Iodine-based contrast media, multiple myeloma and monoclonal gammopathies: literature review and ESUR Contrast Media Safety Committee guidelines

Since 1954, a number of case reports have linked the use of high osmolality ionic iodine- based contrast media to the development of acute renal failure in patients with multiple myeloma (MM) and monoclonal gammopathies (MG) who had undergone excretory urography and/or, less frequently, retrograde pyelography, cholecystography or angiography [1, 2].

Concern about the use of iodine-based contrast medium in myeloma patients has been challenged since the 1980s, when it was suggested that the deterioration in renal function was due to dehydration, pre-existing renal failure, diabetes mellitus, hypercalcaemia and the use of nephrotoxic drugs, rather than to the iodine-based contrast medium [3].

However, many radiologists and clinicians still consider MM and MG a contraindication to contrast medium use. They often require checks for Bence-Jones proteinuria before contrast-enhanced CT examinations, and deny clinically indicated investigations in myeloma patients. A survey among 2,000 practicing radiologists, members of the American College of Radiology (ACR), showed that 36 % of them never consider the use of iodine-based contrast media in myeloma patients [4], and the ACR still considered MM a possible risk factor for post-contrast acute kidney injury as recently as 2016 [5].

In view of these facts, the ESUR Contrast Media Safety Committee (CMSC) considered it necessary to undertake a systematic review of the available literature about the incidence of post-contrast acute kidney injury (PC-AKI) in patients with MM and MG, in order to produce evidence-based recommendations for the use of iodine-based contrast media in these patients. This study and the resulting guidelines were extensively discussed by the CMSC academic members and were also reviewed by the representatives of the pharmaceutical companies who are consultants to the Committee. A consensus report was agreed by the CMSC academic members at their meeting in February 2017.

For this systematic review, data collection and analysis were performed according to the guidelines of the PRISMA statement 2009 [10]. Eligibility criteria and methods of analysis were specified in advance. Cohort studies and case-control studies reporting changes in renal function in patients with MM or MG following administration of iodine-based contrast media were included. Both non-controlled and controlled investigations, defined as studies in which patients with MM or MG were directly compared with patients without myeloma from the same community, were included. Studies in which a relationship between contrast medium administration and renal function changes could not be confirmed were excluded.

The search and selection procedures used are shown in Fig. 1. Most studies were excluded during title and abstract review because they were not relevant to the clinical problem being studied. A total of 55 publications were considered potentially relevant and were retrieved in full text. Of these, 41 were excluded for a variety of reasons: 14 were case reports, 12 were review articles, two were in vitro studies in which no patients were investigated and nine were surveys, letters, consensus documents or editorials. In three studies the number of patients having iodine-based contrast medium or MM was not reported. The last paper was not about myeloma.

This left 14 observational studies that met the eligibility criteria used for this review [2, 13‐25] (Table 2); 11 were retrospective and three were prospective [16, 21, 25]. Thirteen were cohort studies and one was a case-control study [25]. The Newcastle-Ottawa scores indicated quality levels ranging between 5 and 9 on a scale of grades 0–9 for cohort studies and 0–8 for case-control studies, except for one investigation [17] with a score of 1 (Table 3). This last study reported anecdotally on 18 intravenous urograms in 16 myeloma patients in whom no complications were observed and it was excluded from the systematic review. This left 13 studies with average Newcastle-Ottawa score grade 6.2 for evaluation. Of these, eight studies in which there was either no control group or the control group could not be evaluated [18] had lower scores of 5–6.

The 13 selected studies were markedly heterogeneous both in relation to type of investigation and contrast medium (Table 2). They report a total of 824 iodine-based contrast medium administrations in 642 patients with MM (639 administrations in 543 patients) or MG (185 administrations in 99 patients), in which 12 unconfounded cases of post contrast acute kidney injury were found (1.6 %). In 11 of the studies high osmolality ionic contrast media were used. Low osmolality non-ionic contrast media were used in two studies in which contrast-enhanced CT was performed 210 times in 76 patients with myeloma (n=46) or gammopathies (n=30) [20, 25]. PC-AKI was observed in 4/210 (1.9 %) cases [20]. These four patients had normal creatinine levels ranging from 0.9 to 1.3 mg/dl before contrast medium administration, and these increased slightly within 48 h after contrast injection (range: 1.2–1.6 mg/dl).

Contrast-enhanced studies with iodine-based contrast media are not routinely performed to stage MM or to investigate MG, but may be required to detect complications of the disease. However, many radiologists withhold iodine-based contrast media from all patients with MM or MG because they are considered at very high risk of acute kidney injury [4]. Until 2016, the ACR Manual on Contrast Media (version 10.2) stated that “paraproteinaemias, particularly MM, are known to predispose patients to irreversible renal failure after high osmolality contrast media administration due to tubular protein precipitation and aggregation; however, there is no data predicting risk with the use of low osmolality or iso-osmolality agents” [5]. This statement no longer appears in the 2017 ACR Manual (Version 10.3) [26]. As early as 1992 McCarthy and Becker [27] reviewed the literature on renal failure after high osmolality contrast media, and stated that major risk factors for acute renal failure in myeloma patients were not intravenous contrast media as once suspected, but rather hypercalcaemia, dehydration, infection and Bence-Jones proteinuria. They also noted that it was uncertain whether high osmolality contrast further increases these risks and that some of the older contrast media precipitate Bence-Jones protein in vitro.

Our review showed that the literature available is both limited and heterogeneous. There are a number of case reports. De Fronzo et al. [2] in 1975 collected 29 published case reports of acute renal failure in patients with MM who underwent intravenous urography (16 apparently with baseline normal renal function and 13 with chronic renal insufficiency). No randomised and very few controlled trials are available, and most studies are retrospective. Many studies were published before 1980. Most of the myeloma patients had intravenous urography after preparatory dehydration and purgation and ionic high osmolar contrast media that have been withdrawn from the market in most countries were used. Also, a variety of imaging techniques were used and there were no studies using intra-arterial contrast injection. Furthermore, different criteria for detecting post-contrast renal function deterioration were used. Only two studies considered the use of the non-ionic contrast media that are in wide use currently in patients with MM and MG. All these features limit the value of our systematic review.

The recent retrospective study by Pahade et al. [20] showed that the incidence of AKI following non-ionic contrast medium administration (ioversol or iodixanol) in patients with MM with a normal SCr is low and correlates with β₂-microglobulin levels (which increase both with higher tumour burden and diminished renal function). Additionally, Preda et al. [25] carried out a prospective study showing that the use of a non-ionic dimer (iodixanol) is safe in patients with MG and an eGFR ≥60 ml/min/1.73 m².

Although the evidence provided by the literature is rather poor, it appears that MM and MG alone cannot be considered a risk factor for AKI following intravenous iodine-based contrast medium administration. However, the risk may become significant when SMM and MM are associated with impaired renal function [8]. It therefore appears that, in cases of SMM or MM with normal renal function, it is not necessary to measure the urinary light chains before iodine-based contrast administration. In fact, if renal function is preserved, urinary light chains are unable to cause renal damage whatever their concentration. Therefore, in patients with normal renal function there is no need to check for Bence-Jones proteinuria, since this test cannot be considered as a surrogate biomarker of kidney function [8, 20]. When there is renal impairment, the usual rules for preventing PC-AKI should be considered, such as the possibility of an alternative imaging method not using iodine-based contrast media and volume expansion [28]. If contrast media are required for clinical reasons in patients with SMM or MM, measuring the serum calcium is much more important than checking the urinary FLCs. High concentrations of serum calcium are relatively common in any stage of SMM or MM, and are an important risk factor for AKI. Hypercalcaemia induces vasoconstriction and can inhibit antidiuretic hormone activity, so causing dehydration, which further increases the risk of myeloma casts, leading to worsening of the renal impairment [8]. Haematologists are fully aware of the risk of hypercalcaemia in SMM and MM, and serum calcium measurement is now one of the tests routinely performed in the follow-up of all stages of the disease. Also, hypercalcaemia is usually symptomatic causing malaise, constipation, anorexia, nausea, lethargy, confusion, coma and cardiovascular manifestations such as shortening of the QT interval and dysrhythmias. Therefore, it is very unlikely that an imaging method requiring iodine-based contrast medium administration will be requested without knowledge of the patient’s serum calcium. The treatment of hypercalcaemia is usually easy and includes aggressive re-hydration followed by diuresis with frusemide, which increases urinary calcium excretion, and intravenous bisphosphonate (pamidronate or zoledronic acid).

Modern non-ionic iodine-based contrast media can safely be administered to patients with MM or MG who have normal renal function. However, comorbidity, such as impaired renal function and hypercalcaemia, which increases the risk of AKI, frequently coexists in these patients and close cooperation between radiologists and referring clinicians is needed for optimal management of these patients. Simple guidelines are proposed (Table 4).