Chronic interstitial nephritis in agricultural communities (CINAC) and lysosomal tubulopathy: Is there a place for anti-oxidants?
Introduction
Chronic Kidney Disease (CKD) is emerging as a global health issue leading to a large socio-economic burden [1]. Its high prevalence is attributed to an aging population and the presence of disorders such as diabetes and hypertension. More recently, a poorly defined chronic interstitial nephropathy named Chronic Interstitial Nephritis in Agricultural Communities (CINAC), and previously known Chronic Kidney Disease of Unknown Etiology or CKDu, began to emerge in young adults in several agricultural communities of Central American (e.g. El Salvador), Middle East (Egypt) and South Asia (India, Sri Lanka). Its terminology was changed in recognition of its commonly seen histopathology and high prevalence in agricultural communities [2]. Globally, more than 70,000 have died, partly due to the lack of effective preventive measures and treatment [3]. The paper discusses the potential role for antioxidants in reducing the progress of renal damage in CINAC.
Several aetiological factors have been proposed for CINAC [1], [4]. These include high fluoride in drinking water in combination with Na+ ions or magnesium ions in hard water, aluminum from cooking utensils, cadmium, lead and chromium contaminated food, glyphosate and arsenic, organochlorines, heat stress, high intakes of fructose-rich drinks together with exposure to pesticides.
Section snippets
Pathogenesis
The principle histological feature is a chronic interstitial nephritis due to environmental toxins [5], [6]. There are non-specific features that include varying degrees of tubular atrophy, tubulointerstitial fibrosis, glomerulosclerosis, glomerulomegaly and vascular sclerosis [5], [6]. The presence of a chronic renal disease with comparable histopathology in agricultural communities from different locations of the globe suggest the presence of a similar group of nephrotoxins or a final common
Oxidative stress as a final common pathway
Oxidative stress is due to an imbalance between oxidative free radical production (e.g. from xenobiotics) and antioxidant defenses (produced endogenously or from dietary sources). Overwhelming the latter leads to excess peroxides and free radicals that cause lipid peroxidation, oxidize proteins, and damage DNA/RNA. The molecular damages lead to cellular effects such as membrane dysfunction, metabolic inefficiencies, electrolyte leakage, loss of organelle functions, reduced carbon fixation,
Oxidative stress in CKD
CKD is a high oxidative state, due to underlying chronic inflammation and associated mitochondrial dysfunction. Four molecular pathways of oxidative stress are identified: (i) generation of superoxides; (ii) chlorinated stress from hypochlorous acid produced by hydrogen peroxide reacting with chloride ions; (iii) nitrosative stress from the peroxynitrite molecules produced from superoxide anions reacting with nitric oxide; (iv) carbonyl stress from increased formation of advanced glycolation
Lysosomal proximal tubulopathy in CINAC
Of emerging interest is the discovery of a lysosomal proximal tubulopathy characterized by enlarged dysmorphic lysosomes containing aggregates, associated with varying degrees of epithelial atrophy, cell fragment shedding and weak proximal tubular cell proliferative capacity [13]. This has been proposed as the hallmark of CINAC and described as an inclusion body tubulopathy. Interestingly, toxicity from Calcineurin inhibitors (CNIs, e.g. cyclosporine and tacrolimus) show similar lysosomal
Oxidative stress in calcineurin inhibitor-related lysosomal disease
Acute toxicity from CIs results in tubular vacuolization and thrombotic angiopathy while chronic toxicity shows glomerular sclerosis, arterial hyalinosis, interstitial fibrosis and tubular atrophy [14]. Nodular hyaline deposits are seen in the afferent arteriolar media and is regarded as a hallmark of CI nephrotoxicity. Cyclosporine or tacrolimus induce renal vasoconstriction, which leads to local ischemia of the tubulointerstitial compartment which promotes formation of free radicals or
A potential role for anti-Oxidants in CINAC
The potential benefits of antioxidants in CINAC can be considered under the mechanisms described in the previous section: non-specific inhibition of progressing CKD, preventing renal toxicity from calcineurin inhibitors, and promoting lysosomal stability. A recent systematic review had reported that anti-oxidants significantly lowered serum creatinine, improved creatinine clearance and slowed the development of end-stage kidney disease (ESKD) in pre-dialyzes patients [16]. The beneficial
Antioxidants in toxicity from calcineurin inhibitors
Vitamin E had a beneficial effect on cyclosporine-induced renal damage. In vitro studies have shown that cyclosporine A induces renal microsomal lipid peroxidation [17]. Malondialdehyde (MDA) used as an index of lipid peroxidation was increased in rats given cyclosporine A, a process inhibited by vitamin E. Administration of the drug to rats deficient in vitamin E and selenium was accompanied by a greater increase in arterial MDA and fall in renal function.
Antioxidants and lysosomal integrity
Lysosomes are responsible to pH-dependent degradation of intracellular macromolecules usingthree processes of autophagy: macroautophagy in which a double-membraned autophagosome delivers cytoplasmic material to lysosomes, chaperone-mediated autophagy and microautophagy, which occur directly on the lysosome [18].
Oxidative stress and damage by free radicals alter the autophagy degradation pathway, inhibits lysosome enzyme function, damages lysosome membranes and leads to cell death [19]. Hydrogen
Conclusion
CINAC continues to challenge scientists investigating its potential aetio-pathogenesis. Reports of a specific lysosomal inclusion body tubulopathy is significant step in our understanding of its etiology. Despite these new findings there continues to be a theoretical role for antioxidants to mitigate or retard the progress of the disorder.
Financial support and disclosures
University of Colombo Research Grant – AP/3/2/2016/CG/25.
Ethical approval and informed consent
Not relevant.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Cited by (4)
Fluoride exposure induces lysosomal dysfunction unveiled by an integrated transcriptomic and metabolomic study in bone marrow mesenchymal stem cells
2022, Ecotoxicology and Environmental SafetyCitation Excerpt :Lysosomes widely exist in eukaryotic cells and sustain intracellular homeostasis by eliminating cellular debris, damaged organelles and invading microorganisms. Recent studies have recognized that fluoride exposure leads to lysosomal dysfunction attributed to dysmorphic morphology containing aggregates and then causes tubulopathy (Rodrigo et al., 2021). Recently, fluoride exposure was shown to affect the expression of piwi-interaction RNAs (piRNAs) and the lysosomal signaling pathway, which led to failure in the fertilization process (Jiang et al., 2019; Li et al., 2021a, 2021b, 2021c, 2021d).
Mesoamerican nephropathy: A not so unknown chronic kidney disease
2021, NefrologiaCitation Excerpt :In fact, the presence of leukocytosis has been established in some specific work as a predictor of good renal prognosis.41 Anecdotally, the use of anti-oxidants (vitamins C and E) has been proposed as possible treatments in NeM.42 The prognosis for MeN is poor, with high rates of progression to advanced CKD and with significant mortality.
Chronic kidney disease of unknown aetiology: A comprehensive review of a global public health problem
2023, Tropical Medicine and International Health