Nephrogenic Systemic Fibrosis


Continuing Education Activity

Nephrogenic systemic fibrosis is a progressive multiorgan fibrosing condition mainly caused by patients' exposure to gadolinium-based contrast agents used in magnetic resonance imaging. This condition is primarily characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. This activity reviews the evaluation and management of nephrogenic systemic fibrosis and explains the healthcare team's role in improving care for patients with this condition.

Objectives:

  • Identify the etiology of nephrogenic systemic fibrosis.
  • Review the evaluation of nephrogenic systemic fibrosis.
  • Outline the management options available for nephrogenic systemic fibrosis.
  • Describe some interprofessional team strategies to prevent and improve care coordination in patients with nephrogenic systemic fibrosis and improve outcomes.

Introduction

Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition mainly caused by patients' exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI).[1] This condition is primarily characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. The clinical features may involve any fibrous tissue in the body, including the internal organs such as the liver, heart, muscles, and lungs.[2][3][4] NSF is a clinically highly variable condition. Some patients may have only mild skin affection, other patients may have limited movement, and rarely, the disease may be lethal.[2]

The condition was first described in 2000; however, several years later, a group of nephrologists explained the pathophysiology and the important role of GBCAs to induce this condition.[1][5][6] It occurs in patients with acute or severe chronic renal failure with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m^2.[7][8] The condition was initially called nephrogenic fibrosing dermopathy due to the cutaneous manifestations.[5][6][9][10][11] The term gadolinium-induced fibrosis or gadolinium-induced NSF has also been used.[1][12][13] 

Patients with severe renal insufficiency are at high risk of developing this condition if GBCAs are used in MRI. The incidence rate was dramatically reduced in the last years due to strict adherence of the health care providers with the regulatory guidelines that advise the radiologists to avoid using high-risk GBCAs in severe renal failure.

Etiology

Nephrogenic systemic fibrosis is a rare disease associated with the use of GBCAs connected to impaired kidney function. Since 1988 when gadopentetate dimeglumine was approved for clinical practice, GBCAs had been intravenously applied to improve MRI examinations' visibility. Gadolinium (Gd) is a known heavy metal, and it is considered highly toxic in the biological systems. To be used as a contrast agent, gadolinium must be bound to ligands. GBCAs consists of gadolinium ions and chelating molecules, which could be cyclic or linear. The linear molecules are less stable and provide a weaker link to the gadolinium ion; thus, they are considered high-risk agents.[1][14] The macrocyclic molecules offer better binding to gadolinium ions and provide better protection. The American College of Radiology (ACR) classified the GBCAs into three groups as the following:

  1. Group I (gadopentetate dimeglumine, gadodiamide, gadoversetamide)
  2. Group II (gadobenate dimeglumine, gadoterate meglumine, gadoteridol, gadobutrol) 
  3. Group III (gadoxetic acid disodium).

Epidemiology

Nephrogenic systemic fibrosis is an iatrogenic disease, first identified in 2000. Annually, about 4.5 million Americans are exposed to GBCAs, according to a report by the United States Food and Drug Administration (FDA).[15] Until 2019, the FDA reported 3,094 cases of NSF, including 742 deaths and 2,962 serious cases. The United States has the second-highest MRI utilization rate than any other country after Germany.[15][16] 

NSF has no preference for race, sex, or age.[1][7][4] It is reported in both adults and children.[12] The risk for developing NSF depends on the amount of residual renal function and the type of GBCA used. The amount of initial dose and the cumulative dose of GBCA can also increase the risk.[7] According to a systematic review, very young patients and those older than 80 have a lower risk.[17] However, the validity of this finding has been questioned.[14] A chronic kidney disease patient with a stage 5 is defined as chronic dialysis dependency or as having an eGFR < 15 mL/min/1.73 m^2; stage 4 is defined as having an eGFR < 30 mL/min/1.73 m^2; and stage 3 as having an eGFR < 60 mL/min/1.73 m^2).[1]

When the high-risk group I GBCAs were used, the estimated incidence was 36.5 cases per 100,000 gadolinium-enhanced MRI examinations; however, the incidence was reduced to four cases per 100,000 tests after the screening for risk was instituted in 2007.[18] A systematic review showed that only seven biopsy-confirmed cases had been reported with GBCAs exposure after 2008.[17] After the group II GBCAs usage commenced, a systematic review found that no patients developed NSF among 4931 patients receiving group II GBCAs, for an estimated risk of less than 0.07%.[8] Another systematic review found no patients who developed NSF among 80,932 patient exposures receiving group II or III (macrocyclic or newer linear) GBCAs.[19]

Pathophysiology

The exact pathogenesis is unknown, but most studies hypothesized that gadolinium might dissociate from its chelate and become free Gd.[7] This cation can interact with tissue receptors macrophages or monocytes and stimulate the production of chemokines, profibrotic cytokines, and collagen formation, resulting in fibrosis of the tissues. These cells may stimulate circulating fibrocytes to differentiate into fibroblasts, which preserve a profibrotic phenotype producing elevated amounts of the extracellular matrix.[1][7] This mechanism perpetuates and creates the clinical manifestation of dermal and visceral fibrosis. It is essential to note that patients with severe renal dysfunction (eGFR < 30 mL/min/1.73 m^2) exposed to GBCAs are more likely to be affected than patients with normal kidney function.[1] 

In patients with advanced kidney disease, the injected GBCA remains for more hours than those with normal renal function. Gadolinium is more likely to dissociate from its chelate when the less stable GBCAs are used.[1] Another hypothesis suggests that Gd ion may activate a vicious fibrotic cycle of transforming growth factor-beta 1 (TGF-β1) production and dendritic cell maturation, resulting in excessive collagen deposition in soft tissues.[20] In a mice model, the C-C chemokine receptor 2 has been implicated in the production of NSF.[15][21] Proinflammatory events, hyperphosphatemia, and b-blockers had been reported as contributing factors.[17]

Histopathology

Skin biopsies usually demonstrate dermal fibrosis without signs of inflammation. A significant increase in cellularity is also noted. These cells are described as being spindle-shaped fibroblasts, fibrohistiocytic, fibroblast-like, or polygonal epithelioid fibroblasts.[9][22] Under light microscopy, the dermal collagen is increased with bundles arranged haphazardly associated with mucin deposition. The abundant spindle-shaped cells often express type I procollagen and CD34.[7][9][23][24]

History and Physical

NSF's clinical manifestations may occur days or even years after GBCAs exposure but usually present within 2-10 weeks.[7] Early clinical features include burning pain, pruritus, weakness, and cutaneous papules or plaques, usually accompanied by edema.[1]

Further progression of the disease leads to thickened and hyperpigmented skin. The disease may involve both the lower and upper extremities, progresses from the distal extremity to the proximal one, and always spares the face. Joint involvement usually results in disability and contractures. The fibrosis may also involve the renal tubules, lungs, dura mater, ocular sclera, and skeletal and cardiac muscles.[1] If the lungs are affected, the mortality rate increases, particularly if the diaphragm is involved.[12]

Evaluation

There is no specific test that accurately diagnoses NSF. The diagnosis is usually made with a good history, appropriate physical examination, and exclusion of other differential diagnoses. The health professional should consider the clinical scenario of this condition while making the diagnosis. The typical clinical scenario is a patient with severe renal insufficiency (eGFR < 30 mL/min/1.73 m^2) exposed to GBCAs during an MRI examination. It is essential to know that patients with mild or moderate renal insufficiency may also be affected by this condition, but this occurred when older high-risk GBCAs were utilized. The biopsy of the affected organ, including the skin with the typical findings, may furtherly support the diagnosis.[1]

Treatment / Management

To date, there are no proven treatments that cure NSF. Restoration of renal function, if feasible, is essential to prevent further progression as it appears to slow or hold the progression.[7] Some studies showed limited skin lesions improvement by using intravenous immunoglobulin, photopheresis, and local administration of interferon.[1][7][25] 

New research documented that using steroids and methotrexate combined with ultraviolet A (UV-A) phototherapy may relieve cutaneous symptoms. UV-A phototherapy can decrease skin induration by suppressing the production of procollagen and TGF-β1.[20] Methotrexate is thought to reduce the systemic immune and inflammatory reactions while suppressing profibrotic factors' activities.[26] 

Narcotic analgesics may be required to control pain secondary to contractures.[1] Physical therapy is an important part of the treatment to maintain and improve joint motion and reduce contractures.[1] Renal transplantation may improve or produce symptom reduction.[7][27][28][29] Restoration of renal function had shown symptomatic improvements.[17]

Differential Diagnosis

NSF diagnosis relies on excluding the other differential diagnosis; thus, the health professional should be aware of these differentials while making the final diagnosis. The following diseases encompass the most likely differential diagnosis:[1]

  • β-Microglobulin amyloidosis
  • Calciphylaxis
  • Chronic graft vs. host disease
  • Carcinoid syndrome
  • Borreliosis
  • Dermatofibrosarcoma protuberans
  • Lipodermatosclerosis
  • Early cellulitis
  • Early panniculitis
  • Eosinophilic fasciitis
  • Fibroblastic rheumatism
  • Drug-induced fibrosis
  • Radiation-induced fibrosis
  • Scleroderma
  • Scleromyxedema
  • Phenylketonuria
  • Porphyria cutanea tarda
  • Superficial fibromatosis

It is essential to note that the history of GBCAs exposure during the MRI examination will favor NSF among the differential diagnosis.[23] 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]

Prognosis

Nephrogenic systemic fibrosis is considered a debilitating, rapidly 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. Thus, the prognosis depends on the extent of the visceral fibrosis. It is documented that the mortality rate associated with this condition increases as the disease progresses. The high mortality rate does not come from the cutaneous lesions but rather from visceral fibrosis, particularly in the cardiac and respiratory systems.[30]

Complications

The most debilitating NSF sequelae are the fibrosis of the visceral organs such as the heart, lungs, renal tubules, and skeletal muscles. Even though visceral fibrosis is often asymptomatic, it may contribute to the development of pulmonary hypertension, cardiomyopathy, and skeletal muscle weakness. Patients with this condition may experience blood vessel thrombosis; as the disease progresses, these patients may develop significant hypotension, affecting their ability to tolerate the hemodialysis.[31] Flexion contractures may lead to wheelchair dependence within weeks in many patients.

Consultations

  • Dermatology
  • Nephrology
  • Radiology
  • Pneumology
  • Physical therapy and rehabilitation

Deterrence and Patient Education

Since this disease is caused by GBCAs exposure in patients with severe renal impairment, optimization of the medical therapy could slow down the progression to end-stage kidney disease, especially after an acute kidney injury. Patients with this condition should be informed that there are no proven treatments that could cure the NSF, and the current therapies could only relieve some symptoms. However, if the disease progresses and visceral fibrosis develops, medication adherence may improve the patients' quality of life.[20]

For patients with severe kidney disease, health care professionals should discuss and guide patients on the potential risks of GBCAs. Physicians should discuss the MRI study's risks and benefits over the alternative use of contrast-enhanced computed tomographic (CT) scan, producing a loss of residual renal function and precipitate dialysis initiation.[11][19] The use of group II GBCAs in patients with stage 4 or 5 chronic kidney disease and those in dialysis may be safer than the use of contrast-enhanced CT scan as the residual kidney function is better protected, associated with a survival benefit.[32] Those patients who have received group I GBCAs in the past should be more careful as effects can be cumulative.[11]

Pearls and Other Issues

  • The incidence rate of NSF is drastically reduced when the regulatory authorities like the FDA, ACR, and the European Society of Urogenital Radiology (ESUR) implemented precautionary guidelines that advise the radiologist to avoid high-risk GBCAs if the patient has severe renal insufficiency.[2]
  • The chelate of GBCAs is categorized into two groups; the first is linear and less stable; the other is macrocyclic, which is more stable and provides better protection.
  • The lowest possible dose of GBCA to obtain the essential clinical information should be used.[7][11][33]
  • A second dose of GBCA should be delayed for several days to a week or avoided if possible.[7][11]
  • The diagnostic benefit of GBCAs in the imaging study must be weighed cautiously against the significant risk of developing this debilitating disease.[11][34]
  • There is no prophylactic agent that prevents the development of NSF.
  • Patients at risk must be recognized before administering a GBCA to prevent the development of NSF.[7]
  • In patients who are in chronic hemodialysis, early hemodialysis is recommended following the GBCA MRI examination.[11][17][19]
  • High-risk GBCAs (group 1) is contraindicated for patients with acute kidney injury or severe chronic kidney disease.
  • The use of GBCAs (group 2 or 3) is not contraindicated for any patient, including those with acute kidney injury or severe chronic kidney disease (eGFR < 30 mL/min/1.73 m2).[7][17][19][35]
  • A systematic review found that no patient with stage 4 or 5 chronic kidney disease developed NSF after receiving a group II GBCAs and estimated the risk for developing NSF at less than 0.07%.[8] This result was independent of the patient's chronic kidney disease stage or if the patient was receiving dialysis.[36]
  • Performing a clinically indicated MRI using a group II GBCA in a patient with acute kidney injury or severe chronic kidney disease despite the potentially harmful effect may outweigh the risk of developing NSF.[33]

Enhancing Healthcare Team Outcomes

The prevalence of NSF is higher among individuals with acute or chronic severe kidney disease. It is rational to avoid high-risk GBCAs if the eGFR < 30 mL/min/1.73 m^2. The management of this disease requires the collaboration of the entire healthcare team. The radiologist should avoid high-risk GBCAs in patients with severely injured kidneys. The primary physician should be aware of this disease if the patients presented with symptoms after exposure to GBCAs. Good history taking, thorough physical examination, and excluding the other differential diagnosis is the cornerstone for making the correct diagnosis. After confirming the diagnosis, nurses, pharmacists, and physical therapists are essential for better health outcomes. Referral to the appropriate specialist should be a consideration if the disease progresses further.[34]

The ACR recommends screening patients by identifying risk factors for compromised renal function (age >60 years, hypertension, diabetes mellitus, dialysis, kidney surgery, kidney transplant, kidney cancer, or single kidney). If the patient presents one of the risk factors, obtaining serum creatinine before GBCA administration is warranted. According to the ESUR, 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.[7]


Article Details

Article Author

Younus Shamam

Article Editor:

Orlando De Jesus

Updated:

2/7/2021 6:13:10 AM

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