| General IntroductionMalnutrition is a major complication of chronic renal failure (CRF). Although renal replacement therapy has been developed, the mortality of patients with end-stage renal disease (ESRD) is still very high. Malnutrition plays an important role in a number of causes of death. According to statistics, in the patients with ESRD, there were 20%-50% patients complicated with malnutrition Malnutrition can lead to immune dysfunction, anemia, frequent infections, even lead to multiple organ failure, which not only affects the prognosis of patients with CRF, but also affected its mortality rate. There are many reasons which can cause malnutrition in chronic renal failure, which mainly include the following aspects:1. Reduced nutrient intake. 2. Metabolic and endocrine disorders:an increase in protein synthesis and a decrease in protein degradation which is caused by uremic toxins, metabolic acidosis, endocrine disorders, inflammation, lipid metabolism disorders, etc.3.CRF anemia.4. protein loss in the process of hemodialysis. With the improvement of dialysis technology, patients with maintenance dialysis increased, while the incidence of malnutrition in CRF was much higher. Nowadays, a-keto acid (brand name: Ketosteril) is the main medicinal treatment on malnutrition in CRF. But the price is high and most patient can't afford it. The efficacy of other treatment, such as intravenous albumin, energy mixture, water-soluble vitamins, recombinant growth hormone, is short-term and limited. So their adverse reactions unavoidably limit their clinical application. Traditional Chinese herbal compound has better effects on malnutrition of CRF patients, but it is inconvenient to take and the effects are not uniform and the quality is difficult to control. Therefore, there is urgent need to seek for alternative remedies for Crohn's diseases and the Chinese drugs preparation may be the best choice.Granule of Shengshuai Yangzhen (SSYZ) was empirical prescription based on "Renshen Yangrongtang", by which WeiLian-bo professor treated malnutrition in chronic renal failure for many years. It was composed of Milkvetch Root, Largehead Atractylodes Rhizome and so on. Our pre-clinical observation showed that total effective rate of therapeutic effect on malnutrition of CRF patients was 81.7%, which was more effective than Ketosteril control group (effective rate 63.2%, P<0.01) and could effectively relieve the state of anemia in CRF. Therefore, it has important social significance and economic value to explore it.In this study we established two types of CRF rat model with malnutrition to investigate the protective effects and improvement of Granule of SSYZ on renal of rats and nutritional status and complete the main pharmacodynamics research of Granule of SSYZ treat CRF rats with malnutrition according to Chinese medicine as 6(1) catalog required.Objective1.To establish CRF rat modle with malnutrition by 5/6 nephrectomy or by adenine and to investigate the onset time of malnutrition and its malnutrition status dynamically.2. To detected the blood parameters including serum creatinine(Scr), blood urea nitrogen (BUN),24-hour urinary protein (24h Upro), albumin(ALB) and hemoglobin (Hb) and the level of IGF-1, EPO, Tf and PTH of animals and to investigate the effects of SSYZ on these indicatrixes above and to explore its possible mechanism to complete its main pharmacodynamics research according to Chinese medicine as 6 (1) catalog required.MethodsTo establish two types of CRF rats with malnutrition. Model I:Rats were received 5/6 nephrectomy for preparation of CRF models, and fed wiht 4% casein at the same time to make malnutrition of CRF rats. Model II:Rats were fed with 0.5% adenine and 4% caseinum to make malnutrition of CRF rats. The onset time of malnutrition and correlated parameters were dynamically observed in two types of model. Those contented with malnutrition of CRF were randomized into normal control group, model control group, Ketosteril group, broth of SSYZ group and Granule of SSYZ high, middle, low group. All rats were treated with corresponding drugs for 8 weeks. The general status of rats, food-intake, body weight were observed during the experiment. During and after treatment, the blood parameters, such as ALB, BUN, Scr,24hUpro, Hb, PA, IGF-1, EPO, Tf, PTH, K, Na, Ca, P and so on, were observed, and the macroscopic appearance changes and pathological change of renal tissue were observed, too.Results1. Preparation of the two models:Model I:Malnutrition status in CRF rats by 5/6 nephrectomy began at the end of 8th week after model establishment.50 rats were consistent with CRF malnutrition model. The correlated parameters were detected as following:Scr:(123.43±18.00)μmol/L, BUN:(23.68±5.65)mmol/L, ALB:(30.02±1.80) g/L,24hUpro:(62.91±5.12)mg/24h, when weigh reduced 20% contrast to normal group (327.28±35.39 vs 419.63±29.91)g.29 rats were dead in the process of modeling. The survival rate was 61.84%. ModelⅡ:Malnutrition status in CRF rats fed with 0.5% adenine began at the end of 8 week. The correlated parameters were detected as following:Scr:(113.02±17.27)μmol/L, BUN:(28.30±4.34)mmol/L, ALB:(29.38±2.74)g/L,24hUpro:(68.65±5.79)mg/24h, when weigh reduced 20% contrasted to normal group (276.45±32.26vs 419.63±29.91)g.14 rats were dead in the process of modeling. The survival rate was 81.58%. During the preparation of the two models, normal rats were lively, responsive, their coats were moist. They had good appetite, normal urine, and their body weight were gradually increased. While CRF rats with malnutrition had bad spirit and poor apathetic and were unresponsive and their urine outputs were decreased and weight lost and there was significant difference between the normal group and the model (P<0.05). 2. After 8-weeks treatment, the experimental results of the two types of models were similar. Compared to model control group, the general status of the treatment groups was obviously relieved. The weight was significantly increased (P<0.05).3. After 8-weeks treatment, the levels of 24hUPro, Scr and BUN in treatment groups were significantly lower than the model group (P<0.05). In malnutrition rats with CRF by 5/6 nephrectomy:the levels of 24hUPro and BUN had no difference among Ketosteril group, broth of SSYZ group and Granule of SSYZ high, middle, low group(P>0.05), while the level of Scr in SSYZ group was significantly reduced compared with Ketosteril group(P<0.05). In malnutrition rats with chronic renal failure by adenine:the levels of 24hUPro and Scr in SSYZ group were significantly lower than Ketosteril group(P<0.05) and there was no difference in other parameters among Ketosteril group, broth of SSYZ group and Granule of SSYZ high, middle, low group. The expression of BUN was significantly higher than Ketosteril group (P<0.05) and there was no difference among other groups.4. The status of malnutrition of rats after 8-weeks treatment.In CRF rats with malnutrition by 5/6 nephrectomy:the level of RBC count of SSYZ group was markedly increased compared with the model group(P<0.05), while there was increase in Ketosteril group. In contrast with the model group, the levels of Hb, Hct, ALB, PA, IGF-1, EPO and Tf in serum were all elevated in treatment groups, while the expression of PTH in model group was significantly higer than the normal group and was decreased after given corresponding drugs. SSYZ significantly alleviated the levels of blood lipid and electrolyte in model group. In CRF rats with malnutrition by adenine:the levels of RBC count, Hb, Hct, ALB, PA, IGF-1, EPO and Tf in all treatment groups were markedly increased compared with the model group(P<0.05). The expression of PTH in model group was significantly higer than the normal group and was decreased after given corresponding drugs. SSYZ significantly alleviated the levels of blood lipid and electrolyte in model group.5. The comparation of pathological change of renal tissueIn CRF rats with malnutrition by 5/6 nephrectomy:In control group, the glomeruli structure, regular arrayed renal cells, complete basal laminal, no inflammatory cell infiltration and fibroplasias can be clearly detected, while in the model group, obviously compensatory hypertrophy of glomeruli, wider mesangial region, proliferation of rat mesangial cells can be observered; in parts of renal tissue, hypertrophy of glomeruli, degeneration, necrosis, abscission and groundmass increase, thickening vessel wall even can be detected. Lymphocyte infiltrated in renal interstitium. However, histological analysis of renal tissue from drug-treated rats showed greatly reduced inflammatory cell infiltration, hypertrophy of glomeruli and hypertrophy of glomeruli. The effects of Granule of SSYZ high and middle groups on the pathological changes were better than that of Granule of SSYZ low and broth of SSYZ group and the effect of Ketosteril group is inferior to Granule of SSYZ middle group.In CRF rats with malnutrition by adenine:In normal group, normal glomeruli structure, regular arrayed renal cells, nocrystal deposition in renal tubule were observed. In model group, the numbers of glomeruli was significantly reduced. Interstitial fibrosis, tubular atrophy, glomerular sclerosis and the extension of capsular space were detected. The atrophy, necrosis of the nephric tubule, the enlargement of capsular space could also be detected. There were an amount of some black needle crystal in the nephric tubule, which showed protein cast, cellular cast, serious interstitial fibrosis and inflammatory cell infiltration. Granule of SSYZ groups and Ketosteril group obviously reduced the pathological changes of the renal tissue from CRF with malnutrition. Mild proliferation of mesangial cells and mild expansion of tubular were obsevered. There were only a few of inaurate crystal in the lumina and a few inflammatory cell infiltration in the renal interstitium.ConclusionsIn this study we established two types of CRF rats with malnutrition by 5/6 nephrectomy or Adenine simultaneously 4% casein fed. At the end of 8th week after model establishment, the weigh and the level of ALB in model group were significantly reduced, while 24hUpro, BUN and Scr were obviously increased compared with normal group, which indicated that the status of malnutrition had already been existed. During the process of intervention, the general status of CRF rats with malnutrition without treatment were bad, their weight was obviously declined and the levels of RBC, Hb, Hct, ALB, PA, IGF-1, EPO and Tf was decreased, while BUN, Scr and 24hUpro were obviously increased, contrast to normal group. It also had lipid metabolism and electrolyte disorders, low calcium, high phosphorus and high PTH hyperlipidemia and the observation of renal pathology showed glomerular sclerosis and necrosis. All the evidence showed that CRF rats with malnutrition had an increase in protein degradation and a decrease in protein synthesis which was caused by uremic toxins, metabolic acidosis, endocrine disorders, inflammation, lipid metabolism disorders, etc. The mutual effects of these reasons finally led to the genesis of CRF with malnutrition. After administratment of corresponding drugs, the malnutrition status of rats were relieved, the expression of RBC, Hb, Hct, ALB, PA, IGF-1, EPO and Tf were significantly elevated and 24hUpro, BUN, Scr and PTH were reduced. The disorders of electrolytes and lipid metabolism were effectively corrected. All these data suggested that Granule of SSYZ could effectively alleviate the symptoms of the malnutrition of CRF and relieved the sclerosis and necrosis of glomerular, whic might work through multi-channel and multi-target. There was no difference in the efficacy of Granule of SSYZ on CRF malnutrition in comparison with Ketosteril but superior to broth of SSYZ group. The results indicated that it was worthy of exploring Granule of SSYZ and it would filled the Chinese Medicines blank treated CRF malnutrition. |
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