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Using the geometric framework for nutrition to explore the longitudinal effects of dietary macronutrient consumption on renal structure and function with ageing

Amelia Fotheringham (1, 2), Samantha Solon-Biet (3, 4, 5), Aisling McMahon (3, 4, 6), J. William Ballard (7), Kari Ruohonen (8), Helle Bielefeldt-Ohmann (9, 10), Mitchell A Sullivan (1), Domenica McCarthy (1), Danielle Borg (1, 2), David Raubenheimer (3, 11), David Le Couteur (3, 4, 6), Stephen Simpson (3, 5) and Josephine Forbes (1, 2)

  1. Glycation and Diabetes Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia

  2. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia

  3. Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia

  4. Centre for Education and Research on Aging, and Aging and Alzheimers Institute, Concord Hospital, Sydney, New South Wales, Australia

  5. School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia

  6. ANZAC Research Institute, Concord Repatriation General Hospital, University of Sydney, Sydney, New South Wales, Australia

  7. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia

  8. Cargill Aqua Nutrition, Sandnes, Norway

  9. School of Veterinary Science, Faculty of Science, University of Queensland, Gatton Campus, Gatton, Queensland, Australia

  10. School of Chemistry & Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia

  11. Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, Australia


Aging and diet are major risk factors for chronic kidney disease (CKD), yet the long-term influence of macronutrient combinations on kidney function is not known. Here, we use the geometric framework for nutrition to assess the lifetime effects of macronutrient/caloric intake on markers of CKD.


C57BL/6J mice (♂/♀; N=187) were given 15 months ad-libitum access to 1 of 25 diets representing a spectrum of macronutrient combinations (protein, (5-60%) carbohydrate (20-75%) and fat (20-75%)), stratified by energy content (low, medium or high). Markers of CKD (serum cystatin C, (surrogate for glomerular filtration rate (GFR)), urea, fibrosis, glomerulosclerosis, tubular casts, leukocyte infiltration, kidney injury molecule-1 (KIM-1), klotho, and inflammatory cytokines within the renal cortex) were assessed. Generalised additive models (GAMs) were used to quantify the impacts of macronutrients as main effects and interactions and were considered in conjunction with existing data for the CKD risk factors; adiposity, glucose intolerance, hypertension(BP) and dyslipidaemia.


GFR was increased with protein intake (P=0.03) and decreased with carbohydrate intake (P=0.01). Renal expression of klotho and concentrations of the inflammatory cytokine IL-23 were also inversely related to protein intake (P=0.05, P=0.002 respectively) and therefore highest in mice consuming less protein. Lower protein consumption and higher fat intake also increased renal IL-1β concentrations (P=0.01, P=0.05 respectively) and as an interactive variable with carbohydrate intake, low protein also increased renal IFNγ (P=0.006) and IL12p70 (P=0.05). Highest KIM-1 concentrations were also seen in mice consuming the least calories from protein and highest fat, in the context of increased calories (P=0.001). Surprisingly, macronutrient combinations which elevated BP, lipids or blood glucose did not associate with adverse kidney outcomes.


Macronutrient intake individually and in combination, influences kidney function and inflammation, seemingly independent of established risk factors. Additional markers of progressive CKD including leukocyte infiltration and fibrosis are being assessed.