Uremic pruritus

Abstract

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) μ-opioid receptor antagonists and κ-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 μ-opioid-receptor—antagonists (i.e., naltrexone) or κ-opioid-receptor 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. 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) μ-opioid receptor antagonists and κ-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 μ-opioid-receptor—antagonists (i.e., naltrexone) or κ-opioid-receptor 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. 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.Pisoni R.L. Wikström B. Elder S.J. et al.Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2006; 21: 3495-3505Crossref PubMed Scopus (369) Google Scholar The prevalence and the burden of this symptom are often underestimated by nephrologists.2.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: 1328-1330Crossref PubMed Scopus (38) Google Scholar 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.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: 969-974Crossref PubMed Scopus (133) Google Scholar, 4.Balaskas E.V. Uldall R.P. Erytropoietin does not improve uremic pruritus.Perit Dial Int. 1992; 12: 330-331PubMed Google Scholar, 5.Peer G. Kivity S. Agami O. et al.Randomised crossover trial of naltrexone in uraemic pruritus.Lancet. 1996; 348: 1552-1554.14Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 6.Pauli-Magnus C. Mikus G. Alscher D.M. et al.Naltrexone does not relieve uremic pruritus: results of a randomized, placebo-controlled crossover-study.J Am Soc Nephrol. 2000; 11: 514-519PubMed Google Scholar 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. 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.Narita I. Alchi B. Omori K. et al.Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients.Kidney Int. 2006; 69: 1626-1632Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar,8.Ponticelli C. Bencini P.L. Uremic pruritus: a review.Nephron. 1992; 60: 1-5Crossref PubMed Scopus (78) Google Scholar In the remaining patients, CKD-aP seems to affect predominantly back, face, and shunt arm, respectively.9.Gilchrest G.A. Stern R.S. Steinman T.I. et al.Clinical features of pruritus among patients undergoing maintenance hemodialysis.Arch Dermatol. 1982; 118: 154-156Crossref PubMed Scopus (115) Google Scholar 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.Mathur V.S. Lindberg J. Germain M. et al.A longitudinal study of uremic pruritus in hemodialysis patients.Clin J Am Soc Nephrol. 2010; 5: 1410-1419Crossref PubMed Scopus (164) Google Scholar 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. 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. Although in the early days of dialysis treatment, CKD-aP was a very common problem afflicting up to 85% of patients11.Young A.W. Sweeney E.W. David D.S. et al.Dermatologic evaluation of pruritus in patients on hemodialysis.NY St J Med. 1973; 73: 2670-2674PubMed Google Scholar its incidence declined to 50–60% in the late eighties.12.Mettang T. Fritz P. Weber J. Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The role of plasma histamine and skin mast cells.Clin Neprol. 1990; 34: 136-141PubMed Google Scholar However, numbers are difficult to compare as chronic itch has rarely been analyzed and instruments used to assess the intensity of itch diverge. A recent large-scale investigation on several thousand patients reported that >40% of patients undergoing hemodialysis suffer from chronic pruritus1.Pisoni R.L. Wikström B. Elder S.J. et al.Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2006; 21: 3495-3505Crossref PubMed Scopus (369) Google Scholar (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.Schwab M. Mikus G. Mettang T. Urämischer pruritus im Kindes- und Jugendalter.Monatszeitschrift Kinderheilkunde. 1999; 147: 232Google Scholar 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.Mettang T. Fritz P. Weber J. Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The role of plasma histamine and skin mast cells.Clin Neprol. 1990; 34: 136-141PubMed Google Scholar,14.Tessari G. Dalle Vedove C. Loschiavo C. et al.The impact of pruritus on the quality of life of patients undergoing dialysis: a single centre cohort study.J Nephrol. 2009; 22: 241-248PubMed Google Scholar 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.Figure 3Prevalence 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 (χ2 test according to Schwab et al.13.Schwab M. Mikus G. Mettang T. Urämischer pruritus im Kindes- und Jugendalter.Monatszeitschrift Kinderheilkunde. 1999; 147: 232Google Scholar.View Large Image Figure ViewerDownload (PPT) The pathogenesis of CKD-aP remains obscure.15.Mettang T. Pauli-Magnus C. Alscher D.M. Uraemic pruritus—new perspectives and insights from recent trials.Nephrol Dial Transplant. 2002; 17: 1558-1563Crossref PubMed Scopus (126) Google Scholar Various substances have been discussed as potential pruritogens in 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.Massry S. Popovzer M.M. Coburn J.M. et al.Interactable pruritus as a manifestation of secondary hyperparathyroidism in uremia.N Engl J Med. 1968; 279: 697-700Crossref PubMed Scopus (181) Google Scholar,17.Hampers C.L. Katz A.I. Wilson R.E. et al.Disappearence of uremic itching after subtotal parathyreoidectomy.N Engl J Med. 1968; 279: 695-697Crossref PubMed Scopus (117) Google Scholar 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.Stahle-Bäckdahl M. Hägermark O. Lins L.E. et al.Experimental and immunohistochemical studies on the possible role of parathyroid hormone in uremic pruritus.J Intern Med. 1989; 225: 411-415Crossref PubMed Scopus (49) Google Scholar Stockenhuber et al.19.Stockenhuber F. Kurz R.W. Sertl K. et al.Increased plasma histamine in uremic pruritus.Clin Sci. 1990; 79: 477-482Crossref PubMed Scopus (46) Google Scholar 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.Mettang T. Fritz P. Weber J. Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The role of plasma histamine and skin mast cells.Clin Neprol. 1990; 34: 136-141PubMed Google Scholar 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.Weisshaar E. Dunker N. Röhl F.W. et al.Antipruritic effects of two different 5-HT3 receptor antagonists and an antihistamine in haemodialysis patients.Exp Dermatol. 2004; 13: 298-304Crossref PubMed Scopus (61) Google Scholar Interestingly, increased levels of tryptase, another substance released by mast cells were observed in patients with CKD-aP.21.Dugas-Breit S. Schopf P. Dugas M. Baseline serum levels of mast cell tryptase are raised in hemodialysis patients and associated with severity of pruritus.J Dtsch Dermatol Ges. 2005; 3: 343-347Crossref PubMed Scopus (62) Google Scholar 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.Blachley J.D. Blankenship D.M. Menter A. et al.Uremic pruritus: skin divalent ion content and response to ultraviolet phototherapy.Am J Kidney Dis. 1985; 5: 237-241Abstract Full Text PDF PubMed Scopus (119) Google Scholar 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.Szepietowski J.C. Reich A. Schwartz R.A. Uraemic xerosis.Nephrol Dial Transplant. 2004; 19: 2709-2712Crossref PubMed Scopus (65) Google Scholar 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 μ-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 oral application of the μ-opioid receptor antagonist naltrexone.5.Peer G. Kivity S. Agami O. et al.Randomised crossover trial of naltrexone in uraemic pruritus.Lancet. 1996; 348: 1552-1554.14Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar 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 μ- and κ-opioid receptors in favor of μ-receptor activation. For this reason, application of a κ-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.Virga G. Visentin I. La Milia V. et al.Inflammation and pruritus in haemodialysis patients.Nephrol Dial Transplant. 2002; 17: 2164-2169Crossref PubMed Scopus (60) Google Scholar,25.Kimmel M. Alscher D.M. Dunst R. et al.The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients.Nephrol Dial Transplant. 2006; 21: 749-755Crossref PubMed Scopus (146) Google Scholar furthermore, relatively increased proinflammatory relevant TH1-cells and raised interleukin-6 concentrations could be detected in these patients by our study group.25.Kimmel M. Alscher D.M. Dunst R. et al.The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients.Nephrol Dial Transplant. 2006; 21: 749-755Crossref PubMed Scopus (146) Google ScholarFigure 4 summarizes the potential pathogenic factors in CKD-aP. 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 μ-opioid receptor antagonists and κ-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.Table 1Selection of most important randomized, placebo-controlled trials in patients with CKD-aPAuthorIntervention/medicationDesignNumber of patients treatedDuration of treatmentResultsGunal et al.31.Gunal A.I. Ozalp G. Yoldas T.K. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial.Nephrol Dial Transplant. 2004; 19: 3137-3139Crossref PubMed Scopus (204) Google ScholarGabapentin 300mg p.o. three times a weekRCT crossover254 WeeksHighly significant effectRazeghi et al.32.Razeghi E. Eskandari D. Ganji M.R. et al.Gabapentin and uremic pruritus in hemodialysis patients.Ren Fail. 2009; 31: 85-90Crossref PubMed Scopus (80) Google ScholarGabapentin 100mg p.o. three times a weekRCT crossover344 WeeksHighly significant effectWikström et al.34.Wikström B. Gellert R. Ladefoged S.D. et al.μ-Opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies.J Am Soc Nephrol. 2005; 16: 3742-3747Crossref PubMed Scopus (242) Google ScholarNalfurafine 5μg i.v. three times a weekMeta-analysis of two RCTs1442–4 WeeksSignificant effectKumagai et al.35.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: 1251-1257Crossref PubMed Scopus (234) Google ScholarNalfurafine 2.5 vs. 5μg p.o. dailyRCT3372 WeeksSignificant effectPeer et al.5.Peer G. Kivity S. Agami O. et al.Randomised crossover trial of naltrexone in uraemic pruritus.Lancet. 1996; 348: 1552-1554.14Abstract Full Text Full Text PDF PubMed Scopus (248) Google ScholarNaltrexone 50mg p.o. dailyRCT crossover157 DaysHighly significant effectPauli-Magnus et al.6.Pauli-Magnus C. Mikus G. Alscher D.M. et al.Naltrexone does not relieve uremic pruritus: results of a randomized, placebo-controlled crossover-study.J Am Soc Nephrol. 2000; 11: 514-519PubMed Google ScholarNaltrexone 50mg p.o. dailyRCT crossover2328 DaysNo effect (no difference between placebo and verum)Silva et al.37.Silva S.R. Viana P.C. Lugon N.V. et al.Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial.Nephron. 1994; 67: 270-273Crossref PubMed Scopus (145) Google ScholarThalidomide100mg p.o. dailyRCT297 DaysModerate but significant effect (P<0.05)Duo41.Duo L.J. Electrical needle therapy of uremic pruritus.Nephron. 1987; 47: 179-183Crossref PubMed Scopus (84) Google ScholarElectro-acupuncture 3 × weeklyControlled (sham acupuncture)62 WeeksSignificant effectChe-Yi et al.42.Che-yi C. Wen C.W. Min-Tsung K. et al.Acupuncture in haemodialysis patients at the Quchi (LI11) acupoint for refractory uraemic pruritus.Nephrol Dial Transplant. 2005; 20: 912-915Crossref Scopus (91) Google ScholarAcupuncture 3 × weeklyControlled (sham acupuncture)401 MonthSignificant effectKo et al.40.Ko M.J. Yang J.Y. Wu H.Y. et al.Narrowband ultraviolet B phototherapy for patients with refractory uremic pruritus: a randomized controlled trial.Br J Dermatol. 2011; 165: 633-639Crossref PubMed Scopus (65) Google ScholarPhoto therapy (UVB-narrow band)Single blinded216 WeeksNo significant effectDuque et al.29.Duque M.I. Yosipovitch G. Fleischer A.B. 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: 519-521Abstract Full Text Full Text PDF PubMed Scopus (71) Google ScholarTacrolimus 0.01%-ointment daily 2 × dailyVehicle controlled224 WeeksNo significant difference between vehicle and verumChen et al.30.Chen Y.C. Chiu W.T. Wu M.S. Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus.Am J Kidney Dis. 2006; 48: 69-76Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar2.2% Gamma linolenic acid–containing ointment 3 × dailyRCT crossover172 WeeksSignificant effect (P<0.0001)Abbreviations: CKD-aP, chronic kidney disease-associated pruritus; i.v., intravenous; RCT, randomized controlled trial; UVB, ultraviolet light B. Open table in a new tab Abbreviations: CKD-aP, chronic kidney disease-associated pruritus; i.v., intravenous; RCT, randomized controlled trial; UVB, ultraviolet light B. Daily topical treatment using rehydrating emollients should be regarded as baseline therapy. Addition of cooling substances such as menthol to emollients may further improve its antipruritic effect. However, properly controlled studies are lacking. Topical treatment with tacrolimus has been shown to completely or partially resolve eczema and pruritus in atopic dermatitis.26.Gianni L.M. Sulli M.M. Topical tacrolimus in the treatment of atopic dermatitis.Ann Pharmacother. 2001; 35: 943-946Crossref PubMed Scopus (28) Google Scholar 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.Pauli-Magnus C. Klumpp S. Alscher D. et al.Short-term efficacy of tacrolimus ointment in severe uremic pruritus.Perit Dial Int. 2000; 6: 802-803Google Scholar Our observation was confirmed in a proof of concept study by Kuypers et al.28.Kuypers D.R. Claes K. Evenepoel P. et al.A prospective proof of concept study of the efficacy of tacrolimus ointment on uraemic pruritus (UP) in patients on chronic dialysis therapy.Nephrol Dial Transplant. 2004; 19: 1895-1901Crossref PubMed Scopus (76) Google Scholar 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 double-blind, vehicle-controlled study conducted on 22 hemodialysis patients with pruritus29.Duque M.I. Yosipovitch G. Fleischer A.B. 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: 519-521Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar 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. In a study conducted by Chen et al.30.Chen Y.C. Chiu W.T. Wu M.S. Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus.Am J Kidney Dis. 2006; 48: 69-76Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 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 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. 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.Gunal A.I. Ozalp G. Yoldas T.K. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial.Nephrol Dial Transplant. 2004; 19: 3137-3139Crossref PubMed Scopus (204) Google Scholar involving 25 patients on hemodialysis with CKD-aP, 300mg 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 100mg gabapentin orally three times a week.32.Razeghi E. Eskandari D. Ganji M.R. et al.Gabapentin and uremic pruritus in hemodialysis patients.Ren Fail. 2009; 31: 85-90Crossref PubMed Scopus (80) Google Scholar 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.Rayner H. Baharani J. Smith S. et al.Uraemic pruritus: relief of itching by gabapentin and pregabalin.Nephron Clin Pract. 2013; 122: 75-79Crossref Scopus (64) Google Scholar A placebo-controlled, double-blind, crossover trial by Peer et al.5.Peer G. Kivity S. Agami O. et al.Randomised crossover trial of naltrexone in uraemic pruritus.Lancet. 1996; 348: 1552-1554.14Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar 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 placebo-controlled, 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 50mg 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.Pauli-Magnus C. Mikus G. Alscher D.M. et al.Naltrexone does not relieve uremic pruritus: results of a randomized, placebo-controlled crossover-study.J Am Soc Nephrol. 2000; 11: 514-519PubMed Google Scholar The findings of Peer et al.5.Peer G. Kivity S. Agami O. et al.Randomised crossover trial of naltrexone in uraemic pruritus.Lancet. 1996; 348: 1552-1554.14Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar 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. As κ-opioid receptors primarily mediate μ-opioid receptor-antagonistic effects, and as κ-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 is a highly selective κ-opioid-receptor agonist. A meta-analysis of two randomized double-blind 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.Wikström B. Gellert R. Ladefoged S.D. et al.μ-Opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies.J Am Soc Nephrol. 2005; 16: 3742-3747Crossref PubMed Scopus (242) Google Scholar 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 5μg daily for 2 weeks.35.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: 1251-1257Crossref PubMed Scopus (234) Google Scholar On treatment with the test substance, the itch intensity, measured by VAS (0–100mm), significantly decreased by 22 (5μg) and 23mm (2.5μg), respectively, after 7 days of application, while it merely dropped by 13mm in the placebo group. However, the incidence of undesired drug actions (insomnia in particular) was substantially higher in both verum groups (35.1% on 5μg and 25% on 2.5μg) compared with the placebo group (16.2%). Moreover, the effect of medication was wearing off fast once treatment was stopped. Suggesting that CKD-aP is mediated by systemic micro-inflammation, 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 600mg 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.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: 2727-2728Crossref PubMed Scopus (15) Google Scholar 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, 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.Silva S.R. Viana P.C. Lugon N.V. et al.Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial.Nephron. 1994; 67: 270-273Crossref PubMed Scopus (145) Google Scholar 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. In the late 1970s, Gilchrest et al.38.Gilchrest B.A. Rowe J.W. Brown R.S. et al.Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanisms of action.Ann Intern Med. 1979; 91: 17-21Crossref PubMed Scopus (148) Google Scholar 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.Tan J.K.L. Haberman H.F. Coldman A.J. Identifying effective treatments for uremic pruritus.J Amer Acad Dermatol. 1991; 25: 811-818Abstract Full Text PDF PubMed Scopus (50) Google Scholar, 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.Ko M.J. Yang J.Y. Wu H.Y. et al.Narrowband ultraviolet B phototherapy for patients with refractory uremic pruritus: a randomized controlled trial.Br J Dermatol. 2011; 165: 633-639Crossref PubMed Scopus (65) Google Scholar 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. An interesting approach to treat CKD-aP is acupuncture. Electro-acupuncture or sham-electro-stimulation was applied to six patients on hemodialysis in a blinded manner in a study by Duo41.Duo L.J. Electrical needle therapy of uremic pruritus.Nephron. 1987; 47: 179-183Crossref PubMed Scopus (84) Google Scholar. 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 2cm 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.Che-yi C. Wen C.W. Min-Tsung K. et al.Acupuncture in haemodialysis patients at the Quchi (LI11) acupoint for refractory uraemic pruritus.Nephrol Dial Transplant. 2005; 20: 912-915Crossref Scopus (91) Google Scholar Given these results, acupuncture at least in experienced hands might be a useful tool in the treatment of CKD-aP. 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 randomized-controlled trials.43.Manenti L. Tansinda P. Vaglio A. Uraemic pruritus: clinical characteristics, pathophysiology and treatment.Drugs. 2009; 69: 251Crossref PubMed Scopus (71) Google Scholar Treatment of CKD-aP remains a frustrating endeavor and continues to present a significant therapeutic challenge. Besides topical treatment, gabapentin, immunomodulatory 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.Altmeyer P. Kachel H.G. Schäfer G. et al.Normalisierung der urämischen Hautveränderungen nach Nierentransplantation.Hautarzt. 1986; 37: 217-221PubMed Google ScholarFigure 5 shows a potential therapeutic algorithm of CKD-aP. 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.Staender S. Raap U. Weisshaar E. et al.The pathogenesis of pruritus.JDDG. 2011; 9: 456-463Google Scholar 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.