Search Results (41)

Background/Objectives: Chronic kidney disease of unknown etiology (CKDu) disproportionately affects young male agricultural workers who are otherwise healthy. There is a scarcity of biomarkers for early detection of this type of kidney disease. We hypothesized that small extracellular vesicles (sEVs) released into urine may provide novel biomarkers. Methods: We obtained two urine samples at the start and the end of a workday in the fields from a limited set of workers with and without kidney impairment. Isolated sEVs were characterized for size, surface marker expression, and purity and, subsequently, their lipid composition was determined by mass spectrometry. Results: The number of particles per ml of urine normalized to osmolality and the size variance were larger in workers with possible CKDu than in control workers. Surface markers CD9, CD63, and CD81 are characteristic of sEVs and a second set of surface markers suggested the kidney as the origin. Differential expression of CD25 and CD45 suggested early inflammation in CKDu workers. Of the twenty-one lipids differentially expressed, several were bioactive, suggesting that they may have essential functions. Remarkably, fourteen of the lipids showed intermediate expression values in sEVs from healthy individuals with acute creatinine increases after a day of work. Conclusions: We identified twenty-one possible lipid biomarkers in sEVs isolated from urine that may be able to distinguish agricultural workers with early onset of CKDu. Differentially expressed surface proteins in these sEVs suggested early-stage inflammation. This pilot study was limited in the number of workers evaluated, but the approach should be further evaluated in a larger population. Full article

Renal aging is a physiological process characterized by structural and functional changes in the kidneys. The presence of disorders or pathologies can exacerbate these age-related changes, potentially leading to organ dysfunction. Chronic kidney disease (CKD), a significant global public health issue, is particularly prevalent in the elderly and is often associated with the age-related decline in kidney function. Anemia is one of the most frequent complications of CKD and is also highly prevalent in the elderly. Mild anemia, often multifactorial, is the most common presentation. Understanding the mechanisms driving anemia in this population is crucial to ensure appropriate treatment. The primary etiologies include nutritional deficiency, anemia of unknown cause, and anemia of chronic diseases, including CKD. This review provides an in-depth exploration of the complex pathophysiological mechanisms underlying anemia in elderly patients with CKD. Full article

Chronic Kidney Disease of Unknown Etiology (CKDu) is a worldwide hidden health threat that is associated with progressive loss of kidney functions without showing any initial symptoms until reaching end-stage renal failure, eventually leading to death. It is a growing health problem in Asia, Central America, Africa, and the Middle East, with identified hotspots. CKDu disease mainly affects young men in rural farming communities, while its etiology is not related to hypertension, kidney stones, diabetes, or other known causes. The main suspected causal factors are heat-stress, dehydration, exposure to agrochemicals, heavy metals and use of hard water, infections, mycotoxins, nephrotoxic agents, altitude, and genetic factors. This review gives an overview of CKDu and sheds light on its medical history, geographic distribution, and worldwide prevalence. It also summarizes the suspected causal factors, their proposed mechanisms of action, as well as the main methods used in the CKDu prior detection and surveillance. In addition, mitigation measures to reduce the burden of CKDu are also discussed. Further investigation utilizing more robust study designs would provide a better understanding of the risk factors linked to CKDu and their comparison between affected regions. Full article

Genetic or hereditary kidney disease stands as a pivotal cause of chronic kidney disease (CKD). The proliferation and widespread utilization of DNA testing in clinical settings have notably eased the diagnosis of genetic kidney diseases, which were once elusive but are now increasingly identified in cases previously deemed CKD of unknown etiology. However, despite these diagnostic strides, research into disease pathogenesis and novel drug development faces significant hurdles, chiefly due to the dearth of appropriate animal models and the challenges posed by limited patient cohorts in clinical studies. Conversely, the advent and utilization of human-induced pluripotent stem cells (hiPSCs) offer a promising avenue for genetic kidney disease research. Particularly, the development of hiPSC-derived kidney organoid systems presents a novel platform for investigating various forms of genetic kidney diseases. Moreover, the integration of the CRISPR/Cas9 technique into this system holds immense potential for efficient research on genetic kidney diseases. This review aims to explore the applications of in vitro kidney organoids generated from hiPSCs in the study of diverse genetic kidney diseases. Additionally, it will delve into the limitations of this research platform and outline future perspectives for advancing research in this crucial area. Full article

The rural population in the Dry Zone of Sri Lanka is largely affected by Chronic Kidney Disease of Unknown etiology (CKDu). According to the multidisciplinary research carried out so far, quality of groundwater is considered one of the possible causative factors for CKDu. Therefore, assessment of the quality of groundwater being used for drinking and its evolution mechanism is the key to identifying the linkage between CKDu and drinking water. This study aimed to perform a detailed investigation on groundwater sources using isotopic, chemical, and hydrogeological methods in the CKDu-endemic (site A) and the control area (sedimentary formation—site B) in the Malwathu Oya basin and the control areas in the Malala Oya basin (site C) selected for a systematic comparison. Our investigation shows that elevated levels of TDS, magnesium, and fluoride in the shallow groundwater affected by climatic, geochemical, and hydrogeological processes may contribute to the CKDu in the Dry Zone of Sri Lanka. All the groundwater samples analysed have exceeded the hardness threshold. Prominent Mg hardness proportion together with excess F⁻ in the CKDu endemic area may produce nephrotoxic MgF₂ complexes that may trigger renal damage. In contrast, NaF complexes in the CKDu control area leads to reduction of F⁻ toxicity in the human body. Elevated F⁻ and Mg²⁺ are found in site A, low F⁻ and high Mg²⁺ in site B, and either combinations of low F⁻ and low Mg²⁺, high F⁻ and low Mg²⁺, or low F⁻ with high Mg²⁺ in site C. TDS, hardness, Mg²⁺, Na⁺, and F⁻ are formed with different mechanisms in the three selected areas. The primary process that regulates the evolution of groundwater types and contents in sites A and C is the weathering of silicates. Similarly, in site A, carbonate dissolution and reverse ion exchange are quite strong. Cation exchange and evaporite dissolution are more pronounced in site C. Shallow groundwaters are evapo-concentrated, hence their quality deteriorates more significantly than the deep groundwater in the CKDu endemic area. Dilution decreases the ion content in site A while evaporite dissolution increases it in site C after the rainy season. Evaporation and seawater mixing affect the quality of groundwater in site B. It is also found that a statistically significant difference exists in the F⁻/Na⁺, F⁻/Mg²⁺, and F⁻/Ca²⁺ between the endemic and control areas. Intensive rock weathering combined with desorption has added excess F⁻ to the groundwater in site A, while cation exchange and fluorite dissolution are contributing factors in site C. Full article

Anemia is a common hematological disorder that affects 12% of the community-dwelling population, 40% of hospitalized patients, and 47% of nursing home residents. Our understanding of the impact of inflammation on iron metabolism and erythropoiesis is still lacking. In older adults, anemia can be divided into nutritional deficiency anemia, bleeding anemia, and unexplained anemia. The last type of anemia might be caused by reduced erythropoietin (EPO) activity, progressive EPO resistance of bone marrow erythroid progenitors, and the chronic subclinical pro-inflammatory state. Overall, one-third of older patients with anemia demonstrate a nutritional deficiency, one-third have a chronic subclinical pro-inflammatory state and chronic kidney disease, and one-third suffer from anemia of unknown etiology. Understanding anemia’s pathophysiology in people aged 65 and over is crucial because it contributes to frailty, falls, cognitive decline, decreased functional ability, and higher mortality risk. Inflammation produces adverse effects on the cells of the hematological system. These effects include iron deficiency (hypoferremia), reduced EPO production, and the elevated phagocytosis of erythrocytes by hepatic and splenic macrophages. Additionally, inflammation causes enhanced eryptosis due to oxidative stress in the circulation. Identifying mechanisms behind age-related inflammation is essential for a better understanding and preventing anemia in older adults. Full article

Sarcoidosis is a non-necrotizing granulomatous inflammatory multisystemic disorder of unknown etiology. In children, as in adults, it can involve a few or all organ systems to a varying extent and degree, entailing multisystemic manifestations. Kidney involvement in pediatric-onset adult-type sarcoidosis is rare, with a wide range of renal manifestations, most of them related to calcium metabolism. Children with renal sarcoidosis tend to be more symptomatic than adults, although male patients have a higher prevalence. We present the case of a 10-year-old boy who presented with advanced renal failure with nephrocalcinosis and important hepatosplenomegaly. The diagnosis was established by histopathological examination, with consequent cortisone therapy and hemodialysis. This review emphasizes that sarcoidosis should be considered in the differential diagnosis of pediatric patients with acute kidney insufficiency or chronic kidney disease of an unknown etiology. As far as we know, this is the first study regarding extrapulmonary sarcoidosis in children from Romania. Full article

Mesoamerican nephropathy (MeN) is a form of chronic kidney disease found predominantly in young men in Mesoamerica. Strenuous agricultural labor is a consistent risk factor for MeN, but the pathophysiologic mechanism leading to disease is poorly understood. We compared the urine metabolome among men in Nicaragua engaged in sugarcane harvest and seed cutting (n = 117), a group at high risk for MeN, against three referents: Nicaraguans working less strenuous jobs at the same sugarcane plantations (n = 78); Nicaraguans performing non-agricultural work (n = 102); and agricultural workers in Spain (n = 78). Using proton nuclear magnetic resonance, we identified 136 metabolites among participants. Our non-hypothesis-based approach identified distinguishing urine metabolic features in the high-risk group, revealing increased levels of hippurate and other gut-derived metabolites and decreased metabolites related to central energy metabolism when compared to referent groups. Our complementary hypothesis-based approach, focused on nicotinamide adenine dinucleotide (NAD+) related metabolites, and revealed a higher kynurenate/tryptophan ratio in the high-risk group (p = 0.001), consistent with a heightened inflammatory state. Workers in high-risk occupations are distinguishable by urinary metabolic features that suggest increased gut permeability, inflammation, and altered energy metabolism. Further study is needed to explore the pathophysiologic implications of these findings. Full article

(1) Background: Despite ample research, the factors, specific causes, and pathways associated with chronic kidney disease of unknown etiology (CKDu) remain elusive. Therefore, we performed a systematic review to explore the potential etiologies for the development of CKDu globally. (2) Methods: A systematic literature review was conducted using databases CINAHL, Cochrane Library, Embase, Google Scholar, MEDLINE, and PsycINFO on the specific causes and pathophysiology related to CKDu from inception until April 2021. Study selection, data extraction of included articles, and quality appraisal were assessed. The narrative approach was used to summarize and comprehend the findings. (3) Results: Our study included 25 studies, considering 38,351 participants. Twelve studies were case–control, ten were cross-sectional, and three were cohort designs. All articles were from low-and middle-income countries (LMICs). The findings suggest 12 factors are associated with CKDu. Most studies (n = 8) identified farming and water sources as the factors related to CKDu, with heavy metal toxicity coming in second (n = 7). (4) Conclusion: The systematic review reported various factors associated with CKDu, from which most studies reported farming, water sources, and heavy metal poisoning. Considering the findings, the study recommends future strategies and public health initiatives to prevent the epidemiological/environmental factors contributing to CKDu. Full article

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. Full article

Transcription factor PAX8, expressed during embryonic kidney development, has been previously detected in various kidney tumors. In order to investigate expression of PAX8 transcription factor in acute kidney injury (AKI) and chronic kidney diseases (CKD), immunohistochemical analysis was performed. Presence, location and extent of PAX8 expression were analyzed among 31 human kidney samples of AKI (25 autopsy cases, 5 kidney biopsies with unknown etiology and 1 AKI with confirmed myoglobin cast nephropathy), as well as in animals with induced postischemic AKI. Additionally, expression pattern was analyzed in 20 kidney biopsy samples of CKD. Our study demonstrates that various kidney diseases with chronic disease course that results in the formation of tubular atrophy and interstitial fibrosis, lead to PAX8 expression in the nuclei of proximal tubules. Furthermore, patients with PAX8 detected within the damaged proximal tubuli would be carefully monitored, since deterioration in kidney function was observed during follow-up. We also showed that myoglobin provoked acute kidney injury followed with large extent of renal damage, was associated with strong nuclear expression of PAX8 in proximal tubular cells. These results were supported and followed by data obtained in experimental model of induced postischemic acute kidney injury. Considering these findings, we can assume that PAX8 protein might be involved in regeneration process and recovery after acute kidney injury. Thus, accordingly, all investigation concerning PAX8 immunolabeling should be performed on biopsy samples of the living individuals. Full article

Chronic kidney disease of unknown etiology was investigated for metal relations in an endemic area by a cross-sectional study with CKD stages G1, G2, G3a, G3b, G4, G5 (ESRD), and endemic and nonendemic controls (EC and NEC) as groups. Subjects with the medical diagnosis were classified into groups by eGFR (SCr, CKD-EPI) and UACR of the study. It determined 24 metals/metalloids in plasma (ICPMS) and metallothionein (MT) mRNA in blood (RT-PCR). MT1A at G3b and MT2A throughout G2–G5 showed increased transcription compared to NEC (ANOVA, p < 0.01). Both MT1A and MT2A remained metal-responsive as associations emerged between MT2A and human MT inducer Cr (in EC: r = 0.54, p < 0.05, n = 14), and between MT1A and MT2A (in EC pooled with G1–G5: r = 0.58, p < 0.001, n = 110). Human MT (hMT)-inducers, namely Zn, Cu, As, Pb, and Ni; Σ hMT-inducers; 14 more non-inducer metals; and Σ MT-binding metals remained higher (p < 0.05) in EC as compared to NEC. Declining eGFR or CKD progression increased the burden of Be, Mg, Al, V, Co, Ni, Rb, Cs, Ba, Mn, Zn, Sr, Σ hMT-inducers, and Σ MT-binding metals in plasma, suggesting an MT role in the disease. MT1A/2A mRNA followed UACR (PCA, Dendrogram: similarity, 57.7%). The study provides evidence that proteinuric chronic renal failure may increase plasma metal levels where blood MT2A could be a marker. Full article

Background. Intrarenal resistive index (RI) ≥ 0.80 predicts renal outcomes in proteinuric chronic kidney disease (CKD). However, this evidence in non-proteinuric patients with CKD of unknown etiology is lacking. In this study, we assessed the effect of intrarenal RI on renal function and all-cause mortality in non-proteinuric patients with CKD of unknown etiology despite an extensive diagnostic work-up. Methods. Non-proteinuric CKD patients were evaluated in a retrospective longitudinal study. Progression of renal disease was investigated by checking serum creatinine levels at 1, 3, and 5 years and defined by a creatinine level increase of at least 0.5 mg/dL. The discrimination performance of intrarenal RI in predicting the 5-year progression of renal disease was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Results. One-hundred-thirty-one patients (76 ± 9 years, 56% males) were included. The median follow-up was 7.5 years (interquartile range 4.3–10.5) with a cumulative mortality of 53%, and 5-year renal disease progression occurred in 25%. Patients with intrarenal RI ≥ 0.80 had a faster increase of serum creatinine levels compared to those with RI < 0.80 (+0.06 mg/dL each year, 95% CI 0.02–0.10, p < 0.010). Each 0.1-unit increment of intrarenal RI was an independent determinant of 5-year renal disease progression (odds ratio 4.13, 95% CI 1.45–12.9, p = 0.010) and predictor of mortality (hazards ratio 1.80, 95% CI 1.05–3.09, p = 0.034). AUROCs of intrarenal RI for predicting 5-year renal disease progression and mortality were 0.66 (95% CI 0.57–0.76) and 0.67 (95% CI 0.58–0.74), respectively. Conclusions. In non-proteinuric patients with CKD of unknown etiology, increased intrarenal RI predicted both a faster decline in renal function and higher long-term mortality, but as a single marker, it showed poor discrimination performance. Full article

Chronic Kidney Disease of unknown origin (CKDu) has appeared across Sri Lanka’s North Central Province (NCP) since the 1990s as an epidemic, unexplained by conventional associated risk factors. During the past few decades, a large number of studies attempted to determine the unknown etiology of CKDu. Despite these investigations, no concrete conclusions were developed, though a number of contradictory hypotheses emerged. The present ethnographic study was carried out in two endemic areas, labelled as “CKDu hotspots”, and illuminates how curing takes place between biomedicine and traditional cultural practices. Our ethnographic study thoroughly scrutinized three decades of lived experience, lay-perceptions and local discourses on CKDu. We used a qualitative study design with a transcendental phenomenological approach and employed a mixture of ethnographic methods. Data collection techniques included participant observation, in-depth interviews, focus group discussions and key informant interviews. Data was analysed by using an interpretive thematic analysis model. Findings revealed that lay people have constructed a popular discourse on CKDu, and we explored their views on the origin, etiology and prevalence of CKDu in their locality over the past few decades. Patients’ narratives revealed that there were currently a number of gaps in service delivery. These were mainly due to distant relationships between healthcare providers and CKDu patients. Lay people in affected communities were marginalized throughout the investigation process to determine the unknown etiology, their involvement marginalized to merely acting as objects for scientific instigation. The affected communities strongly believed that CKDu was a recent phenomenon resulting from the mismanagement of the natural environment due to social and lifestyle changes. These findings highlight local dynamics of healthcare seeking behaviours which demand complementary medicine system, particularly given the number of limitations in the biomedical system. Empirical evidence generated from this study suggests a conceptual shift to an ethno-medical model to address CKDu. Improving cultural competency and communication skills among healthcare providers in public health are crucial in order to apply a “bio-psychosocial perspective” in healthcare delivery system and bridging the gap between hospital and the community. Full article

CKDu needs to be characterized in fundamental areas to improve etiological understanding and disease management. In a cross-sectional study, blood cell profile and plasma inflammatory cytokines were followed by automated analysis and sandwich ELISA, respectively. Disease development stages and proteinuria were ascertained by eGFR and UACR. Comparison among control and stages (ANOVA/Dunnett’s MRT) revealed time-specific changes (p < 0.05), including decreased erythrocytes (G5) and hematocrit (G5), and increased MCHC (G3b, G4), MCV (G5), and MCH (G5). CKDu decreased (p < 0.05) lymphocytes (G3b, G4, G5), monocytes (G3b), MPV (G3b, G4, G5), and plateletcrit (G3b, G4), and increased basophils (G3a, G3b, G4), N/L (G4) and PLR (G4–G5). MCHC and aforesaid leukocyte variables were in correlation (rho > ±0.03, p < 0.05, Pearson’s test) with disease development. MCP-1 and IL-6 spiked (p > 0.05) at G3b. Multivariate analyses confirmed that MCP-1, lymphocytes, and BMI were related to renal dysfunction, pointing to inflammation, compromised immunity, and muscle wasting as CKDu effects. Nonproteinuric CKDu was prevalent (23.2–35.6% of total CKDu) with (p < 0.05) elevated basophils (G3a), N/L (G4), and depleted lymphocytes (G4). In both forms, G1–G2 were unaffected, and the earliest change was G3a basophils. Results suggest that MCP-1, lymphocyte count, N/L, and PLR may verify the stage and predict impending ESRD in advance proteinuric CKDu. Full article