Nephrogenic systemic fibrosis: a brief review.

Nephrogenic systemic fibrosis is a fibrosing disorder of the skin that develops in patients with advanced renal failure. It mostly presents with progressive hardening or induration of the skin of the extremities. Systemic involvement is also known to occur in this entity. Exposure to gadolinium contrast for radiological evaluation has been identified as the offending agent. The condition is progressive and can be seriously disabling. Therapeutic options are limited and not rewarding in majority of the cases. Awareness of this entity is important so that proper precautionary measures can be taken at the earliest to ameliorate the condition.

Introduction

Nephrogenic systemic fibrosis (NSF) is a scleroderma-like fibrosing disorder that develops in the setting of renal insufficiency. The first case was identified in 1997, and the initial published report of 15 cases of patients with end-stage renal disease (ESRD) appeared in 2000.[1] The disorder was initially called “nephrogenic fibrosing dermopathy (NFD),” indicating the association with renal disease and the apparent involvement of the skin. Subsequently it was found that the fibrosing process was present within muscles, myocardium, lungs, kidneys and testes.[2] Thus the term “nephrogenic systemic fibrosis (NSF)” is now preferred to recognize the potential systemic nature of this disorder. A multidisciplinary team comprising of clinicians and dermatopathologists highly experienced in nephrogenic systemic fibrosis has recently completed a clinicopathological definition of NSF. The definition is currently under peer review and is expected to be published soon. Till the last update, 335 cases have been reported (http://www.icnfdr.org).

Population at Risk

NSF affects both males and females equally. It has been reported in children and the elderly (8 to 87 years), though it most commonly affects middle aged individuals.

Kidney disease appears to be a common factor in the development of NSF. Neither the duration of kidney disease nor its underlying cause is related to the development of NSF. It affects patients with advanced chronic kidney disease [glomerular filtration rate (GFR) , <60 mL/min]. It is known to affect patients on hemodialysis, on peritoneal dialysis, patients with kidney disease not on dialysis, post-renal-transplant patients with graft dysfunction and even patients with acute renal failure.

Earlier, the etiology was largely unknown and attributed to many triggering factors like dialysis fluid/membrane, usage of erythropoietin, angiotensin converting enzyme (ACE) inhibitors, hypercoagulable state and surgical or vascular procedures. A link to gadolinium (Gd) contrast agents was first suggested by Grobner in 2006.[3] Deposits of gadolinium have been shown within NSF skin lesions, strengthening the relevance of the ssociation.[4] The overall risk of developing NSF following GBCA (gadolinium-based contrast agent) usage in patients with renal insufficiency and pro-inflammatory events is 4.6%.[5]

Wahba described two solid-organ-transplant recipients, one with a near-normal glomerular filtration rate who developed NSF with reportedly no previous exposure to GBCAs, suggesting that there may be other additional factors involved.[6]

Clinical Presentation

Onset

Cutaneous lesions of NSF usually develop over a varying period of time (few days to several months) and subsequently assume a chronic, unremitting course. However, the exact interval between GBCA exposure and the appearance of first sign or symptom is difficult to ascertain because it depends on the patients’ awareness and reporting.

In a series of 20 patients, the time to disease onset after GBCA exposure ranged from 16 days to 1,991 days.[7] Swaminathan and Shah[8] proposed that the lesion develops in two phases: acute phase immediately following the exposure of gadolinium; and chronic phase, characterized by appearance of fibrosis.

Approximately 5% of the patients have a rapidly progressive (fulminant) course.

Distribution of lesions

The distribution is often symmetrical, commonly involving the lower extremities up to the knees and the upper extremities up to the elbows. More proximal spread, as well as extension to the trunk, is possible. The face is usually spared.

The clinical distribution of lesions favoring the extremities and sparing the face is the opposite of the expected localization in scleromyxedema. Unlike in patients of scleromyxedema, paraproteins are not detected in the serum in these patients.

Nature of lesion

The primary skin lesions are usually papules or nodules that are erythematous. These coalesce to form erythematous indurated irregular plaque. During early stages, these areas may appear slightly edematous with peau d’orange and erythematous surface features, and can be easily confused with cellulitis, lymphangitis or chronic (lymph)edema. Over time, the skin tends to become bowed down, with “cobblestone” appearance and brawny hyperpigmentation. Objectively, the affected areas and subcutaneous tissues are extremely hard, “woody,” and can be slightly warm to touch. Pruritus and a burning sensation are very common over affected areas.

The skin and the joints involved by the tight fibrotic process are extremely tender. Yellow scleral plaques have been reported in patients with NSF.

Non-cutaneous manifestations

Subcutaneous structures

The involvement of subcutaneous structures such as fascia, muscle, tendons, periarticular tissue, and joints is very much evident from the histopathological findings. The joints underlying NSF lesions are usually involved by a deep fibrotic process causing severe flexion contractures (particularly hands, wrists, ankles and knees) with substantial loss of range of motion and significant disability. Even ambulation can become severely compromised, and patients can be confined to a wheelchair.

Deeper tissues and visceral organ involvement

The first report of systemic involvement in this disorder described a patient whose autopsy revealed fibrosis and calcification of the diaphragm and psoas muscle and fibrosis of the renal tubules and rete testis.[2] Subsequently, Jimenez et al.[9] and Levine et al. [10] reported frequent systemic involvement, including involvement of skeletal muscles, lung and myocardium. Visceral involvement was also reported in 4 of the 13 cases in the form of cardiomyopathy and pulmonary fibrosis, as noted by Swartz et al.[11] Schieren et al.[12] reported systemic involvement, suggested by esophageal dysmotility and liver fibrosis with consecutive esophageal varices.

Cardiovascular system involvement

In a histopathological study of autopsy specimens, Mendoza et al.[13] showed fibrotic changes in the myocardium, as well as perivascular fibrosis in small coronary arterioles. Similar findings were noted by Ting et al. [2]

Pulmonary involvement

In the case series conducted by Mendoza et al.,[13] six out of a total of seven patients in whom carbon monoxide diffusion capacity was examined had a reduction of the same on pulmonary function tests. Radiographic interstitial lung disease was present in one case in the series conducted by Swartz et al.[11] However, in this report the radiographic findings were considered to represent a comorbid condition without direct association with the disease.

Thrombotic events

Thrombotic events, including repeated occlusion of the dialysis graft, peripheral vascular occlusion, transient ischemic attacks and multiple brain infarcts, have been reported in patients with NSF. However, whether the association is causal or comorbid is unclear.

Indian Experience

Literature on Indian experiences is scanty. We had published the first report of nephrogenic fibrosing dermopathy patients from the Indian subcontinent.[14] NFD was diagnosed in 6 (0.28%) of the 2,146 patients on hemodialysis and 2 of the 43 post-transplant patients. All these had histologically proven nephrogenic fibrosing dermopathy. Systemic involvement was not noted in our patients [except for a restrictive pattern on lung function test, which could have been a comorbid feature of systemic lupus erythematosus (SLE)]. Recently a case of NSF in hair-dye-induced acute renal failure following magnetic resonance imaging (MRI) examination has been reported from South India [Table 1].[15]

Table 1

Differential diagnosis of nephrogenic systemic fibrosis

Differential diagnosis

The common differential diagnoses of NSF have been summarized in Table 1.

Pathophysiology

Gadolinium exposure and NSF

Majority of proven nephrogenic systemic fibrosis cases are related to gadodiamide (90%); and some to gadopentetate (10%), which are linear chelates. This may be related to the stability of the chelate complex. Linear nonionic complexes are the least stable, followed by the linear ionic and then the cyclic ones. The unstable chelate complex tends to release free gadolinium (Gd) easily in the surrounding tissue [Table 2].[16]

Table 2

Comparative kinetics and stability of various gadolinium contrast agents

Mechanism

Free-gadolinium hypothesis[16] proposes that increased retention of GBCA brought about by renal insufficiency leads to increased Gd release from GBCA. “Free,” or dechelated, Gd is liberated, and it is postulated to trigger NSF.

“Bioactive” gadolinium chelate hypothesis[17] proposes a direct effect of chelated Gd, and it is plausible that GBCA, under certain conditions, could stimulate inflammatory cells in blood to secrete the mediators essential to the development of NSF.

Recently “circulating fibrocyte (CF) cells”,[18] which express CD34 and CD45RO antigens, are believed to play the interlinking role between deposition of Gd and the initiation of fibrosis. Increased expression of transforming growth factor beta has been reported in dendritic cells in NSF lesions. Transglutaminases, which are known to be directly activated by gadolinium, may also be responsible for inciting fibrosis.[19]

Cumulative risk model created by Swaminathan and Shah[8] is represented in the graphic below [Figure 1].

Figure 1

Cumulative risk model created by Swaminathan and Shah[8]

Biopsy and histopathology

The gold standard of diagnosis is histopathological examination of skin biopsy specimen from an involved site. As the typical changes of NFD extend into the subcutaneous fat and occasionally into the fascia or muscle, deep biopsy specimens are mandatory. Incisional or deep-punch biopsies are preferred.

Biopsy done in earlier stages of NFD (before 20 weeks of clinical onset) shows increased number of dermal spindle cells. Most of these dermal spindle cells are immunohistochemically dual positive for CD34 and procollagen. NFD cases with very deep incisional biopsies have shown spindle cells extending into the fascia and skeletal muscle. Thick bundles of collagen fibers separated by prominent cleft could be seen in the reticular dermis. There are also increased elastic fibers which run parallel to these collagen bundles. Variable infiltrations of CD68-positive mononucleated and multinucleated (3 to 4 nuclei) macrophages and factor XIIIa–positive multinucleated cells (10 to 12 nuclei) are also noted. These foci often contain abundant amount of mucin.

Biopsies done after 20 weeks of clinical onset show prominent large collagen bundles along with elastic fibers. However, there is a diminution of the mucin deposit, which in many cases is not detectable at all. With time, reduction in both CD34-positive dendritic cells and CD68-positive mononucleated and multinucleated cells is also noted.

Muscles and peripheral nerves

The microscopic appearance strongly suggests a denervation injury, perhaps with compression and strangulation of nerve twigs. The contribution of systemic processes known to lead to nerve damage (that is, chronic renal failure, diabetes) is not clear; however, the density of the fibrous tissue seen in NSF cases with muscular involvement is more than that typically observed in other systemic processes, and closely parallels the changes observed in the adjacent dermis.

Treatment

Therapeutic modalities that have been used include oral and topical steroids, pentoxyfilline, photopheresis, plasmapheresis, psoralen plus ultraviolet light, intravenous immunoglobulin, sodium thiosulfate and physical therapy. Improvement of renal function has been shown to terminate the progression of NSF and to occasionally allow the disease to resolve slowly. Therefore, the best currently available option of treatment for patients with ESRD who have NSF is renal transplantation. However, in some cases kidney transplantation has not resulted in an obvious improvement of the lesions. It seems to be important to transplant the patient as soon as possible to reverse the fibrosing process before the NSF becomes sufficiently established to lead to permanent and irreversible disability.

Preventive Strategies for Gd-induced NSF

Chronic kidney disease (CKD) stage 3

Consider alternatives to Gd-enhanced MRI.

If indicated, apply macrocyclic Gd (limitation to 0.2 mmol/kg body weight or less if possible).

CKD stages 4 to 5

Check alternatives to Gd-enhanced MRI. If clinically indicated and the benefits outweigh the risks, then use low dosages of macrocyclic contrast agents (CA) (limitation to 0.1 mmol/kg body weight). Abstain from repetitive Gd-enhanced MRI within 10 days.[20] For patients on maintenance hemodialysis, timing the MRI just before hemodialysis is important to ensure more efficient removal of Gd before it gets deposited in tissues. Other precautionary measures include usage of ultra-pure dialysate, increasing dialysate bicarbonate concentration to correct acidosis and longer and slower dialysis therapies to avoid hypotension during dialysis.

The half-life of GBCA in patients with normal kidney function is about 90 minutes. In patients with kidney disease, the elimination half-life can be longer than 30 hours.[21] The half-life of Gd is increased by 20-fold in patients treated with standard dialysis techniques compared to patients with normal kidney function.

Over 98% of free Gd is eliminated after three hemodialysis sessions.[22]

Since hemodialysis can only remove Gd from blood, the tissue clearance of free Gd by dialysis and the benefits of dialysis for prevention and treatment of nephrogenic systemic fibrosis have not been established. So the efficacy of hemodialysis as a preventive strategy will become significant only when it is initiated early and removes the gadolinium before it gets deposited in the tissues.

Disease Course and Prognosis

The prognosis depends on the extent, severity and rapidity of cutaneous involvement and the severity of systemic involvement.

Spontaneous resolution is described in some reports, typically coincident with improved/ resolved renal disease. In most patients, nephrogenic systemic fibrosis is a progressive condition. Many patients report marginal improvement and stabilization of the condition after years.

Todd et al.[23] found that the 2-year mortality rates in patients on maintenance hemodialysis were higher in patients with cutaneous changes suggestive of NSF as compared to hemodialysis patients who did not have any cutaneous manifestation (48% and 20%, respectively; adjusted hazard ratio, 2.9; 95% confidence interval, 1.4-5.9).

Conclusion

Nephrogenic systemic fibrosis is an uncommon fibrosing systemic disorder with predominant cutaneous manifestation which occurs exclusively in patients with renal insufficiency. It has been attributed largely to the usage of gadolinium-based contrast agents. It is a progressive debilitating disorder with limited therapeutic options. So physicians and nephrologists need to be aware of this condition and try to limit the usage of MRI investigation in patients with renal insufficiency. Precautionary measures need to be taken in unavoidable circumstances to ameliorate the condition of patients suffering from this devastating disorder.