Friday, March 31, 2023
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NSF, previously known as nephrogenic fibrosing dermopathy, is a scleroderma-like fibrosing disorder that occurs in patients with CKD, renal transplant recipients and patients with acute kidney injury. The condition is characterized by painful and debilitating, progressive fibrosis and thickening of the skin, with occasional involvement of other organs and tissues such as the lungs, heart, liver, esophagus, testes, dura mater and striated muscles.[79] The first cases of NSF were reported in 1997, and the international NSF 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 confluence of erythematous lesions ensues and the skin becomes markedly thickened with a woody texture and brownish peau d'orange (orange-peel) indurations; these changes increasingly restrict the movement of adjacent joints, which results in contractures and immobilization[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 ultimately lead to prolonged hospital stays and are associated with a 30% mortality.[79,81,82]
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Figure 5. (click image to zoom) Nephrogenic systemic fibrosis in a 56-year-old patient. (A) The typical red discoloration and orange-peel thickening of the skin (peau d'orange) of the upper arm with a 'woody' texture.
(B) Secondary thrombosis of the arteriovenous fistula in the left arm (arrow) owing to progressive tightening of the skin. Permission obtained from Oxford University Press © Evenepoel P et al. (2004) Nephrol Dial Transplant 19: 469-473.[82] (C) The patient's left hand is severely affected with limited movement of the digital joints, which resulted in contractures.
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Factors reported to be associated with NSF (without definitive proof) include coagulation abnormalities (e.g. a hypercoagulable state), recent vascular surgery, deep vein thrombosis or a thrombosed arteriovenous access, failure or primary nonfunction of a transplanted kidney, hepatic disease, hyperphosphatemia and the use of high doses of recombinant erythropoietin.[79,81,82] Angiotensin-converting-enzyme inhibitors, on the other hand, might protect against NSF.[83,84] High doses of erythropoietin increase numbers of circulating hematopoietic stem cells and can trigger an exaggerated, fibrin-induced, wound-repair response; both of these events occur in NSF.[85] Exposure to gadolinium-based MRI contrast agents is associated with the development of NSF in patients with CKD.[86-89]
The diagnosis of NSF is made on the basis of a patient's history and medical examination and is confirmed by skin biopsy (Figure 6). Histology shows a thickened dermis with pathologic changes that include the marked proliferation of spindle cells with interstitial mucin deposition, the presence of thickened collagen bundles and a lack of inflammatory cells. Dendritic cells and histiocytes are present.[90,91] Dermal spindle cells stain positive for CD34 and procollagen I and are thought to be derived from circulating fibrocytes that are positive for both CD34 and procollagen I. Metastatic calcifications and even ossifications have been described in some cases. Whole-body PET scans of patients with NSF using 18F-fluorodeoxyglucose have shown that metabolic activity is increased at the sites of clinical lesions.[82] This technique can be used to confirm the diffuse inflammatory skin changes associated with active NSF and theoretically might be useful for evaluating the response to therapy.[82]
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Figure 6. (click image to zoom) Typical histology of skin lesions associated with nephrogenic systemic fibrosis. (A) Hematoxylin and eosin stain (original magnification × 25) that shows the thickened dermis. The arrow points to a fibrotic septum between the fat lobules of the subcutis. (B) CD68 immunostain that shows macrophages (original magnification × 100). (C) Alcian blue stain that shows mucin depositions (original magnification × 100). (D) CD34-immunostained section that shows dermal, fibroblast-like spindle cells (original magnification × 100). Abbreviations: d, dermis; e, epidermis; sc, subcutis.
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The differential diagnosis of NSF includes systemic sclerosis (scleroderma), scleromyxedema, eosinophilic fasciitis, lipodermatosclerosis, and to a lesser extent, graft-versus-host disease, dermatomyositis and amyloidosis.
The role of gadolinium in the development of NSF is now clearly recognized: exposure to gadolinium before the onset of disease was confirmed in over 95% of reported cases.[86-89] Free gadolinium ions are highly toxic to tissues, and, therefore, gadolinium is used in the form of inert chelates bound to large organic molecules such as diethylenetriaminepentaacetic acid.[92] Some chelating agents dissociate more easily from gadolinium than others. Such dissociation depends on characteristics of the chelate: configuration (macrocyclic or linear), charge (ionic or nonionic), thermodynamic stability and the amount of excess chelate that is present. Metabolic acidosis and high levels of endogenous ions such as Zn2+, Cu2+, Ca2+ and Fe3+ might enhance dissociation of gadolinium from its chelate through the transmetalation process.[92,93]
Under normal circumstances, gadolinium-based contrast agents are eliminated by the kidney through glomerular filtration. The half-life of these agents increases from approximately 1.3 h in individuals with normal renal function to 60 h in those with a reduced glomerular filtration rate (<15 ml/min/1.73m2); the increased half-life increases the risk of gadolinium becoming dissociated from its chelate.[92] This increased dissociation is thought to lead to increased tissue uptake of free gadolinium, particularly in proinflammatory conditions. Gadolinium in the tissues undergoes phagocytosis by macrophages, which in turn attract circulating fibrocytes positive for CD34 and procollagen I; the latter cells can transform into dermal fibroblast-like cells and produce excessive amounts of mucin constituents such as hyaluronan and sulfated glycosaminoglycans.[94,95] Transforming growth factor β, produced by CD68+ and factor XIIIa+-activated dendritic cells, has also been implicated in this profibrotic process.[94-96] The hypothesis that increased tissue uptake of free gadolinium occurs as a result of increased dissociation has been strengthened by the demonstration that tissue gadolinium levels are 35-fold to 150-fold higher in patients with NSF than in healthy volunteers exposed to gadolinium contrast agents.[97-100] 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 preparations gadodiamide (Omniscan®; GE Healthcare, Chalfont St Giles, Buckinghamshire, UK) and gadopentetate dimeglumine (Magnevist®; Bayer HealthCare Pharmaceuticals, Montville, NJ) are responsible for over 85% of cases of NSF because these agents are more likely to dissociate than other preparations. Other gadolinium-based contrast agents have been implicated in the development of NSF only rarely (gadoversetamide [OptiMARK®; Mallinckrodt, Hazelwood, MO]) or not at all (gadobenate dimeglumine [MultiHance®; Bracco Diagnostics Princeton, NJ] and gadoteridol [Prohance®; Bracco Diagnostics]).[92] The interval between exposure to a gadolinium-based contrast agent and first signs of NSF varies greatly, ranging from 2 days to 18 months, which is possibly the result of variable gadolinium mobilization from bone stores over time.
At present, NSF has no effective treatment. Numerous anecdotal reports that described various medical therapies have been published, but none provides convincing evidence of a generally applicable treatment for NSF. Therapies that have been tested include corticosteroids, thalidomide, cyclophosphamide, sirolimus, ciclosporin, immunoglobulins, topical calcipotriene, psoralen and ultraviolet A (PUVA) therapy, interferon γ, sodium thiosulfate, plasmapheresis, imatinib mesylate and extracorporeal photopheresis (after administration of 8-methoxypsoralen).[79,81,82,102-106] In cases of NSF associated with acute kidney injury, restoration of renal function is a primary goal. Physiotherapy, deep-tissue massage and swimming are advocated in all patients with NSF in order to maintain mobility and prevent contractures.
At present, prevention of NSF seems more important than any of the currently available interventions and widespread clinical awareness of this condition is required.[107] The use of gadolinium contrast should be limited to an absolute minimum in patients with CKD; low osmolar or iso-osmolar iodine-based contrast agents provide a valid alternative to gadolinium-based agents in most instances.[91] Some prophylactic strategies for the prevention of 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 gadolinium eliminated after two dialysis sessions (and 99% after three sessions).[92] Such a strategy could, therefore, be considered in patients with stages 4 and 5 CKD who require MRI with gadolinium contrast.[92] However, no prospective study has demonstrated a clinical benefit of hemodialysis in the prevention of NSF. A retrospective analysis published in 2008 suggested that hemodialysis helped to prevent NSF in patients with an estimated glomerular filtration rate below 15 ml/min/1.73m2 who received high doses of gadolinium-based contrast agent.[109] Peritoneal dialysis is not effective for the elimination of gadolinium.[110] Patients with stages 4 or 5 CKD should be informed about the benefits and risks of receiving gadolinium-based contrast agents for diagnostic procedures.
No consensus guidelines have yet been formulated regarding gadolinium contrast use for patients with stage 3 CKD, but avoidance of large volumes of linear, nonionic, gadolinium-based contrast agent seems advisable. Whether prompt dialysis after exposure would be beneficial in this particular group of patients is even less clear than it is for those with stages 4 and 5 CKD.
