Research On Oxidative Stress In Chronic Renal Failure And The Role Of Low Molecular Weight Heparin As An Antioxidant

Oxidative stress defines an imbalance between formation of reactive oxidative species(ROS) and anti-oxidative defense mechanisms.There is convincing clinical and experimental evidence that formation of reactive oxygen species(ROS) is augmented during this chronic inflammatory process due to an imbalance between synthesis of ROS and neutralizing anti-oxidative defense mechanisms.Oxidative stress is the important factor that accelerates chronic kidney disease and its com plication.It is recognized that oxidative stress is the independent risk factor of CKD progression and its complications.It is found that oxidative stress is especially serious in some kinds of kidney disease,for example,mesangial proliferative glomerulo-nephritis and diabetic nephropathy.Few studies answer that whether oxidative stress increases due to the decreased kidney function.Also,much effort has been spent searching for substance capable of preventing oxidative stress.However,few can be proved effective in clinical.Low molecular weight heparin(LMWH) is the common drug of kidney disease.Besides anticoagulation,LMWH also has the role of antifirmed inflammatory,anti-oxidant and so on.Several experiments in vitro or in vivo con that LMWH can prevent oxidative stress.Part1Research on Oxidative Stress in Chronic Renal FailureObjective:To investigate the relationship between increased oxidative stress and decreased kidney function and to observe the levels of markers of oxidative stress in chronic kidney disease.Efforts were made to establish a series of methods to reflect the real situation of oxidative stress in CKD patients.Method:According to the definition of CKD in K/DOQI(2006),seventy-three patients between CKD stages 1-5 were enrolled.The following index were measured: hemoglobin,blood fat,C-reactive protein,albumin,glutathione peroxidase(GSH-PX), superoxide dismutase(SOD),malonaldehyde(MDA),catalase(CAT) and advanced oxidative protein product(AOPP).Ten patients in department of orthopaedics who didn't suffer from kidney disease were enrolled as control group. Results:(1) Plasma AOPP was significantly higher in CKD stage 1 to 5 compared with control group(P＜0.05).AOPP was higher in CKD stage 2 than CKD stage 1,in CKD stage 3 than CKD stage 2,in CKD stage 4 than CKD stage 3,in CKD stage 5 than CKD stage 4(P＜0.05).(2) Plasma GSH-PX was significantly lower in CKD stage 1 to 5 compared with control group(PO.05).GSH-PX was higher in CKD stage 3 than CKD stage 4 (128.78±34.58vs120.17±39.41x10~4U/L,P＜0.05).But,there is no difference in CKD stage 1 to 3 and between CKD stage 4 and CKD stage 5(P＞0.05).(3) Plasma MDA was significantly higher in CKD stage 1 to 5 compared with control group(P＜0.05).MDA was significantly higher in CKD stage 3than CKD stage 2 and in CKD stage 4 than CKD stage 3(4.76±1.45vs2.96±1.55nmol/ml,5.03±1.14 vs4.76±1.45nmol/ml,P＜0.05,respectively).But,there is no difference between CKD stage 1 and CKD stage 2 and between CKD stage 4 and CKD stage 5 (P＞0.05).(4) Plasma SOD was significantly lower in CKD stage 1 to 5 compared with control group(P＜0.05).SOD was significantly lower in CKD stage 4 than CKD stage 3 (P＜0.05),there is no difference in CKD stage 1 to 3 and between CKD stage 4 andCKDstage5(P＞0.05).(5) Plasma CAT was significantly lower in CKD stage 1 to 5 compared with control group(P<＜0.05).CAT was significantly lower in CKD stage 5 than CKD stage 4 (P＜0.05),but was significantly higher in CKD stage 4 than CKD stage 3 (P＜0.05).(6) Hemoglobin was lower in CKD stage 4 than CKD stage 3(P＜0.05),and lower in CKD stage 5 than CKD stage 4(P＜0.05).There is no difference in CKD stage 1 to 3.Total cholesterol and LP(a) were higher in CKD stage 4 than CKD stage 3 (P＜0.05),and higher in CKD stage 5 than CKD stage 4(P＜0.05).There is no difference in CKD stage 1 to 3.(7) SOD,GSH-PX correlated well with total cholesterol,LP(a) and HB(P＜O.05). There was an almost linear correlation between AOPP and cholesterol (r=0.897,P=0.039).MDA level showed an relationship to total cholesterol and LP(a)(r=0.763,P=0.034;r=0.718,P=0.042).(8) hs-CRP correlated well with AOPP,SOD,GSH-PX and MDA. Conclusion:(1) Oxidative stress was serious in chronic renal failure compared with control group.(2) Oxidative stress becomes serious with the progression of kidney function.(3) Plasma AOPP increased with the progression of kidney function.AOPP might be more eligible and reliable to delineate the status of oxidative stress.The next is plasma MDA and GSH-PX.(4) Anaemia and disorder of lipid metabolism get more serious with the progression of kidney function.Oxidative stress becomes serious with the aggravation of anemia and disorder of lipid metabolism.(5) hs-CRP correlated well with micro-inflammation.Part 2Research on the Role of Low Molecular Weight Heparin as an AntioxidantObject:To identify the anti-oxidative effect of Low Molecular Heparin in chronic kidney disease.Method:Thirty-seven patients between CKD stage 3 to CKD stage 5 was randomly separated into two groups,that is glutathione group(normal saline NS 250ml plus Glutathione 1.8g/d×l0d) and LMWH group(Fraxiparine 0.4ml/d×l0d).The levels of malondialdehyde(MDA),advanced oxidation protein product(AOPP),superoxide dismutase(SOD),catalase(CAT),activity of glutathione peroxidase(GSH-PX )in plasma were measured at the beginning and the end of administering glutathione or LMWH(Fraxiparine).Result:(1) Both LMWH and glutathione supplementation decreased the levels of plasma AOPP(130.82±21.95 vs 127.96±25.11μmol/l,P＜0.05 and 117.23±19.53 vs 112.34±20.07μmol/l,P＜0.05,respectively).Compared with group LMWH, AOPP was significantly decreased in group glutathione(P＜0.05)(2) GSH-PX:LMWH supplementation increased the levels of plasma GSH-PX (115.51±41.35vsl26.31±36.42xl0~4U/L,P＜0.05).Also,glutathione can increased it(122.76±33.34 vsl20.28±46.08×l0~4U/L,P＜0.05).There is no difference between the effects of glutathione and LMWH.(3) MDA:There was no significant change in plasma levels of MDA in LMWH group(P＞0.05),while glutathione supplementation decreased the levels of plasma MDA(P＜0.05). (4) There was no significant change in plasma levels of CAT both in LMWH group and glutathione group(P＞0.05).(5) There was no significant change in plasma levels of SOD both in group LMWH and group glutathione(P＞0.05).Conclusion:LMWH ameliorates oxidative stress state without apparent side effect,although farther observation are needed.But in glutathione group,AOPP was significantly decreased compared with in LMWH group.