Relationship between serum lithium concentration and kidney damage in a preclinical model

Objectives: The aim of the present study was to assess whether there is a relationship between serum lithium concentrations and the magnitude of kidney damage in a preclinical model. Methods: Thirty Wistar male rats were randomized into three groups: control group fed ad libitum powered standard diet for 3 months; and experimental groups fed ad libitum the same diet supplemented with 30 or 60 mmol/kg diet for 3 months (LowLi and HighLi groups respectively). Laboratory parameters were assessed at months 1 and 3 and histopathological changes were evaluated after 3 months. Results: Serum lithium levels in experimental rats were within therapeutic range used in humans throughout the entire experiment. After 3 months of treatment, lithium levels were statistically higher in HighLi group. Rats of the LowLi group showed dilation of cortical tubules although with similar clearance of creatinine. Rats from the HighLi group had greater histopathological damage in addition to lower creatinine clearance than the other two groups. Conclusions: Our study suggests that during long-term treatments, even with serum lithium levels within the therapeutic range used in humans, the risk of kidney damage could increase proportionally to the serum lithium concentration.Fil: Ossani, Georgina Paula. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Alemán. Laboratorio de Medicina Experimental; ArgentinaFil: Uceda, Ana Margarita. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Lago, Néstor R.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Martino, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin

Variable Number Tandem Repeats in the promoter region of prostacyclin synthase gene in choline deficient rats.

Weanling Sprague-Dawley rats were fed on a choline-deficient diet with hydrogenated vegetable oil and corn oil as lipids develop acute renal failure. Pathogenesis of the latter is controversial and an ischemic mechanism has been proposed. Arachidonic acid derivatives are involved in the regulation of vascular tonus. Vasospasm could be due to an increase in tromboxane A2-mediated vasoconstriction or to a decrease in prostacyclin-induced vasodilatation. Enzymes involved in the synthesis of both compounds are tromboxane A2- and prostacyclin-synthase respectively. The aim of this study was to identify the variable number tandem repeats (VNTR) in the promoter region of prostacyclin synthase gene and verify if there exists a relationship between the occurrence of VNTR in those choline-deficient rats which die because of acute renal failure and those which do not. We verified the presence of the VNTR in the prostacyclin synthase rat gene, but we did not find any difference in the molecular weight of the alleles between experimental and control rats. Renal reparation of the acute kidney injury due to choline deficiency in some rats is not related with differences in VNTR in the promoter region of the prostacyclin synthase gene. Weanling Sprague-Dawley rats fed a choline-deficient diet with hydrogenated vegetable oil and corn oil as lipids develop acute renal failure. Its pathogenesis is controversial. The ischemic mechanism has been proposed. Derivatives from arachidonic acid are involved in the regulation of vascular tone. Vasospasm could be due to an increase in vasoconstriction mediated by tromboxane A2 or a decrease in vasodilatation by prostacyclin. Enzymes involved in the synthesis of them are tromboxane A2 and prostacyclin synthase respectively. The aim of this study is to identify the variable number tandem repeats (VNTR) in the promoter region of prostacyclin synthase gene and verify if there exists a relationship between the VNTR and those rats which dye as a consequence of acute renal failure due to choline deficiency and those which do not die. The VNTR presence was detected by molecular methods. We verified the presence of the VNTR in the prostacyclin synthase rat gene. We did not find difference in the molecular weight of the alleles between experimental and control rats. Renal reparation of the acute kidney injury due to choline deficiency in Sprague-Dawley rats is not related with differences in prostacyclin synthase VNTR, in the promoter region of this gene.Fil: Denninghoff, Valeria Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Ossani, Georgina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Uceda, Ana Margarita. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Avagnina Iribarren, Maria Alejandra. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Elsner, Boris. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Monserrat, Alberto Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentin

Chronic kidney disease and renal failure due to lithium treatment

El litio fue aprobado para la terapéutica del trastorno bipolar en la década de 1970 y aún hoy se considera como una droga de primera línea para el tratamiento de esta patología. Teniendo en cuenta que el trastorno bipolar comienza frecuentemente entre los 15-35 años y requiere tratamiento a largo plazo, el monitoreo de los efectos adversos de los fármacos empleados es de fundamental importancia. En los últimos años se ha renovado el interés sobre el riesgo de enfermedad renal crónica y falla renal inducidas por litio, con hallazgos que sugieren que ambas complicaciones serían más frecuentes de que lo que se consideraba. Estos datos han llevado a cuestionar las medidas tradicionales de monitoreo de la función renal como los niveles de urea y creatinina plasmática, que muestran incrementos significativos sólo luego de que la tasa de filtración glomerular se redujo a la mitad. Datos preliminares han sugerido que ciertos biomarcadores de injuria renal, como la lipocalina asociada a la gelatinasa de neutrófilos urinaria, podrían ser indicadores más sensibles del daño renal. El empleo de nuevos biomarcadores que permitan una detección precoz del daño renal podría ser de gran utilidad para seguimiento de pacientes tratados con litio.Lithium has been approved for the treatment of bipolar disorder since the 1970s and even today it is considered a first-line drug for the treatment of this disease. As bipolar disorder often begins between 15-35 years of age and requires long-term treatment, the assessment of the adverse effects of the drugs used is critical. Recently, there has been renewed interest on the risk of chronic kidney disease and kidney failure induced by lithium, with findings suggesting that both complications could be more frequent than previously considered. These data have led to question traditional measures of monitoring renal function such as levels of urea and creatinine, which show significant increases only after an important reduction of the glomerular filtration rate. Preliminary data have suggested that certain biomarkers of kidney injury, such as neutrophil gelatinase-associated lipocalin, may be more sensitive indicators of renal damage. The use of new biomarkers that allow early detection of kidney damage could be useful for the monitoring of patients treated with lithium.Fil: Ossani, Georgina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Martino, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias. Programa de Trastornos Bipolares; ArgentinaFil: Toblli, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Hospital Alemán. Laboratorio de Medicina Experimental; Argentin

Relationship between serum lithium concentration and kidney damage in a preclinical model

Objectives: The aim of the present study was to assess whether there is a relationship between serum lithium concentrations and the magnitude of kidney damage in a preclinical model. Methods: Thirty Wistar male rats were randomized into three groups: control group fed ad libitum powered standard diet for 3 months; and experimental groups fed ad libitum the same diet supplemented with 30 or 60 mmol/kg diet for 3 months (LowLi and HighLi groups respectively). Laboratory parameters were assessed at months 1 and 3 and histopathological changes were evaluated after 3 months. Results: Serum lithium levels in experimental rats were within therapeutic range used in humans throughout the entire experiment. After 3 months of treatment, lithium levels were statistically higher in HighLi group. Rats of the LowLi group showed dilation of cortical tubules although with similar clearance of creatinine. Rats from the HighLi group had greater histopathological damage in addition to lower creatinine clearance than the other two groups. Conclusions: Our study suggests that during long-term treatments, even with serum lithium levels within the therapeutic range used in humans, the risk of kidney damage could increase proportionally to the serum lithium concentration.Fil: Ossani, Georgina Paula. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Alemán. Laboratorio de Medicina Experimental; ArgentinaFil: Uceda, Ana Margarita. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Lago, Néstor R.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Martino, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin

Oxidative damage: The biochemical mechanism of cellular injury and necrosis in choline deficiency

Oxidative stress and damage are characterized by decreased tissue antioxidant levels, consumption of tissue α-tocopherol, and increased lipid peroxidation. These processes occur earlier than necrosis in the liver, heart, kidney, and brain of weanling rats fed a choline deficient (CD) diet. In tissues, water-soluble antioxidants were analyzed as total reactive antioxidant potential (TRAP), α-tocopherol content was estimated from homogenate chemiluminescence (homogenate-CL), and lipid peroxidation was evaluated by thiobarbituric acid reactive substances (TBARS). Histopathology showed hepatic steatosis at days 1-7, tubular and glomerular necrosis in kidney at days 6 and 7, and inflammation and necrosis in heart at days 6 and 7. TRAP levels decreased by 18%, 48%, 56%, and 66% at day 7, with t1/2 (times for half maximal change) of 2.0, 1.8, 2.5, and 3.0 days in liver, kidney, heart, and brain, respectively. Homogenate-CL increased by 97%, 113%, 18%, and 297% at day 7, with t1/2 of 2.5, 2.6, 2.8, and 3.2 days in the four organs, respectively. TBARS contents increased by 98%, 157%, 104%, and 347% at day 7, with t1/2 of 2.6, 2.8, 3.0, and 5.0 days in the four organs, respectively. Plasma showed a 33% decrease in TRAP and a 5-fold increase in TBARS at day 5. Oxidative stress and damage are processes occurring earlier than necrosis in the kidney and heart. In case of steatosis prior to antioxidant consumption and increased lipid peroxidation, no necrosis is observed in the liver.Fil: Repetto, Marisa Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Ossani, Georgina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Monserrat, Alberto Juan. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Boveris, Alberto Antonio. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Renal Damage During Continuous Versus Intermittent Treatment with Lithium

The aim of this study was to evaluate renal damage in animals treated with lithium continuously versus intermittently. Rats were randomized into three groups: control group fed ad libitum powered standard diet for 3 months and two experimental groups, one of them fed ad libitum the same diet or the same diet supplemented with 60 mmol of lithium/kg diet every alternate week, for 3 months and the other fed ad libitum powered standard diet for one and a half month and the same diet supplemented with 60 mmol of lithium/kg diet for the last month and a half. Lithemias in experimental groups were within therapeutic range used in humans. At the end of the protocol, diuresis was higher in experimental groups compared to control group. There was no difference in serum creatinine and creatinine clearance. Both experimental groups showed hypertrophy, hyperplasia, and dilatation of cortical collecting tubules although dilatation was greater in continuous group. Longer studies are necessary to clarify the evolution of renal damage. Our preliminary study shows that histopathological damage associated with the use of lithium occurs during both continuous and intermittent treatment, but it seems to be somewhat greater in the continuous group.Fil: Ossani, Georgina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Aleman. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; ArgentinaFil: Uceda, Ana Margarita. Hospital Aleman. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; ArgentinaFil: Ponzo, Osvaldo Juan. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Lago, Néstor R.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; ArgentinaFil: Martino, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin

Menhaden oil rich diet and experimental renal damage due to ischemia reperfusion

Renal necrosis can be induced in weanling rats due to choline deficient diet. Menhaden oil has a protective effect against the development of renal necrosis in choline deficient weanling rats. The aim of this work was to determine the effects of menhaden oil in a model of acute kidney injury due to ischemia reperfusion. Wistar rats were divided into two groups and fed vegetable oils or menhaden oil as lipids. Unilateral renal ischemia was performed for 30 minutes and animals were sacrificed 48 hours later. Histopathological examination showed no significant differences between groups. Menhaden oil did not prevent histopathological lesions.Fil: Ossani, Georgina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Marcotegui, Ariel R.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Uceda, Ana Margarita. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Monserrat, Alberto Juan. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Lago, Néstor Rubén. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Perazzo, Juan C.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentin

Short-term Menhaden Oil Rich Diet Changes Renal Lipid Profile in Acute Kidney Injury

Weanling male Wistar rats fed a choline-deficient diet develop acute kidney injury. Menhaden oil, which is a very important source of omega-3 fatty acids, has a notorious protective effect. The mechanism of this protection is unknown; one possibility could be that menhaden oil changes renal lipid profile, with an impact on the functions of biological membranes. The aim of this work was to study the renal lipid profile in rats fed a choline-deficient diet with menhaden oil or vegetable oil as lipids. Rats were divided into 4 groups and fed four different diets for 7 days: choline-deficient or choline-supplemented diets with corn and hydrogenated oils or menhaden oil. Serum homocysteine, vitamin B12, and folic acid were analyzed. Renal lipid profile, as well as the fatty acid composition of the three oils, was measured. Choline-deficient rats fed vegetable oils showed renal cortical necrosis. Renal omega-6 fatty acids were higher in rats fed a choline-deficient diet and a choline-supplemented diet with vegetable oils, while renal omega-3 fatty acids were higher in rats fed a choline-deficient diet and a choline-supplemented diet with menhaden oil. Rats fed menhaden oil diets had higher levels of renal eicosapentaenoic and docosahexaenoic acids. Renal myristic acid was increased in rats fed menhaden oil. The lipid renal profile varied quickly according to the type of oil contented in the diet.Fil: Ossani, Georgina Paula. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Denninghoff, Valeria Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; ArgentinaFil: Uceda, Ana Margarita. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Díaz, Maria L.. Hospital Británico de Buenos Aires; ArgentinaFil: Uicich, Raúl. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Monserrat, Alberto Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentin

Ocular lesions and experimental choline deficiency

Previous studies have shown ocular heaemorrhages in choline-deficient rats. The aim of this paper is to study further the relationship between ocular and renal lesions and biochemical alterations in rats fed a choline- deficient diet. Fifty one weanling male Wistar rats, were divided into two groups. Thirty one of them were fed a choline-deficient diet and the rest was fed a choline- supplemented diet ad libitum.  Animals from both groups were killed between the fifth and the eighth day. Urea, creatinine and homocysteine concentrations in blood were determined. Eyes were used for light microscopy study; high resolution light microscopy and the study of the retina as “rétine a plat”. Kidneys were studied by light microscopy. Choline-supplemented rats did not show ocular or renal lesion. Choline-deficient rats that showed renal lesions, tubular or cortical necrosis, did not always have ocular changes. There were no ocular changes in the only choline-deficient rat without renal lesion. The ocular changes consisted mainly in haemorrhage in both cameras and ciliary and vitreous bodies. Correlations between ocular and renal lesion (r=0.72, p<0.0001, CI95%: 0.48-0.86); ocular lesion and creatinine (r=0.86, p<0.0001, CI95%: 0.72-0.93) and ocular lesion and urea (r=0.70, p<0.0001, CI95%: 0.44-0.85) were positive. Choline-deficiency induces ocular haemorrhagic lesions after the development of renal necrosis. The ocular pathology could be due to the immaturity of the ocular vasculature at this age. The hyaloid, choroid and retinal system are involved.Fil: Ossani, Georgina Paula. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Pelayes, David. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Diaz, Maria L.. Hospital Británico de Buenos Aires; ArgentinaFil: Lago, Néstor Rubén. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Fariña, Silvia L.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Monserrat, Alberto Juan. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; ArgentinaFil: Zarate, Jorge O.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentin

Role of Oxidative Stress in Lithium-Induced Nephropathy

Long-term lithium treatment was associated with chronic kidney disease and renal failure although the underlying pathogenic mechanisms are not certainty known. The aim of this study was to evaluate changes in oxidative stress measures as well as renal functional and structural alterations associated with chronic use of lithium in rats. Forty Wistar male rats were randomized into four groups: control groups fed ad libitum powered standard diet for 1 and 3 months and experimental groups fed ad libitum the same diet supplemented with 60 mmol/kg diet for 1 and 3 months. Histopathological changes, laboratory parameters, and oxidative stress measurements were assessed at months 1 and 3. The experimental animals showed alteration of the cortical tubules from the first month of lithium-treatment and a decrease in the glomerular filtration rate and in the glomerular area at the third month. There was an increase in thiobarbituric acid reactive substances and carbonyls, as well as an increase in reduced glutathione, in the kidney of rats exposed to lithium. These changes were evident from the first month of treatment and remained throughout the experiment. Our results suggest that, oxidative stress could be one of the pathogenic mechanisms involved in the structural and functional alterations of the kidney associated with prolonged use of lithium. The study of the pathogenic mechanisms involved in lithium-induced nephropathy is a critical issue for the development of new strategies for prevention and/or early detection.Fil: Ossani, Georgina Paula. Hospital Aleman. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Uceda, Ana Margarita. Hospital Aleman. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; ArgentinaFil: Acosta, Juan M.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Lago, Néstor Rubén. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; ArgentinaFil: Repetto, Marisa Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Martino, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Toblli, Jorge Eduardo. Hospital Aleman. Laboratorio de Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin