Calcium citrate ameliorates the progression of chronic renal injury

BACKGROUND: Metabolic acidosis is a consequence of chronic renal failure and it may produce bone demineralization, muscle proteolysis, and progression of chronic renal failure. The aim of this study was to evaluate the effects of correction of metabolic acidosis with calcium citrate in an experimental model of renal mass ablation. METHODS: Wistar rats were subjected to 5/6 nephrectomy and were randomly assigned to one of 4 groups: nontreated (NFX); treated with calcium citrate (1.45 g/100 g feed) (NFX-CIT); treated with captopril (500 mg/L water) (NFX-CAP); or treated with both (NFX-CAP-CIT) during 1, 10, or 20 weeks. Body weight, systolic blood pressure, proteinuria, arterial bicarbonate concentration, urine citrate excretion, plasma calcium, and inulin clearance were measured. Histologic glomerular and tubulointerstitial damage scores were measured at 1, 10, and 20 weeks, and glomerular and tubular proliferating cell nuclear antigen (PCNA)-positive cells, alpha-smooth muscle actin, and desmin staining were studied by immunohistochemistry at 1 and 10 weeks. RESULTS: The treated groups showed significantly less glomerular and tubulointerstitial cellular proliferation in the first week (P < 0.05), less glomerular cell transdifferentiation and higher plasma bicarbonate at 10 weeks (P < 0.05), as well as diminished histologic glomerular and tubulointerstitial damage scores at 20 weeks (P < 0.05). Inulin clearances were higher (P < 0.05), and urine protein excretion rates were lower (P < 0.05) than in the NFX non-treated group, but arterial blood pressure was not significantly different in the NFX-CIT group. CONCLUSION: Calcium citrate slows the progression of chronic renal injury in the 5/6 NFX model. It improves metabolic acidosis and diminishes cell proliferation and transdifferentiation without changes in systolic blood pressure.     

Increased cGMP phosphodiesterase activity mediates renal resistance to ANP in rats with bile duct ligation

BACKGROUND: Liver disease resulting from common bile duct ligation (CBDL) causes abnormal sodium metabolism that is manifested by resistance to the natriuretic action of atrial natriuretic peptide (ANP). This resistance is corrected both in vitro and in vivo by zaprinast, a selective inhibitor of a guanosine cyclic-3'-5'-monophosphate (cGMP)-specific phosphodiesterase (PDE5). Several other PDEs with affinity for cGMP are expressed in kidney and could also be involved in this response. METHODS: We measured cGMP hydrolysis in inner medullary collecting duct (IMCD) cell homogenates from kidneys of sham-operated and CBDL rats and quantitated the amount of PDE5 protein by Western blotting and immunoprecipitation studies. We also characterized ANP responsiveness in vivo of kidneys of anesthetized sham and CBDL rats by measuring sodium excretion before and after volume expansion (VE). RESULTS: Kinetic analysis of PDE5 activity in homogenates of IMCD cells isolated from kidneys of sham-operated rats indicated a Vmax of 85.3 +/- 1.7 versus 157 +/- 2.9 pmol/mg/min from CBDL rats (P < 0.01), without a difference in Km. Enzyme activity was inhibited competitively by 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazol[3,4d]-pyrimidin-4-(5H)-one (DMPPO), a potent and specific inhibitor of PDE5, with an apparent Ki of 4.5 +/- 0.7 and 4.9 +/- 0.7 nmol/L and an IC50 of 6.1 +/- 0.8 and 8.7 +/- 0.7 nmol/L in sham and CBDL rats, respectively (P = NS). DMPPO exhibited very poor inhibitory activity against the calcium-calmodulin-dependent PDE1 in IMCD homogenates from sham rats (Ki 1.3 +/- 0.1 micromol/L and IC50 1.9 +/- 0.2 micromol/L). Western analysis using an antiserum made against bovine lung PDE5 revealed a twofold increase in PDE5 protein in cytosolic extracts from IMCD of CBDL rat kidneys compared with sham-operated controls, and immunoprecipitation studies indicated that the increase in PDE5 protein accounted for the observed increase in cGMP hydrolysis. DMPPO (10 nmol/L) normalized the blunted ANP-dependent cGMP accumulation by IMCD cells from CBDL rats in vitro. Intrarenal infusion of DMPPO (0.5 nmol/min) in CBDL rats corrected both the impaired natriuretic response to VE and the blunted VE-related increase in urinary cGMP excretion from the infused, but not the contralateral kidney. CONCLUSION: These results demonstrate that renal resistance to ANP in CBDL rats is accompanied by heightened activity of PDE5, which is due largely to an increase in PDE5 protein. Other PDEs could contribute only a minor part to the enhanced cGMP hydrolysis observed in kidneys of CBDL rats. This PDE5-dependent ANP resistance may represent an important contributor to the sodium retention of liver disease.     

Mechanisms of progression of chronic renal damage

The amount of protein in the urine is a strong predictor of subsequent loss of renal function. Proteinuria and tubular atrophy have been linked with progressive renal insufficiency. In the last few years several studies have indicated that smoking is also a risk factor in the progression of renal disease. In addition, a number of studies have suggested that higher levels of blood pressure are associated with a faster decline in renal function. A number of cytokines, vasoactive compounds, chemoattractant molecules and growth factors are upregulated during the course of progressive renal disease in experimental animals. Recent data indicate that vasoconstrictor substances have a key role in the initial phases of this process. In particular, angiotensin II is increased following the development of renal injury. Angiotensin in turn upregulates the expression of other factors including: transforming growth factor beta, tumor necrosis alpha, nuclear factor kappaB and several chemoattractant compounds. Other vasoactive compounds (endothelin, thromboxane A2 and prostaglandins) may also be upregulated during the course of progressive renal disease     

Tubulointerstitial damage and progression of renal failure

The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure.     

Predictors of renal allograft histologic damage progression

The objective of this study was to analyze factors that are involved in the progression of renal allograft damage in the first 6 mo after transplantation. Donor and 6-mo protocol biopsies of 83 patients who received a renal transplant were classified using the Chronic Allograft Damage Index (CADI). Histologic changes were compared and correlated to clinical parameters at transplantation, at 6 mo, and annually over 2 yr. All CADI components increased significantly in the 6-mo posttransplantation period, except chronic vascular changes and the percentage of glomerulosclerosis. Total cholesterol and LDL- cholesterol at the time of biopsy correlated positively with mesangial matrix increase, and HDL cholesterol correlated negatively with vascular intima increase. High BP at biopsy was associated with tubular atrophy. Diastolic BP at biopsy correlated with 6-mo CADI (CADI-6). Patients with diastolic BP > or =85 mmHg at biopsy had a higher difference between CADI score in protocol biopsies and CADI score in donor biopsies (DeltaCADI) and higher creatinine at 1 and 2 yr. CADI in donor biopsies (CADI-0) >1 was more frequently found in older (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01 to 1.14) and nontraumatic dead donors (OR, 3.89; 95% CI, 1.13 to 13.33). CADI-6 >3 was more frequently found in those with CADI-0 >1 (OR, 3.82; 95% CI, 1.19 to 12.21), older donors (OR, 1.05; 95% CI, 1.01 to 1.10), and number of AB mismatches (OR, 2.36; 95% CI, 1.09 to 5.10). CADI-0, CADI-6, and DeltaCADI correlated significantly with serum creatinine at hospital discharge, at 6 mo, and at 2 yr. DeltaCADI was affected by initial percentage of glomerulosclerosis (OR, 1.10; 95% CI, 1.02 to 1.19) and creatinine at hospital discharge (OR, 1.01; 95% CI, 1.00 to 1.02). Donor-related as well as nonimmunologic factors, such as hypertension and dyslipidemia, are associated with increased risk for renal allograft damage progression.     

Tranilast ameliorates renal tubular damage in unilateral ureteral obstruction

PURPOSE: We determined whether tranilast, the anti-allergic agent N-(3, 4-dimethoxyciannamoyl)-anthranilic acid, would diminish renal transforming growth factor-beta (TGF-beta) levels in unilateral ureteral obstruction and concomitantly affect renal tubular apoptosis and proliferation in that condition. MATERIALS AND METHODS: Tranilast (150 mg./kg.) was administered to rats 1 day before unilateral ureteral obstruction and each day thereafter. Kidneys were harvested day 14 after unilateral ureteral obstruction. Tissue TGF-beta was measured by bioassay using mink lung epithelial cells. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cell nuclear antigen and the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay, respectively. Fibrosis was assessed by measuring collagen deposition with trichrome stained slides. RESULTS: TGF-beta bioassay showed that obstructed kidneys in controls contained significantly higher mean TGF-beta plus or minus standard deviation than unobstructed kidneys in controls (73.7 +/- 13.6 versus 14.1 +/- 5.5 pg./mg. tissue) and tranilast significantly decreased tissue TGF-beta in obstructed kidneys (15.9 +/- 4.8 pg./mg. tissue). The terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay demonstrated that obstructed kidneys in controls had significantly more mean tubular apoptosis than the unobstructed counterparts (36.6 +/- 6.7 versus 5.8 +/- 5.5 nuclei per high power field) and tranilast significantly decreased mean renal tubular apoptosis in obstructed kidneys (16.2 +/- 1.7 nuclei per high power field). In addition, immunostaining proliferating cell nuclear antigen showed that obstructed kidneys in controls had significantly more mean renal tubular proliferation than unobstructed kidneys (20.7 +/- 3.4 versus 6.2 +/- 2.1 per high power field) and tranilast significantly increased proliferating renal tubules in obstructed and unobstructed kidneys (26.5 +/- 8.3 and 14.5 +/- 3.4 per high power field, respectively). Control obstructed kidneys exhibited significantly more fibrosis, which was also blunted by tranilast. CONCLUSIONS: Tranilast significantly decreases tissue TGF-beta, resulting in a reduction in tubular apoptosis and an increase in tubular proliferation. This finding suggests that tranilast is a promising agent for preventing renal tubular damage in unilateral ureteral obstruction.     

Early treatment of urinary infection prevents renal damage on cortical scintigraphy

Diagnosis of urinary infection in young children is often delayed, which may result in renal damage. However, it remains to be clarified how soon the treatment should be started to prevent renal changes. The present study prospectively enrolled young children with diagnosis of their first febrile urinary infection who underwent technetium-99m dimercaptosuccinate renal cortical scintigraphy within 120 h of initiation of treatment. Patients with abnormal renoscintigraphy received antibiotics for 2 weeks and scintigraphy was repeated 1 year later. Twenty-two children were enrolled from July 1995 through March 2000. Acute-phase renoscintigraphy identified focal defects in 0 of the 14 children who were treated within 24 h of the disease, 1 of the 3 treated in 24-48 h, and 2 of the 5 treated in 48-72 h. Repeat renoscintigraphy showed disappearance of the focal defects in all 3 children. The present study has shown that early treatment within 24 h of onset of the fever due to urinary infection should deter renal changes. Fever for more than 24 h prior to diagnosis indicates a high risk for renal changes and needs an immediate effective treatment to avoid renal damage.     

Long-term mineralocorticoid receptor blockade ameliorates progression of experimental diabetic renal disease

The final end point of diabetic renal disease is the accumulation of excess collagen. A number of studies have shown that aldosterone antagonism ameliorates progression of renal fibrosis. This study was designed to examine the effect of the mineralocorticoid receptor blocker eplerenone (EPL) on progression in streptozotocin (STZ)-treated spontaneously hypertensive rats (SHR), an accelerated model of Type I diabetes. STZ-treated SHRs with a blood glucose >18 mmol/L were randomly divided into treatment (100 mg/kg/day EPL) and non-treatment groups. Sham-injected SHR animals were used as a control. Functional parameters were monitored for 16 weeks, with structural parameters assessed at completion. Both hyperglycaemic groups developed progressive albuminuria, but the increase was ameliorated by EPL from Week 12. STZ-SHRs had elevated kidney weight/body weight ratio, glomerular size, glomerular macrophages (ED-1-positive cells), tissue transforming growth factor beta 1 (TGFβ1) concentrations and glomerular collagen IV staining (all P < 0.05 versus control animals). EPL reduced glomerular volume, TGFβ1 expression and glomerular collagen IV without changing glomerular macrophage infiltration. The ability of EPL to ameliorate these functional and structural changes in hyperglycaemic SHRs suggest that EPL has a renoprotective role in diabetic renal disease.     

Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury

BACKGROUND: Hepatocyte growth factor (HGF) has been reported to prevent injury in several models of renal disease; however, whether HGF can also retard progression of established renal disease is not known. METHODS: The aim of the present study was to examine the effects of HGF on progression of chronic renal disease in rats with remnant kidneys and established injury. Studies were performed in rats that underwent subtotal nephrectomy, were observed for two weeks without therapy, and then randomized to receive HGF or vehicle by continuous infusion for an additional two weeks. RESULTS: HGF administration was associated with a reduction in morphologic evidence of interstitial, but not glomerular injury. The beneficial effects of HGF were not associated with reductions in the expression of transforming growth factor-beta (TGF-beta), or in the extent epithelial cell apoptosis or transdifferentiation. Rather, HGF appeared to induce fibrinolytic pathways by increasing expression of metalloproteinase-9 (MMP-9) and decreasing levels of plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-1 (TIMP-2). HGF administration was also associated with an apparent increase in renal endothelin production and a significant reduction in glomerular capillary pressure. CONCLUSION: These findings suggest that HGF can retard progression of chronic renal disease even after injury is already established, primarily by promoting matrix degradation.     

Dietary supplementation with L-arginine ameliorates the progression of renal disease in rats with subtotal nephrectomy.

We studied the effect of dietary supplementation with L-arginine for 6 weeks on the progression of renal disease in female Sprague-Dawley rats subjected to sham-operation (groups 1 and 2) or surgical ablation of 85% to 90% of the total renal mass (groups 3 and 4). All rats were fed a standard rat chow containing 22.8% protein. Rats in groups 1 (n = 5) and 3 (n = 9) served as controls and drank tap water ad libitum. Rats in groups 2 (n = 6) and 4 (n = 6) drank tap water supplemented with 1% L-arginine. Rats in groups 1 and 2 had similar values for glomerular and tubular function and serum chemistries 6 weeks after sham-operation. Sham-operated rats given L-arginine had significantly greater urine urea excretion than similar rats drinking tap water. Rats with subtotal nephrectomy (groups 3 and 4) had a significantly higher blood pressure, greater proteinuria, and a significantly lower plasma albumin than sham-operated rats (groups 1 and 2). Rats with remnant kidneys given 1% L-arginine (group 4) had significantly greater values for glomerular filtration rate (GFR) and P-amino hippurate (PAH) clearance than similar rats given tap water (group 3), despite comparable levels of systemic blood pressure, hematocrit, body weight, plasma chemistries, including L-arginine, and urine chemistries, except urea excretion. The remnant kidney of rats given L-arginine (group 4) had a greater number of normal or minimally abnormal glomeruli and fewer interstitial changes than that of rats given tap water (group 3).(ABSTRACT TRUNCATED AT 250 WORDS)     

Reflux nephropathy and hypertension: correlation with the progression of renal damage

The aim of this study was to evaluate the relationship between blood pressure (BP), measured with ambulatory blood pressure monitoring (ABPM), and the progression of renal damage in 100 (70 females, 30 males) normotensive children with reflux nephropathy (RN). The patients, mean age of 13.5+/-5 years and almost 5 years of follow-up, were divided according to degree of RN into group A (I/II) and group B (III/IV). For each subject, 24-h systolic and diastolic BP (SBP-DBP), load (percentage of BP readings that exceeded the age- and sex-specific 95th percentile), and biochemical parameters were recorded. There was no significant difference in casual BP between the groups. The mean 24-h SBP-DBP and load were significantly higher in group B than A. There was a significant difference in creatinine (Cr) levels between the groups, and Cr correlated with BP in both groups. In group B, microalbuminuria correlated with ambulatory BP, and plasma renin activity failed to decrease with chronological age. Elevated load was shown in 8 of 50 patients in group A and in 21 of 50 in group B. In 3 of 12 patients of group B, with increased load BP, left ventricular geometry, by integrated backscatter, was abnormal. ABPM was useful in selected children at risk of hypertension.     

Blockade of TGF-beta action ameliorates renal dysfunction and histologic progression in anti-GBM nephritis

BACKGROUND: We tested whether the entire soluble extracellular domain of the human transforming growth factor-beta (TGF-beta) type II receptor, fused to the Fc portion of human immunoglobulin G (IgG1) (Tbeta-ExR) and expressed in skeletal muscles by adenovirus-mediated gene transfer (AdTbeta-ExR), can ameliorate renal dysfunction and histologic progression in a rat experimental anti-glomerular basement membrane (GBM) nephritis. METHODS: Anti-GBM nephritis was induced in Wistar Kyoto rats by an intravenous injection of anti-rat glomerular basement membrane (GBM) sera. At day 1 (24 hours after induction), AdTbeta-ExR (1 x 109 pfu/mL) was injected into the femoral muscle in the treatment group, and an adenovirus vector-expressing bacterial beta-galactosidase (AdLacZ) was injected into the control group. Then, clinical and histologic changes were examined for 3 weeks after the induction of anti-GBM nephritis. RESULTS: Tbeta-ExR was detected in the serum at day 7, but the serum concentration of Tbeta-ExR had decreased below the detectable level by day 14. Although blood pressure and the degree of proteinuria were similar in both groups, the deterioration of renal function was significantly blunted in the treatment group. Crescent formation and interstitial fibrosis were also ameliorated in the treatment group. These histologic improvements were accompanied by the decreased interstitial infiltration of macrophages and the decreased alpha-smooth muscle actin (alpha-SMA)-positive cells in the glomeruli and the interstitium. CONCLUSION: This study demonstrated for the first time that the blockade of TGF-beta action by AdTbeta-ExR in the early stage of anti-GBM nephritis ameliorates the clinical and histologic progression. In addition, this study shed light on the development of a specific gene therapy for human crescentic glomerulonephritis.     

Factors influencing the progression of renal damage in patients with unilateral renal agenesis and remnant kidney

BACKGROUND: Although some studies have shown that the risk to develop proteinuria and renal insufficiency is increased in patients with a remnant kidney (RK) or unilateral renal agenesis (URA), other patients maintain normal renal function and negative proteinuria, and the reasons to explain these different outcomes are not known. METHODS: We performed a retrospective study of 54 patients with a severe reduction in renal mass (33 patients with URA and 21 with RK). Follow-up was 100 +/- 72 months. RESULTS: Twenty patients (group 1) showed normal renal function at presentation, whereas the 34 remaining (group 2) had proteinuria, and some of them renal insufficiency. Group 2 patients were older and had a higher blood pressure and BMI than group 1 patients. Eleven patients of group 1 remained normal throughout follow-up (group 1A), whereas the remaining 9 developed proteinuria/renal insufficiency (group 1B). BMI at presentation was significantly higher in group 1B: 27 +/- 3.6 kg/m(2) versus 21.6 +/- 2.6 kg/m(2), and BMI was the only factor statistically associated with the risk to develop proteinuria/renal insufficiency in group 1. Among group 2 patients, renal function remained stable in 20 (group 2A), and deteriorated (>50% increase of baseline serum creatinine) in the remaining 14 patients (group 2B). BMI at presentation and treatment with ACEI during follow-up were the only factors statistically associated with the risk for renal failure progression among group 2 patients. CONCLUSION: Overweight plays a fundamental role in the appearance of proteinuria and renal damage in patients with severe renal mass reduction.     

Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis

Background

Increasing evidence indicates that locally blocking renin–angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN.

Methods

Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system.

Results

Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS?+?aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels.

Conclusion

This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis.     

Urinary trypsin inhibitor ameliorates renal tissue oxygenation after ischemic reperfusion in rats

PURPOSE: In order to determine the mechanism of the protective effect of a urinary trypsin inhibitor (UTI) on renal ischemic reperfusion injury, we measured the tissue oxygen partial pressure pO2 in both the renal cortex and medulla in rats, using electron paramagnetic resonance (EPR) oximetry. METHODS: We allocated the rats to three groups: normal saline (NS) group, a UTI 50,000 U x kg(-1) (LD) group, and a UTI 150,000 U x kg(-1) (HD) group, with the normal saline and UTI being administered 30 min before ischemia. Renal ischemia was achieved by inflating the balloon of a vascular occluder that had been placed around the abdominal aorta just above the bifurcation of the renal artery. Cortical and medullary pO2 were measured every 10 min during ischemia (30 min) and reperfusion (60 min) by EPR oximetry; also, systemic cardiopulmonary parameters were measured. RESULTS: The pO2 in the cortex and medulla decreased to less than 2 mmHg during ischemia in all groups. At 60 min after reperfusion, the pO2 values in the NS group were not fully restored, whereas those in the LD and HD groups were completely restored to the pre-ischemic values. There were no significant differences between the HD and LD groups. There were no differences between any groups in cardiopulmonary parameters. CONCLUSION: Because UTI improved renal oxygenation after reperfusion without changing cardiopulmonary parameters, the pharmacological properties of UTI, such as its renal protection and anti-shock activity, may be explained in part, by this improvement in tissue oxygenation.     

Early use of a phosphodiesterase inhibitor after brachytherapy restores and preserves erectile function

OBJECTIVE: To investigate whether the early use of phosphodiesterase inhibitors (PDEIs) after brachytherapy (BT) is associated with better erectile function, as of men potent before BT 38-70% have erectile dysfunction afterward. PATIENTS AND METHODS: We evaluated a prospectively created database of 2500 patients who had had BT at our institution since 1992. We measured baseline age, cancer stage, Gleason grade, prostate specific antigen (PSA) level at diagnosis, implant type, use of neoadjuvant and adjuvant hormonal suppression therapy, use of external beam radiotherapy in conjunction with interstitial therapy, and follow-up PSA levels. Men were stratified by their use of PDEIs at <1 year (early group) or >1 year after implantation (late group). We excluded all men who did not have baseline Sexual Health Inventory for Men (SHIM) scores and at least one follow-up SHIM score; the latter were obtained at 6-month intervals after BT. Data were analysed using the Mann-Whitney U-test. RESULTS: In all, 210 men met the inclusion criteria; 85 began using PDEIs within a year of BT, and 125 started after a year. The mean time to PDEI use was 191 days in the early and 595 days in the late group. The median age was 62 years in the early and 63 years in the late group (P = 0.02). Baseline Gleason scores did not differ, nor did PSA levels between the groups. Of men in the early group, 48% received neoadjuvant and/or adjuvant hormonal suppression therapy, vs half of men in the late group. Baseline SHIM scores were not significantly different, nor were scores at the first two follow-up assessments, but the scores at 18-36 months after BT were significantly different. CONCLUSION: The early use of PDEIs after BT is associated with a significant improvement in and maintenance of erectile function compared with late use. Men undergoing BT should be encouraged to use PDEIs early after implantation, to preserve erectile function.     

Quercetin ameliorates methotrexate-induced renal damage,apoptosis and oxidative stress in rats

Abstract

Background: In the present study, the protective and therapeutic effects of quercetin (QE) on renal injury induced by methotrexate (MTX) have been examined. Materials and methods: A total of 24 male rats were divided into the following three groups: control group, MTX group, and MTX?+?QE group. Rats in MTX group received 20?mg/kg of single dose of MTX, while those in MTX?+?QE group received 20?mg/kg of single dose MTX, in addition to 15?mg/kg of QE administered 30?min prior to MTX and in the following 5-day period as a single daily dose. At the end of the experimental period, renal tissues were removed for histopathological and biochemical assessments. Results: Light microscopic examination showed a disruption of the renal structure in rats in MTX group in the form of tubular degeneration and dilation, with shedding of the tubular epithelial cells into the lumen. QE treatment was associated with less marked degenerative changes, with a similar histological appearance to that of controls. Furthermore, QE treatment resulted in decreased the number of apoptotic cells. Biochemical assessments showed significantly higher malondialdehyde (MDA) levels in MTX group as compared to control and MTX?+?QE groups. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels showed a significant decrease in MTX group as compared to controls. However, QE significantly suppressed MDA level, compensated deficits in the anti-oxidant defenses [reduced SOD, GSH-Px, and CAT levels] in kidney tissue resulted from MTX administration. Conclusions: In conclusion, renal toxic effects of MTX may be alleviated by QE.     

N-acetyl-seryl-aspartyl-lysyl-proline ameliorates the progression of renal dysfunction and fibrosis in WKY rats with established anti-glomerular basement membrane nephritis

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is hydrolyzed by angiotensin-converting enzyme, is a natural regulator of hematopoiesis. Here it is shown that Ac-SDKP inhibits TGF-beta action in mesangial cells. Because TGF-beta is thought to play a pivotal role in the development and progression of glomerulonephritis, the therapeutic effects of Ac-SDKP on an established model of renal dysfunction and histologic alteration in Wistar-Kyoto rats with anti-glomerular basement membrane nephritis was examined. Fourteen days after the induction of anti-glomerular basement membrane nephritis, the rats were treated subcutaneously with Ac-SDKP at a dose of 1 mg/kg per d for 4 wk. Treatment with Ac-SDKP significantly improved proteinuria and renal dysfunction, including increased plasma blood urea nitrogen and creatinine levels and decreased creatinine clearance. Histologic examination showed severe glomerulosclerosis and interstitial fibrosis in the vehicle-treated rats, whereas these histologic injuries were significantly ameliorated in rats that were treated with Ac-SDKP. The histologic improvements were accompanied by the suppression of gene and protein expression of fibronectin, interstitial collagen, and TGF-beta1 in the nephritic kidney. Furthermore, treatment with Ac-SDKP resulted in the inhibition of Smad2 phosphorylation, an increase in Smad7 expression in the kidney, and reduction of macrophage accumulation into the glomeruli and tubulointerstitium in nephritic rats. In conclusion, Ac-SDKP significantly ameliorated the progression of renal dysfunction and fibrosis even after the establishment of nephritis. The inhibitory effect of Ac-SDKP was mediated in part by the inhibition of TGF-beta/Smad signal transduction and the inflammatory response. These findings suggest that Ac-SDKP treatment may be a novel and useful therapeutic strategy for the treatment of progressive renal diseases.     

Prediction of early progression of metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitor

Background:There are various alternative first-line therapeutic options besides tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). To inform therapeutic decision-making for such patients, this study aimed to identify predictive factors for resistance to TKI.Materials and methods:A total of 239 cases of mRCC patients who received first-line TKI therapy were retrospectively studied. Patients with a radiologic diagnosis of progressive disease within 3 months after initiating therapy were classified as primary refractory cases; the others were classified as non-primary refractory cases. The association between primary refractory cases and age, gender, pathology findings, serum c-reactive protein (CRP) level, metastatic organ status, and 6 parameters defined by the International Metastatic Renal Cell Carcinoma Database Consortium were analyzed.Results:Of 239 cases, 32 (13.3%) received a radiologic diagnosis of progressive disease within 3 months after initiating therapy. The rates of sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, presence of liver metastasis, anemia, and time from diagnosis to treatment interval of less than a year were significantly higher in the primary refractory group. Multivariate analysis showed that sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, and liver metastasis were independently associated with primary refractory disease. A risk-stratified model based upon the number of patients with these factors indicated rates of primary refractory disease of 4.0%, 10.1%, and 45.0% for patients with 0, 1, and 2 or more factors, respectively.Conclusions:Sarcomatoid differentiation, hypercalcemia, an elevated serum CRP level, and presence of liver metastasis were associated with primary refractory disease in mRCC patients receiving first-line TKI therapy. These results provide clinicians with useful information when selecting a first-line therapeutic option for mRCC patients.