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Dysregulated Mineral Metabolism in AKI

      Summary: Dysregulated mineral metabolism is a nearly universal sequalae of acute kidney injury (AKI). Abnormalities in circulating mineral metabolites observed in patients with AKI include hypocalcemia, hyperparathyroidism, hyperphosphatemia, decreased vitamin D metabolite levels, and increased fibroblast growth factor 23 levels. We review the pathophysiology of dysregulated mineral metabolism in AKI with a focus on calcium, phosphate, parathyroid hormone, and vitamin D metabolites. We discuss how mineral metabolite levels can serve as novel prognostic markers for incident AKI and other related outcomes in various clinical settings. Finally, we discuss how vitamin D metabolites potentially could be used as novel therapeutic agents for AKI prevention and treatment.

      Keywords

      Calcium and phosphate play essential physiologic roles in cellular metabolism, muscle and nerve function, skeletal development, hemostasis, and signal transduction pathways. Circulating levels of calcium and phosphate represent less than 1% of total body stores, with the majority being stored in bones in the form of hydroxyapatite, available to be released into the circulation depending on the body's metabolic requirements. In patients with normal kidney function, circulating levels of calcium and phosphate are maintained within a narrow physiologic range by three key hormones acting in concert: parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25D), and fibroblast growth factor 23 (FGF23).
      • Bergwitz C
      • Juppner H
      Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23.
      • Goltzman D
      • Mannstadt M
      • Marcocci C
      Physiology of the calcium-parathyroid hormone-vitamin D axis.
      The primary target organs of these hormones are the kidneys, bone, intestine, and parathyroid glands, although numerous off-target or nonclassic effects also have been identified. The complex interplay between these three hormones with calcium and phosphate involves multiple endocrine feedback loops, as illustrated in Figure 1.
      Figure 1.
      Figure 1Overview of normal mineral metabolism homeostasis. Multiple endocrine feedback loops regulate calcium and phosphate balance. FGF23 and PTH form one loop, whereby PTH stimulates FGF23 and FGF23 inhibits PTH.
      • Ben-Dov IZ
      • Galitzer H
      • Lavi-Moshayoff V
      • et al.
      The parathyroid is a target organ for FGF23 in rats.
      • Lavi-Moshayoff V
      • Wasserman G
      • Meir T
      • et al.
      PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop.
      ,
      • Knab VM
      • Corbin B
      • Andrukhova O
      • et al.
      Acute parathyroid hormone injection increases C-terminal but not intact fibroblast growth factor 23 levels.
      FGF23 and PTH have opposite effects on 1,25D synthesis: the former suppresses its production and the latter stimulates it. 1,25D, in turn, acts in a negative endocrine feedback loop with both FGF23 and PTH.
      • Bergwitz C
      • Juppner H
      Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23.
      • Shimada T
      • Hasegawa H
      • Yamazaki Y
      • et al.
      FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
      In its soluble form, klotho, a co-receptor for FGF23 in the kidneys, forms another negative feedback loop with FGF23.
      • Smith RC
      • O'Bryan LM
      • Farrow EG
      • et al.
      Circulating alphaKlotho influences phosphate handling by controlling FGF23 production.
      Both FGF23 and PTH increase renal phosphate excretion and calcium reabsorption.
      • Andrukhova O
      • Smorodchenko A
      • Egerbacher M
      • et al.
      FGF23 promotes renal calcium reabsorption through the TRPV5 channel.
      Up-regulation is shown in red; down-regulation in shown in black.

      OVERVIEW OF MINERAL METABOLISM IN HEALTH AND CHRONIC KIDNEY DISEASE

      PTH

      PTH is the primary regulator of systemic calcium homeostasis. PTH is synthesized in the parathyroid glands, where it is stored in secretory vesicles as an 84-amino acid protein, ready to be secreted immediately in response to low circulating calcium or 1,25D levels. PTH has a very short half-life of only 2 to 4 minutes in the circulation, and is metabolized in the kidneys as well as the liver.
      • Daugaard H
      • Egfjord M
      • Olgaard K
      Metabolism of intact parathyroid hormone in isolated perfused rat liver and kidney.
      • Hesch RD
      • Ebel H
      • Hehrmann R
      • et al.
      Endocrinological aspects of PTH metabolism in the kidney.
      PTH acts on a variety of target tissues to restore low circulating calcium and 1,25D levels. These target tissues include bone and kidney directly, and the gut indirectly. Specifically, PTH exerts its classic effects on calcium homeostasis through binding to PTH receptor 1, a 7-transmembrane G-protein–coupled receptor expressed on the surface of cells.
      • Cheloha RW
      • Gellman SH
      • Vilardaga JP
      • et al.
      PTH receptor-1 signalling-mechanistic insights and therapeutic prospects.
      In bone, PTH binding to PTH receptor 1 on osteoblastic cells stimulates osteoclast activity through the receptor activator of nuclear factor-κB ligand pathway, thereby inducing calcium release into the circulation.
      • McSheehy PM
      • Chambers TJ
      Osteoblast-like cells in the presence of parathyroid hormone release soluble factor that stimulates osteoclastic bone resorption.
      Interestingly, this effect depends on the length of exposure to PTH, with chronic exposure leading to increased osteoclast activity and bone loss, and pulsatile exposure leading to increased bone formation.
      • Potts JT
      Parathyroid hormone: past and present.
      In the kidneys, PTH has three major actions: (1) it increases the expression of calcium-transport proteins (such as transient receptor potential cation channel subfamily V member 5, expressed on the apical surface of the late distal convoluted and connecting tubules), thereby increasing the reabsorption of filtered calcium
      • van Abel M
      • Hoenderop JG
      • van der Kemp AW
      • et al.
      Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone.
      ; (2) it increases the excretion of filtered phosphate by down-regulating the major sodium-dependent phosphate transporter, Npt2a, expressed on the apical surface of proximal tubular cells
      • Pfister MF
      • Lederer E
      • Forgo J
      • et al.
      Parathyroid hormone-dependent degradation of type II Na+/Pi cotransporters.
      ; and (3) it up-regulates the cytochrome P450 enzyme, 1-α hydroxylase (CYP27B1), which converts 25-hydroxyvitamin D (25D) to 1,25D.
      • Kremer R
      • Goltzman D
      Parathyroid hormone stimulates mammalian renal 25-hydroxyvitamin D3-1 alpha-hydroxylase in vitro.
      • Fraser DR
      • Kodicek E
      Regulation of 25-hydroxycholecalciferol-1-hydroxylase activity in kidney by parathyroid hormone.
      1,25D and calcium, in turn, each inhibit PTH secretion in the parathyroid glands through a negative endocrine feedback loop (Fig. 1).
      • Silver J
      • Naveh-Many T
      • Mayer H
      • et al.
      Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat.
      1,25D also acts on the gut to increase absorption of both calcium and phosphate, the latter mediated by increased intestinal expression of Npt2b.
      • Katai K
      • Miyamoto K
      • Kishida S
      • et al.
      Regulation of intestinal Na+-dependent phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3.

      1,25D

      Vitamin D is derived from dietary sources and sunlight-induced cutaneous synthesis, and is converted to 25D in the liver.
      • Masumoto O
      • Ohyama Y
      • Okuda K
      Purification and characterization of vitamin D 25-hydroxylase from rat liver mitochondria.
      Circulating 25D is converted to its biologically active form, 1,25D, in the kidneys, immune cells, and other tissues by CYP27B1.
      • Kawashima H
      • Torikai S
      • Kurokawa K
      Localization of 25-hydroxyvitamin D3 1 alpha-hydroxylase and 24-hydroxylase along the rat nephron.
      A separate P450 enzyme, 24-hydroxylase (CYP24A1), catabolizes both 25D and 1,25D. 1,25D is a hormone that has both genomic and nongenomic actions. Nongenomic actions include effects on intestinal calcium absorption and secretion of insulin by pancreatic β cells.
      • Hii CS
      • Ferrante A
      The non-genomic actions of vitamin D.
      Genomic effects, including inhibition of PTH production,
      • Demay MB
      • Kiernan MS
      • DeLuca HF
      • et al.
      Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3.
      are mediated through 1,25D binding to the intracellular vitamin D receptor, which is expressed nearly ubiquitously.
      • An L
      • Liu CT
      • Yu MJ
      • et al.
      Heme oxygenase-1 system, inflammation and ventilator-induced lung injury.
      The 1,25D–vitamin D receptor complex translocates into the nucleus, where it binds to DNA sequence elements in vitamin D–responsive genes, ultimately influencing the expression of more than 200 target genes, including many genes involved in inflammation and immunity.
      • Ramagopalan SV
      • Heger A
      • Berlanga AJ
      • et al.
      A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.

      FGF23

      FGF23 is an osteocyte-derived hormone initially discovered for its pathologic role in rare syndromes of urinary phosphate wasting, including autosomal-dominant hypophosphatemic rickets and tumor-induced osteomalacia.
      ADHR Consortium
      Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.
      • Jonsson KB
      • Zahradnik R
      • Larsson T
      • et al.
      Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.
      In the kidneys, FGF23 down-regulates Npt2a and Npt2c in proximal tubular cells, resulting in increased urinary phosphate excretion,
      • Kronenberg HM
      NPT2a–the key to phosphate homeostasis.
      and also inhibits CYP27B1 expression, resulting in decreased 1,25D production.
      • Hasegawa H
      • Nagano N
      • Urakawa I
      • et al.
      Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease.
      FGF23-mediated inhibition of CYP27B1 also has been shown in extrarenal tissues, such as monocytes.
      • Bacchetta J
      • Sea JL
      • Chun RF
      • et al.
      Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes.
      Other actions of FGF23 include down-regulation of each of the following: PTH,
      • Ben-Dov IZ
      • Galitzer H
      • Lavi-Moshayoff V
      • et al.
      The parathyroid is a target organ for FGF23 in rats.
      erythropoiesis,
      • Coe LM
      • Madathil SV
      • Casu C
      • et al.
      FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis.
      and klotho (Fig. 1).
      • Marsell R
      • Krajisnik T
      • Goransson H
      • et al.
      Gene expression analysis of kidneys from transgenic mice expressing fibroblast growth factor-23.
      • Meyer MH
      • Dulde E
      • Meyer Jr., RA
      The genomic response of the mouse kidney to low-phosphate diet is altered in X-linked hypophosphatemia.
      FGF23, in turn, is up-regulated by numerous stimuli, including 1,25D, PTH, phosphate loading, inflammation, and iron deficiency.
      • David V
      • Martin A
      • Isakova T
      • et al.
      Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production.
      • Farrow EG
      • Yu X
      • Summers LJ
      • et al.
      Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.
      • Burnett SM
      • Gunawardene SC
      • Bringhurst FR
      • et al.
      Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women.
      • Saito H
      • Maeda A
      • Ohtomo S
      • et al.
      Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo.
      • Knab VM
      • Corbin B
      • Andrukhova O
      • et al.
      Acute parathyroid hormone injection increases C-terminal, but not intact fibroblast growth factor 23 levels.

      Klotho

      Klotho is a single-pass transmembrane domain protein expressed primarily in the kidneys and parathyroid glands. Although three isoforms of klotho have been described, only α-klotho (referred to hereafter as simply klotho) is relevant to mineral metabolism homeostasis. Klotho acts as a co-receptor to facilitate binding of FGF23 to FGF receptors, thereby enhancing FGF23 signaling in the kidneys and elsewhere.
      • Urakawa I
      • Yamazaki Y
      • Shimada T
      • et al.
      Klotho converts canonical FGF receptor into a specific receptor for FGF23.
      The extracellular domain of klotho can be cleaved into the circulation and is referred to as soluble klotho. Soluble klotho also can be synthesized as a secreted protein through alternative splicing, and, similar to membrane-bound klotho, is able to facilitate FGF23 signaling by binding to the FGF receptor.
      • Matsumura Y
      • Aizawa H
      • Shiraki-Iida T
      • et al.
      Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein.
      • Chen G
      • Liu Y
      • Goetz R
      • et al.
      alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.
      In addition, the extracellular domain of membrane-bound klotho has enzymatic activity, which allows it to modulate calcium
      • Imura A
      • Tsuji Y
      • Murata M
      • et al.
      alpha-Klotho as a regulator of calcium homeostasis.
      and potassium
      • Cha SK
      • Hu MC
      • Kurosu H
      • et al.
      Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho.
      absorption in the distal tubule (independently of FGF23). Finally, soluble klotho can act as a phosphaturic hormone.
      • Hu MC
      • Shi M
      • Zhang J
      • et al.
      Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule.

      Dysregulated Mineral Metabolism in CKD

      Given the intimate involvement of the kidneys in the regulation of calcium, phosphate, and vitamin D homeostasis, it is unsurprising that dysregulated mineral metabolism is a nearly universal feature of chronic kidney disease (CKD). Abnormalities in circulating mineral metabolites in CKD include increased levels of phosphate, PTH, and FGF23, and decreased levels of calcium and vitamin D metabolites. In addition, renal klotho expression is decreased in CKD.
      • Hu MC
      • Shi M
      • Zhang J
      • et al.
      Klotho deficiency causes vascular calcification in chronic kidney disease.
      • Barker SL
      • Pastor J
      • Carranza D
      • et al.
      The demonstration of alphaKlotho deficiency in human chronic kidney disease with a novel synthetic antibody.
      These abnormalities begin at different times in the course of CKD, and become progressively altered as CKD progresses. The precise sequence of changes is still under debate, but in a cross-sectional study of nearly 4,000 CKD patients the earliest observed changes were increases in circulating FGF23 and decreases in 1,25D.
      • Isakova T
      • Wahl P
      • Vargas GS
      • et al.
      Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.
      The earlier-described changes that occur in mineral metabolism lead to altered bone remodeling as well as extraskeletal deposition of calcium and phosphate.
      • Isakova T
      • Nickolas TL
      • Denburg M
      • et al.
      KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).
      In addition, increased levels of PTH and FGF23 and reduced levels of klotho and 1,25D also likely contribute to the development of other comorbidities common in CKD, including anemia, chronic inflammation, immune dysfunction, and left ventricular hypertrophy.
      • Richter B
      • Faul C
      FGF23 Actions on target tissues–with and without klotho.
      • Neyra JA
      • Hu MC
      Potential application of klotho in human chronic kidney disease.
      Consistent with these data, epidemiologic studies consistently have shown that abnormalities in mineral metabolites, including increased circulating FGF23 and decreased vitamin D metabolite levels, are strong and independent predictors of cardiovascular and all-cause mortality in CKD patients.
      • Isakova T
      • Xie H
      • Yang W
      • et al.
      Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.
      • Wolf M
      • Shah A
      • Gutierrez O
      • et al.
      Vitamin D levels and early mortality among incident hemodialysis patients.
      Targeting these abnormalities pharmacologically and otherwise as a strategy to improve outcomes in CKD therefore has been an area of active investigation for decades.

      DYSREGULATED MINERAL METABOLISM IN AKI

      Overview

      Many of the mineral metabolite abnormalities that occur in CKD also commonly occur in AKI. These include hypocalcemia, hyperparathyroidism, hyperphosphatemia, decreased 1,25D, increased FGF23, and decreased renal klotho expression. An overview of these mineral metabolite abnormalities is shown in Figure 2. The current article focuses on abnormalities of calcium, phosphate, PTH, and vitamin D metabolites in AKI. The regulation of FGF23 and klotho in AKI is discussed in detail in Christov et al
      • Krejs GJ
      • Nicar MJ
      • Zerwekh JE
      • et al.
      Effect of 1,25-dihydroxyvitamin D3 on calcium and magnesium absorption in the healthy human jejunum and ileum.
      in this issue.
      Figure 2.
      Figure 2Overview of dysregulated mineral metabolism pathways in AKI. (1) Renal and potentially extrarenal conversion of 25D to 1,25D is impaired in AKI. Proposed mechanisms include decreased CYP27B1 activity,
      • Ghazarian JG
      • Garancis JC
      • Yanda DM
      • et al.
      Changes in 25-hydroxyvitamin D3 alpha- and 24-hydroxylase activities of kidney cells isolated from rats with either unilateral kidney damage or acute renal insufficiency.
      • Viaene L
      • Evenepoel P
      • Meijers B
      • et al.
      Uremia suppresses immune signal-induced CYP27B1 expression in human monocytes.
      which may be caused by increased circulating FGF23 levels
      • Bacchetta J
      • Sea JL
      • Chun RF
      • et al.
      Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes.
      • Shimada T
      • Hasegawa H
      • Yamazaki Y
      • et al.
      FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
      and by decreased delivery of 25D substrate. The latter may be caused by decreased circulating levels of DBP,
      • Afshinnia F
      • Belanger K
      • Palevsky PM
      • et al.
      Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: secondary analysis of the acute renal failure trial network study.
      or by down-regulation of megalin and cubulin expression in renal proximal tubular cells.
      • Schreiber A
      • Theilig F
      • Schweda F
      • et al.
      Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney.
      (2) Hyperphosphatemia results from decreased renal clearance of PO4. (3) Hypocalcemia results from a combination of at least two factors: increased circulating levels of PO4, which sequesters Ca, and decreased circulating levels of 1,25D, which decreases Ca absorption from the gut and decreases Ca reabsorption from the kidneys. (4) Decreased circulating levels of both 1,25D and Ca each contribute to secondary hyperparathyroidism. (5) Despite increased PTH levels, skeletal resistance to PTH prevents restoration of serum Ca levels to normal. (6) In addition, the stimulatory effects of PTH on renal CYP27B1 expression may be blunted in AKI. (7) FGF23 production is increased in AKI via unclear mechanisms. (8) Increased circulating FGF23 levels may contribute to decreased renal and extrarenal CYP27B1 expression. Arrows shown in dotted lines represent pathways that are less well established.

      Calcium and AKI

      Mechanisms of hypocalcemia in AKI

      Low circulating calcium levels have been reported consistently in clinical studies of patients with established AKI (Table 1). Multiple etiologies have been proposed to account for this finding, and are summarized in Table 2. These include decreased renal synthesis of 1,25D, which results in decreased calcium absorption from the gut, decreased calcium reabsorption from the kidneys, and decreased calcium release from bone.
      • Christov M
      • Neyra JA
      • Gupta S
      • Leaf DE
      Fibroblast growth factor 23 and klotho in AKI.
      • Finch JL
      • Brown AJ
      • Slatopolsky E
      Differential effects of 1,25-dihydroxy-vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phosphorus resorption in bone.
      Hyperphosphatemia, which frequently is observed in patients with AKI (Table 1), also may decrease total serum calcium levels via sequestration of calcium in the circulation. This effect is particularly apparent under conditions of massive tissue breakdown (eg, tumor lysis syndrome and rhabdomyolysis), in which large amounts of phosphate are acutely released into the circulation from intracellular stores. In addition, although PTH production increases in AKI in response to both hypocalcemia and low circulating 1,25D levels, skeletal resistance to PTH in AKI attenuates its procalcemic actions (Fig. 2), thereby limiting the ability of PTH to restore serum calcium levels to normal (discussed further later in the section on PTH). An additional potential mechanism of hypocalcemia in AKI is up-regulation of the calcium-sensing receptor (CaSR) in both the kidneys and parathyroid glands, which occurs in response to proinflammatory cytokines.
      • Canaff L
      • Hendy GN
      Calcium-sensing receptor gene transcription is up-regulated by the proinflammatory cytokine, interleukin-1beta. Role of the NF-kappaB PATHWAY and kappaB elements.
      This up-regulation of the CaSR may affect the set point for calcium–PTH feedback regulation. Finally, intracellular calcium accumulation may occur in patients with septic AKI.
      • Song SK
      • Karl IE
      • Ackerman JJ
      • et al.
      Increased intracellular Ca2+: a critical link in the pathophysiology of sepsis?.
      Further investigations are needed to elucidate the relative contribution of each of these potential mechanisms, and it is likely that more than one mechanism contributes to hypocalcemia in any individual patient.
      Table 1Human Studies of Dysregulated Calcium, Phosphate, PTH, and Vitamin D Metabolites in Established AKI
      StudyNumber of Patients and SettingFindings
      Dysregulated mineral metabolism resulting from AKI
       Massry et al,
      • Massry SG
      • Arieff AI
      • Coburn JW
      • et al.
      Divalent ion metabolism in patients with acute renal failure: studies on the mechanism of hypocalcemia.
      1974
      10 adult patients with oliguric AKI from various causes↓Ca, ↑PTH, and ↑PO4; Ca and PTH correlated inversely (r = -0.52); infusion of PTH failed to elicit a normal increase in Ca, suggesting skeletal resistance to PTH in AKI
       Pietrek et al,
      • Pietrek J
      • Kokot F
      • Kuska J
      Serum 25-hydroxyvitamin D and parathyroid hormone in patients with acute renal failure.
      1978
      18 adult patients with oliguric AKI from various causes, including post-traumatic shock and sepsis↓Ca, ↑PTH, ↑PO4, and ↓25D

      25D levels continued to decrease over time, reaching a nadir in most patients during the early polyuric phase of AKI
       Llach et al,
      • Llach F
      • Felsenfeld AJ
      • Haussler MR
      The pathophysiology of altered calcium metabolism in rhabdomyolysis-induced acute renal failure. Interactions of parathyroid hormone, 25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol.
      1981
      6 adult patients with oliguric AKI from rhabdomyolysis↓Ca, ↑PTH, ↑PO4, ↓25D, and ↓1,25D
       Madsen et al,
      • Madsen S
      • Olgaard K
      • Ladefoged J
      Suppressive effect of 1,25-dihydroxyvitamin D3 on circulating parathyroid hormone in acute renal failure.
      1981
      10 adult patients with oliguric AKI from various causes (mostly acute GN and AIN), and who were receiving RRT with continuous PD↓iCa and ↑PTH

      5 patients received 1,25D injections every 6 h, the other 5 served as controls

      Suppression of PTH was observed in patients who received 1,25D but not in the control patients

      Because serum Ca was kept constant by PD, the observed reduction of PTH could not be explained by the calcemic effect of 1,25D, and suggested direct feedback regulation by 1,25D on PTH secretion
       Saha et al,
      • Saha H
      • Mustonen J
      • Pietila K
      • et al.
      Metabolism of calcium and vitamin D3 in patients with acute tubulointerstitial nephritis: a study of 41 patients with nephropathia epidemica.
      1993
      41 adult patients (34 of whom had AKI) with nephropathia epidemica
      Nephropathia epidemica is a zoonosis caused by the Puumala virus, and causes an acute hemorrhagic fever and AKI.
      ↓Ca, ↑PTH, ↑PO4, ↓25D, and ↓1,25D in patients with AKI

      iCa and PTH correlated inversely (r = -0.64)
       Shieh et al,
      • Shieh SD
      • Lin YF
      • Lin SH
      • et al.
      A prospective study of calcium metabolism in exertional heat stroke with rhabdomyolysis and acute renal failure.
      1995
      7 adults with exertional rhabdomyolysis and AKI; 11 age-matched controls with heat exhaustion, and 11 healthy controls↓iCa, ↑PTH, ↑PO4, and ↓1,25D in subjects with AKI compared with healthy volunteers; serum 25D levels were similar between groups
       Druml et al,
      • Druml W
      • Schwarzenhofer M
      • Apsner R
      • et al.
      Fat-soluble vitamins in patients with acute renal failure.
      1998
      8 adult patients with AKI requiring RRT and 28 healthy controls↓25D, ↓1,25D, and ↑PTH in patients with AKI compared with healthy controls
       Zhang et al,
      • Zhang M
      • Hsu R
      • Hsu CY
      • et al.
      FGF-23 and PTH levels in patients with acute kidney injury: a cross-sectional case series study.
      2011
      12 critically ill patients with AKI and 8 control patients without AKI↑PO4 in patients with versus without AKI

      Ca and PTH levels were similar between groups
       Leaf et al,
      • Leaf DE
      • Wolf M
      • Waikar SS
      • et al.
      FGF-23 levels in patients with AKI and risk of adverse outcomes.
      2012
      30 hospitalized adult patients with AKI (AKIN
      • Mehta RL
      • Kellum JA
      • Shah SV
      • et al.
      Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.
      stage 1 or greater) and 30 hospitalized control patients without AKI
      ↓Ca, ↑PTH, ↑PO4, and ↓1,25D on enrollment in patients with versus without AKI; a nonsignificant trend (P = .06) was observed for ↓25D in patients with versus without AKI; by day 5, only 25D and 1,25D were lower in patients with versus without AKI (Ca, PO4, and PTH levels were not significantly different between groups)
       Leaf et al,
      • Leaf DE
      • Waikar SS
      • Wolf M
      • et al.
      Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
      2013
      30 hospitalized adult patients with AKI (AKIN stage 1 or greater) and 30 hospitalized control patients without AKI↓DBP and similar levels of bioavailable 25D and 1,25D in patients with versus without AKI
       Lai et al,
      • Lai L
      • Qian J
      • Yang Y
      • et al.
      Is the serum vitamin D level at the time of hospital-acquired acute kidney injury diagnosis associated with prognosis?.
      2013
      200 adult patients with hospital-acquired AKI (defined as ↑SCr ≥50% baseline), and 13 critically ill patients without AKI and 17 healthy control subjects↓1,25D in patients with versus without AKI, but similar 25D levels across groups; 1,25D levels correlated inversely with AKI severity
       Vijayan et al,
      • Vijayan A
      • Li T
      • Dusso A
      • et al.
      Relationship of 1,25 dihydroxy vitamin D levels to clinical outcomes in critically ill patients with acute kidney injury.
      2015
      34 critically ill adult patients with AKI (AKIN stage 2 or 3), and 12 healthy controls↓25D, ↓1,25D, and ↑PTH in patients with AKI compared with healthy controls
       Leaf et al,
      • Leaf DE
      • Christov M
      • Juppner H
      • et al.
      Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery.
      2016
      18 adult patients undergoing cardiac surgery who developed severe AKI (doubling of SCr or need for RRT) and 18 matched controls without AKI↑PO4 and ↓1,25D, particularly on POD3, in patients with versus without AKI

      PTH and 25D levels were not significantly different between groups
       Leaf et al,
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      2018
      400 critically ill adult patients with AKI requiring RRT↓Ca, ↑PTH, ↑PO4, ↓25D, and ↓1,25D
      Dysregulated mineral metabolism resulting from RRT
       Santiago et al,
      • Santiago MJ
      • Lopez-Herce J
      • Urbano J
      • et al.
      Hypophosphatemia and phosphate supplementation during continuous renal replacement therapy in children.
      2009
      47 critically ill pediatric patients with AKI requiring CRRT↓PO4 occurred in 68% of patients overall and in 85% of patients in whom PO4 was not added to the replacement and dialysate solutions
       Broman et al,
      • Broman M
      • Carlsson O
      • Friberg H
      • et al.
      Phosphate-containing dialysis solution prevents hypophosphatemia during continuous renal replacement therapy.
      2011
      42 critically ill adult patients with AKI requiring CRRT; 14 were treated with a standard replacement solution that did not contain PO4↓PO4 occurred in 79% of patients who received a non–PO4-containing replacement solution
       Lim et al,
      • Lim C
      • Tan HK
      • Kaushik M
      Hypophosphatemia in critically ill patients with acute kidney injury treated with hemodialysis is associated with adverse events.
      2017
      96 critically ill adult patients with AKI requiring RRT↓PO4 occurred in 26% of patients
      Abbreviations: AKIN, Acute Kidney Injury Network; AIN, acute interstitial nephritis; CRRT, continuous renal replacement therapy; GN, glomerulonephritis; PD, peritoneal dialysis; POD, postoperative day; RRT, renal replacement therapy.
      low asterisk Nephropathia epidemica is a zoonosis caused by the Puumala virus, and causes an acute hemorrhagic fever and AKI.
      Table 2Mechanisms of Hypocalcemia in AKI
      ↓Renal production of 1,25D
      ↑Circulating PO4, which sequesters Ca
      Skeletal resistance to PTH
      Up-regulation of CaSR expression
      Intracellular Ca accumulation
      Table 3Human Studies of Dysregulated Calcium, Phosphate, PTH, and Vitamin D as Risk Factors for Incident AKI and AKI-Related Adverse Outcomes
      StudyNumber of Patients and SettingFindings
      Calcium
       Chernow et al,
      • Chernow B
      • Zaloga G
      • McFadden E
      • et al.
      Hypocalcemia in critically ill patients.
      1982
      210 critically ill adult patientsCa <8.5 mg/dL on arrival to the ICU was associated with an increased incidence of “renal failure” (definition not provided) in unadjusted analyses
       Afshinnia et al,
      • Afshinnia F
      • Belanger K
      • Palevsky PM
      • et al.
      Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: secondary analysis of the acute renal failure trial network study.
      2013
      685 critically ill adult patients with AKI requiring RRTiCa level at RRT initiation was not associated with 60-day mortality or renal recovery; however, when iCa was assessed as a time-varying exposure, iCa <1 versus ≥1.15 mmol/L was associated independently with increased 60-day mortality
      Phosphate
       Vijayan et al,
      • Vijayan A
      • Li T
      • Dusso A
      • et al.
      Relationship of 1,25 dihydroxy vitamin D levels to clinical outcomes in critically ill patients with acute kidney injury.
      2015
      34 critically ill adult patients with AKI (AKIN stage 2 or 3)Higher PO4 levels were associated with a higher risk of in-hospital mortality in unadjusted analyses (multivariable analyses not shown)
       Jung et al,
      • Jung SY
      • Kim H
      • Park S
      • et al.
      Electrolyte and mineral disturbances in septic acute kidney injury patients undergoing continuous renal replacement therapy.
      2016
      216 adult patients with septic AKI requiring CRRTHigher PO4 levels at the time of CRRT initiation were associated independently with higher 28- and 90-day mortality
       Lim et al,
      • Lim C
      • Tan HK
      • Kaushik M
      Hypophosphatemia in critically ill patients with acute kidney injury treated with hemodialysis is associated with adverse events.
      2017
      96 critically ill adult patients with AKI requiring RRTPO4 < 2.9 mg/dL was associated independently with prolonged mechanical ventilation but not with ICU mortality
       Jung et al,
      • Jung SY
      • Kwon J
      • Park S
      • et al.
      Phosphate is a potential biomarker of disease severity and predicts adverse outcomes in acute kidney injury patients undergoing continuous renal replacement therapy.
      2018
      1,144 adult patients with AKI requiring CRRTHigher PO4 levels at 0 and 24 h after CRRT initiation each were associated independently with higher risk of 28- and 90-day mortality
       Thongprayoon et al,
      • Thongprayoon C
      • Cheungpasitporn W
      • Mao MA
      • et al.
      Admission hyperphosphatemia increases the risk of acute kidney injury in hospitalized patients.
      2018
      5,036 adult patients admitted to a tertiary care hospitalAdmission PO4 >4.4 mg/dL was associated independently with higher risk of developing AKI
      Vitamin D metabolites
       Braun et al,
      • Braun AB
      • Litonjua AA
      • Moromizato T
      • et al.
      Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill.
      2012
      2,075 critically ill adult patientsPreadmission (measured within 1 y before hospitalization) serum 25D levels <15 ng/mL compared with ≥30 ng/mL were associated independently with a higher risk of incident AKI
       Lai et al,
      • Lai L
      • Qian J
      • Yang Y
      • et al.
      Is the serum vitamin D level at the time of hospital-acquired acute kidney injury diagnosis associated with prognosis?.
      2013
      200 adult patients with hospital-acquired AKI (defined as ↑SCr ≥50% baseline), and 13 critically ill patients without AKI and 17 healthy control subjectsNo association between 25D or 1,25D levels at the time of AKI diagnosis and 90-day mortality
       Vijayan et al,
      • Vijayan A
      • Li T
      • Dusso A
      • et al.
      Relationship of 1,25 dihydroxy vitamin D levels to clinical outcomes in critically ill patients with acute kidney injury.
      2015
      34 critically ill adult patients with AKI (AKIN stage 2 or 3)Higher 1,25D levels were associated with a higher risk of in-hospital mortality in unadjusted analyses, but not after adjusting for age and APACHE II score
       Ala-Kokko et al,
      • Ala-Kokko TI
      • Mutt SJ
      • Nisula S
      • et al.
      Vitamin D deficiency at admission is not associated with 90-day mortality in patients with severe sepsis or septic shock: observational FINNAKI cohort study.
      2016
      610 critically ill adult patients with severe sepsis or septic shockLower 25D levels were associated with higher risk of incident AKI (KDIGO criteria
      • Disease Kidney
      • Outcomes Improving Global
      (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury.
      ) and need for RRT in unadjusted analyses (multivariable analyses not shown)
      Studies that simultaneously assessed multiple mineral metabolites
       Leaf et al,
      • Leaf DE
      • Waikar SS
      • Wolf M
      • et al.
      Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
      2013
      30 hospitalized adult patients with AKI (AKIN stage 1 or greater) and 30 hospitalized control patients without AKILower levels of bioavailable 25D, but not total 25D, 1,25D, DBP, Ca, PO4, or PTH were associated with a higher risk of in-hospital mortality after adjustment for age and enrollment SCr
       Hanudel et al,
      • Hanudel MR
      • Wesseling-Perry K
      • Gales B
      • et al.
      Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients.
      2016
      32 pediatric patients undergoing cardiac surgery (20 developed postoperative AKI, defined as an ↑SCr ≥50% from preoperative levels, and 12 did not)Preoperative Ca, PO4, and PTH levels were similar in patients who did or did not develop postoperative AKI; 25D and 1,25D levels were not assessed
       Leaf et al,
      • Leaf DE
      • Jacob KA
      • Srivastava A
      • et al.
      Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
      2017
      113 critically ill adult patients who did not have AKI on enrollmentCa, iCa, PTH, 25D, 1,25D, and DBP were not associated with the composite of incident AKI or in-hospital mortality (AKI/death); higher PO4 levels on ICU admission were associated with a trend toward higher AKI/death (P = .05) in unadjusted analyses
       Leaf et al,
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      2018
      400 critically ill adult patients with AKI requiring RRTCa, PO4, PTH, 25D, and 1,25D did not associate with 60-day mortality in fully adjusted models
      Abbreviations: AKIN, Acute Kidney Injury Network; APACHE, Acute Physiology and Chronic Health Evaluation; CRRT, continuous renal replacement therapy; KDIGO, Kidney Disease: Improving Global Outcomes; RRT, renal replacement therapy; SCr, serum creatinine.

      Measurement of circulating calcium levels in AKI

      Two methods are available in routine clinical practice for the assessment of circulating calcium levels: total serum calcium and plasma ionized calcium (iCa). iCa is considered the gold standard assessment of physiologically relevant free calcium levels in the circulation because total serum calcium measurements assess both biologically active (∼45%) and biologically inactive (∼55%) calcium. The latter is bound to albumin and other organic and inorganic anions such as sulfate, phosphate, and citrate.
      Clinicians frequently rely on total serum calcium levels because measurement of iCa is more cumbersome: the samples must be drawn in a heparinized syringe, transported on ice, and processed immediately. A comparative study of total serum calcium, albumin-corrected total serum calcium,
      • Orrell DH
      Albumin as an aid to the interpretation of serum calcium.
      and iCa levels in patients with AKI has not been performed. However, it is likely that assessment of total serum calcium levels with or without correction for hypoalbuminemia will often fail to accurately identify hypocalcemia, normocalcemia, or hypercalcemia in patients with AKI because multiple factors other than the serum albumin concentration affect the proportion of total serum calcium that is ionized. These factors, which frequently are present in patients with AKI, include acid-base disorders,
      • Oberleithner H
      • Greger R
      • Lang F
      The effect of respiratory and metabolic acid-base changes on ionized calcium concentration: in vivo and in vitro experiments in man and rat.
      hyperphosphatemia, hyperparathyroidism,
      • Ladenson JH
      • Lewis JW
      • McDonald JM
      • et al.
      Relationship of free and total calcium in hypercalcemic conditions.
      and transfusion of blood products with citrate-containing preservative solutions.
      • Abbott TR
      Changes in serum calcium fractions and citrate concentrations during massive blood transfusions and cardiopulmonary bypass.
      • Dzik WH
      • Kirkley SA
      Citrate toxicity during massive blood transfusion.
      Furthermore, albumin-corrected total serum calcium equations have been shown to be unreliable in other clinical settings, such as critical illness,
      • Slomp J
      • van der Voort PH
      • Gerritsen RT
      • et al.
      Albumin-adjusted calcium is not suitable for diagnosis of hyper- and hypocalcemia in the critically ill.
      • Byrnes MC
      • Huynh K
      • Helmer SD
      • et al.
      A comparison of corrected serum calcium levels to ionized calcium levels among critically ill surgical patients.
      CKD,
      • Gauci C
      • Moranne O
      • Fouqueray B
      • et al.
      Pitfalls of measuring total blood calcium in patients with CKD.
      end-stage renal disease,
      • Clase CM
      • Norman GL
      • Beecroft ML
      • et al.
      Albumin-corrected calcium and ionized calcium in stable haemodialysis patients.
      and among patients suspected of having calcium metabolic disease.
      • Thode J
      • Juul-Jorgensen B
      • Bhatia HM
      • et al.
      Comparison of serum total calcium, albumin-corrected total calcium, and ionized calcium in 1213 patients with suspected calcium disorders.
      Thus, we recommend iCa as the preferred method for assessment of calcium levels in patients with AKI.

      Clinical relevance of hypocalcemia in AKI

      Among the myriad clinical manifestations that may result from hypocalcemia, adverse effects on the cardiovascular system, including both hemodynamic and arrhythmogenic effects, are among the most relevant to AKI-related outcomes. Specifically, hypotension may occur in patients with hypocalcemia owing to decreased systemic vascular resistance
      • Scheidegger D
      • Drop LJ
      • Schellenberg JC
      Role of the systemic vasculature in the hemodynamic response to changes in plasma ionized calcium.
      or decreased myocardial contractility.
      • Szent-Gyorgyi AG
      Calcium regulation of muscle contraction.
      Hypocalcemia also may cause QT interval prolongation, which increases the risk of polymorphic ventricular tachycardia (ie, Torsades de pointes). However, Torsades de pointes caused by hypocalcemia is rare in clinical practice, and this life-threatening arrhythmia is associated more commonly with other electrolyte disorders, such as hypomagnesemia, or other causes, such as QT-prolonging medications.
      • Akiyama T
      • Batchelder J
      • Worsman J
      • et al.
      Hypocalcemic torsades de pointes.
      • Bradley TJ
      • Metzger DL
      • Sanatani S
      Long on QT and low on calcium.
      • Trinkley KE
      • Page 2nd, RL
      • Lien H
      • et al.
      QT interval prolongation and the risk of Torsades de pointes: essentials for clinicians.
      Despite these pathophysiological considerations, only sparse studies have documented an association between hypocalcemia and an increased incidence of AKI-related adverse outcomes. Chernow et al
      • Chernow B
      • Zaloga G
      • McFadden E
      • et al.
      Hypocalcemia in critically ill patients.
      assessed total serum calcium levels on arrival to the intensive care unit (ICU) in 210 critically ill adults, and found that levels less than 8.5 versus 8.5 mg/dL or greater were associated with a higher incidence of “renal failure” (definition not provided) in unadjusted analyses (no multivariable analyses were performed). Afshinnia et al
      • Afshinnia F
      • Belanger K
      • Palevsky PM
      • et al.
      Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: secondary analysis of the acute renal failure trial network study.
      assessed iCa levels at initiation of renal replacement therapy (RRT) in 685 critically ill patients with severe AKI, and found no association with 60-day mortality or renal recovery. However, when iCa was assessed as a time-varying exposure, levels less than 1 versus 1.15 mmol/L or greater were associated independently with increased 60-day mortality.
      • Afshinnia F
      • Belanger K
      • Palevsky PM
      • et al.
      Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: secondary analysis of the acute renal failure trial network study.
      Finally, studies by Leaf et al
      • Leaf DE
      • Waikar SS
      • Wolf M
      • et al.
      Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
      • Leaf DE
      • Jacob KA
      • Srivastava A
      • et al.
      Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      conducted in various settings, including critical illness and established AKI, found no association between total serum calcium levels and AKI-related outcomes (Table 3).

      Hypercalcemia and AKI

      Patients occasionally present with AKI and hypercalcemia. The presence of hypercalcemia in AKI is potentially significant for two reasons: hypercalcemia itself may be an important contributor to the AKI, and it also may be a clue that alerts the clinician to consider alternative etiologies (ie, other than hypercalcemia) for the AKI (Fig. 3). Hypercalcemia can cause AKI directly through a variety of mechanisms: afferent arteriolar vasoconstriction, leading to decreased glomerular filtration rate
      • Levi M
      • Ellis MA
      • Berl T
      Control of renal hemodynamics and glomerular filtration rate in chronic hypercalcemia. Role of prostaglandins, renin-angiotensin system, and calcium.
      ; binding of calcium to the CaSR on the basolateral membrane of the thick ascending limb, resulting in down-regulation of the sodium-potassium-chloride cotransporter, leading to natriuresis and volume depletion
      • Wang WH
      • Lu M
      • Hebert SC
      Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL.
      ; and nephrogenic diabetes insipidus, which occurs as a result of enhanced autophagic degradation of aquaporin-2 channels in the inner medullary collecting ducts.
      • Khositseth S
      • Charngkaew K
      • Boonkrai C
      • et al.
      Hypercalcemia induces targeted autophagic degradation of aquaporin-2 at the onset of nephrogenic diabetes insipidus.
      In addition, hypercalcemia can cause hypercalciuria, nephrolithiasis, and nephrocalcinosis, which can cause both acute and chronic renal impairment.
      Figure 3.
      Figure 3Hypercalcemia and AKI. Multiple myeloma and sarcoidosis can cause AKI by causing hypercalcemia or through effects independent of calcium. Other disorders (eg, malignancy, hyperthyroidism, and so forth) also can cause hypercalcemia-induced AKI. Abbreviations: DI, diabetes insipidus; PHPT, primary hyperparathyroidism.

      Phosphate and AKI

      Mechanisms of hyperphosphatemia in AKI

      Increased circulating phosphate levels have been reported consistently in clinical studies of patients with established AKI (Table 1). Decreased renal excretion of phosphate is the primary cause of hyperphosphatemia in most patients with AKI. In addition, phosphate may be released into the circulation from intracellular stores under conditions of massive tissue breakdown (eg, tumor lysis syndrome and rhabdomyolysis). Rarely, cellular shifts of phosphate out of cells have been reported as a cause of hyperphosphatemia in patients with lactic acidosis or diabetic ketoacidosis,
      • O'Connor LR
      • Klein KL
      • Bethune JE
      Hyperphosphatemia in lactic acidosis.
      • Kebler R
      • McDonald FD
      • Cadnapaphornchai P
      Dynamic changes in serum phosphorus levels in diabetic ketoacidosis.
      which may be present in patients with AKI.

      Clinical relevance of hyperphosphatemia in AKI

      Chronic hyperphosphatemia is an important risk factor for cardiovascular disease and mortality in CKD and end-stage renal disease.
      • Block GA
      • Klassen PS
      • Lazarus JM
      • et al.
      Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.
      In the acute setting, hyperphosphatemia can sequester calcium and thereby cause hypocalcemia (discussed earlier). Increased serum phosphate levels have been associated with a higher risk of developing AKI among hospitalized patients,
      • Thongprayoon C
      • Cheungpasitporn W
      • Mao MA
      • et al.
      Admission hyperphosphatemia increases the risk of acute kidney injury in hospitalized patients.
      as well as a higher risk of short-term mortality among patients with established AKI (Table 3).
      • Vijayan A
      • Li T
      • Dusso A
      • et al.
      Relationship of 1,25 dihydroxy vitamin D levels to clinical outcomes in critically ill patients with acute kidney injury.
      • Jung SY
      • Kim H
      • Park S
      • et al.
      Electrolyte and mineral disturbances in septic acute kidney injury patients undergoing continuous renal replacement therapy.
      • Jung SY
      • Kwon J
      • Park S
      • et al.
      Phosphate is a potential biomarker of disease severity and predicts adverse outcomes in acute kidney injury patients undergoing continuous renal replacement therapy.
      The mechanisms responsible for these findings are unclear. However, rapid and severe increases in the extracellular phosphate concentration can result in acute phosphate nephropathy, in which calcium phosphate deposition is found in the tubular lumina, tubular epithelia, and, less commonly, the peritubular interstitium.
      • Markowitz GS
      • Nasr SH
      • Klein P
      • et al.
      Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing.
      Acute phosphate nephropathy has been reported in patients with tumor lysis syndrome,
      • Boles JM
      • Dutel JL
      • Briere J
      • et al.
      Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia.
      • Kanfer A
      • Richet G
      • Roland J
      • et al.
      Extreme hyperphosphataemia causing acute anuric nephrocalcinosis in lymphosarcoma.
      and more commonly after the use of sodium phosphate–containing oral bowel preparations and enemas.
      • Markowitz GS
      • Stokes MB
      • Radhakrishnan J
      • et al.
      Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure.
      Risk factors for acute phosphate nephropathy from sodium phosphate–containing bowel preparations include the total amount of phosphate administered, CKD, advanced age, and female sex.
      • Russmann S
      • Lamerato L
      • Motsko SP
      • et al.
      Risk of further decline in renal function after the use of oral sodium phosphate or polyethylene glycol in patients with a preexisting glomerular filtration rate below 60 ml/min.
      • Gumurdulu Y
      • Serin E
      • Ozer B
      • et al.
      Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation.
      Use of angiotensin-converting enzyme inhibitors, angiotensin II–receptor blockers, and nonsteroidal anti-inflammatory drugs also have been suggested as possible risk factors.
      • Markowitz GS
      • Stokes MB
      • Radhakrishnan J
      • et al.
      Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure.
      • Heher EC
      • Thier SO
      • Rennke H
      • et al.
      Adverse renal and metabolic effects associated with oral sodium phosphate bowel preparation.
      The US Food and Drug Administration has issued several warnings, most recently in 2014, regarding the potential for AKI in patients receiving sodium phosphate–containing bowel preparations.

      Treatment of hyperphosphatemia in AKI

      Among patients with AKI requiring RRT, extracorporeal clearance of phosphate typically will restore serum phosphate levels to the normal range within 2 to 3 days of RRT initiation.
      • Tan HK
      • Bellomo R
      • M'Pis DA
      • et al.
      Phosphatemic control during acute renal failure: intermittent hemodialysis versus continuous hemodiafiltration.
      Among patients with AKI who do not require RRT, treatment options for hyperphosphatemia are limited. Phosphate binders can be administered in AKI, as they are in CKD, but to be effective they must be administered with meals. Thus, critically ill patients with AKI, many of whom receive nutrition via continuous enteral tube feeds, are unlikely to respond to phosphate binders administered three times daily. We therefore recommend administering phosphate binders at more frequent dosing intervals (eg, every 4-6 h) in patients with AKI who are receiving continuous tube feeds, particularly in cases of severe hyperphosphatemia (ie, >10 mg/dL). Patients with milder degrees of hyperphosphatemia likely do not require treatment acutely, although no randomized controlled trials have been conducted in this area.

      Hypophosphatemia as a consequence of RRT

      Patients with AKI requiring RRT may become hypophosphatemic owing to extracorporeal clearance of phosphate, particularly among those prescribed RRT at higher intensities.
      • Palevsky PM
      • Zhang JH
      • O'Connor TZ
      • et al.
      Intensity of renal support in critically ill patients with acute kidney injury.
      Sharma and Waikar
      • Sharma S
      • Waikar SS
      Phosphate balance in continuous venovenous hemofiltration.
      calculated the daily phosphate balance in 35 patients with AKI undergoing continuous venovenous hemofiltration (CVVH) by subtracting urinary and CVVH losses from dietary (enteral or parenteral) intake. They found that despite use of a protocol-driven phosphate repletion strategy, all patients were in negative phosphate balance, and 34% had overt hypophosphatemia. Furthermore, the daily phosphate balance was persistently negative even after 7 days of CVVH.
      • Sharma S
      • Waikar SS
      Phosphate balance in continuous venovenous hemofiltration.
      These findings are potentially of great clinical relevance because phosphate is needed for many essential cellular functions. Prolonged hypophosphatemia can result in impaired myocardial and diaphragmatic contractility, and hypophosphatemia has been associated with prolonged mechanical ventilation in critically ill patients both with and without AKI.
      • Lim C
      • Tan HK
      • Kaushik M
      Hypophosphatemia in critically ill patients with acute kidney injury treated with hemodialysis is associated with adverse events.
      • Alsumrain MH
      • Jawad SA
      • Imran NB
      • et al.
      Association of hypophosphatemia with failure-to-wean from mechanical ventilation.
      Accordingly, careful attention to phosphate homeostasis is needed in all critically ill patients, and particularly in those with AKI requiring RRT. A preventive strategy that has become increasingly popular in recent years is the use of phosphate-containing replacement solutions and phosphate-containing dialysis solutions in RRT circuits.
      • Broman M
      • Carlsson O
      • Friberg H
      • et al.
      Phosphate-containing dialysis solution prevents hypophosphatemia during continuous renal replacement therapy.

      PTH and AKI

      Mechanisms of hyperparathyroidism in AKI

      Increased circulating PTH levels have been reported consistently in clinical studies of patients with established AKI (Table 1). Hyperparathyroidism in AKI is owing to both hypocalcemia and decreased circulating 1,25D levels, each of which exerts negative feedback on the parathyroid glands to produce and secrete PTH (Fig. 2).
      • Naveh-Many T
      • Silver J
      Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.
      • Slatopolsky E
      • Weerts C
      • Thielan J
      • et al.
      Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients.
      The regulation of PTH by 1,25D in the setting of AKI was elegantly shown in a study by Madsen et al.
      • Madsen S
      • Olgaard K
      • Ladefoged J
      Suppressive effect of 1,25-dihydroxyvitamin D3 on circulating parathyroid hormone in acute renal failure.
      Ten adult patients with oliguric AKI receiving continuous peritoneal dialysis were studied. Five patients received injections of 1,25D every 6 hours, and the other five patients served as controls. Suppression of PTH was observed in patients who received 1,25D but not in the control patients. Because serum calcium levels were maintained constant by peritoneal dialysis, the investigators concluded that the observed reduction in PTH levels could not be explained by the calcemic effect of 1,25D, and instead suggested direct feedback regulation by 1,25D on the parathyroid glands.
      • Madsen S
      • Olgaard K
      • Ladefoged J
      Suppressive effect of 1,25-dihydroxyvitamin D3 on circulating parathyroid hormone in acute renal failure.
      Interestingly, although PTH levels are increased in patients with AKI, PTH often is unable to restore circulating calcium levels to normal. This appears to be owing to skeletal resistance to PTH in AKI, which was first shown by Massry et al
      • Massry SG
      • Arieff AI
      • Coburn JW
      • et al.
      Divalent ion metabolism in patients with acute renal failure: studies on the mechanism of hypocalcemia.
      in 1974. Ten adult patients with oliguric AKI received an infusion of PTH extract, which failed to elicit a normal increase in serum calcium. These findings suggest that AKI causes skeletal resistance to PTH, which also is known to occur in CKD. In the latter setting, skeletal resistance to PTH occurs primarily owing to down-regulation of PTH receptors in bone.
      • Galceran T
      • Martin KJ
      • Morrissey JJ
      • et al.
      Role of 1,25-dihydroxyvitamin D on the skeletal resistance to parathyroid hormone.
      In addition to skeletal resistance, there also may be renal resistance to PTH in AKI, evidenced by low circulating 1,25D levels despite increased PTH (Fig. 2).
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      • Leaf DE
      • Wolf M
      • Waikar SS
      • et al.
      FGF-23 levels in patients with AKI and risk of adverse outcomes.

      Basic science studies of PTH in AKI

      The initial observations in human beings that AKI leads to skeletal resistance to PTH was confirmed by a subsequent study performed in thyroparathyroidectomized rats. In that study, AKI was induced by either bilateral nephrectomy or ureter ligation. In both AKI models, infusion of PTH led to a blunted increase in plasma calcium levels, and these findings were unrelated to abnormalities of vitamin D metabolism because pretreatment with different combinations of vitamin D metabolites failed to correct the resistance to PTH.
      • Somerville PJ
      • Kaye M
      Resistance to parathyroid hormone in renal failure: role of vitamin D metabolites.
      Beyond the observation that AKI is associated with skeletal resistance to PTH, a role for PTH in the pathophysiology of AKI also has been suggested by some studies. Specifically, in a cisplatin-induced AKI rat model, Capasso et al
      • Capasso G
      • Giordano DR
      • de Tommaso G
      • et al.
      Parathyroidectomy has a beneficial effect on experimental cisplatin nephrotoxicity.
      showed that surgical parathyroidectomy before drug exposure attenuated the severity of renal failure, evidenced by smaller increases in blood urea nitrogen and serum creatinine levels. Similar results were reported in a rat model of gentamicin nephrotoxicity,
      • Bennett WM
      • Pulliam JP
      • Porter GA
      • et al.
      Modification of experimental gentamicin nephrotoxicity by selective parathyroidectomy.
      although this finding was not confirmed in a subsequent study.
      • Cronin RE
      • Newman JA
      Protective effect of thyroxine but not parathyroidectomy on gentamicin nephrotoxicity.
      Although the mechanisms underlying these findings are unclear, one proposed mechanism to explain the therapeutic efficacy of parathyroidectomy in attenuating AKI relates to increased drug trafficking across the tubular brush-border membrane.
      • Elliott WC
      • Patchin DS
      • Jones DB
      Effect of parathyroid hormone activity on gentamicin nephrotoxicity.

      Clinical relevance of hyperparathyroidism in AKI

      Although chronically increased circulating PTH levels may contribute to the pathophysiology of mineral and bone disease in CKD, the clinical significance of acutely increased PTH levels in patients with AKI is unclear. Higher PTH levels are not associated with an increased risk of development of AKI among critically ill patients,
      • Leaf DE
      • Jacob KA
      • Srivastava A
      • et al.
      Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
      or associated with an increased risk of 60-day mortality among patients with established AKI (Table 3).
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      Wang et al
      • Wang WJ
      • Chao CT
      • Huang YC
      • et al.
      The impact of acute kidney injury with temporary dialysis on the risk of fracture.
      reported an association between an episode of AKI requiring temporary RRT and a subsequent increased risk of bone fracture among 448 Taiwanese adults. However, whether this observation was the result of persistent abnormalities in PTH or other markers of mineral metabolism, such as FGF23 or vitamin D metabolites, was not assessed. A study conducted in critically ill patients with septic shock found that PTH levels, which were increased acutely, decreased rapidly during the recovery phase of sepsis, despite persistent hypocalcemia.
      • Pinheiro da Silva F
      • Zampieri FG
      • Barbeiro HV
      • et al.
      Decreased parathyroid hormone levels despite persistent hypocalcemia in patients with kidney failure recovering from septic shock.
      Whether PTH and other mineral metabolites remain persistently abnormal after recovery from AKI will be investigated in the ongoing Assessment, Serial Evaluation, and Subsequent Sequelae of AKI study.
      • Go AS
      • Parikh CR
      • Ikizler TA
      • et al.
      The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods.

      Vitamin D Metabolites and AKI

      Mechanisms of decreased 1,25D levels in AKI

      Decreased circulating 1,25D levels have been shown in nearly all studies of patients with established AKI, and decreased 25D levels have been shown in most studies of patients with established AKI (Table 1). Circulating 1,25D is derived primarily from hydroxylation of 25D in the proximal tubular cells of the kidney (Fig. 2),
      • Zhang MY
      • Wang X
      • Wang JT
      • et al.
      Dietary phosphorus transcriptionally regulates 25-hydroxyvitamin D-1alpha-hydroxylase gene expression in the proximal renal tubule.
      • Blomberg Jensen M
      • Andersen CB
      • Nielsen JE
      • et al.
      Expression of the vitamin D receptor, 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase in the human kidney and renal clear cell cancer.
      a process that is catalyzed by the cytochrome P450 enzyme, CYP27B1. Accordingly, decreased circulating 1,25D levels in patients with AKI could reflect either decreased substrate delivery of 25D to the proximal tubular cells and/or decreased CYP27B1 expression owing to tubular injury. Decreased substrate delivery of 25D, in turn, could be due to decreased circulating vitamin D binding protein (DBP), levels of which are known to decrease in AKI and other acute illnesses
      • Leaf DE
      • Waikar SS
      • Wolf M
      • et al.
      Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
      • Leaf DE
      • Jacob KA
      • Srivastava A
      • et al.
      Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
      ,
      • Lee WM
      • Galbraith RM
      • Watt GH
      • et al.
      Predicting survival in fulminant hepatic failure using serum Gc protein concentrations.
      ; decreased glomerular filtration of 25D–DBP complexes in AKI; or decreased uptake of 25D-DBP by megalin and cubilin-mediated endocytosis on the apical side of the renal proximal tubular cells.
      • Nykjaer A
      • Dragun D
      • Walther D
      • et al.
      An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.
      The latter mechanism is supported by studies showing increased urinary DBP levels in patients with contrast-associated AKI.
      • Chaykovska L
      • Heunisch F
      • von Einem G
      • et al.
      Urinary vitamin D binding protein and KIM-1 are potent new biomarkers of major adverse renal events in patients undergoing coronary angiography.
      Alternatively, decreased CYP27B1 expression could account for decreased circulating 1,25D levels in AKI, and has been shown in kidney cells isolated from rats subjected to unilateral kidney damage.
      • Ghazarian JG
      • Garancis JC
      • Yanda DM
      • et al.
      Changes in 25-hydroxyvitamin D3 alpha- and 24-hydroxylase activities of kidney cells isolated from rats with either unilateral kidney damage or acute renal insufficiency.
      Decreased CYP27B1 expression also has been shown in human monocytes cultured in uremic serum,
      • Viaene L
      • Evenepoel P
      • Meijers B
      • et al.
      Uremia suppresses immune signal-induced CYP27B1 expression in human monocytes.
      suggesting that increased circulating factors in the setting of AKI, such as FGF23,
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      • Leaf DE
      • Wolf M
      • Waikar SS
      • et al.
      FGF-23 levels in patients with AKI and risk of adverse outcomes.
      ,
      • Leaf DE
      • Christov M
      • Juppner H
      • et al.
      Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery.
      may be responsible for decreased CYP27B1 expression. Indeed, FGF23 impairs CYP27B1 expression in the kidneys
      • Hasegawa H
      • Nagano N
      • Urakawa I
      • et al.
      Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease.
      and in extrarenal tissues.
      • Bacchetta J
      • Sea JL
      • Chun RF
      • et al.
      Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes.
      • Chanakul A
      • Zhang MY
      • Louw A
      • et al.
      FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues.

      Mechanisms of decreased 25D levels in AKI

      In contrast to 1,25D, decreased circulating 25D levels in AKI cannot be attributed to impaired CYP27B1 activity. Instead, decreased 25D levels in AKI could be due to decreased cutaneous synthesis of vitamin D from a lack of UV light exposure, nutritional deficiency of vitamin D, impaired enteral absorption of vitamin D in the setting of acute illness, decreased circulating DBP levels,
      • Leaf DE
      • Waikar SS
      • Wolf M
      • et al.
      Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
      • Leaf DE
      • Jacob KA
      • Srivastava A
      • et al.
      Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
      ,
      • Lee WM
      • Galbraith RM
      • Watt GH
      • et al.
      Predicting survival in fulminant hepatic failure using serum Gc protein concentrations.
      or enhanced catabolism of 25D by the cytochrome P450 enzyme, CYP24A1. Enhanced catabolism of 25D to its inactive metabolite, 24,25-dihydroxyvitamin D (24,25D), could be mediated by FGF23, which is increased in AKI
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      • Leaf DE
      • Wolf M
      • Waikar SS
      • et al.
      FGF-23 levels in patients with AKI and risk of adverse outcomes.
      ,
      • Leaf DE
      • Christov M
      • Juppner H
      • et al.
      Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery.
      and has been suggested by some studies,
      • Inoue Y
      • Segawa H
      • Kaneko I
      • et al.
      Role of the vitamin D receptor in FGF23 action on phosphate metabolism.
      but not others,
      • Bosworth CR
      • Levin G
      • Robinson-Cohen C
      • et al.
      The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease.
      • Stubbs JR
      • Zhang S
      • Friedman PA
      • et al.
      Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD.
      to up-regulate CYP24A1. However, Leaf et al
      • Leaf DE
      • Wolf M
      • Waikar SS
      • et al.
      FGF-23 levels in patients with AKI and risk of adverse outcomes.
      measured plasma 24,25D levels in hospitalized patients with and without AKI and found that 24,25D levels were actually lower, not higher, in patients with AKI compared with matched controls. Thus, it is likely that mechanisms other than up-regulation of CYP24A1 are responsible for decreased 25D levels in AKI. Furthermore, it is unclear whether 25D levels are truly lower in patients with versus without AKI, or if low 25D levels in AKI are simply a reflection of the severity of illness. An ongoing prospective cohort study of 230 critically ill patients admitted to ICUs in the United Kingdom is seeking to address this question, as well as the kinetics of 25D and 1,25D levels in critically ill patients with and without AKI.
      • Cameron LK
      • Lei K
      • Smith S
      • et al.
      Vitamin D levels in critically ill patients with acute kidney injury: a protocol for a prospective cohort study (VID-AKI).

      Clinical relevance of decreased 25D and 1,25D in AKI

      Conflicting findings have been reported on whether decreased 25D and 1,25D levels are associated with an increased risk of incident AKI and related outcomes. Braun et al
      • Braun AB
      • Litonjua AA
      • Moromizato T
      • et al.
      Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill.
      reported that lower pre-admission circulating 25D levels (<15 compared with ≥30 ng/mL) were associated independently with a higher risk of incident AKI among 2075 critically ill patients (Table 3). Similarly, Ala-Kokko et al
      • Ala-Kokko TI
      • Mutt SJ
      • Nisula S
      • et al.
      Vitamin D deficiency at admission is not associated with 90-day mortality in patients with severe sepsis or septic shock: observational FINNAKI cohort study.
      reported that lower 25D levels measured on arrival to the ICU were associated with a higher risk of incident AKI and need for RRT in unadjusted analyses (multivariable analyses were not performed). However, Leaf et al
      • Leaf DE
      • Jacob KA
      • Srivastava A
      • et al.
      Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
      reported that neither 25D nor 1,25D levels were associated with the composite outcome of incident AKI or in-hospital death among 113 critically ill patients.
      A related question is whether 25D or 1,25D levels are predictive of acute mortality and other clinical outcomes among patients with established AKI. Initial reports found conflicting findings, but these studies likely were underpowered, with sample sizes ranging from 34 to 60 patients (Table 3).
      • Leaf DE
      • Waikar SS
      • Wolf M
      • et al.
      Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
      • Vijayan A
      • Li T
      • Dusso A
      • et al.
      Relationship of 1,25 dihydroxy vitamin D levels to clinical outcomes in critically ill patients with acute kidney injury.
      Leaf et al
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.
      recently published a large study investigating vitamin D metabolites in critically ill patients with AKI. Among 400 patients with AKI requiring RRT, lower levels of 25D, but not 1,25D, were associated with an increased risk of 60-day mortality in unadjusted analyses. However, in fully adjusted models, neither 25D nor 1,25D were associated with death.
      • Leaf DE
      • Siew ED
      • Eisenga MF
      • et al.
      Fibroblast growth factor 23 associates with death in critically ill patients.

      VITAMIN D METABOLITES AS NOVEL THERAPIES IN AKI AND CRITICAL ILLNESS

      Overview

      Among the mineral metabolite abnormalities discussed earlier, decreased circulating levels of vitamin D metabolites represent a unique opportunity for therapeutic intervention in AKI. Beyond their role in maintaining calcium and phosphate homeostasis, vitamin D metabolites influence the expression of more than 200 target genes,
      • Ramagopalan SV
      • Heger A
      • Berlanga AJ
      • et al.
      A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.
      including genes that affect a variety of critical immunomodulatory pathways relevant to AKI.
      • Adams JS
      • Hewison M
      Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity.
      • Bouillon R
      • Lieben L
      • Mathieu C
      • et al.
      Vitamin D action: lessons from VDR and Cyp27b1 null mice.
      In animal models, pre-administration of 1,25D attenuated AKI resulting from a variety of nephrotoxic insults, including ischemia-reperfusion injury,
      • Lee JW
      • Kim SC
      • Ko YS
      • et al.
      Renoprotective effect of paricalcitol via a modulation of the TLR4-NF-kappaB pathway in ischemia/reperfusion-induced acute kidney injury.
      • Azak A
      • Huddam B
      • Haberal N
      • et al.
      Effect of novel vitamin D receptor activator paricalcitol on renal ischaemia/reperfusion injury in rats.
      • Sezgin G
      • Ozturk G
      • Guney S
      • et al.
      Protective effect of melatonin and 1,25-dihydroxyvitamin D3 on renal ischemia-reperfusion injury in rats.
      gentamicin,
      • Park JW
      • Bae EH
      • Kim IJ
      • et al.
      Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats.
      cyclosporine,
      • Park JW
      • Bae EH
      • Kim IJ
      • et al.
      Paricalcitol attenuates cyclosporine-induced kidney injury in rats.
      cisplatin,
      • Park JW
      • Cho JW
      • Joo SY
      • et al.
      Paricalcitol prevents cisplatin-induced renal injury by suppressing apoptosis and proliferation.
      glomerulonephritis,
      • Makibayashi K
      • Tatematsu M
      • Hirata M
      • et al.
      A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis.
      and obstruction.
      • Tan X
      • Li Y
      • Liu Y
      Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy.
      Furthermore, de Braganca et al
      • de Braganca AC
      • Volpini RA
      • Canale D
      • et al.
      Vitamin D deficiency aggravates ischemic acute kidney injury in rats.
      investigated the effects of dietary-induced 25D deficiency on the severity of AKI in rats. They found that rats fed a vitamin D–free diet had a more severe decrease in glomerular filtration rate, greater urinary protein excretion, and increased tubular necrosis after ischemia-reperfusion injury compared with rats fed a standard diet. Although the mechanisms underlying these findings are incompletely understood, potential pathways include up-regulation of anti-inflammatory proteins, such as interleukin 10 and heme oxygenase-1, and induction of anti-inflammatory T-regulatory cell proliferation and differentiation. Each of these targets is inducible in response to 1,25D in both animals and humans,
      • Kovalenko PL
      • Zhang Z
      • Cui M
      • et al.
      1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1.
      • Tiosano D
      • Wildbaum G
      • Gepstein V
      • et al.
      The role of vitamin D receptor in innate and adaptive immunity: a study in hereditary vitamin D-resistant rickets patients.
      • Penna G
      • Adorini L
      1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation.
      • Penna G
      • Roncari A
      • Amuchastegui S
      • et al.
      Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3.
      • Atif F
      • Yousuf S
      • Sayeed I
      • et al.
      Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection.
      • Oermann E
      • Bidmon HJ
      • Witte OW
      • et al.
      Effects of 1alpha,25 dihydroxyvitamin D3 on the expression of HO-1 and GFAP in glial cells of the photothrombotically lesioned cerebral cortex.
      • Kutuzova GD
      • DeLuca HF
      1,25-Dihydroxyvitamin D3 regulates genes responsible for detoxification in intestine.
      • Gregori S
      • Casorati M
      • Amuchastegui S
      • et al.
      Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance.
      • Leaf DE
      • Raed A
      • Donnino MW
      • et al.
      Randomized controlled trial of calcitriol in severe sepsis.
      • Navarro-Gonzalez JF
      • Donate-Correa J
      • Mendez ML
      • et al.
      Anti-inflammatory profile of paricalcitol in hemodialysis patients: a prospective, open-label, pilot study.
      • Prietl B
      • Pilz S
      • Wolf M
      • et al.
      Vitamin D supplementation and regulatory T cells in apparently healthy subjects: vitamin D treatment for autoimmune diseases?.
      • Prietl B
      • Treiber G
      • Mader JK
      • et al.
      High-dose cholecalciferol supplementation significantly increases peripheral CD4(+) Tregs in healthy adults without negatively affecting the frequency of other immune cells.
      • Schleithoff SS
      • Zittermann A
      • Tenderich G
      • et al.
      Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
      and plays an important role in the pathogenesis of AKI.
      • Nath KA
      Heme oxygenase-1 and acute kidney injury.
      • Maines MD
      • Mayer RD
      • Ewing JF
      • et al.
      Induction of kidney heme oxygenase-1 (HSP32) mRNA and protein by ischemia/reperfusion: possible role of heme as both promotor of tissue damage and regulator of HSP32.
      • Tracz MJ
      • Juncos JP
      • Grande JP
      • et al.
      Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1-/- mice.
      • Milwid JM
      • Ichimura T
      • Li M
      • et al.
      Secreted factors from bone marrow stromal cells upregulate IL-10 and reverse acute kidney injury.
      • Togel F
      • Hu Z
      • Weiss K
      • et al.
      Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.
      • Kinsey GR
      • Sharma R
      • Huang L
      • et al.
      Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury.
      • Lee H
      • Nho D
      • Chung HS
      • et al.
      CD4+CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice.
      • Cho WY
      • Choi HM
      • Lee SY
      • et al.
      The role of Tregs and CD11c(+) macrophages/dendritic cells in ischemic preconditioning of the kidney.
      In addition to strong data from preclinical studies, the relevance of decreased circulating vitamin D metabolite levels in human AKI is supported further by epidemiologic studies in critically ill patients. These studies consistently have found that lower levels of 25D associate independently with an increased risk of acute organ injury and death.
      • Leaf DE
      • Waikar SS
      • Wolf M
      • et al.
      Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
      • Braun AB
      • Litonjua AA
      • Moromizato T
      • et al.
      Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill.
      ,
      • Dancer RC
      • Parekh D
      • Lax S
      • et al.
      Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).
      • Braun A
      • Chang D
      • Mahadevappa K
      • et al.
      Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill.
      • Amrein K
      • Zajic P
      • Schnedl C
      • et al.
      Vitamin D status and its association with season, hospital and sepsis mortality in critical illness.
      • Ginde AA
      • Camargo Jr, CA
      • Shapiro NI
      Vitamin D insufficiency and sepsis severity in emergency department patients with suspected infection.
      Accordingly, there is currently great interest in assessing whether administration of vitamin D metabolites improves outcomes in critically ill patients. However, there is no clear consensus on which vitamin D metabolite should be administered in this setting.

      Vitamin D Metabolite Administration in AKI and Critical Illness

      An overview of vitamin D metabolism is shown in Figure 4. Plasma 25D levels, the most commonly used surrogate for vitamin D sufficiency, can be increased indirectly by administering its precursor, vitamin D2 or D3 (hereafter referred to as simply vitamin D), or by administering 25D itself. A disadvantage of vitamin D administration is that it requires several days to saturate adipose tissue stores and increase plasma 25D levels.
      • Amrein K
      • Sourij H
      • Wagner G
      • et al.
      Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study.
      Supporting this notion, a randomized, double-blind, placebo-controlled trial investigated the effects of a large (540,000 IU) enteral dose of vitamin D administration in 492 critically ill patients. Among patients who received vitamin D, only approximately 50% achieved target plasma 25D levels greater than 30 ng/mL on day 3.
      • Amrein K
      • Schnedl C
      • Holl A
      • et al.
      Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial.
      The primary outcome, hospital length of stay, was similar in vitamin D and placebo-treated patients. However, among patients with severe vitamin D deficiency on enrollment (defined as a 25D level ≤ 12 ng/mL), hospital mortality was significantly lower in vitamin D– versus placebo-treated patients. A follow-up phase III trial—Vitamin D to Improve Outcomes by Leveraging Early Treatment—is ongoing to test whether a single enteral dose of 540,000 IU of vitamin D will decrease 90-day mortality in 3,000 critically ill patients at risk of acute respiratory distress syndrome (clinicaltrials.gov NCT03096314).
      Figure 4.
      Figure 4Vitamin D metabolism. Inactivation pathways are shown by dotted lines. Abbreviations: 1,24,25D, 1,24,25-trihydroxyvitamin D; VDR, vitamin D receptor.
      An alternative strategy for increasing plasma 25D levels is administration of 25D itself. In contrast to vitamin D, oral 25D increases plasma 25D levels within hours.
      • Haddad Jr, JG
      • Rojanasathit S
      Acute administration of 25-hydroxycholecalciferol in man.
      Oral 25D, or calcifediol, is available in both modified-release
      • Sprague SM
      • Crawford PW
      • Melnick JZ
      • et al.
      Use of extended-release calcifediol to treat secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease.
      and immediate-release pill formulations,
      • Jetter A
      • Egli A
      • Dawson-Hughes B
      • et al.
      Pharmacokinetics of oral vitamin D(3) and calcifediol.
      but is not readily available as an oral liquid formulation that can be administered via oro/nasogastric tube in a critically-ill, mechanically ventilated patient. Similarly, 25D is not currently available in a parenteral formulation.
      Finally, a third strategy is to administer 1,25D. An advantage of this approach is that 1,25D does not require activation by the liver or kidneys (Fig. 4), either of which may be variably impaired in critical illness. Furthermore, the immunomodulatory effects of vitamin D metabolites showed in preclinical models were shown almost exclusively with 1,25D. Accordingly, Leaf et al
      • Leaf DE
      • Raed A
      • Donnino MW
      • et al.
      Randomized controlled trial of calcitriol in severe sepsis.
      conducted a pilot randomized controlled trial to investigate the immunomodulatory effects of 1,25D administration in 67 critically ill patients with severe sepsis or septic shock. Patients were assigned randomly to receive a single 2-µg intravenous dose of 1,25D or placebo. Those who received 1,25D had higher leukocyte messenger RNA expression of human cathelicidin antimicrobial peptide 18, and higher expression of the anti-inflammatory cytokine, interleukin 10, at 24 hours than patients who received placebo.
      Despite these encouraging preliminary data, administration of 1,25D as a therapeutic strategy in critically ill patients has several limitations, including its potential to cause hypercalcemia, as well as its short half-life, which requires repeated administrations. In addition, circulating 1,25D levels may be less physiologically relevant to nonclassic targets, such as monocytes, than local (ie, intracellularly produced) 1,25D, especially because 1,25D circulates in the blood at approximately 1,000-fold lower concentrations than 25D. Accordingly, increasing circulating 25D levels to augment substrate availability for local conversion to 1,25D by target cells is a strategy that has been advocated by some experts.
      • Adams JS
      • Hewison M
      Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity.
      • Schnedl C
      • Dobnig H
      • Quraishi SA
      • et al.
      Native and active vitamin D in intensive care: who and how we treat is crucially important.

      Activated Vitamin D for the Prevention and Treatment of AKI Study

      To address the earlier pharmacokinetic issues related to 25D versus 1,25D, we designed the Activated Vitamin D for the Prevention and Treatment of AKI study (ACTIVATE-AKI). ACTIVATE-AKI is a randomized, double-blind, 3-arm study being conducted in critically ill adult patients at risk of severe AKI. Eligible patients are enrolled within 48 hours of arrival to the ICU, and are assigned randomly in a 1:1:1 fashion to receive five daily enteral doses of 25D, 1,25D, or placebo. Because an oral liquid formulation of 25D is not commercially available, we developed such a formulation (Investigational New Drug 133057) in medium chain triglyceride oil. The primary end point is a composite of kidney injury (assessed by time-averaged daily serum creatinine concentration for 7 days), need for RRT, or death. Secondary end points and additional study details are available on clinicaltrials.gov (NCT02962102).

      SUMMARY

      AKI causes many of the same mineral metabolite abnormalities that commonly occur in CKD, including hypocalcemia, hyperphosphatemia, hyperparathyroidism, and decreased 1,25D levels. An increasing body of literature over the past decade suggests that these mineral metabolite abnormalities could be leveraged as novel prognostic markers for AKI and related outcomes, or as novel therapeutic targets for AKI prevention and treatment. Randomized controlled trials are ongoing to test whether interventions aimed at correcting some of these abnormalities can improve AKI-related outcomes for patients.

      REFERENCES

        • Bergwitz C
        • Juppner H
        Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23.
        Annu Rev Med. 2010; 61: 91-104
        • Goltzman D
        • Mannstadt M
        • Marcocci C
        Physiology of the calcium-parathyroid hormone-vitamin D axis.
        Front Horm Res. 2018; 50: 1-13
        • Daugaard H
        • Egfjord M
        • Olgaard K
        Metabolism of intact parathyroid hormone in isolated perfused rat liver and kidney.
        Am J Physiol. 1988; 254: E740-E748
        • Hesch RD
        • Ebel H
        • Hehrmann R
        • et al.
        Endocrinological aspects of PTH metabolism in the kidney.
        Contrib Nephrol. 1978; 13: 104-114
        • Cheloha RW
        • Gellman SH
        • Vilardaga JP
        • et al.
        PTH receptor-1 signalling-mechanistic insights and therapeutic prospects.
        Nat Rev Endocrinol. 2015; 11: 712-724
        • McSheehy PM
        • Chambers TJ
        Osteoblast-like cells in the presence of parathyroid hormone release soluble factor that stimulates osteoclastic bone resorption.
        Endocrinology. 1986; 119: 1654-1659
        • Potts JT
        Parathyroid hormone: past and present.
        J Endocrinol. 2005; 187: 311-325
        • van Abel M
        • Hoenderop JG
        • van der Kemp AW
        • et al.
        Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone.
        Kidney Int. 2005; 68: 1708-1721
        • Pfister MF
        • Lederer E
        • Forgo J
        • et al.
        Parathyroid hormone-dependent degradation of type II Na+/Pi cotransporters.
        J Biol Chem. 1997; 272: 20125-20130
        • Kremer R
        • Goltzman D
        Parathyroid hormone stimulates mammalian renal 25-hydroxyvitamin D3-1 alpha-hydroxylase in vitro.
        Endocrinology. 1982; 110: 294-296
        • Fraser DR
        • Kodicek E
        Regulation of 25-hydroxycholecalciferol-1-hydroxylase activity in kidney by parathyroid hormone.
        Nat New Biol. 1973; 241: 163-166
        • Silver J
        • Naveh-Many T
        • Mayer H
        • et al.
        Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat.
        J Clin Invest. 1986; 78: 1296-1301
        • Katai K
        • Miyamoto K
        • Kishida S
        • et al.
        Regulation of intestinal Na+-dependent phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3.
        Biochem J. 1999; 343: 705-712
        • Masumoto O
        • Ohyama Y
        • Okuda K
        Purification and characterization of vitamin D 25-hydroxylase from rat liver mitochondria.
        J Biol Chem. 1988; 263: 14256-14260
        • Kawashima H
        • Torikai S
        • Kurokawa K
        Localization of 25-hydroxyvitamin D3 1 alpha-hydroxylase and 24-hydroxylase along the rat nephron.
        Proc Natl Acad Sci U S A. 1981; 78: 1199-1203
        • Hii CS
        • Ferrante A
        The non-genomic actions of vitamin D.
        Nutrients. 2016; 8: 135
        • Demay MB
        • Kiernan MS
        • DeLuca HF
        • et al.
        Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3.
        Proc Natl Acad Sci U S A. 1992; 89: 8097-8101
        • An L
        • Liu CT
        • Yu MJ
        • et al.
        Heme oxygenase-1 system, inflammation and ventilator-induced lung injury.
        Eur J Pharmacol. 2012; 677: 1-4
        • Ramagopalan SV
        • Heger A
        • Berlanga AJ
        • et al.
        A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.
        Genome Res. 2010; 20: 1352-1360
        • ADHR Consortium
        Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.
        Nat Genet. 2000; 26: 345-348
        • Jonsson KB
        • Zahradnik R
        • Larsson T
        • et al.
        Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.
        N Engl J Med. 2003; 348: 1656-1663
        • Kronenberg HM
        NPT2a–the key to phosphate homeostasis.
        N Engl J Med. 2002; 347: 1022-1024
        • Hasegawa H
        • Nagano N
        • Urakawa I
        • et al.
        Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease.
        Kidney Int. 2010; 78: 975-980
        • Bacchetta J
        • Sea JL
        • Chun RF
        • et al.
        Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes.
        J Bone Miner Res. 2013; 28: 46-55
        • Ben-Dov IZ
        • Galitzer H
        • Lavi-Moshayoff V
        • et al.
        The parathyroid is a target organ for FGF23 in rats.
        J Clin Invest. 2007; 117: 4003-4008
        • Coe LM
        • Madathil SV
        • Casu C
        • et al.
        FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis.
        J Biol Chem. 2014; 289: 9795-9810
        • Marsell R
        • Krajisnik T
        • Goransson H
        • et al.
        Gene expression analysis of kidneys from transgenic mice expressing fibroblast growth factor-23.
        Nephrol Dial Transplant. 2008; 23: 827-833
        • Meyer MH
        • Dulde E
        • Meyer Jr., RA
        The genomic response of the mouse kidney to low-phosphate diet is altered in X-linked hypophosphatemia.
        Physiol Genomics. 2004; 18: 4-11
        • David V
        • Martin A
        • Isakova T
        • et al.
        Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production.
        Kidney Int. 2016; 89: 135-146
        • Farrow EG
        • Yu X
        • Summers LJ
        • et al.
        Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.
        Proc Natl Acad Sci U S A. 2011; 108: E1146-E1155
        • Burnett SM
        • Gunawardene SC
        • Bringhurst FR
        • et al.
        Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women.
        J Bone Miner Res. 2006; 21: 1187-1196
        • Saito H
        • Maeda A
        • Ohtomo S
        • et al.
        Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo.
        J Biol Chem. 2005; 280: 2543-2549
        • Knab VM
        • Corbin B
        • Andrukhova O
        • et al.
        Acute parathyroid hormone injection increases C-terminal, but not intact fibroblast growth factor 23 levels.
        Endocrinology. 2017; 158: 1-10
        • Urakawa I
        • Yamazaki Y
        • Shimada T
        • et al.
        Klotho converts canonical FGF receptor into a specific receptor for FGF23.
        Nature. 2006; 444: 770-774
        • Matsumura Y
        • Aizawa H
        • Shiraki-Iida T
        • et al.
        Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein.
        Biochem Biophys Res Commun. 1998; 242: 626-630
        • Chen G
        • Liu Y
        • Goetz R
        • et al.
        alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.
        Nature. 2018; 553: 461-466
        • Imura A
        • Tsuji Y
        • Murata M
        • et al.
        alpha-Klotho as a regulator of calcium homeostasis.
        Science. 2007; 316: 1615-1618
        • Cha SK
        • Hu MC
        • Kurosu H
        • et al.
        Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho.
        Mol Pharmacol. 2009; 76: 38-46
        • Hu MC
        • Shi M
        • Zhang J
        • et al.
        Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule.
        FASEB J. 2010; 24: 3438-3450
        • Hu MC
        • Shi M
        • Zhang J
        • et al.
        Klotho deficiency causes vascular calcification in chronic kidney disease.
        J Am Soc Nephrol. 2011; 22: 124-136
        • Barker SL
        • Pastor J
        • Carranza D
        • et al.
        The demonstration of alphaKlotho deficiency in human chronic kidney disease with a novel synthetic antibody.
        Nephrol Dial Transplant. 2015; 30: 223-233
        • Isakova T
        • Wahl P
        • Vargas GS
        • et al.
        Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.
        Kidney Int. 2011; 79: 1370-1378
        • Isakova T
        • Nickolas TL
        • Denburg M
        • et al.
        KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).
        Am J Kidney Dis. 2017; 70: 737-751
        • Richter B
        • Faul C
        FGF23 Actions on target tissues–with and without klotho.
        Front Endocrinol. 2018; 9
        • Neyra JA
        • Hu MC
        Potential application of klotho in human chronic kidney disease.
        Bone. 2017; 100: 41-49
        • Isakova T
        • Xie H
        • Yang W
        • et al.
        Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.
        JAMA. 2011; 305: 2432-2439
        • Wolf M
        • Shah A
        • Gutierrez O
        • et al.
        Vitamin D levels and early mortality among incident hemodialysis patients.
        Kidney Int. 2007; 72: 1004-1013
        • Christov M
        • Neyra JA
        • Gupta S
        • Leaf DE
        Fibroblast growth factor 23 and klotho in AKI.
        Semin Nephrol. 2019; 39: 57-75
        • Krejs GJ
        • Nicar MJ
        • Zerwekh JE
        • et al.
        Effect of 1,25-dihydroxyvitamin D3 on calcium and magnesium absorption in the healthy human jejunum and ileum.
        Am J Med. 1983; 75: 973-976
        • Finch JL
        • Brown AJ
        • Slatopolsky E
        Differential effects of 1,25-dihydroxy-vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phosphorus resorption in bone.
        J Am Soc Nephrol. 1999; 10: 980-985
        • Canaff L
        • Hendy GN
        Calcium-sensing receptor gene transcription is up-regulated by the proinflammatory cytokine, interleukin-1beta. Role of the NF-kappaB PATHWAY and kappaB elements.
        J Biol Chem. 2005; 280: 14177-14188
        • Song SK
        • Karl IE
        • Ackerman JJ
        • et al.
        Increased intracellular Ca2+: a critical link in the pathophysiology of sepsis?.
        Proc Natl Acad Sci U S A. 1993; 90: 3933-3937
        • Orrell DH
        Albumin as an aid to the interpretation of serum calcium.
        Clin Chim Acta. 1971; 35: 483-489
        • Oberleithner H
        • Greger R
        • Lang F
        The effect of respiratory and metabolic acid-base changes on ionized calcium concentration: in vivo and in vitro experiments in man and rat.
        Eur J Clin Invest. 1982; 12: 451-455
        • Ladenson JH
        • Lewis JW
        • McDonald JM
        • et al.
        Relationship of free and total calcium in hypercalcemic conditions.
        J Clin Endocrinol Metab. 1979; 48: 393-397
        • Abbott TR
        Changes in serum calcium fractions and citrate concentrations during massive blood transfusions and cardiopulmonary bypass.
        Br J Anaesth. 1983; 55: 753-760
        • Dzik WH
        • Kirkley SA
        Citrate toxicity during massive blood transfusion.
        Transfus Med Rev. 1988; 2: 76-94
        • Slomp J
        • van der Voort PH
        • Gerritsen RT
        • et al.
        Albumin-adjusted calcium is not suitable for diagnosis of hyper- and hypocalcemia in the critically ill.
        Crit Care Med. 2003; 31: 1389-1393
        • Byrnes MC
        • Huynh K
        • Helmer SD
        • et al.
        A comparison of corrected serum calcium levels to ionized calcium levels among critically ill surgical patients.
        Am J Surg. 2005; 189: 310-314
        • Gauci C
        • Moranne O
        • Fouqueray B
        • et al.
        Pitfalls of measuring total blood calcium in patients with CKD.
        J Am Soc Nephrol. 2008; 19: 1592-1598
        • Clase CM
        • Norman GL
        • Beecroft ML
        • et al.
        Albumin-corrected calcium and ionized calcium in stable haemodialysis patients.
        Nephrol Dial Transplant. 2000; 15: 1841-1846
        • Thode J
        • Juul-Jorgensen B
        • Bhatia HM
        • et al.
        Comparison of serum total calcium, albumin-corrected total calcium, and ionized calcium in 1213 patients with suspected calcium disorders.
        Scand J Clin Lab Invest. 1989; 49: 217-223
        • Scheidegger D
        • Drop LJ
        • Schellenberg JC
        Role of the systemic vasculature in the hemodynamic response to changes in plasma ionized calcium.
        Arch Surg. 1980; 115: 206-211
        • Szent-Gyorgyi AG
        Calcium regulation of muscle contraction.
        Biophys J. 1975; 15: 707-723
        • Akiyama T
        • Batchelder J
        • Worsman J
        • et al.
        Hypocalcemic torsades de pointes.
        J Electrocardiol. 1989; 22: 89-92
        • Bradley TJ
        • Metzger DL
        • Sanatani S
        Long on QT and low on calcium.
        Cardiol Young. 2004; 14: 667-670
        • Trinkley KE
        • Page 2nd, RL
        • Lien H
        • et al.
        QT interval prolongation and the risk of Torsades de pointes: essentials for clinicians.
        Curr Med Res Opin. 2013; 29: 1719-1726
        • Chernow B
        • Zaloga G
        • McFadden E
        • et al.
        Hypocalcemia in critically ill patients.
        Crit Care Med. 1982; 10: 848-851
        • Afshinnia F
        • Belanger K
        • Palevsky PM
        • et al.
        Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: secondary analysis of the acute renal failure trial network study.
        Ren Fail. 2013; 35: 1310-1318
        • Leaf DE
        • Waikar SS
        • Wolf M
        • et al.
        Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.
        Clin Endocrinol (Oxf). 2013; 79: 491-498
        • Leaf DE
        • Jacob KA
        • Srivastava A
        • et al.
        Fibroblast growth factor 23 levels associate with AKI and death in critical illness.
        J Am Soc Nephrol. 2017; 28: 1877-1885
        • Leaf DE
        • Siew ED
        • Eisenga MF
        • et al.
        Fibroblast growth factor 23 associates with death in critically ill patients.
        Clin J Am Soc Nephrol. 2018; 13: 531-541
        • Levi M
        • Ellis MA
        • Berl T
        Control of renal hemodynamics and glomerular filtration rate in chronic hypercalcemia. Role of prostaglandins, renin-angiotensin system, and calcium.
        J Clin Invest. 1983; 71: 1624-1632
        • Wang WH
        • Lu M
        • Hebert SC
        Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL.
        Am J Physiol. 1996; 271: C103-C111
        • Khositseth S
        • Charngkaew K
        • Boonkrai C
        • et al.
        Hypercalcemia induces targeted autophagic degradation of aquaporin-2 at the onset of nephrogenic diabetes insipidus.
        Kidney Int. 2017; 91: 1070-1087
        • O'Connor LR
        • Klein KL
        • Bethune JE
        Hyperphosphatemia in lactic acidosis.
        N Engl J Med. 1977; 297: 707-709
        • Kebler R
        • McDonald FD
        • Cadnapaphornchai P
        Dynamic changes in serum phosphorus levels in diabetic ketoacidosis.
        Am J Med. 1985; 79: 571-576
        • Block GA
        • Klassen PS
        • Lazarus JM
        • et al.
        Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.
        J Am Soc Nephrol. 2004; 15: 2208-2218
        • Thongprayoon C
        • Cheungpasitporn W
        • Mao MA
        • et al.
        Admission hyperphosphatemia increases the risk of acute kidney injury in hospitalized patients.
        J Nephrol. 2018; 31: 241-247
        • Vijayan A
        • Li T
        • Dusso A
        • et al.
        Relationship of 1,25 dihydroxy vitamin D levels to clinical outcomes in critically ill patients with acute kidney injury.
        J Nephrol Ther. 2015; 5
        • Jung SY
        • Kim H
        • Park S
        • et al.
        Electrolyte and mineral disturbances in septic acute kidney injury patients undergoing continuous renal replacement therapy.
        Medicine (Baltimore). 2016; 95: e4542
        • Jung SY
        • Kwon J
        • Park S
        • et al.
        Phosphate is a potential biomarker of disease severity and predicts adverse outcomes in acute kidney injury patients undergoing continuous renal replacement therapy.
        PLoS One. 2018; 13e0191290
        • Markowitz GS
        • Nasr SH
        • Klein P
        • et al.
        Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing.
        Hum Pathol. 2004; 35: 675-684
        • Boles JM
        • Dutel JL
        • Briere J
        • et al.
        Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia.
        Cancer. 1984; 53: 2425-2429
        • Kanfer A
        • Richet G
        • Roland J
        • et al.
        Extreme hyperphosphataemia causing acute anuric nephrocalcinosis in lymphosarcoma.
        Br Med J. 1979; 1: 1320-1321
        • Markowitz GS
        • Stokes MB
        • Radhakrishnan J
        • et al.
        Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure.
        J Am Soc Nephrol. 2005; 16: 3389-3396
        • Russmann S
        • Lamerato L
        • Motsko SP
        • et al.
        Risk of further decline in renal function after the use of oral sodium phosphate or polyethylene glycol in patients with a preexisting glomerular filtration rate below 60 ml/min.
        Am J Gastroenterol. 2008; 103: 2707-2716
        • Gumurdulu Y
        • Serin E
        • Ozer B
        • et al.
        Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation.
        J Gastroenterol Hepatol. 2004; 19: 68-72
        • Heher EC
        • Thier SO
        • Rennke H
        • et al.
        Adverse renal and metabolic effects associated with oral sodium phosphate bowel preparation.
        Clin J Am Soc Nephrol. 2008; 3: 1494-1503
        • Tan HK
        • Bellomo R
        • M'Pis DA
        • et al.
        Phosphatemic control during acute renal failure: intermittent hemodialysis versus continuous hemodiafiltration.
        Int J Artif Organs. 2001; 24: 186-191
        • Palevsky PM
        • Zhang JH
        • O'Connor TZ
        • et al.
        Intensity of renal support in critically ill patients with acute kidney injury.
        N Engl J Med. 2008; 359: 7-20
        • Sharma S
        • Waikar SS
        Phosphate balance in continuous venovenous hemofiltration.
        Am J Kidney Dis. 2013; 61: 1043-1045
        • Lim C
        • Tan HK
        • Kaushik M
        Hypophosphatemia in critically ill patients with acute kidney injury treated with hemodialysis is associated with adverse events.
        Clin Kidney J. 2017; 10: 341-347
        • Alsumrain MH
        • Jawad SA
        • Imran NB
        • et al.
        Association of hypophosphatemia with failure-to-wean from mechanical ventilation.
        Ann Clin Lab Sci. 2010; 40: 144-148
        • Broman M
        • Carlsson O
        • Friberg H
        • et al.
        Phosphate-containing dialysis solution prevents hypophosphatemia during continuous renal replacement therapy.
        Acta Anaesthesiol Scand. 2011; 55: 39-45
        • Naveh-Many T
        • Silver J
        Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.
        J Clin Invest. 1990; 86: 1313-1319
        • Slatopolsky E
        • Weerts C
        • Thielan J
        • et al.
        Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients.
        J Clin Invest. 1984; 74: 2136-2143
        • Madsen S
        • Olgaard K
        • Ladefoged J
        Suppressive effect of 1,25-dihydroxyvitamin D3 on circulating parathyroid hormone in acute renal failure.
        J Clin Endocrinol Metab. 1981; 53: 823-827
        • Massry SG
        • Arieff AI
        • Coburn JW
        • et al.
        Divalent ion metabolism in patients with acute renal failure: studies on the mechanism of hypocalcemia.
        Kidney Int. 1974; 5: 437-445
        • Galceran T
        • Martin KJ
        • Morrissey JJ
        • et al.
        Role of 1,25-dihydroxyvitamin D on the skeletal resistance to parathyroid hormone.
        Kidney Int. 1987; 32: 801-807
        • Leaf DE
        • Wolf M
        • Waikar SS
        • et al.
        FGF-23 levels in patients with AKI and risk of adverse outcomes.
        Clin J Am Soc Nephrol. 2012; 7: 1217-1223
        • Somerville PJ
        • Kaye M
        Resistance to parathyroid hormone in renal failure: role of vitamin D metabolites.
        Kidney Int. 1978; 14: 245-254
        • Capasso G
        • Giordano DR
        • de Tommaso G
        • et al.
        Parathyroidectomy has a beneficial effect on experimental cisplatin nephrotoxicity.
        Clin Nephrol. 1990; 33: 184-191
        • Bennett WM
        • Pulliam JP
        • Porter GA
        • et al.
        Modification of experimental gentamicin nephrotoxicity by selective parathyroidectomy.
        Am J Physiol. 1985; 249: F832-F835
        • Cronin RE
        • Newman JA
        Protective effect of thyroxine but not parathyroidectomy on gentamicin nephrotoxicity.
        Am J Physiol. 1985; 248: F332-F339
        • Elliott WC
        • Patchin DS
        • Jones DB
        Effect of parathyroid hormone activity on gentamicin nephrotoxicity.
        J Lab Clin Med. 1987; 109: 48-54
        • Wang WJ
        • Chao CT
        • Huang YC
        • et al.
        The impact of acute kidney injury with temporary dialysis on the risk of fracture.
        J Bone Miner Res. 2014; 29: 676-684
        • Pinheiro da Silva F
        • Zampieri FG
        • Barbeiro HV
        • et al.
        Decreased parathyroid hormone levels despite persistent hypocalcemia in patients with kidney failure recovering from septic shock.
        Endocr Metab Immune Disord Drug Targets. 2013; 13: 135-142
        • Go AS
        • Parikh CR
        • Ikizler TA
        • et al.
        The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods.
        BMC Nephrol. 2010; 11: 22
        • Zhang MY
        • Wang X
        • Wang JT
        • et al.
        Dietary phosphorus transcriptionally regulates 25-hydroxyvitamin D-1alpha-hydroxylase gene expression in the proximal renal tubule.
        Endocrinology. 2002; 143: 587-595
        • Blomberg Jensen M
        • Andersen CB
        • Nielsen JE
        • et al.
        Expression of the vitamin D receptor, 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase in the human kidney and renal clear cell cancer.
        J Steroid Biochem Mol Biol. 2010; 121: 376-382
        • Lee WM
        • Galbraith RM
        • Watt GH
        • et al.
        Predicting survival in fulminant hepatic failure using serum Gc protein concentrations.
        Hepatology. 1995; 21: 101-105
        • Nykjaer A
        • Dragun D
        • Walther D
        • et al.
        An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.
        Cell. 1999; 96: 507-515
        • Chaykovska L
        • Heunisch F
        • von Einem G
        • et al.
        Urinary vitamin D binding protein and KIM-1 are potent new biomarkers of major adverse renal events in patients undergoing coronary angiography.
        PLoS One. 2016; 11e0145723
        • Ghazarian JG
        • Garancis JC
        • Yanda DM
        • et al.
        Changes in 25-hydroxyvitamin D3 alpha- and 24-hydroxylase activities of kidney cells isolated from rats with either unilateral kidney damage or acute renal insufficiency.
        Endocrinology. 1983; 113: 476-484
        • Viaene L
        • Evenepoel P
        • Meijers B
        • et al.
        Uremia suppresses immune signal-induced CYP27B1 expression in human monocytes.
        Am J Nephrol. 2012; 36: 497-508
        • Leaf DE
        • Christov M
        • Juppner H
        • et al.
        Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery.
        Kidney Int. 2016; 89: 939-948
        • Chanakul A
        • Zhang MY
        • Louw A
        • et al.
        FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues.
        PLoS One. 2013; 8: e72816
        • Inoue Y
        • Segawa H
        • Kaneko I
        • et al.
        Role of the vitamin D receptor in FGF23 action on phosphate metabolism.
        Biochem J. 2005; 390: 325-331
        • Bosworth CR
        • Levin G
        • Robinson-Cohen C
        • et al.
        The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease.
        Kidney Int. 2012; 82: 693-700
        • Stubbs JR
        • Zhang S
        • Friedman PA
        • et al.
        Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD.
        Clin J Am Soc Nephrol. 2014; 9: 1965-1973
        • Cameron LK
        • Lei K
        • Smith S
        • et al.
        Vitamin D levels in critically ill patients with acute kidney injury: a protocol for a prospective cohort study (VID-AKI).
        BMJ Open. 2017; 7e016486
        • Braun AB
        • Litonjua AA
        • Moromizato T
        • et al.
        Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill.
        Crit Care Med. 2012; 40: 3170-3179
        • Ala-Kokko TI
        • Mutt SJ
        • Nisula S
        • et al.
        Vitamin D deficiency at admission is not associated with 90-day mortality in patients with severe sepsis or septic shock: observational FINNAKI cohort study.
        Ann Med. 2016; 48: 67-75
        • Adams JS
        • Hewison M
        Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity.
        Nat Clin Pract Endocrinol Metab. 2008; 4: 80-90
        • Bouillon R
        • Lieben L
        • Mathieu C
        • et al.
        Vitamin D action: lessons from VDR and Cyp27b1 null mice.
        Pediatr Endocrinol Rev. 2013; 10: 354-366
        • Lee JW
        • Kim SC
        • Ko YS
        • et al.
        Renoprotective effect of paricalcitol via a modulation of the TLR4-NF-kappaB pathway in ischemia/reperfusion-induced acute kidney injury.
        Biochem Biophys Res Commun. 2014; 444: 121-127
        • Azak A
        • Huddam B
        • Haberal N
        • et al.
        Effect of novel vitamin D receptor activator paricalcitol on renal ischaemia/reperfusion injury in rats.
        Ann R Coll Surg Engl. 2013; 95: 489-494
        • Sezgin G
        • Ozturk G
        • Guney S
        • et al.
        Protective effect of melatonin and 1,25-dihydroxyvitamin D3 on renal ischemia-reperfusion injury in rats.
        Ren Fail. 2013; 35: 374-379
        • Park JW
        • Bae EH
        • Kim IJ
        • et al.
        Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats.
        Am J Physiol Renal Physiol. 2010; 298: F301-F313
        • Park JW
        • Bae EH
        • Kim IJ
        • et al.
        Paricalcitol attenuates cyclosporine-induced kidney injury in rats.
        Kidney Int. 2010; 77: 1076-1085
        • Park JW
        • Cho JW
        • Joo SY
        • et al.
        Paricalcitol prevents cisplatin-induced renal injury by suppressing apoptosis and proliferation.
        Eur J Pharmacol. 2012; 683: 301-309
        • Makibayashi K
        • Tatematsu M
        • Hirata M
        • et al.
        A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis.
        Am J Pathol. 2001; 158: 1733-1741
        • Tan X
        • Li Y
        • Liu Y
        Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy.
        J Am Soc Nephrol. 2006; 17: 3382-3393
        • de Braganca AC
        • Volpini RA
        • Canale D
        • et al.
        Vitamin D deficiency aggravates ischemic acute kidney injury in rats.
        Physiol Rep. 2015; 3
        • Kovalenko PL
        • Zhang Z
        • Cui M
        • et al.
        1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1.
        BMC Genomics. 2010; 11: 26
        • Tiosano D
        • Wildbaum G
        • Gepstein V
        • et al.
        The role of vitamin D receptor in innate and adaptive immunity: a study in hereditary vitamin D-resistant rickets patients.
        J Clin Endocrinol Metab. 2013; 98: 1685-1693
        • Penna G
        • Adorini L
        1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation.
        J Immunol. 2000; 164: 2405-2411
        • Penna G
        • Roncari A
        • Amuchastegui S
        • et al.
        Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3.
        Blood. 2005; 106: 3490-3497