skin problems in chronic kidney disease

MARCH 2009 VOL 5 NO 3 NATURE CLINICAL PRACTICE NEPHROLOGY 157

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Skin problems in chronic kidney diseaseDirk RJ Kuypers

Continuing Medical Education onlineMedscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please go to http://www.medscape.com/cme/ncp and complete the post-test.

Learning objectivesUpon completion of this activity, participants should be able to: 1 Describe the epidemiology and symptoms of uremic

pruritus.2 Identify the first-line treatment for uremic pruritus.3 Describe the symptoms and prognosis of calcific

uremic arteriolopathy.4 Specify the symptoms and prognosis of nephrogenic

systemic fibrosis.

Competing interestsThe author and the Journal Editor C Harman declared no competing interests. The CME questions author CP Vega declared that he has served as an advisor or consultant to Novartis, Inc.

INTRODUCTIONA wide variety of skin diseases occur in patients with chronic kidney disease (CKD; Box 1).13 These diseases are sometimes related to the underlying renal illness but are more frequently directly or indirectly associated with uremia in its broadest sense. With an almost 100% preva-lence in dialysis populations, skin disorders are frequently the subject of patients complaints.1 A basic knowledge of the dermatological condi-tions that can arise in the setting of kidney disease is, therefore, very useful to practicing nephrologists. Skin diseases have a consider-able negative effect on a patients quality of life. They can induce serious discomfort, anxiety, depression and sleeping disorders and have an overall negative effect on mental and physical health. Although the majority of dermatological

SUMMARYSkin disorders associated with chronic kidney disease (CKD) can markedly affect a patients quality of life and can negatively impact their mental and physical health. Uremic pruritus, which is frequently encountered in patients with CKD, is considered to be an inflammatory systemic disease rather than a local skin disorder. Biomarkers of inflammation are increased in patients with uremic pruritus and an imbalance of the endogenous opioidergic system might be involved in the complex pathogenesis of the disease. Treatment options for uremic pruritus include emollients, topical capsaicin cream, ultraviolet B phototherapy, gabapentin, oral activated charcoal and nalfurafine, a -opioid-receptor agonist. Calcific uremic arteriolopathy is triggered by an imbalance of promoters and inhibitors of vascular calcification, caused by the inflammatory changes that occur in uremia. Promising therapeutic strategies for calcific uremic arteriolopathy include bisphosphonates and intravenous sodium thiosulfate. Nephrogenic systemic fibrosis is a devastating condition associated with the use of gadolinium-based contrast agents in patients with CKD. At present, no therapies are available for this complication. Preventive measures include use of iodine-based contrast agents, particularly in patients with CKD stage 4 and 5. If gadolinium contrast is necessary, administration of low volumes of the more stable macrocyclic ionic types of gadolinium-based contrast agent is advocated. Hemodialysis following gadolinium exposure might offer benefits but evidence is lacking.KEYWORDS calcific uremic arteriolopathy, calciphylaxis, nephrogenic fibrosing dermopathy, nephrogenic systemic fibrosis, uremic pruritus

DRJ Kuypers is a Renal Physician in the Department of Nephrology and Renal Transplantation at University Hospitals Leuven, Leuven, Belgium.

CorrespondenceDepartment of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, [email protected]

Received 9 July 2008 Accepted 16 December 2008 Published online 3 February 2009

www.nature.com/clinicalpracticedoi:10.1038/ncpneph1040

REVIEW CRITERIAAn unrestricted PubMed search was performed using the following search terms: uremic pruritus, itching, itch, uremia, chronic kidney disease, chronic renal failure, end-stage renal disease, dialysis, hemodialysis, peritoneal dialysis, calcific uremic arteriolopathy, calciphylaxis, nephrogenic systemic fibrosis, nephrogenic fibrosing dermopathy, acquired perforating dermatosis, Kyrle disease, porphyria cutanea tarda, pseudoporphyria, skin disorders, and skin disease. All abstracts obtained were screened online for type and content and 403 full-text references were formally reviewed. No date or language restrictions were placed on the search.

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2009 Macmillan Publishers Limited. All rights reserved

158 NATURE CLINICAL PRACTICE NEPHROLOGY KUYPERS MARCH 2009 VOL 5 NO 3


dis orders in CKD are relatively benign, a few rare skin diseases have the potential to cause serious morbidity and mortality. Early recognition of these severe skin disorders and prompt initiation of treatment can dramatically alter their course and even save a patients life. In this Review we discuss uremic pruritus (UP), an ongoing therapeutic challenge in patients with CKD. In addition, we discuss calcific uremic arteriolo pathy

(CUA) and nephrogenic systemic fibrosis (NSF), which are potentially dangerous skin diseases that require prompt clinical identification and treatment. Finally, acquired perforating derma-tosis (Kyrle disease) and porphyria cutanea tarda are briefly described.

UREMIC PRURITUSEpidemiology and clinical characteristicsThe prevalence of UP has declined in the past 10 years as a result of improvements in dialy sis and the development of biocompatible dialy sis membranes.4 However, recent surveys (including the Dialysis Outcomes and Practice Patterns Study [DOPPS], which has assessed more than 18,000 patients) reveal that UP is still present in 4252% of adults with CKD.57 These statistics show that UP remains an important clinical symptom and health issue in patients with CKD.

In some patients, UP occurs intermittently and lasts only several minutes, but other patients suffer from prolonged periods of severe pruritus, which can occur throughout the day and night.6 The occurrence, duration and intensity of UP can change over time and the itching is usually worst at night. The areas most commonly affected by UP are the back, limbs, chest and head, but 2050% of patients experience general-ized pruritus.5 External heat, sweat and stress can aggravate UP, and cold or hot showers can alleviate symptoms.4 Contradictory reports have been published on the acute effect of dialysis on UP; some studies have shown that the itch worsens during dialysis sessions while others have shown an immediate beneficial effect of dialysis on UP.5,8 The type of biocompatible dialysis membrane does not seem to affect the incidence of UP, but a recent, noncontrolled study showed the use of polymethylmethacrylate high-flux dialysis membranes to be associated with a significant reduction in pruritus score.9

UP has a substantial effect on quality of life, as it causes serious discomfort, anxiety, depression and sleeping disorders. Sleeping disorders cause chronic fatigue, are associated with disturbance of day and night rhythm and they have a nega-tive influence on mental and physical capacity.4 Recently, both a Japanese study and the DOPPS demonstrated an association between UP and an increased risk of mortality.5,10 This effect was lost in the DOPPS when sleep quality was incorporated into the multivariate analysis. Nevertheless, although UP might not be directly

Box 1 Skin disorders in patients with chronic kidney disease.

Hyperpigmentation

Pallor

Xerosis

Ichthyosis

Pruritus

Prurigo nodularis

Acquired perforating dermatosis (Kyrle disease)

Bacterial, fungal and viral infections (e.g. with Streptococcus species, Staphylococcus aureus, Tinea infections, herpes zoster)

Purpura

Porphyria cutanea tarda

Pseudoporphyria

Calcific uremic arteriolopathy (calciphylaxis)

Benign nodular calcification

Half-and-half nails

Koilonychia

Transverse leukonychia

Onychomycosis

Onycholysis

Splinter hemorrhages

Subungual hyperkeratosis

Brittle hair

Sparse body and scalp hair

Alopecia

Red eyes (pingueculitis)

Angular cheilitis

Uremic frost

Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy)

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MARCH 2009 VOL 5 NO 3 KUYPERS NATURE CLINICAL PRACTICE NEPHROLOGY 159


causally linked with mortality it is increasingly recognized as an indicator of excess mortality risk in patients with CKD.10

UP often leads to considerable mechanical skin damage as a result of continuous scratching, with excoriations, superimposed infections and chronic lesions of prurigo nodularis or skin lichenification often occurring.7 Despite these findings, UP remains an underappreciated complication that adversely affects the quality of life of many patients with CKD.

PathophysiologyThe pathophysiology of UP is complex and many uremic and nonuremic factors contribute to its development. Two hypotheses on the under-lying pathophysiological mechanisms of UP have been postulatedthe immuno hypothesis and the opioid hypothesisand these have been strengthened somewhat by the results of clinical trials.

The immunohypothesis considers UP to be an inflammatory systemic disease rather than a local skin disorder. This idea is supported by studies that have demonstrated beneficial effects of ultraviolet B (UVB) radiation expo-sure on UP, and those that have shown ameliora-tion of UP with thalidomide treatment or calcineurin inhibitors such as tacrolimus.4,8 UVB phototherapy has been shown to attenuate the develop ment of TH1-type lymphocytes in favor of TH2-type lymphocyte differentiation, and hence to decrease the production of inter-leukin (IL) 2.11 The number of CXC chemokine receptor 3 (CXCR3)-expressing and interferon secreting CD4+ cells (which indicate TH1 cell differ entiation) is significantly higher in patients on dialysis with UP than in those without UP.12 In addition, serum levels of inflammatory bio markers, such as C-reactive protein and IL-6, are increased in patients with UP, which confirms the inflammatory nature of the disease.12 The increased mortality risk associated with UP that was observed in epidemiological surveys might be explained by the inflammatory state, and implicates UP as a potentially novel marker of malnutrition inflammation atherosclerosis (MIA) syndrome, a known risk factor for death in dialysis populations.13

The opioid hypothesis proposes that UP is partly a result of changes in the endo genous opioidergic system, with over expression of opioid -receptors in dermal cells and lymphocytes.14 Overactivity of the opioid -receptor (and

concomitant downregulation of opioid -recep-tors) might be caused by the increased serum -endorphin to dynorphin A ratio observed in patients with CKD and could explain the develop-ment of UP.15 Activation of the -opioid system by administration of a -receptor agonist such as nalfurafine reduces the severity of pruritus in patients on hemo dialysis.16 Use of naltrexone, a -receptor antagonist, has also shown beneficial effects, as described below.17

Parathyroid hormone and divalent ions (e.g. calcium, phosphate and magnesium ions) have also been implicated in the patho genesis of UP, as itching frequently accompanies severe secondary hyperparathyroidism and an elevated calciumphosphate product. The lack of consistent correlation between levels of para-thyroid hormone, calcium and phosphorus and UP severity, however, indicates that other factors are more important in the patho genesis of UP.1820

Histamine, which is released from mast cells in response to substance P, has also been impli-cated in UP; the number of dermal mast cells is increased in patients with CKD and increased plasma levels of tryptase and histamine have been reported in individuals with severe UP.21,22 The role of elevated plasma serotonin (5-hydroxy-tryptamine [5-HT]) levels in patients on dialysis with UP is still being debated, however, as clin-ical trials of selective inhibitors of the 5-HT3 receptor have yielded conflicting results.23,24

Xerosis (dry skin) can facilitate the develop-ment of UP in patients with CKD. Xerosis is caused by atrophy of sweat glands and sebaceous glands, impaired sweat secretion, disturbed dermal hydration, and abnormal arborization of free, cutaneous type C nerve fibers.25,26

The pathophysiological processes that underlie UP are clearly very complex and remain largely unknown. An improved understanding of these mechanisms is urgently required to enable the development of efficient therapeutic strategies for this distressing ailment.

TreatmentGeneral measures to control UP in patients on dialysis include optimization of dialysis efficacy, use of biocompatible dialysis membranes and improvement of the nutritional status of the patient. Adequate control of plasma levels of calcium and phosphorus and the concomitant treatment of secondary hyperparathyroidism can ameliorate pruritus symptoms in some cases.19

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In patients with CKD, cases of pruritus caused by liver diseases (e.g. hepatitis), primary skin diseases (e.g. atopic dermatitis, contact derma-titis, psoriasis and urticaria) and endocrine dis orders (e.g. Graves disease, hypo thyroidism and diabetes mellitus) require specific treat-ments. Available treatment options for UP include both topical and systemic therapies. A step-up therapeutic approach for UP in patients with CKD is presented above (Figure 1).

Topical treatmentsTopical treatments for UP include skin emol-lients, capsaicin cream and tacrolimus. The primary therapy in patients with CKD who have UP is the application of skin emollients with a high water content to hydrate the stratum corneum.27,28 The use of simple emollients that do not contain perfumes or other addi-tives is preferable. Many other topical prepara-tions have shown beneficial effects on UP and

they can be tried in cases where simple emol-lients fail. Such preparations include evening primrose oil (which is rich in essential fatty acids such as -linolenic acid), fish oil, olive oil, safflower oil, bath oil that contains polido-canol and creams that contain natural lipids and endo cannabinoids.2931

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a natural alkaloid found in the chili pepper plant (genus Capsicum), reduces levels of substance P in cutaneous type C sensory nerve endings. Clinical studies have shown that the application of a 0.025% capsaicin cream significantly alleviated UP in patients on dialy sis while exhibiting no adverse effects.32,33 Although topical capsaicin might be useful for the treat-ment of localized disease, it is impractical for large areas or generalized pruritus.

Tacrolimus blocks the differentiation of TH1-type lymphocytes and, therefore, suppresses the production of IL-2. A single-center pilot study in 25 patients on chronic dialysis with UP showed that 6 weeks of treatment with tacrolimus ointment (0.03% for 3 weeks and 0.1% for 3 weeks) significantly reduced the severity of UP without detectable systemic exposure or serious adverse effects.34 However, a subsequent, smaller vehicle-controlled trial showed that relief of UP was the same with the vehicle and with the active drug.35 An FDA black-box warning was issued in 2006 against the prolonged topical use of tacrolimus creams and ointments, on the basis of results from animal studies that showed an increased risk of skin malignancies following use of these agents.36 To date, an excess number of skin malignancies has not been observed with the chronic use of tacrolimus ointment in over 9,800 patients with atopic dermatitis.37,38 The results of larger placebo-controlled trials are awaited, but, in the meantime, use of tacrolimus ointment or cream is not advised for prolonged periods or as a first-line therapy for UP.

Systemic treatmentsSystemic treatments that have been used in UP include ultraviolet light, gabapentin, opioid receptor antagonists and agonists, anti histamines, activated charcoal, 5-HT3 antagonists, immunomodulators and erythropoietin.

Ultraviolet light, particularly broadband UVB (wavelength 280315 nm) is an effective treat-ment for UP and is well tolerated aside from occa-sional instances of sunburn.39 The duration of

Optimize dialysis efficacy and use biocompatible membranesImprove nutritional status

Control calcium and phosphorus concentrationsTreat secondary hyperparathyroidism

Skin emollients with a high water contenta


Capsaicin 0.025% cream


Gabapentin after dialysis (100300 mg)


Oral activated charcoal therapy


Nalfurafineb


Broadband or narrow-band ultraviolet B therapy(810 sessions)

Figure 1 Step-up therapeutic approach for uremic pruritus in a patient with chronic kidney disease. aUse of evening primrose oil rich in essential fatty acids (-linolenic acid), bath oil that contains polidocanol and cream that contains natural lipids and endocannabinoids can be attempted if simple emollients fail. bFor intractable uremic pruritus that does not respond to nalfurafine (5 g intravenously thrice weekly for 4 weeks), treatment with short courses of topical tacrolimus ointment (0.1% for 26 weeks) or oral thalidomide (100 mg daily for 24 weeks) can be attempted.

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the antipruritic effect of thrice-weekly, total-body, UVB phototherapy (810 sessions in total) is variable but can last for several months. The potential carcinogenic effect of ultraviolet radia-tion requires serious consideration, particularly in patients with a fair complexion (skin photo-types III). Narrow-band UVB therapy is less erythemogenic than broadband UVB and also seems to be effective for UP.40,41

Gabapentin, a -aminobutyric acid analog used as an anticonvulsant, significantly reduces the severity of CKD-associated pruritus when given at a dose of 100300 mg after each dialy sis session.42,43 Attention must be paid to neuro-toxic adverse effects such as dizziness, somno-lence and coma, and a low starting dose of 100 mg is advocated. Other reported adverse effects of gaba pentin include fatigue and nausea.

Naltrexone, an oral -opioid-receptor antago-nist, effectively reduced the severity of UP in a randomized, cross-over trial in patients on dialysis.17 A large placebo-controlled trial could not, however, confirm a significant difference in efficacy between naltrexone and placebo treat-ments.44 In 2005, a -opioid-receptor agonist, nalfurafine, was investigated for the treatment of UP in two randomized, double-blind, placebo-controlled trials that included 144 patients on dialysis. Itching intensity, excoriations and sleep disturbances were significantly but modestly reduced in patients who received 2 weeks of treatment with the active compound and no excess of drug-related adverse effects occurred with nalfurafine compared with placebo.16 Continued nalfurafine treatment for 4 weeks did not alleviate worst itch symptoms signifi-cantly more than placebo, which suggested a possible attenuation in the beneficial effects of the drug with continued use. Disadvantages of nalfurafine include the fact that it is currently only available in an intravenous formulation, that symptom relief is potentially incomplete during the interdialytic interval, and that its use is associated with adverse effects of the central nervous system such as sleepiness, vertigo, insomnia, headaches, drowsiness and nausea. In a case series of patients without CKD affected by pruritus, intranasal administration of butor phanol, a -opioid-receptor agonist and -opioid-receptor antagonist, reduced the severity of intractable pruritus.4

Classical antihistamines have a limited bene ficial effect in UP that probably results predominantly from their sleep-inducing side effect.45

Oral use of activated charcoal has been shown to completely resolve or significantly reduce pruritus symptoms in patients on chronic dialy sis.46,47 This well tolerated and inexpen-sive substance can be considered in patients with therapy-resistant UP.

Ondansetron, a selective 5-HT3 antagonist, was used successfully in a small group of patients on peritoneal dialysis with UP, but a subsequent, larger, randomized, placebo-controlled study in hemodialysis patients failed to prove efficacy of ondansetron in the treatment of UP.23,24 Granisetron, another selective 5-HT3 antagonist, was effective and well tolerated for UP in a small noncontrolled study.48

Administration of thalidomide, an immuno-modulator, reduced the intensity of UP by 80% in patients on hemodialysis in a placebo-controlled, cross-over study.49 Owing to its teratogenic properties, however, thalidomide should probably be reserved for individuals with therapy-resistant UP who are not of repro ductive age. In addition, prolonged use of thalidomide can cause severe polyneuropathy.

A small, 10-week, placebo-controlled, crossover study in patients receiving dialysis who had severe pruritus showed that administration of erythro-poietin induced a reversible reduction in plasma histamine concentrations and a simultaneous decrease in pruritus score.50

CALCIFIC UREMIC ARTERIOLOPATHY (CALCIPHYLAXIS)Epidemiology and clinical characteristicsCUA, or calciphylaxis, is a potentially life- threatening vasculopathy of the skin and sub cutaneous tissues that is usually associated with CKD. The incidence of CUA is estimated to be approximately 4% in patients on dialysis and less than 1% in patients with CKD.51,52 The reported incidence of CUA has increased over the past 10 years as a result of improved clinical awareness.5355

Risk factors for the development of CUA include obesity, diabetes mellitus, female sex, white ethnicity, time on renal replacement therapy and the use of coumarin anti coagulants.51,53,55 Other factors reported to be associated with CUA include the use of vitamin D analogs, calcium-containing phosphate binders, iron-substitution therapy and gluco corticosteroids.51,53,55

CUA has an insidious onset that is marked by the occurrence of livedo-reticularis-like skin lesions predominantly on the abdomen,

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buttocks and thighs, all of which are areas with large amounts of subcutaneous fat. Over a period of days or weeks, these lesions transform into painful, subcutaneous, purpuric plaques and nodules and subsequently become necrotic ulcers covered by eschars (dry scabs or sloughs formed on the skin)53 (Figure 2). These areas of ischemic, necrotic skin and subcutaneous fat can extend into deeper tissues including muscle and can become infected. The onset of CUA is often associated with a history of recent trauma, the initiation of coumarin treatment or with hypo-tensive episodes. Less commonly, CUA affects distal extremities such as the hands or lower legs; systemic involvement with ischemic infarction of the bowel, myocardium, brain, optic nerve or muscles, has been reported rarely.51,53 CUA is associated with high mortality, with a 1-year survival rate of 45% and a 5-year survival rate of 35%; death is predominantly the result of infectious complications.51,5355

An early clinical diagnosis of the nonulcerative stage of CUA is very important as it allows the early initiation of therapeutic measures, which improves prognosis. The sudden appearance of painful violaceous plaques and nodules on the trunk or proximal extremities of patients with CKD and those on dialysis who are at risk of CUA should trigger prompt further diagnostic work-up. A histological diagnosis is prefer-able but skin biopsies must be obtained with caution as they might produce nonhealing ulcerations. The histological lesions character-istically involve epidermal ulceration, dermal necrosis, and vascular medial wall calcifications

with subintimal or intimal hyperplasia and fibrosis of small and medium-sized blood vessels in the dermis and subcutaneous tissues56 (Figure 3). Thrombotic occlusion of cutaneous vessels and extravascular calcium depositions are conspicuous. The histological lesions described, including calcifying septal panniculitis, are not pathognomonic for CUA.51,56

Radiological assessment with xerography (the X-ray technique used in mammography) might reveal small-vessel calcifications and measure-ment of transcutaneous oxygen saturation can confirm underlying tissue ischemia.57,58 In some patients with CUA, a technetium-99m methy-lene diphosphate bone scan reveals superficial tracer localization in the subcutaneous tissues as well as visceral tracer activity.59

CUA should be differentiated from coumarin-induced skin necrosis, atherosclerotic periph-eral vascular disease, systemic vasculitis, cryo globulinemia, cholesterol embolization, pyoderma gangrenosum, oxalosis and benign nodular calcification (a common condition in patients with CKD).

PathophysiologyCUA is thought to involve an imbalance between inducers and inhibitors of calcifica tion of the vascular wall.6062 In affected patients, the expression of osteopontin and bone morpho-genic protein 4, both inducers of vascular calcification, is increased in vascular smooth muscle cells and dermal cells, respectively.63,64 In addition, vascular smooth muscle cells in CUA transform into (osteogenic) osteo blast-like cells (via expression of core-binding factor-1) and express bone-related proteins such as osteocalcin, bone sialoprotein, type 1 collagen and osteopontin.61,65 Conversely, some researchers have postulated that production of inhibitors of vascular calcification (e.g. fetuin A and osteo protegerin) are suppressed (via the nuclear factor B cascade) by the inflamma-tory changes encountered in uremia.61,66 In addition, the actions of the matrix -carboxy-glutamate (Gla) protein can be inhibited by coumarin-induced inhibition of vitamin-K-dependent carboxylation, which results in increased vascular calcifications.67 Loss of pyro-phosphate (which inhibits mineralization) from endothelial and vascular smooth muscle cells is associated with an increased risk of CUA in patients with CKD.68 This complex balance can be shifted further in favor of tissue calcifica tion

Figure 2 Calcific uremic arteriolopathy in a 48-year-old female patient on hemodialysis with painful abdominal subcutaneous purpuric plaques and nodules and the start of necrotic ulcerations.

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by coexisting disturbances of calcium and phosphate metabolism, the use of vitamin D analogs, hyper parathyroidism, ischemia and deficiencies of proteins C and S. Indeed, very low protein C or protein S activities have been documented in patients on hemodialysis with CUA who have only slightly diminished protein levels.52 Why CUA develops only in a small number of patients with CKD and what trig-gers it is not clear at present, but the occurrence of various procalcific events in concert with ischemia, inflammation and endothelial injury seems to ultimately lead to the initiation of this deva stating disease.

TreatmentThe primary measures used to treat CUA focus on intensive wound care (including repeated surgical resections of necrotic tissue) and provi-sion of systemic antibiotics and adequate opioid analgesia. In some cases, the use of vacuum dressings can be considered to improve wound healing. Aggressive surgical wound cleaning with autologous split-skin grafting has also been successfully attempted.53,54

Secondary treatment measures include restoring the patients calcium and phosphate balance by use of intensified dialysis (with low-calcium dialysate), the use of non-calcium-based phosphate binders (e.g. sevelamer or lanthanum carbonate), and discontinua-tion of vitamin D analogs. In the presence of elevated intact parathyroid hormone levels, urgent parathyroidectomy might be neces-sary.69,70 Case reports have described the calci-mimetic cinacalcet to be effective for the rapid control of secondary hyperparathyroidism in patients with CUA, with complete healing of skin ulcers.71 For patients in whom urgent surgical parathyroidectomy is contraindicated,

calci mimetic therapy can be attempted. Vitamin K supplementation is advised in patients with coumarin-associated CUA.

Sodium thiosulfate, an inorganic salt, reduces metastatic tissue calcifications by chelating calcium from soft tissues. Sodium thiosulfate also acts as an antioxidant and induces endo-thelial nitric oxide synthesis, which improves blood flow and tissue oxygenation. Intravenous sodium thiosulfate at a dosage of 525 g during dialysis seems to be a successful treatment for CUA in combination with the above-mentioned therapies72,73 (Figure 4). The main dose-limiting adverse effect of sodium thiosulfate is nausea. Sodium thiosulfate treatment should be continued for a sufficiently long period (i.e. weeks to months) in order to maintain an initial positive response. A case study reported the successful use of intraperitoneal sodium thiosulfate in a patient with CUA.74

Both intravenous bisphosphonates (e.g. pamidronate and ibandronate) and oral bisphosphonates (e.g. etidronate) have also been used successfully to treat CUA, with rapid reduction in pain and decreased signs of inflammation.7577 The mechanism of action of bisphosphonates in CUA is unknown, but alterations in ectopic deposition of calcium phosphate, suppression of inflammatory changes and direct inhibition of calcification (via the nuclear factor B cascade) are thought to be involved as bisphosphonates are struc-turally similar to pyrophosphate.61 The use of bisphosphonates in patients with CKD and those on dialysis seems to be relatively safe, but only limited data are available.

Hyperbaric oxygen therapy improves oxygen delivery to damaged tissues and promotes wound healing through increased neoangio-genesis and collagen formation and improved

scsc sc

t

t

t

A B C

Figure 3 Histological skin lesions of calcific uremic arteriolopathy. (A) Hematoxylin and eosin stain (original magnification 100) showing calcification (arrow). (B) Von Kossa stain (original magnification 100) showing calcification (arrow). (C) Hematoxylin and eosin stain (original magnification 100) showing a thrombus. Abbreviations: sc, subcutis; t, thrombus.

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neutrophil-mediated bacterial killing. Hyper-baric oxygen therapy has been used successfully in patients with CUA with few adverse effects.78

NEPHROGENIC SYSTEMIC FIBROSISEpidemiology and clinical characteristicsNSF, previously known as nephrogenic fibro-sing dermopathy, is a scleroderma-like fibrosing disorder that occurs in patients with CKD, renal transplant recipients and patients with acute kidney injury. The condition is character-ized by painful and debilitating, progressive fibrosis and thickening of the skin, with occa-sional involvement of other organs and tissues such as the lungs, heart, liver, esophagus, testes, dura mater and striated muscles.79 The first cases of NSF were reported in 1997, and the inter national NSF registry80 now contains more than 215 confirmed cases. The disorder occurs across all ethnicities and affects men and women equally.

Typically, patients with NSF initially complain of tightening and swelling of the skin of the lower or upper extremities, with light or dark red discoloration of the skin.79,81,82 Lesions usually form in symmetrical patterns on the ankles, lower legs, wrists or forearms and appear as plaques, papules or nodules. Over a period of days or weeks, a progressive conflu-ence of erythematous lesions ensues and the skin becomes markedly thickened with a woody texture and brownish peau dorange (orange-peel) indurations; these changes increasingly restrict the movement of adjacent joints, which results in contractures and immobiliza-tion79,81,82 (Figure 5). The lesions expand proximally; they usually spare the head but occasionally a marked swelling of the hands

and feet with secondary bullae occurs. Patients complain of painful tightness in the affected limbs and joints and occasionally mention that they have pruritus, a burning sensation or muscle weakness. Although NSF does not directly cause death, its debilitating course can induce secondary complications that ulti-mately lead to prolonged hospital stays and are associated with a 30% mortality.79,81,82

Factors reported to be associated with NSF (without definitive proof) include coagulation abnormalities (e.g. a hypercoagulable state), recent vascular surgery, deep vein thrombosis or a thrombosed arteriovenous access, failure or primary nonfunction of a transplanted kidney, hepatic disease, hyperphosphatemia and the use of high doses of recombinant erythro-poietin.79,81,82 Angiotensin-converting-enzyme inhibitors, on the other hand, might protect against NSF.83,84 High doses of erythropoietin increase numbers of circulating hemato poietic stem cells and can trigger an exaggerated, fibrin-induced, wound-repair response; both of these events occur in NSF.85 Exposure to gadolinium-based MRI contrast agents is associ-ated with the development of NSF in patients with CKD.8689

The diagnosis of NSF is made on the basis of a patients history and medical examination and is confirmed by skin biopsy (Figure 6). Histology shows a thickened dermis with patho-logic changes that include the marked prolifera-tion of spindle cells with interstitial mucin deposition, the presence of thickened collagen bundles and a lack of inflammatory cells. Dendritic cells and histiocytes are present.90,91 Dermal spindle cells stain positive for CD34 and procollagen I and are thought to be derived from circulating fibrocytes that are positive for both CD34 and procollagen I. Metastatic calcifications and even ossifications have been described in some cases. Whole-body PET scans of patients with NSF using 18F-fluorodeoxy-glucose have shown that metabolic activity is increased at the sites of clinical lesions.82 This technique can be used to confirm the diffuse inflammatory skin changes associated with active NSF and theoretically might be useful for evaluating the response to therapy.82

The differential diagnosis of NSF includes systemic sclerosis (scleroderma), sclero-myxedema, eosinophilic fasciitis, lipodermato-sclerosis, and to a lesser extent, graft-versus-host disease, dermatomyositis and amyloidosis.

A B

Figure 4 Calcific uremic arteriolopathy of the abdomen in a 44-year old male patient on hemodialysis. (A) Before treatment and (B) following treatment with intensified hemodialysis, parathyroidectomy and intravenous sodium thiosulfate 20 g thrice weekly for 7 weeks.

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PathophysiologyThe role of gadolinium in the development of NSF is now clearly recognized: exposure to gado-linium before the onset of disease was confirmed in over 95% of reported cases.8689 Free gado-linium ions are highly toxic to tissues, and, there-fore, gadolinium is used in the form of inert chelates bound to large organic mol ecules such as diethylenetriaminepentaacetic acid.92 Some chelating agents dissociate more easily from gado-linium than others. Such dissocia tion depends on character istics of the chelate: configura-tion (macrocyclic or linear), charge (ionic or non ionic), thermodynamic stability and the amount of excess chelate that is present. Metabolic acidosis and high levels of endo genous ions such as Zn2+, Cu2+, Ca2+ and Fe3+ might enhance dissociation of gadolinium from its chelate through the transmetalation process.92,93

Under normal circumstances, gadolinium-based contrast agents are eliminated by the kidney through glomerular filtration. The half-life of these agents increases from approximately 1.3 h in individuals with normal renal func-tion to 60 h in those with a reduced glomer-ular filtration rate (



TreatmentAt present, NSF has no effective treatment. Numerous anecdotal reports that described various medical therapies have been published, but none provides convincing evidence of a generally applicable treatment for NSF. Therapies that have been tested include cortico-steroids, thalidomide, cyclophosphamide, sirolimus, ciclosporin, immunoglobulins, topical calcipotriene, psoralen and ultraviolet A (PUVA) therapy, interferon , sodium thio-sulfate, plasma pheresis, imatinib mesylate and extracorporeal photopheresis (after administra-tion of 8-methoxypsoralen).79,81,82,102106 In cases of NSF associated with acute kidney injury, restoration of renal function is a primary goal. Physiotherapy, deep-tissue massage and swimming are advocated in all patients with NSF in order to maintain mobility and prevent contractures.

At present, prevention of NSF seems more important than any of the currently available interventions and widespread clinical aware-ness of this condition is required.107 The use of gadolinium contrast should be limited to an

absolute minimum in patients with CKD; low osmolar or iso-osmolar iodine-based contrast agents provide a valid alternative to gadolinium-based agents in most instances.91 Some prophylactic strategies for the preven-tion of radiocontrast-induced nephropathy are available, but these methods are not always effective.108 In cases where administration of gadolinium-based contrast is necessary, use of the lowest doses of the more stable types of gadolinium-based contrast agent, such as gadobenate dimeglumine, is advisable.92

Gadolinium contrast is readily cleared by hemodialysis, with 92% of administered gado-linium eliminated after two dialysis sessions (and 99% after three sessions).92 Such a strategy could, therefore, be considered in patients with stages 4 and 5 CKD who require MRI with gado-linium contrast.92 However, no prospective study has demonstrated a clinical benefit of hemo-dialysis in the prevention of NSF. A retrospec tive analysis published in 2008 suggested that hemo-dialysis helped to prevent NSF in patients with an estimated glomerular filtration rate below 15 ml/min/1.73m2 who received high doses of gadolinium-based contrast agent.109 Peritoneal dialysis is not effective for the elimination of gadolinium.110 Patients with stages 4 or 5 CKD should be informed about the benefits and risks of receiving gadolinium-based contrast agents for diagnostic procedures.

No consensus guidelines have yet been formu-lated regarding gadolinium contrast use for patients with stage 3 CKD, but avoidance of large volumes of linear, nonionic, gadolinium-based contrast agent seems advisable. Whether prompt dialysis after exposure would be beneficial in this particular group of patients is even less clear than it is for those with stages 4 and 5 CKD.

ACQUIRED PERFORATING DERMATOSISAcquired perforating dermatitis (APD, also known as Kyrle disease) has a prevalence of approximately 10% in dialysis populations and occurs predominantly in African Americans and patients with diabetes mellitus.111,112 APD is also associated with other entities such as hepatic disease, thyroid illnesses, malignancies, scabies and AIDS. APD is usually characterized by a linear confluence of papules with a central, oystershell-like keratotic plug on the trunk, proximal extremities, scalp and face.111,112 Lesions are red or pink in white patients, and hyperpigmented in black patients. APD can

sc

d

A B

C D

e

Figure 6 Typical histology of skin lesions associated with nephrogenic systemic fibrosis. (A) Hematoxylin and eosin stain (original magnification 25) that shows the thickened dermis. The arrow points to a fibrotic septum between the fat lobules of the subcutis. (B) CD68 immunostain that shows macrophages (original magnification 100). (C) Alcian blue stain that shows mucin depositions (original magnification 100). (D) CD34-immunostained section that shows dermal, fibroblast-like spindle cells (original magnification 100). Abbreviations: d, dermis; e, epidermis; sc, subcutis.

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initiate intense pruritus with secondary develop-ment of scratch marks (Koebner phenom-enon). The origin of APD lesions is not known; suspected causes include an inflammatory skin reaction secondary to the presence of uremic toxins, uric acid deposits or scratching-induced trauma.111,112 Histological changes include the presence of epidermal invaginations with a central, basophilic, keratotic plug, uric acid and calcium hydroxyapatite deposits and chronic inflammatory granulomas.112

Treatment of APD is often frustrating as lesions can persist and chronic scars can develop. Lubricants, steroids, keratolytics, vitamin A, cryotherapy, UVB therapy and oral or topical isotretinoin preparations have all been tried with variable degrees of success.111,112

PORPHYRIA CUTANEA TARDAPorphyria cutanea tarda (PCT) in patients with CKD commonly presents as bullae on the dorsal surfaces of the hands and feet (Figure 7); bullae sometimes occur on the face as well, usually accompanied by facial hyper pigmentation (sclerodermoid plaques) and hypertrichosis.113 Secondary infection of the bullous lesions often occurs and healing of these lesions is associated with scarring. The sporadic form of PCT occurs in approximately 5% of patients on dialysis; this form is caused by increased uroporphyrin concentrations and can be trig-gered by ingestion of alcohol, estrogens or iron and by chronic infections such as hepatitis B, hepatitis C or HIV.113 Typical linear staining of IgG, C3 and fibrin at the dermoepidermal junction is noted on skin biopsy in patients with PCT; blood vessels are surrounded by periodic acidSchiff-positive material with little inflammation.113 Pseudoporphyria is trig-gered by medications (e.g. amiodarone, tetra-cyclines and naproxen); this condition presents in the same way as PCT but differs from PCT in that the patients uroporphyrin levels are normal.113

Sun protection is a crucial element of treat-ment for patients with PCT. Uroporphyrin levels can be lowered by improving dialysis efficacy through use of high-flux membranes.114 Drastic measures to lower uroporphyrin concentrations further (e.g. phlebotomy) are not routinely advocated. Iron or estrogen supplementation should be interrupted during treatment for PCT, vitamin B1 deficiency should be excluded, and patients should abstain from alcohol.114

CONCLUSIONSSkin disorders are a common problem in patients with CKD and can seriously affect the patients physical and mental health and thus their quality of life. A basic knowledge of the most common dermatological entities encountered in CKD will enable renal physicians to optimize daily patient care and to recognize potentially life-threatening conditions. The clinical management of UP remains a challenge, and a more detailed under-standing of its underlying complex mechanisms is required. Further research into the pathological pathways of UP will ultimately provide novel therapeutic strategies with improved efficacy. CUA is a dangerous complication of CKD that requires prompt diagnosis and treatment to alter its devastating course. Emerging new therapeutic options such as the use of bisphosphonates, sodium thiosulfate, calcimimetics and non-calcium-containing phosphate binders seem to have beneficial effects on CUA and hold promise for the future. NSF is now clearly known to be associated with the use of gadolinium-based contrast agents in patients with CKD. The current lack of any efficient therapy for NSF emphasizes the need for intensive campaigns to increase the clinical awareness of this debilitating condition so that it can be prevented whenever possible. Preventive measures, particularly in patients with stages 4 and 5 CKD, include the use of alternative iodine-based contrast agents if possible, or the administration of low volumes of the more stable types of gadolinium-based contrast agent if this type of agent is necessary. In cases of gadolinium exposure, hemodialysis treatment might theoreti-cally offer benefits, but prospective studies that investigate this option are lacking at present.

Figure 7 Porphyria cutanea tarda in a 50-year-old male patient on hemodialysis. Bullae can be seen on the dorsal surface of the second and third fingers and healing lesions can be seen on the dorsal hand.

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KEY POINTS The treatment of uremic pruritus in patients

with chronic kidney disease (CKD) is a difficult process of trial and error. Skin emollients, topical capsaicin and ultraviolet B phototherapy remain the first-line therapies, and systemic therapies such as gabapentin, activated charcoal and nalfurafine are reserved for therapy-resistant forms of uremic pruritus

The appearanceon the abdomen or other regions containing large amounts of subcutaneous fatof livedo-reticularis-like skin lesions that turn into painful subcutaneous plaques or nodules, should raise clinical suspicion of calcific uremic arteriolopathy in a patient with CKD, particularly in the presence of additional risk factors such as obesity, diabetes, female sex and coumarin anticoagulation

The optimal treatment of calcific uremic arteriolopathy includes prompt and simultaneous initiation of aggressive wound care, antibiotics, optimization of dialysis therapy and rapid control of calcium and phosphate balance and secondary hyperparathyroidism; sodium thiosulfate and bisphosphonates can be administered concurrently in severe cases

Nephrogenic systemic fibrosis is highly suspected in a patient with CKD who has been exposed to gadolinium-based contrast agents and complains of painful tightening and swelling of the skin of the lower or upper extremities and has red or hyperpigmented skin plaques or nodules that become increasingly indurated

For patients with stages 4 and 5 CKD who require contrast-enhanced imaging, low-osmolar or iso-osmolar iodine-based contrast agents should be considered as an alternative to gadolinium-based contrast; if administration of gadolinium is absolutely necessary, use of low volumes of the more stable macrocyclic, ionic types of gadolinium-based contrast agent is advised

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AcknowledgmentsThe author would like to thank Professor Dr Evelyne Lerut for providing the histology microphotographs and Dr Kathleen Claes for her assistance in illustrating the clinical cases.Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Competing interests The author declared no competing interests.

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