The oral adsorbent AST-120 attenuates the progression of hyperlipidemia and glomerulosclerosis in spontaneous hypercholesterolemic rats (SHCRs)

Background. The oral adsorbent, AST-120 Kureha Chemical, has been shown to attenuate the progression of chronic renal failure in rats and humans. Spontaneous hypercholesterolemic male rats, (SHC rats; SHCRs) have been introduced for experimentation because they develop progressive hyperlipidemia and glomerulosclerosis on a cholesterol-free standard diet by their 30th week of life. Methods. The effects of AST-120 were studied in SHCRs. Twenty 10-week-old SHCRs were divided into two groups: a control group (n = 10), and an AST-120 group (n = 10). The experiment was begun at the 12th week and completed at the 34th week of life. Results. At the end of the experiment, we found that the serum levels of total cholesterol were 40% lower in the AST-120 rats than in the control rats (P < 0.01). The creatinine clearance in the AST group was 40% higher than that in the controls (P < 0.05). At the age of 20 weeks, postheparin lipoprotein lipase in the AST-120 SHCRs and in Sprague-Dawley rats with normal serum lipid levels was comparable, but was clearly lower in the control SHCRs. Finally, in a pathological investigation that determined a sclerosis index for all kidneys, this was significantly lower in the AST group than in the control animals (P < 0.01). Conclusions. The reduction of serum lipid levels following the administration of the AST-120 oral adsorbent is associated with amelioration of renal functional and structural changes in SHCRs. Received: January 8, 1999 / Accepted: June 15, 1999     

Effects of oral carbonic adsorbent (AST-120) on kidney of early-stage chronic kidney disease rats

Abstract

Aim: to investigate the therapeutic effects of oral carbonic adsorbent on rats with early-stage renal failure. Methods: The early-stage renal failure model was established with three-fourth subtotal nephrectomy Wistar rats. Four weeks after the subtotal nephrectomy, the rats were randomly divided into four groups: (1) adsorbent diet (AD) rats; (2) low protein diet (LPD) group; (3) low protein and AD rats; and (4) normal diet rats as control (ctrl) group. Sham operation group is set as well. The therapeutic effects of adsorbent were examined after 15 weeks treatment. Results: The level of 24 hours urinary protein excretion, serum creatinine (Scr), index of glomerulosclerosis (GSI) and tubulointerstitial fibrosis score (TIFS) of rats with adsorbent or LPD treatment are significantly lower than ctrl group rats. The combination of adsorbent and LPD lowered level of 24 hours urinary protein excretion, Scr, index of GSI and TIFS compared with LPD or adsorbent treatment alone. Conclusion: Both AST-120 and LPD treatment lowered the Scr and blood urea nitrogen level as well as ameliorated the proteinuria and glomerular and tubulointerstitial damage of rats with early stage renal failure. The combined treatment of oral carbonic adsorbent and LPD showed greater therapeutic effects.     

Correction by oral adsorbent of abnormal digestive tract milieu in rats with chronic renal failure

In order to examine the mechanism by which the oral carbonaceousadsorbent, AST-120 delays the appearance of glomerular sclerosis,experiments were carried out in 120 male Sprague-Dawley ratsweighing 285–320 g. The rats were first subjected to 2/3,3/4, and 4/5 nephrectomy (n=40). The experiments were begunat 2 weeks after the surgery, and were performed over an 8-weekperiod. Half of each group (n=20) was administered 1 g/day ofliquid AST-120, and the other half received liquid vehicle solutionwith pair feeding in each group. In the 2/3 nephrectomized groupthe administration of AST-120 delayed the occurrence of glomerularhypertrophy and prevented the appearance of glomerular sclerosiswithout any significant differences in renal function, systemicblood pressure (SBP), and urinary protein excretion (U-P). Inthe 3/4 nephrectomized group the administration of AST-120 delayedthe appearance of glomerular hypertrophy and sclerosis withsignificant decreases in SBP and U-P. In the 4/5 nephrectomizedgroup the administration of AST-120 delayed the appearance ofglomerular sclerosis and prevented a decrease in renal function.It is concluded that administration of the oral adsorbent AST-120delays the occurrence of glomerular sclerosis by delaying theappearance of glomerular hypertrophy, systemic hypertension,and the increase in proteinuria. It can be therefore mentionedthat the accumulating substances in the digestive tract worsenthe abnormal milieu of chronic renal failure.     

Oral carbonaceous absorbent modifies renal function of renal ablation model without affecting plasma renin-angiotensin system or protein intake

Background. Although it has been repeatedly shown that the oral carbonaceous absorbent AST-120 ameliorates the progression of chronic renal failure, the mechanisms remain unknown.Methods. Male Sprague-Dawley rats (6 weeks old), weighing 180–210g, were 4/5 nephrectomized, and were divided into two groups: one given AST-120 (0.4g/100g body weight BW; n = 9) and the other not given AST-120 (n = 9). Body weight, blood pressure, and serum and urine chemistry, as well as the plasma components of the renin-angiotensin system, were measured for 22 weeks.Results. Proteinuria was significantly greater in the controls than in the AST-120 group (102 ± 22 vs 51 ± 7mg/day at 22 weeks). Urea clearance was lower in the former (3.7 ± 0.4 vs 3.9 ± 0.4ml/min). There were no differences in plasma renin activity (1.4 ± 0.3 vs 1.9 ± 0.4mg/ml per h), or in angiotensin I (756 ± 119 vs 1042 ± 168pg/ml) and II (35.1 ± 7.4 vs 46.6 ± 7.6pg/ml) or angiotensin-converting enzyme activity (39.0 ± 2.4 vs 37.9 ± 2.2IU/l) between the two groups. Protein intake, estimated from urinary urea appearance, was not different. Serum phosphate concentration (6.6 ± 0.3 vs 5.9 ± 0.3mg/dl) was higher in the control than in AST-120, while the urinary phosphate excretion rate (31.5 ± 0.8 vs 28.1 ± 1.8mg/day) tended to be lower in the latter.Conclusions. AST-120 retarded the progression of renal failure in the 4/5 renal ablation model without affecting the plasma renin-angiotensin system or protein intake, both of which were the most important risk factors for the progression of renal failure. We hypothesize that the renal protective effects of the oral absorbent AST-120 may be, at least in part, due to its lowering phosphate absorption from the diet as a phosphorus binder.     

AST-120 Treatment in Pre-Dialysis Period Affects the Prognosis in Patients on Hemodialysis

Background/Aims. An oral adsorbent, AST-120, has been shown to retard the deterioration of renal function in patients with chronic kidney disease (CKD) by decreasing serum nephrotoxic substances such as indoxyl sulfate. Recent studies have suggested that a high level of serum indoxyl sulfate may be one of the mechanisms underlying the progression of atherosclerotic lesion, which is the leading cause of cardiovascular event or death in dialysis patients. In this study, we examined retrospectively whether AST-120 given to patients in the pre-dialysis period influences the prognosis after the initiation of dialysis. Methods. One hundred and ninety-two CKD patients on dialysis were studied. The survival and causes of death after the initiation of dialysis were compared between patients who were administrated AST-120 (AST-120 group, n = 101) and those not administrated AST-120 (non-AST-120 group, n = 91) prior to the initiation of dialysis. Results. The five-year survival rate was 72.6% in the AST-120 group and 52.6% in the non-AST-120 group, and was significantly higher in the AST-120 group (p = 0.018). The risk of death was increased 1.91-fold in the non-AST-120 group. However, no difference in the causes of death was observed between two groups. Conclusion. This study suggests that AST-120 given prior to the initiation of dialysis improves the prognosis of CKD patients under dialysis, although there is no association between AST-120 treatment and death caused by cardiovascular diseases such as heart failure, myocardial infarction, and cerebral hemorrhage. Further studies are needed to elucidate the effect of AST-120 on cardiovascular events and the prognosis in dialysis patients.     

Combination therapy with angiotensin-converting enzyme inhibitor and oral adsorbent of uremic toxins can delay the appearance of glomerular sclerosis and interstitial fibrosis in established renal failure

BACKGROUND/AIM: Angiotensin II plays a central role in the progression of chronic renal failure (CRF), and administration of angiotensin-converting enzyme inhibitor (ACEI) in rats delays the progression of CRF. However, ACEI has little effect on CRF progression in rats with established CRF. We therefore examined whether combination therapy with ACEI and oral adsorbent for uremic toxins in the gastrointestinal tract has the desired effect. METHODS: Rats subjected to subtotal nephrectomy were given enalapril at 20 mg/kg (n = 10, group E), AST-120 at 5 g (n = 10, group A), enalapril and AST-120 together at the same doses (n = 10, group EA), or no treatment (n = 10, group C) 8 weeks after the operation. The substances were administered in 100 g rat chow. All animals were pair-fed, and all were killed after 8 weeks of pair-feeding. RESULTS: Body weight did not differ between groups during the study. Blood pressure at week 8 was significantly lower in groups E and EA than in groups C and A (p < 0.05). Urinary protein excretion level and renal plasma flow rate at week 8 were significantly less in groups E and EA than in group C (p < 0.05, p < 0.01). The glomerular filtration rate at week 8 was significantly higher in group EA than in group C (p < 0.05). The glomerular sclerosis index and interstitial fibrosis area at week 8 were significantly less in group EA than in group C (p < 0.01). CONCLUSION: ACEI and AST-120 in combination can delay progression of established CRF in rats by inhibiting the appearance of glomerular sclerosis and interstitial fibrosis.     

Effect of oral adsorbent (AST-120) on renal function,acquired renal cysts and aortic calcification in rats with adriamycin nephropathy

AIMS: The effect of oral adsorbent, AST-120, on the experimental renal disease induced by adriamycin, uninephrectomy and high protein diet proposed as a model of acquired cystic disease of the kidney was investigated. METHODS: 3 mg of adriamycin was injected into the tail vein of rats and 4 weeks later right-side nephrectomy was performed, 2 weeks thereafter 26 rats with urinary protein excretion between 100 and 358 mg/day were selected from 60 rats. Two groups, 13 rats in each group, namely the AST-120-treated group and control group, both of which had equal renal damage before the administration of AST-120 or placebo. AST-120 (0.4 g/100 g BW/day) was administered for 19 weeks. RESULTS: Serum creatinine and BUN in the AST-120-treated group were significantly lower (serum creatinine: 3.3 +/- 2.1 vs. 7.1 +/- 2.7 mg/dl, p < 0.003) and creatinine clearance was higher (0.62 +/- 0.49 vs. 0.29 +/- 0.30 ml/min, p < 0.05) at the final examination than in the control group. Survival rate which was examined using another set of 9 rats was higher in AST-120-treated rats than in AST-120-untreated rats. Serum indoxyl sulfate was significantly lower at all times after using AST-120 in the AST-120-treated group than in contrast to the control group. Histological examination revealed less severe interstitial and cystic changes in the AST-120-treated group. This suggests that AST-120 can prevent or retard the development of acquired renal cystic disease in this model. Aortic calcification tended to be less severe in the AST-120-treated group because of less serum Ca x P products. CONCLUSION: The AST-120-treated group significantly decreased serum creatinine and increased creatinine clearance with less severe renal cystic changes in this model during the later weeks of administration of AST-120 or at death, accompanied with the tendency of less severe aortic calcification.     

Effect of an oral adsorbent (AST-120) in rats with daunomycin-induced chronic renal failure

The effect of an oral adsorbent (AST-120) was examined in rats with daunomycin-induced chronic renal failure. Sixteen pairs of daunomycin rats which had similar levels of proteinuria at 4 weeks after being injected with daunomycin were selected. One rat of each pair served as a control and was fed on a standard diet, while the other rats were fed on a diet containing AST-120. The blood creatinine and blood urea nitrogen (BUN) were significantly lower in the rats fed with AST-120 than in the controls. Moreover, the life span of the rats fed with AST-120 was significantly prolonged as compared to that of the control rats. These findings suggest that oral administration of AST-120 may help to prevent rapid deterioration of renal function in experimental chronic renal failure induced by daunomycin in rats.     

Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis

BACKGROUND: Imai rats exhibit spontaneous focal glomerulosclerosis (FGS) with progressive proteinuria and hyperlipidemia leading to renal insufficiency by age 34 weeks. Recently, we reported marked down-regulations of skeletal muscle and adipose tissue lipoprotein lipase (LPL) and very low-density lipoprotein (VLDL) receptor in male Imai rats at 32 weeks of age. Dietary protein restriction and oral adsorbent AST-120 (AST) have been shown to slow progression of renal disease and attenuate hyperlipidemia in the Imai rats. This study tested the hypothesis that amelioration of proteinuria by protein restriction or use of oral adsorbent AST-120 beginning at 10 weeks of age may improve renal disease and LPL and VLDL receptor deficiencies in Imai rats. METHODS: Ten-week-old male Imai rats were randomly assigned to those fed either a regular diet, low protein diet (LPD), or regular diet containing the adsorbent preparation, AST-120. Ten-week-old male Sprague-Dawley rats served as controls. The animals were observed for 24 weeks. Six rats were included in each group. All diets were prepared in powder form. RESULTS: The untreated 34-week-old Imai rats showed severe proteinuria, hypoalbuminemia, 50% reduction in creatinine clearance, hypercholesterolemia, hypertriglyceridemia, and elevated plasma VLDL concentration. This was associated with significant reductions in plasma post-heparin LPL activity, hepatic lipase activity, as well as adipose tissue and skeletal muscle immunodetectable LPL and VLDL receptor proteins. Protein restriction mitigated the decline in creatinine clearance, ameliorated proteinuria, hypoalbuminemia, hypertension, and hypercholesterolemia, lowered plasma VLDL, and improved plasma postheparin LPL activity, hepatic lipase activity, LPL, and VLDL receptor proteins in skeletal muscle and adipose tissue. Similar improvements were observed in all parameters with AST administration. CONCLUSION: Moderate protein restriction and use of oral adsorbent can slow progression of renal disease and, thereby, ameliorate LPL, hepatic lipase, and VLDL receptor deficiencies and the associated hyperlipidemia in rats with spontaneous FGS.     

Effect of oral-adsorbent (AST-120) in chronic renal failure (CRF) in rats

The progression of renal failure has been suggested to be altered by dietary manipulation of protein based on the presumption that the progressive nature of CRF may be caused by the vicious cycle driven by some toxic metabolite uncleared by failing kidney. We studied 29 female Sprague-Dawley rats aged 12 weeks weighing 226 to 290 gm subjected to a 5/6 nephrectomy. 2 days after, group C (16 rats) were given a commercially prepared diet (CE-2, Japan Kurea). While group A (13 rats) were given the same diet and 5% AST-120. Initial serum creatinine of both group was 2.2 mg/dl. After 9 weeks, all surviving rats were sacrificed for evaluation of renal histology. During the observation period, survival rate, Ccr, urinary creatinine and urea excretion were significantly better in group A rats. Result also showed a better weight increase with concomitant increase in protein catabolic rate in group A rats. These result showed the beneficial effect of AST-120 in uremic rats in terms of survival rate and delaying the progression of CRF despite the presence of increased protein catabolic rate. Based on this study, one way of preventing the progression of renal failure is through removal of some toxic metabolite in the gastrointestinal tract by the use of oral adsorbent as exemplified by AST-120.     

Comparison of the renal effects of different angiotensin-converting enzyme inhibitors in patients with chronic renal diseases

Background. Angiotensin-converting enzyme inhibitors (ACE-Is) are important agents for preserving renal function in patients with renal diseases. However, the choice of which ACE-I to employ for the treatment of renal disease has not yet been clarified. This study compared the renal effects of enalapril with those of five other ACE-Is in patients with chronic renal diseases. Methods. One hundred and twenty-eight patients with various renal diseases were randomly assigned to six groups according to the ACE-I used: group 1, alacepril (75 mg/day; n = 20); group 2, captopril (37.5 mg/day; n = 19); group 3, cilazapril (1.0 mg/day; n = 23); group 4, delapril (30 mg/day; n = 22); group 5, enalapril (5.0 mg/day; n = 20); and group 6, temocapril (2.0 mg/day; n = 24). Doses of the ACE-I adjusted-converting to the renal function showed similar effects in decreasing blood pressure. Each ACE-I was administered to the patients for 4 months, with monthly examinations. Twenty-four patients dropped out, for various reasons; therefore, results for 104 patients were finally analyzed (group 1, n = 16; group 2, n = 11; group 3, n = 22; group 4, n = 21; group 5, n = 12; group 6, n = 22). Results. There were no differences in absolute or percent changes in mean arterial pressure (MAP), plasma aldosterone (ALDO), the urinary excretion of protein (U-P) and albumin (U-ALB), 24-h creatinine clearance (24-h Ccr), plasma renin activity (PRA), and serum potassium (K) between enalapril and the other ACE-Is, although significant decreases from baseline values in MAP, ALDO, U-P, U-ALB, and 24-h Ccr, and increases in PRA and serum K from baseline values were observed after the administration of enalapril and the other ACE-Is. Conclusions. These results indicated that the renal effects of enalapril were similar to those of the other ACE-Is tested, and suggested, therefore, that any one of the class of ACE-Is could be chosen with the choice being dependent on that considered to lead to best compliance for the patient. The beneficial effects of the class of ACE-Is in patients with renal disease would be expected to be similar. Received: September 6, 2001 / Accepted: November 14, 2001     

Iron restriction prevents diabetic nephropathy in Otsuka Long-Evans Tokushima fatty rat

Abstract

High body iron levels are found in type 2 diabetes mellitus (DM). Iron excess leads to tissue injury through free radical formation. We investigated the effect of iron restriction on renal damage in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2?DM. OLETF rats (n?=?18) were divided into three groups at 10 weeks of age: high fat diet containing 8% NaCl (HFS, n?=?6), HFS diet with iron restricted (HFS?+?IR, n?=?6), and HFS with hydralazine (HFS?+?Hyd, n?=?6). Long-Evans Tokushima (LETO) rats served as control. Iron restriction decreased hemoglobin levels, systolic blood pressure, and urinary excretion of protein and 8-hydroxy-2'-deoxyguanosine in the OLETF rats fed with HFS diet. Compared to the HFS group, the expression of desmin, renal glomerular injury marker and iron deposition in the renal tubules were attenuated in the HFS?+?IR group but not in the HFS?+?Hyd group at 26 weeks of age. Moreover, renal hypoxia (evaluated as pimonidazole adducts) was improved in the HFS?+?IR group compared to the HFS group in spite of anemia. Iron restriction prevented the production of reactive oxygen species and the development of early stage nephropathy in OLETF rats. Iron restriction may be beneficial in prevention of nephropathy in type 2?DM.     

Effects of oral adsorbent in the rat model of chronic renal failure.

The effects of oral adsorbent, AST-120 (Kureha Chemical Ind. Co., Tokyo), were studied in the rat model of subtotal nephrectomy. In 34 female Sprague-Dawley rats, three quarters of the renal mass were removed from the left kidney by ligation of 3 branches of the left renal artery. One week later, the right kidney was removed. Two days after right nephrectomy, control rats were fed standard rat chow ad libitum, while AST-120-treated rats were fed standard rat chow containing AST-120 ad libitum. The animals were observed for 9 weeks. Of the control rats, some became severely ill and appeared to be almost dying before 9 weeks, while paired AST-120-treated rats appeared well. Body weight was maintained better in AST-120-treated rats than in control rats. At completion of the study, levels of BUN and serum creatinine were lower and glomerular filtration rate and renal plasma flow rate were higher in AST-120-treated than in control rats (p < 0.05), although there was no statistically significant difference in proteinuria. Serum uremic peak 2a measured by high-performance liquid chromatography, which is considered to correspond to uremic toxins, was statistically lower in AST-120-treated rats (p < 0.05). Finally, a marked reduction in the degree of glomerular sclerosis was noted in AST-120-treated versus control rats (p < 0.05). The results indicate that AST-120 is effective in the treatment of chronic renal failure in terms of reducing uremic symptoms as well as preserving renal function and glomerular architecture. The data also indicate that a reduction in uremic toxins could delay the progressive damage of renal function and glomerular architecture in chronic renal failure.     

The effect of growth hormone on the growth failure of chronic renal failure

To investigate the effects of growth hormone (GH) on the reversal of growth failure in uremia, recombinant human GH (rhGH) was administered to rats with chronic renal failure (CRF). The dosage of rhGH was 3 IU/day (i.p.) for 13 days after the induction of CRF by 5/6 nephrectomy. Animals were classified into four groups: untreated nephrectomized rats (NX,n=40), GH-treated nephrectomized rats (NX+GH,n=18), sham-operated rats fed ad libitum (SHAMAL,n=27), and sham-operated rats pair-fed with 10 NX rats (SHAMPF,n=10). NX and NX+GH rats developed a similar and moderate degree of CRF, serum urea nitrogen being (mean±SEM) 49±3 and 54±4 mg/dl, respectively, compared with 16±4 and 19±0 mg/dl in SHAMAL and SHAMPF groups. Weight (56.0±3.3 g) and length (3.5±0.1 cm) gains of NX rats were lower than those of SHAMAL rats (94.2±4.0 g,P<-0.0001 and 4.1±0.2 cm,P<-0.01). Growth of the SHAMPF group and the matched NX rats was not significantly different. Weight (56.2±5.0 g) and length (3.4±0.2 cm) gains of NX+GH and NX rats were similar, the beneficial effect of GH therapy on growth being observed in only those animals with more severe degrees of uremia. This growth-promoting action resulted from greater food efficiency and not from stimulated food intake. The hypercholesterolemia seen in NX rats, 81±2 mg/dl versus 55±3 mg/dl in SHAMAL (P0.0001), was not increased in the NX+GH group, 87±3 mg/dl. There was a positive and significant correlation between serum cholesterol and serum urea nitrogen values in NX and NX+GH animals. This study suggests that growth impairment of mild CRF is mainly due to malnutrition and is refractory to GH administration. GH therapy improves the growth rate of animals with advanced CRF without aggravating their lipid abnormalities.     

Effect of etidronate on three-dimensional trabecular structure in ovariectomized or sciatic neurectomized rats

The purpose of this study was to evaluate the effect of etidronate (EHDP) on three-dimensional (3D) trabecular structure in ovariectomized (OVX) and sciatic neurectomized (NX) rats. Eight-week-old female Lewis rats received ovariectomy (n = 19) or sham operation (OVX-sham; n = 10). OVX rats received either vehicle (OVX-control; n = 9) or EHDP (OVX-EHDP; n = 10). Eight-week-old female Lewis rats received NX (n = 20) or sham operation (NX-sham; n = 10). NX rats received either vehicle (NX-control; n = 10) or EHDP (NX-EHDP; n = 10). EHDP at 5mg/kg or vehicle was subcutaneously injected 5 days a week. The treatment was initiated 2 weeks after surgery and was continued for 2 weeks. At 12 weeks of age, the rats were killed, and we scanned the proximal metaphysis of the tibia; this was done using micro-CT; ( CT20; SCANCO Medical). The recovery of structural parameters was not complete in NX rats compared to OVX rats. The 3D micro-CT images showed that the subcortical spongiosa, which was preserved in OVX rats, had marked loss in NX rats. Furthermore, these trabeculae were not restored after the EHDP treatment. In conclusion, the mechanical driving of the control of trabecular structure is inactive in NX, and EHDP treatment for 2 weeks does not restore this condition.     

Urinary albumin and TGF β1 levels as renal damage indices in patients with congestive heart failure

Background. In patients with congestive heart failure (CHF), the pathogenic role of angiotensin II in the development of cardiovascular death has widely been accepted. To study the pathophysiological mechanisms of CHF-associated renal damage, we examined urinary albumin levels as a clinical marker of glomerular hyperfiltration and sclerosis, which may be attributed to the upregulated function of angiotensin II. Methods. Twenty outpatients with mild to moderate CHF without renal failure were examined. They were treated with various combinations of angiotensin-converting enzyme inhibitors (ACEI), (n = 9), calcium antagonists (n = 9), β-blockers (n = 6), and diuretics (n = 12). Urinary (u-) levels of albumin, N-acetyl-β-d-glucosaminidase (NAG), and transforming growth factor β-1 (TGF β1), and circulating levels of endothelin-1 (ET-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured and examined in relation to various clinical parameters and the mode of treatment. Results. (1) CHF patients showed significantly higher mean levels of u-albumin, u-NAG, u-TGF β1, plasma ET-1, and serum TIMP-1 than normal controls. In an age-matched comparison, the u-albumin levels in CHF patients were as high as those in diabetic patients without overt nephropathy and hypertension. (2) The u-albumin level tended to correlate with the u-NAG level (P = 0.051), however, there was no patient with high u-NAG in the subgroup with negative u-albumin levels. (3) The u-albumin level, like the u-TGF β1 and serum TIMP-1 levels, showed a significant positive correlation with the mean arterial pressure (MAP) level (each, P < 0.05), and showed slight, but nonsignificant correlations with the u-TGF β1 (P = 0.08) and serum TIMP-1 levels (P = 0.06). (4) The patients treated with an ACEI showed significantly lower levels of u-albumin (P < 0.01) and serum TIMP-1 (P < 0.05) than those not treated with an ACEI. Treatment with an ACEI tended to decrease positivity for u-TGF β1 (P = 0.09). Conclusions. The correlation between MAP and u-albumin levels and the ameliorative effect of ACEI on u-albumin excretion suggest that urinary albumin excretion may be caused by a glomerular hyperfiltration mechanism produced by both preloading of the systemic blood pressure and afterloading by angiotensin II-mediated constriction of efferent arterioles. In addition, the suppressive effects of ACEI on u-TGF β1 and serum TIMP-1 levels suggest that angiotensin II may accelerate TGF β1-mediated tissue remodeling, including nephrosclerosis, in CHF. Received: February 21, 2001 / Accepted: October 31, 2001     

Exercise Degrades Bone in Caloric Restriction,Despite Suppression of Marrow Adipose Tissue (MAT)

Marrow adipose tissue (MAT) and its relevance to skeletal health during caloric restriction (CR) is unknown: It remains unclear whether exercise, which is anabolic to bone in a calorie-replete state, alters bone or MAT in CR. We hypothesized that response of bone and MAT to exercise in CR differs from the calorie-replete state. Ten-week-old female B6 mice fed a regular diet (RD) or 30% CR diet were allocated to sedentary (RD, CR, n = 10/group) or running exercise (RD-E, CR-E, n = 7/group). After 6 weeks, CR mice weighed 20% less than RD, p < 0.001; exercise did not affect weight. Femoral bone volume (BV) via 3D MRI was 20% lower in CR versus RD (p < 0.0001). CR was associated with decreased bone by μCT: Tb.Th was 16% less in CR versus RD, p < 0.003, Ct.Th was 5% less, p < 0.07. In CR-E, Tb.Th was 40% less than RD-E, p < 0.0001. Exercise increased Tb.Th in RD (+23% RD-E versus RD, p < 0.003) but failed to do so in CR. Cortical porosity increased after exercise in CR (+28%, p = 0.04), suggesting exercise during CR is deleterious to bone. In terms of bone fat, metaphyseal MAT/ BV rose 159% in CR versus RD, p = 0.003 via 3D MRI. Exercise decreased MAT/BV by 52% in RD, p < 0.05, and also suppressed MAT in CR (−121%, p = 0.047). Histomorphometric analysis of adipocyte area correlated with MAT by MRI (R² = 0.6233, p < 0.0001). With respect to bone, TRAP and Sost mRNA were reduced in CR. Intriguingly, the repressed Sost in CR rose with exercise and may underlie the failure of CR-bone quantity to increase in response to exercise. Notably, CD36, a marker of fatty acid uptake, rose 4088% in CR (p < 0.01 versus RD), suggesting that basal increases in MAT during calorie restriction serve to supply local energy needs and are depleted during exercise with a negative impact on bone. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Reversibility of adenine-induced renal failure in rats

Background. A renal failure model prepared from rats fed on an adenine diet provides valuable information about the pathomechanism of various complications associated with a persistent uremic state. To establish an animal experimental model in which the animals survive in a persistent uremic state, it is essential to settle a point of no return, i.e., an irreversible point. We investigated an irreversible point using the rat renal failure model induced by adenine treatment. Methods. Rats were fed on a diet containing 0.75% adenine for 2, 4, or 6 weeks, and they were then fed an adenine-free diet for an additional 4 weeks to evaluate the degree of recovery from renal dysfunction. Results. The rats fed on the adenine diet for 2 weeks showed a decrease in mean serum creatinine(s-Cr) from 1.8 mg/dl before to 0.7 mg/dl after the observation period, with mild anemia. The rats fed on the adenine diet for 4 weeks showed persistent renal dysfunction. Although the mean s-Cr decreased from 2.7 to 2.0 mg/dl, it continued to be higher than the normal range, and the anemia worsened. In the rats fed on the adenine diet for 6 weeks, the mean s-Cr increased from 3.4 to 3.6 mg/dl. Hypoproteinemia was also observed and some animals died. Conclusion. Based on the above results, it was concluded that to prepare a model of chronic renal failure in rats compatible to chronic renal failure seen clinically, the administration of a 0.75% adenine diet for 4 weeks is most appropriate. Received: April 24, 1998 / Accepted: October 12, 1998     

Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-beta(1) expression in spontaneously diabetic (OLETF) rats

Diabetic nephropathy is a common cause of end-stage renal disease. The administration of an oral adsorbent, AST-120, prevents the progression of chronic renal failure in uremic rats and undialyzed uremic patients. This study was designed to determine if AST-120 slows the progression of diabetic nephropathy using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetic mellitus. At 21 weeks of age the OLETF rats were divided into 2 groups: AST-120-administered OLETF rats (n = 7), and control OLETF rats (n = 7). LETO rats, which are genetically similar to the OLETF rats but not diabetic, were also included. After the oral administration of AST-120 for 65 weeks, renal function and pathological changes were investigated in the 3 groups. The administration of AST-120 to the OLETF rats attenuated the progression of glomerular sclerosis, interstitial fibrosis, tubular injury as well as renal dysfunction, and reduced the serum and urinary levels of indoxyl sulfate. Furthermore, AST-120 administration reduced the interstitial expression of transforming growth factor (TGF)-beta(1) and tissue inhibitor of metalloproteinase (TIMP)-1, as well as interstitial infiltration of macrophages. The TGF-beta(1)-stained interstitial area showed positive correlations with the interstitial fibrosis area, the number of TIMP-1-positive cells, and the number of macrophages, and showed a negative correlation with creatinine clearance. In conclusion, AST-120 reduced the interstitial expression of TGF-beta(1) and TIMP-1, and the interstitial infiltration of macrophages, and ameliorates the progression of diabetic nephropathy in OLETF rats.     

An oral adsorbent, AST-120, combined with a low-protein diet and RAS blocker, for chronic kidney disease

BACKGROUND: A low-protein diet and treatment with renin-angiotensin system (RAS) blockers can delay the progression of chronic kidney disease (CKD). The oral adsorbent AST-120 (Kremezin) has a renoprotective effect by reducing serum levels of uremic toxins. We investigated the influence of AST-120 on the preservation of renal function in patients with CKD. METHODS: Twenty-eight patients were randomized to 2 groups: 15 patients receiving 6.0 g of AST-120 daily for 12 months plus a low-protein diet and RAS blocker therapy (group A) and 13 patients who were not given AST-120 (group B). All of them had shown progressive deterioration of renal function with basal treatment. Mean baseline serum creatinine level (+/- standard deviation) was 2.4 +/- 0.8 mg/dL in group A and 2.7 +/- 0.8 mg/dL in group B. There were no significant differences in background parameters before AST-120 therapy. RESULTS: The change in the estimated glomerular filtration rate (eGFR) was significantly smaller in group A than in group B. The change was also significantly smaller in patients with a baseline serum creatinine <2.4 mg/dL and in patients with rapid progression. After 12 months, the slope of the eGFR curve was significantly less steep compared with baseline in group A (-1.77 vs. -0.52 ml/min per month), but there was no significant change in group B. The slope was also significantly less steep in patients with rapid progression. CONCLUSIONS: Adding AST-120 to a low-protein diet and RAS blocker therapy may delay the deterioration of chronic renal failure, especially in patients with early or rapid progression.