Untreated Chronic Renal Failure Research Articles

Uremic stomatitis: A case report

Uremic stomatitis is a rarely reported oral mucosal disorder associated with renal disorder. It is mostly seen in cases of end stage renal disease or undiagnosed or untreated chronic renal failure. Its frequency has diminished due to the advent of renal dialysis. Clinically uremic stomatitis is characterised by the presence of painful plaques and crusts that are usually distributed on the buccal and labial mucosa, dorsal or ventral surface of the tongue, gingiva and the floor of the mouth. Ultimate treatment consists of improvement of blood urea concentration and underlying renal failure is supported by enhancement of oral hygiene with antiseptic mouthwashes and antimicrobial/ antifungal agents, if necessary. Here we report a case of a 50-year-old Male patient who reported to the department with the complaint of inability to open mouth due to ulcers present intra- orally, who was a kidney patient undergoing dialysis, who was then treated with topical steroid and antifungal medications with follow up made once in a week.

Severe uremic stomatitis in a patient with untreated chronic renal failure

A 36-year-old female patient with chronic renal failure was referred by the internal medicine department for severe and painful oral lesions extending to the nasal mucosa. The patient´s medical record revealed that she did not receive dialysis during the last 2 months. Oral examination revealed white hyperkeratotic lesions of the tongue together with a diffuse erythema covered with thick whitish-yellow pseudo membrane. An ulcerated, painful lesion of 3 cm in size was present in the hard palate. Similar lesions were present in the nostrils, especially on the right side. Painful plaques and crusts were also present in both lips. The patient reported severe burning sensation, xerostomia, and halitosis. She was also suffering from loss of appetite, nausea, and dysphagia. Severe weight loss was also noted. Laboratory tests revealed elevated serum creatinine: 711umol/l ( normal 40-115umol), uremia: 32.8mmol/l (normal 2.8-7.2mmol/l), and uric acid 889umol/l (normal 180-420 umol). Protein C reactive was also elevated with 42 mg/l normal

Uremic Stomatitis: A Case Report

Uremic stomatitis is a rarely reported oral mucosal disorder associated with renal disorder. It is mostly seen in cases of end stage renal disease or undiagnosed or untreated chronic renal failure. Its frequency has diminished due to the advent of renal dialysis. Clinically uremic stomatitis is characterised by the presence of painful plaques and crusts that are usually distributed on the buccal and labial mucosa, dorsal or ventral surface of the tongue, gingiva and the floor of the mouth. Ultimate treatment consists of improvement of blood urea concentration and underlying renal failure is supported by enhancement of oral hygiene with antiseptic mouthwashes and antimicrobial/ antifungal agents, if necessary. Here we report a case of a 50 year old Male patient who reported to the department with the complaint of inability to open mouth due to ulcers present intra-orally, who was a kidney patient undergoing dialysis, who was then treated with topical steroid and antifungal medications with follow up made once in a week.

Effects of Chronic Renal Failure on Brain Cytochrome P450 in Rats.

Chronic renal failure (CRF) impedes renal excretion of drugs and their metabolism by reducing the expression of liver cytochrome P450 (P450). Uremic serum contains factors, such as parathyroid hormone (PTH), that decrease liver P450s. The P450s are also involved in the metabolism of xenobiotics in the brain. This study investigates: 1) the effects of CRF on rat brain P450, 2) the role of PTH in the downregulation of brain P450s in CRF rats, and 3) the effects of PTH on P450s in astrocytes. Protein and mRNA expression of P450s were assessed in the brain of CRF and control (CTL) rats, as well as from CTL or CRF rats that underwent parathyroidectomy (PTX) 1 week before nephrectomy. CYP3A activity was measured using 3-[(3, 4-difluorobenzyl) oxy]-5, 5-dimethyl-4-[4-methylsulfonyl) phenyl] furan-2(5H)-1 metabolism in brain microsomal preparation. CYP3A protein expression was assessed in primary cultured astrocytes incubated with serum obtained from CRF or CTL rats or with PTH. Significant downregulations (≥40%) of CYP1A, CYP2C11, and CYP3A proteins were observed in microsomes from CRF rat brains. CYP3A activity reduction was also observed. CYP3A expression and activity were unaffected in PTX-pretreated CRF rats. Serum of PTX-treated CRF rats had no impact on CYP3A levels in astrocytes compared with that of untreated CRF rats. Finally, PTH addition to normal calf serum induced a reduction in CYP3A protein similar to CRF serum, suggesting that CRF-induced hyperparathyroidism is associated with a significant decrease in P450 drug-metabolizing enzymes in the brain, which may have implications in drug response.

Bilateral slipped capital femoral epiphysis in a male adolescent with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), chronic renal failure, and severe hyperparathyroidism

Slipped capital femoral epiphysis (SCFE) is the most common orthopedic hip disorder affecting otherwise healthy adolescents. The majority of SCFE cases are classified as idiopathic; rarely, it may be secondary to different endocrinopathies including hyperparathyroidism due to chronic renal failure (CRF). However, over the last decades, the association between SCFE and CRF has almost disappeared, probably due to better management of renal osteodystrophy. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, OMIM no. 248250) is a rare autosomal recessive tubulopathy characterized by renal wasting of calcium and magnesium leading to hypomagnesemia, hypercalciuria, nephrocalcinosis, and CRF. Patients usually show hyperparathyroidism before the onset of advanced CRF caused by FHHNC-related metabolic disturbances. We report on a 15-year-old patient with FHHNC and CRF who developed extreme hyperparathyroidism and high-grade bilateral SCFE after self-discontinuation of supportive treatment of underlying conditions. We believe that SCFE was caused not only by untreated CRF but also by metabolic disturbances related to FHHNC. To prevent this complication, careful management of disturbances of calcium, phosphate, and magnesium homeostasis seems to be crucial.

Utilization of titanium oxide-like compound as an inorganic phosphate adsorbent for the control of serum phosphate level in chronic renal failure

Hyperphosphatemia adversely affects the prognosis of patients with chronic renal failure (CRF). We synthesized a titanium oxide-like compound (TAP) as a phosphate adsorbent for treatment of hyperphosphatemia in CFR patients. We evaluated the ability of TAP to adsorb inorganic phosphate in vitro and in vivo. TAP was shown to contain sulfate and hydroxyl groups by thermal analysis, which probably involved in phosphate adsorption through an ionic exchange mechanism. TAP constantly adsorbed phosphate (66.20-72.84 mg/g TAP) over a wide pH range (1.22-7.27) in vitro. To evaluate the phosphate binding potential of TAP in vivo, adenine-induced CRF rats were fed AIN-76 diet containing 3% TAP, 10% TAP, 3% sevelamer hydrochloride (clinical phosphate adsorbent), or 3% calcium carbonate, and serum levels of phosphate and calcium and urinary phosphate were compared with those in untreated CRF rats. Orally administered TAP showed the inhibitory effect on serum phosphate level in adenine-induced CRF rats, which was equivalent to that of sevelamer hydrochloride. These results indicate that TAP is a useful alternative phosphate-binder with fewer side effects than sevelamer hydrochloride and calcium carbonate.

Niacin improves renal lipid metabolism and slows progression in chronic kidney disease

Background Mounting evidence points to lipid accumulation in the diseased kidney and its contribution to progression of nephropathy. We recently found heavy lipid accumulation and marked dysregulation of lipid metabolism in the remnant kidneys of rats with chronic renal failure (CRF). Present study sought to determine efficacy of niacin supplementation on renal tissue lipid metabolism in CRF. Methods Kidney function, lipid content, and expression of molecules involved in cholesterol and fatty acid metabolism were determined in untreated CRF (5/6 nephrectomized), niacin-treated CRF (50 mg/kg/day in drinking water for 12 weeks) and control rats. Results CRF resulted in hypertension, proteinuria, renal tissue lipid accumulation, up-regulation of scavenger receptor A1 (SR-A1), acyl-CoA cholesterol acyltransferase-1 (ACAT1), carbohydrate-responsive element binding protein (ChREBP), fatty acid synthase (FAS), acyl-CoA carboxylase (ACC), liver X receptor (LXR), ATP binding cassette (ABC) A-1, ABCG-1, and SR-B1 and down-regulation of sterol responsive element binding protein-1 (SREBP-1), SREBP-2, HMG-CoA reductase, PPAR-α, fatty acid binding protein (L-FABP), and CPT1A. Niacin therapy attenuated hypertension, proteinuria, and tubulo-interstitial injury, reduced renal tissue lipids, CD36, ChREBP, LXR, ABCA-1, ABCG-1, and SR-B1 abundance and raised PPAR-α and L-FABP. Conclusions and general significance Niacin administration improves renal tissue lipid metabolism and renal function and structure in experimental CRF.

Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney

Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g.kg(-1).day(-1) by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-beta, Smad2, alpha-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-kappaB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox), p22(phox)), PAI-1, TGF-beta, connective tissue growth factor, alpha-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-kappaB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.

Assessment of the renal protection and hepatotoxicity of rhubarb extract in rats

Aim of the studyRhubarb is well used to treat chronic renal failure (CRF) in China and Japan, but recent studies reported that the anthraquinone derivatives contained in rhubarb had nephrotoxicity. In this investigation an attempt was made to assess the value and toxic potential of rhubarb to treat CRF. Materials and methodsHistopathologic and biochemical tests combined with toxicokinetic analysis were performed to investigate the nephrotoxic potential and protective effect of rhubarb extract. ResultsIn normal rat groups, no death was observed and no renal lesion was found after repetitive administration of rhubarb for 3 weeks. The survival rate, pathologic conditions and biochemical indexes of CRF rats treated with rhubarb at two dosages were all improved and significant amelioration was found in the low dosage group compared to the untreated CRF group. Rhein was the mainly absorbable anthraquinone derivative into systemic circulation after oral administration and the area under curve of rhein in CRF groups was lower than that in normal groups at same dosage. ConclusionsAfter 3 weeks of administration of rhubarb extract, there was evidence of protective effect to CRF rats, while incidences of hepatotoxicity with minimal to mild hyaline droplets were also observed in normal rats.

The Role of Mesenchymal Stem Cells in the Functional Improvement of Chronic Renal Failure

The most commonly used therapeutic targets in nephrology are the reduction of injury, the delay of progression, or renal replacement therapy. Many animal and human studies demonstrated the role of stem cells in repair and regenerations of kidney. Mesenchymal stem cells (MSCs) have shown to improve outcome of acute renal injury models. It is controversial whether MSCs can reduce injury following a toxic/ischemic event and delay renal failure in chronic kidney disease. We evaluated the hypothesis that the treatment with MSCs could improve renal function and attenuate injury in chronic renal failure (CRF). Sprague-Dawley female rats (8 weeks old, 182.2 +/- 7.2 g) underwent modified 5/6 nephrectomy. Rats in the MSC group received an injection of MSCs (1 x 10(6) cells) via tail vein 1 day after nephrectomy. Blood and urine samples were collected after 7 days and every month thereafter. The kidneys of rats were removed for histologic evaluation after 24-h urine collection and blood sampling. The Y-chromosome stain using fluorescent in situ hybridization was performed to verify the presence of male MSCs in the kidney of female recipients. No significant differences in blood urea nitrogen and creatinine concentration were observed between the MSC group and the untreated CRF group. However, the weight gain in the MSC group was greater than those in the CRF group after 4 months. Proteinuria in the MSC group was less than that in the CRF group over time. Y chromosome was detected in the kidney of MSC group. Although no significances were observed between these two groups, the histologic analysis suggests that MSCs have positive effect against glomerulosclerosis. These results suggest that MSCs help preserve renal function and attenuate renal injury in CRF.

The Effect of Mesenchymal Stem Cells as a Cell Therapy in Renal Ischemia

Introduction: The most commonly used therapeutic targets in nephrology are the reduction of injury, the delay of progression, or renal replacement therapy. Many animal and human studies demonstrated the role of stem cells in repair and regenerations of kidney. Mesenchymal stem cells (MSCs) have shown to improve outcome of acute renal injury models. It is controversial whether MSCs can reduce injury following a toxic/ischemic event and delay renal failure in chronic kidney disease. We evaluated the hypothesis that the treatment with MSCs could improve renal function and attenuate injury in chronic renal failure (CRF).Materials and methods: Sprague-Dawley female rats (8 weeks old, 182.2 ± 7.2g) were underwent modified 5/6 nephrectomy. Rats in the MSC group received an injection of MSCs (1 × 106 cells) via tail vein 1 day after nephrectomy. Blood and urine samples were collected after 7 days and every month thereafter. The kidneys of rats were removed for histologic evaluation after 24-hr urine collection and blood sampling. The Y-chromosome stain using fluorescent in situ hybridization was performed to verify the presence of male MSCs in the kidney of female recipients.Results: No significant differences in blood urea nitrogen and creatinine concentration were observed between MSC group and untreated CRF group. However, the weight gain and creatinine clearance in the MSC group were greater than those of the CRF group. Proteinuria in the MSC group was less after 4 months. Y chromosome was detected in the kidney of MSC group. Although no significances were observed between two groups, the histologic analysis suggests that MSCs have positive effect against glomerulosclerosis.Conclusions: These results suggest that MSCs help preserve renal function and attenuate renal injury in CRF.

Ulcerative uremic stomatitis associated with untreated chronic renal failure: Report of a case and review of the literature

Uremic stomatitis represents a relatively uncommon intraoral complication seen, mostly, in cases of end-stage renal disease or undiagnosed/untreated chronic renal failure. Its incidence has decreased due to the advent of renal dialysis. Clinically uremic stomatitis is characterized by the presence of painful plaques and crusts that are usually distributed on the buccal mucosa, dorsal or ventral surface of the tongue, gingiva, lips, and floor of the mouth. Treatment consists of improvement of urea blood concentration and the underlying renal failure, supported by increased oral hygiene with antiseptic mouthwashes and antimicrobial/antifungal agents if necessary. Although uremic stomatitis occurs in patients with end-stage renal disease, we report a case of a patient who exhibited an ulcerative form of uremic stomatitis related to the sudden relapse of uremia, although not in an advanced stage of her renal disease. A description of the clinical and microscopic appearance is given along with our hypothesis for the pathogenesis of the disease.

Ulcerative Uremic Stomatitis Associated with Untreated Chronic Renal Failure: Report of a Case

Uremic stomatitis is a relatively uncommon intraoral complication of uremia, seen mostly in cases of end-stage or undiagnosed/untreated chronic renal failure. Severe uremia is rare, which explains why reports on uremic stomatitis are exceedingly rare. Two types are generally distinguishable; the most common type is the erythemoplaceous or nonulcerative type, and the second ulcerative type is more rarely seen. The objective of this article is to report an 83-year-old female patient with untreated chronic renal failure who developed the ulcerative type of uremic stomatitis as a complication of the sudden relapse of uremia. Based on the literature data, we will discuss the clinical and microscopic findings along with the pathogenesis of the disease.

Iron and Oxidative Stress in Renal Insufficiency

Background/Aims: Iron (Fe) can cause tissue injury and oxidative stress by catalyzing hydroxyl radical production and lipid peroxidation. Intravenous (i.v.) Fe preparations are routinely administered to treat anemia in patients with chronic renal failure (CRF), a condition marked by oxidative stress and inflammation. In an earlier study, we showed that iron overload augments oxidative stress in the cardiovascular tissues of CRF rats. This study was designed to expand these observations to other major organs. Methods: Rats were randomized into CRF (5/6 nephrectomized) and sham-operated control (CTL) groups. Each group was subdivided into Fe-loaded (single i.v. injection of iron dextran complex, 0.5 g/kg) and placebo-treated subgroups. After 13 weeks, systolic blood pressure, blood hemoglobin (Hb), plasma Fe concentration, lipid peroxidation products, superoxide generating enzyme, NAD(P)H oxidase, and antioxidant enzymes were determined. Results: Systolic blood pressure was equally elevated and creatinine clearance was equally reduced in both CRF groups. Fe administration raised Hb, serum Fe and transferrin saturation in both CRF and CTL groups. The plasma concentration of lipid peroxidation product, malondialdehyde, was increased by Fe injection in CRF rats but not the control group. Renal tissue abundance of gp91^phox subunit of NAD(P)H oxidase was elevated in the untreated CRF group and was partially reduced in the iron dextran-treated CRF group. Tissue abundance of the antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were decreased in both untreated and iron dextran-treated CRF groups. Conclusion: CRF resulted in marked SOD, CAT and GPX deficiencies. A single i.v. administration of iron dextran in rats with CRF induced oxidative stress as measured by increased lipid peroxidation products and decreases in antioxidant enzymes.

HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure

Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and the progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated a favorable response to administration of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF (5/6 nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg x kg(-1) x day(-1)) groups and observed for 6 wk. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma lecithin:cholesterol acyltransferase (LCAT) and the hepatic LDL receptor, elevated hepatic acyl-CoA:cholesterol acyltransferase (ACAT), and no change in hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol-to-HDL cholesterol ratio, and hepatic LDL receptor but did not significantly change either plasma total cholesterol, hepatic cholesterol 7alpha-hydroxylase, total ACAT activity, or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol-to-HDL cholesterol ratio, hepatic HMG-CoA reductase activity, and cholesterol 7alpha-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.

ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure.

Chronic renal failure (CRF) is associated with increased risk of arteriosclerotic cardiovascular disease and profound alteration of plasma lipid profile. Uremic dyslipidemia is marked by increased plasma concentration of ApoB-containing lipoproteins and impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport. These abnormalities are, in part, due to acquired LCAT deficiency and upregulation of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). ACAT catalyzes intracellular esterification of cholesterol, thereby promoting hepatic production of ApoB-containing lipoproteins and constraining HDL-mediated cholesterol uptake in the peripheral tissues. In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced dyslipidemia. 5/6 Nephrectomized rats were treated with either ACAT inhibitor IC-976 (30 mg.kg(-1).day(-1)) or placebo for 6 wk. Sham-operated rats served as controls. Key cholesterol-regulating enzymes, plasma lipids, and creatinine clearance were measured. The untreated CRF rats exhibited increased plasma low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol, unchanged plasma HDL cholesterol, elevated total cholesterol-to-HDL cholesterol ratio, reduced liver microsomal free cholesterol, and diminished creatinine clearance. This was accompanied by reduced plasma LCAT, increased hepatic ACAT-2 mRNA, ACAT-2 protein and ACAT activity, and unchanged hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase. ACAT inhibitor raised plasma HDL cholesterol, lowered LDL and VLDL cholesterol, and normalized total cholesterol-to-HDL cholesterol ratio without changing total cholesterol concentration (hence, a shift from ApoB-containing lipoproteins to HDL). This was accompanied by normalizations of hepatic ACAT activity and plasma LCAT. In conclusion, inhibition of ACAT reversed LCAT deficiency and improved plasma HDL level in CRF rats. Future studies are needed to explore the efficacy of ACAT inhibition in humans with CRF.

The effects of iron dextran on the oxidative stress in cardiovascular tissues of rats with chronic renal failure

Redox-active iron can promote oxidative stress and tissue injury by catalyzing hydroxyl radical generation and lipid peroxidation. Intravenous iron preparations are routinely administered in conjunction with erythropoietin to treat anemia in patients with chronic renal failure (CRF), a condition that is marked by oxidative stress and inflammation. This treatment frequently elevates iron burden, which can potentially intensify oxidative stress and, thus, cardiovascular disease in this population. We studied renal function and oxidative stress parameters in the cardiovascular tissues of CRF (5/6 nephrectomized) and sham-operated control rats 3 months after a single intravenous infusion of iron dextran (500 mg/kg). Arterial pressure was equally elevated and creatinine clearance was equally reduced in both iron-treated and -untreated CRF groups. Iron administration significantly raised the blood hemoglobin, serum iron concentration, and transferrin saturation in both CRF and control groups. Iron administration resulted in a significant rise in plasma concentration of lipid peroxidation product, malondialdehyde in the CRF rats, and an insignificant rise in the control group. Plasma oxidized low-density lipoprotein (LDL) concentration was increased in the CRF groups, and was not affected by iron administrations. Iron administration raised nitrotyrosine abundance in the aorta of CRF but not in the control group. Left ventricular tissue abundance of p22(phox) subunit of NAD(P)H oxidase was elevated in CRF group and was not affected, whereas p67(phox) subunit abundance was raised by prior iron administration. Iron administration insignificantly lowered aorta p22(phox), but had no effect on p67(phox) subunit abundance in the treated CRF group. Previous iron administration significantly lowered superoxide dismutase and catalase abundance in the aorta and glutathione peroxidase in the left ventricle of CRF animals, but did not significantly change these parameters in the iron-treated control animals. A single intravenous injection of iron dextran increased oxidative stress in the cardiovascular tissues in the CRF group, but not the control rats, pointing to heightened susceptibility to iron-mediated toxicity in CRF. However, administration of iron dextran did not adversely affect kidney function, and favorably affected hemoglobin concentration in rats with CRF induced by renal mass reduction. Further studies are needed to explore the effects of other parenteral iron preparations, repeated intravenous iron administration, and presence of comorbid conditions such as diabetes.

Possible involvement of nuclear factor-κB inhibition in the renal protective effect of oral adsorbent AST-120 in a rat model of chronic renal failure

Oral adsorbent, AST-120 removes uremic toxins (such as indoxyl sulfate) and retards the progression of chronic renal failure (CRF). However, its mechanism of action has not been precisely clarified. Since indoxyl sulfate elicits renal tubular nuclear factor-kappaB (NF-kappaB) activation in vitro, the present experiments were conducted to elucidate the involvement of NF-kappaB in the beneficial effects of AST-120 using rats with 3/4 nephrectomy, a model of early-stage CRF. Daily administration of AST-120 was started at 6 weeks after 3/4 nephrectomy and continued for 18 weeks. Sham-operated rats, untreated CRF rats and AST-120-treated CRF rats were compared for NF-kappaB DNA-binding activity, gene expression and renal histology. Systolic blood pressure was increased in CRF rats, and this increase was not affected by AST-120. Blood urea nitrogen, serum creatinine and urinary protein were increased in CRF rats. Although AST-120 attenuated these increases, it did not do so to a statistically significant extent. Indoxyl sulfate, which was accumulated in serum of CRF rats, was significantly eliminated by AST-120. Renal cortical NF-kappaB DNA-binding activity was increased in CRF rats. AST-120 significantly inhibited this increase. Monocyte/macrophage infiltration and increased monocyte chemoattractant protein-1 (MCP-1) mRNA observed in CRF rats were attenuated by AST-120. Furthermore, AST-120 significantly blocked renal fibrosis with concomitant inhibition of transforming growth factor beta1 (TGF-beta1) gene expression. It appeared that AST-120 reduced NF-kappaB activation and possibly the activity of NF-kappaB-dependent pathways of interstitial inflammation including MCP-1 expression and macrophage infiltration. The anti-inflammatory effect of AST-120 mediated via inhibition of NF-kappaB is a possible mechanism by which AST-120 retards the progression of renal fibrosis in CRF.

Elevated Myocardial Cytosolic Calcium Impairs Insulin-Like Growth Factor-1-Stimulated Protein Synthesis in Chronic Renal Failure

Rats and humans with chronic renal failure (CRF) are reported to have resistance to recombinant human insulin-like growth factor-1 (rhIGF-1). Because basal cytosolic calcium ([Ca2+]i), a second messenger, may be increased in CRF, this study was conducted to examine whether elevated basal [Ca2+]i may cause resistance to IGF-1. Cardiomyocytes from four groups of rats were studied: untreated CRF, CRF with parathyroidectomy (PTX), CRF with the calcium channel blocker felodipine (F), and sham operation of the kidney (SO). CRF was created by ligation of two-thirds of the left renal artery and contralateral nephrectomy. Rats from each group were pair-fed the same diet for 20 to 22 d. Basal [Ca2+]i in cardiomyocytes (nM) in the CRF rats (102.0 +/- 2.8; SEM), was significantly higher than in each of the CRF-PTX, CRF-F, and SO groups (65.2 +/- 1.9, 63.8 +/- 2.6, and 63.5 +/- 2.0, respectively; P < 0.01). rhIGF-1 increased cardiomyocyte [Ca2+]i in all four groups of rats. The rise in [Ca2+]i was significantly diminished in the CRF rats (P < 0.05) and did not differ among the CRF-PTX, CRF-F, and SO rats. Protein synthesis after incubation with 0, 50, 100, 200, or 400 ng/ml rhIGF-1 was lower in cardiomyocytes from CRF rats than in each of the other three groups (P < 0.05) and was significantly less in the CRF-F rats compared with SO animals. IGF-1 receptor mRNA and IGF-1 receptor number and affinity were not different among the four groups. These findings suggest that cardiomyocytes from CRF rats display elevated basal [Ca2+]i and attenuated rhIGF-1-induced increase in [Ca2+]i; basal protein synthesis is decreased, and IGF-1-stimulated protein synthesis is impaired; elevated basal [Ca2+]i seems to contribute to this diminished response to rhIGF-1.

Elevated SCF levels in the serum of patients with chronic renal failure.

Serum stem cell factor (SCF) and soluble KIT (sKIT) levels were estimated in patients with chronic renal failure (CRF) and anaemia, and compared with clinical parameters of blood cells and renal function. Serum SCF levels in CRF patients were 5-fold higher than those in healthy controls. However, serum sKIT levels in haemodialysis (HD)-CRF patients were only slightly higher than those of healthy controls. In untreated CRF patients and healthy controls, serum SCF levels were significantly correlated with blood urea nitrogen (BUN), creatinine. haemoglobin, red blood cell (RBC) count and sKIT. In untreated CRF patients, serum SCF levels were significantly correlated with BUN, creatinine, and sKIT. These results suggest that serum SCF levels increased with the deterioration of renal function and might be related to erythropoiesis.