RESUMEN
AIMS: Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, has been shown to play a role in kidney diseases. However, its role in hyperoxaluria-induced renal tubular epithelial cells (TECs) injury remains unclear. MATERIALS AND METHODS: A hyperoxaluria rat model was established by providing 0.5% ammonium chloride and drinking water containing 1% ethylene glycol. TECs were exposed to oxalate stress. The 3-DZNeP, a selective EZH2 inhibitor, was administered in vivo and in vitro. Cell viability, ROS production, and apoptosis ratio were evaluated. Crystal deposition was detected by Von Kossa staining and kidney tissue injury was detected by HE staining and TUNEL. EZH2, H3K27me3, cleaved-caspase3, IL-6, and MCP-1 were examined by western blot or immunohistochemistry. KEY FINDINGS: Inhibition of EZH2 by 3-DZNeP significantly attenuated hyperoxaluria-induced oxidative and inflammatory injury and CaOx crystal deposition in vivo. Similarly, inhibition of EZH2 using 3-DZNeP or shRNA restored cell viability, suppressed LDH release and the production of intracellular ROS in vitro. Furthermore, the MAPK signaling pathway and FoxO3a levels were activated or elevated in TECs exposed to oxalate. EZH2 inhibition using 3-DZNeP blocked these effects. CC90003 (ERK inhibitor) or SB203580 (p38 inhibitor) did not significantly affect the expression of FoxO3a in TECs treated with 3-DZNeP and oxalate; only SP600125 (JNK inhibitor) significantly decreased FoxO3a expression. SIGNIFICANCE: EZH2 inhibition protects against oxalate-induced TECs injury and reduces CaOx crystal deposition in the kidney may by modulating the JNK/FoxO3a pathway; EZH2 may be a promising therapeutic target in TECs injury.
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Lesión Renal Aguda/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Hiperoxaluria/metabolismo , Lesión Renal Aguda/fisiopatología , Animales , Apoptosis/efectos de los fármacos , China , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Células Epiteliales/metabolismo , Proteína Forkhead Box O3/fisiología , Hiperoxaluria/fisiopatología , Riñón/metabolismo , Enfermedades Renales/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Enteric hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric hyperoxaluria was completed as part of a Kidney Health Initiative-sponsored project to describe enteric hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.
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Hiperoxaluria/fisiopatología , Hiperoxaluria/terapia , Enfermedades Gastrointestinales/complicaciones , Humanos , Hiperoxaluria/etiologíaRESUMEN
BACKGROUND: In this article, we present two cases of patients with acute renal insufficiency with a history of exocrine pancreatic insufficiency. In one case, this was caused by pancreaticoduodenectomy; in the other, by alcohol abuse. Neither patient had considerable proteinuria or haematuria. Their renal biopsies showed tubulopathy with widespread oxalate crystals, characterised by their birefringence in light microscopy. Restricting oxalate intake and prescribing oxalate binding agents reduced serum oxalate levels. Renal function partially recovered in both patients. Oxalate nephropathy is associated with exocrine pancreatic insufficiency, gastric and pancreatic surgery, and inflammatory bowel disease. Normally, dietary calcium binds oxalate to form calcium oxalate, which is excreted in the stool. In patients with pancreatic insufficiency, fatty acids bind calcium instead, allowing oxalate to be absorbed in the colon. The resulting hyperoxaluria can cause oxalate crystal formation, tubulopathy, and renal insufficiency. Treatment relies on decreasing the amount of absorbable oxalate in the intestinal lumen, as well as lowering urinary oxalate concentrations. CONCLUSION: Secondary hyperoxaluria is a common cause of renal insufficiency and should be considered in patients with a medical history of pancreatic insufficiency and progressive kidney injury.
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Insuficiencia Pancreática Exocrina/complicaciones , Hiperoxaluria/complicaciones , Anciano , Alcoholismo/complicaciones , Humanos , Hiperoxaluria/diagnóstico , Hiperoxaluria/fisiopatología , Hiperoxaluria/terapia , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Oxalate is a toxic byproduct of metabolism and is normally produced in quantities easily removed from the body. However, under specific circumstances oxalate production is increased resulting in deposition of calcium oxalate (CaOx) crystals in the kidneys as well as other organs causing inflammation and injury. Excessive buildup of crystal deposits in the kidneys causes eventual loss of renal function requiring renal transplantation. Areas covered: Cellular exposure to CaOx crystals induces the production of reactive oxygen species (ROS) with the involvement of renin-angiotensin aldosterone system (RAAS), mitochondria, and NADPH oxidase. Inflammasomes are activated and pro-inflammatory cytokines, such as IL-1ß and IL-18 are produced. We reviewed results of experimental and clinical studies of crystal renal epithelial cell interactions with emphasis on cellular injury and ROS production. Expert opinion: Treatment should depend upon the level of hyperoxaluria and whether it is associated with CaOx crystal deposition. Persistent low grade or intermittent hyperoxaluria can be treated with antioxidants, free radical scavengers. Hyperoxaluria associated with CaOx crystal deposition will require administration of angiotensin II receptor blockers, and NADPH oxidase or NLRP3 inflammasome inhibitors. DASH-style diet will be beneficial in both cases.
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Hiperoxaluria/terapia , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/farmacología , Oxalato de Calcio/metabolismo , Depuradores de Radicales Libres/farmacología , Humanos , Hiperoxaluria/fisiopatologíaRESUMEN
Most kidney stones (KS) are composed of calcium oxalate and small increases in urine oxalate enhance the stone risk. Obesity is a risk factor for KS, and urinary oxalate excretion increases with increased body size. We previously established the obese ob/ob ( ob) mice as a model (3.3-fold higher urine oxalate) to define the pathogenesis of obesity-associated hyperoxaluria (OAH). The purpose of this study was to test the hypothesis that the obesity-associated enhanced small intestinal paracellular permeability contributes to OAH by increasing passive paracellular intestinal oxalate absorption. ob Mice have significantly higher jejunal (1.6-fold) and ileal (1.4-fold) paracellular oxalate absorption ex vivo and significantly higher (5-fold) urine [13C]oxalate following oral gavage with [13C]oxalate, indicating increased intestinal oxalate absorption in vivo. The observation of higher oxalate absorption in vivo compared with ex vivo suggests the possibility of increased paracellular permeability along the entire gut. Indeed, ob mice have significantly higher fractions of the administered sucrose (1.7-fold), lactulose (4.4-fold), and sucralose (3.1-fold) excreted in the urine, reflecting increased gastric, small intestinal, and colonic paracellular permeability, respectively. The ob mice have significantly reduced gastrointestinal occludin, zonula occludens-1, and claudins-1 and -3 mRNA and total protein expression. Proinflammatory cytokines and oxidative stress, which are elevated in obesity, significantly enhanced paracellular intestinal oxalate absorption in vitro and ex vivo. We conclude that obese mice have significantly higher intestinal oxalate absorption and enhanced gastrointestinal paracellular permeability in vivo, which would likely contribute to the pathogenesis of OAH, since there is a transepithelial oxalate concentration gradient to drive paracellular intestinal oxalate absorption. NEW & NOTEWORTHY This study shows that the obese ob/ob mice have significantly increased gastrointestinal paracellular oxalate absorption and remarkably enhanced paracellular permeability along the entire gut in vivo, which are likely mediated by the obesity-associated increased systemic and intestinal inflammation and oxidative stress. A transepithelial oxalate concentration gradient driving gastrointestinal paracellular oxalate absorption exists, and therefore, our novel findings likely contribute to the hyperoxaluria observed in the ob/ob mice and hence to the pathogenesis of obesity-associated hyperoxaluria.
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Tracto Gastrointestinal/metabolismo , Hiperoxaluria/fisiopatología , Mucosa Intestinal/metabolismo , Obesidad/metabolismo , Animales , Inflamación/metabolismo , Absorción Intestinal/fisiología , Intestino Delgado/metabolismo , Yeyuno/metabolismo , Ratones Endogámicos C57BL , PermeabilidadRESUMEN
Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80%) and total protein (- 62%) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity-associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets.
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Hiperoxaluria/etiología , Secreciones Intestinales/metabolismo , Yeyuno/metabolismo , Obesidad/complicaciones , Oxalatos/metabolismo , Animales , Antiportadores/metabolismo , Células CACO-2 , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Humanos , Hiperoxaluria/metabolismo , Hiperoxaluria/fisiopatología , Mediadores de Inflamación/metabolismo , Absorción Intestinal , Yeyuno/fisiopatología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/fisiopatología , Vías Secretoras , Transportadores de Sulfato/metabolismoRESUMEN
Experimental induction of hyperoxaluria by ethylene glycol (EG) administration is disapproved as it causes metabolic acidosis while the oral administration of chemically synthesized potassium oxalate (KOx) diet does not mimic our natural system. Since existing models comprise limitations, this study is aimed to develop an improved model for the induction of dietary hyperoxaluria, and nephrocalcinosis in experimental rats by administration of naturally available oxalate rich diet. Male albino Wistar rats were divided into five groups. Group I, control; group II rats received 0.75% EG, group III rats fed with 5% KOx diet and group IV and V rats were administered with spinach extract of 250 and 500 mg soluble oxalate/day respectively, for 28 d. Urine and serum biochemistry were analyzed. After the experimental period, rats were sacrificed, liver and kidney tissue homogenates were used for antioxidant and lipid peroxidation assay. Relative change in expression of kidney injury molecule-1 (KIM-1) and crystal modulators genes in kidney tissues were evaluated. Tissue damage was assessed by histology studies of liver and kidney. Experimental group rats developed hyperoxaluria and crystalluria. Urine parameters, serum biochemistry, antioxidant profile, lipid peroxidation levels and gene expression analysis of experimental group II and III rats reflected acute kidney damage compared to group V rats. Histopathology results showed moderate hyperplasia in liver and severe interstitial inflammation in kidneys of group II and III than group V rats. Ingestion of naturally available oxalate enriched spinach extract successfully induced dietary hyperoxaluria and nephrocalcinosis in rats with minimal kidney damage.
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Modelos Animales de Enfermedad , Enfermedades Transmitidas por los Alimentos/etiología , Hiperoxaluria/etiología , Nefrocalcinosis/etiología , Ácido Oxálico/envenenamiento , Hojas de la Planta/efectos adversos , Spinacia oleracea/efectos adversos , Administración Oral , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Biomarcadores/orina , Cristalización , Glicol de Etileno/toxicidad , Enfermedades Transmitidas por los Alimentos/metabolismo , Enfermedades Transmitidas por los Alimentos/patología , Enfermedades Transmitidas por los Alimentos/fisiopatología , Regulación de la Expresión Génica/efectos de los fármacos , Hiperoxaluria/metabolismo , Hiperoxaluria/patología , Hiperoxaluria/fisiopatología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Nefrocalcinosis/metabolismo , Nefrocalcinosis/patología , Nefrocalcinosis/fisiopatología , Ácido Oxálico/administración & dosificación , Ácido Oxálico/química , Ácido Oxálico/metabolismo , Extractos Vegetales/efectos adversos , Extractos Vegetales/química , Hojas de la Planta/química , Ratas Wistar , Insuficiencia Renal/etiología , Spinacia oleracea/químicaRESUMEN
BACKGROUND: Primary hyperoxaluria (PH) is a rare, genetic disorder which involves the overproduction of endogenous oxalate, leading to hyperoxaluria, recurrent urolithiasis and/or progressive nephrocalcinosis and eventually resulting in kidney failure and systemic oxalosis. The aim of this trial was to investigate whether treatment involving an oxalate-metabolising bacterium (Oxalobacter formigenes) could reduce urinary oxalate excretion in PH patients. METHODS: The efficacy and safety of O. formigenes (Oxabact® OC5; OxThera AB, Stockholm, Sweden) was evaluated in a randomised, placebo-controlled, double-blind study for 8 weeks. The primary objective was reduction in urinary oxalate excretion (Uox). Secondary objectives included faecal O. formigenes count and decrease in plasma oxalate concentration (Pox). RESULTS: Twenty-eight patients randomised 1:1 to the treatment group (OC5) or the placebo group completed the study. After 8 weeks of treatment, there was no significant difference in the change in Uox (mmol/24 h/1.73 m2) between the groups (OC5: +0.042, placebo: -0.140). Post-hoc analysis showed a statistically significant increase in Uox per urinary creatinine excretion in the OC5 group (OC5: +5.41, placebo: -15.96; p = 0.030). Change in Pox from baseline was not significantly different between groups (p = 0.438). The O. formigenes cell count was significantly increased in OC5-treated patients (p < 0.001) versus placebo. The treatment response to O. formigenes was related to individual stage of kidney deterioration, and Pox was directly correlated to kidney function, even for early-stage patients (chronic kidney disease stage 1). No safety issues were observed. CONCLUSIONS: Treatment with OC5 did not significantly reduce Uox or Pox over 8 weeks of treatment. The treatment was well tolerated and successfully delivered to the gastrointestinal tract.
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Hiperoxaluria/terapia , Oxalobacter formigenes , Adolescente , Carga Bacteriana , Niño , Preescolar , Método Doble Ciego , Heces/microbiología , Femenino , Humanos , Hiperoxaluria/fisiopatología , Hiperoxaluria/orina , Pruebas de Función Renal , Masculino , Ácido Oxálico/orina , Probióticos/administración & dosificación , Probióticos/efectos adversos , Probióticos/uso terapéutico , Comprimidos Recubiertos , Resultado del Tratamiento , Adulto JovenRESUMEN
Objective: This case demonstrates the difficulty of diagnostics of oxalate nephropathy and possibility of development of acute kidney injury. Summary: The paper describes a patient with oxalate nephropathy and acute kidney injury. Specific features of oxalate diathesis are discussed as well as approaches to its diagnosis. Clinical peculiarities and diagnostic difficulties are described. Conclusions: Early diagnosis of oxalate nephropathy and treatment permits to improve prognosis.
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Lesión Renal Aguda , Hiperoxaluria , Riñón/diagnóstico por imagen , Ácido Oxálico/metabolismo , Pielonefritis/diagnóstico , Diálisis Renal/métodos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/terapia , Adulto , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Humanos , Hiperoxaluria/complicaciones , Hiperoxaluria/diagnóstico , Hiperoxaluria/fisiopatología , Hiperoxaluria/terapia , Pruebas de Función Renal/métodos , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Ultrasonografía/métodosRESUMEN
The purpose of the present study was to evaluate the nephro-protective potential of N-acetylcysteine against hyperoxaluria-induced renal mitochondrial dysfunction in rats. Nine days dosing of 0.4 % ethylene glycol +1 % ammonium chloride, developed hyperoxaluria in male wistar rats which resulted in renal injury and dysfunction as supported by increased level of urinary lactate dehydrogenase, calcium, and decreased creatinine clearance. Mitochondrial oxidative strain in hyperoxaluric animals was evident by decreased levels of superoxide dismutase, glutathione peroxidase, glutathione reductase, reduced glutathione, and an increased lipid peroxidation. Declined activities of respiratory chain enzymes and tricarboxylic acid cycle enzymes showed mitochondrial dysfunction in hyperoxaluric animals. N-acetylcysteine (50 mg/kg, i.p.), by virtue of its -SH reviving power, was able to increase the glutathione levels and thus decrease the oxidative stress in renal mitochondria. Hence, mitochondrial damage is, evidently, an essential event in ethylene glycol-induced hyperoxaluria and N-acetylcysteine presented itself as a safe and effective remedy in combating nephrolithiasis.
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Acetilcisteína/farmacología , Hiperoxaluria/fisiopatología , Mitocondrias/efectos de los fármacos , Enfermedades Mitocondriales/tratamiento farmacológico , Sustancias Protectoras/farmacología , Animales , Calcio/orina , Ciclo del Ácido Cítrico/efectos de los fármacos , Creatinina/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Hiperoxaluria/metabolismo , Hiperoxaluria/orina , Riñón/metabolismo , Riñón/fisiopatología , L-Lactato Deshidrogenasa/orina , Peroxidación de Lípido/efectos de los fármacos , Masculino , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/fisiopatología , Enfermedades Mitocondriales/orina , Nefrolitiasis/metabolismo , Nefrolitiasis/fisiopatología , Nefrolitiasis/orina , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Secondary hyperoxaluria is a multifactorial disease affecting several organs and tissues, among which stand native and transplanted kidneys. Nephrocalcinosis and nephrolithiasis may lead to renal insufficiency. Patients suffering from secondary hyperoxaluria, should be promptly identified and appropriately treated, so that less renal damage occurs. The aim of this review is to underline the causes of hyperoxaluria and the related pathophysiologic mechanisms, which are involved, along with the description of seven cases of irreversible renal graft injury due to secondary hyperoxaluria.
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Hiperoxaluria/epidemiología , Insuficiencia Renal/epidemiología , Diagnóstico Diferencial , Progresión de la Enfermedad , Humanos , Hiperoxaluria/diagnóstico , Hiperoxaluria/etiología , Hiperoxaluria/fisiopatología , Cálculos Renales/epidemiología , Fallo Renal Crónico/patología , Trasplante de Riñón , Síndromes de Malabsorción/complicaciones , Factores de RiesgoRESUMEN
Studies have shown that compensatory adaptations in gastrointestinal oxalate transport can impact the amount of oxalate excreted by the kidney. Hyperoxaluria is a major risk factor in the formation of kidney stones, and oxalate is derived from both the diet and the liver metabolism of glyoxylate. Although the intestine generally absorbs oxalate from dietary sources and can contribute as much as 50% of urinary oxalate, enteric oxalate elimination plays a significant role when renal function is compromised. While the mechanistic basis for these changes in the direction of intestinal oxalate movements in chronic renal failure involves an upregulation of angiotensin II receptors in the large intestine, enteric secretion/excretion of oxalate can also occur by mechanisms that are independent of angiotensin II. Most notably, the commensal bacterium Oxalobacter sp. interacts with the host enterocyte and promotes the movement of oxalate from the blood into the lumen, resulting in the beneficial effect of significantly lowering urinary oxalate excretion. Changes in the passive permeability of the intestine, such as in steatorrhoea and following gastric bypass, also promote oxalate absorption and hyperoxaluria. In summary, this report highlights the two-way physiological signalling between the gut and the kidney, which may help to alleviate the consequences of certain kidney diseases.
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Derivación Gástrica , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Ácido Oxálico/metabolismo , Insuficiencia Renal Crónica/metabolismo , Adaptación Fisiológica , Animales , Humanos , Hiperoxaluria/metabolismo , Hiperoxaluria/fisiopatología , Absorción Intestinal , Eliminación Intestinal , Intestinos/microbiología , Intestinos/fisiopatología , Riñón/fisiopatología , Cálculos Renales/metabolismo , Cálculos Renales/fisiopatología , Ácido Oxálico/orina , Permeabilidad , Eliminación Renal , Insuficiencia Renal Crónica/fisiopatología , Transducción de SeñalRESUMEN
La hiperoxaluria primaria (HOP) se debe a un desorden metabólico hereditario autosómico recesivo, del metabolismo del glioxalato, que causa una producción excesiva de oxalato. El trastorno más frecuente y grave se debe al déficit enzimático de alanin: glioxalato aminotransferasa (HOP tipo I) específico en el peroxisoma hepático. Dado que el oxalato no se metaboliza en los humanos y se elimina por vía renal, el riñón es el primer órgano afectado, dando lugar a la aparición de litiasis de repetición, nefrocalcinosis e insuficiencia renal precoz. Con la progresión de la insuficiencia renal, especialmente en pacientes sometidos a hemodiálisis (HD), el oxalato cálcico se deposita masivamente en los tejidos, denominándose a esto último oxalosis. El diagnóstico se basa en los antecedentes familiares, la presencia de urolitiasis y/o nefrocalcinosis, hiperoxaluria, depósitos tisulares de oxalato formando granulomas en formas avanzadas, análisis molecular de ADN y análisis enzimático si procede. Se requiere una alta sospecha diagnóstica, por lo que, desafortunadamente, en muchos casos se diagnostica tras su recidiva en el trasplante renal. El manejo conservador de la enfermedad (alta ingesta líquida, piridoxina e inhibidores de la cristalización) debe ser precoz, para retrasar el daño renal. El tratamiento con diálisis es inefectivo para depurar el exceso de oxalatos. Tras el trasplante renal suele observarse una rápida aparición de los depósitos de oxalato en el injerto y los resultados de esta técnica, salvo excepciones, son desalentadores. El trasplante hepático anticipado, o simultáneo con el trasplante renal cuando ya existe daño irreversible de este órgano, es la opción terapéutica de elección para corregir la enfermedad de base y suprimir la sobreproducción de oxalatos. Dada la condición de enfermedad rara y su heterogeneidad genética y clínica, no es posible obtener evidencias a través de ensayos clínicos aleatorizados. Por lo tanto, las recomendaciones las establecen grupos de expertos apoyados en publicaciones de acreditado rigor científico. En este sentido, un grupo de expertos europeos (OxalEurope) ha elaborado unas recomendaciones diagnósticas y terapéuticas publicadas en 2012 (AU)
Primary hyperoxaluria (PH) occurs due to an autosomal recessive hereditary disorder of the metabolism of glyoxylate, which causes excessive oxalate production. The most frequent and serious disorder is due to enzyme deficit of alanine-glyoxylate aminotransferase (PH type I) specific to hepatic peroxisome. As oxalate is not metabolised in humans and is excreted through the kidneys, the kidney is the first organ affected, causing recurrent lithiasis, nephrocalcinosis and early renal failure. With advance of renal failure, particularly in patients on haemodialysis (HD), calcium oxalate is massively deposited in tissues, which is known as oxalosis. Diagnosis is based on family history, the presence of urolithiasis and/or nephrocalcinosis, hyperoxaluria, oxalate deposits in tissue forming granulomas, molecular analysis of DNA and enzyme analysis if applicable. High diagnostic suspicion is required; therefore, unfortunately, in many cases it is diagnosed after its recurrence following kidney transplantation. Conservative management of this disease (high liquid intake, pyridoxine and crystallisation inhibitors) needs to be adopted early in order to delay kidney damage. Treatment by dialysis is ineffective in treating excess oxalate. After the kidney transplant, we normally observe a rapid appearance of oxalate deposits in the graft and the results of this technique are discouraging, with very few exceptions. Pre-emptive liver transplantation, or simultaneous liver and kidney transplants when there is already irreversible damage to the kidney, is the treatment of choice to treat the underlying disease and suppress oxalate overproduction. Given its condition as a rare disease and its genetic and clinical heterogeneity, it is not possible to gain evidence through randomised clinical trials. As a result, the recommendations are established by groups of experts based on publications of renowned scientific rigour. In this regard, a group of European experts (OxalEurope) has drawn up recommendations for diagnosis and treatment, which were published in 2012 (AU)
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Humanos , Hiperoxaluria/fisiopatología , Glioxilatos/metabolismo , Nefrolitiasis/fisiopatología , Insuficiencia Renal/fisiopatología , Nefrocalcinosis/fisiopatología , Trasplante de Riñón , Trasplante de HígadoRESUMEN
Renal oxalate deposition can be seen with primary hyperoxaluria, malabsorptive states, ethylene glycol toxicity and, rarely, with excessive vitamin C ingestion. We report a case of secondary hyperoxaluria in which the diagnosis was not considered initially because there was no past history of urinary calculi and no evidence of nephrocalcinosis on plain X-ray of the abdomen and ultrasonography. The disease was detected and diagnosed only after kidney transplantation. Secondary oxalosis can cause graft loss or delayed graft function. Biopsy of the allograft should be carefully examined for oxalate deposits even in the absence of a family history. When oxalosis is diagnosed, intensifying hemodialysis (HD) to eliminate calcium oxalate can help in the recovery of renal function in some cases. Systematic vitamin C supplementation in HD patients should be avoided as it can be a cause of secondary oxalosis.
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Ácido Ascórbico/efectos adversos , Hiperoxaluria/inducido químicamente , Fallo Renal Crónico/terapia , Trasplante de Riñón , Riñón/efectos de los fármacos , Diálisis Renal , Adulto , Biopsia , Femenino , Humanos , Hiperoxaluria/diagnóstico , Hiperoxaluria/fisiopatología , Hiperoxaluria/terapia , Riñón/patología , Riñón/fisiopatología , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/cirugía , Diálisis Renal/efectos adversos , Resultado del TratamientoRESUMEN
Crystal-cell interaction has been reported as one of the most crucial steps in urinary stone formation. Hyperoxaluria-induced apoptotic changes in renal tubular epithelial cells is the end-stage of this interaction. We aimed to evaluate the possible pathways responsible in the induction of apoptosis within the involved cells by assessing the receptoral expression of three different pathways. 16 male Spraque-Dowley rats were divided into two groups: Group 1 (n:8) received only distilled water; Group 2 (n:8) received 0.75 % ethylene glycol (EG) in their daily water to induce hyperoxaluria for 2 weeks. After 24 h urine collection, all animals were euthenized and right kidneys were removed and fixed for immunohistochemical evaluation. Oxalate and creatinine levels (in 24 h-urine) and FAS, tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor-2 expressions (in tissue) have been assessed. In addition to TNF (p = 0.0007) expression; both FAS (p = 0.0129 ) and FASL (p = 0.032) expressions significantly increased in animals treated with EG. The expressions of TRAIL (p = 0.49) and TRAIL-R2 (p = 0.34) receptors did not change statistically after hyperoxaluria induction. Although a positive correlation with cytokine expression density and 24 h-urinary oxalate expression (mg oxalate/mg creatinine) has been assessed with TNF (p = 0.04, r = 0.82), FAS (p = 0.05, r = 0.80), FAS-L (p = 0.04, r = 0.82); no correlation could be demonstrated between TRAIL and TRAIL R2 expressions. Our results indicate that apoptosis induced by oxalate is possibly mediated via TNF and FAS pathways. However, TRAIL and TRAIL-R2 seemed to have no function in the cascade. Correlation with urinary oxalate levels did further strengthen the findings.
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Apoptosis/fisiología , Hiperoxaluria/patología , Hiperoxaluria/fisiopatología , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Factores de Necrosis Tumoral/fisiología , Animales , Citocinas/fisiología , Proteína Ligando Fas/fisiología , Hiperoxaluria/complicaciones , Masculino , Nefrolitiasis/etiología , Nefrolitiasis/patología , Nefrolitiasis/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF/fisiologíaRESUMEN
PURPOSE: We determined the effect of dietary fat and oxalate on fecal fat excretion and urine parameters in a rat model of Roux-en-Y gastric bypass surgery. MATERIALS AND METHODS: Diet induced obese Sprague-Dawley® rats underwent sham surgery as controls (16), or Roux-en-Y gastric bypass surgery (19). After recovery, rats had free access to a normal calcium, high fat (40%) diet with or without 1.5% potassium oxalate for 5 weeks and then a normal (10%) fat diet for 2 weeks. Stool and urine were collected after each period. Fecal fat was determined by gas chromatography and urine metabolites were evaluated by assay spectrophotometry. RESULTS: Daily fecal fat excretion remained low in controls on either diet. However, Roux-en-Y gastric bypass rats ingested a food quantity similar to that of controls but had eightfold higher fecal fat excretion (p <0.001) and heavier stools (p = 0.02). Compared to controls, gastric bypass rats on the high fat diet with potassium oxalate had a fivefold increase in urine oxalate excretion (p <0.001), while gastric bypass rats without potassium oxalate had a twofold increase in urine calcium (p <0.01). Lowering dietary fat in gastric bypass rats with potassium oxalate led to a 50% decrease in oxalate excretion (p <0.01), a 30% decrease in urine calcium and a 0.3 U increase in urine pH (p <0.001). CONCLUSIONS: In this Roux-en-Y gastric bypass model high fat feeding resulted in steatorrhea, hyperoxaluria and low urine pH, which were partially reversible by lowering the dietary fat and oxalate content. Roux-en-Y gastric bypass rats on normal fat and no oxalate diets excreted twice as much oxalate as age matched, sham operated controls. Although Roux-en-Y gastric bypass hyperoxaluria appears primarily mediated by gut and diet, secondary causes of oxalogenesis from liver or other mechanisms deserve further exploration.
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Grasas de la Dieta/metabolismo , Derivación Gástrica/efectos adversos , Hiperoxaluria/etiología , Obesidad/cirugía , Oxalatos/metabolismo , Esteatorrea/etiología , Animales , Modelos Animales de Enfermedad , Heces/química , Derivación Gástrica/métodos , Hiperoxaluria/fisiopatología , Masculino , Obesidad/complicaciones , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/fisiopatología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Medición de Riesgo , Esteatorrea/fisiopatología , Resultado del Tratamiento , UrinálisisRESUMEN
BACKGROUND AND OBJECTIVES: Enteric overabsorption of oxalate may lead to hyperoxaluria and subsequent acute oxalate nephritis (AON). AON related to chronic pancreatitis is a rare and poorly described condition precluding early recognition and treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We collected the clinical characteristics, treatment, and renal outcome of 12 patients with chronic pancreatitis-associated AON followed in four French renal units. RESULTS: Before AON, mild to moderate chronic kidney disease was present in all patients, diabetes mellitus in eight (insulin [n = 6]; oral antidiabetic drugs [n = 2]), and known chronic pancreatitis in only eight. At presentation, pancreas imaging showed gland atrophy/heterogeneity, Wirsung duct dilation, calcification, or pseudocyst. Renal findings consisted of rapidly progressive renal failure with tubulointerstitial profile. Acute modification of glomerular filtration preceded the AON (i.e., diarrhea and diuretics). Increase in urinary oxalate excretion was found in all tested patients and hypocalcemia in nine (<1.5 mmol/L in four patients). Renal biopsy showed diffuse crystal deposits, highly suggestive of oxalate crystals, with tubular necrosis and interstitial inflammatory cell infiltrates. Treatment consisted of pancreatic enzyme supplementation, oral calcium intake, and an oxalate-free diet in all patients and renal replacement therapy in five patients. After a median follow-up of 7 months, three of 12 patients reached end-stage renal disease. CONCLUSION: AON is an under-recognized severe crystal-induced renal disease with features of tubulointerstitial nephritis that may occur in patients with a long history of chronic pancreatitis or reveal the pancreatic disease. Extrinsic triggering factors should be prevented.
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Oxalato de Calcio/metabolismo , Hiperoxaluria/etiología , Fallo Renal Crónico/etiología , Riñón/metabolismo , Nefritis Intersticial/etiología , Pancreatitis Crónica/complicaciones , Insuficiencia Renal/etiología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Francia , Tasa de Filtración Glomerular , Humanos , Hiperoxaluria/metabolismo , Hiperoxaluria/patología , Hiperoxaluria/fisiopatología , Hiperoxaluria/terapia , Riñón/fisiopatología , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/patología , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Nefritis Intersticial/metabolismo , Nefritis Intersticial/patología , Nefritis Intersticial/fisiopatología , Nefritis Intersticial/terapia , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/patología , Pancreatitis Crónica/fisiopatología , Pancreatitis Crónica/terapia , Insuficiencia Renal/metabolismo , Insuficiencia Renal/patología , Insuficiencia Renal/fisiopatología , Insuficiencia Renal/terapia , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Vitamin E was previously reported to reduce calcium oxalate (CaOx) crystal formation. This study explored whether vitamin E deficiency affects intrarenal oxidative stress and accelerates crystal deposition in hyperoxaluria. The control (C) group of rats received a standard diet and drinking water, while the experimental groups received 0.75% ethylene glycol (EG) in drinking water for 42 days. Of the latter, one group received a standard diet (EG group), one received a low-vitamin E (LE) diet (EG+LE group), and the last received an LE diet with vitamin E supplement (4 mg) (EG+LE+E group). The C+LE and C+LE+E groups were the specific controls for the last two experimental groups, respectively. In a separate experiment, EG and EG+LE rats were studied on days 3-42 to examine the temporal relationship between oxidative change and crystal formation. Urinary biochemistry and activity/levels of antioxidative and oxidative enzymes in glomeruli and tubulointerstitial specimens (TIS) were examined. In EG rats, CaOx crystal accumulation was associated with low antioxidative enzyme activity in TIS and with increased oxidative enzyme expression in glomeruli. In the EG+LE group, marked changes in antioxidative and oxidative enzyme levels were seen and correlated with massive CaOx deposition and tubular damage. The increased oxidative stress seen with EG+LE treatment was largely reversed by vitamin E supplementation. A temporal study showed that decrease in antioxidative defense and increased free radical formation in the EG+LE group occurred before crystal deposition. This study shows that low vitamin E disrupts the redox balance and causes cell death, thereby favoring crystal formation.
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Oxalato de Calcio/metabolismo , Hiperoxaluria/metabolismo , Riñón/metabolismo , Estrés Oxidativo/fisiología , Deficiencia de Vitamina E/metabolismo , Animales , Cristalización , Suplementos Dietéticos , Modelos Animales de Enfermedad , Glicol de Etileno , Radicales Libres/metabolismo , Hiperoxaluria/inducido químicamente , Hiperoxaluria/fisiopatología , Riñón/fisiopatología , Masculino , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Superóxidos/metabolismo , Vitamina E/metabolismo , Vitamina E/farmacología , Xantina Oxidasa/metabolismoRESUMEN
This retrospective survey examines the etiology of nephrocalcinosis (NC) in 40 patients (26 boys), over an 8-year period. The median age at onset of symptoms and presentation was 36 months and 72 months, respectively. Clinical features included marked failure to thrive (82.5%), polyuria (60%) and bony deformities (52.5%). The etiology of NC included distal renal tubular acidosis (RTA) in 50% patients and idiopathic hypercalciuria and hyperoxaluria in 7.5% each. Other causes were Bartter syndrome, primary hypomagnesemia with hypercalciuria, severe hypothyroidism and vitamin D excess. No cause for NC was found in 12.5% patients. Specific therapy, where possible, ameliorated the biochemical aberrations, although the extent of NC remained unchanged. At a median (range) follow up of 35 (14-240) months, glomerular filtration rate (GFR) had declined from 82.0 (42-114) ml/min per 1.73 m2 body surface area to 70.8 (21.3-126.5) ml/min per 1.73 m2 body surface area (P = 0.001). Our findings confirm that, even with limited diagnostic facilities, protocol-based evaluation permits determination of the etiology of NC in most patients.