Intravenous iron-induced hypophosphatemia and kidney stone disease

Abstract

Patients with Crohn's disease are at increased risk for symptomatic nephrolithiasis. Stones in these patients are most commonly composed of calcium oxalate monohydrate or mixed calcium-oxalate and calcium-phosphate. Precipitation of both minerals depends on urinary pH, calcium, phosphate and oxalate excretion. The present manuscript reports on two patients with Crohn's disease and bowel resection, in whom the onset of symptomatic urolithiasis occurred after repeated infusions of ferric carboxymaltose - a drug, which is known to cause hyperphosphaturia. The present study shows that ferric carboxymaltose-induced hyperphosphaturia can be associated with kidney stone formation and symptomatic urolithiasis, especially in patients treated with calcitriol. Calcitriol has been shown to mitigate ferric carboxymaltose-induced secondary hyperparathyroidism and hyperphosphaturia, but is known to increase urinary calcium excretion. Chemical analysis of recovered stones revealed that they were mixed calcium oxalate and phosphate stones. Ring-like deposition of iron detected by spatially resolved elemental analysis using laser ablation-inductively coupled plasma mass spectrometry, showed that the stones also contained iron. Based on our findings, we propose that patients with inflammatory bowel disease requiring intravenous iron therapy should be carefully monitored for the development of hypophosphatemia and urolithiasis. If hypophosphatemia occurs in such patients, calcitriol should be used with caution.

Keywords: Calcitriol; Hyperphosphaturia; Hypophosphatemia; IV iron; Kidney stone; Urolithiasis.

Graphical abstract

Fig. 1

Clinical and treatment course of Patient 1 (A) and Patient 2 (F). Correlation between ferric carboxymaltose infusions (red squares), serum phosphate concentrations, serum calcium concentration, PTH, iFGF23 and symptomatic kidney stone events/colics (green triangles). Lower limit of normal (LLN) for serum calcium and serum phosphate (blue horizontal line) and upper limit of normal (ULN) of PTH and intact FGF23 are marked. (B-E) Serial computed tomography scans (patient 1). Axial CT scan (B, D) showing a calcification at the tip of the papilla in the left kidney in Jan 2013, which disappeared after stone passage indicating that stone formation was initiated in collecting duct plugs and not in Randall plaques. 3D reconstructions of CT scans shown in (C, E) confirming disappearance of renal calculi.

Fig. 2

Stone analysis. (A) Epiluminenscence microscopic image of the stone (distance between vertical lines is 1 mm) (B) Epiluminenscence microscopic image of a cut and polished section of the epoxy resin embedded stone showing the ring like stone structure. (C—F) Quantitative analysis of ¹³C, ³¹P, ⁴⁴Ca and ⁵⁶Fe of the stone surface by laser ablation-inductively coupled plasma mass spectrometry. (G) SRμCT analysis showing aggregate structure of the stone with multiple intersected rings. The CT investigation was performed using Synchrotron Radiation at the beamline P05 operated by Hereon at the Synchrotron Radiation facility PETRA III at DESY, Hamburg, Germany. (H) Stone section under polarized light showing radial and concentric stone structure.

Fig. 3

Upper left panel: Under normal conditions, adequate FGF23 and calcitriol (1,25(OH)₂ VitD) cause normal urinary phosphate (P_i) and calcium (Ca²⁺) excretion without precipitation of either calcium-phosphate or calcium oxalate. Upper right panel: Ferric carboxymaltose (FCM) can cause an increase in intact FGF23, resulting in increased urinary phosphate excretion. High FGF23 also inhibits calcitriol production, causing reduced intestinal calcium absorption, mild hypocalcemia and low urinary calcium excretion. Lower left panel: Treatment of FCM-induced hypophosphatemia with oral or IV phosphate results in increased urinary phosphate excretion, which can trigger calcium phosphate precipitation and urolithiasis. Lower right panel: Treatment of FCM-induced hypocalcemia and secondary hyperparathyroidism with calcitriol supplementation causes increased intestinal absorption of calcium and urinary calcium excretion, which can also trigger urolithiasis.