Nephrogenic systemic fibrosis (NSF) is a recently described systemic fibrosing disorder that has been reported almost exclusively in patients with renal insufficiency. It was first described by Cowper et al.1 in 2000 as a cutaneous scleromyxedema-like disorder in patients with ESRD and was initially called nephrogenic fibrosing dermopathy.2 Clinical and autopsy data now suggest the presence of a systemic fibrogenic reaction with evidence of involvement of muscle, tendons, diaphragm, testes, cardiac atrium, lungs, and duramater.3 The disease henceforth has been referred to as nephrogenic systemic fibrosis.4
More than 200 cases of NSF have been reported to the Food and Drug Administration and to the NSF registry at Yale University. The estimated prevalence of NSF, however, is likely to be inaccurate because it still is not a widely recognized clinical entity. In addition, subclinical forms of NSF that could be recognized only with a skin biopsy might remain undiagnosed. In this review, we describe novel clinical manifestations of NSF and discuss our views on its pathogenesis. Specifically, we present a general paradigm in which different risk factors may be tied to a common pathogenic mechanism.
CLINICAL AND LABORATORY FEATURES
NSF is a severely disabling systemic fibrosing condition associated with increased morbidity and mortality.5–7 Our observations suggest that clinical features of NSF may include an acute phase that immediately follows exposure to gadolinium-based contrast media (GBCM) and an overlapping chronic phase characterized by progressive fibrosis (Table 1). Features in the acute phase are variably present and mimic systemic inflammatory response syndrome: Fever, hypotension,acute kidney injury, anemia, leukoerythroblastic picture, thrombocytopenia or thrombocytosis, leukocytosis, eosinophilia, monocytosis, elevated γ-glutamyl peptidase, elevated lipase, and elevated D-dimer.8 Decreased total iron-binding capacity, elevated serum ferritin, low serum albumin, and elevated C-reactive protein are invariably present.7 Because many patients have critical illnesses such as sepsis, acute pancreatitis, hepatorenal syndrome, or acute graft dysfunction that precedes NSF, the acute phase of systemic fibrogenesis may go unrecognized. Onset of the chronic phase is also variable: As early as 4 d or as late as several months after GBCM exposure.9 Early cutaneous manifestations in the chronic phase are usually limited to generalized edema followed closely by the development of a plaque-like skin rash with woody induration (Figure 1A). The condition tends to affect either dependent parts of the body, such as extremities or the presacral area, or high blood-flow areas, such as the skin overlying an arteriovenous dialysis fistula.5,6 Facial involvement is very unusual except in severe, advanced cases in which temporal regions of the face may be involved (S. Swaminathan, 2006, personal observation). Moderate to severe pain is more typical. Alopecia, yellowish scleral nodules, hyperpigmentation of extremities, and yellowish discoloration of facial skin are observed in some patients. Additional systemic findings that have been observed in patients with NSF include the development of acute pancreatitis, vascular thrombosis, and frequent infection.5,10 The disease is severely disabling, and many patients become wheelchair dependent or bed bound. Severe depressive illness often ensues, and a significant number of patients quit dialysis.
The diagnosis of NSF is established by performing a deep-skin biopsy from affected areas. Biopsy findings (Figure 1B) that confirm NSF include dermal spindle cell (fibroblast) proliferation (usually CD34+) with frequent extension into subcutaneous tissue, presence of dermal mucin, variable infiltration of CD68+ macrophages, and presence of broad collagen bundles with clefts and fragmented elastin. Osseous metaplasia, osteoclast-like giant cells, and calciphylaxis can be seen in some NSF biopsies.11–13 On a technetium99-diphosphosphonate scan, areas of increased uptake can be observed in muscles.14,15 On magnetic resonance imaging, axial T1- and fat-suppressed T2-weighted images show symmetric skin thickening and soft tissue edema.15
The differential diagnoses of NSF include scleroderma, scleromyxedema, eosinophilic fasciitis, and graft-versus-host disease. An absence of facial involvement and circulating paraprotein, temporal relation to GBCM exposure, and the appropriate clinical context helps in differentiating NSF from these other conditions.
RISK FACTORS FOR NSF
The major risk factors associated with NSF include exposure to GBCM,9,16,17 high-dosage erythropoietin (EPO) therapy,7 elevated parathyroid hormone (PTH),7 hypothyroidism,17 and antiphospholipid antibodies.17 Significant vascular disease is also a risk factor.17 On the basis of current understanding, an interaction of low GFR; exposure to GBCM; and presence of additional risk factors such as high-dosage EPO, elevated PTH, vascular disease, and systemic inflammation seem necessary for the development of NSF in the majority of cases. In this “cumulative risk factor model” proposed by us and detailed in the following section, patients with more cumulative risk (risk factor load) may only need low dosages of GBCM to trigger NSF or vice versa (Figure 2).
IMPAIRED RENAL FUNCTION
NSF is seen in patients both with acute kidney injury and with chronic kidney disease (CKD). No specific cause of kidney disease except hepatorenal syndrome15 has been associated with heightened risk. NSF is seen in patients receiving either hemodialysis or peritoneal dialysis as well as in patients with posttransplantation allograft dysfunction. Singularly, a low GFR is a major prerequisite for NSF to develop. In patients with CKD, on the basis of current reports as well as personal observations, the risk for NSF seems to be limited to those with stage 3 or worse CKD (GFR ≤60 ml/min). Recently, Sadowski et al. reported the risk for NSF after gadolinium exposure at various levels of estimated GFR (eGFR), and in their series, NSF developed predominantly in those with eGFR <30 ml/min.10 NSF also developed in two patients with an apparently higher eGFR in the setting of acute kidney injury, where formula-based estimates for GFR cannot be used. In our personal experience, we have observed, after GBCM exposure, that NSF can develop in patients with an eGFR as high as 40 ml/min. However, imprecision of formula-based eGFR in accurately predicting renal function in stage 3 CKD limits our ability to interpret these findings18 or arrive at a precise and safe cutoff of GFR above which the risk for NSF is negligible.
GADOLINIUM TOXICITY: ROLE OF IRON AND TRANSMETALLATION
In addition to several reports on the epidemiologic association of GBCM exposure and NSF, demonstration of gadolinium in NSF tissues has strengthened the causal link between the two.19 A higher dosage and multiple repeated exposures to GBCM increase the risk for NSF.10 The mechanisms through which administration of GBCM results in toxicity and NSF are still evolving. However, several important clues appear from current published literature. First, overt NSF develops in only 3 to 5% of patients after GBCM exposure.9,10,16 Second, some patients with NSF do not manifest any clinical signs, even when they were previously exposed to GBCM. Third, demonstration of significant quantities of insoluble gadolinium in the skin of patients with NSF, months after GBCM exposure and after extensive tissue processing, suggest that gadolinium might have undergone transmetallation in vivo. This finding is of significance because free gadolinium is toxic.20
Supporting the importance of transmetallation, all NSF cases reported thus far have been associated with linear magnetic resonance contrast agents9,16,21,22 that have inferior thermodynamic stability23–26 and a kinetic or conditional stability that favors transmetallation. The mechanism by which GBCM may undergo transmetallation in vivo or cause toxicity is still under investigation. In an initial report, acidosis was thought to induce gadolinium's dissociation from its chelate16; however, a subsequent report failed to confirm this.9 Administration of magnetic resonance contrast agents is widely known to cause transient (up to 72 h) elevations in serum iron, even in 15 to 30% of healthy volunteers.27,28 Because iron is tightly bound to ferritin and hemosiderin, it has been suggested that its free concentration is insufficient to induce transmetallation of GBCM25,29; however, we recently reported that GBCM administration in patients who have CKD and subsequently develop NSF results in a marked decrease in total iron-binding capacity, iron mobilization, profound transferrin oversaturation, and systemic inflammation.8 In patients with renal insufficiency, several factors may aggravate free iron release, including prolonged retention of GBCM (t½ 13.4 to 89.2 h versus 1.5 h controls),30 additional exogenous treatment with parenteral iron and low total iron-binding capacity secondary to malnutrition, urinary protein (transferrin) loss, sepsis, and chronic inflammation.31–33 Available data suggest that iron is most potent in inducing transmetallation of GBCM because the thermodynamic stability of Fe3+-DTPA-BMA (1021.9) far exceeds the thermodynamic stability constant of gadolinium-DTPA-BMA (1016.9)34 (Table 2).
Gadolinium-mobilized iron can also be directly toxic to tissues through the induction of oxidative stress by Fenton reaction (Figure 3).35 In addition, catalytic iron released by systemic inflammation35 and gadolinium-mediated cellular acquisition of catalytic iron might contribute to the development of NSF.35–38 Thus, a combination of free gadolinium, catalytic iron, systemic inflammation,10 and oxidative stress may result in initial injury and a subsequent systemic-fibrosing illness characteristic of NSF. Recent descriptions19,39 of significant iron and gadolinium deposition in NSF tissues support our findings. Collectively, these observations suggest the development of NSF after GBCM exposure needs not only a prolonged retention of GBCM but also a process by which GBCM induces toxicity, a process whereby iron may play an important role.
ROLE OF EPO, INFLAMMATION, AND VASCULAR INJURY
We and others7,17,40 recently reported that patients with NSF also receive higher dosages of EPO, suggesting that EPO might play a role in pathogenesis. On the basis of our clinical experience with 70 patients with NSF and other available large case series,7,8,17 it is uncommon that patients do not receive any EPO before NSF diagnosis. It is possible that endogenous EPO released during stress-induced erythropoiesis, which could be several hundred-fold,41 or other growth factors that synergize with EPO42 might be important in patients who do not receive exogenous EPO before a diagnosis of NSF. In addition, in applying the cumulative risk model (Figure 1), exogenous EPO may not be a necessary prerequisite in all cases.
There are many compelling reasons for why EPO might participate in the pathogenesis of NSF. Its pleiotropic biologic effects and/or systemic inflammation associated with an EPO-resistant state may be important (Table 3). Theoretically, EPO therapy influences all key elements of the pathogenesis of NSF: Endothelial dysfunction, inflammation, cell proliferation, and wound healing. EPO is a potent cytokine with stimulatory effects on vascular endothelium,43 smooth muscle cells,44,45 and platelets.46 EPO administration induces a release of vasoactive factors such as monocyte chemoattractant protein-1,45,47 endothelin-1,48 thromboxane A2, and selectin.46,49 It can also induce endothelial dysfunction by inhibiting dimethylarginine dimethylaminohydrolase, thereby increasing asymmetric dimethyl arginine.50 Furthermore, EPO is a potent stimulant of endothelial and progenitor cell proliferation,51,52 as well as wound-healing responses53 that are reminiscent of histologic changes seen in NSF. EPO51,52,54 and PTH55 are also strong stimuli for a systemic release of CD34+ progenitor cells, which are known to participate in wound healing.56–58 Vascular endothelial cell injury could similarly contribute to the pathogenesis of NSF by inducing the release of vasoactive factors and CD34+ progenitors,41,59 and in this setting, EPO's detrimental effect on endothelia is further aggravated.60,61 In addition, chronic inflammation62 associated with an EPO-resistant state and high-dosage EPO45,47 might also contribute to the fibrogenesis seen in NSF.
CELLULAR BASIS FOR THE PERSISTENCE OF FIBROSIS IN NSF
As with any other systemic fibrosing condition,63 possible origins of fibroblasts in NSF include resident mesenchymal cell populations, epithelial-to-mesenchymal transition of local epithelia, and bone marrow–derived cells. Cowper and Bucala64 demonstrated that the spindle cells in NSF skin lesions express CD34 and procollagen 1 and suggested that circulating fibrocytes mediate the fibrosis in NSF. Even though the presence of these markers suggests a contribution from circulating fibrocytes, it is important to note that these markers are not unique to fibrocytes65; fibrocyte's contribution to fibrosis is highly variable in different organs66 and is affected by additional factors such as cell turnover rates. Supporting this, Fathke et al.,67 using cross-transplantation (bone marrow) experiments in an EGFP transgenic mouse model, nicely demonstrated that both CD45+ and CD45− bone marrow–derived stem cells contribute to dermal collagen deposition and wound repair. In addition, they observed a role for local dermal cells and endothelial progenitor cells in dermal wound healing. Similarly, using tissue reconstitution experiments with single hematopoietic stem cells (HSC), Ogawa et al.56 showed that HSC significantly contribute to myofibroblast population in tissues. EPO, PTH, and an oxidative stress-induced “stimulated hematopoietic environment”41,51,55,68,69 may thus contribute to fibrosis through increased production of tissue myofibroblasts. It is unknown, however, whether fibrocytes are a necessary intermediate in this process of transformation of HSC into myofibroblasts in vivo; therefore, it is likely that both resident fibroblasts and diverse types of bone marrow–derived cells that are released in response to injury and cytokines such as EPO, including HSC (likely to be the most significant contributor), endothelial progenitor cells, mesenchymal precursors,65 and monocyte-derived cell fibrocytes,64 contribute to fibrogenesis in NSF (Figure 4). Any contribution of epithelial-to-mesenchymal transition to fibrogenesis in NSF, although potentially possible, has not been evaluated. Like other chronic fibrosing disorders, persistent or progressive fibrosis, even after the original trigger is removed, may lead to NSF. This occurrence possibly relates to the concept of a “persistently activated fibroblast phenotype,” which could be mediated by factors such as ongoing chronic endothelial injury in uremia.70,71
TREATMENT
There are no good therapies for the cutaneous symptoms of NSF or, more important, to prevent its associated high mortality; therefore, our first recommendation is prevention. On the basis of the available data and our personal experience, we recommend the following measures for NSF prevention:
Renal function should be checked in all high-risk patients before GBCM administration (age >50 yr; infants; history of renal disease, diabetes, hypertension, or liver disease; and critically ill patients).
Avoid GBCM in patients with an eGFR <40 ml/min.
If clinically indicated and benefits outweigh risks, then use low dosages of GBCM (preferably macrocyclic agents) in patients with an eGFR of 40 to 60 ml/min.
GBCM is absolutely contraindicated in patients who are on peritoneal dialysis, because gadolinium is poorly cleared by the peritoneum.
In patients who are on hemodialysis, GBCM should be administered only if the benefits of obtaining a contrast-enhanced magnetic resonance image substantially outweigh the risk. At the completion of imaging, patients should go directly to the hemodialysis unit for initiation of dialysis, and dialysis treatment should be administered for 3 consecutive days.
Avoid intravenous iron immediately before or after GBCM exposure.
Treatment of NSF involves a multidisciplinary approach. Aggressive physical therapy, pain control, and psychologic support are essential cornerstones of therapy in this severely disabling disease. The severity of pain usually necessitates opiate analgesics. Topical treatments include the use of moisturizers, emollients, and anti-inflammatory creams. Deep tissue massage and hydrotherapy may be helpful. On the basis of potential pathogenic mechanisms, control of PTH levels and limiting administration of EPO and intravenous iron enough to maintain recommended hemoglobin targets are likely to help. Limiting systemic inflammation by decreasing infection episodes such as catheter-related bacteremia may also be beneficial. Other treatment approaches that could result in variable and modest improvements include a combination of hydroxychloroquine and low-dosage steroids (S. Swaminathan, 2006, personal observation), extracorporeal photopheresis, and topical ultraviolet-A therapy. However, none of these options has been uniformly effective in patients with NSF. Renal transplantation that results in a well-functioning allograft usually leads to a substantial resolution of the disease, and maintaining lower cyclosporine and tacrolimus targets may also potentially help in limiting fibrogenesis.72–74 Secondary worsening of NSF after initial improvement but without new GBCM exposure can occur, but the mechanisms involved in these relapses are unclear. No data are available on the benefit of using chelation therapy to remove gadolinium in NSF. A better understanding of the pathogenesis in this devastating disease may lead to new interventions, which may be relevant not only to NSF but other fibrosing conditions.
Disclosures
None.
;)
Figure 1: (A) NSF involving legs and hand. Note the induration, edema, plaque-like rash, and joint contractures. (B) Histopathologic appearance of NSF characterized by dermal spindle cell proliferation with extension into subcutaneous tissue.
Figure 2: Cumulative risk factor model of NSF: Conceptual inverse interaction between gadolinium dosage and risk factors in the pathogenesis of NSF.
Figure 3: Transmetallation of gadolinium chelates by endogenous ions: The role of iron.
Figure 4: Cellular basis for fibrosis in NSF: Interaction of multiple risk factors and central role of hematopoietic stem cells.
Table 1: Components of NSF
Table 2: Potency of various endogenous cations in inducing transmetallation of gadolinium-DTPA-BMAa
Table 3: Potential role of EPO in the pathogenesis of NSF
We thank Cindy Reid for technical editing and graphics assistance.
Published online ahead of print. Publication date available at www.jasn.org.
References
1. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE: Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 356 : 1000 –1001, 2000
2. Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE: Nephrogenic fibrosing dermopathy. Am J Dermatopathol 23 : 383 –393, 2001
3. Ting WW, Stone MS, Madison KC, Kurtz K: Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 139 : 903 –906, 2003
4. Cowper SE: Nephrogenic systemic fibrosis: The nosological and conceptual evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis 46 : 763 –765, 2005
5. Cowper SE: Nephrogenic fibrosing dermopathy: The first 6 years. Curr Opin Rheumatol 15 : 785 –790, 2003
6. Swaminathan S, Leung N: Nephrogenic fibrosing dermopathy: Lessons from the past. Int J Dermatol 45 : 639 –641, 2006
7. Swaminathan S, Ahmed I, McCarthy JT, Albright RC, Pittelkow MR, Caplice NM, Griffin MD, Leung N: Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 145 : 234 –235, 2006
8. Swaminathan S, Horn TD, Pellowski D, Abul-Ezz S, Bornhorst JA, Viswamitra S, Shah SV: Nephrogenic systemic fibrosis, gadolinium, and iron mobilization. N Engl J Med 357 : 720 –722, 2007
9. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS: Nephrogenic systemic fibrosis: Suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 17 : 2359 –2362, 2006
10. Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, Djamali A: Nephrogenic systemic fibrosis: Risk factors and incidence estimation. Radiology 243 : 148 –157, 2007
11. Ruiz-Genao DP, Pascual-Lopez MP, Fraga S, Aragues M, Garcia-Diez A: Osseous metaplasia in the setting of nephrogenic fibrosing dermopathy. J Cutan Pathol 32 : 172 –175, 2005
12. Hershko K, Hull C, Ettefagh L, Nedorost S, Dyson S, Horn T, Gilliam AC: A variant of nephrogenic fibrosing dermopathy with osteoclast-like giant cells: A syndrome of dysregulated matrix remodeling? J Cutan Pathol 31 : 262 –265, 2004
13. Edsall LC, English JC 3rd, Teague MW, Patterson JW: Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy. J Cutan Pathol 31 : 247 –253, 2004
14. Gremmels JM, Kirk GA: Two patients with abnormal skeletal muscle uptake of Tc-99m hydroxymethylene diphosphonate following liver transplant: Nephrogenic fibrosing dermopathy and graft vs host disease. Clin Nucl Med 29 : 694 –697, 2004
15. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA: Gadodiamide-associated nephrogenic systemic fibrosis: Why radiologists should be concerned. AJR Am J Roentgenol 188 : 586 –592, 2007
16. Grobner T: Gadolinium: A specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 21 : 1104 –1108, 2006
17. Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents—St. Louis, Missouri, 2002–2006. MMWR Morb Mortal Wkly Rep 56 : 137 –141, 2007
18. Poggio ED, Wang X, Greene T, Van Lente F, Hall PM: Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol 16 : 459 –466, 2005
19. High WA, Ayers RA, Cowper SE: Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 56 : 710 –712, 2007
20. Spencer AJ, Wilson SA, Batchelor J, Reid A, Rees J, Harpur E: Gadolinium chloride toxicity in the rat. Toxicol Pathol 25 : 245 –255, 1997
21. Thomsen HS, Morcos SK, Dawson P: Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol 61 : 905 –906, 2006
22. Thomsen HS: Nephrogenic systemic fibrosis: A serious late adverse reaction to gadodiamide. Eur Radiol 16 : 2619 –2621, 2006
23. Puttagunta NR, Gibby WA, Smith GT: Human in vivo comparative study of zinc and copper transmetallation after administration of magnetic resonance imaging contrast agents. Invest Radiol 31 : 739 –742, 1996
24. Puttagunta NR, Gibby WA, Puttagunta VL: Comparative transmetallation kinetics and thermodynamic stability of gadolinium-DTPA bis-glucosamide and other magnetic resonance imaging contrast media. Invest Radiol 31 : 619 –624, 1996
25. Mann JS: Stability of gadolinium complexes in vitro and in vivo. J Comput Assist Tomogr 17[Suppl 1] : S19 –S23, 1993
26. Kirchin MA, Runge VM: Contrast agents for magnetic resonance imaging: Safety update. Top Magn Reson Imaging 14 : 426 –435, 2003
27. VanWagoner M, O’Toole M, Worah D, Leese PT, Quay SC: A phase I clinical trial with gadodiamide injection, a nonionic magnetic resonance imaging enhancement agent. Invest Radiol 26 : 980 –986, 1991
28. Shellock FG, Kanal E: Safety of magnetic resonance imaging contrast agents. J Magn Reson Imaging 10 : 477 –484, 1999
29. Cacheris WP, Quay SC, Rocklage SM: The relationship between thermodynamics and the toxicity of gadolinium complexes. Magn Reson Imaging 8 : 467 –481, 1990
30. Joffe P, Thomsen HS, Meusel M: Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 5 : 491 –502, 1998
31. Pupim LB, Caglar K, Hakim RM, Shyr Y, Ikizler TA: Uremic malnutrition is a predictor of death independent of inflammatory status. Kidney Int 66 : 2054 –2060, 2004
32. Kaysen GA, Eiserich JP: Characteristics and effects of inflammation in end-stage renal disease. Semin Dial 16 : 438 –446, 2003
33. Pupim LB, Evanson JA, Hakim RM, Ikizler TA: The extent of uremic malnutrition at the time of initiation of maintenance hemodialysis is associated with subsequent hospitalization. J Ren Nutr 13 : 259 –266, 2003
34. Idee JM, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C: Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: A review. Fundam Clin Pharmacol 20 : 563 –576, 2006
35. Shah SV, Alam MG: Role of iron in atherosclerosis. Am J Kidney Dis 41 : S80 –S83, 2003
36. Olakanmi O, Stokes JB, Pathan S, Britigan BE: Polyvalent cationic metals induce the rate of transferrin-independent iron acquisition by HL-60 cells. J Biol Chem 272 : 2599 –2606, 1997
37. Olakanmi O, Stokes JB, Britigan BE: Gallium-inducible transferrin-independent iron acquisition is a property of many cell types: Possible role of alterations in the plasma membrane. J Investig Med 53 : 143 –153, 2005
38. Olakanmi O, Rasmussen GT, Lewis TS, Stokes JB, Kemp JD, Britigan BE: Multivalent metal-induced iron acquisition from transferrin and lactoferrin by myeloid cells. J Immunol 169 : 2076 –2084, 2002
39. High WA, Ayers RA, Chandler J, Zito G, Cowper SE: Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 56 : 21 –26, 2007
40. Marckmann P, Skov L, Rossen K, Heaf JG, Thomsen HS: Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant 17 : 2359 –2362, 2007
41. Socolovsky M: Molecular insights into stress erythropoiesis. Curr Opin Hematol 14 : 215 –224, 2007
42. Sigounas G, Steiner M, Anagnostou A: Synergism of hemopoietic growth factors on endothelial cell proliferation. Angiology 48 : 141 –147, 1997
43. Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M: Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 87 : 5978 –5982, 1990
44. Ammarguellat F, Llovera M, Kelly PA, Goffin V: Low doses of EPO activate MAP kinases but not JAK2-STAT5 in rat vascular smooth muscle cells. Biochem Biophys Res Commun 284 : 1031 –1038, 2001
45. Desai A, Zhao Y, Lankford HA, Warren JS: Nitric oxide suppresses EPO-induced monocyte chemoattractant protein-1 in endothelial cells: Implications for atherogenesis in chronic renal disease. Lab Invest 86 : 369 –379, 2006
46. Stohlawetz PJ, Dzirlo L, Hergovich N, Lackner E, Mensik C, Eichler HG, Kabrna E, Geissler K, Jilma B: Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 95 : 2983 –2989, 2000
47. De Marchi S, Cecchin E, Falleti E, Giacomello R, Stel G, Sepiacci G, Bortolotti N, Zanello F, Gonano F, Bartoli E: Long-term effects of erythropoietin therapy on fistula stenosis and plasma concentrations of PDGF and MCP-1 in hemodialysis patients. J Am Soc Nephrol 8 : 1147 –1156, 1997
48. Carlini RG, Dusso AS, Obialo CI, Alvarez UM, Rothstein M: Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. Kidney Int 43 : 1010 –1014, 1993
49. Kahraman S, Yilmaz R, Kirkpantur A, Genctoy G, Arici M, Altun B, Erdem Y, Yasavul U, Turgan C: Impact of rHuEPO therapy initiation on soluble adhesion molecule levels in haemodialysis patients. Nephrology (Carlton) 10 : 264 –269, 2005
50. Scalera F, Kielstein JT, Martens-Lobenhoffer J, Postel SC, Tager M, Bode-Boger SM: Erythropoietin increases asymmetric dimethylarginine in endothelial cells: Role of dimethylarginine dimethylaminohydrolase. J Am Soc Nephrol 16 : 892 –898, 2005
51. Bahlmann FH, DeGroot K, Duckert T, Niemczyk E, Bahlmann E, Boehm SM, Haller H, Fliser D: Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int 64 : 1648 –1652, 2003
52. George J, Goldstein E, Abashidze A, Wexler D, Hamed S, Shmilovich H, Deutsch V, Miller H, Keren G, Roth A: Erythropoietin promotes endothelial progenitor cell proliferative and adhesive properties in a PI 3-kinase-dependent manner. Cardiovasc Res 68 : 299 –306, 2005
53. Galeano M, Altavilla D, Bitto A, Minutoli L, Calo M, Lo Cascio P, Polito F, Giugliano G, Squadrito G, Mioni C, Giuliani D, Venuti FS, Squadrito F: Recombinant human erythropoietin improves angiogenesis and wound healing in experimental burn wounds. Crit Care Med 34 : 1139 –1146, 2006
54. Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, Mildner-Rihm C, Martin H, Zeiher AM, Dimmeler S: Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 102 : 1340 –1346, 2003
55. Ballen K: Targeting the stem cell niche: Squeezing blood from bones. Bone Marrow Transplant 39 : 655 –660, 2007
56. Ogawa M, LaRue AC, Drake CJ: Hematopoietic origin of fibroblasts/myofibroblasts: Its pathophysiologic implications. Blood 108 : 2893 –2896, 2006
57. Haroon ZA, Amin K, Jiang X, Arcasoy MO: A novel role for erythropoietin during fibrin-induced wound-healing response. Am J Pathol 163 : 993 –1000, 2003
58. Sayan H, Ozacmak VH, Guven A, Aktas RG, Ozacmak ID: Erythropoietin stimulates wound healing and angiogenesis in mice. J Invest Surg 19 : 163 –173, 2006
59. Wojakowski W, Tendera M, Michalowska A, Majka M, Kucia M, Maslankiewicz K, Wyderka R, Ochala A, Ratajczak MZ: Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation 110 : 3213 –3220, 2004
60. Ando M, Iwata A, Ozeki Y, Tsuchiya K, Akiba T, Nihei H: Circulating platelet-derived microparticles with procoagulant activity may be a potential cause of thrombosis in uremic patients. Kidney Int 62 : 1757 –1763, 2002
61. Coleman TR, Westenfelder C, Togel FE, Yang Y, Hu Z, Swenson L, Leuvenink HG, Ploeg RJ, d’Uscio, LV, Katusic ZS, Ghezzi P, Zanetti A, Kaushansky K, Fox NE, Cerami A, Brines M: Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci U S A 103 : 5965 –5970, 2006
62. Meneghin A, Hogaboam CM: Infectious disease, the innate immune response, and fibrosis. J Clin Invest 117 : 530 –538, 2007
63. Wynn TA: Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117 : 524 –529, 2007
64. Cowper SE, Bucala R: Nephrogenic fibrosing dermopathy: Suspect identified, motive unclear. Am J Dermatopathol 25 : 358 , 2003
65. Kuwana M, Okazaki Y, Kodama H, Izumi K, Yasuoka H, Ogawa Y, Kawakami Y, Ikeda Y: Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation. J Leukoc Biol 74 : 833 –845, 2003
66. Iredale JP: Models of liver fibrosis: Exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 117 : 539 –548, 2007
67. Fathke C, Wilson L, Hutter J, Kapoor V, Smith A, Hocking A, Isik F: Contribution of bone marrow-derived cells to skin: Collagen deposition and wound repair. Stem Cells 22 : 812 –822, 2004
68. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT: Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425 : 841 –846, 2003
69. Liu J, Finkel T: Stem cell aging: What bleach can teach. Nat Med 12 : 383 –384, 2006
70. Dou L, Bertrand E, Cerini C, Faure V, Sampol J, Vanholder R, Berland Y, Brunet P: The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int 65 : 442 –451, 2004
71. Laplante P, Raymond MA, Gagnon G, Vigneault N, Sasseville AM, Langelier Y, Bernard M, Raymond Y, Hebert MJ: Novel fibrogenic pathways are activated in response to endothelial apoptosis: Implications in the pathophysiology of systemic sclerosis. J Immunol 174 : 5740 –5749, 2005
72. McMorrow T, Gaffney MM, Slattery C, Campbell E, Ryan MP: Cyclosporine A induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells. Nephrol Dial Transplant 20 : 2215 –2225, 2005
73. Ceol M, Anglani F, Vianello D, Murer L, Del Prete D, Forino M, Favaro S, Gambaro G, D’Angelo A: Direct effect of chronic cyclosporine treatment on collagen III mRNA expression and deposition in rat kidneys. Clin Nephrol 53[Suppl 8–9] , 2000
74. Johnson DW, Saunders HJ, Johnson FJ, Huq SO, Field MJ, Pollock CA: Fibrogenic effects of cyclosporin A on the tubulointerstitium: Role of cytokines and growth factors. Exp Nephrol 7 : 470 –478, 1999
