Sodium Thiosulfate

Nature Clinical Practice Nephrology | Skin problems in chronic kidney ...
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http://www.nature.com/nrneph/journal/v5/n3/full/ncpneph1040.html
REVIEW
Nature Clinical Practice Nephrology (2009) 5, 157-170
doi:10.1038/ncpneph1040
Received 9 July 2008 | Accepted 16 December 2008 | Published online: 3 February 2009
Skin problems in chronic kidney disease

Dirk RJ Kuypers About the author
Correspondence Department of Nephrology and Renal Transplantation, University Hospitals
Leuven, Herestraat 49, B-3000 Leuven, Belgium
Email dirk.kuypers@uz.kuleuven.ac.be
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Upon 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.
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SUMMARY
Skin disorders associated with chronic kidney disease (CKD) can markedly
affect a patient's 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 -opioidreceptor 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
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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.
REVIEW CRITERIA
An 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.
Keywords: calcific uremic arteriolopathy, calciphylaxis, nephrogenic
fibrosing dermopathy, nephrogenic systemic fibrosis, uremic
pruritus
INTRODUCTION
A wide variety of skin diseases occur in patients with chronic kidney disease
(CKD; Box 1).1, 2, 3 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% prevalence in dialysis
populations, skin disorders are frequently the subject of patients' complaints.1 A
basic knowledge of the dermatological conditions that can arise in the setting of
kidney disease is, therefore, very useful to practicing nephrologists. Skin
diseases have a considerable negative effect on a patient's 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 disorders 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 patient's life. In this Review
we discuss uremic pruritus (UP), an ongoing therapeutic challenge in patients
with CKD. In addition, we discuss calcific uremic arteriolopathy (CUA) and
nephrogenic systemic fibrosis (NSF), which are potentially dangerous skin
diseases that require prompt clinical identification and treatment. Finally,
acquired perforating dermatosis (Kyrle disease) and porphyria cutanea tarda are
briefly described.
BOX 1 SKIN DISORDERS IN PATIENTS WITH CHRONIC KIDNEY
DISEASE.
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perpigmentation
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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UREMIC PRURITUS
EPIDEMIOLOGY AND CLINICAL CHARACTERISTICS
The prevalence of UP has declined in the past 10 years as a result of
improvements in dialysis and the development of biocompatible dialysis
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.5, 6, 7
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 generalized 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 negative 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 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.
PATHOPHYSIOLOGY
The pathophysiology of UP is complex and many uremic and nonuremic factors
contribute to its development. Two hypotheses on the underlying
pathophysiological mechanisms of UP have been postulatedthe
immunohypothesis 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 exposure on UP,
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and those that have shown amelioration of UP with thalidomide treatment or

calcineurin inhibitors such as tacrolimus.4, 8 UVB phototherapy has been
shown to attenuate the development of TH1-type lymphocytes in favor of
TH2-type lymphocyte differentiation, and hence to decrease the production of
interleukin (IL) 2.11 The number of CXC chemokine receptor 3 (CXCR3)expressing and interferon secreting CD4+ cells (which indicate TH1 cell
differentiation) is significantly higher in patients on dialysis with UP than in
those without UP.12 In addition, serum levels of inflammatory biomarkers, 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
endogenous opioidergic system, with overexpression of opioid -receptors in
dermal cells and lymphocytes.14 Overactivity of the opioid -receptor (and
concomitant downregulation of opioid -receptors) might be caused by the
increased serum -endorphin to dynorphin A ratio observed in patients with
CKD and could explain the development 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 hemodialysis.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 pathogenesis of UP, as
itching frequently accompanies severe secondary hyperparathyroidism and an
elevated calciumphosphate product. The lack of consistent correlation between
levels of parathyroid hormone, calcium and phosphorus and UP severity,
however, indicates that other factors are more important in the pathogenesis of
UP.18, 19, 20
Histamine, which is released from mast cells in response to substance P, has
also been implicated 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-hydroxytryptamine [5-HT]) levels in patients on dialysis with UP
is still being debated, however, as clinical trials of selective inhibitors of the
5-HT3 receptor have yielded conflicting results.23, 24
Xerosis (dry skin) can facilitate the development 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.
TREATMENT
General measures to control UP in patients on dialysis include optimization of
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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 In
patients with CKD, cases of pruritus caused by liver diseases (e.g. hepatitis),
primary skin diseases (e.g. atopic dermatitis, contact dermatitis, psoriasis and
urticaria) and endocrine disorders (e.g. Graves disease, hypothyroidism and
diabetes mellitus) require specific treatments. 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).
Figure 1 Step-up therapeutic approach for uremic pruritus in a
patient with chronic kidney disease.
a Use
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.
Full figure and legend (82K)
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Topical treatments
Topical treatments for UP include skin emollients, 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 additives is preferable. Many other topical preparations have shown
beneficial effects on UP and they can be tried in cases where simple emollients
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 polidocanol and creams that contain natural lipids and
endocannabinoids.29, 30, 31
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 dialysis while exhibiting no adverse effects.32, 33 Although topical capsaicin
might be useful for the treatment 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
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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 treatments
Systemic treatments that have been used in UP include ultraviolet light,
gabapentin, opioid receptor antagonists and agonists, antihistamines, activated
charcoal, 5-HT3 antagonists, immunomodulators and erythropoietin.
Ultraviolet light, particularly broadband UVB (wavelength 280315 nm) is an
effective treatment for UP and is well tolerated aside from occasional instances
of sunburn.39 The duration of 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 radiation requires
serious consideration, particularly in patients with a fair complexion (skin
phototypes 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 dialysis session.42, 43 Attention must be paid to
neurotoxic adverse effects such as dizziness, somnolence and coma, and a low
starting dose of 100 mg is advocated. Other reported adverse effects of
gabapentin include fatigue and nausea.
Naltrexone, an oral -opioid-receptor antagonist, effectively reduced the severity
of UP in a randomized, cross-over trial in patients on dialysis.17 A large placebocontrolled trial could not, however, confirm a significant difference in efficacy
between naltrexone and placebo treatments.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
significantly 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 butorphanol, a -opioid-receptor agonist and -opioidreceptor antagonist, reduced the severity of intractable pruritus.4
Classical antihistamines have a limited beneficial 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
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significantly reduce pruritus symptoms in patients on chronic dialysis.46, 47

This well tolerated and inexpensive 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 immunomodulator, 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
reproductive 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 erythropoietin
induced a reversible reduction in plasma histamine concentrations and a
simultaneous decrease in pruritus score.50
CALCIFIC UREMIC ARTERIOLOPATHY (CALCIPHYLAXIS)

CUA, or calciphylaxis, is a potentially life-threatening vasculopathy of the skin
and subcutaneous 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, 52The reported incidence of CUA has increased over
the past 10 years as a result of improved clinical awareness.53, 54, 55
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 anticoagulants.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 glucocorticosteroids.51, 53, 55
CUA has an insidious onset that is marked by the occurrence of livedoreticularis-like skin lesions predominantly on the abdomen, 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
hypotensive 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, 53, 54, 55
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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.
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 preferable but skin biopsies must be obtained with
caution as they might produce nonhealing ulcerations. The histological lesions
characteristically 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
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.
Radiological assessment with xerography (the X-ray technique used in

mammography) might reveal small-vessel calcifications and measurement of
transcutaneous oxygen saturation can confirm underlying tissue ischemia.57, 58
In some patients with CUA, a technetium-99m methylene 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 peripheral vascular disease, systemic vasculitis,
cryoglobulinemia, cholesterol embolization, pyoderma gangrenosum, oxalosis
and benign nodular calcification (a common condition in patients with CKD).
PATHOPHYSIOLOGY
CUA is thought to involve an imbalance between inducers and inhibitors of
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calcification of the vascular wall.60, 61, 62 In affected patients, the expression of

osteopontin and bone morphogenic 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) osteoblast-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
osteoprotegerin) are suppressed (via the nuclear factor B cascade) by the
inflammatory changes encountered in uremia.61, 66 In addition, the actions of
the matrix -carboxyglutamate (Gla) protein can be inhibited by coumarininduced inhibition of vitamin-K-dependent carboxylation, which results in
increased vascular calcifications.67 Loss of pyrophosphate (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 calcification by coexisting disturbances
of calcium and phosphate metabolism, the use of vitamin D analogs,
hyperparathyroidism, 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
triggers 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 devastating disease.
TREATMENT
The primary measures used to treat CUA focus on intensive wound care
(including repeated surgical resections of necrotic tissue) and provision 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 patient's 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 discontinuation of vitamin D analogs. In the presence of
elevated intact parathyroid hormone levels, urgent parathyroidectomy might be
necessary.69, 70 Case reports have described the calcimimetic 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, calcimimetic therapy can be
attempted. Vitamin K supplementation is advised in patients with coumarinassociated 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 endothelial 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
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the successful use of intraperitoneal sodium thiosulfate in a patient with CUA.74

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.
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.75, 76, 77 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 structurally 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 neoangiogenesis and collagen
formation and improved neutrophil-mediated bacterial killing. Hyperbaric
oxygen therapy has been used successfully in patients with CUA with few
adverse effects.78
NEPHROGENIC SYSTEMIC FIBROSIS

NSF, previously known as nephrogenic fibrosing 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
characterized by painful and debilitating, progressive fibrosis and thickening of
the skin, with occasional 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 international 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 confluence of erythematous lesions ensues
and the skin becomes markedly thickened with a woody texture and brownish
peau d'orange (orange-peel) indurations; these changes increasingly restrict the
movement of adjacent joints, which results in contractures and
immobilization79, 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
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burning sensation or muscle weakness. Although NSF does not directly cause
death, its debilitating course can induce secondary complications that
ultimately lead to prolonged hospital stays and are associated with a 30%
mortality.79, 81, 82
Figure 5 Nephrogenic systemic fibrosis in a 56-year-old patient.
(A) The typical red discoloration and orange-peel thickening of the
skin (peau d'orange) of the upper arm with a 'woody' texture. (B)
Secondary thrombosis of the arteriovenous fistula in the left arm
(arrow) owing to progressive tightening of the skin. Permission
obtained from Oxford University Press Evenepoel P et al. (2004)
Nephrol Dial Transplant 19: 469473.82 (C) The patient's left hand
is severely affected with limited movement of the digital joints, which
resulted in contractures.
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 erythropoietin.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 hematopoietic stem cells and can trigger an exaggerated, fibrininduced, wound-repair response; both of these events occur in NSF.85 Exposure
to gadolinium-based MRI contrast agents is associated with the development of
NSF in patients with CKD.86, 87, 88, 89
The diagnosis of NSF is made on the basis of a patient's history and medical
examination and is confirmed by skin biopsy (Figure 6). Histology shows a
thickened dermis with pathologic changes that include the marked proliferation
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-fluorodeoxyglucose 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
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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The differential diagnosis of NSF includes systemic sclerosis (scleroderma),

scleromyxedema, eosinophilic fasciitis, lipodermatosclerosis, and to a lesser
extent, graft-versus-host disease, dermatomyositis and amyloidosis.
PATHOPHYSIOLOGY
The role of gadolinium in the development of NSF is now clearly recognized:
exposure to gadolinium before the onset of disease was confirmed in over 95% of
reported cases.86, 87, 88, 89 Free gadolinium ions are highly toxic to tissues,
and, therefore, gadolinium is used in the form of inert chelates bound to large
organic molecules such as diethylenetriaminepentaacetic acid.92 Some
chelating agents dissociate more easily from gadolinium than others. Such
dissociation depends on characteristics of the chelate: configuration
(macrocyclic or linear), charge (ionic or nonionic), thermodynamic stability and
the amount of excess chelate that is present. Metabolic acidosis and high levels
of endogenous 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 function to
60 h in those with a reduced glomerular filtration rate (<15 ml/min/1.73m2);
the increased half-life increases the risk of gadolinium becoming dissociated
from its chelate.92 This increased dissociation is thought to lead to increased
tissue uptake of free gadolinium, particularly in proinflammatory conditions.
Gadolinium in the tissues undergoes phagocytosis by macrophages, which in
turn attract circulating fibrocytes positive for CD34 and procollagen I; the latter
cells can transform into dermal fibroblast-like cells and produce excessive
amounts of mucin constituents such as hyaluronan and sulfated
glycosaminoglycans.94, 95 Transforming growth factor , produced by CD68+
and factor XIIIa+-activated dendritic cells, has also been implicated in this
profibrotic process.94, 95, 96 The hypothesis that increased tissue uptake of free
gadolinium occurs as a result of increased dissociation has been strengthened
by the demonstration that tissue gadolinium levels are 35-fold to 150-fold
higher in patients with NSF than in healthy volunteers exposed to gadolinium
contrast agents.97, 98, 99, 100 Scanning electron microscopy and energydispersive X-ray spectroscopy have confirmed the presence of gadolinium in
tissues of patients with NSF.101
Some degree of renal insufficiency seems to be required for the development of
NSF. The linear, nonionic, gadolinium chelate preparations gadodiamide
(Omniscan; GE Healthcare, Chalfont St Giles, Buckinghamshire, UK) and
gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals,
Montville, NJ) are responsible for over 85% of cases of NSF because these
agents are more likely to dissociate than other preparations. Other
gadolinium-based contrast agents have been implicated in the development of
NSF only rarely (gadoversetamide [OptiMARK; Mallinckrodt, Hazelwood,
MO]) or not at all (gadobenate dimeglumine [MultiHance; Bracco Diagnostics
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Princeton, NJ] and gadoteridol [Prohance; Bracco Diagnostics]).92 The

interval between exposure to a gadolinium-based contrast agent and first signs
of NSF varies greatly, ranging from 2 days to 18 months, which is possibly the
result of variable gadolinium mobilization from bone stores over time.
TREATMENT
At 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 corticosteroids, thalidomide, cyclophosphamide,
sirolimus, ciclosporin, immunoglobulins, topical calcipotriene, psoralen and
ultraviolet A (PUVA) therapy, interferon , sodium thiosulfate, plasmapheresis,
imatinib mesylate and extracorporeal photopheresis (after administration of
8-methoxypsoralen).79, 81, 82, 102, 103, 104, 105, 106 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 awareness 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 prevention of radiocontrastinduced 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 gadolinium 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 gadolinium contrast.92
However, no prospective study has demonstrated a clinical benefit of
hemodialysis in the prevention of NSF. A retrospective analysis published in
2008 suggested that hemodialysis 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 formulated 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 DERMATOSIS

Acquired 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
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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 initiate intense
pruritus with secondary development of scratch marks (Koebner phenomenon).
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 TARDA

Porphyria 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
hyperpigmentation (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 triggered 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
triggered by medications (e.g. amiodarone, tetracyclines and naproxen); this
condition presents in the same way as PCT but differs from PCT in that the
patient's uroporphyrin levels are normal.113
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.
Sun protection is a crucial element of treatment 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
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alcohol.114
CONCLUSIONS
Skin disorders are a common problem in patients with CKD and can seriously
affect the patient's 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 understanding 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
theoretically offer benefits, but prospective studies that investigate this option
are lacking at present.
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
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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
Acknowledgments
The 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.
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Competing interests
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Subject areas under which this article appears: Imaging and radiology | Progression of renal
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thiosulfate. Nephrogenic systemic fibrosis is a devastating condition associated

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Nature Clinical Practice Nephrology | Skin problems in chronic kidney ...

and those that have shown amelioration of UP with thalidomide treatment or

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dialysis efficacy, use of biocompatible dialysis membranes and improvement of

of evening primrose oil rich in essential fatty acids ( -linolenic

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significantly reduce pruritus symptoms in patients on chronic dialysis.46, 47

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Figure 2 Calcific uremic arteriolopathy in a 48-year-old female

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calcification of the vascular wall.60, 61, 62 In affected patients, the expression of

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the successful use of intraperitoneal sodium thiosulfate in a patient with CUA.74

Both intravenous bisphosphonates (e.g. pamidronate and ibandronate) and oral

NEPHROGENIC SYSTEMIC FIBROSIS

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Factors reported to be associated with NSF (without definitive proof) include

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Full figure and legend (182K)

The differential diagnosis of NSF includes systemic sclerosis (scleroderma),

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Princeton, NJ] and gadoteridol [Prohance; Bracco Diagnostics]).92 The

ACQUIRED PERFORATING DERMATOSIS

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PORPHYRIA CUTANEA TARDA

Sun protection is a crucial element of treatment for patients with PCT.

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CKD who has been exposed to gadolinium-based contrast agents and

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14. Umueuchi H et al. (2003) Involvement of central -opioid system in the

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18951901 | Article | PubMed | ChemPort |

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280287 | Article | PubMed | ISI | ChemPort |

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81. DeHoratius DM et al. (2006) Nephrogenic systemic fibrosis: an emerging threat

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Nature Clinical Practice Nephrology

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