RESUMO
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.
Assuntos
Transtornos de Estresse por Calor , Nefrologia , Insuficiência Renal Crônica , Humanos , Mudança Climática , Desidratação/complicações , Insuficiência Renal Crônica/complicações , Rim , Transtornos de Estresse por Calor/complicaçõesRESUMO
BACKGROUND: Spasticity is a frequent symptom of multiple sclerosis (MS), which may negatively influence daily living activities (ADL). OBJECTIVES: To (1) explore the feasibility to conduct a structured interview by specialist nurses about limitations in ADL; (2) determine the percentage of people with MS (PwMS) with limitations in ADL related to spasticity; (3) to assess the knowledge about spasticity and describe its clinical features. DESIGN: Observational, cross-sectional, multicentre study in 16 MS units of Catalonia (Spain). Participants were recruited from the outpatient facility and day-care hospital between July 2018 and June 2019 and met the following criteria: (1) age 18 or older, (2) diagnosis of MS according to McDonald criteria 2010 and (3) no clinical relapse in previous 30 days. METHODS: Specialist nurses conducted a structured interview divided in two parts: the assessment of (1) limitations in the ADL and (2) the presence of spasticity and associated symptoms. The usefulness of this intervention was requested. This study met the STROBE reporting guidelines checklist for observational studies. RESULTS: Three hundred sixty eight pwMS (244 women) with a mean age of 46 years and a median Expanded Disability Status Scale score of 2.5 (range, 0-8.5) were included. 262 (71%) pwMS had limitations in the ADL, and spasticity was reported as the most limiting symptom in 59 (23%). As a result of the interview, spasticity was observed in 199 (76%) participants; 47 (24%) of them were unaware that they had spasticity and 102 (51%) would not have reported it spontaneously. The level of the interview satisfaction was high (90%). CONCLUSIONS: Spasticity is a complex and limiting symptom in MS. The structured interview conducted by specialist nurses is feasible and has good acceptance. PATIENT CONTRIBUTION: Specialist nurses can be proactive in MS clinical assessment, which may help to detect symptoms with negative impact on quality of life.
Assuntos
Esclerose Múltipla , Espasticidade Muscular , Enfermeiros Especialistas , Esclerose Múltipla/complicações , Enfermeiras e Enfermeiros , Atividades Cotidianas , Qualidade de Vida , Humanos , Masculino , Feminino , Adolescente , Pessoa de Meia-Idade , Espanha , Adulto , Idoso , Estudos TransversaisRESUMO
In this narrative review, we present the hypothesis that key mutations in two genes, occurring 15 and 10 million years ago (MYA), were individually and then collectively adaptive for ancestral humans during periods of starvation, but are maladaptive in modern civilization (i.e., "thrifty genes"), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Both mutations occurred when ancestral apes were experiencing loss of fruit availability during periods of profound climate change or environmental upheaval. The silencing of uricase (urate oxidase) activity 15 MYA enhanced survival by increasing the ability for fructose present in dwindling fruit to be stored as fat, a consequence of enhanced uric acid production during fructose metabolism that stimulated lipogenesis and blocked fatty acid oxidation. Likewise, a mutation in class IV alcohol dehydrogenase ~10 MYA resulted in a remarkable 40-fold increase in the capacity to oxidize ethanol (EtOH), which allowed our ancestors to ingest fallen, fermenting fruit. In turn, the EtOH ingested could activate aldose reductase that stimulates the conversion of glucose to fructose, while uric acid produced during EtOH metabolism could further enhance fructose production and metabolism. By aiding survival, these mutations would have allowed our ancestors to generate more fat, primarily from fructose, to survive changing habitats due to the Middle Miocene disruption and also during the late-Miocene aridification of East Africa. Unfortunately, the enhanced ability to metabolize and utilize EtOH may now be acting to increase our risk for alcoholism, which may be yet another consequence of once-adaptive thrifty genes.
Assuntos
Adaptação Biológica/genética , Álcool Desidrogenase/genética , Alcoolismo/genética , Hominidae/genética , Urato Oxidase/genética , Animais , Evolução Biológica , Mudança Climática , Etanol/metabolismo , Frutose/metabolismo , Hominidae/metabolismo , Humanos , Mutação , Seleção GenéticaRESUMO
Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.
Assuntos
Frutose/metabolismo , Leptina/sangue , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Obesidade/induzido quimicamente , Cloreto de Sódio na Dieta/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Diabetes Mellitus/induzido quimicamente , Frutoquinases/genética , Humanos , Leptina/genética , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/metabolismo , Sacarose/efeitos adversos , Sacarose/análogos & derivados , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Understanding fructose metabolism might provide insights to renal pathophysiology. To support systemic glucose concentration, the proximal tubular cells reabsorb fructose as a substrate for gluconeogenesis. However, in instances when fructose intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflammation, and fibrosis in the kidney. A recent scientific advance is the discovery that fructose can be endogenously produced from glucose under pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac hypertrophy, and with dehydration. Why humans have such a deleterious mechanism to produce fructose is unknown, but it may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.
Assuntos
Frutose/metabolismo , Rim/metabolismo , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Nefropatias Diabéticas/metabolismo , Açúcares da Dieta/efeitos adversos , Açúcares da Dieta/farmacocinética , Metabolismo Energético , Ácidos Graxos/biossíntese , Frutose/efeitos adversos , Gluconeogênese/fisiologia , Humanos , Nefropatias/etiologia , Nefropatias/metabolismo , Túbulos Renais Proximais/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Sorbitol/metabolismo , Ácido Úrico/metabolismo , Vertebrados/metabolismoRESUMO
Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.
Assuntos
Carcinoma de Células Escamosas/patologia , Enzima Desubiquitinante CYLD/genética , Neoplasias Cutâneas/patologia , Animais , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Enzima Desubiquitinante CYLD/metabolismo , Genes Supressores de Tumor , Imunocompetência , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , NF-kappa B/metabolismo , Neovascularização Patológica/genética , Ésteres de Forbol/toxicidade , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Dietary, fructose-containing sugars have been strongly associated with the development of nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that fructose also can be produced via the polyol pathway in the liver, where it may induce hepatic fat accumulation. Moreover, fructose metabolism yields uric acid, which is highly associated with NAFLD. Here, using biochemical assays, reporter gene expression, and confocal fluorescence microscopy, we investigated whether uric acid regulates aldose reductase, a key enzyme in the polyol pathway. We evaluated whether soluble uric acid regulates aldose reductase expression both in cultured hepatocytes (HepG2 cells) and in the liver of hyperuricemic rats and whether this stimulation is associated with endogenous fructose production and fat accumulation. Uric acid dose-dependently stimulated aldose reductase expression in the HepG2 cells, and this stimulation was associated with endogenous fructose production and triglyceride accumulation. This stimulatory mechanism was mediated by uric acid-induced oxidative stress and stimulation of the transcription factor nuclear factor of activated T cells 5 (NFAT5). Uric acid also amplified the effects of elevated glucose levels to stimulate hepatocyte triglyceride accumulation. Hyperuricemic rats exhibited elevated hepatic aldose reductase expression, endogenous fructose accumulation, and fat buildup that was significantly reduced by co-administration of the xanthine oxidase inhibitor allopurinol. These results suggest that uric acid generated during fructose metabolism may act as a positive feedback mechanism that stimulates endogenous fructose production by stimulating aldose reductase in the polyol pathway. Our findings suggest an amplifying mechanism whereby soft drinks rich in glucose and fructose can induce NAFLD.
Assuntos
Tecido Adiposo/metabolismo , Aldeído Redutase/metabolismo , Frutose/biossíntese , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polímeros/metabolismo , Ácido Úrico/farmacologia , Animais , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Frutose/metabolismo , Células Hep G2 , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Polímeros/análise , Ratos , Ratos Wistar , Células Tumorais Cultivadas , Ácido Úrico/metabolismoRESUMO
Intake of sugars, especially the fructose component, is strongly associated with the development of obesity and metabolic syndrome, but the relative role of taste versus metabolism in driving preference, intake, and metabolic outcome is not fully understood. We aimed to evaluate the preference for sweet substances and the tendency to develop metabolic syndrome in response to these sugars in mice lacking functional taste signaling [P2X2 (P2X purinoreceptor 2)/P2X3 (P2X purinoreceptor 3) double knockout mice (DKO)] and mice unable to metabolize fructose (fructokinase knockout mice). Of interest, our data indicate that despite their inability to taste sweetness, P2X2/3 DKO mice still prefer caloric sugars (including fructose and glucose) to water in long-term testing, although with diminished preference compared with control mice. Despite reduced intake of caloric sugars by P2X2/3 DKO animals, the DKO mice still show increased levels of the sugar-dependent hormone FGF21 (fibroblast growth factor 21) in plasma and liver. Despite lower sugar intake, taste-blind mice develop severe features of metabolic syndrome due to reduced sensitivity to leptin, reduced ability to mobilize and oxidize fats, and increased hepatic de novo lipogenesis. In contrast to P2X2/3 DKO and wild-type mice, fructokinase knockout mice, which cannot metabolize fructose and are protected against fructose-induced metabolic syndrome, demonstrate reduced preference and intake for all fructose-containing sugars tested but not for glucose or artificial sweeteners. Based on these observations, we conclude that sugar can induce metabolic syndrome in mice independently of its sweet properties. Furthermore, our data demonstrate that the metabolism of fructose is necessary for sugar to drive intake and preference in mice.
Assuntos
Sacarose Alimentar/efeitos adversos , Síndrome Metabólica/etiologia , Obesidade/etiologia , Paladar/fisiologia , Animais , Sacarose Alimentar/administração & dosagem , Preferências Alimentares/fisiologia , Frutose/administração & dosagem , Frutose/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Purinérgicos P2X2/deficiência , Receptores Purinérgicos P2X2/fisiologia , Receptores Purinérgicos P2X3/deficiência , Receptores Purinérgicos P2X3/fisiologiaRESUMO
We report a case of a patient who developed dialysis-requiring acute kidney injury (AKI) after the use of canagliflozin. A 66-year-old man with type 2 diabetes who was recovering from left knee septic arthritis at a rehabilitation facility was admitted with oliguric AKI 5 days after starting treatment with canagliflozin, an inhibitor of sodium/glucose cotransporter 2 (SGLT2). The patient presented with hematuria, non-nephrotic-range proteinuria, and serum creatinine level of 6.8 (baseline, 1.1-1.3) mg/dL. There was no recent use of radiocontrast agents or exposure to other nephrotoxins. The patient subsequently required hemodialysis. Due to recent antibiotic use (ampicillin-sulbactam), acute interstitial nephritis was considered in the differential diagnosis. Kidney biopsy was performed, which showed the presence of osmotic nephropathy. The patient's kidney function returned to baseline after 2 weeks of hemodialysis. This case provides evidence of an association of osmotic nephropathy with the use of canagliflozin and discusses potential mechanisms. We recommend kidney biopsy for cases of severe AKI associated with SGLT2 inhibitors to better understand the relationship of this complication with the use of this class of medications.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico por imagem , Canagliflozina/efeitos adversos , Nefrose/induzido quimicamente , Nefrose/diagnóstico por imagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Injúria Renal Aguda/metabolismo , Idoso , Diuréticos Osmóticos/efeitos adversos , Humanos , Masculino , Nefrose/metabolismoRESUMO
BACKGROUND: Nature offers numerous examples of animal species exhibiting harmonious collective movement. Unfortunately, the motorized Homo sapiens sapiens is not included and pays a price for it. Too often, drivers who simply follow other drivers are caught in the worst road threat after a crash: congestions. In the past, the solution to this problem has gone hand in hand with infrastructure investment. However, approaches such as the Nagoya Paradigm propose now to see congestion as the consequence of multiple interacting particles whose disturbances are transmitted in a waveform. This view clashes with a longlasting assumption ordering traffic flows, the rational driver postulate (i.e., drivers' alleged propensity to maintain a safe distance). Rather than a mere coincidence, the worldwide adoption of the safety-distance tenet and the worldwide presence of congestion emerge now as cause and effect. Nevertheless, nothing in the drivers' endowment impedes the adoption of other car-following (CF) strategies. The present study questions the a priori of safety-distance, comparing two elementary CF strategies, Driving to keep Distance (DD), that still prevails worldwide, and Driving to keep Inertia (DI), a complementary CF technique that offsets traffic waves disturbances, ensuring uninterrupted traffic flows. By asking drivers to drive DD and DI, we aim to characterize both CF strategies, comparing their effects on the individual driver (how he drives, how he feels, what he pays attention to) and also on the road space occupied by a platoon of DD robot-followers. METHODS: Thirty drivers (50% women) were invited to adopt DD/DI in a driving simulator following a swinging leader. The design was a repeated measures model controlling for order. The CF technique, DD or DI, was the within-subject factor. Order (DD-DI / DI-DD) was the between-subjects factor. There were four blocks of dependent measures: individual driving performance (accelerations, decelerations, crashes, distance to lead vehicle, speed and fuel consumption), emotional dimensions (measures of skin conductance and self-reports of affective states concerning valence, arousal, and dominance), and visual behavior (fixations count and average duration, dwell times, and revisits) concerning three regions of the driving scene (the Top Rear Car -TRC- or the Bottom Rear Car -BRC- of the leading vehicle and the surrounding White Space Area -WSA). The final block concerned the road space occupied by a platoon of 8 virtual DD followers. RESULTS: Drivers easily understood and applied DD/DI as required, switching back and forth between the two. Average speeds for DD/DI were similar, but DD drivers exhibited a greater number of accelerations, decelerations, speed variability, and crashes. Conversely, DI required greater CF distance, that was dynamically adjusted, and spent less fuel. Valence was similar, but DI drivers felt less aroused and more dominant. When driving DD visual scan was centered on the leader's BRC, whereas DI elicited more attention to WSA (i.e., adopting wider vision angles). In spite of DI requiring more CF distance, the resulting road space occupied between the leader and the 8th DD robot was greater when driving DD.
RESUMO
Obesity and metabolic syndrome are well-known risk factors for chronic kidney disease (CKD); however, less is known about the mechanism(s) by which metabolic syndrome might accelerate kidney disease. We hypothesized that metabolic syndrome should accelerate the development of kidney disease and that it might be associated with alterations in energy metabolism. We studied the pound mouse (which develops early metabolic syndrome due to a leptin receptor deletion) and wild-type littermates and compared the level of renal injury and muscle wasting after equivalent injury with oral adenine. Renal function, histology, and biochemical analyses were performed. The presence of metabolic syndrome was associated with earlier development of renal disease (12 mo) and earlier mortality in pound mice compared with controls. After administration of adenine, kidney disease was worse in pound mice, and this was associated with greater tubular injury with a decrease in kidney mitochondria, lower tissue ATP levels, and worse oxidative stress. Pound mice with similar levels of renal function as adenine-treated wild-type mice also showed worse sarcopenia, with lower tissue ATP and intracellular phosphate levels. In summary, our data demonstrate that obesity and metabolic syndrome accelerate the progression of CKD and worsen CKD-dependent sarcopenia. Both conditions are associated with renal alterations in energy metabolism and lower tissue ATP levels secondary to mitochondrial dysfunction and reduced mitochondrial number.
Assuntos
Metabolismo Energético , Rim/metabolismo , Mitocôndrias/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Adenina/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Testes de Função Renal , Túbulos Renais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Sarcopenia/etiologia , Sarcopenia/metabolismoRESUMO
An epidemic of chronic kidney disease of unknown etiology (Mesoamerican nephropathy) has emerged in hot regions of Central America. We have demonstrated that dehydration associated with recurrent heat exposure causes chronic kidney disease in animal models. However, the independent influence of core body temperature on kidney injury has not been explored. In the present study, we tested the hypothesis that kidney injury could be accelerated by increasing body temperature independent of external temperature. Wild-type mice were exposed to heat (39.5°C, 30 min, 2 times daily) with or without the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) for 10 days. Core temperature, renal function, proteinuria, and renal histological and biochemical analyses were performed. Isolated mitochondria markers of oxidative stress were evaluated from kidney tissue. DNP increased body core temperature in response to heat by 1°C (42 vs. 41°C), which was transient. The mild increase in temperature correlated with worsening albuminuria (R = 0.715, P < 001), renal tubular injury, and interstitial infiltration of monocytes/macrophages. Tubular injury was marked in the outer medulla. This was associated with a reduction in kidney tissue ATP levels (nonheated control: 16.71 ± 1.33 nmol/mg and DNP + heat: 13.08 ± 1.12 nmol/mg, P < 0.01), reduced mitochondria, and evidence for mitochondrial oxidative stress. The results of the present study suggest that kidney injury in heat stress is markedly worsened by increasing core temperature. This is consistent with the hypothesis that clinical and subclinical heat stroke may play a role in Mesoamerican nephropathy.
Assuntos
Febre , Resposta ao Choque Térmico , Nefropatias/etiologia , 2,4-Dinitrofenol/toxicidade , Animais , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Medula Renal , Masculino , Camundongos , Mitocôndrias , Fatores de TempoRESUMO
PURPOSE OF REVIEW: Excessive sugar and particularly fructose consumption has been proposed to be a key player in the pathogenesis of metabolic syndrome and kidney disease in humans and animal models. However, besides its dietary source, fructose can be endogenously produced in the body from glucose via the activation of the polyol pathway. In this review, we aim to describe the most recent findings and current knowledge on the potential role of endogenous fructose production and metabolism in disease. RECENT FINDINGS: Over the recent years, the activation of the polyol pathway and endogenous fructose production has been observed in multiple tissues including the liver, renal cortex, and hypothalamic areas of the brain. The activation occurs during the development and progression of metabolic syndrome and kidney disease and results from different stimuli including osmotic effects, diabetes, and ischemia. Even though the potential toxicity of the activation of the polyol pathway can be attributed to several intermediate products, the blockade of endogenous fructose metabolism either by using fructokinase deficient mice or specific inhibitors resulted in marked amelioration of multiple metabolic diseases. SUMMARY: New findings suggest that fructose can be produced in the body and that the blockade of tis metabolism could be clinically relevant for the prevention and treatment of metabolic syndrome and kidney disease.
Assuntos
Frutose , Doenças Metabólicas/metabolismo , Animais , Carboidratos da Dieta/metabolismo , Fígado Gorduroso/metabolismo , Frutoquinases/metabolismo , Frutose/metabolismo , Frutose/fisiologia , Humanos , Nefropatias/metabolismo , Redes e Vias Metabólicas/fisiologia , Camundongos , Polímeros/metabolismoRESUMO
The worldwide increase in temperature has resulted in a marked increase in heat waves (heat extremes) that carries a markedly increased risk for morbidity and mortality. The kidney has a unique role not only in protecting the host from heat and dehydration but also is an important site of heat-associated disease. Here we review the potential impact of global warming and heat extremes on kidney diseases. High temperatures can result in increased core temperatures, dehydration, and blood hyperosmolality. Heatstroke (both clinical and subclinical whole-body hyperthermia) may have a major role in causing both acute kidney disease, leading to increased risk of acute kidney injury from rhabdomyolysis, or heat-induced inflammatory injury to the kidney. Recurrent heat and dehydration can result in chronic kidney disease (CKD) in animals and theoretically plays a role in epidemics of CKD developing in hot regions of the world where workers are exposed to extreme heat. Heat stress and dehydration also has a role in kidney stone formation, and poor hydration habits may increase the risk for recurrent urinary tract infections. The resultant social and economic consequences include disability and loss of productivity and employment. Given the rise in world temperatures, there is a major need to better understand how heat stress can induce kidney disease, how best to provide adequate hydration, and ways to reduce the negative effects of chronic heat exposure.
Assuntos
Transtornos de Estresse por Calor/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Mudança Climática , Desidratação , Transtornos de Estresse por Calor/etiologia , Temperatura Alta , Humanos , Insuficiência Renal Crônica/etiologiaRESUMO
An epidemic of chronic kidney disease (CKD) has been observed in Central America among workers in the sugarcane fields. One hypothesis is that the CKD may be caused by recurrent heat stress and dehydration, and potentially by hyperuricemia. Accordingly, we developed a murine model of kidney injury associated with recurrent heat stress. In the current experiment, we tested whether treatment with allopurinol (a xanthine oxidase inhibitor that reduces serum urate) provides renal protection against recurrent heat stress and dehydration. Eight-week-old male C57BL/6 mice were subjected to recurrent heat stress (39.5°C for 30 min, 7 times daily, for 5 wk) with or without allopurinol treatment and were compared with control animals with or without allopurinol treatment. Mice were allowed ad libitum access to normal laboratory chow (Harlan Teklad). Kidney histology, liver histology, and renal function were examined. Heat stress conferred both kidney and liver injury. Kidneys showed loss of proximal tubules, infiltration of monocyte/macrophages, and interstitial collagen deposition, while livers of heat-stressed mice displayed an increase in macrophages, collagen deposition, and myofibroblasts. Allopurinol provided significant protection and improved renal function in the heat-stressed mice. The renal protection was associated with reduction in intrarenal uric acid concentration and heat shock protein 70 expression. Heat stress-induced renal and liver injury can be protected with allopurinol treatment. We recommend a clinical trial of allopurinol for individuals developing renal injury in rural areas of Central America where the epidemic of chronic kidney disease is occurring.
Assuntos
Alopurinol/farmacologia , Inibidores Enzimáticos/farmacologia , Transtornos de Estresse por Calor/prevenção & controle , Temperatura Alta , Hipertermia Induzida , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Proteínas de Choque Térmico HSP70/metabolismo , Transtornos de Estresse por Calor/etiologia , Transtornos de Estresse por Calor/metabolismo , Transtornos de Estresse por Calor/patologia , Rim/metabolismo , Rim/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Ácido Úrico/metabolismo , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismoRESUMO
Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPN-/- mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN-/- mice did not show histological differences. However, nephritic kidneys from OPN-/- mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN-/- mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN-/- mice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPN-/- mice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPN-/- mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN-/- macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN-/- mice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis.
Assuntos
Inflamação/metabolismo , Glomérulos Renais/lesões , Macrófagos/patologia , Osteopontina/metabolismo , Animais , Modelos Animais de Doenças , Glomerulonefrite/patologia , Glomérulos Renais/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Knockout , Sistema Urinário/metabolismoRESUMO
We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1,3-galactosyltransferase gene knockout pigs with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4-Ig once a week from the second postoperative week or no CTLA4-Ig. The non-CTLA4-Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non-CTLA4-Ig groups had to be euthanized before POD 60. In contrast, CTLA4-Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti-CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno-transplantation with improved survival.
Assuntos
Antígeno B7-1/metabolismo , Regulação da Expressão Gênica , Glomérulos Renais/imunologia , Transplante de Rim , Podócitos/imunologia , Proteinúria/imunologia , Abatacepte/imunologia , Animais , Animais Geneticamente Modificados , Ligante de CD40/imunologia , Antígeno CTLA-4/imunologia , Galactosiltransferases/genética , Imunoglobulina G/imunologia , Rim/metabolismo , Nefropatias/imunologia , Nefropatias/cirurgia , Nefrose , Nefrose Lipoide , Papio , Suínos , Transplante Heterólogo , UrináliseRESUMO
BACKGROUND: Fructose intake, mainly as table sugar or high fructose corn syrup, has increased in recent decades and is associated with increased risk for kidney stones. We hypothesized that fructose intake alters serum and urinary components involved in stone formation. METHODS: We analyzed a previously published randomized controlled study that included 33 healthy male adults (40-65 years of age) who ingested 200 g of fructose (supplied in a 2-L volume of 10% fructose in water) daily for 2 weeks. Participants were evaluated at the Unit of Nephrology of the Mateo Orfila Hospital in Menorca. Changes in serum levels of magnesium, calcium, uric acid, phosphorus, vitamin D, and intact PTH levels were evaluated. Urine magnesium, calcium, uric acid, phosphorus, citrate, oxalate, sodium, potassium, as well as urinary pH, were measured. RESULTS: Ingestion of fructose was associated with an increased serum level of uric acid (p < 0.001), a decrease in serum ionized calcium (p = 0.003) with a mild increase in PTH (p < 0.05) and a drop in urinary pH (p = 0.02), an increase in urine oxalate (p = 0.016) and decrease in urinary magnesium (p = 0.003). CONCLUSIONS: Fructose appears to increase urinary stone formation in part via effects on urate metabolism and urinary pH, and also via effects on oxalate. Fructose may be a contributing factor for the development of kidney stones in subjects with metabolic syndrome and those suffering from heat stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT00639756 March 20, 2008.
Assuntos
Frutose/efeitos adversos , Resposta ao Choque Térmico/fisiologia , Cálculos Renais/induzido quimicamente , Cálculos Renais/urina , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/urina , Adulto , Idoso , Oxalato de Cálcio/urina , Frutose/administração & dosagem , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Cálculos Renais/epidemiologia , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Ácido Úrico/urinaRESUMO
BACKGROUND: Increasing evidence suggests heat stress induced chronic kidney disease (CKD) may be mediated by endogenous fructose generation and may be exacerbated by rehydration by fructose-containing solutions. We have recently reported a model of CKD induced by heat stress. Here we test the hypothesis that rehydration with fructose may induce worse kidney injury than rehydration with equal amounts of water, and we also test if this fructose-induced injury is associated with activation of inflammasomes in the kidney. METHODS: Mice were recurrently exposed to heat (39.5 C0 for 30 min/h, 5 times daily for 5 wks) with rehydration consisting of 6 ml each night of water (Heat, n = 7) or fructose (Heat+F, 10%, n = 7), and were compared to control mice on water (Control, n = 7) or fructose (Fructose, n = 7). Various markers of renal injury were assessed. RESULTS: Compared to control animals, there was a progressive worsening of renal injury (inflammation and fibrosis) with fructose alone, heat stress alone, and heat stress with fructose rehydration (P < 0.01 by ANOVA). The combination of heat stress with rehydration with fructose was associated with increased intrarenal expression of the inflammasome markers, NLRP3 and IL-18, compared to heat stress alone. In addition, heat stress with or without fructose was associated with increased expression of caspase - 3 and monocyte chemoattractant protein-1 levels. Fructose administration was also associated with an increase in serum copeptin levels (a biomarker of vasopressin) and elevated copeptin was also observed in mice undergoing heat stress alone. CONCLUSIONS: These studies suggest that heat stress may activate intrarenal inflammasomes leading to inflammation and renal injury, and provide evidence that rehydration with fructose may accelerate the renal injury and inflammatory response.
Assuntos
Desidratação/induzido quimicamente , Hidratação/métodos , Frutose/toxicidade , Resposta ao Choque Térmico/efeitos dos fármacos , Temperatura Alta/efeitos adversos , Insuficiência Renal Crônica/induzido quimicamente , Animais , Desidratação/tratamento farmacológico , Desidratação/patologia , Hidratação/efeitos adversos , Frutose/administração & dosagem , Resposta ao Choque Térmico/fisiologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Túbulos Renais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Água/administração & dosagemRESUMO
Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2 receptor-dependent pathway.