Increased Plasma Creatinine Levels Research Articles

Development of cardiovascular disease due to renal insufficiency in male sheep following fetal unilateral nephrectomy

Renal insufficiency is associated with the development of cardiovascular disease. This study investigated whether reduced fetal renal mass resulted in renal insufficiency, hypertension, cardiac dysfunction and whether these changes progressed with age. Fetal uninephrectomy was performed at 100-day gestation (term, 150 days) and studies performed in male sheep from 6 weeks to 24 months of age. Renal function declined with age in sham animals as demonstrated by increasing plasma creatinine levels and urinary excretion of albumin. The age-related decline in renal function was exacerbated in animals that had undergone fetal uninephrectomy. Evidence of renal insufficiency was indicated from as early as 6 weeks of age with elevations in plasma creatinine (Ptreatment < 0.001), urea (Ptreatment < 0.001) and sodium (Ptreatment < 0.05) levels in uninephrectomized lambs as compared with sham animals. At 6 months, urinary albumin excretion (P < 0.001) was increased and urinary sodium excretion (P < 0.001) decreased in the uninephrectomized animals. By 24 months, renal function had deteriorated further with significant progression of albuminuria (P(treatment x age) < 0.001). Elevation of mean arterial pressure (approximately 15 mmHg) was associated with significantly increased cardiac output, stroke volume and plasma volume at 6 months; arterial pressure (approximately 27 mmHg) had increased further in uninephrectomized animals at 24 months and was driven by increased total peripheral resistance. Cardiac functional reserve (dobutamine challenge) was reduced in uninephrectomized animals at 6 and 24 months of age (Ptreatment < 0.001), and this was associated with left ventricular enlargement (P < 0.001) and reduced fractional shortening (P < 0.01). Fetal uninephrectomy causing a reduction in nephron endowment results in an accelerated age-related decline in renal function. This is associated with an early onset of elevated blood pressure and impairments in cardiac structure and function.

Renal haemodynamic, microcirculatory, metabolic and histopathological responses to peritonitis-induced septic shock in pigs

IntroductionOur understanding of septic acute kidney injury (AKI) remains incomplete. A fundamental step is the use of animal models designed to meet the criteria of human sepsis. Therefore, we dynamically assessed renal haemodynamic, microvascular and metabolic responses to, and ultrastructural sequelae of, sepsis in a porcine model of faecal peritonitis-induced progressive hyperdynamic sepsis.MethodsIn eight anaesthetised and mechanically ventilated pigs, faecal peritonitis was induced by inoculating autologous faeces. Six sham-operated animals served as time-matched controls. Noradrenaline was administered to maintain mean arterial pressure (MAP) greater than or equal to 65 mmHg. Before and at 12, 18 and 22 hours of peritonitis systemic haemodynamics, total renal (ultrasound Doppler) and cortex microvascular (laser Doppler) blood flow, oxygen transport and renal venous pressure, acid base balance and lactate/pyruvate ratios were measured. Postmortem histological analysis of kidney tissue was performed.ResultsAll septic pigs developed hyperdynamic shock with AKI as evidenced by a 30% increase in plasma creatinine levels. Kidney blood flow remained well-preserved and renal vascular resistance did not change either. Renal perfusion pressure significantly decreased in the AKI group as a result of gradually increased renal venous pressure. In parallel with a significant decrease in renal cortex microvascular perfusion, progressive renal venous acidosis and an increase in lactate/pyruvate ratio developed, while renal oxygen consumption remained unchanged. Renal histology revealed only subtle changes without signs of acute tubular necrosis.ConclusionThe results of this experimental study argue against the concept of renal vasoconstriction and tubular necrosis as physiological and morphological substrates of early septic AKI. Renal venous congestion might be a hidden and clinically unrecognised contributor to the development of kidney dysfunction.

INTRAPERITONEAL GLYCEROL INDUCES OXIDATIVE STRESS IN RAT KIDNEY

1. Glycerol has been used for the treatment of intracranial hypertension, cerebral oedema and glaucoma. Experimentally, intramuscular administration of hypertonic glycerol solution is used to produce acute renal failure. In this model, glycerol causes rhabdomyolysis and myoglobinuria, resulting in the development of renal injury. The pathogenesis is thought to involve vascular congestion, the formation of casts and oxidative stress. However, the effect of glycerol itself independent of rhabdomyolysis has not been investigated. Therefore, the aim of the present study was to investigate the effects of i.p. glycerol on some biochemical and oxidative stress parameters in the kidney of young rats. 2. Rats received 10 mL/kg, i.p., hypertonic glycerol solution (50% v/v) or saline (NaCl 0.85 g%) followed by 24 h water deprivation. Twenty-four hours after the administration of glycerol, rats were killed. Creatinine levels and the activity of creatine kinase (CK) and lactate dehydrogenase (LDH) were determined in the plasma. In addition, CK, pyruvate kinase and LDH activity and oxidative stress parameters (free radical formation, lipid peroxidation and protein carbonylation) were measured in renal tissue. 3. Glycerol did not alter plasma CK activity and increased plasma creatinine levels, suggesting renal insufficiency and the absence of rhabdomyolysis. Renal CK and pyruvate kinase activity was decreased, suggesting diminution of energy homeostasis in the kidney. Plasma and renal LDH activity was decreased, whereas the formation of free radicals, lipid peroxidation and protein carbonylation were increased, suggesting oxidative stress. 4. These results are similar to those described after the intramuscular administration of glycerol. Therefore, it is possible that glycerol may provoke renal lesions by mechanisms other than those induced by rhabdomyolysis.

Renal Medullary Hemodynamics in Response to Contrast Media

Contrast media induced nephropathy (CIN) is the third leading cause for acute renal failure. Pathophysiology of CIN is poorly understood, but involves hypoxia of the outer medulla. Until today, the role of osmolality of contrast media (CM) is considered the essential feature causing CIN. Here we describe a novel, perhaps most relevant characteristic of CM regarding the pathophysiology of CIN: The rheological properties, i.e. viscosity of CM. In 122 rats, we administered CM of equivalent iodine concentrations but differing physiocochemical properties: the high‐osmolality iopromide was compared to the high‐viscosity iodixanol. In addition, the non‐iodinated substances mannitol (equivalent osmolality to iopromide) and dextran (equivalent viscosity to iodixanol) were also studied. Both types of CM transiently increased renal blood flow. The high‐osmolality agents iopromide and mannitol markedly increased urine production where as iodixanol, which caused less diuresis, significantly enhanced urine viscosity. Only the high‐viscosity agents iodixanoland dextran decreased renal medullary blood flux, erythrocyte concentration, and pO2. Moreover, iodixanol prolonged the tubuloglomerular feedback response and increased plasma creatinine levels to a greater extent than iopromide or dextran. Thus, viscosity of CM may play a significant role in CIN.

Decreased Expression of Na+/K+-ATPase, NHE3, NBC1, AQP1 and OAT in Gentamicin-induced Nephropathy

The present study was aimed to determine whether there is an altered regulation of tubular transporters in gentamicin-induced nephropathy. Sprague-Dawley male rats (200~250 g) were subcutaneously injected with gentamicin (100 mg/kg per day) for 7 days, and the expression of tubular transporters was determined by immunoblotting and immunohistochemistry. The mRNA and protein expression of OAT was also determined. Gentamicin-treated rats exhibited significantly decreased creatinine clearance along with increased plasma creatinine levels. Accordingly, the fractional excretion of sodium increased. Urine volume was increased, while urine osmolality and free water reabsorption were decreased. Immunoblotting and immunohistochemistry revealed decreased expression of Na(+)/K(+)-ATPase, NHE3, NBC1, and AQP1 in the kidney of gentamicin-treated rats. The expression of OAT1 and OAT3 was also decreased. Gentamicin-induced nephropathy may at least in part be causally related with a decreased expression of Na(+)/K(+)-ATPase, NHE3, NBC1, AQP1 and OAT.

Viscosity of Contrast Media Perturbs Renal Hemodynamics

Contrast-induced nephropathy is a common cause of acute renal failure, and the mechanisms underlying this injury are not completely understood. We sought to determine how physicochemical properties of contrast media may contribute to kidney damage in rats. We administered contrast media of equivalent iodine concentrations but differing physiocochemical properties: the high-osmolality iopromide was compared to the high-viscosity iodixanol. In addition, the non-iodinated substances mannitol (equivalent osmolality to iopromide) and dextran (equivalent viscosity to iodixanol) were also studied. Both types of contrast media transiently increased renal and hindquarter blood flow. The high-osmolality agents iopromide and mannitol markedly increased urine production whereas iodixanol, which caused less diuresis, significantly enhanced urine viscosity. Only the high-viscosity agents iodixanol and dextran decreased renal medullary blood flux, erythrocyte concentration, and pO2. Moreover, iodixanol prolonged the tubuloglomerular feedback response and increased plasma creatinine levels to a greater extent than iopromide or dextran. Therefore, the viscosity of contrast media may play a significant role in contrast-induced nephropathy.

Efectos renales y sistémicos en la prevención de la nefrotoxicidad por contraste con sueros salino (0,9%) e hiposalino (0,45%)

Physiological and hypotonic saline solutions have been used interchangeably for preventing contrast media nephrotoxicity. No analysis of the possible differential effects of the two solutions on the milieu interieur or intercompartmental fluid volumes has been performed. Our aim was to study the systemic and renal effects of two types of saline solution regularly used to prevent contrast media nephrotoxicity in patients undergoing coronary angiography. Changes in electrolyte levels and volume distribution were studied in 71 individuals who were randomized to receive either 0.9% isotonic saline (n=36) or 0.45% hypotonic saline (n=35) during the 12 hours before and after contrast injection (2000 mL in each period). The creatinine level was elevated equally often in the isotonic and hypotonic saline groups. Isotonic saline administration led to reductions in hemoglobin level, hematocrit and plasma albumin level, and to increases in plasma volume, by 12.3% and 10.4% at 24 and 48 hours, respectively. These changes were significant compared with baseline measurements and compared with the group that received hypotonic saline. Neither of the two saline solutions resulted in a change in plasma atrial natriuretic peptide level. Plasma and urine osmolality decreased only with hypotonic saline. The increase in plasma creatinine level was similar with both isotonic and hypotonic saline. During standard therapy for preventing contrast media nephrotoxicity, (1) isotonic saline, but not hypotonic saline, increased plasma volume; (2) this increase did not raise the atrial natriuretic peptide level; and (3) no difference in the increase in serum creatinine level was observed between the two saline solutions. These findings provide evidence that 0.45% saline, at a dose suitable for preventing contrast media nephrotoxicity, is associated with a lower risk of volume expansion. This result is important for patients with severely impaired ventricular function.

Effects of resveratrol on glycerol-induced renal injury

Glycerol-induced renal lesions can have many causes, including increased oxidative stress and inflammation. Resveratrol, a polyphenolic phytoalexin found in grapes and red wine, is an antioxidant agent with anti-inflammatory effects. In the present study, we investigated the possible protective effect of resveratrol on glycerol-induced nephrotoxicity. Male Wistar rats were injected intramuscularly with 8 ml/kg of either 50% glycerol ( n = 18), glycerol + resveratrol ( n = 22), 0.15 M saline ( n = 14), saline + carboxymethylcellulose ( n = 10) or saline + resveratrol ( n = 8). The rats were killed 3 days after the injections, at which time the kidneys were removed for histological and immunohistochemical studies and lipid peroxidation determination. Blood and urine samples were collected in order to quantify sodium and creatinine. The results of the histological and immunohistochemical studies were scored according to the extent of damage and immunostaining, respectively, in the cortical tubulointerstitium. Lipid peroxidation was estimated by measuring malondialdehyde in renal tissue samples collected from control rats and glycerol-injected rats. By postinjection day 3, glycerol-only treated rats presented increases in plasma creatinine levels, as well as in fractional excretion of sodium and potassium ( P < 0.001). These increases were less pronounced in glycerol + resveratrol-treated rats ( P < 0.05). Cortical expression of macrophages, lymphocytes, nuclear factor-kappa B, heme oxygenase-1 and nitrotyrosine was greater in glycerol-treated rats than in controls ( P < 0.001). In addition, the histological findings for glycerol-treated rats were characteristic of acute tubular necrosis. Resveratrol attenuated all of these alterations ( P < 0.001). We conclude that resveratrol ameliorates glycerol-induced renal injury by suppressing the inflammatory process and by inhibiting lipid peroxidation.

Wen-pi-tang-Hab-Wu-ling-san attenuates kidney ischemia/reperfusion injury in mice: A role for antioxidant enzymes and heat-shock proteins

The purpose of this study was to investigate the effects of Wen-pi-tang-Hab-Wu-ling-san (WHW) extract, which has been used for treatment of renal diseases, on kidney ischemia/reperfusion (I/R) injury. Thirty minutes of bilateral renal ischemia resulted in disruption of kidney tubular epithelial cells and increased plasma creatinine levels in mice, however these effects were significantly attenuated when WHW was administered prior to I/R. WHW-administration also inhibited post-ischemic decreases of catalase, copper–zinc superoxide dismutase (CuZnSOD), and manganese superoxide dismutase (MnSOD) activity in kidney tissue, leading to decreased tissue hydrogen peroxide levels and lipid peroxidation. Post-ischemic increases of heat-shock protein (HSP)-27 and -72 expressions were greater in mouse kidneys that received WHW. In conclusion, WHW-administration reduced kidney susceptibility to I/R injury, and this reduced susceptibility was associated with greater post-ischemic activation of catalase, CuZnSOD and MnSOD, resulting in reduced hydrogen peroxide levels and lipid peroxidation, as well as higher post-ischemic expression of HSP-27 and -72.

Increased expression of p38 mitogen- activated protein kinase is related to the acute renal lesions induced by gentamicin

Mitogen-activated protein kinases (MAPK) may be involved in the pathogenesis of acute renal failure. This study investigated the expression of p-p38 MAPK and nuclear factor kappa B (NF-kappaB) in the renal cortex of rats treated with gentamicin. Twenty rats were injected with gentamicin, 40 mg/kg, i.m., twice a day for 9 days, 20 with gentamicin + pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor), 14 with 0.15 M NaCl, i.m., twice a day for 9 days, and 14 with 0.15 M NaCl , i.m., twice a day for 9 days and PDTC, 50 mg kg(-1) day(-1), i.p., twice a day for 15 days. The animals were killed 5 and 30 days after the last of the injections and the kidneys were removed for histological, immunohistochemical and Western blot analysis and for nitrate determination. The results of the immunohistochemical study were evaluated by counting the p-p38 MAPK-positive cells per area of renal cortex measuring 0.05 mm2. Creatinine was measured by the Jaffé method in blood samples collected 5 and 30 days after the end of the treatments. Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. In addition, animals killed 5 days after the end of gentamicin treatment presented acute tubular necrosis and increased nitrate levels in the renal cortex. Increased expression of p-p38 MAPK and NF-kappaB was also observed in the kidneys from these animals. The animals killed 30 days after gentamicin treatment showed residual areas of interstitial fibrosis in the renal cortex, although the expression of p-p38 MAPK in their kidneys did not differ from control. Treatment with PDTC reduced the functional and structural changes induced by gentamicin as well as the expression of p-p38 MAPK and NF-kappaB. The increased expression of p-p38 MAPK and NF-kappaB observed in these rats suggests that these signaling molecules may be involved in the pathogenesis of tubulointerstitial nephritis induced by gentamicin.

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (+/+) mice and HO-2 knockout (-/-) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (-/-) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (+/+). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (-/-) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (-/-) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (-/-) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.

Hydrochlorothiazide increases plasma or tissue angiotensin-converting enzyme-inhibitor drug levels in rats with myocardial infarction: Differential effects on lisinopril and zofenopril

Sodium depletion with diuretics augments the efficacy of angiotensin-converting enzyme-inhibitor therapy for hypertension and renal dysfunction, and possibly for left ventricular dysfunction after myocardial infarction. Underlying mechanisms may involve altered angiotensin-converting enzyme-inhibitor pharmacokinetics. We hypothesized that the diuretic hydrochlorothiazide causes increased steady-state levels of the angiotensin-converting enzyme-inhibitors lisinopril and zofenopril in rats with myocardial infarction. Rats were subjected to coronary ligation to induce myocardial infarction. After 1 week, rats were randomized to 50 mg/kg/day hydrochlorothiazide or control treatment for 3 weeks. The last week, rats received lisinopril or zofenopril in equipotentent dosages (3.3 and 10 mg/kg/day, respectively). Rats were sacrificed at T max after the last dose of angiotensin-converting enzyme-inhibitor, and tissues were collected for analysis of drug concentrations. Lisinopril concentrations in plasma were significantly increased by hydrochlorothiazide, at unchanged tissue concentrations. This increase could be fully explained by decreased renal function, as evidenced by increased plasma creatinine levels (lisinopril + hydrochlorothiazide 82 ± 5 μM versus lisinopril 61 ± 5 μM, P < 0.001). In contrast, zofenoprilat levels in kidney and non-infarcted left ventricle were markedly increased by hydrochlorothiazide, whereas plasma concentrations were unchanged. Although hydrochlorothiazide tended to increase plasma creatinine in zofenopril-treated rats as well, this increase was less pronounced (zofenopril + hydrochlorothiazide 61 ± 3 μM versus zofenopril 54 ± 2 μM, P = 0.15). Hydrochlorothiazide increases steady-state angiotensin-converting enzyme-inhibitor drug levels, most likely by affecting their renal clearance. Notably, the lipophilic angiotensin-converting enzyme-inhibitor zofenopril accumulated in tissue, whereas the hydrophilic lisinopril increased in plasma. Whether combining different angiotensin-converting enzyme-inhibitors with hydrochlorothiazide translates into distinct clinical profiles requires further study.

Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a heritable disorder of connective tissue, affecting mainly skin, eye and the cardiovascular system. PXE is characterized by dystrophic mineralization of elastic fibres. The condition is caused by loss of function mutations in ABCC6. We generated Abcc6 deficient mice (Abcc6-/-) by conventional gene targeting. As shown by light and electron microscopy Abcc6-/- mice spontaneously developed calcification of elastic fibres in blood vessel walls and in Bruch's membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Newly developed monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6-/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. We conclude that the phenotype of the Abcc6-/- mouse shares calcification of elastic fibres with human PXE pathology, which makes this model a useful tool to further investigate the aetiology of PXE. Our data support the hypothesis that PXE is in fact a systemic disease.

Mechanisms of antioxidant and pro-oxidant effects of α-lipoic acid in the diabetic and nondiabetic kidney

alpha-Lipoic acid is a potent antioxidant that improves renal function in diabetes by lowering glycemia, however, the mechanisms by which alpha-lipoic acid exerts its antioxidant effects are not completely understood. Metabolic parameters, renal function, and morphology, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunit expression were analyzed in nondiabetic and streptozotocin-induced diabetic rats fed normal rat chow (control) with or without alpha-lipoic acid (30 mg/kg body weight) for 12 weeks. Blood glucose was increased with diabetes (nondiabetic + control 89 +/- 3 mg/dL and diabetic + control 336 +/- 28 mg/dL) and was similar with alpha-lipoic acid treatment (diabetic +alpha-lipoic acid 351 +/- 14 mg/dL). In contrast, alpha-lipoic acid attenuated albuminuria (nondiabetic + control 8.9 +/- 1.3 mg/day; diabetic + control 28.1 +/- 4.6 mg/day; and diabetic +alpha-lipoic acid 17.8 +/- 1.2 mg/day) associated with diabetes. Similarly, alpha-lipoic acid attenuated glomerulosclerosis (nondiabetic + control 0.22 +/- 0.01; diabetic + control 0.55 +/- 0.04; diabetic +alpha-lipoic acid 0.36 +/- 0.03), tubulointerstitial fibrosis (nondiabetic + control 0.42 +/- 0.18; diabetic + control 1.52 +/- 0.05; diabetic +alpha-lipoic acid 1.10 +/- 0.05), superoxide anion (O(.-) (2)) generation (nondiabetic +control 15.8 +/- 1.7; diabetic +control 87.1 +/- 3.5; diabetic +alpha-lipoic acid 25.5 +/- 3.3 RLU/mg protein), and urine 8-isoprostane (8-iso) excretion (nondiabetic + control 7.4 +/- 1.4; diabetic + control 26.0 +/- 4.5; diabetic +alpha-lipoic acid 19.6 +/- 5.6 ng/day) associated with diabetes. alpha-Lipoic acid also reduced kidney expression of NADPH oxidase subunits p22phox and p47phox. Surprisingly, alpha-lipoic acid appears to cause pro-oxidant effects in nondiabetic animals, resulting in increased albuminuria (nondiabetic +alpha-lipoic acid 14.2 +/- 1.2 mg/day), increase in plasma creatinine levels (nondiabetic + control 59 +/- 6; diabetic + control 68 +/- 6; nondiabetic +alpha-lipoic acid 86 +/- 9; diabetic +alpha-lipoic acid 69 +/- 7 mumol/L), exacerbated glomerulosclerosis and tubulointerstitial fibrosis, increased O(.-) (2) generation, up-regulated p22phox and p47phox expression and increased 8-iso excretion. We conclude that alpha-lipoic acid improves albuminuria and pathology in diabetes by reducing oxidative stress, while in healthy animals, alpha-lipoic acid may act as a pro-oxidant, contributing to renal dysfunction.

Angiotensin II and Endothelin in the Renal Cortex During the Evolution of Glycerol-Induced Acute Tubular Necrosis

Hypertonic glycerol injection is one of the most frequently used models of experimental acute renal failure. Late structural changes such as interstitial fibrosis in the renal cortex and tubular atrophy have been detected after severe acute tubular necrosis (ATN). The aim of this study was to investigate the expression of angiotensin II (AII) and endothelin during the evolution of the ATN induced by glycerol and their relationships with the late structural changes observed in the kidneys. Forty-nine male Wistar rats were injected with a 50% glycerol solution, 8 mL/kg, divided into equal amounts, each administered into one hind leg, and 18 with 0.15 M NaCl solution. Blood and urine samples were collected 1, 5, 30, and 60 days after the injections to quantify sodium and creatinine; the animals were killed and the kidneys removed for histologic and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining in the cortical tubulointerstitium. Glycerol-injected rats presented a transitory increase in plasma creatinine levels and in fractional sodium excretion. The immunohistochemical studies showed increased AII and endothelin staining in the renal cortex from rats killed 5 days after glycerol injection (p < 0.001) compared with control that persisted until day 60. The animals killed on days 30 and 60 also presented chronic lesions (fibrosis, tubular dilatation, and atrophy) in the renal cortex, despite the recovery of renal function. AII and endothelin may have contributed to the development of renal fibrosis in these rats.

Inhibition of Nuclear Factor-κB Activation Attenuates Tubulointerstitial Nephritis Induced by Gentamicin

Background: Animals treated with gentamicin can show residual areas of interstitial fibrosis in the renal cortex. This study investigated the expression of nuclear factor-ĸB (NF-ĸB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate (PDTC), an NF-ĸB inhibitor. Methods: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + PDTC, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. Results: Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-ĸB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented fibrosis in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by gentamicin. Conclusions: These data show that inhibition of NF-ĸB activation attenuates tubulointerstitial nephritis induced by gentamicin.

Maximum limits of organic and inorganic mercury in fish feed

The relatively high levels of mercury found in fish feeds might form a fish health and food safety risk. The present study aims to establish sublethal toxic threshold levels in fish and assess feed-fillet transfer of dietary mercury. Atlantic salmon (Salmo salar L.) parr were fed for 4 months on fish meal-based diets supplemented with mercuric chloride (0, 0.1, 1, 10 or 100 mg Hg kg−1 dry weight (DW)) or methylmercuric chloride (0, 0.1, 0.5, 5 or 10 mg MeHg kg−1 DW). At the end of the experiment, dietary inorganic mercury mainly accumulated in intestine (80% of body burden) and assimilation was low (6%). In contrast, methylmercury readily accumulated in internal organs and muscle (80% of body burden) and had a relatively high assimilation (23%). Highest accumulation of dietary inorganic mercury was observed in the gut and kidney. Fish fed 10 mg Hg kg−1 had an early (after 2 months) significant increase in renal metallothionein (MT) level and intestinal cell proliferation, followed by intestinal pathological conditions after 4 months of exposure. At 100 mg Hg kg−1, intestinal and renal function were reduced as seen from the significantly reduced protein and glycogen digestibility and increased plasma creatinine levels. For dietary methylmercury (MeHg), highest accumulation was found in blood and muscle. Intestinal cell proliferation and liver MT significantly increased at 5 mg MeHg kg−1 after 2 months of exposure. At the end of the experiment, blood haematology was significantly affected in fish fed 5 mg MeHg kg−1 and these fish exceeded the current food safety limit for mercury. Tissue MT induction and intestinal cell proliferation appeared to be useful and quantifiable early indicators of toxic mercury exposures. Based on the absence of induction of these early biological markers such as MT and cell proliferation, nonobserved effect levels (NOELs) could be set to 0.5 mg Hg kg−1 for dietary methylmercury and 1 mg Hg kg−1 for inorganic mercury. Lowest observed effect levels (LOELs) levels could be set to 5 mg kg−1 for methylmercury and 10 mg Hg kg−1 for inorganic mercury.

In vivo evidence suggesting a role for purine-catabolizing enzymes in the pathogenesis of cisplatin-induced nephrotoxicity in rats and effect of erdosteine against this toxicity.

The aim of this experimental study was to investigate the possible role of adenosine deaminase (AD) and xanthine oxidase (XO) in the pathogenesis of cisplatin-induced nephrotoxicity and the effect of erdosteine in decreasing the toxicity. The intraperitoneal injection of cisplatin (7 mg kg(-1) body weight) induced a significant increase in plasma creatinine level and blood urea nitrogen (BUN), and plasma and damaged renal tissue activities of AD and XO in rats. Co-treatment with erdosteine (10 mg kg(-1)day(-1)) attenuated the increase in the plasma creatinine and BUN levels, and significantly prevented the increase in tissue and plasma AD and XO activities (P<0.05). The results of this study revealed that XO and AD may play an important role in the pathogenesis of cisplatin-induced nephrotoxicity. The potent free radical scavenger erdosteine may have protective potential in this process and it will become a promising drug in the prevention of this undesired side-effect of cisplatin, but further studies are needed to illuminate the exact protection mechanism of erdosteine against cisplatin-induced nephrotoxicity.

Protective Effect of Quercetin on the Evolution of Cisplatin-Induced Acute Tubular Necrosis

Background: The mechanism of cisplatin-induced nephrotoxicity is unknown, but has been associated with renal lipid peroxidation. The bioflavonoid quercetin may be a potential alternative to reduce cisplatin-induced nephrotoxicity. The aim of this study was to evaluate the effect of quercetin on the evolution of cisplatin-induced acute tubular necrosis. Methods: One hundred and three male Wistar rats were injected with cisplatin (5 mg/kg, i.p.), 43 of them received quercetin (50 mg/kg, by gavage) before cisplatin injection. Blood and urine were collected 5 and 20 days after the injection for the determination of plasma creatinine, urine volume and osmolality. The kidneys were removed for the determination of renal malondialdehyde (MDA) and for histological and immunohistochemical studies. The renal expression of fibronectin, α-smooth muscle actin, vimentin, Jun N-terminal kinase, nuclear factor-ĸB, and macrophages during the evolution of the acute tubular necrosis induced by cisplatin and the histological changes observed in the kidneys were analyzed. Results: Cisplatin-treated rats presented a transitory increase in plasma creatinine levels, tubular cell necrosis and increased immunostaining for vimentin, α-SM-actin, fibronectin, ED1, NF-ĸB, and p-JNK in the renal cortex and outer medulla. These alterations were less intense in animals treated with quercetin. Conclusion: Quercetin treatment attenuated the functional, histological and immunohistochemical alterations induced by cisplatin.

Analgesic use and change in kidney function in apparently healthy men

Background:Studies using a single creatinine measurement have yielded inconsistent results regarding analgesic use and kidney function. Methods:This is a prospective cohort study of 4,494 US male physicians who provided blood samples in both 1982 and 1996. Outcomes measured were increase in plasma creatinine level of 0.3 mg/dL or greater (≥26.5 μmol/L) and decline in glomerular filtration rate (GFR) of 29.0 mL/min/1.73 m2 or greater during this 14-year period. Self-reported use of aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAIDs) was classified as never (<12 pills during the study period), 12 to 1,499 pills, 1,500 to 2,499 pills, and 2,500 or greater pills during the study period. Results:Blood measurements made 14 years apart showed increased creatinine levels in 242 participants and decreased GFRs in 224 participants. Compared with never use, multivariable-adjusted odds ratios (ORs) of increased creatinine levels were 0.98 (95% confidence interval [CI], 0.43 to 2.23) for 2,500 or greater pills of aspirin, 1.02 (95% CI, 0.55 to 1.90) for 2,500 or greater pills of acetaminophen, and 1.12 (95% CI, 0.67 to 1.87) for 2,500 or greater pills of other NSAIDs. For decreased GFRs, ORs for intake of 2,500 or greater pills were 0.75 (95% CI, 0.35 to 1.57) for aspirin, 1.22 (95% CI, 0.66 to 2.26) for acetaminophen, and 1.11 (95% CI, 0.65 to 1.90) for other NSAIDs. Use of aspirin, but not acetaminophen or other NSAIDs, was associated with a reduced risk for change in kidney function in participants without cardiovascular risk factors and a possible but nonsignificant increase in those with cardiovascular risk factors. Conclusion:Occasional to moderate analgesic intake of aspirin, acetaminophen, or NSAIDs does not appear to increase the risk for decline in kidney function during a period of 14 years.