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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00518440.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1:

Selection of study cohort. Only patients enrolled until December 31, 2014 were considered for inclusion. TmP/GFR, renal threshold phosphate concentration. APAP, acetaminophen. ALF, acute liver failure. Group sizes are indicated in parentheses.

Figure 2:

Relationship between serum phosphate and renal threshold phosphate excretion (TmP/GFR). Data are graphed separately for patients with APAP-induced (n = 42; black solid line denotes regression; p

Figure 3:

Relationship between Loge transformed urinary kidney damage marker / urinary creatinine ratios and renal threshold phosphate excretion (TmP/GFR). Data are graphed separately for patients with APAP-induced (black solid line denotes regression) and non-APAP-induced (grey dashed line denotes regression) ALF. (A) Data graphed for urine NGAL in APAP-induced (n = 41; y = −0.00005x+1.4; R2 = 0.00000002; p = 1.00) and non-APAP-induced (n = 34; y = 0.11x+2.27; R2 = 0.05; p = 0.18) ALF. (B) Data graphed for urine cystatin C in APAP-induced (n = 40; y = −0.03x+1.48; R2 = 0.005; p = 0.66) and non-APAP-induced (n = 34; y = 0.14x+2.22; R2 = 0.09; p = 0.09) ALF. (C) Data graphed for urine protein in APAP-induced (n = 41; y = −0.09x+1.41; R2 = 0.01; p = 0.50) and non-APAP-induced (n = 33; y = −0.003x+2.39; R2 = 0.00001; p = 0.99) ALF. (D) Data graphed for urine glucose in APAP-induced (n = 41; y = −0.01x+1.40; R2 = 0.0002; p = 0.93) and non-APAP-induced (n = 31; y = −0.22x+2.09; R2 = 0.02; p = 0.44) ALF. APAP, acetaminophen. ALF, acute liver failure. NGAL, neutrophil gelatinase-associated lipocalin.

Figure 4:

Relationship between Loge transformed phosphaturic substances and renal threshold phosphate excretion (TmP/GFR). Data are graphed separately for patients with APAP-induced (black solid line denotes regression) and non-APAP-induced (grey dashed line denotes regression) ALF. (A) Data graphed for PTH in APAP-induced (n = 34; regression line y = −0.11x+1.96; R2 = 0.05; p = 0.22) and non-APAP-induced (n = 26; regression line y= −0.27x+3.71; R2 = 0.06; p = 0.24) ALF. (B) Data graphed for FGF23 in APAP-induced (n = 42; y = −0.01x+1.46; R2 = 0.0002; p = 0.93) and non-APAP-induced (n = 34; y = 0.25x+1.55; R2 = 0.07; p = 0.13) ALF. (C) Data graphed for α-Klotho in APAP-induced (n = 41; y = 0.08x+1.25; R2 = 0.01; p = 0.49) and non-APAP-induced (n = 34; y = −0.13x+2.70; R2 = 0.02; p = 0.37)) ALF. APAP, acetaminophen. ALF, acute liver failure.