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Nephrogenic Systemic Fibrosis

Author: Younus M. Shamam Author: Muhammad F. Hashmi Editor: Orlando De Jesus Updated: 11/1/2024 2:03:15 PM

Introduction

Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition caused by exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) in the setting of low glomerular filtration rate (GFR).[1] This condition is characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. The clinical features may also involve skeletal muscle and any fibrous tissue in the body, including the internal organs such as the liver, heart, and lungs.[2][3][4] NSF is a clinically highly variable condition. Some patients may have only mild effects on the skin, but many patients develop significant debility. In some patients, the disease may be lethal.[2]

The condition was first described in 2000 when several physicians across the United States (US) noted patients with a scleroderma-type illness, and the association with GBCA administration in the setting of renal failure was solidified as more cases were presented.[1][5][6] NSF occurs in patients with acute or severe chronic renal failure, usually stage 4 or 5 chronic kidney disease (CKD), but it has also been described in patients with stage 3 CKD.[7] The condition was initially called nephrogenic fibrosing dermopathy due to the cutaneous manifestation. Still, the terminology changed to gadolinium-induced fibrosis or NSF as more systemic manifestations came to light.[1][8][9] Fortunately, the incidence of this condition has significantly decreased since 2007, when the US Food and Drug Administration placed a black box warning on using gadolinium-containing products in patients with severely decreased GFR. However, 32 cases were reported annually in 2019 and 2020.[10]  

Etiology

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Etiology

Gadolinium is a paramagnetic element that enhances soft tissue and is used to visualize a variety of body compositions. Gadolinium (Gd) is toxic to humans but can be combined with organic chelates to prevent the release of Gd ions; this is the basis of GBCAs. Gd can be classified into linear versus cyclic and ionic versus nonionic (see Table. Gd Types). Linear molecules bind Gd less tightly and are at higher risk of causing NSF.[10] 

Table. Gd Types

  Ionic Nonionic
Linear Gadopentetate dimeglumine, gadobenate dimeglumine, gadoxetate disodium Gadodiamide, gadoversetamide
Cyclic Gadoterate meglumine Gadoteridol, gadobutrol

Each category has a different risk of NSF as classified by the Committee for Medicinal Products for Human Use as follows:

  • High-risk includes gadopentetate dimeglumine (Magnevist), gadodiamide (Omniscan), and gadoversetamide (OptiMARK).
  • Medium-risk includes gadoxetate disodium (Primovist) and gadobenate dimeglumine (MultiHance). Although gadoxetate disodium is a linear molecule, it is excreted 50% by the kidney and 50% through bile.
  • Low-risk includes gadobutrol (Gadovist),  gadoteridol (ProHance), and gadoterate meglumine (Dotarem).

The American College of Radiology also has a similar classification system of 3 groups, with group 1 being the highest risk and group 3, the lowest:

  • Group 1: Gadodiamide, gadoversetamide, gadopentetate dimeglumin
  • Group 2: Gadobenate dimeglumine, gadobutrol, gadoteric acid, gadoterido
  • Group 3: Gadoxetate disodium [11]

Other relevant characteristics of GBCA include thermodynamic stability and relaxivity. Higher relaxivity allows endogenous metals such as iron, copper, and zinc to displace the Gd. The Gd molecule can bind with endogenous ions such as carbonate (CO32−) and phosphate (PO43−), forming insoluble compounds that deposit in tissues.[11] Gd is cleared almost entirely by the kidneys. The Gd is cleared within 90 minutes in patients with normal renal function. However, in patients with impaired kidney function, the half-life can be up to 30 hours, allowing Gd to dissociate and form insoluble compounds. Using hemodialysis immediately after GBCA decreases the risk of NSF but does not eliminate it, as not all the GBCA is cleared via hemodialysis.[10] 

Gd has also been shown to be immunogenic in vitro, activating toll-like receptors, macrophages, and dendritic cells.[11] This initiates a vicious fibrotic cycle of transforming growth factor-beta 1 production and dendritic cell maturation, resulting in excessive collagen deposition in the extracellular matrix and soft tissues.[7] Activation of dermal fibroblasts is a key component in the pathogenesis of NSF. The dermal fibroblasts synthesize excess glycosaminoglycans, particularly hyaluronan, which is partially responsible for the characteristic skin thickening.[12] Factors contributing to NSF include total gadolinium exposure, hypercalcemia, hyperphosphatemia, high-dose erythropoietin therapy, hepatorenal syndrome, immunosuppression, and vasculopathy. Results from one notable study showed that the risk of NSF was increased by 25 times when infection was present.[13]

Epidemiology

Nephrogenic systemic fibrosis is an iatrogenic disease first identified in 2000. According to a report by the FDA, about 4.5 million Americans are exposed to GBCAs annually.[14]  Until 2019, the FDA reported 3094 cases of NSF, including 742 deaths and 2922 serious cases. Of note, the US has the second-highest MRI utilization rate after Germany.[15] As noted above, 32 cases were reported in each of 2019 and 2020. 

NSF affects any ethnicity, sex, or age.[1][8][16] The risk of developing NSF depends on the amount of residual renal function and the type of GBCA used. The amount of the initial dose and the cumulative dose of GBCA can also increase the risk.[16] When the high-risk group 1 GBCAs were used, the estimated incidence was 36.5 cases per 100,000 gadolinium-enhanced MRI examinations.[17] Systematic reviews have found that no patients developed biopsy-proven NSF among patients receiving group 2 or 3 GBCAs; the estimated risk of NSF when using group 2 or 3 GBCAs is less than 0.07%.[18][19]   

Pathophysiology

Various Hypotheses Concerning Underlying Pathogenic Mechanisms

The following discussion is essential for historical reasons, as the understanding of NSF has significantly evolved.

  • In 2002, a group proposed that hemodialysis patients with hepatitis C would be more at risk of developing NSF due to high levels of fibroblast growth factor or TGF-β1.[20] 
  • In 2003, another group put forward 2 theories to explain the pathogenesis of NSF. First, they observed that anticardiolipin or antiphospholipid antibodies had a significant role in the development of NSF. Second, they believed that edema coupled with the suppressed immune system in patients with antiphospholipid antibodies triggers a physiologic response, leading to the proliferation of fibroblast-like cells and mucin deposition in the dermis.[21]
  • In 2004, the histopathology of NSF was studied, and it was found that the fibrotic process of NSF was not limited to the dermis. Instead, it extended to the subcutaneous tissues, fascia, skeletal muscles, lungs, and myocardium. The skin contained large cluster of differentiation (CD)68/factor 13a dendritic cells and an abundance of TGF-β1.
  • The prevailing theory is that Gd exposure is prolonged in patients with renal disease, allowing the Gd to dissociate from its organic chelators and bind with calcium, phosphate, and other endogenous compounds to deposit in the skin and tissues. This sets off a fibrotic reaction involving the proliferation of fibroblasts in the dermis and the replacement of normal tissue with thickened collagen and extracellular matrix hyaluronan. Deposition also occurs in other tissues and leads to multi-organ involvement.
  • Abnormal calcium and phosphorus metabolism has also been found in patients who develop NSF compared to patients with a similar estimated glomerular filtration rate who did not develop NSF, and calcium and phosphorus deposits have also been found in the gadolinium-containing deposits of NSF.[22] Traumatic calcinosis cutis, osseous metaplasia, calciphylaxis, and metastatic calcification have also been observed in dialysis patients with NSF.[23][24] A variant of NSF has been referred to as a pathology of dysregulated matrix remodeling, and it appears to involve osteoclast-like giant cells. 

Histopathology

Findings on skin biopsy will evolve. Initially, gadolinium may be present, but the amount of Gd does not correlate with disease severity. Most notable is collagen deposition in thick bundles, mucin, and widened subcutaneous septae. A significant increase in cellularity is also noted. These cells are spindle-shaped fibroblasts, fibroblast-like, or polygonal epithelioid fibroblasts. The abundant spindle-shaped cells often express type 1 procollagen and CD34.[25][26][27][28] 

Electron microscopy may show increased elastic fibers as opposed to dendritic cell processes. Inflammation is usually absent.[28] Over time, the collagen bundles thicken, and fibrocytes and mucin become "sandwiched" between these bundles. The dermis becomes involved with increased fibrocytes, collagen, mucin, and elastic fibers. The fibrous tissue creates a microlobular architecture; calcification has also been described.[27]

History and Physical

Clinical manifestations of nephrogenic systemic fibrosis (NSF) may occur days or even years after GBCA exposure but usually present within 2 to 10 weeks. One case report describes a patient on hemodialysis who developed NSF 10 years after his last Gd exposure.[16][29] All patients will have a history of renal impairment of varying severity and duration and gadolinium exposure. Many patients are on renal replacement therapy—namely hemodialysis, peritoneal dialysis, or renal transplantation. However, patients not on renal replacement therapy who have residual renal function can also develop nephrogenic systemic fibrosis.[1] 

Dermatologic

One of the first and most common manifestations is acute thickening and hardening of the skin. The first noted cases were described as "scleroderma-like." This condition may develop quickly or slowly. Pruritis and burning sensations are the most common symptoms. Patients may describe tightening or thickening of the skin or that their skin looks shinier. The skin is often lumpy with nodular thickening and indurated plaques with a fluctuating leading edge.

The affected areas have been described as hard and "woody." The plaques are usually symmetrical and start on the hands or feet and progress medially (in contrast, scleroderma usually starts on the trunk and progresses distally). The Rodnan skin thickness score can measure skin thickness, and skin is often discolored to a brawny color. The skin can have a peau d'orange appearance (ie, induration overlying hard subcutaneous tissue). The face is almost always spared.[1][12] 

Major criteria include patterned plaques, joint contractures, or pronounced induration (peau d’ orange), while minor criteria consist of linear banding, superficial plaques, dermal papules, and scleral plaques.[28] Later manifestations of NSF may evolve into wrinkled, redundant skin (ie, cutis laxa) with symmetrical hair loss and epidermal atrophy. One biopsy of this skin showed collagen thickening and elastolysis in the dermis.[27]

Musculoskeletal

NSF has also been observed to involve joints and skeletal muscle.[30] Joint involvement usually results in disability and contractures. The palms may have superficial flesh-colored or pink macules or papules, which can coalesce into scaly plaques. Hand and foot blistering has also been noted.[12] The joints under the affected skin often become fibrosed, causing severe flexion contractures. Loss of ambulation is common.[30][31] 

Eyes/Cranial

Although the face is usually spared, yellow scleral plaques have been reported and are a minor criterion. Vision is not usually compromised. The dura mater can also be involved.[1][12]

Renal 

The fibrosis may also involve the renal tubules, although this has not been described histologically.[1] 

Cardiopulmonary

Cardiac involvement can lead to cardiomyopathy or pulmonary hypertension. Calcification may occur in the coronary arteries or along the cardiac valves.[27] The mortality rate increases if the lungs are affected, particularly if the diaphragm is involved.[8][12]

Evaluation

NSF is a clinicopathologic diagnosis that can be made by the history and physical and supported by a skin biopsy. The biopsy findings are described in the Histology section. A deep punch skin biopsy should be performed, including the dermis, subcutaneous fat, and fascia. Care should be taken not to introduce metal contamination from the biopsy device or handle the specimen (eg, forceps).[32]

Rarely, some patients with NSF are found to have the following in their blood:

  • Peripheral eosinophilia
  • Antinuclear antibodies
  • Anticardiolipin or antiphospholipid antibodies
  • Hypercoagulability

Nerve conduction abnormalities have been reported in some patients. To evaluate for cardiac involvement, an electrocardiogram should also be performed.

Treatment / Management

To date, there are no proven treatments that cure nephrogenic systemic fibrosis, and most often, combination therapy is used. Restoration of renal function, if feasible, is essential to prevent further progression as it appears to slow or hold the progression.[16][33][34] In 2005, photodynamic therapy was reported to be a successful treatment option for NSF and has been used since that time with variable success. Ultraviolet (UV) therapy includes UVA, UVB, and UVA with psoralen.[34][35][36][37](A1)

Extracorporeal photopheresis (ECP) is a promising treatment option for nephrogenic systemic fibrosis. In this procedure, blood is drawn, and the white blood cells are separated and treated with the drug psoralen (8-methoxypsoralen) and UV light. The treated lymphocytes are then infused back into the patient. This is anti-inflammatory without being immunosuppressive. NSF is considered a class 3 indication for ECP—"inconclusive evidence."[34][38][39](A1)

There have been anecdotal reports of improvement in NSF lesions after treatment with the following agents:

  • Methotrexate
  • Rapamycin
  • Sodium thiosulfate
  • Pentoxifylline
  • Glucocorticoids
  • Imatinib
  • Thalidomide
  • Interferon alpha
  • Topical calcipotriene
  • Topical betamethasone
  • Plasmapheresis
  • Intravenous immunoglobulin [1][16][40][41][42][43][44][45]
    • (B2)

Narcotic analgesics may be required to control pain secondary to contractures. Physical therapy is an important part of the treatment to maintain and improve joint motion and reduce contractures.[1] Renal transplantation may also improve symptoms.[46][47][48] (B3)

Differential Diagnosis

Nephrogenic systemic fibrosis diagnosis relies on excluding the other differential diagnoses; thus, healthcare professionals should be aware of these differentials. The following diseases encompass the most likely differential diagnosis:

  • β-microglobulin amyloidosis
  • Borreliosis
  • Calciphylaxis
  • Chronic graft versus host disease
  • Drug-induced fibrosis
  • Dermatofibrosarcoma protuberans
  • Early cellulitis
  • Early panniculitis
  • Eosinophilic fasciitis
  • Fibroblastic rheumatism
  • Lipodermatosclerosis
  • Radiation-induced fibrosis
  • Scleroderma
  • Scleromyxedema
  • Phenylketonuria
  • Porphyria cutanea tarda
  • Superficial fibromatosis [1]

Noting the history of GBCA exposure during the MRI examination will favor NSF among the differential diagnosis.[49] Among the differential diagnoses, only β2-microglobulin amyloidosis occurs exclusively in individuals with advanced renal disease; however, it usually affects the shoulders, volar wrists, and tongue.[1] As noted above, in contrast to NSF, scleroderma usually starts at the trunk and moves peripherally, while scleromyxedema usually involves the head and neck (the face is not involved in NSF).[27]

Prognosis

Nephrogenic systemic fibrosis is considered a debilitating, progressive disease. This condition causes visceral and cutaneous fibrosis in patients with severe renal insufficiency exposed to GBCAs. Although skin changes associated with NSF may be improved after the restoration of kidney function, especially after recovery from acute kidney injury, this condition does not usually regress spontaneously and almost always progresses relentlessly. The high mortality rate does not come from the cutaneous lesions but rather from visceral fibrosis, particularly in the cardiac and respiratory systems.[50]

One group observed that 24-month mortality following examination was 48% in patients with skin changes and 20% in the cases where skin changes were absent.[50] Within a few weeks of disease onset, most patients became wheelchair-bound due to contractures; patients can also experience flexion contractures if the condition involves a joint. Mortality in many patients has been attributed to falls and other complications due to limited mobility. In addition, many patients have reported causalgia and maddening pruritus. 

Complications

Nephrogenic systemic fibrosis complicates the already existing kidney disease. The complications of NSF include:

  • The most debilitating NSF sequelae are the fibrosis of visceral organs such as the heart, lungs, renal tubules, and skeletal muscles. Although visceral fibrosis is often asymptomatic, it may contribute to the development of pulmonary hypertension, cardiomyopathy, and skeletal muscle weakness.
  • Patients with NSF may experience blood vessel thrombosis; as the disease progresses, these patients may develop significant hypotension, affecting their ability to tolerate the hemodialysis.[51]
  • Flexion contractures may lead to wheelchair dependence within weeks in many patients.
  • Falls are common in these patients, and fractures can also occur.

Consultations

The diagnosis and management of NSF need a multidisciplinary team. The following specialties work as a team for NSF management: 

  • Dermatology
  • Nephrology
  • Radiology
  • Pulmonology
  • Histopathology
  • Physical medicine and rehabilitation

Deterrence and Patient Education

Since this disease is caused by GBCA exposure in patients with severe renal impairment, optimization of renal function is pivotal. Patients with this condition should be informed that no proven treatments can cure NSF, and the current therapies can only relieve some symptoms. However, if the disease progresses and visceral fibrosis develops, medication adherence may improve patients' quality of life.[7]

For patients with severe kidney disease, healthcare professionals should discuss and guide patients on the potential risks of GBCAs. Clinicians should discuss the MRI study's risks and benefits over the alternative use of a contrast-enhanced computed tomography (CT) scan, which can potentially produce a loss of residual renal function and precipitate dialysis initiation.[19][52] Group 2 or 3 GBCAs may be safer than a CT scan with intravenous contrast in patients with stage 4 or 5 chronic kidney disease who still have residual function, as the contrast may eliminate the remaining renal function.[53] Those patients who have received group 1 GBCAs in the past should be aware of their exposure, as effects can be cumulative.[52]

Pearls and Other Issues

Other important information to note includes the following:

  • The incidence rate of NSF has been drastically reduced since regulatory authorities like the FDA, American College of Radiology, and the European Society of Urogenital Radiology implemented precautionary guidelines advising radiologists to avoid high-risk GBCAs if the patient has severe renal insufficiency.
  • The chelate of GBCAs is categorized into different groups based on the risk of NSF. In general, molecules bound to a cyclic chelate structure are more stable than those that are bound to a linear chelate (except gadoxetate disodium/Primovist, which, although a linear molecule, is excreted 50% by the kidney and 50% through bile.)
  • The lowest possible dose of GBCA to obtain the essential clinical information should be used.
  • Further doses of GBCA should be delayed several days to a week or avoided if possible.
  • The diagnostic benefit of GBCAs in the imaging study must be weighed cautiously against the significant risk of developing this debilitating disease.
  • There is no prophylactic agent that prevents the development of NSF aside from choosing a class 2/3 Gd agent.
  • High-risk GBCAs (group I) are contraindicated for patients with acute kidney injury or severe chronic kidney disease.
  • Early hemodialysis following the GBCA is recommended in patients with chronic hemodialysis, but it does not remove all the contrast medium.
  • Skin thickening causes significant morbidity in patients related to pain, pruritus, and flexion contractures. 
  • Visceral fibrosis can lead to significant mortality.
  • No treatments have been proven to reverse the changes of NSF, but UV light therapy and extracorporeal photopheresis are effective in case reports.

Enhancing Healthcare Team Outcomes

NSF occurs in patients with renal failure who are exposed to gadolinium. Managing this disease requires the collaboration of the entire healthcare team. The radiologist should avoid high-risk GBCAs in patients with renal failure. The primary clinician should be aware of this disease in patients presenting with symptoms after exposure to GBCAs. After confirming the diagnosis, nurses, pharmacists, and physical therapists are essential for better health outcomes. Dermatologists and dermatopathologists are vital to obtaining and interpreting skin biopsy results. Dermatologists and hematologists/oncologists often administer the variable therapeutic options available. 

The American College of Radiology recommends screening patients by identifying risk factors for compromised renal function (aged 60 and older, hypertension, diabetes mellitus, dialysis, kidney surgery, kidney transplant, kidney cancer, or single kidney). If the patient presents with 1 of the risk factors, obtaining serum creatinine before GBCA administration is warranted. According to the European Society of Urogenital Radiology, patient assessment is based on the type of GBCA used. If a high-risk GBCA is to be used, serum creatinine and clinical assessment before contrast medium administration must be performed. For intermediate and low-risk GBCAs, a questionnaire assessment of the renal function is sufficient.

A strategic approach is equally crucial, involving evidence-based strategies to optimize treatment plans and minimize adverse events. Ethical considerations must guide decision-making, ensuring informed consent and respecting patient autonomy in treatment choices, especially considering that NSF is iatrogenic and avoidable. Each healthcare professional must know their responsibilities and contribute their unique expertise to the patient's care plan, fostering a multidisciplinary approach.

Effective interprofessional communication is paramount, allowing seamless information exchange and collaborative decision-making among the team members. Care coordination plays a pivotal role in ensuring that the patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient safety. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance in the management of nephrogenic systemic fibrosis.

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