Risk of Nephrogenic Systemic Fibrosis in Patients With Stage 4 or 5 Chronic Kidney Disease Receiving a Group II Gadolinium-Based Contrast Agent: A Systematic Review and Meta-analysis

JAMA Intern Med. 2020 Feb 1;180(2):223-230. doi: 10.1001/jamainternmed.2019.5284.


Importance: Risk of nephrogenic systemic fibrosis (NSF) to individual patients with stage 4 or 5 chronic kidney disease (CKD; defined as estimated glomerular filtration rate of <30 mL/min/1.73 m2) who receive a group II gadolinium-based contrast agent (GBCA) is not well understood or summarized in the literature.

Objective: To assess the pooled risk of NSF in patients with stage 4 or 5 CKD receiving a group II GBCA.

Data sources: A health sciences informationist searched the Ovid (MEDLINE and MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citation, and Daily and Versions), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Open Grey databases from inception to January 29, 2019, yielding 2700 citations.

Study selection: Citations were screened for inclusion in a multistep process. Agreement for final cohort inclusion was determined by 2 blinded screeners using Cohen κ. Inclusion criteria consisted of stage 4 or 5 CKD with or without dialysis, administration of an unconfounded American College of Radiology classification group II GBCA (gadobenate dimeglumine, gadobutrol, gadoterate meglumine, or gadoteridol), and incident NSF as an outcome. Conference abstracts, retracted manuscripts, narrative reviews, editorials, case reports, and manuscripts not reporting total group II GBCA administrations were excluded.

Data extraction and synthesis: Data extraction was performed for all studies by a single investigator, including publication details, study design and time frame, patient characteristics, group II GBCA(s) administered, total exposures for patients with stage 4 or stage 5 CKD, total cases of unconfounded NSF, reason for GBCA administration, follow-up duration, loss to follow-up, basis for NSF screening, and diagnosis.

Main outcomes and measures: Pooled incidence of NSF and the associated upper bound of a 2-sided 95% CI (risk estimate) for the pooled data and each of the 4 group II GBCAs.

Results: Sixteen unique studies with 4931 patients were included (κ = 0.68) in this systematic review and meta-analysis. The pooled incidence of NSF was 0 of 4931 (0%; upper bound of 95% CI, 0.07%). The upper bound varied owing to different sample sizes for gadobenate dimeglumine (0 of 3167; upper bound of 95% CI, 0.12%), gadoterate meglumine (0 of 1204; upper bound of 95% CI, 0.31%), gadobutrol (0 of 330; upper bound of 95% CI, 1.11%), and gadoteridol (0 of 230; upper bound of 95% CI, 1.59%).

Conclusions and relevance: This study's findings suggest that the risk of NSF from group II GBCA administration in stage 4 or 5 CKD is likely less than 0.07%. The potential diagnostic harms of withholding group II GBCA for indicated examinations may outweigh the risk of NSF in this population.

Trial registration: PROSPERO identifier: CRD42019123284.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Contraindications, Drug
  • Contrast Media / adverse effects*
  • Gadolinium / adverse effects
  • Glomerular Filtration Rate
  • Heterocyclic Compounds / adverse effects
  • Humans
  • Meglumine / adverse effects
  • Meglumine / analogs & derivatives
  • Nephrogenic Fibrosing Dermopathy / chemically induced*
  • Organometallic Compounds / adverse effects
  • Practice Guidelines as Topic
  • Renal Insufficiency, Chronic / metabolism*
  • Risk
  • Severity of Illness Index
  • United States
  • United States Food and Drug Administration


  • Contrast Media
  • Heterocyclic Compounds
  • Organometallic Compounds
  • gadoteridol
  • gadobenic acid
  • gadobutrol
  • Meglumine
  • gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate
  • Gadolinium