What is Nephrogenic Systemic Fibrosis (NSF) and what are its symptoms?

Nephrogenic Systemic Fibrosis: Definition and Clinical Manifestations

Nephrogenic Systemic Fibrosis (NSF) is a potentially debilitating and sometimes fatal systemic fibrotic condition that occurs almost exclusively in patients with acute kidney injury (AKI) or severe chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m² who have been exposed to gadolinium-based contrast agents (GBCA). 1

Pathophysiology and Risk Factors

NSF is triggered by exposure to GBCAs, particularly those classified as group I (linear) agents. The development of NSF after GBCA exposure is idiosyncratic, with the mechanism still poorly understood. 1 The highest risk patients include:

• Patients undergoing renal replacement therapy
• Patients with AKI
• Patients with stage 4 or 5 CKD (eGFR < 30 mL/min/1.73m²)
• Those exposed to group I GBCAs, especially at repeated or higher doses 1

The incidence of NSF can be as high as 19% in high-risk patients with AKI who receive high-dose group I GBCAs. 1

Clinical Manifestations of NSF

Patients with NSF typically present with the following symptoms:

Skin and Subcutaneous Manifestations

• Skin thickening and induration 1, 2
• Contractures leading to joint immobility 1, 3
• Pruritus (itching) 1
• Hyperpigmentation 1, 3
• Symmetrical distribution of affected areas, primarily on the lower legs 3
• Epidermal atrophy and hairlessness in affected regions 3
• Two distinct presentations in late stages:
  • Confluent dermal plaques with thickening and hardening (most common)
  • Wrinkled, redundant skin similar to cutis laxa (less common) 3

Ocular Findings

• Scleral plaques 1

Systemic/Visceral Involvement

• Fibrosis of internal organs including:
  • Lungs
  • Esophagus
  • Heart 1, 4
• Joint contractures that can lead to severe disability 5
• Musculoskeletal complications:
  • Periosteal reaction on long bones
  • Intra-articular and periarticular calcifications
  • Heterotopic ossification
  • Joint ankylosis 5

Disease Course and Timing

• Symptoms typically begin between the same day and approximately 10 years after GBCA exposure
• Median time to symptom onset is 42 days after exposure 1
• The disease can significantly impact quality of life, with NSF patients scoring much worse on quality of life indices compared to controls 3
• NSF can lead to significant disability and contribute to death 4

Diagnosis

The diagnosis of NSF requires:

• Clinical history of GBCA exposure in a patient with renal impairment
• Clinical criteria using a specified scoring system
• Deep skin biopsy 1

For patients with symptoms that began within a month after MRI with contrast:

• eGFR testing should be performed
• If eGFR <30 mL/min/1.73m², NSF should be considered in the differential diagnosis 2

Prevention and Management

The most effective approach is prevention:

• Use group II (macrocyclic) GBCAs which have the lowest risk profile in patients with impaired renal function 2
• Use the lowest effective dose possible 2
• In patients who have received GBCA and developed NSF, renal transplantation may lead to resolution of skin fibrosis 5

Important Considerations

• NSF has become extremely rare since the implementation of guidelines restricting GBCA use in patients with severe renal impairment 1, 2
• There is no established therapy that consistently benefits NSF patients, making prevention crucial 4
• The clinical presentation can sometimes be confused with other scleroderma-like disorders, but NSF typically spares the face and lacks the serologic abnormalities seen in systemic sclerosis 6

Understanding the clinical manifestations of NSF is essential for early recognition and appropriate management of this serious condition in high-risk patients.