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Mechanisms by Which Dehydration May Lead to Chronic Kidney Disease

Authors:
Carlos A Roncal at University of Colorado
Carlos A Roncal
Miguel Lanaspa at University of Colorado
Miguel Lanaspa
T Jensen
T Jensen
T Jensen
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Laura Gabriela Sánchez-Lozada at National Institute of Cardiology
Laura Gabriela Sánchez-Lozada
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Abstract and Figures

Dehydration, a condition that characterizes excessive loss of body water, is well known to be associated with acute renal dysfunction; however, it has largely been considered reversible and to be associated with no long-term effects on the kidney. Recently, an epidemic of chronic kidney disease has emerged in Central America in which the major risk factor seems to be recurrent heat-associated dehydration. This has led to studies investigating whether recurrent dehydration may lead to permanent kidney damage. Three major potential mechanisms have been identified, including the effects of vasopressin on the kidney, the activation of the aldose reductase-fructokinase pathway, and the effects of chronic hyperuricemia. The discovery of these pathways has also led to the recognition that mild dehydration may be a risk factor in progression of all types of chronic kidney diseases. Furthermore, there is some evidence that increasing hydration, particularly with water, may actually prevent CKD. Thus, a whole new area of investigation is developing that focuses on the role of water and osmolarity and their influence on kidney function and health. © 2015 S. Karger AG, Basel.
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... This is where an increase in serum osmolality causes movement of water out of the intracellular compartment by osmosis, leading to cell shrinkage and the subsequent release of the hormone arginine vasopressin (AVP). An increase in circulating AVP is thought to be a key mechanism by which hypohydration may increase renal injury (Sugiura et al. 1999;Roncal-Jimenez et al. 2015;García-Arroyo et al. 2017;Mansour et al. 2019;Butler-Dawson et al. 2020). Though it is a limitation of the present study that AVP (or it is more stable surrogate: copeptin) was not measured, an increase in serum osmolality is the primary stimulus for the release of AVP, and thus, AVP concentrations have been shown to correlate with serum and urine osmolality (Robertson et al. 1973). ...
... animal models and in vitro experiments on human cells, with no known biomarker capable of quantifying the activation of this pathway in vivo in humans (Chapman et al. 2020). A third potential mechanism via which hypohydration may increase renal injury is by hyperuricemia (Roncal-Jimenez et al. 2015. However, in the present study, there was no difference between trials with regards to serum uric acid concentrations. ...
... However, in the present study, there was no difference between trials with regards to serum uric acid concentrations. Therefore, this mechanism is likely to be more relevant to exercise-induced hypohydration, where muscle damage and a significant decrease in renal blood flow (Poortmans 1984) may increase uric acid production and impair uric acid excretion, respectively (Knochel et al. 1974;Roncal-Jimenez et al. 2015). ...
24 h severe fluid restriction increases a biomarker of renal injury in healthy males
Article
Full-text available
  • Mar 2025
  • EUR J APPL PHYSIOL
Purpose Exercise-induced hypohydration exacerbates biomarkers of renal injury, but studies isolating the effects of hypohydration without exercise have produced mixed findings. This study investigated the effects of 24-h severe fluid restriction on biomarkers of renal injury and glucose tolerance. Methods Fifteen males (age: 27 ± 5 y; BMI: 24.1 ± 3.8 kg/m²) completed two randomised trials, involving consuming either 40 mL/kg body mass water to maintain euhydration (EU) or severe fluid restriction via limiting water consumption to 100 mL (HYP). A standardised dry food diet was consumed in both trials (~ 300 g water). At baseline and 24 h post-baseline, nude body mass, and blood and urine samples (additional urine sample at 12 h) were collected. An oral glucose tolerance test was conducted after 24-h post-baseline measurements (n = 12). Results At 24 h, body mass loss (HYP: − 1.52 ± 0.34%, EU: − 0.24 ± 0.40%), plasma volume loss, serum, and urine osmolality were greater in HYP than EU (P ≤ 0.004). Osmolality-corrected urinary kidney injury molecule-1 (uKIM-1) concentrations were greater in HYP at 12 (HYP: 1.097 ± 0.587 ng/mOsm, EU: 0.570 ± 0.408 ng/mOsm; P < 0.001) and 24-h (HYP: 1.932 ± 1.173 ng/mOsm, EU: 1.599 ± 1.012 ng/mOsm; P = 0.01). There was no trial-by-time interactions for osmolality-corrected urinary neutrophil gelatinase-associated lipocalin concentrations (P = 0.781) or plasma glucose (P = 0.550) and insulin (P = 0.193) concentrations. Conclusion Hypohydration produced by 24-h fluid restriction increased proximal tubular injury but did not affect glucose tolerance.
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... The developed brown color was measured at 540 nm. ALT activity was stated in IU/L [22,23]. ...
... The developed brown color was measured at 540 nm. AST activity was expressed in IU/L [22,23]. ...
Role of traditional and new biomarkers in the assessment of chronic kidney diseases: a comprehensive analysis of the biochemical, molecular and clinical dimensions
Article
Full-text available
  • Apr 2025
  • MOL BIOL REP
Background Kidney function is necessary for the diagnosis and treatment of renal diseases. Traditional biomarkers like creatinine have limitations due to their susceptibility to interference and fluctuation. This study's objective is to test and compare the efficacy of conventional and innovative biomarkers in evaluating kidney function and disease. Methods We looked at creatinine, cystatin C, parathyroid hormone (PTH), electrolytes, interleukin-6 (IL-6), C-reactive protein (CRP), the APA I gene, and kidney injury molecule-1 (KIM-1). The present study focused on the stability, sensitivity, and specificity of biomarkers using a combination of traditional and innovative analytical techniques. Results Present results showed that creatinine, although commonly used as a measure, frequently overestimates renal function as a result of chromogenic interference. On the other hand, cystatin C showed better sensitivity and was less reliant on influences outside the kidneys. Kidney biomarkers, such as KIM-1, exhibit the potential for identifying acute kidney injury at an early stage. Furthermore, there was a positive correlation between increased levels of CRP and PTH and the progression of kidney disease to more advanced stages. Conclusion This study emphasizes the importance of combining traditional and new biomarkers to improve the accuracy of diagnosing and managing kidney illness. The more effective use of biomarkers will result in improved patient outcomes.
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... NIOSH standards 362 recommending water intake every 15-20 minutes were insufficient to prevent 363 dehydration, which worsened despite the provision of water, drinking vessels, and 364 designated breaks (33,44). Regular water intake alone failed to counteract 365 dehydration, a risk factor for AKI (44,55), which is also exacerbated by hyperthermia 366 and physical labor (56). Electrolyte drinks and oral rehydration solution (ORS) have 367 been identified as more effective in replenishing lost fluids and electrolytes, with 368 ORS showing superior fluid retention during exertion (57,58). ...
International Migrant Workers, Heat Exposure, and Climate Change: A Systematic Review of Health Risks and Protective Interventions
Preprint
Full-text available
  • Jun 2025
Background: International migrant workers, representing 170 million people globally, often face hazardous working conditions, including extreme heat exposure. This increases their risk of occupational heat strain, exacerbated by poor working conditions. This systematic review aims to identify the health risks of occupational heat exposure among international migrant workers globally, and document existing protective interventions and measures, in order to inform policies that protect this vulnerable population. Methods: We searched four electronic databases (Medline, Embase, Ovid Global Health and PsychINFO) for primary research studies (January 2014 to April 2024) on international migrant workers experiencing adverse health outcomes following high working temperatures. Records were screened, and data extracted by two independent reviewers. Assessment of study quality was done using Joanna-Briggs Institute checklists. Results were synthesised narratively and reported following PRISMA 2020 guidelines. The protocol was registered in PROSPERO (CRD42024519547). Results: Of the 646 records screened, 19 studies involving 2,322 migrant workers across six countries were included in the analysis, with most studies from high-income countries (n=14, 74%), mainly the USA. Studies focused on workers in construction (48%) and agriculture (42%), with migrant workers originating from 14 countries, predominantly India, Mexico, and Nepal. Reported health outcomes included heat-related illnesses (n=12), dehydration (n=5), kidney disease (n=2), and poor skin health (n=2). Common symptoms included headaches, muscle cramps, and heavy sweating. Interventions focused on water, rest, shade, skin protection, and education, but evaluations were limited and some measures failed to address heat exposure effectively. Conclusions: Occupational heat exposure poses significant health risks for international migrant workers. Where interventions exist, barriers to effectiveness remain, with a knowledge gap as to the situation in low- and middle- income countries. Amid rising global temperatures improved worker education, worker-tailored and co-designed interventions, updated protocols, and increased healthcare accessibility are urgently needed.
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... Previous studies have indicated the sufficient water intake is essential for healthy kidney function, and dehydration can aggravate kidney disease [18]. Dehydration is generally seen a short-term, reversible condition linked to acute renal disease and does not cause chronic kidney disease [19]. Chronic kidney disease on the other hand, is associated with chronic dehydration particularly in farming societies where prolonged exposure to heat is common [20]. ...
Assessing the Effects of Water Quality and Intake on Chronic kidney Disease Progression in Western Libya
Article
Full-text available
  • May 2025
Chronic kidney disease (CKD) has become a worldwide health problem driven by both identified and obscure causes. Besides the well-known causes of CKD, such as uncontrolled diabetes and hypertension, the quality of drinking water, particularly the hardness level, has been suggested by researchers as one of the causes of CKD. Monitoring and improving drinking water quality and quantity for CKD patients could delay the progression of kidney impairment. This cross-sectional study aims to evaluate the impact of water quality and quantity on the progression of CKD by analyzing biochemical parameters, serum electrolytes, and estimated glomerular filtration rate (e-GFR) in CKD patients. The study includes 106 CKD patients, comprising 50.9% males and 49.1% females. Among the study participants, over 40% were aged above 60 years. The majority (71.7%) consumed Reverse Osmosis (RO) water, while 28.3% drank well water. Regarding water intake, 52.8% of participants consumed one to two liters daily. Most participants (68%) had stage 4 CKD based on e-GFR. Urea and creatinine levels were elevated in both water source groups, though without statistical significance. However, significant differences were observed in serum electrolytes, with higher sodium (p=0.027), phosphate (p=0.025), and potassium (p=0.001) levels in the well water group. Additionally, e-GFR levels are significantly associated with water sources and water intake (chi-square = 0.041 and chi-square = 0.039, respectively). The study revealed that CKD patients consuming RO water and maintaining a moderate daily water intake (1–2 liters) exhibited better kidney function than those drinking well water or consuming significantly higher or lower amounts of water. These findings highlight the importance of both water quality and adequate intake in the clinical management of CKD patients.
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... Kuge et al. [12] supported this relationship in children with acute gastroenteritis. Roncal-Jimenez C et al. [13] proposed that hyperuricemia is one of the mechanisms by which chronic recurrent dehydration leads to chronic kidney disease. Nevertheless, we cannot exclude that other mechanisms are involved in uric acid elevation [14] in patients with nephrotic syndrome: for example, hyperuricemia could simply be an independent indicator of the severity of the disease at onset, and therefore of its ability to respond to therapy. ...
Time to remission in childhood steroid sensitive nephrotic syndrome: a change in perspective
Article
Full-text available
  • Mar 2025
  • Eur J Pediatr
Time to remission (TTR) has been largely considered one of the predictive factors for the risk of relapse and steroid dependency in childhood steroid-sensitive nephrotic syndrome, yet conflicting opinions exist. However, the factors influencing TTR have never been studied. We performed a post-hoc analysis of the prospective pediatric cohort enrolled in a previous multicenter study (ClinicalTrials.gov Id: NCT01386957) to evaluate the possible influence of some clinical and laboratory parameters at INS onset on the timing of TTR. A total of 136 children were evaluated. In simple linear regression models, TTR was directly correlated with serum uric acid, urea, potassium, and urinary protein levels at onset. TTR showed a non-linear inverse correlation with age at onset. A multiple linear regression model of TTR showed that hyperuricemia (p = 0.0000007), non linear age (p = 0.0006) and proteinuria (especially in binary form) (p = 0.02) were significant predictors of TTR, and that there was a significant positive interaction between uricemia and proteinuria as predictors of TTR (p = 0.004). Conclusions: In our analysis, TTR appears to be associated to a nephrotic status at clinical diagnosis characterized by more severe proteinuria and hyperuricemia. Moreover, younger age at onset, notably associated with prognosis, is also associated with a longer TTR. What is Known: • Corticosteroids are the first-line treatment in childhood nephrotic syndrome. • Over the years, time to remission has been considered a potential predictive factor for the risk of relapse and steroid dependency in childhood nephrotic syndrome, with conflicting results. What is New: • Clinical and laboratory parameters at nephrotic syndrome onset are associated with prolonged time to remission in children.
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... As this disease occurs independent of common risk factors such as age, diabetes, and hypertension, it is suspected that environmental factors may be contributing to pathogenesis [12][13][14]. Exposure to agricultural toxicants, heat stress, dehydration, and exertional injury have all been identified as major occupational concerns [15][16][17][18]. Sugarcane ash is one such occupational exposure that has been gaining increased attention as a potential contributor to CKDu [11]. ...
Modulation of the thiol redox proteome by sugarcane ash-derived silica nanoparticles: insights into chronic kidney disease of unknown etiology
Article
Full-text available
  • Feb 2025
Introduction Chronic kidney disease of unknown etiology (CKDu) is an epidemic which is increasingly prevalent among agricultural workers and nearby communities, particularly those involved in the harvest of sugarcane. While CKDu is likely multifactorial, occupational exposure to silica nanoparticles (SiNPs), a major constituent within sugarcane ash, has gained increased attention as a potential contributor. SiNPs have high potential for generation of reactive oxygen species (ROS), and their accumulation in kidney could result in oxidative stress induced kidney damage consistent with CKDu pathology. Methods In order to characterize the impact of sugarcane ash derived (SAD) SiNPs on human kidney proximal convoluted tubule (PCT) cells and identify potential mechanisms of toxicity, HK-2 cells were exposed to treatments of either pristine, manufactured, 200 nm SiNPs or SAD SiNPs and changes to cellular energy metabolism and redox state were determined. To determine how the cellular redox environment may influence PCT cell function and toxicity, the redox proteome was examined using cysteine-targeted click chemistry proteomics. Results Pristine, 200 nm SiNPs induced minimal changes to energy metabolism and proteomic profiles in vitro while treatment with SAD SiNPs resulted in mitochondrial membrane hyperpolarization, inhibited mitochondrial respiration, increased reactive oxygen species generation, and redox proteomic trends suggesting activation of aryl hydrocarbon receptor (AHR) and other signaling pathways with known roles in mitochondrial inhibition and CKD progression. Conclusion Results suggest that PCT cell exposure to SAD SiNPs could promote glycolytic and fibrotic shifts consistent with CKDu pathology via oxidative stress-mediated disruption of redox signaling pathways.
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... According to Yao et al. (2023) and Chou et al. (2023), abnormal kidney functions were linked to high concentrations of microbiological pollutants such as Leptospira interrogans and microcystins. Furthermore, Roncal-Jiménez et al. (2015) state that dehydration caused by inadequate water intake may impact kidney function. Concurrently, several studies, including Imbulana et al. (2021), Wasana et al. (2015), and Gobalarajah et al. (2020), believe that long-term exposure to contaminants in water could be the cause of chronic kidney disease (CKD). ...
Hydrogeochemical Characterization and Source Evaluation of Groundwater Contamination in Parts of the Uddanam CKDu Area, Southern India: Integrating Statistical, Geochemical Modeling, Pollution, and Health Indices
Article
Full-text available
  • Jan 2025
  • INT J ENVIRON RES
Hydrogeochemical characteristics and ionic sources of groundwater contamination were examined to understand the potential health risk factors behind the chronic kidney illness in parts of the Uddanam CKDu area, Southern India. For this, a total of 50 groundwater samples were obtained during the pre and post-monsoon seasons of 2021 and examined for physicochemical metrics. pH, electrical conductivity (EC), and total dissolved solids (TDS) in groundwater were measured with the handheld meter HI991300P. The major ions in groundwater were analyzed using standard procedures by the American Public Health Association (APHA), followed by an ion balance assessment (IBA) to ensure analytical accuracy. Then water quality evaluation encompassing potability, pollution status, its spatial patterns, and human health risks were determined using Bureau of Indian Standards (BIS), pollution index of groundwater (PIG), ArcGIS 10.4 and the United States Environmental Protection Agency (USEPA) guidelines. Moreover, the source evaluation of mineral species and ions was performed using saturation indices (SI) by pH redox equilibrium written in C computer language (PHREEQC) 3.7.3 geochemical model and statistical analysis employed factor analysis (FA) and Pearsons’s correlation matrix using MINTAB22 software. Moreover, conventional graphical diagrams, including Piper, Gibbs and scatter plots, were also portrayed to elucidate the controlling factors of groundwater chemistry and ionic sources. Significant findings of this study are elevated levels of Ca2+, Mg2+, TDS, TH, NO3− and Si in groundwater; High to moderate pollution; High nitrate pollution vulnerability, primarily affecting children followed by women and men; Precipitation of carbonate and silicate minerals; Mixing Ca–Mg–SO4–Cl followed by Ca–Mg–HCO3 water facies; Geological and Anthropogenic influences. Notably, these findings may have critical implications for the prevalence of chronic kidney disease in the Uddanam CKDu region. Hence, before water consumption, proper treatment is necessary. Proper waste disposal facilities can reduce the risk of leaching contaminants. Rainwater recharge through invasive structures may reduce the pollutants through the dilution process. These findings assist researchers and policymakers in developing sustainable water management strategies to prevent potential health risks posed to humans.
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The Exposome and the Kidney: A Silent Dialogue Shaping Chronic Kidney Disease
Article
  • May 2025
Genetic predisposition accounts for less than 20% of the global disease burden, highlighting the substantial role of environmental factors in health outcomes. In chronic kidney disease (CKD), a growing global prevalence, understanding the interplay between genes and the environment is crucial. Emerging research in the exposome and genome underscores how environmental exposures interact with genetic variants to influence the development and progression of CKD. The term “exposome” encompasses a variety of factors, including personal behaviors like smoking, a sedentary lifestyle, and making specific dietary choices (such as consuming ultra-processed foods, sugar, or fat). It also includes broader determinants such as pesticides, air, water, and soil pollution, nanoplastics, global warming, stressful life events, and socioeconomic status. Research on the exposome significantly increases our understanding of toxicological processes and individual variations in susceptibility to environmental stressors. This narrative review aims to explore the exposome associated with CKD, highlight key environmental exposures in its development, and discuss potential preventive and therapeutic strategies informed by these exposure-related factors.
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Airborne particulate matter exposure in male sugarcane workers at risk for chronic kidney disease in Guatemala
Article
  • Mar 2025
Background There is an international epidemic of chronic kidney disease of unknown cause (CKDu) in agricultural working populations. Particulate air pollution is a likely contributing factor in populations at risk for CKDu, but there is little personal breathing zone data for these workers. Methods We collected 1 to 3 personal breathing zone particulate matter <5 microns (PM5) gravimetric measurements in 143 male sugarcane harvesters over 2 seasons and concurrent ambient samples using personal sampling pumps and cyclone inlets as a sampling train. Due to very high concentrations observed during a pilot of these methods, personal breathing zone sampling duration was set to 4 h, beginning either at the start of a work shift (AM) or delayed for 4 h (PM). To obtain full-shift exposure concentrations we calculated 8-h time-weighted average (TWA, in µg/m3) estimates of each worker’s full-shift personal breathing zone PM5 exposure concentration by averaging their individual monitored concentration with the median concentration of the unmonitored AM or PM segment from all workers that day to obtain an 8-h TWA. Results Median full-shift personal TWA PM5 concentrations were 449 μg/m3 (range 20.5 to 1,930 μg/m3), which were much higher than ambient concentrations in these fields (median 136, range 22.5 to 2,360 μg/m3). These findings document very high personal breathing zone PM5 exposure in workers at risk for CKDu: median concentrations for all workers were 3.5 (range <1 to 33.6) times as high as concurrent ambient concentrations. Significance These findings suggest that ambient measurements of particulate matter are insufficient to estimate personal exposure in this population and that personal breathing zone monitoring should be used to fully explore air pollution as a risk factor for CKDu. Given that particulate matter from this source likely has multiple hazardous constituents, future research should focus on characterizing all constituents and explore associations with biomarkers of kidney injury.
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Ambient temperature and wet bulb globe temperature outperform heat index in predicting hydration status and heat perception in a semi-arid environment
Article
Full-text available
  • Feb 2025
Background Climate change is increasing temperatures, frequency of heatwaves, and erratic rainfall, which threatens human biology and health, particularly in already extreme environments. Therefore, it is important to understand how environmental heat stress measures are tied to human water needs and thermoregulation under increasingly hot conditions. Aim To test how ambient temperature, heat index, and wet bulb globe temperature (WBGT) relate to hydration status and thermal heat perception in a hot, semi-arid environment. Subjects and methods Urine samples, perceived heat stress, and anthropometrics were collected among Daasanach semi-nomadic pastoralists (n = 187 children, n = 231 adults) in northern Kenya. Environmental heat stress measures were recorded at sample collection; samples’ urine specific gravity (USG) was measured. Results Multiple linear and logistic regressions indicate that all environmental heat stress measures were associated with USG, odds of dehydration, and heat perception. Ambient temperature performed marginally better than WBGT, and both performed better than heat index. These associations were stronger among children than adults. Conclusion In a hot, semi-arid climate, ambient temperature and WBGT accurately predict human water needs and heat stress, with children more vulnerable to dehydration. To mitigate consequences of extreme heat, local bioculturally-appropriate hydration (e.g. tea) and cooling (e.g. shade) strategies should be encouraged.
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Chronic kidney disease of uncertain aetiology: Prevalence and causative factors in a developing country
Article
Full-text available
  • Aug 2013
  • BMC Nephrol
Background This study describes chronic kidney disease of uncertain aetiology (CKDu), which cannot be attributed to diabetes, hypertension or other known aetiologies, that has emerged in the North Central region of Sri Lanka. Methods A cross-sectional study was conducted, to determine the prevalence of and risk factors for CKDu. Arsenic, cadmium, lead, selenium, pesticides and other elements were analysed in biological samples from individuals with CKDu and compared with age- and sex-matched controls in the endemic and non-endemic areas. Food, water, soil and agrochemicals from both areas were analysed for heavy metals. Results The age-standardised prevalence of CKDu was 12.9% (95% confidence interval [CI] = 11.5% to 14.4%) in males and 16.9% (95% CI = 15.5% to 18.3%) in females. Severe stages of CKDu were more frequent in males (stage 3: males versus females = 23.2% versus 7.4%; stage 4: males versus females = 22.0% versus 7.3%; P < 0.001). The risk was increased in individuals aged >39 years and those who farmed (chena cultivation) (OR [odds ratio] = 1.926, 95% CI = 1.561 to 2.376 and OR = 1.195, 95% CI = 1.007 to 1.418 respectively, P < 0.05). The risk was reduced in individuals who were male or who engaged in paddy cultivation (OR = 0.745, 95% CI = 0.562 to 0.988 and OR = 0.732, 95% CI = 0.542 to 0.988 respectively, P < 0.05). The mean concentration of cadmium in urine was significantly higher in those with CKDu (1.039 μg/g) compared with controls in the endemic and non-endemic areas (0.646 μg/g, P < 0.001 and 0.345 μg/g, P < 0.05) respectively. Urine cadmium sensitivity and specificity were 70% and 68.3% respectively (area under the receiver operating characteristic curve = 0.682, 95% CI = 0.61 to 0.75, cut-off value ≥0.397 μg/g). A significant dose–effect relationship was seen between urine cadmium concentration and CKDu stage (P < 0.05). Urine cadmium and arsenic concentrations in individuals with CKDu were at levels known to cause kidney damage. Food items from the endemic area contained cadmium and lead above reference levels. Serum selenium was <90 μg/l in 63% of those with CKDu and pesticides residues were above reference levels in 31.6% of those with CKDu. Conclusions These results indicate chronic exposure of people in the endemic area to low levels of cadmium through the food chain and also to pesticides. Significantly higher urinary excretion of cadmium in individuals with CKDu, and the dose–effect relationship between urine cadmium concentration and CKDu stages suggest that cadmium exposure is a risk factor for the pathogensis of CKDu. Deficiency of selenium and genetic susceptibility seen in individuals with CKDu suggest that they may be predisposing factors for the development of CKDu.
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Fructokinase activity mediates dehydration-induced renal injury
Article
Full-text available
  • Dec 2013
  • KIDNEY INT
The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.Kidney International advance online publication, 11 December 2013; doi:10.1038/ki.2013.492.
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Uric acid and chronic kidney disease: Which is chasing which?
Article
Full-text available
  • Mar 2013
  • NEPHROL DIAL TRANSPL
Serum uric acid is commonly elevated in subjects with chronic kidney disease (CKD), but was historically viewed as an issue of limited interest. Recently, uric acid has been resurrected as a potential contributory risk factor in the development and progression of CKD. Most studies documented that an elevated serum uric acid level independently predicts the development of CKD. Raising the uric acid level in rats can induce glomerular hypertension and renal disease as noted by the development of arteriolosclerosis, glomerular injury and tubulointerstitial fibrosis. Pilot studies suggest that lowering plasma uric acid concentrations may slow the progression of renal disease in subjects with CKD. While further clinical trials are necessary, uric acid is emerging as a potentially modifiable risk factor for CKD. Gout was considered a cause of CKD in the mid-nineteenth century [1], and, prior to the availability of therapies to lower the uric acid level, the development of end-stage renal disease was common in gouty patients. In their large series of gouty subjects Talbott and Terplan found that nearly 100% had variable degrees of CKD at autopsy (arteriolosclerosis, glomerulosclerosis and interstitial fibrosis) [2]. Additional studies showed that during life impaired renal function occurred in half of these subjects [3]. As many of these subjects had urate crystals in their tubules and interstitium, especially in the outer renal medulla, the disease became known as gouty nephropathy. The identity of this condition fell in question as the presence of these crystals may occur in subjects without renal disease; furthermore, the focal location of the crystals could not explain the diffuse renal scarring present. In addition, many subjects with gout also had coexistent conditions such as hypertension and vascular disease, leading some experts to suggest that the renal injury in gout was secondary to these latter conditions rather than to uric acid per se [4]. Indeed, gout was removed from the textbooks as a cause of CKD, and the common association of hyperuricemia with CKD was solely attributed to the retention of serum uric acid that is known to occur as the glomerular filtration rate falls. Renewed interest in uric acid as a cause of CKD occurred when it was realized that invalid assumptions had been made in the arguments to dismiss uric acid as a risk factor for CKD [5]. The greatest assumption was that the mechanism by which uric acid would cause kidney disease would be via the precipitation as crystals in the kidney, similar to the way it causes gout. However, when laboratory animals with CKD were made hyperuricemic, the renal disease progressed rapidly despite an absence of crystals in the kidney [6]. Since this seminal study, there has been a renewed interest in the potential role uric acid may have in both acute and CKD. We briefly review some of the major advances that have occurred in this field in the last 15 years.
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Disorders of Water Metabolism
Article
  • Jan 2010
Disorders of serum sodium are very frequently encountered particularly in hospitalized elderly patients. Most often these reflect disorders in water balance. This chapter reviews normal water regulation, and how dysregulation culminates in hyponatremic and hypernatremic states. The complications of these electrolyte disorders, particularly as they relate to neurological adaptations and sequelae, are discussed. An approach to the diagnosis, evaluation, and treatment of these disorders is presented with emphasis on assessment of extracellular fluid volume status, interpretation of urinary osmolality and urinary sodium, and calculation of water excess and deficits. The central role of the presence or absence of vasopressin in the pathogenesis and treatment of dysnatremias permeates the entire chapter. © 2013 Springer Science+Business Media New York. All rights are reserved.
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Changes in kidney function among Nicaraguan sugarcane workers
Article
  • Jan 2015
Background: There is an epidemic of chronic kidney disease (CKD) of unknown etiology in Central American workers. Objectives: To investigate changes and job-specific differences in kidney function over a 6-month sugarcane harvest season, explore the potential role of hydration, and measure proteinuria. Methods: We recruited 284 Nicaraguan sugarcane workers performing seven distinct tasks. We measured urine albumin and serum creatinine and estimated glomerular filtration rate (eGFR). Results: eGFR varied by job and decreased during the harvest in seed cutters (-8·6 ml/min/1·73 m(2)), irrigators (-7·4 ml/min/1·73 m(2)), and cane cutters (-5·0 ml/min/1·73 m(2)), as compared to factory workers. The number of years employed at the company was negatively associated with eGFR. Fewer than 5% of workers had albumin-to-creatinine ratio (ACR) >30 mg/g. Conclusions: The decline in kidney function during the harvest and the differences by job category and employment duration provide evidence that one or more risk factors of CKD are occupational.
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Burnt sugarcane harvesting is associated with acute renal dysfunction
Article
  • Sep 2014
Sugarcane harvesting has been associated with an epidemic of chronic kidney disease in Central America mainly affecting previously healthy young workers. Repeated episodes of acute kidney dysfunction are hypothesized to be one of the possible mechanisms for this phenomenon. Therefore, this exploratory study aimed to assess the acute effects of burnt sugarcane harvesting on renal function among 28 healthy non-African Brazilian workers. Urine and blood samples were collected at the beginning and at the end of the harvesting season and before and at the end of a harvesting workday. All individuals decreased their estimated glomerular filtration rate by ∼20% at the end of the daily shift, and 18.5% presented with serum creatinine increases consistent with acute kidney injury. Those changes were associated with increased serum creatine phosphokinase (a known marker for exertional rhabdomyolysis) and oxidative stress-associated malondialdehyde levels, increased peripheral blood white cell counts, decreased urinary and serum sodium, decreased calculated fractional sodium excretion, and increased urine density. Thus, burnt sugarcane harvesting caused acute renal dysfunction in previously healthy workers. This was associated with a combination of dehydration, systemic inflammation, oxidative stress, and rhabdomyolysis.Kidney International advance online publication, 17 September 2014; doi:10.1038/ki.2014.306.
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0401 Repeated pre and post-shift urinalyses show kidney dysfunction among Costa Rican sugarcane cutters exposed to heat stress
Article
  • Jun 2014
Objectives Sugarcane harvesters in Costa Rica are exposed to heat stress, a likely major risk factor in the Mesoamerican nephropathy epidemic. Routine urinalyses provide important information about kidney function, but have not been reported in detail for this population. Method Sugarcane cutters (n = 48) provided six spot urine samples, pre- and post-workshift for three days during one week in mid-harvest. Chemical analyses with dipstick and microscopic examinations of sediment were performed. Changes over the workday in markers for hydration status and kidney responses to heat stress were evaluated with McNemar test on paired proportions. Results Preliminary results indicate percentages of workers with specific parameters in at least one morning versus in at least one afternoon sample were with dipstick: pH ≤5 30% vs 82%, specific gravity ≥1.025 30% vs 51%, proteinuria (1+ and up) 86% vs 8%, and blood (traces and up) 28% vs 12%; and in sediment: >5 leucocytes 76% vs 57%, >3 erythrocytes 50% vs 37%, and casts (granular, leukocyte and some erythrocyte) 75% vs 39%. Except for erythrocytes in sediment, these differences were statistically significant. Conclusions Concentration and acidification of urine over the workday indicate insufficient hydration. Positive blood on dipstick may be a sign of low-grade hematuria or mild rhabdomyolysis. Predominance of proteinuria, leucocytes, erythrocytes and casts in morning urine was unexpected but may reflect improvement in glomerular filtration with hydration overnight or, alternatively, effects from vasopressin at night. This study adds to an increasing body of evidence of kidney dysfunction among heat stress exposed sugarcane workers.
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CKD of Unknown Origin in Central America: The Case for a Mesoamerican Nephropathy
Article
  • Jan 2014
  • AM J KIDNEY DIS
An epidemic of chronic kidney disease of unknown origin has emerged in the last decade in Central America and has been named Mesoamerican nephropathy. This form of chronic kidney disease is present primarily in young male agricultural workers from communities along the Pacific coast, especially workers in the sugarcane fields. In general, these men have a history of manual labor under very hot conditions in agricultural fields. Clinically, they usually present with normal or mildly elevated systemic blood pressure, asymptomatic yet progressive reduction in estimated glomerular filtration rate, low-grade non-nephrotic proteinuria, and often hyperuricemia and or hypokalemia. Diabetes is absent in this population. Kidney biopsies that have been performed show a chronic tubulointerstitial disease with associated secondary glomerulosclerosis and some signs of glomerular ischemia. The cause of the disease is unknown; this article discusses and analyzes some of the etiologic possibilities currently under consideration. It is relevant to highlight that recurrent dehydration is suggested in multiple studies, a condition that possibly could be exacerbated in some cases by other conditions, including the use of nonsteroidal anti-inflammatory agents. At present, Mesoamerican nephropathy is a medical enigma yet to be solved.
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Clinical and Pathological Characterization of Mesoamerican Nephropathy: A New Kidney Disease in Central America
Article
  • Jul 2013
  • AM J KIDNEY DIS
An endemic of chronic kidney disease (CKD) of unknown cause among rural inhabitants in Central America has been identified. Young and otherwise healthy men working in plantations are frequently affected. The name Mesoamerican nephropathy (MeN) has been suggested. Clinically, MeN presents with low-grade proteinuria and progressive kidney failure. The renal pathology of this disease has not yet been described. Case series. 8 male patients with CKD of unknown cause and clinically suspected MeN were recruited from a nephrology unit in El Salvador. All recruited patients had been working on plantations. Kidney biopsies, blood, and urine samples were collected. Renal morphology examined with light microscopy, immunofluorescence, and electron microscopy; clinical and biochemical characteristics. A similar pattern was seen in all 8 biopsy specimens, with extensive glomerulosclerosis (29%-78%) and signs of chronic glomerular ischemia in combination with tubular atrophy and interstitial fibrosis, but only mild vascular lesions. Electron microscopy indicates podocytic injury. Biochemical workup showed reduced estimated glomerular filtration rate (27-79 mL/min/1.73 m(2) with the CKD Epidemiology Collaboration [CKD-EPI] creatinine equation), low-grade albuminuria, and increased levels of tubular injury biomarkers. Hypokalemia was found in 6 of 8 patients. Small number of patients from one country. This study is the first report of the biochemical and morphologic findings in patients with MeN. Our findings indicate that MeN constitutes a previously unrecognized kidney disease with damage to both glomerular and tubulointerstitial compartments.
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