Fasting-Mimicking Diet Shields Kidneys From Injury by Blocking Inflammatory Monocyte Recruitment
Mouse study shows FMD cycles dramatically reduce acute kidney injury and CKD progression by suppressing CCL2-driven monocyte infiltration.
Summary
Researchers at Icahn School of Medicine at Mount Sinai tested fasting-mimicking diet (FMD) cycles in mice with aristolochic acid- or folic acid-induced kidney injury. FMD significantly lowered serum creatinine, BUN, tubular necrosis scores, and kidney injury marker KIM-1 compared to ad libitum-fed controls. It reduced infiltrating inflammatory monocytes and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while suppressing pro-fibrotic genes and boosting reparative EGF expression. Blocking CCR2 — the receptor for the monocyte-recruiting chemokine CCL2 — abolished FMD's protective effects, identifying the CCL2/CCR2 axis as a key mediating pathway. Simple caloric restriction yielded similar benefits, and FMD initiated even at peak AKI accelerated repair, suggesting broad translational potential for dietary interventions in kidney disease.
Detailed Summary
Acute kidney injury (AKI) affects up to one-third of ICU patients and frequently progresses to chronic kidney disease (CKD), yet no dietary interventions have been rigorously evaluated for nephroprotection. This study asked whether the fasting-mimicking diet (FMD) — five-day cycles of very-low-calorie intake followed by normal refeeding — could reduce AKI severity and slow the AKI-to-CKD transition by modulating innate immune recruitment.
Using murine models of AKI and CKD induced by aristolochic acid (AA) or folic acid (FA), the researchers compared FMD cycles, a continuous low-caloric diet, and ad libitum feeding in male BALB/c mice. FMD was started one week before nephrotoxin administration and continued through day 35. The team tracked kidney function (BUN, serum creatinine), histology (H&E tubular injury and inflammation scores), injury biomarkers (KIM-1 immunofluorescence), and extensive flow cytometry of renal immune infiltrates. Gene expression profiling covered pro-inflammatory cytokines, pro-fibrotic factors, and repair markers.
FMD mice showed significantly lower BUN and serum creatinine from day 14 through day 35, less tubular necrosis and inflammation on histology, and markedly reduced KIM-1 staining. Renal expression of IL-1β, IL-6, TNF-α, TGF-β, CTGF, and IL-33 was substantially lower in FMD animals, while EGF — a tubular repair promoter — was elevated at day 35. Flow cytometry revealed fewer total CD45+ renal immune cells, fewer CD45+CD11b+Ly6G− macrophages, and a shift away from pro-inflammatory Ly6Chi monocytes toward protective Ly6Clow phenotypes in FMD mice. Splenic TNF-α-producing Ly6Chi monocytes were also reduced, suggesting a systemic anti-inflammatory effect. FMD lowered renal and circulating CCL2 levels; critically, pharmacological CCR2 blockade eliminated FMD's renal protection, directly implicating the CCL2/CCR2 monocyte-recruitment axis.
Notably, initiating FMD only at the peak of AKI (rather than prophylactically) still accelerated kidney repair and attenuated inflammation, broadening the therapeutic window. Simple caloric restriction produced nephroprotection comparable to full FMD cycles, suggesting caloric deficit itself — not specific dietary composition — drives the benefit. A folic acid model of AKI reproduced the protective findings, lending cross-model validity.
These results position dietary caloric restriction as a tractable, non-pharmacological strategy to limit kidney immunopathology. Because FMD protocols already exist for human use and are generally well tolerated, clinical translation is feasible. However, all experiments were conducted in young male inbred mice with chemically induced nephrotoxicity, so applicability to elderly or comorbid patients, ischemia-reperfusion injury, and other AKI etiologies remains to be established.
Key Findings
- FMD cycles significantly reduced BUN, serum creatinine, and KIM-1 tubular injury marker vs. ad lib diet through day 35.
- FMD decreased renal Ly6Chi pro-inflammatory monocytes and total macrophage infiltrates while favoring Ly6Clow repair-associated phenotypes.
- CCR2 blockade abolished FMD's nephroprotection, directly implicating the CCL2/CCR2 monocyte-recruitment axis.
- FMD started at peak AKI (not only prophylactically) still accelerated repair and reduced inflammation.
- Simple caloric restriction produced similar kidney protection as full FMD cycles, suggesting caloric deficit is the key driver.
Methodology
Male BALB/c mice received aristolochic acid or folic acid to induce AKI/CKD and were randomized to FMD cycles, continuous low-caloric diet, or ad libitum feeding starting one week pre-injury. Outcomes included serial kidney function tests, histology, KIM-1 immunofluorescence, renal cytokine/gene expression, and multiparameter flow cytometry of renal immune infiltrates; CCR2 pharmacological blockade was used to dissect the mechanistic pathway.
Study Limitations
All experiments used young male inbred mice with chemical nephrotoxicity models, limiting generalizability to human AKI from ischemia, sepsis, or contrast agents, and to elderly or female patients. The mechanistic role of CCL2 suppression may partly reflect downstream effects of broader anti-inflammatory actions rather than a primary causal pathway.
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