Download The debate between gadolinium versus erythropoietin in a renal

REVIEW
JNEPHROL 2013; 26 ( 01 ) : 48- 54
DOI: 10.5301/jn.5000159
The debate between gadolinium versus
erythropoietin in a renal transplant patient
with nephrogenic systemic fibrosis
Pantea Hashemi 1, Bahram Sina 2, William Rietkerk 1,
Bijan Safai 1
Introduction
Abstract
Nephrogenic systemic fibrosis (NSF), previously known
as nephrogenic fibrosing dermopathy, is a debilitating
skin condition that causes fibrotic changes in the setting of renal failure. Gadolinium-based contrast agents
(GBCA), erythropoietin (EPO), and vascular intervention are the most widely known associated factors in
the pathogenesis. A 53-year-old female with chronic
renal insufficiency secondary to fibrillary glomerulonephritis (FGN) presented with generalized hardening
of skin 1 week after her renal transplant. Due to her
numerous medical and surgical health problems, she
had received six imaging procedures with GBCA with
the last being eight months prior to the onset of her
skin symptoms. She had also historically been treated
with high doses of EPO. Histopathologic examination
was consistent with NSF. In susceptible renal failure patients who develop NSF after GBCA exposure,
the onset of symptoms is usually within a 2-3 month
time frame, which undermines but not eliminates the
proposed role of GBCA in our patient. It can be proposed that despite having various risk factors, while
being exposed to high doses of EPO, vascular trauma during renal transplant facilitated the onset of her
symptoms.
Key words: Erythropoietin, Fibrillary glomerulonephri-
tis, Gadolinium, Nephrogenic systemic fibrosis, Renal
transplant
48
Department of Dermatology, New York Medical College,
New York, NY - USA
2
Department of Dermatology, University of Maryland
Medical Center, Baltimore, MD - USA
1
Nephrogenic fibrosing dermopathy/nephrogenic systemic
fibrosis (NFD/NSF) is a distinct fibrosing disorder that occurs
in patients with renal dysfunction. This disorder is characterized as a process of dermal fibrous hyperplasia highlighted
by an increase in fibrocytes, dermal dendrocytes, and collagen fibers (1). Although the etiologic path and pathogenesis remain uncertain, multiple factors have been reported
in this association. The most frequently reported factor has
been exposure to gadolinium (2, 3) and to a far lesser degree
NFD/NSF has been associated with acute and/or chronic
infections, vascular injury, and impaired calcium metabolism that accompany renal failure. An increasing number of
sources have also discussed erythropoietin (EPO) as a possible etiologic factor (4).
We review a case of NFD/NSF in a 53-year-old woman with
chronic renal insufficiency who presented with generalized
hardening of skin one week after her renal transplant. She
also received large doses of EPO infusion before and after
her transplant. This review highlights the roles of EPO and
gadolinium in the context of other potential factors in the
pathogenesis of NSF.
Review of a case
A 53-year-old woman visited our clinic for a second opinion
regarding her skin tightening, aching joints, and stiffness
with induration of her extremities which commenced one
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 01 ) : 48- 54
Fig. 1 - Histopathologic examination of the lesion from right
thigh reveals normal appearing collagen bundles separated
by clear spaces, and proliferation of spindle-shaped cells in
the thickened dermis (Hematoxylin-eosin x 40).
Fig. 2 - Higher magnification reveals fine collagen bundles
surrounded by clefts with slightly increased mucin (Hematoxylin-eosin x 200).
week after her renal transplant in 2007.
Her past medical history revealed the presence of kidney
stones, pyelonephritis, osteoarthritis, spinal osteoporosis,
traumatic right knee injury, cephalalgia, chronic renal failure,
and protracted anemia. In 1999, her kidney function deteriorated. Histopathologic and electron microscopic assessment of her kidney biopsy at that time revealed mesangial
proliferative glomerulonephritis with deposition of randomly
arranged fibrils in the mesangium and glomerular basement
membrane and negative staining for amyloid confirming the
diagnosis of fibrillary glomerulonephritis (FGN). In addition,
recurrent pyelonephritis of her right kidney in the presence
of vesicouretral reflux, and obstructive uropathy because of
nephrolithiasis further worsened her right kidney function.
This had prompted her care providers to perform a right
nephrectomy to preserve the left kidney function. However,
after further deterioration, her left kidney failed in 2003. She
underwent peritoneal dialysis from 2004 until her kidney
transplant in 2007. A cadaveric renal transplant was performed in May 2007 on her right iliac fossa. Earlier in the
course of the disease, she was diagnosed with hyperparathyroidism and anemia, associated with her chronic renal
failure and treatment with EPO was commenced and continued for many years. She had also received other supplements including ferrous sulfate 325 mg orally three times a
day, 1,25(OH) 2 D3, and phosphate binders (calcium citrate)
during the course of her illness. The patient had a number of
surgeries during this time including right knee replacement,
diskectomy, laminectomy for herniated disks, and spinal fusion. Because of her numerous medical and surgical health
problems, she received a number of imaging procedures
including Magnetic Resonance Imaging (MRI) with gadolinium-based contrast agents (GBCA). There were a total of six
MRI procedures with contrast to assess the lumbar spine
for her back pain. The last MRI with GBCA was performed
eight months prior to the onset of her skin symptoms. Her
medical records indicated a pruritic skin condition consistent with prurigo nodularis present before her renal failure
and worsened during her renal dysfunction. There was no
complaint of skin thickening or joint immobility related to her
cutaneous findings before her transplant.
During her first visit in May 2007, physical examination revealed thickened skin with hyperpigmented, woody-indurated papules and plaques, involving both the upper and lower
extremities. Laboratory workup had revealed impaired renal
function in 2003. A complete blood count in 2007 showed the
continuation of her chronic anemia with hemoglobin of 10-11
g/dL (12-16 g/dL), treated with prolonged high doses of EPO
(10 000 to 20 000 units three times weekly) since 2001.
Two punch biopsies were taken from affected skin on her
right and left thighs during her initial examination. These
biopsies showed normal appearing collagen bundles separated by clear spaces with slightly increased mucin (stained
with colloidal iron), scant inflammatory cells, and increased
CD-34+, spindle-shaped cells (Figs. 1-3) confirming the diagnosis of nephrogenic systemic fibrosis. The dermal spindle
cells were positive for CD34 and procollagen-1, identical to
“circulating fibrocytes” as recently reported (5). Extracorporeal photophoresis commenced in early 2008 and the patient
experienced modest improvement with treatment.
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
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Hashemi et al: Review on nephrogenic systemic fibrosis
Fig. 3 - Higher magnification shows a proliferation of small,
uniform spindle-shaped cells associated with fibrosis and no
significant inflammatory infiltrate (Hematoxylin-eosin x 200).
Discussion
NSF is a sclerosing disorder that affects patients with renal
dysfunction. It was first reported in 2000 as a scleromyxedema-like disease in 15 dialysis patients (6). Since then over
215 cases have been reported (7). Clinically, NSF is characterized by acute onset of hardening and thickening of the
skin, brawny hyperpigmented papules, plaques and nodules predominantly on the extremities followed by trunk, and
rarely the face (8, 9). Unusual presentations, such as localized plaque-like lesions also occur (10). The skin lesions can
progress rapidly, sometimes leading to flexion contractures
around the joints and inability to walk. Reports of cases of
NSF with organ involvement suggest the systemic nature
of this disease, and hence addition of NSF to the nomenclature (11, 12). NSF is an uncommon disorder and its prevalence was reported to be 0.9% in 705 patients with renal
transplant in a recent study (13).
Bone marrow derived circulating fibrocytes (CD34 +) are
proposed to be the main cells in the pathogenesis of NSF
(14). After being stimulated from the bone marrow, they are
recruited into cutaneous tissues where they generate the fibrosis leading to NSF (5, 14). The exact mechanism under
which CD 34+ cells are activated is not clear. However, gadolinium, EPO and other factors have received more attention in the literature.
NSF was originally thought to occur only in hemodialysis
patients (6). Subsequently, it was reported in peritoneal
dialysis patients and transplant recipients who have never
received dialysis (8). Renal insufficiency, characterized by
50
low GFR, remains a major prerequisite for the development
of NSF. However, the absence of NSF in most patients with
renal insufficiency is suggestive of other factors necessary
for its pathogenesis. Furthermore, dialysis does not prevent
the development of NSF (15).
GBCA, which has been historically used as an MRI contrast
agent, has been cited as a triggering factor in the development of NSF in patients with renal insufficiency (16-21).
One theory is based on the premise that the administration of
magnetic resonance contrast agents cause a transient elevation in serum iron. In patients with chronic kidney disease
(CKD) this leads to a marked decrease in total iron binding
capacity and an increase in transferrin saturation and systemic inflammation (22, 23). Gadolinium–mobilized iron can be
directly toxic to tissues by means of induction of oxidative
stress. Thus a combination of free gadolinium, catalytic iron,
systemic inflammation, and oxidative stress may lead to primary injury and subsequent systemic fibrosis (24, 25). On the
other hand, according to the Cowper et al model, deposited
ionic gadolinium may act as an antigen and induce proliferation of fibroblasts (CD34+) in a dose-dependent manner (26,
27). The prolonged half-life and circulation time of GBCA in
patients with renal impairment also increases the likelihood
that ionic gadolinium becomes deposited in tissues. In the
other theory, macrophages after engulfing ionized gadolinium produce free oxygen radicals and cytokines that further
attract circulating fibrocytes to the tissue (28). Interestingly,
GBCA has been detected in skin samples of NSF patients
by means of electron-dispersive x-ray spectroscopy (3, 29).
In addition, a survey of patients enrolled in the International
NSF registry at Yale University (New Haven, Conn) has revealed that more than 95% of patients were exposed to a
gadelinium chelate within 2-3 months prior to the onset of
symptoms (7, 30). Table I presents the time of onset of NSF
symptoms with regard to GBCA in different patient cohorts.
However, there are some documented reports of NSF without an exposure to GBCA, which weaken the argument of
GBCA as the sole element in the development of NSF (31,
32). The low incidence of NSF suggests that various factors
need to occur simultaneously, or in a specific manner, for a
patient to develop the condition. Hence, it is hypothesized
that GBCA intake and some pro-inflammatory conditions,
such as recent surgery, transplant and vascular trauma, are
more likely to induce NSF in patients with renal failure.
Recently, EPO infusion has been identified as a potential risk factor for NSF (4). Patients on hemodialysis with
NSF were reported to have received considerably higher
doses of erythropoietin than dialysis patients without NSF
(4). Development of localized scar-like plaque directly after
intravenous infusion of erythropoietin was also described in
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( 01 ) : 48- 54
Table I
Time frame of NSF symptoms from exposure to GBCA in selected studies
Number of patients
Time span of NSF symptoms
from exposure to GBCA
>100
2-3 months
Grobner T, et al (2)
5
2-4 weeks
Richmond H, et al (61)
5
1-8 weeks
Introcaso CE, et al (62)
2
2-6 months
Khurana A, et al (63)
6
2-8 weeks
Marckmann P, et al (19)
13
2-75 days (median 25)
Wiginton CD, et al (15)
7
3 weeks-18 months
Edward M, et al (27)
6
16-441 days
Lemy AA et, al (13)
5
1 week to 11 months
Wiedemeyer K, et al (64)
1
3 months
Moreno-Romero JA, et al (65)
3
2-8 weeks
Broome DR, et al (21)
12
2-11 weeks
Deo A, et al (66)
3
Within 2 months
Authors
ICNSFR (7)
GBCA = Gadolinium-based contrast agents; NSF = Nephrogenic systemic fibrosis.
a recent case report (10). Erythropoietin is an endogenous
cytokine that stimulates hematopoeisis and activates most
of the cells involved in the pathogenesis of NSF, including
vascular endothelium, smooth muscle cells, mesangial cells,
and platelets (33-38). In a murine model, EPO stimulates angiogenesis in wound healing, and by releasing vasoactive
factors, induces endothelial dysfunction and generates an
exaggerated fibrin-induced wound healing response (39).
EPO also stimulates the production of transforming growth
factor-β1 (TGF-β1) by activated macrophages that have expressed EPO receptor during healing process. TGF-β1 is a
cytokine with profibrotic properties and has been associated
with fibrosis of internal organs (40). In a recent study, TGF-β1
as well as its second messengers Smad 2/3, were postulated
to be involved in the pathogenesis of NSF (41). Specifically,
TGF-β1 has been shown to be increased in the lesions of NSF
patients (42). The mechanism of action of plasma exchange
in the treatment of NSF, by removing the TGF-β1, supports
this hypothesis (43). EPO is also a strong trigger for systemic
release of CD34 proginator cells subsequently recruited into
tissues (4). However, the occurrence of NSF in some patients
with no exposure to exogenous EPO, disputes its role as a
necessary prerequisite in the pathogenesis of NSF.
Other predisposing factors include dialysis, recent vascular procedures, hyperparathyroidism, and administration of
Vitamin D analogs, hypercoagulable states, autoimmune
disorders, and antiphospholipid antibodies (4, 14, 41, 44).
Vascular endothelial cell injury by releasing vasoactive factors and CD34 proginator cells can lead to fibrosis in NSF
patients. Vascular intervention immediately prior to the development of NSF symptoms has been reported in approximately 90% of cases (14). Migration of circulating fibrocytes
to the subcutaneous tissue and areas of endothelial damage results in uncontrolled fibrosis and is the likely reason
most cases of NSF develop following surgical vascular interventions (45). Likewise, hyperparathyroidism stimulates
CD34 progenitor cells that participate in wound healing. Parathyroid hormone (PTH) also leads to elevated calcium production, which has been implicated in the pathogenesis of
osseous metaplasia, seen in the late stages of NSF (32, 46).
Cowper et al. reported the pathologic findings in patients
with NFD/NSF within twenty weeks of the clinical onset and
beyond (1). The characteristic changes in early stage of NSF
include proliferation of small and spindle-shaped CD34 fibrocytes and dendritic cells, thin collagen bundles, increased elastic fibers, and mucin deposition (Figs. 1-3). Older
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428
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Hashemi et al: Review on nephrogenic systemic fibrosis
lesions, however, show less prominent clefts, scant mucin,
and thick collagen fibers alternating with neurovascular and
appendageal structures. Cases with vascular and stromal
calcification, osteoclast-like giant cells, and osseous metaplasia have also been reported (32, 46). A consensus scoring system integrating clinical and histopathologic features
of NSF has recently been created to standardize and facilitate the assessment and diagnosis of NSF (47).
There are variable causes for renal failure associated with NSF
with no predominant or specific subtype (48). Our patient had
fibrillary glomerulonephritis (FGN) in her renal biopsy. FGN
is a rare kidney disorder characterized by infiltration of mesangium and glomerular basement membrane by fibrillary
deposits that are negative on congo-red staining (49-51). A
characteristic finding on electron microscopy is identification
of glomerular deposits of nonbranching, randomly arranged
fibrils, distinguishable from amyloid fibrils by their larger size
and lack of reactivity with congo red (50, 52, 53). Interstitial fibrosis and glomerular sclerosis are commonly seen in biopsy
specimens (52, 53). The outcome for the patient is poor with
progression to end-stage renal disease in half of the cases
(52, 54). Several studies have shown the recurrence of the
disease in renal transplants (55, 56). Interestingly, extraglomerular fibrillary deposits have been observed in the alveolar capillary membrane, pancreas, liver, and spleen of the
affected patients suggesting the systemic nature of FGN (57,
58). Although NSF is a sclerosing disorder rather than infiltrating process, the authors speculate that the development
of NSF in the setting of FGN is likely to be more than mere
coincidence. In addition, the diagnosis of FGN as a cause of
renal failure may be underreported, as electron microscopy is
not routinely performed on biopsy specimens (59).
With reference to the clinical course and the histologic findings, it is concluded that the changes observed in our patient most likely presented an early stage of NSF. The patient
developed new-onset NSF immediately after her kidney
transplant. She had numerous risk factors that preceded or
coincided with the onset of her NSF that made her susceptible to the development of this condition. Most notably, she
received high doses of EPO before and after the transplant.
Chronic renal failure and the associated impaired calcium/
phosphate metabolism, prolonged use of high doses of
EPO, various infections (60), and surgery (44), all proposed
etiologic factors in the pathogenesis of NSF, were documented in her medical record. Furthermore, the patient had
been exposed to GBCA approximately eight months prior to
the onset of her NSF symptoms. In susceptible renal failure
patients who develop NSF after GBCA exposure, the onset
of symptoms is usually within a two to three month time
frame (7, 30) (Tab. I), which undermines but not eliminates
the proposed role of GBCA in our case. Her symptoms, on
the other hand, developed four to five days after her renal
transplant while receiving high doses of EPO. It can be proposed that despite having various risk factors, while being
exposed to high doses of EPO, vascular trauma during renal
transplant facilitated the onset of her symptoms. After this
time, she complained of skin tightening, tethering and swelling of her hands, feet and ankles that commenced distally
and progressed proximally. Her clinical diagnosis was consequently confirmed by histopathology.
In conclusion, the combination of the reviewed factors in a
susceptible patient with renal insufficiency may lead to the
development of NSF. However, the reviewed risk factors of
NSF need to be further investigated in large-scale studies
and compared to their controls to better define their role in
the pathogenesis of NSF.
Acknowledgements
The authors would like to thank Anthony Gaspari MD, chief of
Dermatology at the University of Maryland Medical Center for
his support.
Financial support: None declared.
Conflict of interest statement: Bahram Sina is an expert witness
for General Electric Healthcare. The rest of the authors do not
have any conflicts of interest.
Address for correspondence:
Pantea Hashemi
1901 First Avenue, #1208
New York, NY 10029, USA
[email protected]
ment of nephrogenic fibrosing dermopathy and nephro-
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Accepted: March 15, 2012
© 2012 Società Italiana di Nefrologia - ISSN 1121-8428