Production of Acetylcholine by Podocytes and its Protection from Kidney Injury in Glomerulonephritis.

BACKGROUND: One of the most important factors modulating endothelial health is acetylcholine, and while it is associated as a cholinergic neurotransmitter; it is also expressed by non-neuronal cells. However, its role in the kidney, which does not receive cholinergic innervation, remains unknown. METHODS: To determine if acetylcholine is produced in the kidney, we used ChAT(BAC)-eGFP (ChAT mice) transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed under the control of the endogenous choline acetyltransferase (ChAT) transcriptional regulatory elements. We then investigated the role of acetylcholine in kidney disease by inducing anti- glomerular basement membrane glomerulonephritis (anti-GBM GN) in ChAT transgenic mice. RESULTS: We demonstrate ChAT, the sole enzyme responsible for acetylcholine production, was expressed in glomerular podocytes and produced acetylcholine. We also show during anti-GBM GN in ChAT transgenic mice, ChAT expression was induced in the glomeruli, mainly in podocytes and protects mice from kidney injury with marked reduction of glomerular proliferation/fibrinoid necrosis (by 71%) crescent formation (by 98%), and tubular injury (by 78%). In contrast, specific knockout of podocyte ChAT worsened the severity of the disease. The mechanism of protection included reduction of inflammation, attenuation of angiogenic factors reduction, and increase of eNOS expression. In vitro and in vivo studies demonstrated available drugs like cholinesterase inhibitors and ChAT inducers increased the expression of podocyte-ChAT and acetylcholine production. CONCLUSIONS: These findings suggest de novo synthesis of acetylcholine by podocytes protected against inflammation and glomerular endothelium damage in anti-GBM glomerulonephritis.

Role of the Immune System in Hypertension.

High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system. Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation. Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance. Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease.

Intranasal Administration of Sugarcane Ash Causes Chronic Kidney Disease in Rats.

Background. Silica nanoparticles found in sugarcane ash have been postulated to be a toxicant contributing to chronic kidney disease of unknown etiology (CKDu). However, while the administration of manufactured silica nanoparticles is known to cause chronic tubulointerstitial disease in rats, the effect of administering sugarcane ash on kidney pathology remains unknown. Here we investigate whether sugarcane ash can induce CKD in rats. Methods. Sugarcane ash was administered for 13 weeks into the nares of rats (5 mg/day for 5d/week), and blood, urine and kidney tissues were collected at 13 weeks (at the end of ash administration) and in a separate group of rats at 24 weeks (11 weeks after stopping ash administration). Kidney histology was evaluated, and inflammation and fibrosis (collagen deposition) measured. Results. Sugarcane ash exposure led to the accumulation of silica in the kidneys, lungs, liver and spleen of rats. Mild proteinuria developed although renal function was largely maintained. However, biopsies showed focal glomeruli with segmental glomerulosclerosis, and tubulointerstitial inflammation and fibrosis that tended to worsen even after the ash administration had been stopped. Staining for the lysosomal marker, LAMP-1, showed decreased staining in ash administered rats consistent with lysosomal activation. Conclusion. Sugarcane ash containing silica nanoparticles can cause CKD in rats.

Controversies and practical management of patients with gout and chronic kidney disease.

Uric acid is a toxin retained with advancing kidney disease. Clinical manifestations of hyperuricemia include gout and systemic inflammation that are associated with increased risk of cardiovascular mortality. As many as one-third of all patients with chronic kidney disease have a history of gout, yet <25% of these patients are effectively treated to target serum urate levels of ≤6 mg/dl. A major reason for ineffective management of gout and hyperuricemia is the complexity in managing these patients, with some medications contraindicated and others requiring special dosing, potential drug interactions, and other factors. Consequently, many nephrologists do not primarily manage gout despite it being a common complication of chronic kidney disease, leaving management to the primary physician or rheumatologist. We believe that kidney specialists should consider gout as a major complication of chronic kidney disease and actively manage it in their patients. Here, we present insights from nephrologists and rheumatologists for a team approach to gout management that includes the nephrologist.

Health burden of sugarcane burning on agricultural workers and nearby communities.

Sugarcane is the most widely cultivated crop in the world, with equatorial developing nations performing most of this agriculture. Burning sugarcane is a common practice to facilitate harvest, producing extremely high volumes of respirable particulate matter in the process. These emissions are known to have deleterious effects on agricultural workers and nearby communities, but the extent of this exposure and potential toxicity remain poorly characterized. As the epidemicof chronic kidney disease of an unknown etiology (CKDu) and its associated mortality continue to increase along with respiratory distress, there is an urgent need to investigate the causes, determine viable interventions to mitigate disease andimprove outcomes for groups experiencing disproportionate impact. The goal of this review is to establish the state of available literature, summarize what is known in terms of human health risk, and provide recommendations for what areas should be prioritized in research.

A longitudinal assessment of heat exposure and biomarkers of kidney function on heat shock protein 70 and antibodies among agricultural workers.

BACKGROUND: Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by hot temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body's cellular response to a hot environment. OBJECTIVE: This longitudinal study investigated the impact of elevated temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. METHODS: We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. RESULTS: At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices, heat index, and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (ß: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. CONCLUSIONS: These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.

Differential Rates of Glycation Following Exposure to Unique Monosaccharides.

A complication of reducing sugars is that they can undergo Maillard chemical reactions, forming advanced glycation end-products (AGEs) that can induce oxidative stress and inflammation via engagements with the main receptor for AGEs (RAGE) in various tissues. Certain sugars, such as glucose and fructose, are well known to cause AGE formation. Recently, allulose has emerged as a rare natural sugar that is an epimer of fructose and which is of low caloric content that is minimally metabolized, leading to it being introduced as a low-calorie sugar alternative. However, the relative ability of allulose to generate AGEs compared to glucose and fructose is not known. Here we assess the accumulation of AGEs in cell-free, in vitro, and in vivo conditions in response to allulose and compare it to glycation mediated by glucose or fructose. AGEs were quantified in cell-free samples, cell culture media and lysates, and rat serum with glycation-specific ELISAs. In cell-free conditions, we observed concentration and time-dependent increases in AGEs when bovine serum albumin (BSA) was incubated with glucose or fructose and significantly less glycation when incubated with allulose. AGEs were significantly elevated when pulmonary alveolar type II-like cells were co-incubated with glucose or fructose; however, significantly less AGEs were detected when cells were exposed to allulose. AGE quantification in serum obtained from rats fed a high-fat, low-carb (HFLC) Western diet for 2 weeks revealed significantly less glycation in animals co-administered allulose compared to those exposed to stevia. These results suggest allulose is associated with less AGE formation compared to fructose or glucose, and support its safety as a low-calorie sugar alternative.

CYSTOCENTESIS AND URINALYSIS IN ZOOMEDICINE: AN UNDERESTIMATED TOOL FOR LARGE FELID STANDARD HEALTH CHECKS.

Chronic kidney disease (CKD) is a prevalent disease among felids; yet its origin is still poorly understood, and the disease often remains asymptomatic for years, underscoring the need for early diagnosis. This study aimed to investigate the diagnostic value of urinalysis in accurately staging CKD, particularly as routine health checks in large felids often overlook its significance. In this research, ultrasound-guided cystocentesis (UGC) was performed on 50 captive nondomestic felids during routine veterinary health checks under general anesthesia. Urinalysis included microscopic examination of the sediment, measurement of urine specific gravity (USG) and protein to creatinine ratio (UPC). Additional serum kidney markers, such as creatinine and symmetric dimethylarginine, were compared with USG and UPC to assess their diagnostic value as urinary biomarkers. The results demonstrated proteinuria (UPC > 0.4) or borderline proteinuria (UPC 0.2-0.4) in 49% of the animals. Among these cases, 62% were of renal origin, and 38% were postrenal causes. USG was significantly higher in felids with borderline proteinuria compared to those with proteinuria. A moderate, but significant negative correlation between serum parameters and USG was observed, emphasizing the importance of assessing both diagnostic parameters during kidney evaluations. Additionally, felids with CKD have an increased risk of urinary tract infections, necessitating microscopic urinalysis and bacterial culture analysis. Abnormalities, including hematuria, pyuria, crystalluria, and bacteriuria, were found in approximately 38% of cases through microscopical examination of urine. No complications associated with UGC were observed and abnormal findings were detected in 60% of the cases. Based on these results, the authors recommend the inclusion of UGC and urinalysis as standard diagnostic tools in general health checks for nondomestic felids. This approach provides valuable insights into the early detection and staging of CKD, supporting early intervention and supportive medical care to prolong renal health in these animals.

Fructose: A New Variable to Consider in SIADH and the Hyponatremia Associated With Long-Distance Running?

Fructose has recently been proposed to stimulate vasopressin secretion in humans. Fructose-induced vasopressin secretion is not only postulated to result from ingestion of fructose-containing drinks but may also occur from endogenous fructose production via activation of the polyol pathway. This raises the question of whether fructose might be involved in some cases of vasopressin-induced hyponatremia, especially in situations where the cause is not fully known such as in the syndrome of inappropriate secretion of diuretic hormone (SIADH) and exercise-associated hyponatremia, which has been observed in marathon runners. Here we discuss the new science of fructose and vasopressin, and how it may play a role in some of these conditions, as well as in the complications associated with rapid treatment (such as the osmotic demyelination syndrome). Studies to test the role of fructose could provide new pathophysiologic insights as well as novel potential treatment strategies for these common conditions.

Climate change and nephrology.

Climate change should be of special concern for the nephrologist, as the kidney has a critical role in protecting the host from dehydration, but it is also a favorite target of heat stress and dehydration. Here we discuss how rising temperatures and extreme heat events may affect the kidney. The most severe presentation of heat stress is heat stroke, which can result in severe electrolyte disturbance and both acute and chronic kidney disease (CKD). However, lesser levels of heat stress also have multiple effects, including exacerbating kidney disease and precipitating cardiovascular events in subjects with established kidney disease. Heat stress can also increase the risk for kidney stones, cause multiple electrolyte abnormalities and induce both acute and chronic kidney disease. Recently there have been multiple epidemics of CKD of uncertain etiology in various regions of the world, including Mesoamerica, Sri Lanka, India and Thailand. There is increasing evidence that climate change and heat stress may play a contributory role in these conditions, although other causes, including toxins, could also be involved. As climate change worsens, the nephrologist should prepare for an increase in diseases associated with heat stress and dehydration.

Lessons from evolution by natural selection: An unprecedented opportunity to use biomimetics to improve planetary health.

Planetary health embraces the concept that long-term human welfare depends on the well-being of its ecological systems. Current practices, however, have often ignored this concept and have led to an anthropocentric world, with the consequence of increased greenhouse gas emissions, heat stress, lack of clean water and pollution, that are threatening the environment as well as the health and life of Homo sapiens and many other species. One consequence of environmental stressors has been the stimulation of inflammatory and oxidative stress that may not only promote common lifestyle diseases, but the ageing process. Despite the harshness of the current reality, treatment opportunities may exist 'in our backyard'. Biomimicry is an emerging field of research that explores how nature is structured and aims to mimic ingenious solutions that have evolved in nature for different applications that benefit human life. As nature always counteracts excesses from within, biodiversity could be a source of solutions that have evolved through the natural selection of animal species that have survived polluted, warm, and arid environments - i.e. the same presumptive changes that now threaten human health. One example from the emerging science suggests that animals use the cytoprotective Nrf2 antioxidant pathway to combat environmental stress and this may be a case example that we can apply to better human health. Learning from nature may provide opportunities for environmental management and solutions to the most challenging issue that face the future of the planet.

Inhaled silica nanoparticles cause chronic kidney disease in rats.

Silica nanoparticles (SiNPs) released during the burning of sugarcane have been postulated to have a role in chronic kidney disease of unknown etiology. We tested the hypothesis that pristine SiNPs of the size present in sugarcane might cause chronic kidney injury when administered through the lung in rats. We administered 200- or 300-nm amorphous SiNPs twice weekly (4 mg/dose), or vehicle by oropharyngeal aspiration for 13 wk to rats followed by euthanasia after an additional 13 wk (26 wk total). Tissues were evaluated for the presence of SiNPs and evidence of histological injury. Both sizes of SiNPs caused kidney damage, with early tubular injury and inflammation (at week 13) that continued to inflammation and chronic fibrosis at week 26 despite discontinuation of the SiNP administration. Both sizes of SiNPs caused local inflammation in the lung and kidney and were detected in the serum and urine at week 13, and the 200-nm particles were also localized to the kidney with no evidence of retention of the 300-nm particles. At week 26, there was some clearance of the 200-nm silica from the kidneys, and urinary levels of SiNPs were reduced but still significant in both 200- and 300 nm-exposed rats. In conclusion, inhaled SiNPs cause chronic kidney injury that progresses despite stopping the SiNP administration. These findings support the hypothesis that human exposure to amorphous silica nanoparticles found in burned sugarcane fields could have a participatory role in chronic kidney disease of unknown etiology.NEW & NOTEWORTHY Inhalation of silica nanoparticles (SiNPs) released during the burning of sugarcane has been postulated to have a role in chronic kidney disease of unknown etiology (CKDu). We administered 200- and 300-nm amorphous SiNPs to rats by aspiration and observed kidney damage with tubular injury and inflammation that persisted even after stopping the SiNP exposure. These findings support the hypothesis that human exposure to SiNPs found in sugarcane ash could have a participatory role CKDu.

Sirtuin deficiency and the adverse effects of fructose and uric acid synthesis.

Fructose metabolism and hyperuricemia have been shown to drive insulin resistance, metabolic syndrome, hepatic steatosis, hypertension, inflammation, and innate immune reactivity in experimental studies. We suggest that these adverse effects are at least in part the result of suppressed activity of sirtuins, particularly Sirtuin1. Deficiency of sirtuin deacetylations is a consequence of reduced bioavailability of its cofactor nicotinamide adenine dinucleotide (NAD+). Uric acid-induced inflammation and oxidative stress consume NAD+ and activation of the polyol pathway of fructose and uric acid synthesis also reduces the NAD+-to-NADH ratio. Variability in the compensatory regeneration of NAD+ could result in variable recovery of sirtuin activity that may explain the inconsistent benefits of treatments directed to reduce uric acid in clinical trials. Here, we review the pathogenesis of the metabolic dysregulation driven by hyperuricemia and their potential relationship with sirtuin deficiency. In addition, we discuss therapeutic options directed to increase NAD+ and sirtuins activity that may improve the adverse effects resulting from fructose and uric acid synthesis.

Prevalence and Outcomes Associated with Hyperuricemia in Hospitalized Patients with COVID-19.

INTRODUCTION: Coronavirus 2019 (COVID-19) can increase catabolism and result in hyperuricemia. Uric acid (UA) potentially causes kidney damage by alteration of renal autoregulation, inhibition of endothelial cell proliferation, cell apoptosis, activation of the pro-inflammatory cascade, and crystal deposition. Hyperuricemia in patients with COVID-19 may contribute to acute kidney injury (AKI) and poor outcomes. METHODS: We included 834 patients with COVID-19 who were >18 years old and hospitalized for >24 h in the Mount Sinai Health System and had at least 1 measurement of serum UA. We examined the association between the first serum UA level and development of acute kidney injury (AKI, defined by KDIGO criteria), major adverse kidney events (MAKE, defined by a composite of all-cause in-hospital mortality or dialysis or 100% increase in serum creatinine from baseline), as well as markers of inflammation and cardiac injury. RESULTS: Among the 834 patients, the median age was 66 years, 42% were women, and the median first serum UA was 5.9 mg/dL (interquartile range 4.5-8.8). Overall, 60% experienced AKI, 52% experienced MAKE, and 32% died during hospitalization. After adjusting for demographics, comorbidities, and laboratory values, a doubling in serum UA was associated with increased AKI (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.9-4.1), MAKE (OR 2.5, 95% CI 1.7-3.5), and in-hospital mortality (OR 1.7, 95% CI 1.3-2.3). Higher serum UA levels were independently associated with a higher level of procalcitonin (ß, 0.6; SE 0.2) and troponin I (ß, 1.2; SE 0.2) but were not associated with serum ferritin, C-reactive protein, and interleukin-6. CONCLUSION: In patients admitted to the hospital for COVID-19, higher serum UA levels were independently associated with AKI, MAKE, and in-hospital mortality in a dose-dependent manner. In addition, hyperuricemia was associated with higher procalcitonin and troponin I levels.

Uric acid levels in adult patients with severe eating disorders.

OBJECTIVE: To investigate serum uric acid (UA) levels in patients with extreme forms of eating disorders, at admission and discharge, following weeks of nutritional rehabilitation and weight restoration. METHOD: This observational study enrolled 160 patients diagnosed with anorexia nervosa restricting subtype (AN-R), AN binge-purge subtype (AN-BP), or avoidant restrictive food intake disorder (ARFID). Serum UA levels were drawn on admission and discharge. RESULTS: Most of the cohorts were admitted with serum UA levels on the lower end of normal. Mean serum uric level for women was 4.3 mg/dl (SD: 2.3). Patients diagnosed with AN-BP had significantly higher UA levels on admission compared to patients with AN-R and ARFID; p < .0001, η2  = 0.13. High UA levels positively correlated with purging and admission serum blood urea nitrogen (r = .5, p = .009). DISCUSSION: Serum UA levels tended to be in the low-normal range in most patients with severe AN-R, but not in AN-BP. However, levels did increase with nutritional intake and weight gain. There may be clinical value in checking UA levels on admission for patients with eating disorders.

Manipulating the exposome to enable better ageing.

The sum total of life course exposures creates an exposome that has a significant impact on age-related health. Understanding the interplay between exposome factors and the (epi) genome, offers pertinent insights into the ageing process and its relationship with the accumulation of allostatic load. We propose to exploit this to develop a biomimetic approach that will provide insight into how evolution through natural selection in other species has solved many age related human health issues. In particular, we will emphasise the need to reconnect a more mechanistic approach to medical science with a broader natural sciences approach, using biomimetics to mitigate the global burden of age related ill health. In particular, we will discuss how such an approach indicates leverage of the activities of the Nrf 2 gene to enhance health span via reintroduction of the classical 'Food as Medicine' concept, including modulation of the microbiome and the creation of more salutogenic and biophilic environments. Additionally, we will discuss how this approach integrates with novel and developing senotherapies.

Does gouty nephropathy exist, and is it more common than we think?

Gout is present in one third of subjects with CKD but is usually an exclusion criterion in clinical trials investigating the role of uric acid in kidney disease. Bardin et al. report that one third of gouty subjects have hyperechoic medullas by ultrasound (consistent with crystalline deposits) that correlates with increased risk for hypertension and kidney dysfunction and which were not observed in >500 controls. If validated, a "gouty nephropathy" from microcrystalline deposits could be an important, unrecognized cause of CKD.

Lean NAFLD: an underrecognized and challenging disorder in medicine.

Classically, Non-Alcoholic Fatty Liver Disease (NAFLD) has been thought to be driven by excessive weight gain and obesity. The overall greater awareness of this disorder has led to its recognition in patients with normal body mass index (BMI). Ongoing research has helped to better understand potential causes of Lean NAFLD, the risks for more advanced disease, and potential therapies. Here we review the recent literature on prevalence, risk factors, severity of disease, and potential therapeutic interventions.

Mini Review: Reappraisal of Uric Acid in Chronic Kidney Disease.

Hyperuricemia predicts the development of chronic kidney disease (CKD) and metabolic complications, but whether it has a causal role has been controversial. This is especially true given the 2 recently conducted randomized controlled trials that failed to show a benefit of lowering uric acid in type 1 diabetes-associated CKD and subjects with stage 3-4 CKD. While these studies suggest that use of urate-lowering drugs in unselected patients is unlikely to slow the progression of CKD, there are subsets of subjects with CKD where reducing uric acid synthesis may be beneficial. This may be the case in patients with gout, hyperuricemia (especially associated with increased production), and urate crystalluria. Here, we discuss the evidence and propose that future clinical trials targeting these specific subgroups should be performed.

Fructose and Uric Acid as Drivers of a Hyperactive Foraging Response: A Clue to Behavioral Disorders Associated with Impulsivity or Mania?

Several behavioral disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and aggressive behaviors are linked with sugar intake and obesity. The reason(s) for this association has been unclear. Here we present a hypothesis supporting a role for fructose, a component of sugar and high fructose corn syrup (HFCS), and uric acid (a fructose metabolite), in increasing the risk for these behavioral disorders. Recent studies have shown that the reason fructose intake is strongly associated with development of metabolic syndrome is that fructose intake activates an evolutionary-based survival pathway that stimulates foraging behavior and the storage of energy as fat. While modest intake may aid animals that would like to store fat as a protective response from food shortage or starvation, we propose that high intake of sugar and HFCS causes a hyperactive foraging response that stimulates craving, impulsivity, risk taking and aggression that increases the risk for ADHD, bipolar disease and aggressive behavior. High glycemic carbohydrates and salty foods may also contribute as they can be converted to fructose in the body. Some studies suggest uric acid produced during fructose metabolism may mediate some of these effects. Chronic stimulation of the pathway could lead to desensitization of hedonic responses and induce depression. In conclusion, a hyperactive foraging response driven by high glycemic carbohydrates and sugars may contribute to affective disorders.