Skin Lesions in Dialysis - Part 3

Nephrogenic Systemic Fibrosis (NSF)

No post or summary on skin disorders in renal failure can omit NSF. This has been mentioned in multiple previous posts on RFN - although never summarized:

The first cases of this disorder were noted between 1997 and 2000. Nearly all have been in patients with gadolinium exposure. Most of these patients had severe CKD or were on dialysis. The onset of NSF post gadolinium exposure ranges from 2 months to 15 years. The risk of NSF in dialysis patients has been reported as between 2.5 and 5%. Most centers have stopped using gadolinium if the GFR is less than 30ml/min/1.73m2. Starting or increasing EPO dose has also been associated with NSF. This disorder is a systemic disease. Skin disease typically presents with symmetrical, bilateral fibrotic, indurated papules, plaques or subcutaneous nodules. Lesions start in the hands, feet and ankles and move proximally. Rarely are lesions found on the abdomen and the head is spared. Lesions are edematous and may look like cellulitits initially. Sharp pain, pruritis and burning are also a feature. Joints lose flexibility due to fibrosis. Histological findings are variable: Increased dermal cellularity, CD34+ cells with tram tracking, collagen bundles, septal involvement and osseous metaplasia are typical findings. A comprehensive screen for other causes of severe skin disease is important. NSF has a poor prognosis and one review of the literature suggests a mortality of 28%. There is no treatment for NSF other than recovery of renal function. The preventative measure of avoiding gadolinium exposure in those at risk has significantly reduced the incidence of NSF. A good website by The International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) can be found at http://www.icnfdr.org/.

Posted by Andrew Malone

Gadolinium Beliefs

Poll results from last week:  The majority of individuals (60%) felt that it was definitely unsafe giving gadolinium to ESRD patients, with 45% of individuals also agreeing that it was unsafe in CKD stage 4.  As is consistent with the literature, most people did not feel that giving an individual with CKD Stage 3 gadolinium to be a problem.  The epidemiological data linking gadolinium to nephrogenic systemic fibrosis (NSF) (summarized nicely in this review by Dr. Derrick Todd of my home institution, Mass General Hospital) has been somewhat controversial given the frequency with which gado is administered and the relative rarity of NSF, but appears to be gaining acceptance.  Whether or not dialysis immediately after gadolinium exposure is effective in preventing NSF is still quite controversial, but my hospital has incorporated it into its policy to dialyze CKD4/5/ESRD patients exposed to gadolinium as the compound is removed by serial dialysis.  

Check out the new, politically-themed poll question of the week!

Can dialysis prevent nephrogenic systemic fibrosis?

There has been a lot of literature over the past few years regarding the identification of gadolinium-based contrast dye as the driving force behind the dermatologic fibrosing condition nephrogenic systemic fibrosis (NSF). While there remain doubters that gadolinium has definitively been shown to be the cause of this disease--an admittedly difficult claim in that the condition is overall pretty rare and the key epidemiologic studies use case numbers that are small--this theory has by and large been accepted by most nephrology departments.

At our institution, the official policy is to NOT give gadolinium to any patient with ESRD or advanced (Stage 4 or greater) CKD. Despite this policy, one could envision circumstance in which an individual with advanced renal failure is administered gadolinium dye--either if there is an oversight (e.g., the creatinine is not checked before doing the MRI) or if the benefit of doing a particular gadolinium-enhanced contrast study is so great that it outweighs the risk of NSF--which appears to be a pretty low risk in any case. The question arises in these instances: should dialysis be performed to "dialyze off" the gadolinium and therefore minimize the risk of NSF?

On the surface, the answer might seem to be yes: studies have shown that 68% of gadolinium is eliminated after a 3-hour dialysis session and approximately 98% could be removed after three consecutive dialysis sessions. However, most of the available evidence would say that dialysis is *not* effective in preventing gado-induced contrast injury. Several ESRD patients with NSF have been identified in which daily dialysis was initiated within 9-21 hours of being given gadolinium, proving that this strategy is not likely to be uniformly effective for prevention. It is postulated by some that the Gd3+ ion dissociated from the parent dye compound then deposits in tissue within a dialysis-inaccessible compartment--if this process occurs quickly, then one might guess that only dialysis initiated immediately (e.g., within a few hours) after dye exposure would be beneficial.

One could argue that much of the acceptance by nephrologists of the gadolinium-NSF link is out of a medicolegal necessity, due to the many lawfirms taking cases of dialysis patients administered gado-containing contrast. I would imagine that for the most part these current lawsuits are being directed at the manufacturers of contrast dye, though it's a good bet that such lawsuits could in the future target physicians who "knowingly gave a patient a substance contraindicated in patients with kidney disease."

Sporadic Hypocalcemia and Gadolinium

It turns out that not only do gadolinium-based contrast agents result in nephrogenic systemic fibrosis (NSF), but certain ones can also interfere with some of the common assays for quantifying serum calcium, leading to sporadic hypocalcemia. The two widely used gado agents associated with this phenomenon are gadodiamide and gadoversetamide. It is especially true in patients with underlying renal insufficiency, as the gadolinium will hang around longer.

Gleevec for Nephrogenic Systemic Fibrosis?

Nephrogenic Systemic Fibrosis (NSF) has recently been linked to the gadolinium-based contrast used for MRI imaging in patients with advanced stage (e.g., Stages 4-5) CKD and ESRD. This appears to be most true for the agent gadodiamide (Omniscan) but there are some suggestions that all gadolinium-based agents carry some unacceptably high risk in this patient population.

There is certainly no consensus yet as to how to treat NSF, but things which have been tried and may work in a subset of patients are prednisone, thalidomide, and photopheresis. In addition, a group headed by Rheumatologist Jonathan Kay at Massachusetts General Hospital is initiating a clinical trial using imatinib mesylate (Gleevec) to treat NSF based on some positive responses in a few patients. Gleevec was initially designed to inhibit the tyrosine kinase activity of the bcr-abl gene fusion product which is constitutively active in most forms of chronic myelogenous leukemia (CML). Apparently Gleevec does have some activity against endogenous tyrosine kinases which is postulated to lead to decreased secretion of critical basement membrane components thought to be involved in the fibrotic reaction which occurs in NSF.