Nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF), also known as nephrogenic fibrosing dermopathy, occurs almost exclusively in patients with renal impairment and is associated with administration of gadolinium-based contrast agents (GBCAs) used in MRI. 

It is characterised by "firm, erythematous, and indurated plaques of the skin associated with subcutaneous oedema" ¹. Eventually, flexure contractures develop, with restriction to movement, pain and pruritus. Although the skin is primarily involved, many other organs (e.g. lungs, heart, diaphragm, liver, kidneys, esophagus, and skeletal muscles) can also be involved, eventually leading to death ⁷. 

The American College of Radiology (ACR) has divided gadolinium-based contrast agents into three groups reflecting their associated risk of NSF (Group I: highest risk; Group II: very low risk; Group III: likely very low risk but limited data available) ⁹. The number of reported cases of NSF has significantly decreased since 2008, likely secondary to regulatory actions, reduced administration of Group I GBCAs, and changes in clinical practice guidelines ¹¹. Application of preventive guidelines on usage of gadolinium based contrast agents in patients with reduced renal function has been shown to be extremely effective in protection of patients from NSF ⁵. 

Screening

Patients should be screened for the possible risk of developing NSF by using institutional screening questionnaires and calculating the eGFR ^2,7,9:

• history of renal disease: renal transplant (20% develop NSF), dialysis, single kidney, renal malignancy, renal surgery; should have eGFR checked
• liver failure patients: should have eGFR checked
• hypertension requiring medication 
• diabetes mellitus
• outpatient screening (not on dialysis): eGFR use is controversial as they rarely develop NSF

Note is made of new consensus that kidney function screening is optional for the use of Group II GBCAs ⁹.

Recommendations

Recommendations pertaining to the administration of gadolinium-based contrast agents (GBCAs) in patients with kidney disease have recently been updated, specifically with regard to the three different groups of GBCAs.

The 2021 ACR Committee on Drugs and Contrast Media considers the risk of NSF among patients administered standard doses of group II GBCAs "sufficiently low or possibly nonexistent such that assessment of renal function with a questionnaire or laboratory testing is optional prior to intravenous administration" ¹².

Group II GBCAs may be administered to high-risk patients without kidney function screening and without contact with the referring provider, depending on individual practice patterns ⁹.

American College of Radiology recommendations

Joint consensus statements by the American College of Radiology (ACR) and the National Kidney Foundation was released in November 2020 which stated:

"Since the risk of nephrogenic systemic fibrosis is so low with group II gadolinium-based contrast [agents] (GBCAs), the potential harms of delaying or withholding group II GBCAs for a clinically indicated MRI in a patient with acute kidney injury or estimated glomerular filtration rate less than 30 mL/min per 1.73 m2 may outweigh the risk of NSF in most clinical situations, regardless of dialysis status. The safety margin of group II GBCAs should be considered with the potential harm of delayed diagnosis or misdiagnosis. 

The risk estimate of NSF for group II GBCAs in patients with stage 5 chronic kidney disease is based on data from 2581 individuals. It is possible that NSF may rarely occur in this population" ⁹.

• Group I GBCAs:
  • nearly all unconfounded cases of NSF have been linked to one of the three linear Group I GBCAs
  • these GBCAs are no longer advertised in the United States and have been withdrawn from the market in other countries
• Group II GBCAs:
  • few, if any, unconfounded cases of NSF have been associated with Group II GBCAs
  • Group II GBCAs should not be withheld or delayed if harm would result from not proceeding with an indicated contrast-enhanced MRI
  • kidney screening is optional for Group II GBCAs
• Group III GBCAs:
  • few, if any, unconfounded cases of NSF have been associated with Group III GBCAs but there is insufficient confirmatory evidence to date
  • kidney function screening is necessary for group III GBCAs
  • communication between the radiologist and referring provider regarding risk of NSF is suggested for Group III GBCAs

The above recommendations are not altered for infants, children and in patients receiving:

• nephrotoxic medications (which do not need to be withheld prior to administration of group II or group III GBCAs at on-label doses)
• chemotherapy
• dialysis
• contrast-enhanced CT

Previous advice

Previous advice regarding gadolinium-containing contrast agents is below, it remains largely applicable for Group I and Group III GBCAs.

Avoid gadolinium-containing contrast agents in patients whose:

• eGFR is <30 mL/min/1.73 m²

​Cautionary use of gadolinium-containing contrast agents in patients whose ^1,3:

• eGFR is <60 mL/min/1.73 m²

"When contrast-enhanced MR imaging is requested for a patient with renal insufficiency who is hospitalised due to major surgery, major infection, or a thrombotic vascular event, alternative imaging is indicated to avoid the use of gadolinium-based contrast agents; this decision should be made after consultation with the referring service and the patient" ¹.

In cases where contrast still needs to be given ²:

• if eGFR <30 mL/min
  • take informed consent (risk of NSF <1/10,000 patients with eGFR <30 mL/min)
  • the maximum dose of 0.1 mmol/kg
  • adequate hydration must be provided
• if the patient is on dialysis: (inpatient)
  • MRI should be done just before dialysis as the contrast can be removed by subsequent dialysis
  • some centres consider dialysis a strict contraindication

Clinical presentation

• typically presents weeks to months after the administration of Gd
• typically involves the dermis in the extremities symmetrically, less commonly the trunk with the face spared, typically sparing the antecubital and popliteal fossae
• presentation resembles scleromyxoedema or eosinophilic fasciitis
• skin lesions: hyperpigmented, thickened brawny induration
• joint contractures
• pain, pruritus, skin tightness or burning sensation

Pathology

The development of NSF with exposure to Group I gadolinium-containing MRI contrast agents has been strongly reported in patients with moderate to end-stage renal impairment. This could be due to transmetallation, which is the replacement of the gadolinium from the chelate and forming a free gadolinium ion, free gadolinium ions may then deposit in different tissues and result in inflammation and fibrosis. Prolonged clearance times of gadolinium-based contrast agents in significant renal insufficiency contributes to this transmetallation process ⁷. Low stability gadolinium contrast media show the strongest association with NSF ³. 

Additional positive risk factors include:

• concurrent infectious/inflammatory condition
• concurrent infarcted/ischaemic tissue (e.g. peripheral arterial thromboembolism)
• recent surgery/trauma

Histology

• deep dermal biopsy required
• however findings are non-specific: thickened collagen bundle, mucin deposition, spindle cell proliferation, CD3 + fibroblasts

Contrast agents

The medical literature review has shown that ~78% of all unconfounded, single-agent cases of NSF have been associated with Omniscan^® (gadodiamide), while ~20% have been associated with Magnevist^® (gadopentetate dimeglumine), and less than 2%, with OptiMARK^® (gadoversetamide) ⁴.

Radiographic features

• diffuse soft tissue tracer uptake on bone scans
• skin thickening and subcutaneous stranding on multiple modalities
• skin and muscle activity on PET

Treatment and prognosis

• no consistently effective therapy
• improved renal function: renal transplant, recovery from acute renal failure (ARF)
• physical therapy
• extracorporeal photopheresis, plasmapheresis, immunoglobulin therapy, steroids and other immunosuppressive agents