Lutfi Z. Clinical Hospital-Tetova - Department of Internal and Haemodia- lysis, Hospital for Nephrology and Haemodialysis ,,VITA Medical Group “ – TetovoThe research paper published by IJSER journal is about Changes of lipoapoproteins and the Role of Statins of Patients with Terminal Chronic Renal Insuf-ficiency treated with repeated hemodialysis 1
ISSN 2229-5518
Changes of lipoapoproteins and the Role of Statins of Patients with Terminal Chronic Renal Insufficiency treated with repeated hemodialysis
Lutfi Zylbeari, Gazmend Zylbeari, Elita Masha, Zamira Bexheti, Merition Ballazhi, Muhamedin Rushiti
Abstract— Disorders of lipid metabolism in patients with ESRD for the first time are described in 1827 by Dr. Bright, particularly in p atients with nephrotic syndrome [4]. Replacing of physiological apolipoproteins with pathological and high degree of their influence in atherogenity are phenomena still undiscovered and therefore whitening of the above processes are necessary experimental and multicentric numerous studies with the most duration of research. Purpose of research paper is to assess the abnormalities(changes) of apolipoproteins in ESRD patients treated with repeated hemodialysis more than 7 years in Clinical Hospital Tetovo,Hemodialysis Unit,randomized b y gender (male or female) and effects of hypolipidemic drugs (statins) on improvement of apolipoproteins abnormalities.Also importance has been given to HDL-ch metabolism disorder which is supposed that is responsible and main factor in controlling the progress and pace of atherogenesis mechanism in uremic patients.
Index Terms— Apolipoproteines, statin, total lipids, total cholesterol, tryglicerides. .
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pact of uremic toxins to the structure and compositions of
It is proved that patients with ESRD treated with repe-ated
hemodialysis suffer from a secondary and complex form of dyslipidaemia and are potential candidates for development of atherosclerosis respectively cardiovascular and cerebrovascular complications. Major disorders of apolipoproteins manifested more in the concentration of triglicerides TG, HDL, LDL, remaining par- ticles, small LDL-6. Concentrations of LDL-6 are mostly increasing in patients with ESRD treated with hemodialysis, but the basic re- sponsible disease remains diabetes compared with the others basic disease such HTA, chronic glomerulonephritis, polycystic renal disease. Abnormalities of apolipoproteins during uremic syn- drome including all apolipoproteins particles. Due to increasing concentrations of tryglicerides in the compositions of VLDL, IDL, LDL and HDL-ch is dominates hypertrygliceridemia.
Total cholesterol in patients with ESRD treated with hemodia-
lysis not show any significant difference compared with his own values obtained during examination of helthy population.
Replacement of physiological lipo-apoproteins with pha- tological, high rate of their atherogenesis and additional im-
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Lutfi Z. Clinical Hospital-Tetova - Department of Internal and Haemodia- lysis, Hospital for Nephrology and Haemodialysis ,,VITA Medical Group “ – Tetovo
Elita M. Clinical Hospital-Tetova - Department of Internal and Haemodia- lysis
Zamira B. Hospital for Nephrology and Haemodialysis ,,VITA Medical
Group “ – Tetovo
Gazmend Z. Hospital for Nephrology and Haemodialysis ,,VITA Medical
Group “ – Tetovo
Merition B. State University of Tetovo - Faculty of Medical Sciences - Macedonia
lipo-apoproteins in uremic medium are phenomena still un- discovered therefore more experimentals and multicentric studies are needed. There are confirmed and documented facts that all values of LDL-ch, Apo B-100, VLDL, LDL, remnants lipoproteins, LDL-6 , IDL, ,LDL-0X, lipoapolipoproteins A-1, lipo- apoproteins A-2, lipoapoproteins A-4, lipoapoproteins-E polymor- phism), lipoapo-proteins - C are same atherogenic and inde- pendent from each other.several studies have verified that qualitative changes in morphology and size of lipoapo- proteins particles to patients with ESRD treated with hemo- dialysis increase their atherogenic impact and have high ca- pability for climbing to arterial subendothel in the presence of oxidized cholesterol LDL-ox (LDL-6) and also have greater predisposition to attacks cardiovascular system.
The most frequent manifestation appear in uremic pa-
tients are in these diseases: ischemic heart diseases, acute myocardial infarction, peripheral vascular disease (PVD), peripheral artery occlusive disease (PAOD), cerebrovascular diseases, cerebrovascular accident (CVA). LCAT (Lecithin- Cholesterol- Acyltransferasa) in normal plasma plays role in HDL-cholesterol remodeling and is an enzyme that converts free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestred into the core of lipoprotein particle, making the newly synthesized HDL spherical. In uremic patients LCAT activity is reduced 30% and optimal conversion is compromised and reduced [2]. Ex
Perimental clinical investigation (incubation of plasma in
Muhamedin R. Hospital for Nephrology and Haemodialysis ,,VITA Medi-
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The research paper published by IJSER journal is about Changes of lipoapoproteins and the Role of Statins of Patients with Terminal Chronic Renal Insuf-ficiency treated with repeated hemodialysis 2
ISSN 2229-5518
uremic patients with LCAT inhibitor or without LCAT- inhibitor confirm that atherosclerotic processes are directly dependent from ß1-HDL catabolism disorder . ERSD patients treated with HD due to toxic effects often are treated with hypolipidemic drugs.
In clinical practice more efficient and appropriate hypo-
lipidemic agents are those who are excreted and eliminated via hepar(HMG-CoA reductasae inhibitors-Statins) compared with hypolipidemic drugs who are excreted by the kidneys. Genetic prediction in appearance of early atherosclerosis and familial predisposition is disorders in reverse cholesterol transport (RVS) and disorders of gene encoding LDL recep- tors.
In our study are included 120 patients (66 male and 54 female) with ESRD treated with hemodialysis in Clinical Hospital in Tetovo, Nephrology and Hemodialysis Unit. The average age of patients treated with HD, gender male is
58.50±15.80 years, while for female gender is 59.80 ± 12.00 years. Controll group consists of 120 helthy individuals with average age for male 57.30 ± 10.80 years and for female
59.00±12.40 years.
Receipt of material (blood) is realized in morning after a minimum of 12 hours not eating in lying position. All the re- sults obtained from the examined patients are compared with obtained results on the control group of helthy individuals according by gender, age and nationality. All patients ex- amined, a minimum of 6 months prior to study were not treated with antihyperlipidemic therapy and have not used drugs that can affect the concentrations of lipids and apolipo- proteins.Before the start of the study to all patients was veri- fied normal plasma activity of enzymes such: AP, LDH, ALT, AST, CPK, CK-MB which are marker for muscle and liver diseases. Patients examined are treated with repeated hemo- dialysis a minimum 7 years.The body weight exceeded nor- mal values of 14 female patients (BMI = 25.0 ± 38.9 kg) while the body weigh exceeded normal values of 18 in male pa- tients (BMI = 45 - 40kg).
In our study we did the division of patients according to
renal diseases such as: with chronic glomerulonephritis- 30 patients, diabetic nephropathy - 18 patients, with HTA and nephroarteriosclerosis – 28 ,with autosomal polycystic kidney disease in adults-12 patients, with opstructive nephropathy-7 patients and undifferentiated nephropathies-7 patients (Tab.
1). To all patients before study is made examination of apoli- poproteins and then began treatment with Statins (HMG CoA
reductase inhibitors) in the duration of 24 weeks. Statins do-
sage was 20 mg every night before sleeping, while in some cases of extreme hyperlipidemia the dosage was 40 mg.
Achieved results are presented in charts / graphics as fol- lows. Results obtained by patients and control groups to the lab parameters examined such: Total lipids(g/l),Triglycerides (TG), Total cholesterol (TC), LDL-ch, HDL-ch (mmol/l), Apo- A1, Apo-B100, Apo-C-2, Apo-C- Apo-E (mg/dl), Lipoprotein lipase (LPL (U/I) ) and Lipoprotein - a [ Lp (a) mg/dl] are presented in tables number 4 and 5 by calculating the average value of three successive measurements.
TABLE 1
DISTRIBUTION OF PATIENTS BY BASIC RENAL DISESASE
TABLE 2 A
DISTRIBUTION OF PATIENTS BY GENDER AND AVERAGE AGE
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TABLE 2 B
DISTRIBUTION OF CONTROLLS GROUP BY GENDER AND AVERAGE AGE
TABLE 3
NORMAL LEVELS OF LIPIDS AND SERUM APOLIPOPROTEINS
TABLE 4
VALUES LEVELS ACQUIRED FROM CONTROLL GROUP FROM EXAMINATED PARAMETHERS
( NO=120 )
Results show that the concentration of TG, LDL-ch, ApoC-2,3, ApoB-100, Apo-E, Lp(a) , LPL (Lipoprotein Lipasae)
were significantly increased while the values of HDL-ch ear
ned Apo-A1,2
were lower (by reference) to ESRD patients
treated with repeated HD compared with control group by gender and age with p<0.005.
TABLE 5
PRESENTATION OF AVERAGE VALUES OBTAINED FROM THE EXAMINED PARAMETERS IN PATIENTS
WITH ESRD TREATED WITH HEMODIALYSIS
Difference that is registreted with average values of the parameters examined between two groups by gender and nationality belonging is statistically significant p < 0.0005 for the parameters LDL-ch, HDL-ch, ApoA-1, Lp(a), ApoC-2 and TG whereas in the other parameters is not identified any sig-
nificant difference (table.4)
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The research paper published by IJSER journal is about Changes of lipoapoproteins and the Role of Statins of Patients with Terminal Chronic Renal Insuf-ficiency treated with repeated hemodialysis 4
ISSN 2229-5518
LDL-ch | 120 | 3.60 | 0.50 | 0.0001 |
ApoA-I | 120 | 1.04 | 0.38 | 0.0001 |
ApoB-100 | 120 | 2.86 | 0.86 | 0.0001 |
Lp(a) | 120 | 48.03 | 40.10 | 0.0001 |
Table 5 present significant diffirence -p between the ex- amined parameters in patients treated with hemodialysis and control group. Difference that is registreted between patients treated with HD and control group is statistically significant for p=0.0001 while no significant difference is registreted only in HDL-ch and Cholesterol (p=0.4234 and p=0.1938), table no.
5.Prior treatment with statins HDL-ch concentrations of the examined patients was close to normal values (for men 1.23+-
0.40 mmol/l and for women 1.28±0.50 mmol/l), while the reference values of control group for HDL-ch were 1.60±0.71 mmol/l. The others lipoproteinic values obtained from con- trol group and patients with ESRD treated with repeated HD are highlighted in tabeles 4 and 5.Liver-muscle enzyme activi- ties (AP,AST,ALT,CPK,CK-MB) before and after treatment with statins in the same patients group was significantly dif- ferent with the exception of LDH where the activity of this enzyme was significantly lower after treatment (for men
154.71.40±27.8 vs 133.7±39.5 U/I,p<0.02) and (for women
159.4±38.6 vs 139.6±39.5 U/L, p<0.05).
Although it is thought that uremic patients in hemodialysis have progressed very fast atherosclerosis and high mortali- ty as a result of complications from it, definitive studies lead- ing to abnormalities apo/lipoproteins and increased freque- ncy of atheromas formation verified with angiography and ultrasono-graphy not yet exist. There is some documented evidence for abnormali-ties of the apolipoproteins values in uremic patients treated with chronic hemodialysis. Patients treated with HD have a reduction in total choleste-rol conce- ntrations and higher concentrations of TG,LDL-ch,ApoB-100, Apo-C2,3, Apo-E, Lp(a), LPL and significantly lower values Apo-A1,2 and HDL-ch [4,7]. In vitro was verified that sta- tin reduce production of oxygen free radicals by interfe-ring
3 with molecules signals NF-κB (nuclear factor kappa-light- chain-enhancer of activated B cells) transcriptase system by inhibiting the production cascade of inflammatory molecules such a Interleukin 6 (In-6) and CRP. The oxidized LDL- ch (LDLox) realizes its effect via stimulation of NADPH –O2. Because statin gradually reduce the overall amou nt of LDL that is necessary for oxide-tive modification of his own-
oxygenation of LDL-choleste-rol, thus practica-lly confirming
the way they operate to reduce high concentra-tions of conce ntrations of LDL-ch. All these lipoproteinic particles contain- ing lipoprotein-B therefore conclude most frequently disorders of apolipoproteins are due to increased TG rich with Apo-B. All components of lipoproteinemia and dyslipidemia are athe- rogenic and independent from each other.
Effects of HMG-CoA reductasae inhibitors-Statins have been shown as the most studied and appropriate medications to apo/lipoproteins disorders in ESRD patients treated with repeated hemodialysis.Effect of statins is blocking the en- zyme HMG CoA and reduce the rate of production (synthe- sis) of LDL-ch. In general population statin arrived reduction LDL-ch for 30-63% and triglycerides 20-40% and raising HDL-ch 10-25% [6] oral published studies on the role of statin have verified that statin had a positive antinflamma- tory effectby decreasing concentrations of CRP. In many stu- dies statin in patients treated with HD showed higher eff- ect on lowering LDL-ch concentrations up to 43% reduction in total cholesterol (TCH), apolipopro-teins-B and decrease conce-ntrateonsof oxidized cholesterol (LDLox)[8,9].
Early dyslipidemia is highly conditional by the dynam- ics of changes in choleste-rol between the lipoproteinic par- ticles and the reverse transport. Statins therapy was mo- re effective in comparison with concentrateons of TG and LDL-ch and their concentration was significantly decreased (p<0.05-0.001) as compared with apolipoproteins improve- ment that is obtained weaker response,because are needed more detailed studies and longer time to be determined with precision the positive effects of statins on improving of apoli- poproteins in ESRD patients treated with HD. Progres- sion of cardiova-scular and cerebrovascular diseases, ocu- lar complications in healthy popula-tions significantly re- duced by decreasing the high values of LDL-ch and TG in patients with ESRD, uremic syndrome treated with HD. The above findings for uremic patients still are not fully verified with precision. This situation is directly dependent on the specific situation of uremic patients and lipoproteins athero- genesis in ESRD patients treated with repeated HD and is more dependent on the concentration of high densi-ty lipo- proteins with Pre-ß (IDL), LDL-6 and not by total fraction of LDL cholesterol. While it is known that the concentration of ApoA-1 and ApoA-2 each time found in serum of healthy patients with ESRD patients treated with reapiting HD, con- centration of ApoA-1 ApoA-2 are reduced to increase of the concentration accounts of Apo-B and Apo-E-2 and re- ducing ApoE-4 and increasing polymorphisms of ApoC-1, ApoC-2, ApoC-3. There are data to support the theory that low values of HDL-ch plasma in patients with ESRD are related to the reduction of synthesis ApoA-1/HDL-ch.
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The research paper published by IJSER journal is about Changes of lipoapoproteins and the Role of Statins of Patients with Terminal Chronic Renal Insuf-ficiency treated with repeated hemodialysis 5
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Mentioned effect of HDL-ch against atherosclero-sis comes from the dual role of mechanism reverse cholestererol tra- nsport to VLDL and LDL with the help of Cholesteryl Ester Transfer Protein. If creatine kinase (CK)values increase- d for 10 times then normal value ,the statins therapy should be discontinued was noted that the cholesterol tran- sfer (RCT) from HDL to VLDL / LDL was lower in the se- rum of patients with ESRD regardless if they are in trea- tment with dialysis or not. If reverse cholesterol transpo- rt is slow then increasing its accu-mulation in tissue, which this breakdown and mechanism helps signifycantly in pa- tients with atherosclerotic processes in ESRD patients and those threated with HD.
Statins in the treatment of dyslipidem-ia and lipoapo- proteins aberations pro-ved very secure in our expe- rience with the dosage of 20 mg in the evening every day to redu-ce high concentrations of LDL-ch, TG, IDL, LDL-6, adjusting the concentrateons of Apo-B ,Apo-C, Apo-E and increasing concentrations of HDL-ch, apolipo- protei-nes subfractions and its-Apo-1,2.4. Patients treated with HD, considering their rare side effects as rhabdo- myoli sis with muscular pain and increase creatine kinase (CK).
Risk of rhabdomyolisis is larger if statin therapy combined with other additional cyclosporine and fibrates. Applica- tion of the statins in the treat-ment of uremic dyslipide- mia should be a regular pharmaceutical components ap- plied to patients with chronic uremia treated with repeated HD.
If taken into consideration all modern theoryes on the treatment of artherosclerotic processes in ESRD patients, drug treatment of apo/lipoproteins abnormalities is thus necessary that will significa-ntly reduce the risk of cardiovascular and cerebrovascular dissease.
[1] Allain CC., Poon LS., Chan CS., Richmond W, Enzymatic determi- nation of total serum cholesterol, 6th Edition Clin. Chem, 20,470-
475(1974).
[2] Agarwal SK. et al. Prevalence of Chronic Renal Failure in adults in
Delhi,India. Nephrol Dial Transplant 2005; (20) :1638-42.
[3] Bucola G., David H, Quantitative determination of serum triglyce- rides by use of enzymes. Clin. Chem, 19, 476- 482 (1973).
[4] Chan MK,Varghese Z, Moorhead JF. Lipid abnormalities in
uremia, dialysis and transplantation. Kidney Int. 1981;(19): 119- 625.
[5] Crook, Errol D.MD; Thallapureddy, Anantha MD. Et al. Lipid ab- normalitie and Renal disease: Is Dyslipidemia a Predictor of Progression of Renal Disease ?. Am J of the Medical Sciences: June 2003-Vol325-Issue
6- pp:340-348
[6] Dornbrook- Lavender KA et al. Effects of atorvastatin on low- density lipoprotein cholesterol phenotype and C-reactive protein levels in patients undergoing long-term dialysis. Pharmacotherapy 25:335-
44,2005
[7] Lutfi Zylbeari. Profili i Dislipidemisë dhe Aberacionet e Apopro- teineve te pacientët e Mjekuar me Hemodializë Perseritëse. Disertacioni
i Doktoraturës. Shkup,2009.
[8] Landray M, Baigent C. et al. The second United Kingdom Heart and Renal Protection(UK-HARP-II) Study: A randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to sim- vastatin as initial therapy among patients with CKD. Am J Kidney Dis
47:385-395,2006 .
[9] Rao P, Reddy GC and Kanagasabapathy AS. Malnutition - Inflammation-Atherosclerosis Syndrome in Chronic Kidney Disease. Indian Journal of Clinical Biochemistry,2008 (23) 209-217.
[10] Sandhu S, Wiebe N, Fried LF, Tonelli M: Statins for improving ren- al outcomes: A meta-analysis. J Am Soc Nephrol 17:2006-2016,2006
[11] Tilly P, et al. Biological and genetic determinants of serum apo C - III concentration: reference limits from the STANISLAS cohort study. J Lipid Res. 2003;44 :430-6.
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