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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 49 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 51 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- References 1. 2. 52 genic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4): Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. 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Accepted: March 15, 2012 © 2012 Società Italiana di Nefrologia - ISSN 1121-8428