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Abstract In the past decades, an epidemic of chronic kidney disease (CKD) has been associated with environmental and occupational factors (heat stress from high workloads in hot temperatures and exposure to chemicals, such as pesticides and metals), which has been termed CKD of non-traditional origin (CKDnt). This descriptive review aims to present recent evidence about heat stress, pesticides, and metals as possible causes of CKDnt and provide an overview of the related Brazilian regulation, enforcement, and health surveillance strategies. Brazilian workers are commonly exposed to extreme heat conditions and other CKDnt risk factors, including increasing exposure to pesticides and metals. Furthermore, there is a lack of adequate regulation (and enforcement), public policies, and strategies to protect the kidney health of workers, considering the main risk factors. CKDnt is likely to be a significant cause of CKD in Brazil, since CKD’s etiology is unknown in many patients and several conditions for its development are present in the country. Further epidemiological studies may be conducted to explore causal associations and estimate the impact of heat, pesticides, and metals on CKDnt in Brazil. Moreover, public policies should prioritize reducing workers´ exposure and promoting their health and safety.

Mesoamerican nephropathy (MeN) is a progressive kidney disease found on the Pacific coast of Central America primarily in young male agricultural workers without typical kidney disease risk factors. While it is generally accepted that environmental exposures contribute to MeN, we hypothesized that there was also an important genetic component. We performed a genome-wide association study comparing individuals with MeN versus individuals with normal kidney function. We found that Native American ancestry was strongly associated with increased risk of MeN. We also identified candidate variants in the OPCML gene, which encodes a protein that binds opioid receptors, that were associated with ~sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; P = 4 × 10 -8 ). Sugarcane workers with the protective OPCML variants had markedly increased urine osmolality suggesting greater ability to defend against hypovolemia. Experiments with Opcml knock-out mice revealed roles for OPCML in fluid balance and temperature regulation consistent with our findings in humans. Our data suggest that heritable differential sensitivity to heat stress and dehydration contributes to high rates of kidney disease in Central America., Competing Interests: Competing interests statement:The authors declare no competing interest.

Chronic kidney disease is globally recognized as a highly impactful non-communicable disease. The inability of early identification contributes to its high mortality rate and financial burden on affected individuals. Chronic kidney disease of uncertain etiology (CKDu) constitutes a significant global public health concern. This condition does not arise from traditional risk factors such as diabetes, hypertension, or glomerulonephritis. More than 150 articles were analysed to understand risk factors of CKDu. This study aimed to investigate the potential association between dissolved organic compounds, such as Polycyclic Aromatic Hydrocarbons and Humic Acid, and the incidence of CKDu. Through a comprehensive literature review, we identified CKDu clusters worldwide, including notable nephropathies, and explored their potential links with organic compounds. Our analysis revealed that organic compounds can leach from sediments and low-rank lignite deposits into groundwater, subsequently contaminating water supplies and food. These compounds have been implicated in the development of diabetes and increased heavy metal mobility, both of which are risk factors for kidney disease. Our findings suggest that exposure to organic compounds may contribute to the etiology of CKDu, underscoring the need for regular monitoring and establishment of baseline and threshold values in water and soil. We also emphasize the importance of analyzing organic compounds in groundwater in CKDu hotspots and establishing distinct registries for CKD and CKDu implementation., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chronic kidney disease of unknown origin (CKDu) has emerged as a serious health risk for farming communities in remote semi-arid lowland regions of Sri Lanka, with geoenvironmental factors widely believed to be associated with the etiology. Although numerous case-control studies have been carried out to determine the causes of CKDu, none have been conducted in at-risk communities. The main objective of this study is to identify the potential geo-environmental risk factors associated with the at-risk community in the Wilgamuwa region, a CKDu endemic area in Sri Lanka. The study collected and analyzed 92 water sources currently or previously used in the study area for major cations, anions, and trace elements, mainly As, Cd, Pd, Mn, Zn, Ba and Sr. The major cations and anions in CKDu-susceptible groundwater varied Si 4+  > Ca 2+  > Na +  > Mg 2+  > K + and HCO 3 -  > Cl -  > SO 4 2-  > NO 3 -  > F -  > PO 4 3-  > Br - . The higher average values of Si 4+ , F - and total hardness (TH) were reported in groundwater consumed by communities at risk of CKDu, with average values (in mg/L) of Si 4+ -46, F - -0.62, and TH-178. Considering the Water Quality Index (WQI) values, 73% of groundwater sources are classified as poor water quality, and the groundwater quality mainly depends on the fluoride distribution in the region. According to the Hazard Quotient (HQ), the risk of adverse health effects from exposure to F - and SiO 2 increased in magnitude in the order of male < female < children. Health hazards due to As, Cd and Pb exposure fell between the 'no-risk' and 'low-risk' categories. As outlined in this study, continuous monitoring of vulnerable communities for environmental exposures to key groundwater constituents is important in the dry zone of Sri Lanka., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Prolonged consumption of foods containing toxic metals can elevate the risk of noncommunicable diseases, including chronic kidney disease of uncertain etiology (CKDu). Despite the increasing number of CKDu cases in Maradankulama and Mahakanadrawa Grama Niladhari Divisions (GN) in Sri Lanka, no prior studies have examined the accumulation of heavy metal(loid)s and their potential association with CKDu prevalence. Furthermore, there is an absence of comprehensive analyses using chemometric techniques such as PCA and hierarchical studies regarding CKDu and heavy metal contamination in Sri Lanka. This study aims to provide initial insights into the accumulation and potential pathways of toxic metals in staple foods within local diets and their subsequent presence in the agricultural environment of examined GNs. Cr, Cd, As, and Ni concentrations in analyzed foods were within permissible limits (MPLs), whereas Pb levels exceeded MPLs in rice (Oryza sativa), gotukola (Centella asiatica), lime (Citrus crenatifolia), and inland fish (Etroplus suratensis). High target hazard quotient (THQt) values in polished rice suggest possible health risks with prolonged intake. Hierarchical analysis suggested a common source of Pb accumulation. PCA and hierarchical clustering revealed the intricate connection between As and Cd, with their concurrent clustering in samples suggesting a potential common origin. This indicates that while individual concentrations comply with acceptable standards, the potential synergistic effects of Cd and As accumulation might pose elevated health risks. Further, the gut tissues of inland fish exhibited pronounced metal concentrations and significant (p < 0.05) positive correlations with toxic metals in the tank sediments suggesting a diet-based bioaccumulation pathway through sediments., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

During the last two decades, an epidemic of a severe form of chronic kidney disease (CKD) unrelated to traditional risk factors (diabetes and hypertension) has been recognized in low- to middle-income countries. CKD of unknown aetiology (CKDu) mainly affects young working-age adults, and has become as an important and devastating public health issue. CKDu is a multifactorial disease with associated genetic and environmental risk factors. This review summarizes the current epidemiological evidence on the burden of CKDu and its probable environmental risk factors contributing to CKD in Africa. PubMed/Medline and the African Journals Online databases were searched to identify relevant population-based studies published in the last two decades. In the general population, the burden of CKD attributable to CKDu varied from 19.4% to 79%. Epidemiologic studies have established that environmental factors, including genetics, infectious agents, rural residence, low socioeconomic status, malnutrition, agricultural practise and exposure to agrochemicals, heavy metals, use of traditional herbs, and contaminated water sources or food contribute to the burden of CKD in the region. There is a great need for epidemiological studies exploring the true burden of CKDu and unique geographical distribution, and the role of environmental factors in the development of CKD/CKDu., (© 2023 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Chronic interstitial nephritis in agricultural communities (CINAC) is an epidemic of kidney disease affecting specific tropical and subtropical regions worldwide and is characterized by progressive CKD in the absence of traditional risk factors, such as hypertension and diabetes. CINAC prevalence is higher among young, male agricultural workers, but it also affects women, children, and nonagricultural workers in affected areas. Biopsies from patients with CINAC across regions commonly demonstrate tubular injury with lysosomal aggregates, tubulointerstitial inflammation, and fibrosis and variable glomerular changes. Each endemic area holds environmental risk factors and patient/genetic milieus, resulting in uncertainty about the cause(s) of the disease. Currently, there is no specific treatment available for CINAC. We highlight survey findings of Houston-based migrant workers with CINAC and draw similarities between kidney injury phenotype of patients with CINAC and mice treated chronically with paraquat, an herbicide used worldwide. We propose potential pathways and mechanisms for kidney injury in patients with CINAC, which may offer clues for potential therapies., (Copyright © 2023 by the American Society of Nephrology.)

Background: Mesoamerican nephropathy is a leading contributor to premature mortality in Central America. Efforts to identify the cause are hampered by difficulties in distinguishing associations with potential initiating factors from common exposures thought to exacerbate the progression of all forms of established chronic kidney disease (CKD). We explored evidence of disease onset or departure from the healthy estimated glomerular filtration rate distribution [departure from ∼eGFR(healthy)] in an at-risk population., Methods: Two community-based cohorts (adults aged 18-30 years, n = 351 and 420) from 11 rural communities in Northwest Nicaragua were followed up over 7 and 3 years respectively. We examined associations with both (i) incident CKD and (ii) the time point of departure from ∼eGFR(healthy), using a hidden Markov model., Results: CKD occurred in men only (male incidence rate: 0.7%/year). Fifty-three (out of 1878 visits, 2.7%) and 8 (out of 1067 visits, 0.8%) episodes of probable departure from ∼eGFR(healthy) occurred in men and women, respectively. Cumulative time in sugarcane work and symptoms of excess occupational sun exposure were associated with incident CKD. The same exposures were associated with probability of departure from ∼eGFR(healthy) in time-updated analyses along with measured and self-reported weight loss, nausea, vomiting and cramps, as well as non-steroidal anti-inflammatory drug use., Conclusions: CKD burden in this population is high and risk factors for established disease are occupational. Additionally, a syndrome suggesting an alternative exposure is associated with evidence of disease onset supporting a possible separate unknown initiating factor for which further investigation is needed. Interventions to reduce the impact of occupational risks should be pursued meanwhile., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Chronic kidney disease of unknown etiology (CKDu) is an endemic disease in the dry zone of farming communities, Sri Lanka. The drinking water in a CKDu prevalent area contains a high concentration of F - , hardness and other environmental pollutants, including heavy metals and microcystin, which are considered possible etiology of CKDu in these areas. Here, multi-omics data with host transcriptome, metabolome and gut microbiomes were obtained using simulated local drinking water of Sri Lanka after their exposure to adult zebrafish. Based on an integrated multi-omics analysis in the context of host physiology in the kidney injury samples with different pathologic grades, two common pathways necroptosis and purine metabolism were identified as potentially important pathways that affect kidney injury. The key metabolite acetyl adenylate in the purine metabolism pathway was significantly positively correlated with Comamonas (rho = 0.72) and significantly negatively correlated with Plesiomonas (rho = -0.58). This crucial metabolite and two key gut bacteria genera may not only be potential markers but also potential therapeutic targets in the uric acid metabolic pathway, which is an important factor in the pathogenesis of acute kidney injury (AKI) in general, as well as of chronic kidney disease (CKD). Based on this, we revealed the urea metabolism pathway of kidney injury in zebrafish and provided a new avenue for the treatment of CKDu in Sri Lanka., Competing Interests: 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The objectives of this study were to determine selected Hofmeister anions and cations that are important for kidney health, in raw rice samples from selected Chronic Kidney Disease of unknown etiology (CKDu) endemic and non-endemic areas in Sri Lanka and their intake. The anions and cations were analyzed by Ion Chromatography and Microwave Plasma Atomic Emission Spectrometry (MP-AES), respectively, after alkaline and acid digestion in thirty raw rice samples each from CKDu endemic and non-endemic areas, and the dietary intake was estimated. The mean concentrations of fluoride (F - ), chloride (Cl - ), phosphate (PO 4 3- ), sulfate (SO 4 2- ), sodium (Na + ), magnesium (Mg 2+ ), potassium (K + ), and calcium (Ca 2+ ) in raw rice in CKDu endemic areas were 53.317, 1515.3, 2799.6, 2704.9, 30.603, 300.76, 1001.3, and 90.075 mg/kg, respectively. The mean concentration of the anions and cations in raw rice from CKDu non-endemic areas were 22.850, 947.52, 4418.7, 6080.2, 23.862, 364.45, 955.78, and 96.780 mg/kg, respectively. Significantly higher differences (p < 0.05) were reported in the mean concentration of F - , Cl - , and Na + in raw rice from CKDu endemic areas in comparison with the samples from non-endemic areas. The aggregated estimated daily intake (EDI) and cumulative EDI of F - via consumption of cooked non-traditional samba rice from CKDu endemic areas for adults were the highest (0.155 and 0.172 mg/kg bw/d, respectively), which were higher than the recommended tolerable upper intake value (0.15-0.2 mg/kg bw/d). In contrast, the traditional rice from CKDu non-endemic areas for adolescents, reported the lowest values (0.0210 and 0.0470 mg/kg bw/d, respectively). Adults who consume non-traditional samba rice from CKDu endemic areas were at health risk, while children were the most vulnerable group due to their low body weight. These results indicate that the consumption of rice rich in Hofmeister ions may contribute to the total intake and act as risk factors to negatively affect weak kidneys in CKDu endemic areas. Further research to analyze Hofmeister ions in cooked rice and rice from different countries is recommended., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Global rise in the prevalence of endemic chronic kidney disease of unknown etiology (CKDu) possess major health issues. The prevalence of CKDu is also rising in the Indian population. Besides environmental factors, genetic factors play an important role in the predisposition to CKDu. In the present study, we have analyzed the association of single nucleotide polymorphisms (SNPs) in three genes with the susceptibility to CKDu. This was a case-control study with a total of 180 adult subjects (CKD = 60, CKDu = 60, Healthy = 60) from central India. We performed KASP genotyping assay to determine the allele frequency of SNP genotypes. We used the odds ratio (OR) to assess the association of individual SNPs, rs34970857 of KCNA10, rs6066043 of SLC13A3, and rs2910164 of miR-146a with CKDu and CKD susceptibility. In the case of rs34970857 of the KCNA10 gene, we noted a significantly increased OR for CKDu versus healthy control (Dominant model; CKDu versus control, CT + CC versus TT, OR = 3.96, p = 0.004). In the recessive and homozygous model, we observed significantly increased OR for rs6066043 of SLC13A3 gene, CKDu versus healthy control {(Recessive model; CKDu versus control, GG versus AA + GA, OR = 2.41, p = 0.03; homozygous model, GG versus AA, OR = 3.54, p = 0.04)}. CC genotype of rs34970857 of the KCNA10 gene and the GG genotype of the SLC13A3 gene are significantly associated with the susceptibility of CKDu., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The term chronic kidney disease of unknown aetiology (CKDu) refers to chronic kidney disease (CKD) in the absence of diabetes, long-standing hypertension, glomerulonephritis, obstructive uropathy or other apparent causes. An increasing number of CKDu cases have been reported from Latin America, Sri Lanka, India and others over the last two decades. These regional nephropathies share the following common attributes: (a) they affect low-to-middle income countries with tropical climates, (b) involve predominantly rural agricultural communities, (c) male predilection, (d) absence of significant proteinuria and hypertension, and (e) chronic tubulointerstitial nephritis on kidney biopsy. The current body of literature suggests that CKDu may be caused by heat stress, agrochemicals, contaminated drinking water or heavy metals; however, considerable regional disparities in CKDu research make it difficult to establish a common causal link. In the absence of a definite aetiology, specific preventive and therapeutic interventions are lacking. Improvement of working conditions of farmers and labourers, provision of safe drinking water and changes in agricultural practices are some of the measures that have been implemented; however, there is lack of data to assess their impact on the incidence and progression of CKDu. There is a need for a concerted global effort to address the current knowledge gaps, and to develop effective and sustainable strategies to tackle this devastating disease., (© 2023 John Wiley & Sons Ltd.)

Hydro-geochemistry of drinking water was characterized in chronic kidney disease of unknown etiology (CKDu) endemic areas in Girandurukotte (GK) and Dehiattakandiya (DH) and non-endemic areas in GK, DH, and Sewanagala (SW) in Sri Lanka to comprehend any potential risk factors for CKDu. Groundwater (n = 142) and surface water (n = 08) were sampled during wet and dry seasons and analyzed for major anions, cations and stable isotopes of hydrogen and oxygen (δ 2 H and δ 18 O). Besides the typical water quality analysis, the water quality status was determined using the weighted arithmetic water quality index (WQI) and Hofmeister ion exposure levels. The measured average groundwater F - level was higher than the permissible level assigned by regulatory agencies for tropical countries at CKDu locations in GK, DH and non-CKDu locations in DH and SW. Significant differences in the content of total hardness (p = 0.017) and total dissolved solids (p = 0.003) were observed between CKDu and non-CKDu locations whereas the differences were insignificant for F - (p = 0.985) and alkalinity (p = 0.203). Weathering of silicate and carbonate minerals was found to be the main governing factor of groundwater compositions in both CKDu and non-CKDu areas, while recharging of groundwater is mainly determined by the rainfall than the surface water inputs. Higher ionic strength of groundwater in non-CKDu areas suggested that the potential environmental CKDu risk factors might be suppressed from dissolution into groundwater. The WQI calculations revealed that the both CKDu and non-CKDu locations were frequently presented with poor water quality. This study highlights the water quality status of the CKDu and non-CKDu locations and signifies the potential health risks that could arise even in non-CKDu areas due to the consumption of poor quality water. Accordingly, regular monitoring of water quality and assessment of Hofmeister ions exposure from food and beverages are highly warranted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Meththika Vithanage reports financial support was provided by National Science Foundation, Sri Lanka and the Natural Science Foundation of China., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chronic kidney disease of uncertain aetiology (CKDu) is an advanced version of chronic kidney disease (CKD) which bears a high burden on the world health economy. More than 200 articles were analysed to understand the disease responsible for more than 30,000 deaths per year. CKDu is a non-communicable occupational disease that has a progressive deterioration of the kidney in the absence of CKD risk factors such as hypertension, diabetes and glomerulonephritis, while the diagnosis is only possible at the later stages when kidney function is no longer effective. Published evidence for the existence of CKDu was found for around 35 countries. This is a growing health issue in Asia, Central America, Africa and Middle East with identified hot spots. Despite many research studies over decades, the exact root causes are still uncertain. Six main suspected causative factors are identified. Those are heat stress, strenuous labour, dehydration, use of agrochemicals, exposure to heavy metals and the use of polluted water and agricultural lands. This review summarizes four key areas which are CKDu and its general medical background, worldwide prevalence, suspected causative factors and potential circumventing steps to mitigate against CKDu. The importance of further studies addressing early detection and surveillance methods, contribution of nephrotoxins in environmental health, soil chemistry on transporting nephrotoxins, geological parameters which influence the prevalence of the disease and other related sectors to overcome the mysterious nature is highlighted. Mitigation steps to lessen the burden of CKDu are also identified., (© 2022. The Author(s).)

Chronic kidney disease of unknown etiology (CKDu) has posed a serious threat to human health around the world. The link between the prevalence of CKDu and groundwater geochemistry is not well understood. To identify the potential geogenic risk factors, we collected 52 groundwater samples related to CKDu (CKDu groundwater) and 18 groundwater samples related to non-CKDu (non-CKDu groundwater) from the typical CKDu prevailing areas in Sri Lanka. Results demonstrated that CKDu groundwater had significantly higher Si (average 30.1 mg/L, p < 0.05) and F - (average 0.80 mg/L, p < 0.05) concentrations than those of non-CKDu groundwater (average 21.0 and 0.45 mg/L, respectively), indicating that Si and F - were the potential risk factors causing CKDu. The principal hydrogeochemical process controlling local groundwater chemistry was chemical weathering of silicates in Precambrian metamorphic rocks. Groundwater samples were mostly undersaturated with respect to amorphous silica and clay minerals such as talc and sepiolite, which was conducive to silicate weathering and elevated Si concentrations in groundwater. Decreased Ca 2+ being facilitated by calcite precipitation and cation exchange between Ca 2+ and Na + favored fluorite dissolution and thus led to high groundwater F - concentrations. Competitive adsorption between [Formula: see text] and F - also enhanced the release of F - from solid surfaces. This study highlights the CKDu potential risk factors regarding groundwater geochemistry and their enrichment factors, which helps in preventing the prevalence of CKDu., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Chronic kidney disease of unknown etiology (CKDu) has been a growing concern in the Indian population causing significant morbidity and mortality in these recent years. Thus, it is vital to understand the probable risk factors associated with its manifestation. This study aims to assess the distribution of various etiologies among CKD patients, investigate all the probable risk factors associated with CKDu, and estimate the health-related quality of life (QoL) among all CKDu patients in the study area., Materials and Methods: It was an analytical, observational, cross-sectional study where one objective had a case-control study design. It was conducted at Bankura Sammilani Medical College in Bankura district, West Bengal, during July 2022-August 2022. A total of 198 patients have been studied through detailed interviews using a predesigned, pretested, semi-structured schedule. Potential risk factors and their strength of association were analyzed with the help of multivariate logistic regression., Results: It was found that the prevalence of CKDu was almost 71% in the study population, mostly affecting agricultural workers (67.17%), daily laborers (46.46%), and construction workers. Perceived heat stress, excessive daily dietary intake of salt, and drinking contaminated water are the factors that had shown the strongest association with the occurrence of CKDu in this population. The deterioration in QoL in CKDu pretty much mirrors that of CKD., Conclusion: CKDu is definitely an occupational disease, mostly affecting the wage workers and farmers spending long hours in unhealthy work environments. Environmental exposure to heavy metals must be checked and dietary modification must be done through counseling to regulate salt intake. CKDu, as a rising public health concern certainly needs special attention and immediate planning as it has a different etiopathology than CKD and the affected population, disease progression, and risk factors are markedly distinctive as well., Competing Interests: None

Dietary exposure of selected Hofmeister ions-fluoride, chloride, sulfate, phosphate, sodium, potassium, magnesium, and calcium from black tea consumption in chronic kidney disease of unknown etiology (CKDu) prevalent areas in Sri Lanka-were assessed in order to understand exposure and risk. Black tea samples (n = 25) were collected from CKDu prevalent areas and control areas (n = 15). Total fluoride content in alkali fused digested black tea samples was determined. The available Hofmeister ions in tea infusions prepared using deionized water and the groundwater collected by CKDu endemic areas were compared. Dietary exposure was calculated by chronic daily intake data. Total fluoride concentrations ranged from 80 to 269 mg/kg in tea collected from the CKDu endemic regions and 62.5-123.5 mg/kg in non-endemic regions. The fluoride content in infusions ranged from 1.45 to 2.04 mg/L in CKDu endemic areas and 1.11-1.38 mg/L in control samples. The infusions prepared with local groundwater from the CKDu endemic areas showed an elevated level of fluoride 95% than that of the infusion prepared using same tea with deionized water. Aggregated chronic daily intake value from tea and groundwater exceeds the estimated adequate daily intake value of fluoride. The hazard quotient (HQ) values of fluoride in 5 min and 120 min tea infusions were 1.60 and 2.20, respectively, and indicate an adverse health risk. Potassium content in tea infusions collected from CKDu endemic areas is higher than in the control. Even though these values are less than the adequate intake, it may pose an impairment on a weak kidney. Chronic daily intake of Hofmeister ions, i.e., fluoride and potassium from black tea consumed in CKDu endemic areas may induce a risk for CKDu., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chronic kidney disease of unknown cause (CKDu), also known as Mesoamerican nephropathy, typically presents as an ischemic nephropathy with chronic tubulointerstitial fibrosis in normotensive patients, rapidly progressing to kidney failure. In this first-in-human, open-label, safety study, we followed 18 patients with CKDu (stages 3-5) for 36 months after receiving a single infusion of angiogenic/anti-fibrotic autologous adipose-derived stromal vascular fraction (SVF) cells into their kidneys bilaterally via renal artery catheterization. SVF therapy was safe and well tolerated. There were no SVF-related serious adverse events and no procedural complications. Color Doppler evaluation at 2 months demonstrated increased perfusion to the interlobar and/or arcuate artery levels in each kidney evaluated (36/36) with a reduction in resistance index at the hilar artery (35/36) kidneys. Beyond 12 months, patients with initial eGFR <30 mL/minute/1.73 m2 deteriorated, whereas those ≥30 mL/minute/1.73 m2 further sustained their renal function, suggesting a possible renal protective effect in that group., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Cases for chronic kidney disease of unknown etiology (CKDu) are increasing in specific disease hotspots located in rural agricultural communities over Central America. The goal of the study was to estimate the prevalence and geographic distribution of self-reported work-related CKD and associated risk factors for CKDu by industry sector in Central America., Methods: We calculated the prevalence and distribution of self-reported CKD, work-related CKD, and suspected CKDu risk factors among the 9032 workers in the Second Central American Survey of Working Conditions and Health (II ECCTS, 2018). We mapped the distribution of suspected CKDu risk factors to work-related CKDu and weather conditions using average annual temperatures., Results: The primary and secondary industry sectors showed the highest proportion of males, suspected CKDu risk factors, and work-related CKD. Age (30-49 years: OR = 2.38, 95% CI 1.03-5.51), ethnicity (mestizo: OR, 7.44, 95% CI: 2.14-25.82), and exposure to high physical work demands (OR = 2.45, 95% CI: 1.18-5.09) were associated with work-related CKD. The majority of work-related CKD were reported in the western parts of Honduras and Nicaragua, in hot temperature regions, and overlapped with those areas with a high density of CKDu risk factors. Finally, some areas clustered CKDu risk factors without any work-related CKD points, mainly in the western part of Guatemala., Conclusion: Our findings supplement prior CKDu findings regarding a high prevalence of work-related CKD among 30- to 49-year-old mestizo males in the primary and secondary sectors, in hot temperature areas, in the central and western region, and overlapping with persons reporting two or more CKDu risk factors. Moreover, several geographic areas with CKDu risk factor clusters had no reported work-related CKD. These areas represent new industries and sectors to be monitored for possible future increases of CKDu cases.

Background: Chronic kidney disease of unknown etiology (CKDu) is reported among male paddy farmers in the dry zone of Sri Lanka. The exact cause of this disease remains undetermined. Genetic susceptibility is identified as a major risk factor for CKDu Objectives: In this study, small urinary RNAs were characterized in CKDu patients, healthy endemic and non-endemic controls. Differently expressed urinary miRNAs and their associated pathways were identified in the study population., Methods: Healthy and diseased male volunteers (n = 9) were recruited from Girandurukotte (endemic) and Mawanella (non-endemic) districts. Urinary small RNAs were purified and sequenced using Illumina MiSeqTM. The sequence trace files were assembled and analyzed. Differentially ex-pressed miRNAs among these three groups were identified and pathway analysis was conducted., Results: The urine samples contained 130,623 sequence reads identified as non-coding RNAs, PIWI-interacting RNAs (piRNA), and miRNAs. Approximately four percent of the total small RNA reads represented miRNA, and 29% represented piRNA. A total of 409 miRNA species were ex-pressed in urine. Interestingly, both diseased and endemic controls population showed significantly low expression of miRNA and piRNA. Regardless of the health status, the endemic population ex-pressed significantly low levels of miR-10a, miR-21, miR-148a , and miR-30a which have been linked with several environmental toxins Conclusion: Significant downregulation of miRNA and piRNA expression in both diseased and healthy endemic samples indicates an epigenetic regulation of CKDu involving genetic and environmental interaction. Further studies of specific miRNA species are required to develop a miRNA panel to identify individuals susceptible to CKDu., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Chronic kidney disease of uncertain etiology (CKDu) is an environmental nephropathy in which the etiological factors are yet uncertain. Leptospirosis, a spirochetal infection that is common among agricultural communities, has been identified as a potential etiology for CKDu beyond environmental nephropathy. Although CKDu is a chronic kidney disease, in endemic regions, an increasing number of cases are reported with features suggestive of acute interstitial nephritis without any known reason (AINu), with or without background CKD. The study hypothesizes that exposure to pathogenic leptospires is one of the causative factors for the occurrence of AINu., Method: This study was carried out using 59 clinically diagnosed AINu patients, 72 healthy controls from CKDu endemic region (endemic controls [ECs]), and 71 healthy controls from CKDu non-endemic region (non-endemic controls [NECs])., Results: The seroprevalence of 18.6, 6.9, and 7.0% was observed in the AIN (or AINu), EC, and NEC groups, respectively, from the rapid IgM test. Among 19 serovars tested, the highest seroprevalence was observed at 72.9, 38.9, and 21.1% in the AIN (AINu), EC, and NEC groups, respectively, by microscopic agglutination test (MAT), particularly for serovar Leptospira santarosai serovar Shermani. This emphasizes the presence of infection in AINu patients, and this also suggests that Leptospira exposure might play an important role in AINu., Conclusion: These data suggest that exposure to Leptospira infection could be one of the possible causative factors for the occurrence of AINu, which may lead to CKDu in Sri Lanka., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Gut dysbiosis and changes in short-chain fatty acids (SCFAs) occur in end-stage chronic kidney disease (CKD); however, the degree of these changes in the gut microbiome and serum SCFA profiles in the early stages of CKD,‍ ‍particularly in‍ ‍CKD‍ ‍of unknown etiology (CKDu), is unclear. We herein investigated the gut microbiome and SCFA profiles of early-stage CKD patients (CKD stages 1-3) in a community in Khon Kaen Province, Thailand. Seventy-two parasite-free participants were distributed among a healthy control group (HC, n=18) and three patient groups (an underlying disease group [UD, n=18], early-stage CKD with underlying disease [CKD-UD, n=18], and early-stage CKD of unknown etiology, [CKDu, n=18]). Fecal DNA was individually extracted and pooled for groups of six individuals (three pools in each group) to examine the composition of the gut microbiome using next-generation sequencing. A SCFA ana-lysis was performed on serum samples from each individual using gas chromatography-mass spectrometry. The results revealed that microbial abundance differed between the healthy group and all patient groups (UD, CKD-UD, and CKDu). [Eubacterium]&#95;coprostanoligenes&#95;group was more abundant in the CKDu group than in the HC and CKD-UD groups. Furthermore, serum concentrations of acetate, a major SCFA component, were significantly lower in all patient groups than in the HC group. The present results indicate that minor changes in the gut microbiome and a significant decrease in serum acetate concentrations occur in early-stage CKDu, which may be important for the development of prevention strategies for CKD patients.

Background. Chronic kidney disease of unknown aetiology (CKDu) is a major public health problem in Sri Lanka, especially among agrarian communities. Although the cause of CKDu is still unknown, hantavirus infection has been proposed as a risk factor. Methods. This study was performed using serological samples collected from two CKDu-endemic areas, Anuradhapura (2010) and Badulla districts (2010 and 2016), and a non-endemic area, Matale (2016) district. The presence of anti-Thailand orthohantavirus IgG antibodies was investigated in serum samples. Hantavirus seroprevalence and demographic data were epidemiologically analysed. Results. Seroprevalence was higher in CKDu patients (40.6-60.0 %) and healthy individuals in CKDu-endemic areas (17.6-25.5 %) than in healthy individuals in non-endemic areas (3.0 %). Statistically significant odds ratios (ORs) for hantavirus infection in CKDu patients were detected in CKDu-endemic areas [ORs: 3.2 and 3.1; 95 % confidence interval (CI): 1.8-5.5 and 1.8-5.2 in Anuradhapura and Badulla districts in 2010; and OR: 4.4, 95 % CI: 2.3-8.5 in 2016 in Badulla district). Furthermore, the OR for hantavirus infection in Badulla district has increased in the last decade from 3.1 (95 % CI: 1.8-5.3) to 4.4 (95 % CI: 2.3-8.5). Conclusion. Hantavirus infection has been prevalent in two distant CKDu-endemic areas since 2010. The observed significant association of hantavirus seropositivity with CKDu indicates a possible role of hantavirus infection in CKDu pathogenesis.

Objective: Estimate agricultural work's effect on hemoglobin (Hgb) level in men. A negative effect may indicate presence of chronic kidney disease of uncertain etiology., Methods: We use Demographic and Health Surveys data from seven African and Asian countries and use matching to control for seven confounders., Results: On average, Hgb levels were 0.09 g/dL lower among agricultural workers compared with matched controls. Significant effects were observed in Ethiopia, India, Lesotho, and Senegal, with effects from 0.07 to 0.30 g/dL lower Hgb level among agricultural workers. The findings were robust to multiple control groups and a modest amount of unmeasured confounding., Conclusions: Men engaged in agricultural work in four of the seven countries studied have modestly lower Hgb levels. Our data support integrating kidney function assessments within Demographic and Health Surveys and other population-based surveys., Competing Interests: Conflict of Interest: None declared., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Introduction: Chronic kidney disease (CKD) is emerging as a serious health problem in Odisha, India. A new form of severe CKD affecting adults, not due to traditional risk factors like diabetes, hypertension, glomerulonephritis, has been reported in Sri Lanka, Central America, and Egypt in the last two decades. This has been named CKD of unknown origin (CKDu), and it is fatal due to late recognition and rapid disease progression. The aim of the study was to elucidate the association between different sociodemographic, and biochemical parameters with renal morphology in CKD of unknown origin patients., Methods: A cross-sectional study was conducted on 124 consecutive patients with CKD from the period January 2018 to December 2018. Patients in the age group 18-60 years who met clinical criteria for CKD were included. Participants answered a questionnaire. After the necessary history, clinical evaluation, and blood and urine analyses, a kidney biopsy was undertaken. Kidney biopsy was feasible in 51 patients as the rest 61 patients had shrunken kidneys and 12 patients did not give consent. Patients with diabetes mellitus (DM), hypertension, glomerulonephritis, polycystic kidney disease, obstructive kidney disease or any other congenital diseases, snakebite, pregnancy, malignancy, gout, primary hyperparathyroidism, infectious diseases like human immunodeficiency virus (HIV), TB, Hepatitis B and C, malaria, syphilis, leprosy and coagulopathies were excluded. Among the 51 patients, 23 had CKDu, 25 had chronic glomerulonephritis and three biopsies were inconclusive., Results: The mean age of CKDu patients was 36.78 ± 9.85 years. Males (73.9%) were predominantly affected. A family history of CKD was seen in 82.6% of CKDu cases. Hyponatremia and hypokalemia were predominant biochemical abnormalities in our CKDu cases. Binary logistic regression showed rural residence, family history of CKD, exposure to smoke from burning coal, charcoal, or biomass fuels, low socioeconomic status, and low body mass index were strongly associated with CKDu. There was an increased risk of developing CKDu in persons with a family history of CKD [p = 0.003, odds ratio (OR)- 17.58], persons exposed to smoke from burning coal, charcoal or biomass fuels (p = 0.003, OR- 32.4), and patients with low socio-economic status (p = 0.001, OR- 15.87). Interstitial fibrosis (IF), interstitial inflammation with mononuclear infiltration, tubular atrophy (TA), and global glomerulosclerosis (GS) were pertinent histopathological findings in our study., Conclusion: There is no strong evidence for a single cause for CKDu, and multiple environmental, occupational and social factors are probably involved. We need to design consistent and comparative multisite studies to identify etiologies of CKDu, across high-risk populations that may help elucidate the importance of region-specific vs global risk factors., (© Journal of the Association of Physicians of India 2011.)

Mesoamerican endemic nephropathy (MeN) is a type of chronic kidney disease (CKD) of uncertain etiology that occurs along the Pacific coast of the southern part of Mexico and Central America. During the past 20 years MeN has become a leading cause of death in the region, clamming close to 50,000 lives, with 40% of these deaths occurring in young people. The cause remains unknown, but most researchers believe in a multifactorial etiology that includes social determinants of poverty. Existing evidence suggests that subclinical kidney injury begins early in life and leads to a higher than expected prevalence of CKD among children in Central America. Access to health services in the region, specifically kidney replacement therapy, remains limited. We proposed a strategy to address the perceived needs and urge coordinated efforts of governments, academic organizations, and international bodies to develop a comprehensive plan of action to mitigate this situation among the vulnerable and economically disadvantaged population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: The etiology of chronic kidney disease of unclear etiology, also known as Mesoamerican nephropathy, remains unclear. We investigated potential etiologies for Mesoamerican nephropathy in an immigrant dialysis population., Design, Setting, Participants, & Measurements: Migrants with Mesoamerican nephropathy kidney failure ( n =52) were identified by exclusion of known causes of kidney disease and compared using a cross-sectional survey with demographically similar patients with kidney failure from other causes ( n =63) and age/sex/place of origin-matched healthy participants ( n =16). Survey results were extended to the bench; C57BL/6 mice ( n =73) received 10-15 weekly intraperitoneal injections of paraquat (a reactive oxygen species-generating herbicide) or vehicle. Kidney function, histology, and expression of organic cation transporter-2 (proximal tubule entry for paraquat) and multidrug and toxin extrusion 1 (extrusion pathway) were examined. Kidney biopsies from Nicaraguan patients with acute Mesoamerican nephropathy were stained for the above transporters and compared with patients with tubulointerstitial nephritis and without Mesoamerican nephropathy., Results: Patients with Mesoamerican nephropathy and kidney failure were young agricultural workers, almost exclusively men; the majority were from Mexico and El Salvador; and they had prior exposures to agrochemicals, including paraquat (27%). After adjustment for age/sex, exposure to any agrochemical or paraquat was associated with Mesoamerican nephropathy kidney failure (odds ratio, 4.86; 95% confidence interval, 1.82 to 12.96; P =0.002 and odds ratio, 12.25; 95% confidence interval, 1.51 to 99.36; P =0.02, respectively). Adjusted for age/sex and other covariates, 1 year of agrochemical exposure was associated with Mesoamerican nephropathy kidney failure (odds ratio, 1.23; 95% confidence interval, 1.04 to 1.44; P =0.02). Compared with 16 matched healthy controls, Mesoamerican nephropathy kidney failure was significantly associated with exposure to paraquat and agrochemicals. Paraquat-treated male mice developed kidney failure and tubulointerstitial nephritis consistent with Mesoamerican nephropathy. Organic cation transporter-2 expression was higher in male kidneys versus female kidneys. Paraquat treatment increased organic cation transporter-2 expression and decreased multidrug and toxin extrusion 1 expression in male kidneys; similar results were observed in the kidneys of Nicaraguan patients with Mesoamerican nephropathy., Conclusions: Exposure to agrochemicals is associated with Mesoamerican nephropathy, and chronic exposure of mice to paraquat, a prototypical oxidant, induced kidney failure similar to Mesoamerican nephropathy., (Copyright © 2022 by the American Society of Nephrology.)