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Hypophosphatemia in acute liver failure of a broad range of etiologies is associated with phosphaturia without kidney damage or phosphatonin elevation

  • CHRISTOPH Zechner
    Correspondence
    Reprint requests: Christoph Zechner, Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX-75390-8857.
    Affiliations
    Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA

    Department of Pharmacology. UT Southwestern Medical Center, Dallas, Texas, USA

    Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA
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  • BEVERLEY ADAMS-HUET
    Affiliations
    Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA

    Division of Biostatistics, Population and Data Sciences, Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, Texas, USA
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  • BLAKE GREGORY
    Affiliations
    Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA

    Division of Primary Care, Department of Internal Medicine, Alameda Health System, Oakland, California, USA
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  • JAVIER A. NEYRA
    Affiliations
    Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA

    Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA

    Division of Nephrology, Bone and Mineral Metabolism, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA
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  • JODY A. RULE
    Affiliations
    Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
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  • XILONG LI
    Affiliations
    Division of Biostatistics, Population and Data Sciences, Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, Texas, USA
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  • JORGE RAKELA
    Affiliations
    Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, Arizona, USA
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  • ORSON W. MOE
    Affiliations
    Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, Texas, USA

    Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA

    Department of Physiology, UT Southwestern Medical Center, Dallas, Texas, USA
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  • WILLIAM M. LEE
    Correspondence
    Reprint requests: William M. Lee, Digestive and Liver Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Dallas, TX 75390-8887.
    Affiliations
    Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
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  • for theAcute Liver Failure Study Group
      Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R2 = 0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins.

      Abbreviations:

      ALF (acute liver failure), APAP (acetaminophen), PTH (parathyroid hormone), FGF (fibroblast growth factor), AKI (Acute kidney injury), ALFSG (Acute Liver Failure Study Group), INR (international normalized ratio of prothrombin time), CKD (chronic kidney disease), TmP/GFR (maximal renal tubular phosphate reabsorption), TRP (fractional tubular reabsorption of phosphate), NGAL (neutrophil gelatinase-associated lipocalin), IQR (interquartile range), PH (partial hepatectomy)
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