NEWSLETTER 23: NEPHROGENIC SYSTEMIC SCLEROSIS

NSF made its appearance in 1997, when the first case was diagnosed, and it was formally recognized in 2000.

At first it was seen as a skin disorder and was called Nephrogenic Fibrosing Dermopathy (NFD). But gradually wider symptoms were described and it is now considered a systemic disorder, as it affects internal organs as well as the skin.

NSF has been connected to the use of Gadolinium, a contrast agent used in preparation for MRIs (Magnetic Resonance Imaging) and MRAs (Magnetic Resonance Angiogram). Gadolinium is an ingredient in the injection, which is given before these procedures, with the purpose of creating visual contrast on the printed films, between normal and abnormal tissue. This enables the doctor to see your condition more clearly.

Since this is a recently discovered disease, there is little known about it and few studies have been done. The FDA approved Gadolinium in 1988, but since the number of NSF cases has been increasing, the FDA issued Advisories to medical professionals, warning them to use all possible caution when treating patients with chronic kidney disease.

Nephrogenic Systemic Fibrosis (NSF) is a rare and serious disease that involves fibrosis of joints, eyes, skin and internal organs. The cause of Nephrogenic Systemic Fibrosis (NSF) is not fully understood by the medical community, but it definitely appears to be associated with exposure to gadolinium which is used as a contrast dye substance for MRIs and MRAs. Gadolinium is a silvery white, malleable and ductile rare earth metal with a metallic luster used as a component of MRI contrast agents to help enhance images in medical magnetic resonance imaging (MRI).

Patients with Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD) may develop large areas or patches of hardened skin or thickened skin with fibrotic nodules and plaques. These areas of thick skin and flexion contractures can severely limit a patient's range of motion. Nephrogenic Systemic Fibrosis (NSF) resembles scleromyxedema at the histologic (microscopic) level; it shows a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin. Click on this link.

GUIDELINES FOR THE USE OF GADOLINIUM IN PATIENTS WITH RENAL IMPAIRMENT
Updated August 9, 2007
 
BACKGROUND
In June 2006, December 2006, January, 2007, and again in May 2007, the Federal Drug Administration (FDA) issued advisories concerning the risk for patients who have severe renal insufficiency or renal failure and receive gadolinium agents of developing the debilitating complication of nephrogenic systemic sclerosis/dermatosis (NSF/NSD)¹. Recent advisories from the European community help clarify some of these issues². To date, it also appears to be most often associated with only certain gadolinium agents (primarily with Omniscan^®; isolated reports with OptiMARK^® and Magnevist^®). The risk of NSF may be up to 5% in patients with severe renal impairment who receive Omniscan⁴.

   RISK FACTORS FOR NSF: 

1. Renal insufficiency: GFR less than 30 ml/min.
2. Chronic hemodialysis. Risk with chronic peritoneal dialysis is likely similar.
3. Acute renal failure (ARF): Risk of NSF may occur at a higher GFR. In ARF, calculating a GFR is appropriate only if the creatinine is in steady state; otherwise, any calculation my grossly overestimate the actual GFR.
4. Large doses of gadolinium, e.g. for MRA.
5. Active systemic pro-inflammatory conditions (vascular surgery, transplantation surgery, or other major surgery; sepsis, pneumonia, osteomyelitis, or other major infection; and arterial or venous thrombosis that has caused ischemia and organ or limb damage).
6. Liver transplantation: Scheduled for, or following, liver transplantation.
7. Possibly children < 1 year and pregnant patients.

PROCEDURE:
Always Consider Alternative Imaging Strategies:

1. MR without gadolinium (e.g. SSSP, TOF imaging).
2. CT with intravenous iodinated contrast for patients on chronic dialysis. Discuss with patient's clinician since residual renal function may be important to consider even if on dialysis; this is particularly true for peritoneal dialysis patients.
3. Non-contrast examinations
4. Alternative modalities: ultrasonography, nuclear medicine.
 

1.     Inpatients with a known serum Creatinine within 24 hours:

• Evaluate the GFR value. If is not reported in laboratory values, calculate an estimated GFR.
• If the patient is on chronic (not acute short-term) dialysis, consider CT with i.v. iodinated contrast.
• If the patient is on short-term dialysis for acute, potentially-recoverable renal failure, avoid CT with iodinated contrast.
 

· Use an agent for MRI other than Omniscan^® , Magnevist^®, or OptiMARK^® 

• If the GFR is < 30 ml/min (deep orange or red on the slide rule), or
• If the patient has acute renal impairment and the GFR is < 60mLs/min (orange or red on the slide rule)

· In these settings always:

1. Discuss with clinician and patient the risk/benefit of MR with gadolinium.
2. Obtain informed consent.
3. Do not use the agents (above) that are associated with NSF.
4. For patients already on chronic dialysis: schedule dialysis (or the MRI) so dialysis occurs within 12 hours following gadolinium. Optimally, the planned MRI and subsequent dialysis should be discussed with the Renal Fellow (on call) prior to scheduling of the exam so that it can be coordinated appropriately.
5. For patients with advanced renal disease (GFR <30 in chronic and <60 in acute renal failure) who are NOT on dialysis, gadolinium agents should not be used or, if gadolinium is considered necessary, at present there is no indication for dialysis after the study.
 

2. Inpatients without a known serum Creatinine within 24 hours:
· Phone floor and ask them to order a creatinine prior to arriving in radiology if they have had a serum creatinine of > 1.5 mg/dL in the past.

  3. Outpatients
Ask all patients scheduled for a contrast-enhanced MRI whether they:

• Are currently or have ever been on dialysis?
• Have known kidney disease?
Outpatients who have a history of kidney disease.

1. Obtain a serum creatinine within 24 hours prior to gadolinium administration.
2. Follow the "Inpatient" recommendations for administration of gadolinium in patients with a creatinine within 24 hours.
 
Outpatients not on dialysis and who have no history of kidney disease.

1. Administer any gadolinium agent.
 
DOSING:

• Use regular doses of gadolinium (0.1 mmol/kg). Do not double-dose patients using Omniscan^®. Do not double-dose patients with severe renal impairment (GFR < 30 ml/min).
Martin Gunn, MD and William Bush, MD, August 9, 2007
 
1. FDA Drug Advisory: [www.fda.gov/cder/drug/advisory/gadolinium_agents.htm.]
2. Academic members of the European Society of Urogenital Radiology Contrast Safety Committee: Guidelines and position statement; July, 2007 (www.esur.org)
3. Sadowski et al, Radiology April 2007, 10.1148 (Online pre-publication version)
4. Kanal E, ACR Guidance Document for Safe MR Practices: 2007, AJR (June) 2007; 188:1-27.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Member, ACFEI (American College of Forensic Examiners Institute of Forensic Science)
Expert Medical Witness, ExpertMD
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the APPI (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Member, SIMPD (Society for Innovative Medical Practice Design)
Member, ACPM (American College Preventive Medicine)
Ethics Committee Member, Jupiter Medical Center
IRB Member, Jupiter Medical Center
Founder, CertifiedResearchers.com