Recently, Schouten et al. reported hypophosphatemia associated with diminished tubular phosphate reabsorption and diminished levels of bi-hydroxylated vitamin D3 3 to 6 weeks after intravenous administration of iron polymaltose in eight iron-deficient female patients without abnormal renal or parathyroid function. The mechanism by which this complication occurred was hypothesized to be mediated by an increase in fibroblast growth factor 23 levels (1). In addition, studies of intravenous iron carboxymaltose administration in the postpartum setting have revealed a moderate decrease in serum phosphate levels that is generally asymptomatic and transient (2).
This adverse effect of intravenous iron administration has not been studied extensively in kidney transplant recipients, even though iron deficiency and anemia are frequent problems after transplantation (3). Currently, in many centers, intravenous route of administration is becoming increasingly used because of increased efficacy and better gastrointestinal tolerance, when compared with oral iron therapy. The new iron carboxymaltose preparations also allow for significant shortening of administration time and are considered to be more convenient and potentially cost effective (4).
A 42-year-old female patient received a living donor kidney allograft in May 2008 for end-stage renal disease because of autosomal dominant polycystic kidney disease, with an uneventful postoperative course and good allograft function (estimated glomerular filtration rate of 50 mL/min/1.73 m2) on a triple drug immunosuppressive regimen of tacrolimus (levels of 6–8 μg/L), enteric-coated mycophenolic acid (360 mg twice daily), and prednisone (tapered to 5 mg once daily at 4 months posttransplantation). She developed posttransplantation diabetes requiring insulin with adequate glycemic control (HbA1c 5.7%) and had mild chronic hypomagnesemia that was stable over time (0.5 mM; normal range 0.6–1 mM). There was no persistent hyperparathyroidism (parathyroid hormone 40 ng/L; normal range 10–70 ng/L), and she received routine long-term calcium and vitamin D supplements for osteoporosis prophylaxis.
At 18 months after transplantation, she received three intravenous infusions (500 mg each) of iron carboxymaltose (Ferinject; Vifor Pharma, Switzerland), after a first test dose of 100 mg, at intervals of 10 days for mild anemia (Fig. 1). One month after initiating therapy, the patient developed generalized weakness. New onset profound hypophosphatemia was diagnosed (0.16 mM; normal range 0.8–1.4 mM) associated with mild hypocalcemia (corrected calcium 2.07 mM; normal range 2.1–2.5 mM) and inappropriate phosphaturia (urinary phosphate 3.5 mM, tubular reabsorption of phosphate 91%). There were a newly diminished 1,25-OH-vitamin D3 level (36 pmol/L; normal range 48–160 pmol/L) that returned to normal after 1 month and transient hyperparathyroidism (parathyroid hormone 141 ng/L) that was not present on blood samples 1 month before and 2 months thereafter. Levels of 25-OH-vitaminD3 remained normal (26 μg/L; normal range 8.4–52 μg/L). There were no cardiopulmonary, gastrointestinal, or hematologic manifestations. She was admitted to the hospital for the intravenous phosphate administration, followed by oral phosphate therapy and calcitriol treatment.
Additional plasma measurements revealed normal values of sodium (142 mM), potassium (3.5 mM), protein (69 g/L), albumin (42 g/L), and liver function tests. There was no glucosuria or proteinuria on urinalysis. Fibroblast growth factor 23 levels were not determined.
As plasma phosphate levels began to increased after phosphate repletion, her clinical condition rapidly improved, and she could leave the hospital after 48 hr. Within 2 weeks, her phosphatemia had normalized on phosphate therapy, and her symptoms resolved.
Along with preliminary results indicating good safety and efficacy of iron carboxymaltose (Ferinject) in patients on dialysis, recent clinical studies in chronic kidney disease and kidney transplant patients have found a satisfactory safety profile (4). However, in these studies, no laboratory values other than routine hematologic parameters and creatinine were mentioned, and the follow-up was short.
Herein, we report a striking and potentially life-threatening complication of intravenous administration of Ferinject in a kidney transplant recipient, who presented with severe and symptomatic hypophosphatemia shortly after initiating therapy. Although hypophosphatemia has been described in the nontransplant setting, to our knowledge, this is the first case to be reported after organ transplantation. In our patient, there was no evidence of persistent hyperparathyroidism or vitamin D deficiency. However, the patient was receiving long-term tacrolimus therapy with some evidence of tubular toxicity, as indicated by her mild hypomagnesemia. Whether chronic tacrolimus (or cyclosporine) use in the setting of moderate kidney failure may predispose transplant recipients to this adverse effect of iron carboxymaltose, or contribute to its severity, remains to be determined.
Meanwhile, clinicians should be aware of this potential complication and carefully evaluate indications for intravenous iron substitution after transplantation, particularly in tacrolimus (or cyclosporine)-treated kidney transplant recipients. In addition, close monitoring of phosphate balance should be performed after such treatment. Further research is required to study the incidence and mechanism of this complication and to determine whether lower doses of intravenous Ferinject may be preferred in this patient population.
Centre Hospitalier Universitaire Vaudois
1. Schouten BJ, Hunt PJ, Livesey JH, et al. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: A prospective study. J Clin Endocrinol Metab
2009; 94: 2332.
2. Seid MH, Derman RJ, Baker JB, et al. Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: A randomized controlled trial. Am J Obstet Gynecol
2008; 199: 435. el.
3. Mudge DW, S, MTan Kiles R, Johnson DW, et al. Intravenous versus oral iron supplementation for correction of post-transplant anemia in renal transplant patients. BMC Nephrol
2009; 10: 14.
4. Grimmelt AC, Cohen CD, Fehr T, et al. Safety and tolerability of ferric carboxymaltose (FCM) for treatment of iron deficiency in patients with chronic kidney disease and in kidney transplant recipients. Clin Nephrol
2009; 71: 125.