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NDT Advance Access published online on November 28, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn655
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Acute phase reaction to gadolinium-DTPA in dialysis patients

Henning Steen1, Evangelos Giannitsis1, Claudia Sommerer2, Udo Bahner3, Margit Brandl3, Christoph Merbach1, Constanze Merten1, Eberhard Ritz2, Hugo A. Katus1, Martin Zeier2 and Vedat Schwenger2

1 Division of Cardiology, Department of Internal Medicine 2 Division of Nephrology, University of Heidelberg, Heidelberg 3 kfh-Nierenzentrum Würzburg, Germany

Correspondence and offprint requests to: Vedat Schwenger, Division of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Tel: +49-6221-9112-0; Fax: +49-6221-9112-229; E-mail: vedat.schwenger{at}med.uni-heidelberg.de



   Abstract
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 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Several late sequelae of the administration of gadolinium (Gd)-containing MRI contrast agents have been described in patients with advanced renal failure. In an observational series, we found a remarkable frequency of peracute reactions after administration of Gd-DTPA used for cardiovascular evaluation before renal transplantation.

Methods. In a 26-month observational period, 13 of 136 haemodialyzed or CAPD patients exhibited onset of fever, chills and nausea within hours after administration of Gd-DTPA peracute. A minority showed persistent cessation of residual diuresis. We performed blood cultures in most patients and evaluated white blood cell (WBC) counts, eosinophils, CRP, heart rate and blood pressure.

Results. Within an average of 12 h (range 12–36 h) after Gd administration, the 13 patients (9 males, 4 females; median age 61 years, range 47–79) developed consistent symptomatology with fever (median 39.0°C, range 37.5–39.5), chills, malaise, hypotension, vomiting, dyspnoea—initially raising suspicion of septicaemia. Subsequent blood cultures on bacterial contamination of the injected product remained negative throughout; bacterial or endotoxin contamination of the reagent was excluded. Steroids were tried in the first two patients without a noticeable effect. In all subsequent patients, symptoms were attenuated during the first 5 h dialysis (F60HPS with 280 ml/min blood flow) and disappeared within 72 h. CRP levels remained markedly elevated up to 14 days. Lymphopenia was seen in all patients, and polymorphic neutrophils (PMN) remained normal. Two polyuric patients developed persistent anuria. After a median of 16 months, none of these patients developed nephrogenic systemic fibrosis.

Conclusion. This series with unusually severe acute phase reactions was caused by one specific preparation. Such peracute reactions may be relevant for the so-far largely unresolved pathogenesis of the skin reaction to some Gd products in end-stage renal disease (ESRD) patients. It remains unresolved whether the reaction observed with Gd-DTPA do in principle also occur with other Gd reagents.

Keywords: acute phase reaction; acute renal failure; dialysis; gadolinium; lymphopenia



   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Since the first observation [1], there have been numerous reports on gadolinium (Gd)-induced nephrogenic systemic fibrosis (NSF) [2–4], which is at least partially explained by an endothelial cell reaction [5]. In addition, in some polyuric patients acute renal failure was provoked by the administration of Gd [6]. In several recent reports, the authors mention that symptoms developed in the course of 3 weeks to 18 months after administration of Gd [7].

Here we report an acute phase reaction to at least one of the Gd compounds used for MRI investigation, i.e. diethylenetriamine penta-acetic acid (Gd-DTPA). It is currently unclear whether this complication is related to the late cutaneous sequelae of Gd.



   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Gd-DTPA (Magnevist®, Schering, Berlin, Germany) was administered to 136 patients on haemodialysis or CAPD, 76 in Heidelberg and 60 in Würzburg. One hundred twenty-eight patients were on haemodialysis and 8 patients on CAPD. The indication for the administration of Gd-DTPA was cardiovascular evaluation before renal transplantation (cardio MRI in Heidelberg and cardio MRI or peripheral angiography in Würzburg). All patients received contrast enhancement MRI using Gd-DTPA at a dose between 0.28 and 0.34 ml/kg body weight (bw) of standard dose 0.5 mmol Gd-DTPA. Consecutive blood samples were drawn only from the 13 patients who developed symptoms.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Of these 136 patients, the 13 patients (6/76 in Heidelberg, 7/60 in Würzburg, 9 males, 4 females; median age 61 years; range 47–79) developed a consistent symptomatology within an average of 12 h (range 12–36 h): without any skin reaction patients had fever (median 39.0°C, range 37.5–39.5), chills with shivering, malaise, hypotension, vomiting, and dyspnoea initially raising suspicion of septicaemia. Because of suspicion of bacterial contamination of the injected contrast agent, blood cultures were obtained in all but two patients and remained negative throughout; the producer excluded bacterial or endotoxin contamination of the reagent (personal communication). Owing to the alternative suspicion of an anaphylactic reaction, we administered steroids to the two initial patients. Because in all subsequent patients clinical signs and symptoms were attenuated during the first 5 h dialysis (F60HPS with 280 ml/min blood flow) and disappeared completely within 72 h, subsequent steroid administration was halted. Two of the six polyuric patients in Heidelberg developed persistent anuria, necessitating maintenance haemodialysis in one CAPD patient.

This dramatic acute symptomatology was accompanied by a marked and extended elevation of CRP for up to 14 days (Table 1, Figure 1). It increased from a median at baseline of 7 mg/dl (range 2–19 mg/dl) to an average maximum on Day 3 (median 265 mg/dl, range 61–410). In two of the six Heidelberg patients (differential blood count was performed only in the Heidelberg patients), an increase of eosinophils up to 22% (1.8/nl) was observed. Immunoglobulin E (IgE), not available in all patients, rose up to 615 kU/l. All patients developed marked lymphopaenia (median 0.6/nl, range 0.6–1.3/nl, median relative cell count 10%, range 6–15%), and polymorphic neutrophils (PMN) remained within the normal range in all patients (median 5.3/nl, range 5.3–7.4, median relative cell count 72.3%, range 58–77.8%). Spleen size (by sonography) did not change.


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  		Table 1 Demographic data of 13 dialysis patients with acute reaction to administration of gadolinium-DTPA

 

Figure 1
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  		Fig. 1 CRP levels in dialysis patients after administration of gadolinium-DTPA.

 
None of the patients had a history of allergy or autoimmune disease, and specifically none had a history of adverse reactions to radiocontrast. The underlying renal diseases were glomerulonephritis 4/13; diabetic nephropathy 4/13; hypertension (n = 1); reflux nephropathy (n = 1); hepatorenal syndrome (n = 1) and unknown (n = 2). After a 16-month follow-up, none of the 13 (but 1 of the 123 without acute response to Gd administration) patients has so-far developed evidence of nephrogenic systemic fibrosis (NSF).



   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The extensive literature on NSF deals extensively with the cutaneous and renal complications from the administration of Gd compounds in patients with advanced renal failure [2–4]. So far the majority of reported cases concerned Omniscan [2], and only a minority was reported after administration of Gd-DTPA, the compound used in the present series [2].

To the best of our knowledge, the above constellation of acute signs and symptoms has not been reported before. So far, there is no evidence that the observed symptomatology generally ensues after Gd administration. An early report mentioned rash and urticaria (which was not observed in our patients) in 25 of 13219 patients receiving gadopentetate dimeglumine, but no reaction was considered to be serious and no fever was mentioned [8]. However, this severe systemic response to Gd administration seems to be specific, or at least aggravated in renal failure patients.

The present observation does not permit conclusions as to whether this acute reaction was triggered by Gd per se (potentially released by transmetallation), by the chelate or by contaminants. One has to consider that transmetallation is accentuated, when the half-life of Gd is prolonged [9]. Gd chelates are distributed in the extra-cellular space and eliminated almost exclusively by the kidneys through glomerular filtration [9]. Renal failure impairs but maintains renal Gd excretion without resorting to a non-renal route [10]. For example, the gadodiamide half-life in healthy volunteers is 1.3 h. In end-stage renal disease (ESRD) patients, it is 34.3 h and in peritoneal dialysis patients even 52.7 h [10].

One can only speculate about the pathogenesis of the Gd-induced acute reaction in dialysis patients. In this context, it is of interest that Gd chloride not only blocks phagocytosis by Kupffer cells but also disrupts Kupffer cells [11]. There is evidence that circulating lipopolysaccharides (LPS), which are an important stimulus of proinflammatory cytokine synthesis, are cleared primarily by the liver [11,12]. In the case of Kupffer cell destruction or blocked phagocytosis (which occurs after Gd exposition), LPS clearance might be impaired. In this regard, it is remarkable that treatment with Gd chloride and elimination of Kupffer cells cause a significant increase of liver TNF-{alpha} transcripts [13]. This consideration may be of particular importance in dialysis patients. Increased plasma concentrations of LPS have been demonstrated in patients with chronic heart failure and hypervolaemia [14]. The authors argued that oedema of the bowel wall permits translocation of bacterial LPS [15] and the same might well be true for hypervolaemic dialysis patients as well.

The present series with unusually severe acute reactions was caused by Gd-DTPA, but we cannot exclude that it represents only the tip of the iceberg. We are currently aware of a substantial number of uraemic patients who have left radiology departments after administration of Gd compounds and developed a similar symptomatology at home or in dialysis units. We suspect that a non-negligible number of unreported cases exist.

NSF did not develop in our 13 patients. However, we cannot definitely conclude that the two reactions are unrelated.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant (2006) 21:1104–1108.[Free Full Text]
  2. Broome DR. Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol (2008) 66:208–212.[CrossRef][Web of Science][Medline]
  3. Saab G, Abu-Alfa A. Nephrogenic systemic fibrosis—implications for nephrologists. Eur J Radiol (2008) 66:208–212.[CrossRef][Web of Science][Medline]
  4. Shabana WM, Cohan RH, Ellis JH, et al. Nephrogenic systemic fibrosis: a report of 29 cases. AJR Am J Roentgenol (2008) 190:736–741.[Abstract/Free Full Text]
  5. LeBoit PE. What nephrogenic fibrosing dermopathy might be. Arch Dermatol (2003) 139:928–930.[Free Full Text]
  6. Gemery J, Idelson B, Reid S, et al. Acute renal failure after arteriography with a gadolinium-based contrast agent. AJR Am J Roentgenol (1998) 171:1277–1278.[Free Full Text]
  7. Wiginton CD, Kelly B, Oto A, et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR Am J Roentgenol (2008) 190:1060–1068.[Abstract/Free Full Text]
  8. Nelson KL, Gifford LM, Lauber-Huber C, et al. Clinical safety of gadopentetate dimeglumine. Radiology (1995) 196:439–443.[Abstract/Free Full Text]
  9. Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol (2003) 76:513–518.[Abstract/Free Full Text]
  10. Rosenthal DI, Becerra CR, Toto RD, et al. Reversible renal toxicity resulting from high single doses of the new radiosensitizer gadolinium texaphyrin. Am J Clin Oncol (2000) 23:593–598.[CrossRef][Web of Science][Medline]
  11. Hardonk MJ, Dijkhuis FW, Hulstaert CE, et al. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol (1992) 52:296–302.[Abstract]
  12. Sehic E, Li S, Ungar AL, et al. Complement reduction impairs the febrile response of guinea pigs to endotoxin. Am J Physiol (1998) 274:R1594–R1603.[Web of Science][Medline]
  13. Rai RM, Zhang JX, Clemens MG, et al. Gadolinium chloride alters the acinar distribution of phagocytosis and balance between pro-and anti-inflammatory cytokines. Shock (1996) 6:243–247.[Web of Science][Medline]
  14. Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet (1999) 353:1838–1842.[CrossRef][Web of Science][Medline]
  15. Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet (2000) 356:930–933.[CrossRef][Web of Science][Medline]
Received for publication: 29. 7.07
Accepted in revised form: 31.10.08


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