AKI is a prevalent and, when severe, devastating condition associated with significant morbidity and mortality. While advancements in critical care have improved survival rates, AKI remains a major public health concern, particularly among hospitalized patients. The complex pathophysiology of AKI involves a multitude of factors, including volume and metabolic derangements, inflammation, and oxidative stress.
The nutritional management of patients with AKI must consider the metabolic derangements and proinflammatory state associated with renal failure, the underlying disease process and comorbidities, as well as nutrient imbalance caused by RRT. Nutrition in AKI is an under-researched area,1 and very few systematic studies have assessed the effect of nutrition on clinical end points in human AKI.2
In recent years, there has been growing interest in the role of phosphate metabolism in AKI. Phosphate is a crucial mineral involved in various cellular processes, including energy production, bone mineralization, and cell signaling. In the setting of AKI, phosphate retention can aggravate metabolic acidosis, which has been associated with numerous adverse outcomes, including increased inflammation, worsening renal function, and mortality.3
In this issue,4 Hamid and colleagues published an investigation into the effect of a low-phosphorus diet, provided before kidney insult, on various aspects of mineral metabolism, kidney markers, and overall systemic effects, including survival, in a mouse model of AKI and recovery. The investigation provides novel associations and insights, implying that dietary phosphate restriction may offer a therapeutic strategy to mitigate AKI-associated complications.
The authors used a murine model of folic acid–induced AKI and demonstrated that phosphate restriction, while not directly kidney protective, significantly attenuated the rise in plasma fibroblast growth factor 23, phosphate, parathyroid hormone, and calcitriol, all of which are key players in phosphate homeostasis. Furthermore, phosphate restriction prevented the development of metabolic acidosis and mitigated inflammation, calciprotein particle formation, cardiac dysfunction, and mortality.
The study included both normal mice and mice lacking parathyroid hormone (Pth-null mice). Despite expectations of elevated plasma phosphorus levels in Pth-null mice, they exhibited levels similar to wild-type mice under a normal diet, and P-restriction was not reported. While providing insights into mechanisms, the investigation of Pth-null mice did not contribute to the study's primary objectives.
A notable distinction between human AKI and the AKI model used in this research lies in the dietary context. Patients with severe AKI often exhibit anorexia with reduced protein intake, leading to lower phosphorus consumption. Yet, especially in hypercatabolic AKI, they may still present with hyperphosphatemia even in the absence of dietary phosphorus intake. By contrast, in this study, the transition to a low-phosphorus diet occurred several days before the onset of AKI, implying that the mice were likely phosphorus depleted by the time injury was induced. Moreover, it remains unclear whether the low-phosphorus chow differed in other aspects from the normal chow, which could potentially exert phosphorus-independent effects on the study's outcomes, confounding the effects of phosphorus restriction.
Nonetheless, the findings of Hamid et al. are particularly significant given the limited treatment options currently available for AKI. While supportive care remains the mainstay of therapy, there is a paucity of specific interventions that directly target the underlying mechanisms of AKI. Phosphate restriction, as demonstrated by this study, may provide a novel therapeutic approach to address a critical aspect of AKI pathophysiology and potentially improve patient outcomes. Clinical trials are needed to evaluate the safety and efficacy of phosphate restriction in patients with AKI, acknowledging that some patients with AKI may present with hypo- rather than hyperphosphatemia or develop refeeding-related hypophosphatemia.5
In conclusion, the study by Hamid and colleagues highlights the potential of phosphate restriction as a therapeutic strategy to mitigate AKI-associated complications (in addition to its more accepted role in preventing complications of CKD6) (Figure 1). By addressing the issue of phosphate retention and associated metabolic acidosis and inflammatory response, phosphate restriction may offer an approach to improve patient outcomes in this condition.
Figure 1.
Shared and distinct mechanisms linking hyperphosphatemia to organ damage in AKI and CKD. CPP, calciprotein particles; LVH, left ventricular hypertrophy; miR, microRNA; RANK, receptor activator of nuclear factor kappa-B; ROS, reactive oxygen species.
Acknowledgments
The content of this article reflects the personal experience and views of the authors and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or JASN. Responsibility for the information and views expressed herein lies entirely with the authors.
Footnotes
Published Online Ahead of Print. Publication date available at www.jasn.org
See related article, “Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid–Induced AKI,” on pages 261–280.
Disclosures
M. Abbasi reports Ownership Interest: COCA-COLA CO COM; and Other Interests or Relationships: CJASN Visual Abstract Team. All remaining authors have nothing to disclose.
Funding
None.
Author Contributions
Conceptualization: Iddo Z. Ben-Dov.
Writing – original draft: Momen Abbasi, Iddo Z. Ben-Dov, Assaf Potruch.
Writing – review & editing: Momen Abbasi, Iddo Z. Ben-Dov, Assaf Potruch.
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