. DISCLOSURE
Severe Quality of dialysis (Kt/V)
KtV < 1.2
KtV > 1.2
Increase dose of dialysis
TM has served as a scientific consultant for FMC and received speakers honorary from Roche, Amgen, Sanofi, and Baxter. AEK declared no competing interests.
Persisting
REFERENCES 1.
Moisturing ointment /oil bath
2.
and Gabapentin 100-300 mg
or
UVB phototherapy or
Charcoal Nalfurafine or (6g/die) 2.5 – 5.0 mg p.o.
Persisting
3.
4. 5.
Naltrexone
or
Tacrolimus ointment
or
(Electro-) acupuncture
6.
Persisting
7. Consider kidney transplantation
Figure 5 | Therapeutic algorithm in chronic kidney disease-associated pruritus (CKD-aP). Kt/V, urea clearance in relation to urea distribution volume; UVB, ultraviolet light B. 6
8. 9.
Pisoni RL, Wikstro¨m B, Elder SJ et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2006; 21: 3495–3505. Weisshaar E, Matterne U, Mettang T. How do nephrologists in haemodialysis units consider the symptom of itch? Results of a survey in Germany. Nephrol Dial Transplant 2009; 24: 1328–1330. De Marchi S, Cecchin E, Villalta D et al. Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 1992; 326: 969–974. Balaskas EV, Uldall RP. Erytropoietin does not improve uremic pruritus. Perit Dial Int 1992; 12: 330–331. Peer G, Kivity S, Agami O et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348: 1552–1554.14. Pauli-Magnus C, Mikus G, Alscher DM et al. Naltrexone does not relieve uremic pruritus: results of a randomized, placebo-controlled crossoverstudy. J Am Soc Nephrol 2000; 11: 514–519. Narita I, Alchi B, Omori K et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006; 69: 1626–1632. Ponticelli C, Bencini PL. Uremic pruritus: a review. Nephron 1992; 60: 1–5. Gilchrest GA, Stern RS, Steinman TI et al. Clinical features of pruritus among patients undergoing maintenance hemodialysis. Arch Dermatol 1982; 118: 154–156. Kidney International
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43. 44.
45.
patients on chronic dialysis therapy. Nephrol Dial Transplant 2004; 19: 1895–1901. Duque MI, Yosipovitch G, Fleischer AB et al. Lack of efficacy of tacrolimus ointment 0.1% for treatment of hemodialysis-related pruritus: a randomized, double-blind vehicle-controlled study. J Am Acad Dermatol 2005; 52: 519–521. Chen YC, Chiu WT, Wu MS. Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. Am J Kidney Dis 2006; 48: 69–76. Gunal AI, Ozalp G, Yoldas TK. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 2004; 19: 3137–3139. Razeghi E, Eskandari D, Ganji MR et al. Gabapentin and uremic pruritus in hemodialysis patients. Ren Fail 2009; 31: 85–90. Rayner H, Baharani J, Smith S et al. Uraemic pruritus: relief of itching by gabapentin and pregabalin. Nephron Clin Pract 2013; 122: 75–79. Wikstro¨m B, Gellert R, Ladefoged SD et al. m-Opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol 2005; 16: 3742–3747. Kumagai H, Ebata T, Takamori K. Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a phase III, randomized, double-blind, placebo-cpntrolled study. Nephrol Dial Transplant 2010; 25: 1251–1257. Mettang T, Krumme B, Bohler J et al. Pentoxifylline as treatment for uraemic pruritus—an addition to the weak armentarium for a common clinical symptom? Nephrol Dial Transplant 2007; 22: 2727–2728. Silva SR, Viana PC, Lugon NV et al. Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial. Nephron 1994; 67: 270–273. Gilchrest BA, Rowe JW, Brown RS et al. Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanisms of action. Ann Intern Med 1979; 91: 17–21. Tan JKL, Haberman HF, Coldman AJ. Identifying effective treatments for uremic pruritus. J Amer Acad Dermatol 1991; 25: 811–818. Ko MJ, Yang JY, Wu HY et al. Narrowband ultraviolet B phototherapy for patients with refractory uremic pruritus: a randomized controlled trial. Br J Dermatol 2011; 165: 633–639. Duo LJ. Electrical needle therapy of uremic pruritus. Nephron 1987; 47: 179–183. Che-yi C, Wen CW, Min-Tsung K et al. Acupuncture in haemodialysis patients at the Quchi (LI11) acupoint for refractory uraemic pruritus. Nephrol Dial Transplant 2005; 20: 912–915. Manenti L, Tansinda P, Vaglio A. Uraemic pruritus: clinical characteristics, pathophysiology and treatment. Drugs 2009; 69: 251. Altmeyer P, Kachel HG, Scha¨fer G et al. Normalisierung der ura¨mischen Hautvera¨nderungen nach Nierentransplantation. Hautarzt 1986; 37: 217–221. Staender S, Raap U, Weisshaar E et al. The pathogenesis of pruritus. JDDG 2011; 9: 456–463.
7
http://www.kidney-international.org & 2013 International Society of Nephrology
Uremic pruritus Thomas Mettang1 and Andreas E. Kremer2 1
Department of Nephrology, Deutsche Klinik fu¨r Diagnostik, Wiesbaden, Germany and 2Department of Medicine 1, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient’s quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) l-opioid receptor antagonists and j-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as l-opioid-receptor—antagonists (i.e., naltrexone) or j-opioidreceptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on ‘high urgency’-status, as successful kidney transplantation will relieve patients from CKD-aP. Kidney International advance online publication, 8 January 2014; doi:10.1038/ki.2013.454 KEYWORDS: chronic kidney disease; hemodialysis; itch; peritoneal dialysis; uremic pruritus
Correspondence: Thomas Mettang, Department of Nephrology, Deutsche Klinik fu¨r Diagnostik, Aukammallee 33, Wiesbaden 65191, Germany. E-mail: [email protected] Received 3 March 2013; revised 14 August 2013; accepted 22 August 2013 Kidney International
Uremic pruritus or more accurately termed ‘chronic kidney disease-associated pruritus’ (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease.1 The prevalence and the burden of this symptom are often underestimated by nephrologists.2 Effective treatment options are limited because of a low number of randomized, placebo-controlled trials with most of them reporting only limited therapeutic success. In addition, several times in the past, reports on putative effective novel treatment options were followed by studies with contradictory results.3–6 The lack of effective treatment modalities also results from a still incomplete knowledge of the underlying pathophysiological mechanisms. This review highlights the recent clinical and experimental findings focusing on the pathogenesis and current treatment options of CKD-aP. CLINICAL FEATURES OF CKD-aP
Intensity and spatial distribution of pruritus in patients with chronic renal insufficiency may vary significantly over time. The degree of CKD-aP may range from sporadic discomfort to complete restlessness during day- and nighttime strongly reducing the patient’s quality of life. The skin of affected patients is often unchanged, resembling that of patients without pruritus, which in most cases presents dry and scaly. In contrast to dermatological pruritus, primary skin lesions are not observed in patients with CKD-aP. However, excoriations with and without impetigo, linear crusts, papules, ulcerations, and less commonly prurigo nodularis may be seen as secondary skin changes due to intense scratching activity (Figure 1a–c). Up to 50% of patients with CKD-aP complain about generalized pruritus.7,8 In the remaining patients, CKD-aP seems to affect predominantly back, face, and shunt arm, respectively.9 Interestingly, in about 25% of patients pruritus is reported most severe during or immediately after dialysis. Once patients have developed CKD-aP, this symptom will in most cases last for month or years.10 In patients with generalized pruritus, other causes such as dermatological, hepatobiliary, hematological, endocrinological, neurological and psychiatric disorders, drug intake as well as solid tumors need to be ruled out. The diagnosis of CKD-aP may be challenging. Many patients with CKD in advanced stages (IV–V) are suffering from other diseases, such as cardiovascular diseases, diabetes mellitus, chronic liver or hematological diseases, which by itself or by medication given to treat these entities may provoke itch. 1
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In some cases, the clinical appearance (localization, pattern, quality of itch, and so on) may be helpful to categorize the itch in these patients. Quite often, however, a definitive diagnosis cannot be established and treatment has to be initiated according to considerations of likelihood. Epidemiology
Although in the early days of dialysis treatment, CKD-aP was a very common problem afflicting up to 85% of patients11 its incidence declined to 50–60% in the late eighties.12 However, numbers are difficult to compare as chronic itch has rarely
T Mettang and AE Kremer: Uremic pruritus
been analyzed and instruments used to assess the intensity of itch diverge. A recent large-scale investigation on several thousand patients reported that 440% of patients undergoing hemodialysis suffer from chronic pruritus1 (Figure 2). This study uncovered a higher mortality of patients suffering from pruritus. However, when controlled for sleep disturbance this correlation did not remain statistically significant. Severe pruritus is, however, very rare in pediatric patients on dialysis (Figure 3).13 Data on the prevalence of CKD-aP in patients undergoing peritoneal dialysis are rather scarce. The few reports available, however, permit the conclusion that patients undergoing peritoneal dialysis are similarly affected by pruritus as patients on hemodialysis.12,14 Although prevalence of pruritus has declined during the last decades potentially by improved hemodialysis techniques, this symptom remains a major clinical symptom and in severe cases often a medical challenge. Etiopathology
The pathogenesis of CKD-aP remains obscure.15 Various substances have been discussed as potential pruritogens in
DOPPSI / DOPPSII 30
26
29
29
29
Patients (%)
45% / 42% 20
18
18 15
14
12
10 I
II
I
II
I
II
I
II
10
I
II
0 Somewhat Not n=1555/2135 1768/2105
Moderately 1066/1339
Very much 925/994
Extremely 715/698
Degree of being bothered by itchiness
Figure 2 | Prevalence and intensity of uremic pruritus according to DOPPS-data from 1996 to 1999 (I) and 2002 to 2003 (II) (after Pisoni et al.1). DOPPS, Dialysis Outcome and Practice Patterns Study.
P = 0.0013 600 18.8% Number of patients
500 400 300
505 9.1%
200 100
199 18
0
Figure 1 | Typical skin changes observed in patients suffering from chronic kidney disease-associated pruritus (CKD-aP). (a) Scratch marks with excoriations at the lower leg. (b) Typical hyperkeratotic partly excoriated nodules (prurigo nodularis) located on the forearm. (c) Deep scars and prurigo nodules at the shoulders and back of a female patient. 2
Patients ≤ 18 years Patients on dialysis
95 Patients > 18 years Patients with uremic pruritus
Figure 3 | Prevalence of uremic pruritus in children on dialysis (18 years or younger) and in adult dialysis patients (older than 18 years). Prevalence of uremic pruritus in children is significantly lower than in adult patients (w2 test according to Schwab et al.13). Kidney International
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T Mettang and AE Kremer: Uremic pruritus
CNS • Opioid disbalance • Psychological factors Supplemental influences Stimuli • Parathormone • Histamine • Tryptase • Xenobiotica • Uremic toxins • Cytokines • Inflammation
– Scaly skin, dry skin – Serological factors
Neuropathy Nerve-proliferation
Figure 4 | Schematic synopsis of potential pathogenic factors in chronic kidney disease-associated pruritus (CKD-aP). CNS, central nervous system.
chronic renal diseases; however, a causal relation could never be established. Among others, parathormone and histamine were investigated more closely as presumable pruritogenic factors. Parathormone is believed to be a possible pathogenetic factor based on the observation that persistent pruritus in patients with secondary hyperparathyroidism improved after parathyroidectomy.16,17 In contrast, parathormone did not elicit any cutaneous reaction upon intradermal application in humans and could not be detected in skin biopsies of affected patients.18 Stockenhuber et al.19 observed increased levels of histamine in patients with CKD-aP and suggested that accumulation of this classical pruritogen would have a key role. Nevertheless, contradictory data on the impact of histamine have been reported.12 The absence of typical skin changes such as wheals and the regularly observed therapeutic failure of antihistamines in patients with CKD-aP challenge the concept of histamine as a major pruritogen.20 Interestingly, increased levels of tryptase, another substance released by mast cells were observed in patients with CKD-aP.21 The impact of xenobiotic agents and uremia toxins has not yet been established. There is also some controversy about the influence of other factors, that is, increased tissue concentrations of vitamin A and metastatic microcalcifications caused by calcium and magnesium salts.22 Xerosis of the skin is described in a large number of patients with renal failure and was suspected as a significant pathogenetic factor in CKD-aP. However, many patients with marked xerosis do not necessarily suffer from itch but those who do often do better by moisturizing and rehydrating the skin. Thus, it is likely that xerosis adds to the intensity of itch if CKD-aP is present.23 Special attention has been focused on neuropathic changes, nerve proliferations of the pruritus-mediating cells, and central nervous alterations. Similar to cholestatic pruritus, enhanced stimulation of the central m-opioid receptors by cumulated endorphins or cumulated endogenic morphines has been suggested as a cause for CKD-aP. This hypothesis was underlined by the observation in a single study showing a substantial amelioration of itching in uremic patients after the Kidney International
oral application of the m-opioid receptor antagonist naltrexone.5 This positive anti-pruritic effect could, however, not be confirmed in a large-scale study of our group on hemodialysis patients presenting with pruritus. A more recent hypothesis on CKD-aP reported on an imbalance between the activities of the mostly antagonistic acting m- and k-opioid receptors in favor of m-receptor activation. For this reason, application of a k-agonist was recommended for the treatment. More recent research points to microinflammation on skin and probably systemic level as an etiopathologically relevant factor in CKD-aP. In this regard, elevated levels of c-reactive protein were observed in serum of hemodialysis patients with chronic pruritus;24,25 furthermore, relatively increased proinflammatory relevant TH1-cells and raised interleukin-6 concentrations could be detected in these patients by our study group.25 Figure 4 summarizes the potential pathogenic factors in CKD-aP. Treatment options
Pruritus may be extremely vexing at times and difficult to control. Therapeutic options in CKD-aP are, however, limited. Most studies on this symptom are not reliable because of inadequate documentation of patient’s characteristics, concomitant diseases, therapeutic measures taken, and often very low case numbers. Moreover, effects that might be statistically significant may not necessarily be clinically relevant and vice versa. To give an example, a reduction of itch intensity from 8 to 6 on a visual analog scale (VAS), even though not statistically significant, might mean a great improvement in the torture of itch, whereas a reduction from 3.5 to 2.5 may be statistically significant without a subjective improvement for the patient. Owing to a meticulous study by Staender et al. done in 192 patients with pruritus, the minimal clinical important difference is 1.40 for the improvement of pruritus on a VAS ranging from 0 to 10 (personal communication). For future studies, improved strategies for the assessment of itch are required that do better reflect the burden of suffering of our patients. In the following, the most consequential approaches to treatment are presented: Topical treatment Gabapentin Systemic treatment with m-opioid receptor antagonists and k-agonists Drugs with an anti-inflammatory action Phototherapy Acupuncture Others Table 1 summarizes most of the randomized controlled trials on the above-mentioned treatment options. TOPICAL TREATMENT
Daily topical treatment using rehydrating emollients should be regarded as baseline therapy. Addition of cooling 3
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T Mettang and AE Kremer: Uremic pruritus
Table 1 | Selection of most important randomized, placebo-controlled trials in patients with CKD-aP Number of Duration of patients treated treatment Results
Author
Intervention/medication
Design
Gunal et al.31 Razeghi et al.32 Wikstro¨m et al.34 Kumagai et al.35 Peer et al.5 Pauli-Magnus et al.6
Gabapentin 300 mg p.o. three times a week RCT crossover Gabapentin 100 mg p.o. three times a week RCT crossover Nalfurafine 5 mg i.v. three times a week Meta-analysis of two RCTs Nalfurafine 2.5 vs. 5 mg p.o. daily RCT Naltrexone 50 mg p.o. daily RCT crossover Naltrexone 50 mg p.o. daily RCT crossover
Silva et al.37
Thalidomide100 mg p.o. daily
RCT
Duo41
Electro-acupuncture 3 weekly
Che-Yi et al.42
Acupuncture 3 weekly
Ko et al.40 Duque et al.29
Photo therapy (UVB-narrow band) Tacrolimus 0.01%-ointment daily 2 daily
Controlled (sham acupuncture) Controlled (sham acupuncture) Single blinded Vehicle controlled
Chen et al.30
2.2% Gamma linolenic acid–containing ointment 3daily
RCT crossover
25 34 144
4 Weeks 4 Weeks 2–4 Weeks
Highly significant effect Highly significant effect Significant effect
337 15 23
2 Weeks 7 Days 28 Days
29
7 Days
6
2 Weeks
Significant effect Highly significant effect No effect (no difference between placebo and verum) Moderate but significant effect (Po0.05) Significant effect
40
1 Month
Significant effect
21 22
6 Weeks 4 Weeks
17
2 Weeks
No significant effect No significant difference between vehicle and verum Significant effect (Po0.0001)
Abbreviations: CKD-aP, chronic kidney disease-associated pruritus; i.v., intravenous; RCT, randomized controlled trial; UVB, ultraviolet light B.
substances such as menthol to emollients may further improve its antipruritic effect. However, properly controlled studies are lacking. Tacrolimus ointments
Topical treatment with tacrolimus has been shown to completely or partially resolve eczema and pruritus in atopic dermatitis.26 As microinflammatory processes may be involved in the pathogenesis of CKD-aP, we tested this drug in a preliminary study of three patients on peritoneal dialysis with severe CKD-aP. Patients applied tacrolimus 0.03% ointment twice daily to the most affected areas for a period of 7 days and scored itch intensity on a VAS before, during, and after treatment. Tacrolimus ointment strongly improved pruritus during treatment period; however, pruritus rose back to baseline values within days after end of treatment.27 Our observation was confirmed in a proof of concept study by Kuypers et al.28 reporting about 25 patients treated with tacrolimus ointment for a period of 6 weeks with a reduction of itch intensity by 43%. A more recent doubleblind, vehicle-controlled study conducted on 22 hemodialysis patients with pruritus29 showed a strong reduction of itch intensity in both the verum and vehicle group of about 80%. A difference between tacrolimus and vehicle could not be demonstrated. However, the highly unexpected improvement on the basic cream (vehicle) could not be explained by the authors. One should note that no serious adverse reactions were seen in this study using either tacrolimus or the carrier. Gamma linolenic acid ointment
In a study conducted by Chen et al.30, a cream containing high concentrations of gamma linolenic acid (GLA), an essential fatty acid derived from certain plant seed oils, was tested on 17 patients with CKD-aP. In this randomized 4
double-blind, placebo-controlled, crossover study patients were treated for 6 weeks, with a washout period of 2 weeks in between the two treatment phases. Paired analysis showed that the intensity of pruritus was significantly reduced following GLA treatment whereas pruritus scores after placebo treatment revealed a nonsignificant reduction. This investigation suggests that GLA can exert an improved antipruritic effect over vehicle and may serve as a useful adjunct in providing symptomatic relief. It was speculated that the mechanism of action of this therapeutic agent may be the formation of anti-inflammatory acting prostaglandins, which are derived from the ‘prodrug’ GLA. SYSTEMIC TREATMENT Gabapentin and pregabalin.
Gabapentin, an anticonvulsant and centrally acting calcium-channel-blocker, has been shown to exert a pain-modulating effect in patients with neuropathic pain. In a study by Gunal et al.31 involving 25 patients on hemodialysis with CKD-aP, 300 mg of oral gabapentin administered three times weekly for 4 weeks was safe and highly effective in reducing pruritus. Itch intensity as determined by a VAS dropped from 8.4 before treatment to 1.2 after 4 weeks of treatment. Similar results could be obtained in another double-blind, controlled, crossover study treating 34 patients with 100 mg gabapentin orally three times a week.32 Our group has seen comparable beneficial effects in the use of gabapentin. As this drug is largely well tolerated, it should be considered as a promising treatment option in the management of CKD-aP if topical treatment is ineffective. There are a couple of reports that pregabalin is reducing CKD-aP. One recent trial suggests that patients on dialysis not responding to or not tolerating gabapentin might be switched to pregabalin with good success and tolerability.33 Kidney International
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T Mettang and AE Kremer: Uremic pruritus
l-Opioid receptor antagonists Naltrexone. A placebo-controlled, double-blind, cross-
over trial by Peer et al.5 showed that administration of oral naltrexone for 1 week led to an almost complete resolution of pruritus in 15 patients with severe CKD-aP. However, when trying to confirm these results by a 4-week lasting placebocontrolled, double-blind, crossover study in 23 patients with severe CKD-aP, we failed to demonstrate a significant effect of treatment with a daily dose of 50 mg naltrexone compared with placebo. Itch intensity decreased by 29.2% during naltrexone and by 16.9% during placebo treatment as determined by VAS without being statistically significant.6 The findings of Peer et al.5 are in sharp contrast to the results of our study and cannot be explained by differences in patients compliance, naltrexone dose, or study design, as both studies were randomized, placebo-controlled, double-blind, and crossover trials. The studies merely differed as to the intensity of pruritus in the evaluated groups. Although the trial by Peer et al. exclusively concentrated on patients most seriously afflicted with pruritus (mean VAS 10), the mean intensity of pruritus in our patients was found to be VAS 6. This and other differences, for instance, regarding hemodialysis treatment, the material used, divergent lifestyle, eating habits, and environmental circumstances in different parts of the world may well have been involved in causing these contradicting results.
Pentoxifylline
Suggesting that CKD-aP is mediated by systemic microinflammation, we investigated the use of pentoxifylline in seven hemodialysis patients with CKD-aP who did not respond to treatment with gabapentin or ultraviolet light B (UVB)-phototherapy. Pentoxifylline, a weak tumor necrosis factor-alpha inhibitor, was administered at 600 mg intravenously three times a week (at the end of each dialysis session) for 4 weeks. Those patients tolerating the drug experienced an almost complete resolution of pruritus, which continued for at least 4 weeks after cessation of therapy. However, four patients discontinued therapy due to treatment-related or -unrelated health problems.36 Considering the rather modest tolerance of the agent at least with the dose chosen, this approach may only be recommended in severe refractory cases. Thalidomide
Thalidomide, which is currently used as an immunomodulator to treat graft-versus-host reactions and myeloma, suppresses production of tumor necrosis factor-alpha and may therefore be effective in the treatment of CKD-aP.37 A placebo-controlled, crossover, randomized double-blind study of thalidomide for the treatment of refractory uremic pruritus demonstrated improvements in itch scores in approximately 55% of patients in both phases of the trial. Aside from the suppression of tumor necrosis factor-alpha, a centrally abating effect might be responsible for beneficial antipruritic effects.
j-Opioid receptor agonists
As k-opioid receptors primarily mediate m-opioid receptorantagonistic effects, and as k-agonistic drugs are known to suppress morphine-induced itch, it was assumed that these substances might be capable of alleviating pruritus. These substances are likely to act on spinal cord level by inhibiting the itch impulse transmitted by the first neuron. Nalfurafine. Nalfurafine is a highly selective k-opioidreceptor agonist. A meta-analysis of two randomized doubleblind and placebo-controlled studies on a total of 144 hemodialysis patients with CKD-aP corroborated an antipruritic effect of nalfurafine. In these studies, the substance was administered as a short infusion following hemodialysis three times weekly for a total period of 4 weeks. A moderate, but significant effect of nalfurafine could be demonstrated.34 In another randomized, prospective, placebo-controlled phase-III-study a total of 337 hemodialysis patients with pruritus were treated orally with nalfurafine hydrochloride at doses of 2.5 or 5 mg daily for 2 weeks.35 On treatment with the test substance, the itch intensity, measured by VAS (0–100 mm), significantly decreased by 22 (5 mg) and 23 mm (2.5 mg), respectively, after 7 days of application, while it merely dropped by 13 mm in the placebo group. However, the incidence of undesired drug actions (insomnia in particular) was substantially higher in both verum groups (35.1% on 5 mg and 25% on 2.5 mg) compared with the placebo group (16.2%). Moreover, the effect of medication was wearing off fast once treatment was stopped. Kidney International
PHOTOTHERAPY
In the late 1970s, Gilchrest et al.38 reported on the effectiveness of sunburn-spectrum UVB-phototherapy on patients with CKD-aP. Although long-wave UVA radiation treatment did not improve itch intensity, 9 of 10 subjects treated with UVB phototherapy reported a marked reduction in pruritus. Subsequently, a series of studies explored the effectiveness of phototherapy in CKD-aP, particularly using radiation with broadband UVB. According to a meta-analysis by Tan et al.39, the most promising phototherapy for uremic itch is UVB radiation, whereas UVA does not appear to be effective. More recent research suggested that side effects of narrow-band UVB-radiation were less frequent and treatment is just as effective as treatment using broadband UVB. However, in newer studies the effectiveness of narrow-band UVB-radiation could not be verified.40 The risk for skin malignancies following UVB irradiation and long-term systemic immunosuppression remains a matter of debate, especially in immunocompromised patients suffering from advanced disease or in those scheduled to receive immunosuppressive treatment after renal transplantation. Thus, patients should be carefully evaluated before considering UVB therapy. ACUPUNCTURE
An interesting approach to treat CKD-aP is acupuncture. Electro-acupuncture or sham-electro-stimulation was applied 5
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T Mettang and AE Kremer: Uremic pruritus
to six patients on hemodialysis in a blinded manner in a study by Duo41. Patients on acupuncture showed a significantly higher reduction in pruritus determined by a score than the sham-treated patients. In another study, 40 patients with CKD-aP were treated with acupuncture either at the Quchi (LI11) acupoint or at a non-acupoint 2 cm lateral thrice weekly for 1 month. Patients treated using the correct acupoint revealed a substantial reduction in pruritus using a score regarding severity, distribution, and sleep disturbance ending up with maximum 45 points (38.3±4.3, 17.3±5.5, and 16.5±4.9 start vs. 4 weeks vs. 12 weeks later), whereas pruritus in patients with sham-acupuncture did not change substantially (38.3±4.3, 37.5±3.2 and 37.1±5 start vs. 4 weeks vs. 12 weeks later).42 Given these results, acupuncture at least in experienced hands might be a useful tool in the treatment of CKD-aP. OTHERS
Many other substances such as orally applied activated charcoal, erythropoietin, and ondansentron have been reported to be effective in case reports or case series, however, their beneficial effects could not be proven in randomizedcontrolled trials.43 Treatment of CKD-aP remains a frustrating endeavor and continues to present a significant therapeutic challenge. Besides topical treatment, gabapentin, immunomodulatory
Exclusion of other causes for pruritus
Assessment of severity of pruritus
Moisturing ointment oil bath
Weak
drugs, and kappa-receptor agonists may be helpful in severe cases. A stepwise approach is suggested in choosing a therapeutic modality, and whenever possible, treatment should be initiated with the drug exhibiting the most favorable safety and efficacy profiles (Figure 5). In desperate cases patients principally eligible for a kidney transplant may be switched to ‘high urgency’ status, which will decrease their waiting time. In most cases, successful kidney transplantation will relieve patients from CKD-aP.44 Figure 5 shows a potential therapeutic algorithm of CKD-aP. PERSPECTIVES
During the last decade basic research on pruritus has considerably emerged. Besides novel insights into central itch processing, peripheral itch-signaling neurons, receptors, and intracellular signaling pathways could be identified. It became apparent that different forms of itch are conveyed by distinct pathways and that various mechanisms and factors are involved in the pathogenesis of pruritus.45 Beside mast cells, eosinophilic granulocytes may contribute on skin level to itch by release of neurotrophins, neuropeptides, and their cytotoxic granule proteins. Another interesting approach would be to study the role of novel receptors being involved in itch induction such as the mas-related G-protein coupled receptors being activated by histamine and the anti-malaria drug chloroquine, the protease-activated receptors 2 and 4, which can be altered by exogenous and endogenous proteases and the recently described histamine-4-receptor. Which of those cells and receptors may have a role in CKD-aP warrant further investigations. Thus, development of a causal pharmacological treatment for those patients remains on the distant horizon. DISCLOSURE
Severe Quality of dialysis (Kt/V)
KtV < 1.2
KtV > 1.2
Increase dose of dialysis
TM has served as a scientific consultant for FMC and received speakers honorary from Roche, Amgen, Sanofi, and Baxter. AEK declared no competing interests.
Persisting
REFERENCES 1.
Moisturing ointment /oil bath
2.
and Gabapentin 100-300 mg
or
UVB phototherapy or
Charcoal Nalfurafine or (6g/die) 2.5 – 5.0 mg p.o.
Persisting
3.
4. 5.
Naltrexone
or
Tacrolimus ointment
or
(Electro-) acupuncture
6.
Persisting
7. Consider kidney transplantation
Figure 5 | Therapeutic algorithm in chronic kidney disease-associated pruritus (CKD-aP). Kt/V, urea clearance in relation to urea distribution volume; UVB, ultraviolet light B. 6
8. 9.
Pisoni RL, Wikstro¨m B, Elder SJ et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2006; 21: 3495–3505. Weisshaar E, Matterne U, Mettang T. How do nephrologists in haemodialysis units consider the symptom of itch? Results of a survey in Germany. Nephrol Dial Transplant 2009; 24: 1328–1330. De Marchi S, Cecchin E, Villalta D et al. Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 1992; 326: 969–974. Balaskas EV, Uldall RP. Erytropoietin does not improve uremic pruritus. Perit Dial Int 1992; 12: 330–331. Peer G, Kivity S, Agami O et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348: 1552–1554.14. Pauli-Magnus C, Mikus G, Alscher DM et al. Naltrexone does not relieve uremic pruritus: results of a randomized, placebo-controlled crossoverstudy. J Am Soc Nephrol 2000; 11: 514–519. Narita I, Alchi B, Omori K et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006; 69: 1626–1632. Ponticelli C, Bencini PL. Uremic pruritus: a review. Nephron 1992; 60: 1–5. Gilchrest GA, Stern RS, Steinman TI et al. Clinical features of pruritus among patients undergoing maintenance hemodialysis. Arch Dermatol 1982; 118: 154–156. Kidney International
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10.
11. 12.
13. 14.
15.
16.
17. 18.
19. 20.
21.
22.
23. 24. 25.
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