RESUMO
For the evaluation of novel therapeutic agents for diabetic kidney disease (DKD), it is desirable to examine their efficacy in animal models by using the glomerular filtration rate (GFR) as an index. For this purpose, animal models that demonstrate a short-term GFR decline because of disease progression are required. Therefore, we aimed to develop such an animal model of DKD by using obese type 2 diabetic spontaneously diabetic Torii (SDT) fatty rats treated with salt loading by drinking water containing sodium chloride with or without unilateral nephrectomy. As a result, we have found that 0.3% salt loading with unilateral nephrectomy or 0.8% salt loading alone caused a rapid GFR decline, hypertension and rapid development of tubulointerstitial fibrosis. Moreover, the addition of losartan to a mixed diet suppressed the GFR decline in SDT fatty rats treated with 0.3% salt loading with unilateral nephrectomy. These results suggest that the model of SDT fatty rats treated with 0.3% salt loading and unilateral nephrectomy could be used as a hypertensive DKD model for evaluating therapeutic agents based on suppression of GFR decline.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Hipertensão , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/cirurgia , Nefropatias Diabéticas/etiologia , Modelos Animais de Doenças , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Hipertensão/cirurgia , Masculino , Nefrectomia/efeitos adversos , Obesidade/complicações , Obesidade/cirurgia , Ratos , Cloreto de Sódio , Cloreto de Sódio na DietaRESUMO
BACKGROUND: The management of congenital nephrotic syndrome of the Finnish type (CNF) is challenging. It is difficult to withdraw intravenous albumin infusions, resulting in long-term hospitalization. In addition, fatal hypotension after bilateral nephrectomy has been reported. In our center, we have performed unilateral nephrectomy during early infancy. METHODS: Infants diagnosed with CNF between 2011 and 2020 in our institution were enrolled. We examined the clinical course before and after unilateral nephrectomy and evaluated the effectiveness of this strategy. RESULTS: Seven patients (all showing NPHS1 mutations) were enrolled. All required daily intravenous albumin infusion via central venous catheter (CVC). Unilateral nephrectomy was performed at a median of 76 days of age (59-208 days). Surgical complications did not occur in any of patients. The mean albumin dose was decreased after unilateral nephrectomy (2.0 vs 0.4 g/kg/day; p = 0.02). Intravenous albumin infusion could be withdrawn at a median of 17 days, the CVC removed at a median of 21 days, and they discharged at a median of 82 days after unilateral nephrectomy. Although bacterial infections were noted seven times before unilateral nephrectomy, only one episode occurred after surgery. Four patients initiated peritoneal dialysis at two to three years of age and all of them underwent kidney transplantation thereafter. CONCLUSIONS: Unilateral nephrectomy during early infancy may be an effective treatment allowing for withdrawal from albumin infusion, prevention of complications, withdrawal from CVCs and shortening hospital stay for patients with CNF.
Assuntos
Transplante de Rim , Síndrome Nefrótica , Diálise Peritoneal , Finlândia , Humanos , Lactente , Nefrectomia/efeitos adversos , Síndrome Nefrótica/diagnósticoRESUMO
Nephron loss stimulates residual functioning nephrons to undergo compensatory growth. Excessive nephron growth may be a maladaptive response that sets the stage for progressive nephron damage, leading to kidney failure. To date, however, the mechanism of nephron growth remains incompletely understood. Our previous study revealed that class III phosphatidylinositol-3-kinase (Pik3c3) is activated in the remaining kidney after unilateral nephrectomy (UNX)-induced nephron loss, but previous studies failed to generate a Pik3c3 gene knockout animal model. Global Pik3c3 deletion results in embryonic lethality. Given that renal proximal tubule cells make up the bulk of the kidney and undergo the most prominent hypertrophic growth after UNX, in this study we used Cre-loxP-based approaches to demonstrate for the first time that tamoxifen-inducible SLC34a1 promoter-driven CreERT2 recombinase-mediated downregulation of Pik3c3 expression in renal proximal tubule cells alone is sufficient to inhibit UNX- or amino acid-induced hypertrophic nephron growth. Furthermore, our mechanistic studies unveiled that the SLC34a1-CreERT2 recombinase-mediated Pik3c3 downregulation inhibited UNX- or amino acid-stimulated lysosomal localization and signaling activation of mechanistic target of rapamycin complex 1 (mTORC1) in the renal proximal tubules. Moreover, our additional cell culture experiments using RNAi confirmed that knocking down Pik3c3 expression inhibited amino acid-stimulated mTORC1 signaling and blunted cellular growth in primary cultures of renal proximal tubule cells. Together, both our in vivo and in vitro experimental results indicate that Pik3c3 is a major mechanistic mediator responsible for sensing amino acid availability and initiating hypertrophic growth of renal proximal tubule cells by activation of the mTORC1-S6K1-rpS6 signaling pathway.
Assuntos
Classe III de Fosfatidilinositol 3-Quinases/genética , Túbulos Renais Proximais/crescimento & desenvolvimento , Rim/efeitos dos fármacos , Néfrons/crescimento & desenvolvimento , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Animais , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Integrases/genética , Rim/crescimento & desenvolvimento , Rim/patologia , Rim/cirurgia , Túbulos Renais Proximais/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Nefrectomia , Néfrons/metabolismo , Fosforilação/genética , Proteína-Lisina 6-Oxidase/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologiaRESUMO
Excessive compensatory nephron hypertrophy (CNH) has been implicated in setting the stage for progressive nephron damage. Lack of a class III phosphatidylinositol 3-kinase (Pik3c3) inhibitor suitable for using in animals and lack of a Pik3c3-deficient animal model preclude the possibility of conclusively defining a role for Pik3c3 in CNH in previous studies. Here, we report that insertion of an Frt-flanked PGK-Neo cassette into intron 19 of the mouse Pik3c3 gene resulted in a hypomorphic allele. This allowed us to create a unique mouse model and provide the first definitive genetic evidence demonstrating whether Pik3c3 is essential for the regulation of CNH. Our results indicate that homozygous Pik3c3 hypomorphic (Pik3c3Hypo/Hypo) mice express significantly low levels of Pik3c3 than heterozygous Pik3c3 hypomorphic (Pik3c3Hypo/WT) littermates, which already express a lower level of Pik3c3 than wild-type (Pik3c3WT/WT) littermates. Interestingly, after unilateral nephrectomy (UNX), Pik3c3Hypo/Hypo mice develop a significantly lower degree of CNH than Pik3c3WT/WT mice and Pik3c3Hypo/WT mice, as revealed by measurement of kidney weight, kidney-to-body weight ratio, renal protein-to-DNA ratio, and morphometric analysis of proximal tubular and glomerular size. Mechanistically, UNX-induced mammalian target of rapamycin complex 1 (mTORC1) signaling to phosphorylation of ribosomal protein S6 (rpS6) in the remaining kidney was markedly inhibited in Pik3c3 hypomorphic mice. In conclusion, the present study reports a Pik3c3 hypomorphic mouse model and provides the first definitive evidence that Pik3c3 controls the degree of compensatory nephron hypertrophy. In addition, our signaling data provide the first definitive in vivo proof that Pik3c3 functions upstream of the mTORC1-S6 kinase 1-rpS6 pathway in the regulation of compensatory nephron hypertrophy.
Assuntos
Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Néfrons/patologia , Animais , Classe III de Fosfatidilinositol 3-Quinases/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Hipertrofia , Íntrons/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Mutagênese Insercional , Nefrectomia , Néfrons/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: In end-stage renal transplant recipients with autosomal-dominant polycystic kidney disease (ADPKD), the imperative, optimal timing, and technique of native nephrectomy remains under discussion. The Freiburg Transplant Center routinely performs a simultaneous ipsilateral nephrectomy. METHODS: From April 1998 to May 2017, we retrospectively analyzed 193 consecutive ADPKD recipients, receiving per protocol simultaneous ipsilateral nephrectomy and compared morbidity, mortality, and outcome with 193 non-ADPKD recipients of a matched pair control. RESULTS: The incidence of surgical complications was similar with respect to severe medical, surgical, urological, vascular, and wound-related complications as well as reoperation rates and 30-day mortality. Intraoperative blood transfusions were required more often in the ADPKD (22.8%) compared with the control group (6.7%; p < 0.0001). Early postoperative urinary tract infections occurred more frequent (ADPKD 40.4%/control 29.0%; p = 0.0246). Time of surgery was prolonged by 30 min (ADPKD 169 min; 95%CI 159.8-175.6 min/control 139 min; 95%CI 131.4-145.0 min; p < 0.0001). One-year patient (ADPKD 96.4%/control 95.8%; p = 0.6537) and death-censored graft survival (ADPKD 94.8%/control 93.7%; p = 0.5479) were comparable between both groups. CONCLUSIONS: With respect to morbidity and mortality, per protocol, simultaneous native nephrectomy is a safe procedure. Especially in asymptomatic ADPKD KTx recipients, the number of total operations can be reduced and residual diuresis preserved up until transplantation. In living donation, even preemptive transplantation is possible.
Assuntos
Transplante de Rim , Nefrectomia/métodos , Rim Policístico Autossômico Dominante/cirurgia , Transfusão de Sangue/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Sobrevivência de Enxerto , Humanos , Incidência , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Duração da Cirurgia , Rim Policístico Autossômico Dominante/mortalidade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Infecções Urinárias/epidemiologiaRESUMO
The congenital nephrotic syndrome is a rare and severe pathology, and its management represents a real challenge for pediatric nephrologists. We report the case of a congenital nephrotic syndrome secondary to a homozygous mutation of the NPHS1. The young patient has a severe clinical course, and benefits of a management by anti-proteinuric treatment and a unilateral nephrectomy. This clinical case illustrates the difficulties of the management of a severe congenital nephrotic syndrome. To date, it is difficult to identify these patients beforehand because there is a poor correlation between the genotype and the phenotype of the NPHS1 mutation. There are two managements described in the literature: an early bilateral nephrectomy at 7 kg of weight with a renal transplant around 10 kg, versus a conservative management via an anti-proteinuric treatment and/or an unilateral nephrectomy. Current evidence is based on retrospective studies and the choice of a conservative approach versus early bilateral nephrectomy should take into account the severity of protein loss and its complications.
Le syndrome néphrotique congénital est une pathologie rare et sévère, dont la prise en charge représente un défi pour les néphrologues pédiatriques. Nous rapportons le cas d'un jeune patient présentant cette pathologie secondaire à une mutation homozygote du gène NPHS1. Il présente un tableau clinique sévère et bénéficie d'un traitement anti-protéinurique et d'une néphrectomie unilatérale. Ce cas clinique illustre les difficultés de la prise en charge des cas sévères, dont l'identification préalable est difficile à ce jour car la corrélation entre le génotype et le phénotype de la mutation NPHS1 est pauvre. Il existe deux prises en charges décrites dans la littérature : une néphrectomie bilatérale précoce vers 7 kg de poids et une greffe rénale vers 10 kg, ou bien une prise en charge conservative via un traitement anti-protéinurique et/ou une néphrectomie unilatérale permettant de postposer la greffe. Les données actuelles n'étant basées que sur des études rétrospectives, le choix entre une approche conservative et une néphrectomie bilatérale précoce doit prendre en compte la sévérité de la déperdition protéique et ses complications.
Assuntos
Síndrome Nefrótica , Criança , Humanos , Lactente , Proteínas de Membrana/genética , Mutação , Fenótipo , Estudos RetrospectivosRESUMO
Renal blood flow (RBF) provides important information regarding renal physiology and nephropathies. Arterial spin labeling-magnetic resonance imaging (ASL-MRI) is a noninvasive method of measuring blood flow without exogenous contrast media. However, low signal-to-noise ratio and respiratory motion artifacts are challenges for RBF measurements in small animals. Our objective was to evaluate the feasibility and reproducibility of RBF measurements by ASL-MRI using respiratory-gating and navigator correction methods to reduce motion artifacts. ASL-MRI images were obtained from the kidneys of Sprague-Dawley (SD) rats on a 7-Tesla Varian MRI system with a spin-echo imaging sequence. After 4 days, the study was repeated to evaluate its reproducibility. RBF was also measured in animals under unilateral nephrectomy and in renal artery stenosis (RST) to evaluate the sensitivity in high and low RBF models, respectively. RBF was also evaluated in Dahl salt-sensitive (SS) rats and spontaneous hypertensive rats (SHR). In SD rats, the cortical RBFs (cRBF) were 305 ± 59 and 271.8 ± 39 ml·min-1·100 g tissue-1 in the right and left kidneys, respectively. Retest analysis revealed no differences ( P = 0.2). The test-retest reliability coefficient was 92 ± 5%. The cRBFs before and after the nephrectomy were 296.8 ± 30 and 428.2 ± 45 ml·min-1·100 g tissue-1 ( P = 0.02), respectively. The kidneys with RST exhibited a cRBF decrease compared with sham animals (86 ± 17.6 vs. 198 ± 33.7 ml·min-1·100 g tissue-1; P < 0.01). The cRBFs in SD, Dahl-SS, and SHR rats were not different ( P = 0.35). We conclude that ASL-MRI performed with navigator correction and respiratory gating is a feasible and reliable noninvasive method for measuring RBF in rats.
Assuntos
Processamento de Imagem Assistida por Computador , Nefropatias/diagnóstico por imagem , Nefropatias/patologia , Imageamento por Ressonância Magnética , Animais , Meios de Contraste , Rim/irrigação sanguínea , Rim/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Ratos Sprague-Dawley , Artéria Renal/patologia , Circulação Renal/fisiologia , Marcadores de SpinRESUMO
Unilaterally nephrectomized rats (UNx) have higher glomerular capillary pressure (PGC) that can cause significant glomerular injury in the remnant kidney. PGC is controlled by the ratio of afferent (Af-Art) and efferent arteriole resistance. Af-Art resistance in turn is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa; and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel (ENaC). Resetting of TGF post-UNx can allow systemic pressure to be transmitted to the glomerulus and cause renal damage, but the mechanism behind this resetting is unclear. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that CTGF is increased after UNx and contributes to TGF resetting. To test this hypothesis, we performed UNx in Sprague-Dawley (8) rats. Twenty-four hours after surgery, we performed micropuncture of individual nephrons and measured stop-flow pressure (PSF). PSF is an indirect measurement of PGC. Maximal TGF response at 40 nl/min was 8.9 ± 1.24 mmHg in sham-UNx rats and 1.39 ± 1.02 mmHg in UNx rats, indicating TGF resetting after UNx. When CTGF was inhibited with the ENaC blocker benzamil (1 µM/l), the TGF response was 12.29 ± 2.01 mmHg in UNx rats and 13.03 ± 1.25 mmHg in sham-UNx rats, indicating restoration of the TGF responses in UNx. We conclude that enhanced CTGF contributes to TGF resetting after UNx.
Assuntos
Retroalimentação , Glomérulos Renais/irrigação sanguínea , Túbulos Renais/irrigação sanguínea , Nefrectomia , Néfrons/irrigação sanguínea , Animais , Arteríolas/fisiologia , Pressão Sanguínea/fisiologia , Canais Epiteliais de Sódio/metabolismo , Taxa de Filtração Glomerular/fisiologia , Túbulos Renais/fisiologia , Nefrectomia/métodos , Ratos Sprague-DawleyRESUMO
BACKGROUND: The aim of this study was to assess long-term residual kidney function after unilateral nephrectomy for non-syndromic Wilms tumor (NSWT). METHODS: Of the patients who underwent one-sided NSWT at Tohoku University Hospital between 1977 and 2003, nine were followed up until age ≥18 years. For these nine patients, we retrospectively evaluated estimated glomerular filtration rate (eGFR) in childhood (3-10 years old), adolescence (11-17 years old) and adulthood (≥18 years). RESULTS: Mean age at the last follow up was 23.0 years. Tumor classification was as follows: stage I tumor, n = 6; stage II tumor, n = 3; mixed-type nephroblastoma, n = 8; and congenital mesoblastic nephroma, n = 1. Mean eGFR was 101.3 ± 21.2 mL/min/1.73 m2 in childhood, 106.0 ± 32.1 mL/min/1.73 m2 in adolescence and 100.5 ± 20.7 mL/min/1.73 m2 in adulthood. Therefore, no significant change in eGFR was observed over the three life stages evaluated. Further, none of the patients met the diagnostic criteria for chronic kidney disease by early adulthood. CONCLUSIONS: eGFR after unilateral nephrectomy in patients with NSWT remained ≥60 mL/min/1.73 m2 during the transition from childhood to early adulthood, with no development of chronic kidney disease or end-stage kidney failure.
Assuntos
Taxa de Filtração Glomerular , Neoplasias Renais/cirurgia , Nefrectomia , Tumor de Wilms/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Neoplasias Renais/fisiopatologia , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Tumor de Wilms/fisiopatologia , Adulto JovemRESUMO
Acute kidney injury is usually associated with distant organ dysfunction. The roles of inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) in this phenomenon were investigated following 2 h unilateral renal ischemia and 24 h reperfusion. There were 3 groups of rats subjected to either unilateral ischemia/reperfusion (UIR group), unilateral nephrectomy (UNX group), or sham operation. Two further groups were given α-tocopherol and aminoguanidine with UIR (treated-UIR group) and UNX (treated-UNX group). Plasma nitrite/nitrate and malondialdehyde were elevated only in the UIR group. Creatinine clearance and blood flow increased in non-ischemic kidney of the UIR, but not to the same extent as remnant kidney of the UNX group, while they had equal compensatory rises in absolute Na(+) and K(+) excretion and urine flow. Non-ischemic kidney of the treated-UIR group, but not remnant kidney of the treated-UNX group, showed more elevation in blood flow, whereas both kidneys had reductions in absolute Na(+) excretion and urine flow. Respiratory functional variable were not different between all groups. Therefore, 2 h unilateral renal ischemia and 24 h reperfusion did not affect lung but had distant effects on contralateral kidney partly mediated by ROS and NO-derived from iNOS to dampen compensatory increases in renal hemodynamics and to decrease tubular reabsorption.
Assuntos
Injúria Renal Aguda/fisiopatologia , Modelos Animais de Doenças , Rim/fisiopatologia , Pulmão/fisiopatologia , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Animais , Antioxidantes/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Guanidinas/uso terapêutico , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Malondialdeído/sangue , Nefrectomia/efeitos adversos , Nitratos/sangue , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Nitritos/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Reabsorção Renal/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Respiração/efeitos dos fármacos , Transtornos Urinários/etiologia , Transtornos Urinários/prevenção & controle , alfa-Tocoferol/uso terapêuticoRESUMO
PURPOSE: Acute kidney injury (AKI) induces acute lung injury (ALI) through releasing injurious mediators or impairing clearance of systemic factors. To determine the links between AKI and ALI, pulmonary and blood variables were evaluated following induction of AKI via different experimental models of bilateral renal ischemia/reperfusion (BIR: renal ischemia with uremia), unilateral renal ischemia/reperfusion (UIR: renal ischemia without uremia), bilateral nephrectomy (BNX: uremia without renal ischemia), and unilateral nephrectomy (UNX: without uremia and renal ischemia). METHODS: Ninety male Sprague-Dawley rats were divided into six groups. Animals had 1-h bilateral or 2-h unilateral renal ischemia followed by 24-h reperfusion in the BIR and UIR groups, respectively, and 24-h period following bilateral or unilateral nephrectomy in the BNX and UNX groups, respectively. There were also sham and control groups with and without sham-operation, respectively. RESULTS: Plasma malondialdehyde and nitric oxide were elevated by BIR more than UIR, but not changed by UNX and BNX. UIR slightly increased plasma creatinine, whereas BIR and BNX largely increased plasma creatinine, urea, K+ and osmolality and decreased arterial HCO3-, pH, and CO2. UNX and UIR did not affect lung, but BIR and BNX induced ALI with equal capillary leak and macrophages infiltration. However, there were more prominent lung edema and vascular congestion following BNX and more severe neutrophils infiltration and PaO2/FiO2 reduction following BIR. CONCLUSION: Acutely accumulated systemic mediators following renal failure in the absence of kidneys vary from those due to combined renal failure with ischemic-reperfused kidneys and consequently they induce ALI with distinct characteristics.
Assuntos
Lesão Pulmonar Aguda/etiologia , Creatinina/sangue , Malondialdeído/sangue , Nefrectomia/efeitos adversos , Traumatismo por Reperfusão/complicações , Injúria Renal Aguda/complicações , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/metabolismo , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Rim/diagnóstico por imagem , Testes de Função Renal , Pulmão/diagnóstico por imagem , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/metabolismoRESUMO
Chronic kidney disease (CKD), an independent risk factor for cardiovascular disease, is associated with abnormal lipoprotein metabolism. We examined whether electronegative low-density lipoprotein (LDL) is mechanistically linked to cardiac dysfunction in patients with early CKD. We compared echocardiographic parameters between patients with stage 2 CKD (n = 88) and normal controls (n = 89) and found that impaired relaxation was more common in CKD patients. Reduction in estimated glomerular filtration rate was an independent predictor of left ventricular relaxation dysfunction. We then examined cardiac function in a rat model of early CKD induced by unilateral nephrectomy (UNx) by analyzing pressure-volume loop data. The time constant of isovolumic pressure decay was longer and the maximal velocity of pressure fall was slower in UNx rats than in controls. When we investigated the mechanisms underlying relaxation dysfunction, we found that LDL from CKD patients and UNx rats was more electronegative than LDL from their respective controls and that LDL from UNx rats induced intracellular calcium overload in H9c2 cardiomyocytes in vitro. Furthermore, chronic administration of electronegative LDL, which signals through lectin-like oxidized LDL receptor-1 (LOX-1), induced relaxation dysfunction in wild-type but not LOX-1(-/-) mice. In in vitro and in vivo experiments, impaired cardiac relaxation was associated with increased calcium transient resulting from nitric oxide (NO)-dependent nitrosylation of SERCA2a due to increases in inducible NO synthase expression and endothelial NO synthase uncoupling. In conclusion, LDL becomes more electronegative in early CKD. This change disrupts SERCA2a-regulated calcium homeostasis, which may be the mechanism underlying cardiorenal syndrome.
Assuntos
Cálcio/metabolismo , Homeostase , Lipoproteínas LDL/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Adulto , Animais , Estudos de Casos e Controles , Demografia , Feminino , Fibrose , Coração , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Miócitos Cardíacos/metabolismo , Nefrectomia , Óxido Nítrico Sintase Tipo II/metabolismo , Nitrosação , Ratos Sprague-Dawley , Receptores de LDL Oxidado/metabolismo , Insuficiência Renal Crônica/diagnóstico por imagem , Sistema Renina-Angiotensina , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Ultrassonografia , Regulação para Cima , Vasodilatação , Proteínas tau/metabolismoRESUMO
BACKGROUND: There have been few prospective controlled studies of kidney donors. Understanding the pathophysiologic effects of kidney donation is important for judging donor safety and improving our understanding of the consequences of reduced kidney function in chronic kidney disease. STUDY DESIGN: Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS: 3-year follow-up of kidney donors and paired controls suitable for donation at their donor's center. PREDICTOR: Kidney donation. OUTCOMES: Medical history, vital signs, glomerular filtration rate, and other measurements at 6, 12, 24, and 36 months after donation. RESULTS: At 36 months, 182 of 203 (89.7%) original donors and 173 of 201 (86.1%) original controls continue to participate in follow-up visits. The linear slope of the glomerular filtration rate measured by plasma iohexol clearance declined 0.36±7.55mL/min per year in 194 controls, but increased 1.47±5.02mL/min per year in 198 donors (P=0.005) between 6 and 36 months. Blood pressure was not different between donors and controls at any visit, and at 36 months, all 24-hour ambulatory blood pressure parameters were similar in 126 controls and 135 donors (mean systolic blood pressure, 120.0±11.2 [SD] vs 120.7±9.7mmHg [P=0.6]; mean diastolic blood pressure, 73.4±7.0 vs 74.5±6.5mmHg [P=0.2]). Mean arterial pressure nocturnal dipping was manifest in 11.2% ± 6.6% of controls and 11.3% ± 6.1% of donors (P=0.9). Urinary protein-creatinine and albumin-creatinine ratios were not increased in donors compared with controls. From 6 to 36 months postdonation, serum parathyroid hormone, uric acid, homocysteine, and potassium levels were higher, whereas hemoglobin levels were lower, in donors compared with controls. LIMITATIONS: Possible bias resulting from an inability to select controls screened to be as healthy as donors, short follow-up duration, and dropouts. CONCLUSIONS: Kidney donors manifest several of the findings of mild chronic kidney disease. However, at 36 months after donation, kidney function continues to improve in donors, whereas controls have expected age-related declines in function.
Assuntos
Transplante de Rim , Doadores Vivos/estatística & dados numéricos , Nefrectomia/efeitos adversos , Albuminúria/epidemiologia , Glicemia/análise , Pressão Sanguínea , Nitrogênio da Ureia Sanguínea , Estudos de Casos e Controles , Ritmo Circadiano , Creatinina/análise , Seguimentos , Taxa de Filtração Glomerular , Homocisteína/sangue , Humanos , Lipídeos/sangue , Hormônio Paratireóideo/sangue , Fósforo/sangue , Estudos Prospectivos , Proteinúria/epidemiologia , Ácido Úrico/sangueRESUMO
A previous animal study compared the nephrotoxic effect of ibandronate (IBN) and zoledronate (ZOL), but interpretation of these study results was limited because of the model of minimal nephrotoxic dosage with a dosage ratio of 1:3. The present study investigated the nephrotoxicity of ibandronate and zoledronate in a 1.5:1 dose ratio, as used in clinical practice and compared the nephrotoxicity in rats with normal and with mildly to moderately impaired renal function. We compared rats with normal renal function (SHAM) and with impaired renal function after unilateral nephrectomy (UNX), treated either with ibandronate 1.5mg/kg, zoledronate 1mg/kg or placebo once (1×) or nine (9×) times. Renal function and markers of tubular toxicity were measured over a 27 week period. After last bisphosphonate treatment the rats were sacrificed and kidneys examined histologically. All bisphosphonate treated animals showed a significant tubular toxicity, which was temporary except in the ZOL-UNX-9×-group. Also the renal function was only transiently reduced except in the ZOL-UNX-9×-group. Histologically, bisphosphonate treatment led to cortical tubuloepithelial degeneration/necrosis and medullary tubuloepithelial swelling which were slightly more pronounced in ibandronate treated animals, when compared to zoledronate treated animals, especially with impaired renal function. In contrast to the previous study we found a similar nephrotoxicity of ibandronate and zoledronate in rats with normal renal function. In rats with impaired renal function the peak of toxicity had not even been fully reached until end of experiment in the zoledronate treated animals. The peak of toxicity seems to be more severe and delayed in rats with impaired renal function compared with rats with normal renal function.
Assuntos
Difosfonatos/toxicidade , Imidazóis/toxicidade , Rim/efeitos dos fármacos , Animais , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/toxicidade , Difosfonatos/administração & dosagem , Feminino , Humanos , Ácido Ibandrônico , Imidazóis/administração & dosagem , Rim/patologia , Rim/fisiologia , Nefrectomia/efeitos adversos , Ratos , Ratos Wistar , Insuficiência Renal/etiologia , Insuficiência Renal/patologia , Insuficiência Renal/fisiopatologia , Ácido ZoledrônicoRESUMO
BACKGROUND: Unliteral nephrectomy (UNX) results in the reduction of kidney mass. The remaining kidney undergoes compensatory renal growth via hypertrophy of the glomeruli and renal tubules to maintain a normal glomerular filtration rate (GFR). These compensatory mechanisms result in increased capillary pressure and glomerular hyperfiltration to increase single nephron GFR. Over time, hyperfiltration may lead to kidney scarring and the development of hypertension. OBJECTIVES: The first objective of this study was to test the hypothesis that a 50% reduction in functioning nephrons in juvenile mice leads to increased blood pressure over a 24-hour phase. The second objective was to test the hypothesis that UNX leads to changes in the expression and activity of kidney proteases in juvenile mice. METHODS: Eight male C57B6 juvenile wild-type mice were subject to UNX and an equal number of mice were subject to sham (SH) surgery. Metabolic cage studies were performed for 5 weeks to collect urine produced during the inactive and active phases. Blood pressure was measured using the tail cuff method twice weekly and tail blood was collected on different days during the inactive or active phase of each animal. The mice were euthanized at the age of 9 weeks. Western blotting and immunohistochemistry were performed to investigate changes in renal protein expression of various cathepsins and renal kallikrein 1 (KLK1) between the two groups. Protease activity assays were performed using kidney lysates and urine samples from each group. RESULTS: Compared to the SH group, UNX mice showed a persistent increase in blood pressure at week 3 which progressed toward the end of the study at week 5 of age. Cathepsin B, D, and S expression and activity were up-regulated in kidney cortex lysates from UNX mice compared to the SH control group. KLK1 protein expression was down-regulated and urinary nitric oxide excretion was decreased in UNX mice compared to the SH control group. CONCLUSION: UNX results in the development of persistent and progressive hypertension. Down-regulation of KLK1 and up-regulation of various cathepsins may contribute to the development of hypertension via multiple mechanisms including a decrease in nitric oxide (NO) production.
RESUMO
Unilateral nephrectomy, a procedure reducing kidney mass, triggers a compensatory response in the remaining kidney, increasing its size and function to maintain a normal glomerular filtration rate (GFR). Recent research has highlighted the role of extracellular vesicles (EVs) in renal physiology and disease, although their involvement in unilateral nephrectomy has been underexplored. In this study, unilateral nephrectomy was performed on young mice, and urinary extracellular vesicles (uEVs) characterization and cargo were analyzed. Kidney volume increased significantly post-nephrectomy, demonstrating compensatory hypertrophy. Serum creatinine, cystatin C, and urinary electrolytes concentrations were similar in both nephrectomized and control groups. Western blot analysis revealed upregulation of sodium-glucose cotransporter 2 (SGLT2) and sodium chloride cotransporter (NCC), and downregulation of sodiumpotassium-chloride co-transporter (NKCC2) and epithelial sodium channel (ENaC) in the nephrectomized group. Metabolomic analysis of uEVs showed an enrichment of certain metabolites, including citrate and stachydrine. Interestingly, uEVs from the nephrectomized group demonstrated a protective effect, downregulating signal transducer and activator of transcription 3 (STAT3) and reducing reactive oxygen species (ROS) in renal proximal cells, compared to uEVs from the control group. This study suggests that uEVs contain bioactive components capable of inducing protective, anti-inflammatory, anti-fibrinolytic, and antioxidative effects in renal cells. These findings contribute to our understanding of uEVs' role in renal compensatory mechanisms after unilateral nephrectomy and may hold promise for future therapeutic interventions in renal diseases.
Assuntos
Vesículas Extracelulares , Hipertrofia , Rim , Nefrectomia , Animais , Vesículas Extracelulares/metabolismo , Camundongos , Rim/metabolismo , Rim/patologia , Hipertrofia/metabolismo , Masculino , Metabolômica/métodos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Most previous studies of living kidney donors have been retrospective and have lacked suitable healthy controls. Needed are prospective controlled studies to better understand the effects of a mild reduction in kidney function from kidney donation in otherwise healthy individuals. STUDY DESIGN: Prospective, controlled, observational cohort study. SETTING & PARTICIPANTS: Consecutive patients approved for donation at 8 transplant centers in the United States were asked to participate. For every donor enrolled, an equally healthy control with 2 kidneys who theoretically would have been suitable to donate a kidney also was enrolled. PREDICTOR: Kidney donation. MEASUREMENTS: At baseline predonation and at 6 months after donation, medical history, vital signs, measured (iohexol) glomerular filtration rate, and other measurements were collected. There were 201 donors and 198 controls who completed both baseline and 6-month visits and form the basis of this report. RESULTS: Compared with controls, donors had 28% lower glomerular filtration rates at 6 months (94.6 ± 15.1 [SD] vs 67.6 ± 10.1 mL/min/1.73 m(2); P < 0.001), associated with 23% greater parathyroid hormone (42.8 ± 15.6 vs 52.7 ± 20.9 pg/mL; P < 0.001), 5.4% lower serum phosphate (3.5 ± 0.5 vs 3.3 ± 0.5 mg/dL; P < 0.001), 3.7% lower hemoglobin (13.6 ± 1.4 vs 13.1 ± 1.2 g/dL; P < 0.001), 8.2% greater uric acid (4.9 ± 1.2 vs 5.3 ± 1.1 mg/dL; P < 0.001), 24% greater homocysteine (1.2 ± 0.3 vs 1.5 ± 0.4 mg/L; P < 0.001), and 1.5% lower high-density lipoprotein cholesterol (54.9 ± 16.4 vs 54.1 ± 13.9 mg/dL; P = 0.03) levels. There were no differences in albumin-creatinine ratios (5.0 [IQR, 4.0-6.6] vs 5.0 [IQR, 3.3-5.4] mg/g; P = 0.5), office blood pressures, or glucose homeostasis. LIMITATIONS: Short duration of follow-up and possible bias resulting from an inability to screen controls with kidney and vascular imaging performed in donors. CONCLUSIONS: Kidney donors have some, but not all, abnormalities typically associated with mild chronic kidney disease 6 months after donation. Additional follow-up is warranted.
Assuntos
Transplante de Rim/fisiologia , Transplante de Rim/tendências , Doadores Vivos , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/cirurgia , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Consentimento Livre e Esclarecido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Adulto JovemRESUMO
Distant renal cell carcinoma (RCC) metastatic disease is mostly seen in the lungs, bones, and lymph nodes. The incidence of local recurrences within the ipsilateral retroperitoneum (RFR) is very low. We report a case of a 79-year-old male with recurrent left renal fossa RCC with pancreatic tail invasion who presented with large bowel obstruction. To the best of our knowledge, no cases have been reported of recurrent left renal fossa RCC initially presenting as extrinsic large bowel obstruction.
RESUMO
A simple renal cyst can become infected spontaneously due to various modes like direct cyst penetration during biopsy or surgical exploration, hematogenous spread of infection, and retrograde infection from the urinary tract. Managing such cases becomes challenging due to the risk of rupture of the cyst, causing sequelae of bacteremia and septic shock. Aspiration of cyst along with imaging modality can strengthen the diagnosis. However, nephrectomy coupled with antibacterial administration is an updated therapeutic intervention for an infected simple renal cyst. Our patient presented with a renal cyst at each pole of the left kidney complicated by infection, and after confirming the diagnosis on computed tomography, we performed a right-sided nephrectomy after proper informed consent. The patient responded well to treatment and improved her quality of life.
RESUMO
Background: Living kidney donation is considered generally safe in healthy individuals; however, there is a need to better understand the long-term effects of donation on blood pressure and kidney function. Objectives: To determine the risk of hypertension in healthy, normotensive adults who donate a kidney compared with healthy, normotensive non-donors with similar indicators of baseline health. We will also compare the 2 groups on the rate of decline in kidney function, the risk of albuminuria, and changes in health-related quality of life. Design Participants and Setting: Prospective cohort study of 1042 living kidney donors recruited before surgery from 17 transplant centers (12 in Canada and 5 in Australia) between 2004 and 2014. Non-donor participants (n = 396) included relatives or friends of the donor, or donor candidates who were ineligible to donate due to blood group or cross-match incompatibility. Follow-up will continue until 2021, and the main analysis will be performed in 2022. The anticipated median (25th, 75th percentile, maximum) follow-up time after donation is 7 years (6, 8, 15). Measurements: Donors and non-donors completed the same schedule of measurements at baseline and follow-up (non-donors were assigned a simulated nephrectomy date). Annual measurements were obtained for blood pressure, estimated glomerular filtration rate (eGFR), albuminuria, patient-reported health-related quality of life, and general health. Outcomes: Incident hypertension (a systolic/diastolic blood pressure ≥ 140/90 mm Hg or receipt of anti-hypertensive medication) will be adjudicated by a physician blinded to the participant's donation status. We will assess the rate of change in eGFR starting from 12 months after the nephrectomy date and the proportion who develop an albumin-to-creatinine ratio ≥3 mg/mmol (≥30 mg/g) in follow-up. Health-related quality of life will be assessed using the 36-item RAND health survey and the Beck Anxiety and Depression inventories. Limitations: Donation-attributable hypertension may not manifest until decades after donation. Conclusion: This prospective cohort study will estimate the attributable risk of hypertension and other health outcomes after living kidney donation.
Contexte: Chez les personnes en bonne santé, faire don d'un rein est généralement considéré comme sûr. Il convient toutefois de mieux comprendre les effets à long terme de ce don sur la pression artérielle et la fonction rénale. Objectifs: Déterminer le risque d'hypertension chez les adultes sains et normotendus qui donnent un rein par rapport à des non-donneurs sains et normotendus ayant des indicateurs de santé de base similaires. Nous comparerons également le taux de réduction de la fonction rénale, le risque d'albuminurie et les changements dans la qualité de vie liée à la santé entre les deux groupes. Cadre type d'étude et participants: Étude de cohorte rétrospective menée sur 1 042 donneurs de rein vivants, recrutés avant la chirurgie dans 17 centres de transplantation (12 au Canada et 5 en Australie) entre 2004 et 2014. Le groupe des non-donneurs (n=396) était constitué de parents ou amis du donneur, ou de candidats donneurs non admissibles à faire un don en raison d'une incompatibilité de groupe sanguin ou lors du test de compatibilité croisée. Le suivi s'est poursuivi jusqu'en 2021 et l'analyse principale sera effectuée en 2022. Le temps de suivi médian prévu (25e percentile, 75e percentile, maximum) après le don est de 7 ans (6, 8, 15 ans). Mesures: Les donneurs et les non-donneurs ont complété le même calendrier de mesures à l'inclusion et pendant le suivi (une date simulée de néphrectomie a été attribuée aux non-donneurs). Des mesures annuelles de pression artérielle, de débit de filtration glomérulaire estimé (DFGe), d'albuminurie, de qualité de vie liée à la santé autodéclarée et de santé générale ont été obtenues. Issues principales: L'hypertension incidente (pression artérielle systolique/diastolique ≥ 140/90 mm Hg ou prise d'un médicament antihypertenseur) sera jugée par un médecin aveugle au statut de don du participant. Nous évaluerons le taux de variation du DFGe à partir de 12 mois après la date de la néphrectomie et la proportion de participants qui développeront un rapport albumine/créatinine ≥ 3 mg/mmol (≥ 30 mg/g) pendant le suivi. La qualité de vie liée à la santé sera évaluée à l'aide du questionnaire de santé RAND de 36 questions et de l'Inventaire d'anxiété et de dépression de Beck. Limites: L'hypertension attribuable au don pourrait ne pas se manifester avant des décennies après le don. Conclusion: Cette étude de cohorte prospective permettra d'estimer le risque d'hypertension attribuable au don et d'autres effets sur la santé du donneur après un don de rein.