Dysregulated Mineral Metabolism in AKI

Dysregulated Mineral Metabolism in AKI D1X XDavid E. Leaf, MD, MMSc, D2X X* and D3X XMarta Christov, MD, PhDD4X†X 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. Semin Nephrol 39:41−56 Ó 2018 Elsevier Inc. All rights reserved. Keywords: AKI, acute kidney injury, mineral metabolism, vitamin D, PTH, calcium, phosphate, FGF23

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alcium 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).1,2 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.

*Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA yDivision of Nephrology, Department of Medcine, New York Medical College, Valhalla, NY Financial support: Supported by grants K23DK106448 (D.E.L.) and K08DK093608 (M.C.) from the National Institute of Diabetes and Digestive Kidney Diseases, by an American Society of Nephrology Foundation for Kidney Research Carl W. Gottschalk Research Scholar Grant (D.E.L.), and also partially supported by the New York Community Trust (M.C.). Conflict of interest statement: none. Address reprint requests to David E. Leaf, MD, MMSc, Division of Renal Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail: [email protected] 0270-9295/ - see front matter © 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.semnephrol.2018.10.004

Seminars in Nephrology, Vol 39, No 1, January 2019, pp 41−56

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.3,4 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.5 In bone, PTH binding to PTH receptor 1 on osteoblastic cells stimulates osteoclast activity through the receptor activator of nuclear factor-kB ligand pathway, thereby inducing calcium release into the circulation.6 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.7 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 calcium8; (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 cells9; and (3) it up-regulates the cytochrome P450 enzyme, 1-a hydroxylase (CYP27B1), which converts 25-hydroxyvitamin D (25D) to 1,25D.10,11 1,25D and calcium, in turn, each inhibit PTH secretion in the 41

D.E. Leaf and M. Christov

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parathyroid glands through a negative endocrine feedback loop (Fig. 1).12 1,25D also acts on the gut to increase absorption of both calcium and phosphate, the latter mediated by increased intestinal expression of Npt2b.13

1,25D Vitamin D is derived from dietary sources and sunlightinduced cutaneous synthesis, and is converted to 25D in the liver.14 Circulating 25D is converted to its biologically active form, 1,25D, in the kidneys, immune cells, and other tissues by CYP27B1.15 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 b cells.16 Genomic effects, including inhibition of PTH production,17 are mediated through 1,25D binding to the intracellular vitamin D receptor, which is expressed nearly ubiquitously.18 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.19

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.20,21 In the kidneys, FGF23 down-regulates Npt2a and Npt2c in proximal tubular cells, resulting in increased urinary phosphate excretion,22 and also inhibits CYP27B1 expression, resulting in decreased 1,25D production.23 FGF23-mediated inhibition of CYP27B1 also has been shown in extrarenal tissues, such as monocytes.24 Other actions of FGF23 include down-regulation of each of the following: PTH,25 erythropoiesis,26 and klotho (Fig. 1).27,28 FGF23, in turn, is up-regulated by numerous stimuli, including 1,25D, PTH, phosphate loading, inflammation, and iron deficiency.29-33 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 a-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.34 The extracellular

Figure 1. Overview 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.25,178,179 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.1,180 In its soluble form, klotho, a co-receptor for FGF23 in the kidneys, forms another negative feedback loop with FGF23.181 Both FGF23 and PTH increase renal phosphate excretion and calcium reabsorption.182 Up-regulation is shown in red; down-regulation in shown in black.

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Dysregulated mineral metabolism in AKI

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.35,36 In addition, the extracellular domain of membrane-bound klotho has enzymatic activity, which allows it to modulate calcium37 and potassium38 absorption in the distal tubule (independently of FGF23). Finally, soluble klotho can act as a phosphaturic hormone.39 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.40,41 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.42 The earlier-described changes that occur in mineral metabolism lead to altered bone remodeling as well as extraskeletal deposition of calcium and phosphate.43 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.44,45 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.46,47 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

Renal resistance to PTH CYP27B1

6

1

25D

1,25D

8 7

3

4

PTH

2 3

PO4

Ca

5

FGF23

Skeletal resistance to PTH

Figure 2. Overview 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,115,116 which may be caused by increased circulating FGF23 levels24,180 and by decreased delivery of 25D substrate. The latter may be caused by decreased circulating levels of DBP,70 or by down-regulation of megalin and cubulin expression in renal proximal tubular cells.183 (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.

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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 al48 in this issue.

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.49,50 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.51 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.52 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. 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.

D.E. Leaf and M. Christov

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,53 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,54 hyperphosphatemia, hyperparathyroidism,55 and transfusion of blood products with citrate-containing preservative solutions.56,57 Furthermore, albumin-corrected total serum calcium equations have been shown to be unreliable in other clinical settings, such as critical illness,58,59 CKD,60 end-stage renal disease,61 and among patients suspected of having calcium metabolic disease.62 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 resistance63 or decreased myocardial contractility.64 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.65-67 Despite these pathophysiological considerations, only sparse studies have documented an association between hypocalcemia and an increased incidence of AKI-related adverse outcomes. Chernow et al68 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 al69 assessed iCa levels at initiation of renal replacement therapy (RRT) in 685 critically ill patients with severe AKI, and found no association

Study

Number of Patients and Setting

Dysregulated mineral metabolism resulting from AKI 10 adult patients with oliguric AKI from various causes Massry et al,99 1974 Pietrek et al,167 1978

18 adult patients with oliguric AKI from various causes, including post-traumatic shock and sepsis

Llach et al,168 1981 Madsen et al,98 1981

6 adult patients with oliguric AKI from rhabdomyolysis 10 adult patients with oliguric AKI from various causes (mostly acute GN and AIN), and who were receiving RRT with continuous PD

Saha et al,169 1993

41 adult patients (34 of whom had AKI) with nephropathia epidemica*

170

Shieh et al,

1995

Druml et al,171 1998 Zhang et al,172 2011

7 adults with exertional rhabdomyolysis and AKI; 11 age-matched controls with heat exhaustion, and 11 healthy controls 8 adult patients with AKI requiring RRT and 28 healthy controls 12 critically ill patients with AKI and 8 control patients without AKI

Leaf et al,101 2012

30 hospitalized adult patients with AKI (AKIN175 stage 1 or greater) and 30 hospitalized control patients without AKI

Leaf et al,70 2013

30 hospitalized adult patients with AKI (AKIN stage 1 or greater) and 30 hospitalized control patients without AKI 200 adult patients with hospital-acquired AKI (defined as "SCr ≥50% baseline), and 13 critically ill patients without AKI and 17 healthy control subjects 34 critically ill adult patients with AKI (AKIN stage 2 or 3), and 12 healthy controls 18 adult patients undergoing cardiac surgery who developed severe AKI (doubling of SCr or need for RRT) and 18 matched controls without AKI 400 critically ill adult patients with AKI requiring RRT

173

Lai et al,

2013

Vijayan et al,80 2015 Leaf et al,117 2016 Leaf et al,72 2018

Dysregulated mineral metabolism resulting from RRT 47 critically ill pediatric patients with AKI requiring CRRT Santiago et al,174 2009 95

Broman et al,

2011

Lim et al,93 2017

42 critically ill adult patients with AKI requiring CRRT; 14 were treated with a standard replacement solution that did not contain PO4 96 critically ill adult patients with AKI requiring RRT

Findings #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 #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 #Ca, "PTH, "PO4, #25D, and #1,25D #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 #Ca, "PTH, "PO4, #25D, and #1,25D in patients with AKI iCa and PTH correlated inversely (r = -0.64) #iCa, "PTH, "PO4, and #1,25D in subjects with AKI compared with healthy volunteers; serum 25D levels were similar between groups #25D, #1,25D, and "PTH in patients with AKI compared with healthy controls "PO4 in patients with versus without AKI Ca and PTH levels were similar between groups #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) #DBP and similar levels of bioavailable 25D and 1,25D in patients with versus without AKI #1,25D in patients with versus without AKI, but similar 25D levels across groups; 1,25D levels correlated inversely with AKI severity

Dysregulated mineral metabolism in AKI

Table 1. Human Studies of Dysregulated Calcium, Phosphate, PTH, and Vitamin D Metabolites in Established AKI

#25D, #1,25D, and "PTH in patients with AKI compared with healthy controls "PO4 and #1,25D, particularly on POD3, in patients with versus without AKI PTH and 25D levels were not significantly different between groups #Ca, "PTH, "PO4, #25D, and #1,25D #PO4 occurred in 68% of patients overall and in 85% of patients in whom PO4 was not added to the replacement and dialysate solutions #PO4 occurred in 79% of patients who received a non−PO4-containing replacement solution #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.

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*Nephropathia epidemica is a zoonosis caused by the Puumala virus, and causes an acute hemorrhagic fever and AKI.

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Table 2. Mechanisms 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

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.69 Finally, studies by Leaf et al70-72 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 rate73; 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 depletion74; and nephrogenic diabetes insipidus, which occurs as a result of enhanced autophagic degradation of aquaporin-2 channels in the inner medullary collecting ducts.75 In addition, hypercalcemia can cause hypercalciuria, nephrolithiasis, and nephrocalcinosis, which can cause both acute and chronic renal impairment. 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,76,77 which may be present in patients with AKI.

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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.78 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,79 as well as a higher risk of short-term mortality among patients with established AKI (Table 3).80-82 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.83 Acute phosphate nephropathy has been reported in patients with tumor lysis syndrome,84,85 and more commonly after the use of sodium phosphate−containing oral bowel preparations and enemas.86 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.87,88 Use of angiotensin-converting enzyme inhibitors, angiotensin II−receptor blockers, and nonsteroidal anti-inflammatory drugs also have been suggested as possible risk factors.86,89 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.90 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

Study

Number of Patients and Setting

Findings

Calcium Chernow et al,68 1982

210 critically ill adult patients

Ca <8.5 mg/dL on arrival to the ICU was associated with an increased incidence of “renal failure” (definition not provided) in unadjusted analyses iCa 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

Afshinnia et al,69 2013 Phosphate Vijayan et al,80 2015 81

Jung et al,

2016

Lim et al,93 2017 82

Jung et al,

2018

Thongprayoon et al,79 2018 Vitamin D metabolites Braun et al,123 2012 Lai et al,173 2013 Vijayan et al,80 2015 Ala-Kokko et al,124 2016

685 critically ill adult patients with AKI requiring RRT

34 critically ill adult patients with AKI (AKIN stage 2 or 3) 216 adult patients with septic AKI requiring CRRT 96 critically ill adult patients with AKI requiring RRT 1,144 adult patients with AKI requiring CRRT 5,036 adult patients admitted to a tertiary care hospital

2,075 critically ill adult patients 200 adult patients with hospital-acquired AKI (defined as "SCr ≥50% baseline), and 13 critically ill patients without AKI and 17 healthy control subjects 34 critically ill adult patients with AKI (AKIN stage 2 or 3) 610 critically ill adult patients with severe sepsis or septic shock

Studies that simultaneously assessed multiple mineral metabolites 30 hospitalized adult patients with AKI (AKIN stage 1 or Leaf et al,70 2013 greater) and 30 hospitalized control patients without AKI Hanudel et al,176 2016 Leaf et al,71 2017

Leaf et al,72 2018

32 pediatric patients undergoing cardiac surgery (20 developed postoperative AKI, defined as an "SCr ≥50% from preoperative levels, and 12 did not) 113 critically ill adult patients who did not have AKI on enrollment 400 critically ill adult patients with AKI requiring RRT

Higher PO4 levels were associated with a higher risk of in-hospital mortality in unadjusted analyses (multivariable analyses not shown) Higher PO4 levels at the time of CRRT initiation were associated independently with higher 28- and 90-day mortality PO4 < 2.9 mg/dL was associated independently with prolonged mechanical ventilation but not with ICU mortality Higher PO4 levels at 0 and 24 h after CRRT initiation each were associated independently with higher risk of 28- and 90-day mortality Admission PO4 >4.4 mg/dL was associated independently with higher risk of developing AKI

Dysregulated mineral metabolism in AKI

Table 3. Human Studies of Dysregulated Calcium, Phosphate, PTH, and Vitamin D as Risk Factors for Incident AKI and AKI-Related Adverse Outcomes

Preadmission (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 No association between 25D or 1,25D levels at the time of AKI diagnosis and 90-day mortality 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 Lower 25D levels were associated with higher risk of incident AKI (KDIGO criteria177) and need for RRT in unadjusted analyses (multivariable analyses not shown) Lower 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 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 Ca, 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 Ca, 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.

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D.E. Leaf and M. Christov

48

Multiple Myeloma

Sarcoidosis

Cast Nephropathy

Interstitial Nephritis

AKI

Ca

Other Disorders Malignancy Hyperthyroidism Milk-alkali syndrome Vitamin D intoxication Adrenal insufficiency Lithium PHPT

1. Afferent arteriolar vasoconstriction 2. Natriuresis-induced volume depletion 3. Nephrogenic DI

Figure 3. Hypercalcemia 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, particularly among those prescribed RRT at higher intensities.91 Sharma and Waikar92 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.92 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.93,94 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.95

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).96,97 The regulation of PTH by 1,25D in the setting of AKI was elegantly shown in a study by Madsen et al.98 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.98 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 al99 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.100 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).72,101

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Dysregulated mineral metabolism in AKI

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.102 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 al103 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,104 although this finding was not confirmed in a subsequent study.105 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 brushborder membrane.106 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,71 or associated with an increased risk of 60-day mortality among patients with established AKI (Table 3).72 Wang et al107 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.108 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.109

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),110,111 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 illnesses70,71,112; 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.113 The latter mechanism is supported by studies showing increased urinary DBP levels in patients with contrast-associated AKI.114 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.115 Decreased CYP27B1 expression also has been shown in human monocytes cultured in uremic serum,116 suggesting that increased circulating factors in the setting of AKI, such as FGF23,72,101,117 may be responsible for decreased CYP27B1 expression. Indeed, FGF23 impairs CYP27B1 expression in the kidneys23 and in extrarenal tissues.24,118

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,70,71,112 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 AKI72,101,117 and has been suggested by some studies,119 but not others,120,121 to up-regulate CYP24A1. However, Leaf et al101 measured plasma 24,25D levels in hospitalized patients with and without

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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.122 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 al123 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 al124 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 al71 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).70,80 Leaf et al72 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.72

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,19

D.E. Leaf and M. Christov

including genes that affect a variety of critical immunomodulatory pathways relevant to AKI.125,126 In animal models, pre-administration of 1,25D attenuated AKI resulting from a variety of nephrotoxic insults, including ischemia-reperfusion injury,127-129 gentamicin,130 cyclosporine,131 cisplatin,132 glomerulonephritis,133 and obstruction.134 Furthermore, de Braganca et al135 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,136-148 and plays an important role in the pathogenesis of AKI.149-156 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.70,123,157-160 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.161 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 3.162 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

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Dysregulated mineral metabolism in AKI

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). 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.163 Oral 25D, or calcifediol, is available in both modifiedrelease164 and immediate-release pill formulations,165 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 al144 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-mg 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.125,166 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

Sunlight

Diet/medication

Vitamin D Target Gene Activation

VDR CYP27B1 1,25D

25D

CYP24A1

24,25D

1,24,25D

Figure 4. Vitamin D metabolism. Inactivation pathways are shown by dotted lines. Abbreviations: 1,24,25D, 1,24,25-trihydroxyvitamin D; VDR, vitamin D receptor.

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.

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