Nephrogenic Systemic Fibrosis: Symptoms, Types, Causes and Treatment

Nephrogenic Systemic Fibrosis (NSF) is a rare, but serious fibrosing disorder that predominantly affects individuals with advanced kidney disease, particularly those exposed to certain gadolinium-based contrast agents (GBCAs) used in MRI imaging. Since its first recognition in 1997, NSF has posed diagnostic and therapeutic challenges, and awareness of its symptoms, types, causes, and management options is crucial for healthcare professionals and patients alike. This article delves deeply into the current understanding of NSF, integrating insights from recent scientific literature.

Symptoms of Nephrogenic Systemic Fibrosis

Recognizing the symptoms of NSF is vital for prompt diagnosis and management. NSF typically presents with skin changes but can progress to involve deeper tissues and other organs, leading to significant morbidity.

Symptom	Description	Frequency/Severity	Reference(s)
Skin Thickening	Hardening, induration, "woody" feel	Very common, often initial sign	1 3 5
Hyperpigmentation	Darkening or discoloration of skin	Common	3 5
Swelling	Symmetric, often in lower limbs	Early sign	4
Pain	Discomfort in affected areas	Variable	3 4
Joint Contractures	Loss of motion, stiffness, flexion	Common; leads to disability	2 4 5 17
Extracutaneous Involvement	Lungs, heart, muscles	Severe, less frequent	2 3 14
Debilitating Disabilities	Wheelchair dependence	Severe cases	1 4 17
Systemic Symptoms	Inflammatory markers, fatigue	Variable	2 7

Table 1: Key Symptoms

Typical Skin and Musculoskeletal Manifestations

The hallmark of NSF is progressive thickening and hardening of the skin, especially on the extremities. This "woody" induration often begins as symmetric swelling, redness, and pain in the lower legs, eventually spreading and causing the skin to feel like "peau d'orange" (orange peel texture) 1 3 4. As the disease advances, skin may become tethered, hyperpigmented, and nodular, severely restricting mobility.

Flexion contractures—where joints become permanently bent—are a significant complication, leading to loss of function and, in severe cases, wheelchair dependence within weeks or months 1 2 4 5 17. Some patients may initially be misdiagnosed with conditions like scleroderma due to these features.

Extracutaneous and Systemic Involvement

NSF is not just a skin disease. In many patients, the fibrosing process extends to deeper tissues such as fascia, muscles, lungs, and even the heart, resulting in reduced lung capacity, muscle weakness, and in rare cases, organ dysfunction 2 3 14. Laboratory findings may reveal elevated inflammatory markers, such as C-reactive protein or erythrocyte sedimentation rate, and low-titer antinuclear antibodies in some patients 2 7.

Course and Severity

The progression of NSF can vary. Some patients experience rapid worsening, while others have a more insidious course. While rare, spontaneous remission is almost unheard of, and the disease tends to stabilize or progress unless renal function is restored 1 17.

Types of Nephrogenic Systemic Fibrosis

While NSF was initially thought to primarily affect the skin, it has become clear that it exhibits a spectrum of manifestations, which can be categorized for clinical clarity.

Type	Main Features	Depth/Organs Involved	Reference(s)
Cutaneous	Skin thickening, plaques	Skin only	3 5 6 11
Musculoskeletal	Contractures, muscle fibrosis	Fascia, muscle	2 5
Systemic	Extracutaneous organ fibrosis	Lungs, heart, diaphragm	2 3 14

Table 2: NSF Types and Organ Involvement

Cutaneous (Skin-Limited) NSF

The majority of NSF cases begin with skin involvement—marked by thickening, hardening, and sometimes nodular lesions—most commonly on the limbs. The face is rarely affected 3 11. This form may remain skin-limited but often progresses to deeper tissues if not addressed.

Musculoskeletal NSF

When fibrosis extends beyond the dermis, the fascia and underlying muscles can become involved. This leads to "woody" muscle induration, loss of motion, and persistent joint contractures that can be severely disabling 2 5. Musculoskeletal involvement is a major determinant of patient quality of life.

Systemic (Extracutaneous) NSF

The realization that NSF can affect internal organs prompted the change in nomenclature from "nephrogenic fibrosing dermopathy" to "nephrogenic systemic fibrosis" 1 2 3 5 6 14. Organs reported to be affected include:

• Lungs (restrictive lung disease, reduced diffusion capacity)
• Heart (myocardial fibrosis)
• Diaphragm
• Esophagus
• Striated muscles

Though systemic involvement may not always be clinically overt, biopsies and advanced imaging have confirmed organ fibrosis in severe cases 2 3 14.

Causes of Nephrogenic Systemic Fibrosis

Understanding the causes of NSF has been pivotal in reducing its incidence. Research shows that NSF is a multifactorial condition, but certain risk factors are overwhelmingly implicated.

Cause/Risk Factor	Description	Significance	Reference(s)
Gadolinium-Based Contrast Agents (GBCAs)	Used in MRI imaging, especially gadodiamide	Main trigger in >90% cases	1 3 4 10 12 13 17
Renal Insufficiency	Advanced CKD, ESRD, or dialysis patients	Required for NSF development	1 2 4 5 7 8 14
Repeated/Cumulative GBCA Exposure	Multiple or high doses	Increases risk and severity	4 13
Hyperphosphatemia, High Calcium	Metabolic disturbances in CKD	Risk enhancers	4 7
Erythropoietin, Iron Therapy	High doses in CKD	Potential co-factors	4 7
Proinflammatory States	Infections, surgery, vascular events	Possible triggers	7 11 17
Other Factors	β-blockers, dialysis modality	Less established	17

Table 3: Main Causes and Risk Factors

Gadolinium-Based Contrast Agents: The Principal Culprit

A defining feature of NSF is its strong temporal association with exposure to certain gadolinium-based contrast agents (GBCAs), particularly in individuals with severe renal impairment 1 3 4 10 12 13 17. The majority of documented NSF cases (over 90%) have occurred after the use of gadodiamide (Omniscan), with other agents such as gadopentetate and gadoversetamide implicated less frequently 12 13 17. Gadolinium is usually excreted by healthy kidneys, but in those with CKD or on dialysis, it persists in the body, allowing it to dissociate from its chelating agent and deposit in tissues, potentially triggering fibrosis 13.

Renal Insufficiency: A Prerequisite

NSF almost exclusively affects patients with advanced renal dysfunction (CKD stages 4-5 or those on dialysis) 1 2 4 5 7 8 14. Without renal impairment, the risk is negligible. The impaired clearance of gadolinium, combined with metabolic disturbances common in kidney failure, creates a high-risk environment.

Additional Risk Factors

• Repeated or high-dose GBCA exposure further increases the likelihood and severity of NSF 4 13.
• Disturbed mineral metabolism (high calcium and phosphate) and high-dose erythropoietin or iron therapy may act as co-factors by promoting a proinflammatory and fibrogenic environment 4 7.
• Recent vascular surgery, infection, or systemic inflammation may serve as additional triggers 7 11 17.
• Other medications (e.g., β-blockers) and dialysis modality have been reported but are less clearly established 17.

Pathogenesis: How Does NSF Develop?

The precise mechanism is not fully understood, but current models suggest that gadolinium, especially when not promptly cleared, disrupts endothelial integrity and triggers the recruitment of circulating fibrocytes. These cells, along with elevated fibrogenic factors like TGF-β1, drive the excessive collagen deposition seen in NSF 6 9. Animal studies show that less stable GBCAs (like Omniscan) are more likely to release free gadolinium and cause NSF-like lesions 13.

Treatment of Nephrogenic Systemic Fibrosis

Treating NSF remains challenging, as no single therapy has proven consistently effective for all patients. However, several strategies can halt or even reverse disease progression, especially with early intervention.

Treatment Option	Mechanism/Approach	Outcome/Effectiveness	Reference(s)
Renal Function Restoration	Transplant or recovery from AKI	Best chance for improvement/cure	1 14 17
Avoidance of GBCAs	Prevention in at-risk patients	Dramatic reduction in incidence	8 14 17
Dialysis (after GBCA)	Attempts to remove gadolinium	May reduce risk; limited effect	14
Physical Therapy	Maintain mobility, delay contractures	Helpful for symptom management	2 5
Imatinib Mesylate	Antifibrotic agent	Some cases show improvement	15
Sodium Thiosulfate	Antioxidant, chelating agent	Case reports of improvement	16
Other Supportive Care	Pain management, treat comorbidities	Symptomatic benefit	5 7

Table 4: Treatment Options and Outcomes

Restoration of Renal Function: The Most Effective Approach

The single most effective intervention is the restoration of renal function, either through kidney transplantation or recovery from acute kidney injury 1 14 17. Many patients experience stabilization or even reversal of symptoms once normal kidney function is restored, as the body can then clear retained gadolinium and fibrogenic mediators more effectively.

Prevention: Avoidance of GBCAs

Preventing exposure to high-risk GBCAs in patients with advanced CKD has dramatically reduced new cases of NSF 8 14 17. Current guidelines recommend:

• Avoiding non-essential gadolinium-based MRI in patients with eGFR <30 ml/min/1.73m²
• Using the lowest possible dose and preferring newer, more stable GBCAs if imaging is essential
• Ensuring adequate time between repeat exposures 14

Supportive and Pharmacological Therapies

• Physical therapy is crucial for maintaining joint mobility and delaying contractures 2 5.
• Imatinib mesylate, a tyrosine kinase inhibitor, has shown promising results in reducing skin thickening and improving joint flexibility in small case series 15. However, relapse is common if treatment is discontinued.
• Sodium thiosulfate has been reported to improve pain and skin changes in isolated cases, possibly by chelating gadolinium and reducing oxidative stress 16.
• Dialysis immediately after GBCA administration may help reduce gadolinium burden but is not foolproof 14.
• Other supportive care includes pain management, wound care, and treating related conditions 5 7.

Limitations and Prognosis

While some patients stabilize or improve, especially with early intervention, many experience persistent disability. Spontaneous remission is rare 1 17. Deaths directly attributable to NSF are uncommon but have been reported, often related to severe systemic involvement 17.

Conclusion

Nephrogenic Systemic Fibrosis is a rare but devastating complication, predominantly seen in patients with advanced kidney disease exposed to certain gadolinium-based contrast agents. Its clinical presentation, systemic reach, and association with imaging agents make it a critical condition for clinicians to recognize and prevent.

Key Takeaways:

• NSF is characterized by progressive skin thickening, pain, and joint contractures, with potential involvement of deeper tissues and organs.
• It primarily affects patients with advanced renal dysfunction exposed to GBCAs, especially less stable agents like gadodiamide.
• The disease can present in cutaneous, musculoskeletal, or systemic forms, depending on the depth and extent of fibrosis.
• Avoidance of high-risk GBCAs in patients with kidney disease has significantly reduced new cases.
• Restoration of renal function offers the best hope for improvement or cure, while other treatments (imatinib, sodium thiosulfate, physical therapy) may provide symptomatic benefits.
• Early recognition and prevention are essential, as NSF can rapidly lead to severe disability and diminished quality of life.

Staying informed of the latest guidelines and therapeutic advances can make a critical difference in the management and outcomes of patients at risk for NSF.