Vitamin D and Acute Kidney Injury: A Reciprocal Relationship

Abstract

Vitamin D is a sterol prohormone with no intrinsic biological activity. Calcitriol, the active form of vitamin D, is synthesized in the kidneys. It has well-known pleiotropic and cytoprotective properties. In addition to regulating parathyroid hormone secretion and enhancing gut calcium absorption, it exhibits antioxidant, anti-inflammatory, antiproliferative, and antineoplastic effects. However, the role of vitamin D in AKI is unclear, unlike in CKD. Thus, this review aimed to understand how dysregulated vitamin D homeostasis occurs in AKI, as well as to explore how vitamin D deficiency and excess influence AKI. A comprehensive literature search was conducted between January 2000 and June 2024 to uncover relevant works detailing vitamin D homeostasis in health as well as investigating the impact of vitamin D deficiency and excess in humans, animals, and in vitro cell models of AKI. According to the findings of this review, vitamin D appears to have a reciprocal relationship with AKI. Acute renal injury, among other factors, can cause hypo- or hypervitaminosis D. Conversely, AKI can also be caused by vitamin D deficiency and toxicity. Even though hypovitaminosis D is associated with AKI, it is uncertain how it impacts AKI outcomes in distinct clinical scenarios. Newer therapeutic options might emerge as a result of understanding these challenges. Vitamin D supplementation may ameliorate renal injury but needs further validation. Furthermore, hypervitaminosis D has also been implicated in AKI by causing hypercalcemia and hyperphosphatemia. It is crucial to avoid prolonged, uncontrolled, and unsupervised supraphysiological vitamin D administration, especially intramuscular injection.

Keywords: 1,25-dihydroxyvitamin D; 25-hydroxyvitamin D; acute kidney injury; calcitriol; hypervitaminosis D; hypovitaminosis D; vitamin D.

Figure 3

Mechanistic pathway of vitamin D action. DBP: vitamin D-binding protein; VDRE: vitamin D response element; CBP/p300: CREB-binding protein-binding protein p300; PCAF: P300/CBP-associated factor; SRC: steroid receptor coactivators. Adapted from Gil A et al. [21].

Figure 4

Mechanisms of non-genomic actions of Vitamin D. The active form, 1,25(OH)₂D₃, initiates rapid cellular responses by binding to membrane-associated vitamin D receptors (PDIA3 and VDR). These interactions activate intracellular signaling pathways, including PKA, PKC, MAPK/ERK, STAT3, and others, often via second messengers such as calcium ions (Ca²⁺), cAMP, IP₃, and DAG. Vitamin D signaling also modulates WNT, NOTCH, and NF-κB pathways. Additionally, vitamin D influences mitochondrial functions and endoplasmic reticulum stress responses. The figure shows both receptor-mediated endocytosis and free hormone entry, reflecting the dual mechanism of membrane signaling and classic genomic pathway activation. 1,25(OH)₂D₃: 1,25-dihydroxyvitamin D₃; VDR: vitamin D receptor; PDIA3: protein disulfide isomerase A3; PKA: protein kinase A; PKC: protein kinase C; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinase; STAT3: signal transducer and activator of transcription 3; NF-κB: nuclear factor kappa B; cAMP: cyclic adenosine monophosphate; IP₃: inositol 1,4,5-triphosphate; DAG: diacylglycerol; Ca²⁺: calcium ion; WNT: wingless/integrated pathway; NOTCH: Notch signaling pathway; SRC: proto-oncogene tyrosine-protein kinase Src; DBP: vitamin D-binding protein; CUBN: cubilin; LRP2: low-density lipoprotein receptor-related protein 2 (megalin); CAV1: caveolin-1; RXR: retinoid X receptor; VDREs: vitamin D response elements; TFs: transcription factors; ROS: reactive oxygen species; CRT: calreticulin; CANX: calnexin; ER: endoplasmic reticulum. Adapted from Żmijewski MA et al. [24].

Figure 1

Chemical structure of the major forms of vitamin D.

Figure 2

Schematic diagram of vitamin D metabolism.