RESUMO
PURPOSE OF REVIEW: This review critically examines the role of hypoxia in chronic kidney disease (CKD). While traditionally viewed as detrimental, recent insights suggest a more nuanced understanding of hypoxia's role during renal disease. RECENT FINDINGS: Emerging evidence challenges the traditional view that hypoxia is universally harmful in CKD context. We review here the recent evidence about hypoxia and HIF activation in CKD. We also discuss the effect of hypoxia on the renal tissue, and the relative inhibition of different HIF isoforms. Recent advancements in therapies, such as HIF prolyl hydroxylase inhibitors (HIF-PHIs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors seem to target the HIF pathway. These drugs impact anemia associated with CKDbut also renoprotection, hinting at a more complex interplay between hypoxia, HIF activation, and renal health. SUMMARY: A certain level of hypoxia and specific HIF pathway activation, especially HIF-α, can be beneficial in CKD progression. Therapeutic strategies targeting HIF stabilization, such as with HIF-PHIs and SGLT2 inhibitors, offer promising avenues for enhancing renal protection. Future investigations should aim at better understanding the precise effects on HIF pathway and optimize their clinical application to improve outcomes for CKD patients.
Assuntos
Hipóxia , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Hipóxia/metabolismo , Animais , Rim/metabolismo , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Valganciclovir (VGC) is administered as prophylaxis to kidney transplant recipients (KTR) CMV donor (D)+/recipient (R)- and CMV R+ after thymoglobulin-induction (R+/TG). Although VGC dose adjustments based on renal function are recommended, there is paucity of real-life data on VGC dosing and associations with clinical outcomes. This is a retrospective Swiss Transplant Cohort Study-embedded observational study, including all adult D+/R- and R+/TG KTR between 2010 and 2020, who received prophylaxis with VGC. The primary objective was to describe the proportion of inappropriately (under- or over-) dosed VGC week-entries. Secondary objectives included breakthrough clinically significant CMV infection (csCMVi) and potential associations between breakthrough-csCMVi and cytopenias with VGC dosing. Among 178 KTR, 131 (73.6%) patients had ≥2 week-entries for the longitudinal data of interest and were included in the outcome analysis, with 1,032 VGC dose week-entries. Overall, 460/1,032 (44.6%) were appropriately dosed, while 234/1,032 (22.7%) and 338/1,032 (32.8%) were under- and over-dosed, respectively. Nineteen (14.5%) patients had a breakthrough-csCMVi, without any associations identified with VCG dosing (p = 0.44). Unlike other cytopenias, a significant association between VGC overdosing and lymphopenia (OR 5.27, 95% CI 1.71-16.22, p = 0.004) was shown. VGC prophylaxis in KTR is frequently inappropriately dosed, albeit without meaningful clinical associations, neither in terms of efficacy nor safety.
Assuntos
Antivirais , Infecções por Citomegalovirus , Transplante de Rim , Valganciclovir , Humanos , Valganciclovir/administração & dosagem , Valganciclovir/uso terapêutico , Transplante de Rim/efeitos adversos , Masculino , Infecções por Citomegalovirus/prevenção & controle , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Adulto , Idoso , Rim/efeitos dos fármacos , TransplantadosRESUMO
Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-ß-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. We also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, we identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.
Assuntos
Carboxiliases/metabolismo , Sequência Conservada , Evolução Molecular , Saúde , Mitocôndrias/fisiologia , NAD/biossíntese , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/metabolismo , Carboxiliases/antagonistas & inibidores , Carboxiliases/química , Carboxiliases/deficiência , Linhagem Celular , Colina , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Fígado/citologia , Fígado/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Masculino , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ratos , Sirtuínas/metabolismoRESUMO
Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by recurrent arterial and venous thromboembolic events. Renal complications occur in 3â % of patients. Renal artery stenosis is the most common, and APS-related nephropathy is the predominant microvascular complication. APS nephropathy has heterogeneous manifestations ranging from hematuria and non-nephrotic range proteinuria to hypertension and multi-organ failure caused by catastrophic antiphospholipid antibody syndrome. Anticoagulation and thromboprophylaxis are key to management. Immunosuppression has been used with some success but lacks randomized controlled trial validation for their use.
Le syndrome des anticorps antiphospholipides (SAPL) est une maladie auto-immune rare caractérisée par des événements thromboemboliques artériels et veineux récurrents. Les complications rénales surviennent chez 3â % des patients. La sténose de l'artère rénale est la plus courante et la néphropathie liée au SAPL représente la complication microvasculaire principale. La maladie rénale liée au SAPL se traduit par des manifestations hétérogènes allant de l'hématurie et de la protéinurie non néphrotique à l'hypertension jusqu'à la défaillance multi-organique causée par le syndrome catastrophique des anticorps antiphospholipides (SCAPL). L'anticoagulation et la thromboprophylaxie sont clés dans la prise en charge. L'immunosuppression a été utilisée avec un certain succès, mais manque de validation par des essais contrôlés randomisés pour leur utilisation.
Assuntos
Síndrome Antifosfolipídica , Doenças Autoimunes , Obstrução da Artéria Renal , Tromboembolia Venosa , Humanos , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/terapia , Doenças RarasRESUMO
Xenotransplantation could be an inexhaustible source of organs and change the life of end-stage kidney disease patients with reduction of morbidity and mortality. Through genetic engineering it is now possible to reduce the risk of hyperacute and acute graft rejection and improve the overall immune compatibility between two different species. Some experiments have already brought promising perspectives. Nevertheless, there are still difficulties to overcome. The risk of animal-related infectious diseases, ethnic limitations, safety, and applicability of large-scale xenotransplantation should be assessed. We still need to improve the technical aspects and define the purpose of these procedures: definitive replacement or temporary solution?
La xénotransplantation pourrait être une source inépuisable d'organes et changer la vie des patients atteints d'une maladie rénale terminale en diminuant la morbidité et la mortalité. Grâce au génie génétique, il est maintenant possible de réduire le risque de rejet hyperaigu et aigu et d'améliorer la compatibilité immunitaire globale entre deux espèces différentes. Certains travaux ont déjà apporté des perspectives prometteuses. Néanmoins, il reste de nombreuses difficultés à surmonter. Le risque de maladies infectieuses liées aux animaux, les considérations ethniques, la sécurité et l'applicabilité de la xénotransplantation à grande échelle devraient être évalués. Nous devons encore améliorer les aspects techniques et définir le but de ces procéduresâ : remplacement définitif ou solution temporaireâ ?
Assuntos
Falência Renal Crônica , Rim , Animais , Humanos , Transplante Heterólogo , Rejeição de Enxerto/prevenção & controleRESUMO
Molecules such as sparsentan and budesonide look promising to treat proteinuric IGA nephropathy. SLGT2 inhibitors have a prominent place in nephroprotection and could be used in the treatment of acute kidney injury due to heart failure as well. High volume hemodiafiltration compared to hemodialysis improves survival in dialysis patients. Lessening dialysate temperature does not improve hemodynamic stability during the dialysis session. Sodium bicarbonate does not seem to protect renal function in renal transplant patients. SGLT2 inhibitors may have a beneficial effect in these patients in terms of nephroprotection.
Dans les formes protéinuriques de néphropathie à IgA, le sparsentan et le budésonide semblent être des molécules prometteuses. Les inhibiteurs du SGLT2 (iSGLT2) confirment leur place primordiale dans la néphroprotection et pourraient être utilisés dans le traitement de l'insuffisance rénale aiguë (IRA) liée à l'insuffisance cardiaque. En hémodialyse, l'hémodiafiltration à haut-débit comparée à l'hémodialyse diminue la mortalité d'environ 22 %. Abaisser la température du dialysat n'améliore pas la stabilité cardiovasculaire durant la séance d'hémodialyse. Le bicarbonate de sodium ne semble pas avoir d'effet néphroprotecteur sur la fonction rénale des greffés rénaux alors que les iSGLT2 pourraient avoir un effet bénéfique.
Assuntos
Injúria Renal Aguda , Insuficiência Cardíaca , Transplante de Rim , Nefrologia , Humanos , Injúria Renal Aguda/terapia , Diálise RenalRESUMO
Phosphoenolpyruvate carboxykinase 1 (PCK1 or PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis, and cataplerosis in the liver. Kidney proximal tubule cells display high expression of this enzyme, whose importance is currently not well defined. We generated PCK1 kidney-specific knockout and knockin mice under the tubular cell-specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal conditions and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia, and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1-deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule, and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigation of PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid-base control, mitochondrial function, and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function.NEW & NOTEWORTHY Phosphoenolpyruvate carboxykinase 1 (PCK1) is highly expressed in the proximal tubule. We show here that this enzyme is crucial for the maintenance of normal tubular physiology, lactate, and glucose homeostasis. PCK1 is a regulator of acid-base balance and ammoniagenesis. Preventing PCK1 downregulation during renal injury improves renal function, rendering it an important target during renal disease.
Assuntos
Acidose , Rim , Animais , Camundongos , Acidose/metabolismo , Glucose/metabolismo , Rim/metabolismo , Lactatos/metabolismo , Mitocôndrias/metabolismo , Fosfoenolpiruvato/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismoRESUMO
BACKGROUND: The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents have yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases. While prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase factor inhibiting HIF (FIH). METHODS: We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-computed tomography imaging. We analysed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies of various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach to assess its relevance in CKD. RESULTS: In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with decreased development of fibrosis. CONCLUSIONS: The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seems promising in proteinuric kidney disease.
Assuntos
Hipóxia , Oxigenases de Função Mista , Humanos , Animais , Camundongos , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Microtomografia por Raio-X , Proteínas Repressoras/genética , Regulação para Baixo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
OBJECTIVE: Several nonconsecutive 24-h urinary collections are considered the gold standard for estimating dietary salt intake. As those samples are logistically demanding, we aimed to describe the variability of 24-h sodium urinary excretion over consecutive days and report its adequacy with sodium intake. METHODS: We enrolled 16 healthy male volunteers in a prospective controlled study. All participants randomly received a low salt diet (LSD) (3 g/day of NaCl), a normal salt diet (NSD) (6 g/day of NaCl), and a high salt diet (HSD) (15 g/day of NaCl) for 7 days in a crossover design without wash-out period. RESULTS: On day 6, median sodium urinary excretion was 258 (216-338), 10 (8-18), and 87 (69-121) mmol/day for HSD, LSD, and NSD, respectively (P < .001). When considering days 4-6, sodium urinary excretion was in steady state as models with and without interaction term "diet type X sample day" were not significantly different (P = .163). On day 6, area under the curve (AUC) of receiver operating characteristic for urinary sodium excretion to detect HSD was 1.0 (1.0-1.0) and a cut-point of 175 mmol/day was 100% sensitive and specific to detect HSD. On day 6, receiver operating characteristic AUC to detect LSD was 0.993 (0.978-1.0) and a cut-point of 53 mmol/day was 96.4% sensitive and 100% specific to detect LSD. CONCLUSION: A steady state of sodium balance, where sodium intake is proportional to its excretion, is reached within a few days under a constant diet in the real-life setting. Categorization of salt consumption into low (3 g/day), normal (6 g/day), or high (15 g/day) based on a single 24-h urine collection is nearly perfect. Based on these results, repeated nonconsecutive urine collection might prove unnecessary to estimate sodium intake in daily clinical practice provided that diet is rather constant over time.
Assuntos
Cloreto de Sódio na Dieta , Sódio na Dieta , Humanos , Masculino , Estudos Prospectivos , Sódio/urina , Cloreto de Sódio , Cloreto de Sódio na Dieta/urina , Coleta de UrinaRESUMO
INTRODUCTION: CKD is associated with alterations of tubular function. Renal gluconeogenesis is responsible for 40% of systemic gluconeogenesis during fasting, but how and why CKD affects this process and the repercussions of such regulation are unknown. METHODS: We used data on the renal gluconeogenic pathway from more than 200 renal biopsies performed on CKD patients and from 43 kidney allograft patients, and studied three mouse models, of proteinuric CKD (POD-ATTAC), of ischemic CKD, and of unilateral urinary tract obstruction. We analyzed a cohort of patients who benefitted from renal catheterization and a retrospective cohort of patients hospitalized in the intensive care unit. RESULTS: Renal biopsies of CKD and kidney allograft patients revealed a stage-dependent decrease in the renal gluconeogenic pathway. Two animal models of CKD and one model of kidney fibrosis confirm gluconeogenic downregulation in injured proximal tubule cells. This shift resulted in an alteration of renal glucose production and lactate clearance during an exogenous lactate load. The isolated perfused kidney technique in animal models and renal venous catheterization in CKD patients confirmed decreased renal glucose production and lactate clearance. In CKD patients hospitalized in the intensive care unit, systemic alterations of glucose and lactate levels were more prevalent and associated with increased mortality and a worse renal prognosis at follow-up. Decreased expression of the gluconeogenesis pathway and its regulators predicted faster histologic progression of kidney disease in kidney allograft biopsies. CONCLUSION: Renal gluconeogenic function is impaired in CKD. Altered renal gluconeogenesis leads to systemic metabolic changes with a decrease in glucose and increase in lactate level, and is associated with a worse renal prognosis.
Assuntos
Gluconeogênese , Insuficiência Renal Crônica , Animais , Gluconeogênese/fisiologia , Humanos , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Camundongos , Insuficiência Renal Crônica/metabolismo , Estudos RetrospectivosRESUMO
Severe cases of IGA nephropathy might benefit from corticosteroid therapy. Inflimidase may be a promising treatment of Goodpasture disease. SGLT2 inhibitors and acetazolamide act synergistically with loop diuretics in the treatment of acute cardiac failure. In hemodialysis, use of lung ultrasound to determine the ultrafiltration seems to decrease hospitalizations due to acute heart failure but does not reduce patient-centered outcomes. Icodextrin may mitigate the loss of ultrafiltration in PD patients who are carriers of the Aquaporin I promotor TT genotype. MICA-antibodies have an impact on the risk of graft rejection. Xenotransplantation may become a reality.
Une corticothérapie peut être proposée dans les formes sévères de néphropathie à IgA. L'inflimidase est une molécule prometteuse dans le traitement de la maladie de Goodpasture. Les inhibiteurs du SGLT2 et l'acétazolamide sont des diurétiques d'appoint aux diurétiques de l'anse dans le traitement de l'insuffisance cardiaque aiguë. En hémodialyse, l'ultrason pulmonaire pour déterminer le volume d'ultrafiltration diminue les hospitalisations pour insuffisance cardiaque mais pas la morbimortalité globale. L'hémodialyse incrémentale gagne en popularité. L'icodextrine permet de pallier la baisse de l'ultrafiltration chez les patients en dialyse péritonéale porteurs du génotype TT du promoteur de l'aquaporine-1. Les anticorps anti-MICA dirigés spécifiquement contre le greffon rénal ont un impact sur le risque de rejet du greffon. La xénotransplantation devient une réalité.
Assuntos
Insuficiência Cardíaca , Nefrologia , Humanos , Diálise Renal , Ultrafiltração , Hospitalização , Insuficiência Cardíaca/terapiaRESUMO
Chronic kidney disease (CKD) has a high prevalence in Cameroon and will become an important public health problem. Its management must be comprehensive, starting with CKD prevention to the implementation of renal replacement therapies best suited to the needs of patients and resources available in Cameroon. Practical interventions involving nephrology departments in both Africa and Europe can contribute to an improved management of CKD in Africa. The current collaboration between the Geneva University Hospitals and the Yaoundé teaching hospitals is a convincing example. It includes a clinical trial on the treatment of metabolic acidosis linked to CKD, assistance with the placement of hemodialysis catheters by sonography and the initiation of a kidney transplantation program with living donors.
La maladie rénale chronique (MRC) a une haute prévalence au Cameroun et va devenir un important problème de santé publique. Sa prise en charge doit être globale, partant de la prévention de la MRC jusqu'à la mise en place des techniques de suppléance extrarénale les plus adaptées aux besoins des patients et aux ressources disponibles localement. Des actions concrètes, dans le cadre d'une néphrologie solidaire, impliquant des services de néphrologie d'Afrique et d'Europe, peuvent y contribuer. La collaboration entre les Hôpitaux universitaires de Genève et ceux de Yaoundé en est un exemple probant, avec la mise en place d'un essai clinique sur le traitement de l'acidose métabolique liée à la MRC, une aide à la pose des cathéters de dialyse par sonographie et l'initiation d'un programme de transplantation rénale avec des donneurs vivants.
Assuntos
Nefrologia , Insuficiência Renal Crônica , Humanos , Camarões , Cognição , Europa (Continente)RESUMO
In nephrology, rare disorders are frequently encountered. In children, about 60% of the renal disorders are rare, with congenital abnormalities of the kidney and urinary tract disorders (CAKUT), being highly prevalent. In adults, about 22% of the disorders leading to renal replacement therapies are rare and include glomerulonephritis and genetic disorders. Rarity may preclude the rapid and extensive access to care for patients suffering of renal disorders, especially in Switzerland, which is small and fragmented. Only collaborative network and access to databases, shared resources and to specific competence may help patient management. Lausanne and Geneva University Hospitals have started specialized outpatient clinics for rare renal disorders several years ago and are part of national and international networks.
Dans le domaine des maladies rénales, la rareté est fréquente. Chez l'enfant, 60 % des maladies touchant les reins sont rares et les malformations de l'axe urinaire sont prépondérantes. Chez l'adulte, près de 22 % des pathologies qui mènent à la maladie rénale terminale sont rares et incluent les glomérulonéphrites et les maladies génétiques. La rareté de ces pathologies fait que les compétences médicales peuvent être difficiles à trouver et l'expérience locale insuffisante. Ainsi, seule la mise en réseau des données, des ressources et des compétences peut permettre d'améliorer la prise en charge de ces patients. Le CHUV et les HUG ont mis en place des consultations spécialisées pour les maladies rénales rares. Elles s'inscrivent dans un réseau national et international.
Assuntos
Nefropatias , Nefrologia , Adulto , Criança , Humanos , Rim , Nefropatias/genética , Nefropatias/terapia , Instituições de Assistência Ambulatorial , Hospitais Universitários , Doenças Raras/terapiaRESUMO
Damage to the proximal tubule (PT) is the most frequent cause of acute kidney injury (AKI) in humans. Diagnostic and treatment options for AKI are currently limited, and a deeper understanding of pathogenic mechanisms at a cellular level is required to rectify this situation. Metabolism in the PT is complex and closely coupled to solute transport function. Recent studies have shown that major changes in PT metabolism occur during AKI and have highlighted some potential targets for intervention. However, translating these insights into effective new therapies still represents a substantial challenge. In this article, in addition to providing a brief overview of the current state of the field, we will highlight three emerging areas that we feel are worthy of greater attention. First, we will discuss the role of axial heterogeneity in cellular function along the PT in determining baseline susceptibility to different metabolic hits. Second, we will emphasize that elucidating insult specific pathogenic mechanisms will likely be critical in devising more personalized treatments for AKI. Finally, we will argue that uncovering links between tubular metabolism and whole-body homeostasis will identify new strategies to try to reduce the considerable morbidity and mortality associated with AKI. These concepts will be illustrated by examples of recent studies emanating from the authors' laboratories and performed under the auspices of the Swiss National Competence Center for Kidney Research (NCCR Kidney.ch).
Assuntos
Injúria Renal Aguda , Túbulos Renais Proximais , Injúria Renal Aguda/metabolismo , Humanos , Rim/metabolismo , Túbulos Renais Proximais/metabolismoRESUMO
Renal ischemia-reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole body irradiation induces renal IPC in mice. Still, the mechanisms remain largely unknown. Furthermore, the impact of kidney-centered irradiation on renal resistance against I/R has not been studied. Renal irradiation (8.5 Gy) was done in male 8- to 12-wk-old C57bl/6 mice using a small animal radiation therapy device. Left renal I/R was performed by clamping the renal pedicles for 30 min, with simultaneous right nephrectomy, at 7, 14, and 28 days postirradiation. The renal reperfusion lasted 48 h. Following I/R, blood urea nitrogen (BUN) and serum creatinine (SCr) levels were lower in preirradiated mice compared with controls; so was the histological Jablonski score of AKI. The metabolomics signature of renal I/R was attenuated in preirradiated mice. The numbers of proliferating cell nuclear antigen (PCNA)-, cluster of differentiation molecule 11b (CD11b)-, and cell surface glycoprotein F4/80-positive cells in the renal parenchyma post-I/R were reduced in preirradiated versus control groups. Such IPC was significantly observed as early as day 14 postirradiation. RNA sequencing showed an upregulation of angiogenesis- and stress response-related signaling pathways in irradiated nonischemic kidneys on day 28. Qualitative RT-PCR confirmed the increased expression of vascular endothelial growth factor (VEGF), activin receptor-like kinase 5 (ALK5), heme oxygenase-1 (HO1), platelet endothelial cell adhesion molecule-1 (PECAM1), NADPH oxidase 2 (NOX2), and heat shock proteins 70 and 27 (HSP70 and HSP27, respectively) in irradiated kidneys compared with controls. In addition, irradiated kidneys showed an increased CD31-positive vascular area compared with controls. A 14-day gavage of irradiated mice with the antiangiogenic drug sunitinib before I/R abrogated the irradiation-induced IPC at both functional and structural levels. Our observations suggest that kidney-centered irradiation activates proangiogenic pathways and induces IPC, with preserved renal function and attenuated inflammation post-I/R.NEW & NOTEWORTHY This study based on a mouse model of renal ischemia-reperfusion (I/R) aimed to 1) test whether and how irradiation strictly centered on the kidney protects against the I/R injury and 2) determine the shortest efficient delay of kidney irradiation to achieve such nephroprotection. Kidney irradiation increased the vascular surface in the renal parenchyma and conferred resistance against renal I/R damage, which highlights novel putative strategies in the field of ischemic acute kidney injury.
Assuntos
Injúria Renal Aguda , Precondicionamento Isquêmico , Traumatismo por Reperfusão , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Isquemia/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Kidney cortical interstitial fibrosis is highly predictive of kidney prognosis and is currently assessed by evaluation of a biopsy. Diffusion-weighted magnetic resonance imaging is a promising non-invasive tool to evaluate kidney fibrosis. We recently adapted diffusion-weighted imaging sequence for discrimination between the kidney cortex and medulla and found that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) correlated with histological interstitial fibrosis. Here, we assessed whether ΔADC as measured with diffusion-weighted magnetic resonance imaging is predictive of kidney function decline and dialysis initiation in chronic kidney disease (CKD) and patients with a kidney allograft in a prospective study encompassing 197 patients. We measured ΔADC in 43 patients with CKD (estimated GFR (eGFR) 55ml/min/1.73m2) and 154 patients with a kidney allograft (eGFR 53ml/min/1.73m2). Patients underwent a kidney biopsy and diffusion-weighted magnetic resonance imaging within one week of biopsy; median follow-up of 2.2 years with measured laboratory parameters. The primary outcome was a rapid decline of kidney function (eGFR decline over 30% or dialysis initiation) during follow up. Significantly, patients with a negative ΔADC had 5.4 times more risk of rapid decline of kidney function or dialysis (95% confidence interval: 2.29-12.58). After correction for kidney function at baseline and proteinuria, low ADC still predicted significant kidney function loss with a hazard ratio of 4.62 (95% confidence interval 1.56-13.67) independent of baseline age, sex, eGFR and proteinuria. Thus, low ΔADC can be a predictor of kidney function decline and dialysis initiation in patients with native kidney disease or kidney allograft, independent of baseline kidney function and proteinuria.
Assuntos
Rim , Insuficiência Renal Crônica , Aloenxertos/diagnóstico por imagem , Aloenxertos/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Fibrose , Taxa de Filtração Glomerular , Humanos , Rim/patologia , Masculino , Estudos Prospectivos , Proteinúria/diagnóstico por imagem , Proteinúria/etiologia , Proteinúria/patologia , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/cirurgiaRESUMO
Glucose levels are tightly regulated at all times. Gluconeogenesis is the metabolic pathway dedicated to glucose synthesis from non-hexose precursors. Gluconeogenesis is critical for glucose homoeostasis, particularly during fasting or stress conditions. The renal contribution to systemic gluconeogenesis is increasingly recognized. During the post-absorptive phase, the kidney accounts for â¼40% of endogenous gluconeogenesis, occurring mainly in the kidney proximal tubule. The main substrate for renal gluconeogenesis is lactate and the process is regulated by insulin and cellular glucose levels, but also by acidosis and stress hormones. The kidney thus plays an important role in the maintenance of glucose and lactate homoeostasis during stress conditions. The impact of acute and chronic kidney disease and proximal tubular injury on gluconeogenesis is not well studied. Recent evidence shows that in both experimental and clinical acute kidney injury, impaired renal gluconeogenesis could significantly participate in systemic metabolic disturbance and thus alter the prognosis. This review summarizes the biochemistry of gluconeogenesis, the current knowledge of kidney gluconeogenesis, its modifications in kidney disease and the clinical relevance of this fundamental biological process in human biology.
Assuntos
Gluconeogênese , Rim , Glucose/metabolismo , Humanos , Insulina/metabolismo , Rim/metabolismo , Lactatos/metabolismoRESUMO
BACKGROUND: Residual kidney function is considered better preserved with incremental haemodialysis (I-HD) or peritoneal dialysis (PD) as compared with conventional thrice-weekly HD (TW-HD) and is associated with improved survival. We aimed to describe outcomes of patients initiating dialysis with I-HD, TW-HD or PD. METHODS: We conducted a retrospective analysis of a prospectively assembled cohort in a single university centre including all adults initiating dialysis from January 2013 to December 2020. Primary and secondary endpoints were overall survival and hospitalization days at 1 year, respectively. RESULTS: We included 313 patients with 234 starting on HD (166 TW-HD and 68 I-HD) and 79 on PD. At the end of the study, 10 were still on I-HD while 45 transitioned to TW-HD after a mean duration of 9.8 ± 9.1 months. Patients who stayed on I-HD were less frequently diabetics (P = .007). Mean follow-up was 33.1 ± 30.8 months during which 124 (39.6%) patients died. Compared with patients on TW-HD, those on I-HD had improved survival (hazard ratio 0.49, 95% confidence interval 0.26-0.93, P = .029), while those on PD had similar survival. Initial kidney replacement therapy modality was not significantly associated with hospitalization days at 1 year. CONCLUSIONS: I-HD is suitable for selected patients starting dialysis and can be maintained for a significant amount of time before transition to TW-HD, with diabetes being a risk factor. Although hospitalization days at 1 year are similar, initiation with I-HD is associated with improved survival as compared with TW-HD or PD. Results of randomized controlled trials are awaited prior to large-scale implementation of I-HD programmes.
Assuntos
Falência Renal Crônica , Diálise Peritoneal , Adulto , Humanos , Diálise Renal/métodos , Estudos Retrospectivos , Terapia de Substituição RenalRESUMO
BACKGROUND: The effects of sodium (Na+) intakes on renal handling of potassium (K+) are insufficiently studied. METHODS: We assessed the effect of Na+ on renal K+ handling in 16 healthy males assigned to three 7-day periods on low salt diet [LSD, 3 g sodium chloride (NaCl)/day], normal salt diet (NSD, 6 g NaCl/day) and high salt diet (HSD, 15 g NaCl/day), with constant K+ intake. Contributions of distal NaCl co-transporter and epithelial Na+ channel in the collecting system on K+ and Na+ handling were assessed at steady state by acute response to 100 mg oral hydrochlorothiazide and with addition of 10 mg of amiloride to hydrochlorothiazide, respectively. RESULTS: Diurnal blood pressure slightly increased from 119.30 ± 7.95 mmHg under LSD to 123.00 ± 7.50 mmHg (P = 0.02) under HSD, while estimated glomerular filtration rate increased from 133.20 ± 34.68 mL/min under LSD to 187.00 ± 49.10 under HSD (P = 0.005). The 24-h K+ excretion remained stable on all Na+ intakes (66.28 ± 19.12 mmol/24 h under LSD; 55.91 ± 21.17 mmol/24 h under NSD; and 66.81 ± 20.72 under HSD, P = 0.9). The hydrochlorothiazide-induced natriuresis was the highest under HSD (30.22 ± 12.53 mmol/h) and the lowest under LSD (15.38 ± 8.94 mmol/h, P = 0.02). Hydrochlorothiazide increased kaliuresis and amiloride decreased kaliuresis similarly on all three diets. CONCLUSIONS: Neither spontaneous nor diuretic-induced K+ excretion was influenced by Na+ intake in healthy male subjects. However, the respective contribution of the distal convoluted tubule and the collecting duct to renal Na+ handling was dependent on dietary Na+ intake.
Assuntos
Potássio , Sódio na Dieta , Pressão Sanguínea , Humanos , Túbulos Renais Distais , Masculino , Natriurese , Potássio na Dieta/farmacologia , Sódio , Cloreto de Sódio na Dieta , Sódio na Dieta/farmacologiaRESUMO
Finerenone is a new mineralocorticoid receptor antagonist with a different structure, volume of distribution and half-life compared to spironolactone. This drug has been tested in two large, randomized trials including diabetic patients with chronic kidney disease (in terms of glomerular filtration rate and albuminuria) and already treated by renin-angiotensin system blockade. Results are positive on hard renal- and cardiac endpoints. Risk of hyperkalaemia is higher than with placebo but is considered as acceptable. An open question that will be tested in further studies is the role of finerenone in the context of a treatment by gliflozins, drugs that also showed cardiorenal protection.
La finérénone est un antagoniste non stéroïdien du récepteur des minéralocorticoïdes avec une structure, un volume de distribution et une demi-vie différents de la spironolactone. Cette molécule a récemment été testée dans deux grands essais randomisés et contrôlés chez des patients avec une néphropathie diabétique avérée (en termes de débit de filtration glomérulaire et d'albuminurie) et un blocage optimal du système rénine-angiotensine-aldostérone (SRAA). Les résultats attestent d'une néphroprotection et d'une cardioprotection conférées par cette molécule, en addition aux bloqueurs du SRAA, sur des critères de jugement durs. Le risque d'hyperkaliémie était supérieur au placebo, mais acceptable. Une question ouverte reste celle de la place de cette molécule par rapport aux gliflozines, ayant aussi prouvé une protection cardiorénale.