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MARCH 2009 VOL 5 NO 3 NATURE CLINICAL PRACTICE NEPHROLOGY 157

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Skin problems in chronic kidney disease
Dirk RJ Kuypers
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Learning objectives
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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INTRODUCTION
A 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
SUMMARY
Skin 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.
Correspondence
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49,
B-3000 Leuven, Belgium
dirk.kuypers@uz.kuleuven.ac.be
Received 9 July 2008 Accepted 16 December 2008 Published online 3 February 2009
www.nature.com/clinicalpractice
doi:10.1038/ncpneph1040
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.
CME
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158 NATURE CLINICAL PRACTICE NEPHROLOGY KUYPERS MARCH 2009 VOL 5 NO 3
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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 PRURITUS
Epidemiology and clinical characteristics
The 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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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 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 T
H
1-type lymphocytes in
favor of T
H
2-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 T
H
1 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-HT
3

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.
Treatment
General 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 treatments
Topical 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 T
H
1-
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 treatments
Systemic treatments that have been used in UP
include ultraviolet light, gabapentin, opioid
receptor antagonists and agonists, anti histamines,
activated charcoal, 5-HT
3
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 membranes
Improve nutritional status
Control calcium and phosphorus concentrations
Treat secondary hyperparathyroidism
Skin emollients with a high water content
a
Skin emollients with a high water content
a
Capsaicin 0.025% cream
Skin emollients with a high water content
a
Gabapentin after dialysis (100300mg)
Skin emollients with a high water content
a
Oral activated charcoal therapy
Skin emollients with a high water content
a
Nalfurafine
b
Skin emollients with a high water content
a
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.
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.
b
For 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-HT
3
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-HT
3
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 characteristics
CUA, 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 tissues
56

(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).
Pathophysiology
CUA 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.
Treatment
The 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
therapies
72,73
(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
sc
sc
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 FIBROSIS
Epidemiology and clinical characteristics
NSF, 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 registry
80
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-
tion
79,81,82
(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
18
F-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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Pathophysiology
The 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 Zn
2+
, Cu
2+
, Ca
2+
and Fe
3+
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 (<15 ml/min/1.73m
2
); the
increased half-life increases the risk of gado-
linium becoming dissociated from its chelate.
92

This increased dissocia tion is thought to lead
to increased tissue uptake of free gadolinium,
particularly in proinflammatory conditions.
Gadolinium in the tissues undergoes phago-
cytosis by macrophages, which in turn attract
circulating fibrocytes positive for CD34 and
procollagen I; the latter cells can transform
into dermal fibro blast-like cells and produce
excessive amounts of mucin constituents
such as hyaluronan and sulfated glycosamino-
glycans.
94,95
Transforming growth factor ,
produced by CD68
+
and factor XIIIa
+
- activated
dendritic cells, has also been implicated in this
profibrotic process.
9496
The hypothesis that
increased tissue uptake of free gadolinium
occurs as a result of increased dissocia tion 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.
97100
Scanning electron microscopy
and energy-dispersive 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 prepara-
tions 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 (gadoverset-
amide [OptiMARK; Mallinckrodt, Hazelwood,
MO]) or not at all (gadobenate dimeglumine
[MultiHance; Bracco Diagnostics Princeton,
NJ] and gadoteridol [Prohance; Bracco
Diagnostics]).
92
The interval between expo-
sure 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.
B C A
Figure 5 Nephrogenic systemic fibrosis in a 56-year-old patient. (A) The typical red discoloration and
orange-peel thickening of the skin (peau dorange) 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 patients left hand is severely affected with limited movement of the digital joints, which
resulted in contractures.
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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 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/1.73m
2
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 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
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 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 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 B
1
deficiency should be excluded, and
patients should abstain from alcohol.
114

CONCLUSIONS
Skin 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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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.
Competing interests
The author declared no
competing interests.
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