Nephrogenic Systemic Fibrosis

A Pathologic Study of Autopsy Cases

Aashiyana F. Koreishi, MD; Rosalynn M. Nazarian, MD; Adam J. Saenz, MD; Veronica E. Klepeis, MD, PhD; Anna G. McDonald, MD; Alton Brad Farris, MD; Robert B. Colvin, MD; Lyn M. Duncan, MD; Rajni V. Mandal, MD; Jonathan Kay, MD

Context.Nephrogenic systemic brosis (NSF) is a rare but serious disorder initially described as a purely dermatologic process. Isolated autopsy reports have described multiorgan involvement by this disease. Objective.To further illustrate the varied and systemic involvement of NSF by describing the autopsy experience at the Massachusetts General Hospital. Design.We describe the ndings in a series of 4 autopsy cases of patients diagnosed with NSF. This report describes the history of renal dysfunction, exposure to gadolinium-containing contrast agents, specic laboratory parameters, and the extent of systemic involvement identied by postmortem examination. Results.Causes of death included systemic thromboembolic disease (n 3) and pneumonia (n 1). Laboratory parameters and type, dose, or timing of gadoliniumephrogenic systemic brosis (NSF) is a recently identied brosing disorder affecting patients with chronic kidney disease and occasionally those with acute renal failure.1 Clinically, the disease manifests as rapidly progressive skin hyperpigmentation, hardening, and tethering to the underlying fascia. Patients may develop debilitating joint contractures.2 Symptoms range from pruritus to severe pain, although some patients are essentially asymptomatic.3 Multiple organ systems may be involved, resulting in signicantly increased mortality.1,411 As of February 2008, 195 biopsy-proven cases of NSF had been reported, to our knowledge, in the medical literature.12 The disorder was rst reported in 2000 as a scleromyxedema-like condition affecting 14 patients, all of whom
Accepted for publication February 27, 2009. From the Department of Pathology, James Homer Wright Pathology Laboratories (Drs Koreishi, Nazarian, Saenz, Klepeis, McDonald, Farris, Colvin, Duncan, and Mandal); and the Division of Rheumatology, Allergy, & Immunology, Department of Medicine (Dr Kay), Massachusetts General Hospital and Harvard Medical School, Boston. Dr Mandal is now located in the Dermatopathology Unit, Department of Dermatology, New York University School of Medicine, New York, New York. The authors have no relevant nancial interest in the products or companies described in this article. Presented in part at the 27th Annual Meeting of the International Academy of Pathology, Athens, Greece, October 1217, 2008. Reprints: Rajni V. Mandal, MD, Department of Dermatopathology, New York University School of Medicine, 530 First Ave, Suite 7J, New York, NY 10016 (e-mail: rajni.mandal@nyumc.org). Arch Pathol Lab MedVol 133, December 2009

containing contrast-agent exposure did not correlate with clinical ndings and outcomes. All patients demonstrated cutaneous manifestations of the disease and nephrocalcinosis, with some exhibiting calcication and brosis of the dura, thyroid, and heart including the cardiac conduction system, on postmortem examination. Soft tissue calcication was associated with concurrent hyperparathyroidism or high serum parathyroid hormone levels. Conclusions.Thromboembolic disease can be a significant clinical complication of NSF. Patients with NSF may also develop characteristic histologic features of brosis and calcication in multiple organs, with signicant morbidity and mortality. This autopsy series highlights the variability of systemic manifestations of NSF. (Arch Pathol Lab Med. 2009;133:19431948) had chronic kidney disease.1 Because of the prominent skin features and associated underlying renal disease, it was named nephrogenic brosing dermopathy.13 After several postmortem examinations of patients diagnosed with this skin disorder revealed more widespread brosis at extracutaneous sites, the name of this condition was changed from nephrogenic brosing dermopathy to NSF.11 The observation in 2006 by Grobner that 5 of 9 patients receiving hemodialysis in his unit developed NSF within 2 to 4 weeks after undergoing magnetic resonance angiography with a gadolinium (Gd)-containing contrast agent (GCCA) suggested that the pathogenesis of this disorder might involve Gd toxicity.14 Gadolinium is a rare earth metal with paramagnetic properties that makes it suitable for use as a contrast agent in magnetic resonance imaging studies.15 Gadolinium-containing contrast agents, administered by intravenous injection, equilibrate rapidly within the extracellular compartment and are excreted unchanged by the kidney.15 The half-life of GCCAs is prolonged by more than 25-fold in patients with renal dysfunction.16 Cutaneous changes of NSF are strongly associated with prior exposure to GCCAs, with an odds ratio of 14.7.2 Gadolinium deposits have been identied in skin and viscera of patients with NSF.7,17 In patients with normal renal function, Gd has not been detected in tissue following exposure to GCCAs.18 However, Gd has been detected in bone from patients without NSF following GCCA exposure, but the renal function of these patients was not reNSF Autopsy Case SeriesKoreishi et al 1943

ported.19 It has been hypothesized that impaired renal excretion may predispose a patient to Gd deposition in tissues; however, the factors that determine in whom and at what sites Gd is deposited are not yet understood. Although 4 patients with chronic kidney disease were reported to have developed NSF with no known history of exposure to a Gd-containing contrast agent, Gd levels were not measured in the skin of these patients to exclude the possibility of an exposure about which the patient might have been unaware.2022 The absence of measurable Gd in tissue samples from 4 other patients with NSF and known prior exposure to a GCCA was most likely due to the lower detection limit of the assay used.23 Because not all patients with stage 5 chronic kidney disease who have received a GCCA develop NSF, Gd exposure appears to be necessary, but not sufcient, to cause NSF.2 Herein, we describe our experience performing autopsies on patients with NSF at the Massachusetts General Hospital, examining the relationship between the history of renal dysfunction, Gd exposure, and various laboratory parameters, with the extent of systemic involvement identied by postmortem examination. MATERIALS AND METHODS Case Selection
We searched the autopsy records of the Department of Pathology at the Massachusetts General Hospital from 20042008 for the diagnostic terms nephrogenic systemic brosis and nephrogenic brosing dermopathy. We identied 6 patients who had one of these diagnoses and who had undergone complete general and neuropathologic autopsy with ample material for analysis. Two of these cases had been reported previously in the literature.6,7 Additional clinical information was obtained from each patients electronic medical record, including age, sex, history of renal disease and dialysis treatment, history of exposure to GCCAs and erythropoietin, and other signicant past medical history. Median laboratory values for the month immediately before death were recorded, including levels of serum urea nitrogen, creatinine, calcium, phosphorus, and parathyroid hormone.

Figure 1. The kidney shows widespread deposition of basophilic calcication around tubules and focally in glomeruli (hematoxylin-eosin, original magnication 100).

Case Reports
Case 1. A 43-year-old, white man, with Buergers disease affecting his peripheral vasculature, hypertension, hypothyroidism, cardiomyopathy of unclear etiology, past pulmonary hemorrhage, stage 5 chronic kidney disease from Goodpasture syndrome, and NSF, developed hypotension and fever after hemodialysis. He was admitted to hospital with left leg cellulitis and dry gangrene of his right hand. During his hospitalization, a cardiac catheterization revealed severe stenosis of his superior vena cava, which prevented him from receiving hemodialysis. Peritoneal dialysis was initiated, but he died 3 weeks after admission from complications of sepsis and renal failure. At autopsy, an organizing thrombus was present in his superior vena cava, composed of brin and foamy histiocytes with focal broblasts and capillaries, and calcication. Numerous brin thrombi were observed histologically in the dermal vasculature of his skin. No thrombi were seen in other organs. Sections of skin also showed a proliferation of dermal broblasts with brosis, consistent with NSF. Sections of kidney showed severe, widespread nephrocalcinosis, characterized by basophilic calcium deposits in the tubular basement membranes around most tubules and focally in glomeruli with vascular calcication (Figure 1). His heart demonstrated cardiomegaly with marked right ventricular hypertrophy, left ventricular dilation, patchy interstitial brosis, myocyte hypertrophy, and multiple, small, recent infarcts. Neuropathologic examination revealed an unremarkable adult brain with bilateral optic-tract degeneration, characterized by severe loss of myelin that was replaced by macrophages, astrocytes, and chronic inammation.
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Case 2. A 72-year-old, African-American woman, with hypothyroidism; deep venous thromboses, treated with bilateral subclavian vein stents and inferior vena cava lter; stage 5 chronic kidney disease due to multiple myeloma; and NSF, experienced multiple episodes of dizziness and hemodynamic instability during dialysis for 3 months. She was diagnosed with sick sinus syndrome, admitted for pacemaker placement, and developed complete heart block. Attempts at placing a pacemaker were unsuccessful because both subclavian venous stents had thrombosed. She died 11 days after admission. At autopsy, the skin of her lower extremities demonstrated extensive brosis of the dermis and underlying subcutaneous tissue, with a proliferation of broblasts (Figure 2). Not only was there cutaneous brosis but also there was extensive systemic brosis that involved the pericardium, heart, lungs, diaphragm, thyroid, and dura mater, including that surrounding the spinal cord. Histologically, dense brosis was associated with calcication and scattered lymphocytic and histiocytic inltrates with multinucleated giant cells. The heart showed multifocal brosis, with signicant brosis and calcication of the atrioventricular nodal region (Figure 3). Her thyroid gland was diffusely replaced by brosis, with a proliferation of spindled broblasts (Figure 4). Both of her kidneys exhibited severe, widespread nephrocalcinosis in addition to amyloidosis. Two hyperparathyroid glands were enlarged and hypercellular (weighing 2.5 g and 1.5 g; reference range, 0.05 g). Both subclavian arteries were occluded by remote and recent organizing thrombi. No thrombi were seen in other organs. Her bone marrow contained plasma cells, both in small clusters and scattered diffusely. Plasma cells comprised less than 5% of the bone marrow cellularity and stained for light chain by in situ hybridization without signicant staining for light chains (Ventana, Tucson, Arizona). Mild systemic amyloid deposition (veried by Congo red stain; Ventana) was present, involving blood vessels in her kidneys, lungs, and heart and, to a lesser extent, her skin. Case 3. A 74-year-old, white woman, with hypertension, atrial brillation, supraventricular tachycardia, celiac sprue, a rightsided cerebrovascular accident 3 years earlier, stage 5 chronic kidney disease due to renovascular hypertension, and NSF, developed nausea, vomiting, and diarrhea. She was admitted for management of dehydration with elevated transaminases, and responded well to intravenous uids and hemodialysis. She died at home a week after discharge from the hospital. At autopsy, there was patchy bronchopneumonia in her right upper and lower lobes. Samples of skin from both arms and legs demonstrated brosis and an increased number of dermal broblasts, consistent with NSF. Both kidneys exhibited nephrocalcinosis. The dura was also stiff, thickened, and revealed brosis on histologic examination. One enlarged, hypercellular parathyroid gland (3.0 cm; weight, 0.1 g) was also identied. Her heart
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Figure 2. A, The skin shows widespread brosis, with widened brous septae extending into the subcutaneous fat. B, A proliferation of spindled broblasts is seen in a background of collagen (hematoxylin-eosin, original magnications 15 [A] and 400 [B]). Figure 3. A, The atrioventricular node is replaced by a white, rm, solid area of calcication. B to C, The conduction system and myocardium are involved by brosis and calcication, surrounded by multinucleated giant cells (hematoxylin-eosin, original magnications 100 [B] and 40 [C]). Arch Pathol Lab MedVol 133, December 2009 NSF Autopsy Case SeriesKoreishi et al 1945

Figure 4. A, The thyroid is diffusely involved by brosis with large areas of calcication. B, Few residual follicles remain, and the calcication is surrounded by multinucleated giant cells (hematoxylin-eosin, original magnications 40 [A] and 100 [B]).

showed moderate coronary artery atherosclerosis and left ventricular concentric hypertrophy. Case 4. A 60-year-old, white woman, with systemic lupus erythematosus complicated by stage 5 chronic kidney disease, antiphospholipid antibody syndrome, thrombocytopenia, hypertension, and NSF, was admitted to the hospital with a left hip hematoma and cellulitis after a fall. During her hospitalization, she developed multiple cerebral infarcts with considerable loss of cerebral cortical mass and became signicantly hypotensive during hemodialysis. Because of her poor prognosis, her family chose not to resuscitate or intubate her, and she died 2 weeks after admission. At autopsy, there were multiple arterial thrombi with evidence of recanalization in the microvasculature of her kidneys, heart, lungs, and brain, with secondary cerebral infarction. Her heart demonstrated multifocal brosis with microscopic, nonbacterial organizing thrombotic endocarditis of the mitral valve, veried by trichrome staining. Subcutaneous septal brosis, with an in-

creased number of broblasts and scattered multinucleated giant cells, was observed in the skin of her legs. Both kidneys showed focal nephrocalcinosis, with calcication only around tubules, as well as end-stage lupus nephritis (Class VI).

Demographic Information, Gd-Containing Contrast-Agent Doses, and Laboratory Parameters

Patient demographic information, causes of renal disease, history of exposure to GCCAs, and median laboratory values during the month immediately before death are listed in Table 1, including those of 2 previously published patients from the Massachusetts General Hospital. Patient 5 had received gadodiamide (Omniscan, GE Healthcare, Waukesha, Wisconsin), whereas the other 5 patients each had received gadopentetate dimeglumine (Magnevist, Bayer HealthCare Pharmaceuticals, Montville, New Jersey) as intravenous contrast during magnetic resonance studies.

Table 1.

Patient Information and Laboratory Values of 6 Patients at the Massachusetts General Hospital Who Died With Nephrogenic Systemic Fibrosis
Dialysis Duration, y, type Type and Volume of GCCA, mL Total GCCA,a doses (mo) Exposure Time,b mo/dose BUN/Cr, mg/dL Ca, mg/dL P, mg/dL PTH, pg/mL

Case No.

Age, y/Sex

Renal Disease

EPO

Goodpasture 4 HD, PD Gadopentetate di5 (44) 15/third 50/4.1 10.9 5.2 55 no syndrome meglumine, 155 2 72/F Multiple myelo- 9 HD Gadopentetate di2 (14) 7/second 33/4.0 9.1 4.5 NA yes ma, diabetes, meglumine, 35 hypertension 3 74/F Renovascular 2 HD Gadopentetate di4 (60) 0.75/fourth 50/4.1 10.6 3.7 439 yes hypertension meglumine, 140 4 60/F Systemic lupus 2 HD Gadopentetate di7 (16) 2/third 32/2.5 8.7 4.2 NA yes erythematomeglumine, 130 sus 5c 71/M Diabetes, hyper- 4 HD Gadodiamide, 116 4 (17) 1/third 19/3.5 11.1 4.6 251 yes tension 6d 48/F Streptococcal 8 HD, PD Gadopentetate di9 (64) 28/eighth 35/1.9 9.6 5.4 367 yes sepsis meglumine, 198 Abbreviations: BUN, blood urea nitrogen (reference range, 825 mg/dL); Ca, serum calcium (reference range, 8.510.5 mg/dL); Cr, serum creatinine (reference range, 0.61.5 mg/dL); EPO, erythropoietin exposure at dialysis; GCCA, gadolinium-containing contrast agent; HD, hemodialysis; NA, not applicable; P, serum phosphorus (reference range 2.64.5 mg/dL); PD, peritoneal dialysis; PTH, serum parathyroid hormone (reference range 1060 pg/mL). a Total No. of GCCA doses during No. of months. b Time after GCCA dose (specic dose shown) to development of symptoms of nephrogenic systemic brosis. c Previously reported by Saenz et al.6 d Previously reported by Kay et al.7 1946 Arch Pathol Lab MedVol 133, December 2009 NSF Autopsy Case SeriesKoreishi et al

43/M

Table 2.
Case No.

Autopsy Findings in Patients With Nephrogenic Systemic Fibrosis (NSF)

Calcication Thrombosis Noncutaneous Organ Involvement by NSF Source, y

Cause of Death

1 2 3 4 5a

Inability to establish dialysis access because of superior vena cava thrombosis, cellulitis/gangrene Complete heart block, inability to place pacemaker because of subclavian vein thrombosis Pneumonia/respiratory failure Acute cerebral infarctions with arterial embolic disease Patients rejection of care because of severity of NSF

Kidney Pericardium, diaphragm, dura, thyroid, heart, kidney Dura, kidney Kidney Skeletal muscle, dura, kidney Heart, muscle, kidneys, lungs, dura Dura, lungs, diaphragm, heart Heart, dura Diaphragm, esophagus Diaphragm, skeletal muscle, kidneys, testes None identied Heart, coronary arteries Heart

Current study Current study Current study Current study Saenz et al,6 2006 Kay et al,7 2008 Krous et al,9 2007 Gibson et al,5 2006 Kucher et al,4 2006 Ting et al,27 2003 Swaminathan et al,8 2008 Swaminathan et al,8 2008 Swaminathan et al,8 2008

6a Pneumonia/respiratory failure 7a Renal failure caused by thrombosis after renal transplant 8a Sepsis 9a Respiratory failure 10a Patients rejection of care because of severity of NSF 11a Limb ischemia and gangrene, myocardial ischemia, hypotension, calciphylaxis 12a Stroke, hypotension 13a Congestive heart failure, arrhythmia
a

Previously reported.

COMMENT The report of these 4 autopsies of patients with NSF represents the largest autopsy case series of patients, to our knowledge, for this recently described brosing disorder that occurs in patients with renal dysfunction. Nephrogenic systemic brosis manifests as rapidly progressive brosis characterized by the deposition of CD34 /CD45RO /type I procollagen /vimentin , broblast-like spindle cells within the skin and other anatomic sites, including dura mater, myocardium, lungs, diaphragm, and skeletal muscle. Although causation has not yet been established denitively, prior exposure to GCCAs has been associated with the clinical appearance of NSF, and Gd deposits have been identied in affected tissues.2,17,23 Prompted by this epidemiologic association between exposure to GCCAs and the subsequent development of NSF, the US Food and Drug Administration in 2006 mandated changes in the labeling of these contrast agents to warn of the potential risk of NSF, and subsequently, individual health care facilities instituted hospital-wide changes in policy regarding the use of Gd-containing contrast in patients with chronic kidney disease and those with acute kidney failure.24 Because of the risk of developing NSF, extreme caution should be observed when considering the administration of GCCAs to patients with impaired renal function. Although still evolving, current guidelines at the Massachusetts General Hospital recommend that all patients with risk factors for having renal impairment undergo laboratory testing to assess serum urea nitrogen and serum creatinine within 1 month of an anticipated imaging study using a Gd-containing contrast agent.25 These risk factors include age older than 60 years, history of renal disease, diabetes mellitus, systemic lupus erythematosus, and multiple myeloma.25 The use of GCCAs is generally not advised for patients with a gloArch Pathol Lab MedVol 133, December 2009

merular ltration rate lower than 30 mL/min/1.73 m2, unless other imaging studies will not provide the medically necessary information.26 Given the current evidence and because of the potential for severe morbidity and mortality, we strongly recommend evaluation of renal function prior to Gd-associated imaging in patients at a high risk of renal failure. The cases presented herein highlight the variable clinical presentation of NSF. In case 2, the brosis and calcication of the atrioventricular node likely resulted in complete heart block and, ultimately, the patients death. Fibrosis of the thyroid, which is a nding not heretofore reported, to our knowledge, in NSF manifested clinically as hypothyroidism. All cases exhibited varying degrees of nephrocalcinosis, including cases 5 and 6. The deposition of calcium in tubules and glomeruli is likely a secondary change to the renal parenchyma because another original cause of renal failure was documented. Some calcium deposition may occur in end-stage renal disease, but the extensive deposition of calcium in the tubular basement membrane, a criterion of nephrocalcinosis, is not common. A query of our institutional database between 1971 and 2004, for nephrectomy cases resected because of end-stage renal disease revealed few cases with nephrocalcinosis (24 of 1444 [1.6%] kidneys in end-stage renal disease, P .001). Consequences of calcium deposition and brosis in NSF, such as diaphragmatic involvement compromising ventilation, have been associated with mortality.4 The mechanism of multiorgan calcication in NSF has not been established; however, this manifestation has been observed in other cases of NSF.27 Hyperparathyroidism, which often occurs in patients with chronic kidney disease, may predispose to tissue calcication and has been associated with dural and cardiac calcication.28,29 In our series, both patient 2 and patient 3 had enlarged parathyroid glands at
NSF Autopsy Case SeriesKoreishi et al 1947

autopsy, and patient 5 and patient 6 exhibited tissue calcication with high serum parathyroid hormone levels. Because it blocks calcium receptors, Gd may have a direct effect on parathyroid responses to systemic calcium levels since it is a calcium receptor blocker. In patch-clamp experiments, ionized Gd inhibited the ability of parathyroid cells to decrease parathyroid hormone secretion in the presence of high, extracellular calcium concentrations.30 Gadolinium-containing contrast agents contain chelated Gd, which can dissociate into metal ion or salt precipitate in patients with low glomerular ltration rate.31 However, studies of human volunteers, with and without renal insufciency, have failed to show any acute changes in serum calcium after GCCA exposure, and our cases had normal serum calcium levels.32 The increased incidence of tissue calcication in our cases, especially in the kidneys, may be due to an underlying susceptibility of tissue to calcify in NSF. The mechanism and effect of clinical management of hyperparathyroidism on tissue calcication in NSF remain to be determined. Swaminathan and colleagues8 hypothesized that Gd deposition in vessels and the heart can cause vascular and cardiac injury with resulting high mortality. Thrombotic events and hypercoagulable states have been described to occur in NSF.3,33 Among the 13 published autopsy cases of NSF, the most common cause of death was thromboembolic disease (5 cases, see Table 2). Our ndings support thrombosis as a signicant cause of mortality in NSF. Of the 4 patients in our series, the cause of death in 3 (75%) was directly attributable to systemic hypercoagulability and thrombosis. In case 4, this may have been enhanced by coexistent antiphospholipid antibody syndrome. Direct myocardial injury by Gd may also be a factor because Gd deposition in the heart was previously reported in case 6.7 Multifocal and patchy myocardial brosis was observed in 3 patients (75%), which may have developed as a result of vascular thrombosis, infarcts, and hypertrophy, as well as from direct myocardial injury by Gd. Our 4 autopsy cases and the 9 published previously illustrate the spectrum of systemic involvement by NSF, with many cases demonstrating brosis and calcication of multiple organs, including the kidney (54%), heart (46%), dura (46%), and diaphragm (31%). The novel autopsy ndings of diffuse calcication with or without brosis of the kidneys, cardiac conduction system and thyroid add to the clinical spectrum of this disease. However, the observed variability in the extent of systemic involvement underscores the need for further study of the factors that predispose to the development of this disabling and potentially fatal disease.
References
1. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous disease in renal-dialysis patients. Lancet. 2000; 356(9234):10001001. 2. Todd DJ, Kagan A, Chibnik LB, Kay J. Cutaneous changes of nephrogenic systemic brosis: predictor of early mortality and association with gadolinium exposure. Arthritis Rheum. 2007;56(10):34333441. 3. Cowper SE. Nephrogenic brosing dermopathy: the rst 6 years. Curr Opin Rheumatol. 2003;15(6):785790. 4. Kucher C, Steere J, Elenitsas R, Siegel DL, Xu X. Nephrogenic brosing dermopathy/nephrogenic systemic brosis with diaphragmatic involvement in a patient with respiratory failure. J Am Acad Dermatol. 2006;54(2)(suppl):S31S34. 5. Gibson SE, Farver CV, Prayson RA. Multiorgan involvement in nephrogenic brosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med. 2006;130(2):209212. 6. Saenz A, Mandal R, Kradin R, Hedley-Whyte ET. Nephrogenic brosing dermopathy with involvement of the dura mater. Virchows Arch. 2006;449(3): 389391.

7. Kay J, Bazari H, Avery LL, Koreishi AF. Case records of the Massachusetts General Hospital case 6-2008: a 46-year-old woman with renal failure and stiffness of the joints and skin. N Engl J Med. 2008;358(8):827838. 8. Swaminathan S, High WA, Ranville J, et al. Cardiac and vascular metal deposition with high mortality in nephrogenic systemic brosis. Kidney Int. 2008; 73(12):14131418. 9. Krous HF, Breisch E, Chadwick AE, Pinckney L, Malicki DM, Benador N. Nephrogenic systemic brosis with multiorgan involvement in a teenage male after lymphoma, Ewings sarcoma, end-stage renal disease, and hemodialysis. Pediatr Dev Pathol. 2007;10(5):395402. 10. Jimenez SA, Artlett CM, Sandor N, et al. Dialysis-associated systemic brosis (nephrogenic brosing dermopathy): study of inammatory cells and transforming growth factor 1 expression in affected skin). Arthritis Rheum. 2004; 50(8):26602666. 11. Daram SR, Cortese CM, Bastani B. Nephrogenic brosing dermopathy/ nephrogenic systemic brosis: report of a new case with literature review. Am J Kidney Dis. 2005;46(4):754759. 12. Broome DR. Nephrogenic systemic brosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol. 2008;66(2):230234. 13. Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic brosing dermopathy. Am J Dermatopathol. 2001;23(5):383393. 14. Grobner T. Gadoliniuma specic trigger for the development of nephrogenic brosing dermopathy and nephrogenic systemic brosis? Nephrol Dial Transplant. 2006;21(4):11041108. 15. 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. 2006;20(6): 563576. 16. Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufciency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol. 1998;5(7):491 502. 17. Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic brosing dermopathy. J Am Acad Dermatol. 2007;56(1):2730. 18. Boyd AS, Sanyal S, Abraham JL. Gadolinium is not deposited in the skin of patients with normal renal function after exposure to gadolinium-based contrast agents. J Am Acad Dermatol. 2008;59(2):356358. 19. Gibby WA, Gibby KA, Gibby WA. Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Invest Radiol. 2004; 39(3):138142. 20. Weiss AS, Lucia MS, Teitelbaum I. A case of nephrogenic brosing dermopathy/nephrogenic systemic brosis. Nat Clin Pract Nephrol. 2007;3(2):111 115. 21. Wahba IM, Simpson EL, White K. Gadolinium is not the only trigger for nephrogenic systemic brosis: insights from two cases and review of the recent literature. Am J Transplant. 2007;7(10):24252432. 22. Anavekar NS, Chong AH, Norris R, Dowling J, Goodman D. Nephrogenic systemic brosis in a gadolinium-naive renal transplant recipient. Australas J Dermatol. 2008;49(1):4447. 23. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic brosis. J Am Acad Dermatol. 2007;56(1):2126. 24. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic brosis: why radiologists should be concerned. AJR. 2007;188(2):586592. 25. Miller JC. Nephrogenic systemic brosis. Mass Gen Hosp Radiol Rounds Newsl. 2007;5(6): Web site. http://www.mghradrounds.org/index.php?src gendocs&link 2007 june. Accessed October 3, 2008. 26. Perazella MA, Reilly RF. Nephrogenic systemic brosis: recommendations for gadolinium-based contrast use in patients with kidney disease. Semin Dial. 2008;21(2):171173. 27. Ting WW, Stone MS, Madison KC, Kurtz K. Nephrogenic brosing dermopathy with systemic involvement. Arch Dermatol. 2003;139(7):903906. 28. Fujimoto S, Hisanaga S, Yamatomo Y, Tanaka K, Hayashi T, Sumiyoshi A. Tertiary hyperparathyroidism associated with metastatic cardiac calcication in a haemodialyzed patient. Int Urol Nephrol. 1991;23(3):285292. 29. Dorenbeck U, Leingartner T, Bretschneider T, Kramer BK, Feuerbach S. Tentorial and dural calcication with tertiary hyperparathyroidism: a rare entity in chronic renal failure. Eur Radiol. 2002;12(suppl 3):S11S13. 30. Chang W, Chen TH, Gardner P, Shoback D. Regulation of Ca(2 )-conducting currents in parathyroid cells by extracellular Ca(2 ) and channel blockers. Am J Physiol. 1995;269(5, pt 1):E864E877. 31. Grobner T, Prischl FC. Patient characteristics and risk factors for nephrogenic systemic brosis following gadolinium exposure. Semin Dial. 2008;21(2): 135139. 32. Zhang HL, Ersoy H, Prince MR. Effects of gadopentetate dimeglumine and gadodiamide on serum calcium, magnesium, and creatinine measurements. J Magn Reson Imaging. 2006;23(3):383387. 33. Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME. Nephrogenic brosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol. 2003;48(1):5560.

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