Elsevier

Medical Hypotheses

Volume 146, January 2021, 110414
Medical Hypotheses

Chronic interstitial nephritis in agricultural communities (CINAC) and lysosomal tubulopathy: Is there a place for anti-oxidants?

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Abstract

Chronic Interstitial Nephritis in Agricultural Communities (CINAC) continues to attract controversy in the scientific community. It was previously known as Chronic Kidney Disease of Unknown Etiology (CKDu) and is not associated with the common aetiological factors such as diabetes. There is general acceptance that it is an environmentally induced disorder due to a combination of toxicities: heavy metals from food, fluoride in drinking water, hard water, heat stress and pesticides. The recent findings of a lysosomal inclusion body tubulopathy is of great interest to those attempting to find therapeutic agents to slow or eliminate its renal damage. The paper argues that despite these new findings, oxidative stress could play a key role and proposes that anti-oxidants such as Vitamin C and E be repurposed for treatment.

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.

References (21)

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