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

• Published in: Translational research : the journal of laboratory and clinical medicine 2021-12, Vol.238, p.1-11
• Main Authors: Zechner, CHRISTOPH, ADAMS-HUET, BEVERLEY, GREGORY, BLAKE, NEYRA, JAVIER A., RULE, JODY A., LI, XILONG, RAKELA, JORGE, MOE, ORSON W., LEE, WILLIAM M.
• Format: Article
• Language: English
• Subjects: Acetaminophen - adverse effects; Adult; Female; Fibroblast Growth Factor-23 - blood; Glomerular Filtration Rate; Humans; Hypophosphatemia - chemically induced; Hypophosphatemia - etiology; Hypophosphatemia, Familial - etiology; Kidney - physiopathology; Lipocalin-2 - blood; Liver Failure, Acute - chemically induced; Liver Failure, Acute - complications; Liver Failure, Acute - etiology; Male; Middle Aged; Parathyroid Hormone - blood; Phosphates - blood
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2021.07.003

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.