Abstract
Hyperfiltration is an important underlying cause of glomerular dysfunction associated with several systemic and intrinsic glomerular conditions leading to chronic kidney disease (CKD). These include obesity, diabetes, hypertension, focal segmental glomerulosclerosis (FSGS), congenital abnormalities and reduced renal mass (low nephron number). Hyperfiltration-associated biomechanical forces directly impact the cell membrane, generating tensile and fluid flow shear stresses in multiple segments of the nephron. Ongoing research suggests these biomechanical forces as the initial mediators of hyperfiltration-induced deterioration of podocyte structure and function leading to their detachment and irreplaceable loss from the glomerular filtration barrier. Membrane lipid-derived polyunsaturated fatty acids (PUFA) and their metabolites are potent transducers of biomechanical stress from the cell surface to intracellular compartments. Omega-6 and ω-3 long-chain PUFA from membrane phospholipids generate many versatile and autacoid oxylipins that modulate pro-inflammatory as well as anti-inflammatory autocrine and paracrine signaling. We advance the idea that lipid signaling molecules, related enzymes, metabolites and receptors are not just mediators of cellular stress but also potential targets for developing novel interventions. With the growing emphasis on lifestyle changes for wellness, dietary fatty acids are potential adjunct-therapeutics to minimize/treat hyperfiltration-induced progressive glomerular damage and CKD.
Highlights
glomerular hyperfiltration (GHF) is considered a surrogate marker of elevated intraglomerular pressure in patients with diabetes mellitus [94] and predictor of chronic kidney disease (CKD) [27] and it associates with increased risk of cardiovascular disease and all-cause mortality [95,96,97]
These include N-acetyl-β-D-glucosaminidase, Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule-1 (KIM1), urinary free Retinol-Binding Protein (RBP) and Cystatin C [131]. (x) Tubulointerstitial oxidative stress, inflammation, hypoxia and fibrosis relate to progression of kidney disease in diabetes [132]
These disparate changes in glomerular basement membrane (GBM) and podocytes result in: (i) areas of the GBM left uncovered by podocyte processes adding to podocyte injury, detachment and loss; (ii) adherence of the capillary to parietal epithelium; (iii) formation of synechia and segmental sclerosis [27,113]
Summary
Higher eGFR reflects an increased rate of glomerular filtration, termed glomerular hyperfiltration (GHF). Maladaptive GHF, while not unique to a specific condition, is an underlying risk factor of early glomerular dysfunction in several diseases where normal kidneys are vulnerable to systemic or primary glomerular pathophysiological changes. Middle: Initially, glomerular filtration rate increases (hyperfiltration), followed by a decrease in in GFR and CKD leading to ESRD. GHF is considered a surrogate marker of elevated intraglomerular pressure in patients with diabetes mellitus [94] and predictor of CKD [27] and it associates with increased risk of cardiovascular disease and all-cause mortality [95,96,97]. A lack of detailed understanding of early hyperfiltration and its mechanism has perhaps hindered the use of hyperfiltration as a clinical indicator of renal dysfunction
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