Nephrogenic systemic fibrosis: a pathologic study of autopsy cases.
* Context.--Nephrogenic systemic fibrosis (NSF) is a rare but
serious disorder initially described as a purely dermatologic process.
Isolated autopsy reports have described multiorgan involvement by this
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 findings 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, specific laboratory parameters, and the extent of systemic involvement identified 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 gadolinium containing contrast-agent exposure did not correlate with clinical findings and outcomes. All patients demonstrated cutaneous manifestations of the disease and nephrocalcinosis, with some exhibiting calcification and fibrosis of the dura, thyroid, and heart including the cardiac conduction system, on postmortem examination. Soft tissue calcification 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 fibrosis and calcification in multiple organs, with significant morbidity and mortality. This autopsy series highlights the variability of systemic manifestations of NSF.
(Arch Pathol Lab Med. 2009;133:1943-1948)
Fibrosis (Case studies)
Kidney diseases (Complications and side effects)
Kidney diseases (Case studies)
Hemodialysis (Health aspects)
Angiography (Health aspects)
Koreishi, Aashiyana F.
Nazarian, Rosalynn M.
Saenz, Adam J.
Klepeis, Veronica E.
McDonald, Anna G.
Farris, Alton Brad
Colvin, Robert B.
Duncan, Lyn M.
Mandal, Rajni V.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: Dec, 2009 Source Volume: 133 Source Issue: 12|
Nephrogenic systemic fibrosis (NSF) is a recently identified
fibrosing 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 significantly increased mortality.
(1,4-11) As of February 2008, 195 biopsy-proven cases of NSF had been
reported, to our knowledge, in the medical literature. (12)
The disorder was first reported in 2000 as a scleromyxedema-like condition affecting 14 patients, all of whom had chronic kidney disease. (1) Because of the prominent skin features and associated underlying renal disease, it was named nephrogenic fibrosing dermopathy. (13) After several postmortem examinations of patients diagnosed with this skin disorder revealed more widespread fibrosis at extra-cutaneous sites, the name of this condition was changed from nephrogenic fibrosing 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 identified 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 reported. (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. (20-22) 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 sufficient, 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 identified by postmortem examination.
We searched the autopsy records of the Department of Pathology at the Massachusetts General Hospital from 2004-2008 for the diagnostic terms nephrogenic systemic fibrosis and nephrogenic fibrosing dermopathy. We identified 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 patient's electronic medical record, including age, sex, history of renal disease and dialysis treatment, history of exposure to GCCAs and erythropoietin, and other significant 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.
Case 1.--A 43-year-old, white man, with Buerger's 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 fibrin and foamy histiocytes with focal fibroblasts and capillaries, and calcification. Numerous fibrin 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 fibroblasts with fibrosis, 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 calcification (Figure 1). His heart demonstrated cardiomegaly with marked right ventricular hypertrophy, left ventricular dilation, patchy interstitial fibrosis, 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 inflammation.
[FIGURE 1 OMITTED]
Case 2.--A 72-year-old, African-American woman, with hypothyroidism; deep venous thromboses, treated with bilateral subclavian vein stents and inferior vena cava filter; 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 fibrosis of the dermis and underlying subcutaneous tissue, with a proliferation of fibroblasts (Figure 2). Not only was there cutaneous fibrosis but also there was extensive systemic fibrosis that involved the pericardium, heart, lungs, diaphragm, thyroid, and dura mater, including that surrounding the spinal cord. Histologically, dense fibrosis was associated with calcification and scattered lymphocytic and histiocytic infiltrates with multinucleated giant cells. The heart showed multifocal fibrosis, with significant fibrosis and calcification of the atrioventricular nodal region (Figure 3). Her thyroid gland was diffusely replaced by fibrosis, with a proliferation of spindled fibroblasts (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 X light chain by in situ hybridization without significant staining for k light chains (Ventana, Tucson, Arizona). Mild systemic amyloid deposition (verified 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 fibrillation, supraventricular tachycardia, celiac sprue, a right-sided 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 fluids 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 fibrosis and an increased number of dermal fibroblasts, consistent with NSF. Both kidneys exhibited nephrocalcinosis. The dura was also stiff, thickened, and revealed fibrosis on histologic examination. One enlarged, hypercellular parathyroid gland (3.0 cm; weight, <0.1 g) was also identified. Her heart showed moderate coronary artery atherosclerosis and left ventricular concentric hypertrophy.
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
[FIGURE 4 OMITTED]
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 significantly 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 fibrosis with microscopic, nonbacterial organizing thrombotic endocarditis of the mitral valve, verified by trichrome staining. Subcutaneous septal fibrosis, with an increased number of fibroblasts and scattered multinucleated giant cells, was observed in the skin of her legs. Both kidneys showed focal nephrocalcinosis, with calcification 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.
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 fibrosing disorder that occurs in patients with renal dysfunction. Nephrogenic systemic fibrosis manifests as rapidly progressive fibrosis characterized by the deposition of [CD34.sup.+]/[CD45RO.sup.+]/type I [procollagen.sup.+]/[vimentin.sup.+], fibroblast-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 definitively, prior exposure to GCCAs has been associated with the clinical appearance of NSF, and Gd deposits have been identified 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 glomerular filtration 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 fibrosis and calcification of the atrioventricular node likely resulted in complete heart block and, ultimately, the patient's death. Fibrosis of the thyroid, which is a finding 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 fibrosis in NSF, such as diaphragmatic involvement compromising ventilation, have been associated with mortality. (4) The mechanism of multiorgan calcification 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 calcification and has been associated with dural and cardiac calcification. (28,29) In our series, both patient 2 and patient 3 had enlarged parathyroid glands at autopsy, and patient 5 and patient 6 exhibited tissue calcification 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 filtration rate. (31) However, studies of human volunteers, with and without renal insufficiency, 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 calcification 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 calcification 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 findings support thrombosis as a significant 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 fibrosis 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 fibrosis and calcification of multiple organs, including the kidney (54%), heart (46%), dura (46%), and diaphragm (31%). The novel autopsy findings of diffuse calcification with or without fibrosis 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.
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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
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 financial 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 12-1 7, 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: firstname.lastname@example.org).
Table 1. Patient Information and Laboratory Values of 6 Patients at the Massachusetts General Hospital Who Died With Nephrogenic Systemic Fibrosis Dialysis Case Age, Duration, No. y/Sex Renal Disease y, type 1 43/M Goodpasture syndrome 4 HD, PD 2 72/F Multiple myeloma, diabetes, hypertension 9 HD 3 74/F Renovascular hypertension 2 HD 4 60/F Systemic lupus erythematosus 2 HD 5c 71/M Diabetes, hypertension 4 HD 6d 48/F Streptococcal sepsis 8 HD, PD Total Case Age, GCCA, (a) No. y/Sex Type and Volume of GCCA, mL doses (mo) 1 43/M Gadopentetate dimeglumine, 155 5 (44) 2 72/F Gadopentetate dimeglumine, 35 2 (14) 3 74/F Gadopentetate dimeglumine, 140 4 (60) 4 60/F Gadopentetate dimeglumine, 130 7 (16) 5c 71/M Gadodiamide, 116 4 (17) 6d 48/F Gadopentetate dimeglumine, 198 9 (64) Exposure Case Age, Time, (b) BUN/Cr, Ca, P, PTH, No. y/Sex mo/dose mg/dL mg/dL mg/dL pg/mL EPO 1 43/M 15/third 50/4.1 10.9 5.2 55 no 2 72/F 7/second 33/4.0 9.1 4.5 NA yes 3 74/F 0.75/fourth 50/4.1 10.6 3.7 439 yes 4 60/F 2/third 32/2.5 8.7 4.2 NA yes 5c 71/M 1/third 19/3.5 11.1 4.6 251 yes 6d 48/F 28/eighth 35/1.9 9.6 5.4 367 yes Abbreviations: BUN, blood urea nitrogen (reference range, 8/25 mg/ dL); Ca, serum calcium (reference range, 8.5/10.5 mg/dL); Cr, serum creatinine (reference range, 0.6/1.5 mg/dL); EPO, erythropoietin exposure at dialysis; GCCA, gadolinium/containing contrast agent; HD, hemodialysis; NA, not applicable; P, serum phosphorus (reference range 2.6/4.5 mg/dL); PD, peritoneal dialysis; PTH, serum parathyroid hormone (reference range 10/60 pg/mL). (a) Total No. of GCCA doses during No. of months. (b) Time after GCCA dose (specific dose shown) to development of symptoms of nephrogenic systemic fibrosis. (c) Previously reported by Saenz et al. (6) (d) Previously reported by Kay et al. (7) Table 2. Autopsy Findings in Patients With Nephrogenic Systemic Fibrosis (NSF) Case No. Cause of Death Calcification Thrombosis 1 Inability to establish dialysis + + access because of superior vena cava thrombosis, cellulitis/gangrene 2 Complete heart block, inability + + to place pacemaker because of subclavian vein thrombosis 3 Pneumonia/respiratory failure + - 4 Acute cerebral infarctions with + + arterial embolic disease 5 (a) Patient's rejection of care + - because of severity of NSF 6 (a) Pneumonia/respiratory failure + + 7 (a) Renal failure caused by + + thrombosis after renal transplant 8 (a) Sepsis + - 9 (a) Respiratory failure - - 10 (a) Patient's rejection of care + - because of severity of NSF 11 (a) Limb ischemia and gangrene, + + myocardial ischemia, hypotension, calciphylaxis 12 (a) Stroke, hypotension + + 13 (a) Congestive heart failure, - - arrhythmia Case Noncutaneous Organ No. Cause of Death Involvement by NSF 1 Inability to establish dialysis Kidney access because of superior vena cava thrombosis, cellulitis/gangrene 2 Complete heart block, inability Pericardium, diaphragm, to place pacemaker because of dura, thyroid, heart, subclavian vein thrombosis kidney 3 Pneumonia/respiratory failure Dura, kidney 4 Acute cerebral infarctions with Kidney arterial embolic disease 5 (a) Patient's rejection of care Skeletal muscle, dura, because of severity of NSF kidney 6 (a) Pneumonia/respiratory failure Heart, muscle, kidneys, lungs, dura 7 (a) Renal failure caused by Dura, lungs, diaphragm, thrombosis after renal heart transplant 8 (a) Sepsis Heart, dura 9 (a) Respiratory failure Diaphragm, esophagus 10 (a) Patient's rejection of care Diaphragm, skeletal because of severity of NSF muscle, kidneys, testes 11 (a) Limb ischemia and gangrene, None identified myocardial ischemia, hypotension, calciphylaxis 12 (a) Stroke, hypotension Heart, coronary arteries 13 (a) Congestive heart failure, Heart arrhythmia Case No. Cause of Death Source, y 1 Inability to establish dialysis Current study access because of superior vena cava thrombosis, cellulitis/gangrene 2 Complete heart block, inability Current study to place pacemaker because of subclavian vein thrombosis 3 Pneumonia/respiratory failure Current study 4 Acute cerebral infarctions with Current study arterial embolic disease 5 (a) Patient's rejection of care Saenz et al, (6) 2006 because of severity of NSF 6 (a) Pneumonia/respiratory failure Kay et al, (7) 2008 7 (a) Renal failure caused by Krous et al, (9) 2007 thrombosis after renal transplant 8 (a) Sepsis Gibson et al, (5) 2006 9 (a) Respiratory failure Kucher et al, (4) 2006 10 (a) Patient's rejection of care Ting et al, (27) 2003 because of severity of NSF 11 (a) Limb ischemia and gangrene, Swaminathan et al, (8) myocardial ischemia, 2008 hypotension, calciphylaxis 12 (a) Stroke, hypotension Swaminathan et al, (8) 2008 13 (a) Congestive heart failure, Swaminathan et al, (8) arrhythmia 2008 (a) Previously reported.
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