Int. Med J Vol. 6 No 2 December 2007
The effect of Nandrolone Decanoate therapy on lipoprotein(a) and homocysteine levels in haemodialysis patients
Amir Ghorbanihaghjo1,2, Hassan Argani1 ,Nadereh Rashtchizadeh1,2, Mohammad Rohbaninoubar1
1Drug Applied Research Center and 2Biotechnology Research center, Tabriz University of Medical Sciences, Tabriz, Iran..
Lipoprotein(a) [Lp(a)] and Homocysteine (Hcy) are two
independent risk factors for atherogenicity in patients with chronic renal
failure (CRF). It has been postulated that Hcy can enhance the toxicity of Lp(a)
via binding to fibrin. As Nandrolone Decanoate (ND), an anabolic steroid,
reduces Lp(a) in CRF this study was designed to evaluate the influence of the
drug on serum total Hcy (tHcy) in addition of Lp(a) levels and their
relationships in 64 chronic hemodialysis patients. The patients received 100mg/I.M./week
for 4 months to improve their anemia. Serum Lp(a) concentrations were determined
by immunoturbidimetric method, and tHcy levels were measured by enzyme-linked
immunosorbent assay. Although marked decrease in Lp(a) levels was observed
(40.6±24mg/dl reached to 31.3±17.2mg/dl p<0.0001) tHcy concentration did not
change significantly (18.4±8.2
mol/L
reached to 19.2±7.2mol/L
p>0.1). Therefore tHcy/Lp(a) ratio (0.67±0.5 vs. 0.86±0.7 p<0.0001) increased.
It was concluded that ND has beneficial effect on lowering serum level of Lp(a).
Because of nearly constant level of tHcy and elevation in tHcy/Lp(a) ratio after
ND therapy, Lp(a) lowering effect of ND therapy alone may have limited
contribution in prevention of atherosclerosis.
Atherosclerotic cardiovascular diseases are responsible for the majority of morbidity and mortality in hemodialysis patients (1-3). Therapies targeted to improve and to prevent anemia are applied routinely in these high risk group patients (4, 5). Although recombinant human erythropoietin (rHuEPO) has been recommended as a standard therapy in the treatment of anemia in hemodialysis patients, for economical problems and its side effects such as production of anti-Epo antibodies and pure red cell aplasia, the use of anabolic steroids especially Nandrolone Decanoate (ND) has been suggested as an adjuvant therapy with erythropoietin (4, 6). In addition of anemia improving the effect of ND, a reduction in lipoprotein(a)[Lp(a)] levels, has been found in hemodialysis patients (5, 7, 8).
Recent studies have shown that increased Lp(a) and homocysteine (Hcy) levels are two independent risk factors for the development of atherosclerosis in patients with CRF (9-11). It has been proposed that the combination of elevated Lp(a) and Hcy levels might have synergistically contribute to atherogenic effect because of the potential biochemical interactions of the two risk factors have been previously (10, 12, 13). Therefore it maybe important clinically to reduce high serum Lp(a) and Hcy levels by therapeutic intervention (12- 14). It has been reported that drugs such as corticotropin (ACTH), Aspirin and L-carnitine reduce serum Lp(a) concentrations by unestablished mechanisms (14- 16). On the other hand many studies have demonstrated that low dietary intake of folate and vitamin B12 deficiency are risk factors for hyperhomocysteinemia and folic acid supplement can reduce the Hcy levels in hemodialysis patients (17, 18). Although the reducing effect of ND on Lp(a) concentration has been proven previously by our study (8), its effect on serum total homocysteine (tHcy) concentration is not clear. Additionally the ND effect on Lp(a) and tHcy inter relationship in hemodialysis patients has not been proven. The purpose of this study was to evaluate the effect of ND therapy on Lp(a), tHcy levels and their inter relationships in patients on chronic hemodialysis as a group at high risk of atherosclerosis.
In this study, 70 patients on hemodialysis for at least 6 months in stable clinical condition were selected from the nephrology department between June 2002 and December 2003 in Iran. All dialysis patients had been on regular hemodialysis (4h) two or three times per week using cellulosic low flux membrane. The dialysis schedule was not modified during the study period. Malnutrition, liver diseases such as active hepatitis, patients on vitamin supplements (except for folic acid), smoking and benign prostatic hypertrophy (in males) were among the exclusion criteria. Six patients were lost to follow-up (3 died of cardiac arrest, 2 received kidney transplant and 1 had abnormal liver function). Sixty four patients (47 male and 17 female), mean age of 63 ±12 years completed the study. The etiology of end-stage renal disease were diabetic nephropathy (n=10), chronic glomerulonephritis (n=17), polycystic disease (n=5), urological problems (n=5), chronic interstitial nephropathy (n=4) and unknown causes (n=23). After the study was approved by the medical ethic committee of university and the patients gave the informed consent, ND 100mg/I.M. was given weekly for 4 months. Before hemodialysis sessions, fasting venous blood samples were collected before the start of ND treatment, 4 months after ND therapy and 2 months after withdrawing treatment.
All the serum samples were stored at -80șC until the analyses. The serum level of Lp(a) was assayed by commercially available immunoturbidimetric kit in an automated chemical analyzer and serum tHcy was measured by enzyme immunoassay method (Axis.Norway).
SPSS 11 for windows was used to perform statistical analysis. Results were expressed as mean±SD, paired t-test and wilcoxon signed ranks test were used to assess the significant differences between the bases, 4 months after starting treatment, and 2 months after withdrawing treatment. The level of statistical significance was defined as p<0.05.
Table shows the effects of 4 months treatment with ND on Lp(a), tHcy and tHcy/Lp(a) ratio. A marked decrease in the concentration of Lp(a) in all of the samples was noticed after 4 months of treatment. No significant change was detected in serum tHcy concentration (p>0.1). tHcy/Lp(a) ratio at outset of ND treatment was 0.67±0.5 and increased to 0.86±0.7 after 4 months treatment (p<0.0001).
After 2 months of treatment withdrawal, evaluation of the above parameters was repeated. As shown in Table, the Lp(a) concentration increased 2 months after withdrawal of ND treatment, but it was still lower than that of the basal value (p<0.0001) . No significant changes was detected in tHcy levels after 2 months of treatment withdrawal (p>0.1).Although the mean±SD tHcy/Lp(a) ratio after withdrawal of ND treatment decreased from 0.86±0.7 to 0.82±0.6, but this ratio as a matter of fact was still significantly higher than that of basal value (p=0.007).
Table: Changes of Lp(a), tHcy and tHcy/Lp(a) ratio at the outset the start of ND treatment, after 4 month treatment
and 2 months after withdrawing treatment in 64 hemodialysis patients.
|
|
Basal (Mean±SD) |
4 months (Mean±SD) |
ND withdrawal 2 months (Mean±SD) |
|
Lp(a) (mg/dl) |
40.6±24.2 |
31.3±17.2 (p<0.0001)a |
33.3±21.8 (p>0.3)c, (p<0.0001)d |
|
tHcy (mmol/L) |
18.4±8.2 |
19.2±7.6 (p>0.1)b |
19.1±7.5 (p>0.8)e, (p>0.1)f |
|
tHcy (mmol/L)/ Lp(a)(mg/dl) |
0.67±0.5 |
0.86±0.7 (p<0.0001)b |
0.82±0.6 (p>0.4)e, (p=0.007)f |
a, Wilcoxon signed rank test was used to assess significance of differences between base and 4 months after ND treatment.
b, Paired sample t-test was used to assess significance of differences between base and 4 months after ND treatment.
c,
Wilcoxon signed rank test was used to assess significance of differences between
4 months of ND treatment and 2 months after withdrawing
reatment.
d, Wilcoxon signed rank test was used to assess significance of differences between base and 2 months after withdrawing treatment.
f, Paired sample t-test was used to assess significance of differences between base and 2 months after withdrawing treatment.
e,
Paired sample t-test was used to assess significance of differences between 4
months of ND treatment and 2 months after withdrawing
treatment.
DISCUSSION:
Prevalence of anemia and atherothrombotic disease in hemodialysis patient is higher than that of general population (1- 5, 19). Although many traditional risk factors have been identified for atherosclerosis, Lp(a) and Hcy have been identified as major non traditional risk factors for atherosclerosis in general population, as well as in hemodialysis patients (9, 10, 20, 21). Lp(a) is a LDL-like particle in which apolipoprotein (apo)B-100 is disulfide linked to a single large glycoprotein, apo(a) (22, 23). Lp(a) levels are determined primarily by genetic factors, the most important of which are the apo(a) gene (24). Nevertheless, it has shown that some agents such as ACTH, Niacin, Neomycin, Stanozolol and L-carnitine may reduce serum Lp(a) levels by unknown mechanisms (14, 16, 25). tHcy, a sulfur-based amino acid, has been suggested as an additional risk factor for cardiovascular disease, and elevated tHcy levels in hemodialysis patients may contribute to the excess vascular morbidity (11, 18, 21, 26). It has been known that Hcy can increase the affinity of apo(a) for plasmin-modified fibrin (12, 13, 21). This hypothesis explains how the presence of Hcy results in greater Lp(a) fibrin binding and promotes atherosclerosis (10,12,13,27).
Previous studies from our laboratory suggest that ND has a beneficial effect on nutritional status and treatment of anemia in hemodialysis patients but it has an adverse effect on the lipid profile (8, 28). In the present study a significant reduction in the serum levels of Lp(a) but not tHcy concentrations in hemodialysis patients after 4 months treatment with ND were observed. These results suggest that ND can be used to decrease the Lp(a) without significant alters in tHcy levels in hemodilaysis patients. This decrease in Lp(a) concentration increases the tHcy / Lp(a) ratio after 4 months of ND therapy. This effect may increases the Lp(a) atherogenecity potential to plasmin-modified fibrin by exposure of additional lysine binding site on apo(a). This finding suggest the hypothesis that although ND administration in hemodialysis patients can decreases Lp(a) concentrations, since tHcy levels is constant, so, Lp(a) lowering effect of ND therapy alone may have limited contribution in prevention of atherosclerosis. Studies involving a large population size should be performed in order to confirm this hypothesis.
REFERENCES
1. Kronenberg F, Lingenhel A, Neyer U, Lhotta K, Konig P, Auinger M, et al: Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients. Kidney Int suppl 2003, 84: S113-S116.
2. Ohkuma T, Minagawa T, Takada N, Ohno M, Oda H, Ohashi H: C-reactive protein, lipoprotein(a), homocysteine, and male sex contribute to carotid atherosclerosis in peritoneal dialysis patients. Am J Kidney Dis 2003, 42(2): 355-361.
3. Bostom AG, Shemin D, Lapane KL, Sutherland P, Nadeau MR, Wilson PW, et al: Hyperhomocysteinemia, hyperfibrinogenemia, and lipoprotein(a) excess in maintenance dialysis patients: a matched case-control study. Atherosclerosis 1996, 125(1): 91-101.
4. Navarro JF: In the erythropoietin era, can we forget alternative or adjunctive therapies for renal anaemia management? The androgen example. Nephrol Dial Transplant 2003, 18(11): 2222-2226.
5.Teruel JL, Lasuncion MA, Rivera M, Aguilera A, Ortega H, Tato A, et al. Nandrolone decanoate reduces serum lipoprotein(a) concentrations in hemodialysis patients. Am J Kidney Dis 1997, 29(4): 569-575.
6. Johnson CA: Use of androgens in patients with renal failure. Semin Dial 2000, 13(1): 36-39.
7. Johansen KL, Mulligan K, Schambelan M: Anabolic effect on nandrolone decanoate in patients receiving dialysis: a randomized controlled trial. JAMA 1999, 281(14): 1275-1281.
8.Ghorbanihaghjo A, Argani H, Rohbaninoubar M, Rashtchizadeh N: Effect of nandrolone decanoate on serum lipoprotein(a) and its isoforms in hemodialysis patients. Lipids Health Dis 2004, 3(1): 16-21.
9.Emanuele E, Lusignani LS, Peros E, Montagna G, DAngelo A,Montagna L, et al:Lipoprotein(a)-associated atherothrombotic risk in hemodialysis patients: Am J Nephrol 2004, 24(2): 221-229.
10.Massy ZA: Importance of homocysteine, lipoprotein(a) and non-classical cardiovascular risk factors (fibrinogen and advanced glycation end-products) for atherogenesis in uraemic patients.Nephrol Dial Transplant 2000, 15(suppl 5): 81-91.
11.Moustapha A, Gupta A, Robinson K, Arheart K, Jacobsen DW, Schreiber MJ, et al: Prevalence and determines of hyperhomocysteinemia in hemodialysis and peritoneal dialysis. Kidney Int 1999, 55(4): 1470-1475.
12.Harpel PC, Chang VT, Borth W: Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 1992, 89(21): 10193-10197.
13.Foody JM, Milberg JA, Robinson K, Pearce GL, Jacobsen DW, Sprecher DL: Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vask Biol 2000, 20(2): 493-499.
14. Arnadottir M, Berg AL, Kronenberg F, Lingenhel A, Hugosson T, Hegbrant J, et al: Corticotropin-induced reduction of plasma lipoprotein(a) concentration in healthy individuals and hemodialysis patients: relation to apolipoprotein(a) size polymorphism. Metabolism 1999, 48(3): 342-346.
15.Akaike M, Azuma H, Kagawa A, Matsumoto K, Hyashi I, Tamura K, et al: Effect of aspirin treatment on serum concentrations of lipoprotein(a) in patients with atherosclerotic diseases. Clin Chem 2002, 48(9): 1454-1459.
16.Sirtori CR, Calabresi L, Ferrara S, Pazzucconi F, Bondioli A, Baldassarre D: L-carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a). Nutr Metab Cardiovasc Dis 2000, 10(5): 247-251.
17.Gonin JM, Nguyen H, Gonin R, Sarna A, Michels A, Masri-Imad F, et al: Controlled trials of very high dose folic acid, vitamin B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD. J Nephrol 2003, 16(4): 522-534.
18.Buccianti G, Baragetti I, Bamonti F, Furiani S, Dorighet V, Patrosso C: Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease: J Nephrol 2004, 17(3): 405-410.
19.Locatelli F, Pisoni RL, Akizawa T, Cruz JM, DeOreo PB, Lameire NH, et al: Anemia management for hemodialysis patients: Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines and Dialysis Outcomes and Practice Patterns Study (DOPPS) findings: Am J Kidney Dis 2004, 44(5): 27-33.
20.Kronenberg F, Lingenhel A, Lhotta K, Rantner B, Kronenberg MF, Konig P, Thiery J, et al: The apolipoprotein(a) size polymorphism is associated with nephritic syndrome. Kidney Int 2004, 65: 606-612.
21.Delport R, Lingenhel AW, Ubbink JB, Kraft HG: Hyperhomocyst(e)inemia is an important risk factor for vascular disease in subjects with high-molecular weight apo(a) isoforms. Cardiovasc J South Afr 2004, 15(5): 207-213.
22.Boonmark NW, Lawn RM: The lysine-binding function of Lp(a).Clin Genet 1997, 52(5): 355-360.
23.Kronenberg F, Utermann G, Dieplinger H: Lipoprotein(a) in renal disease. Am J kidney Dis 1996, 27(1): 1-25.
24.Kronenberg F, Steinmetz A, Kostner GM, Dieplinger H: Lipoprotein(a) in health and disease. Crit Rev Clin Lab Sci 1996, 33(6): 495-543.
25.Gurakar A, Hoeg JM, Kostner G, Papadopoulos NM, Brewer HB Jr: Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis 1985, 57(2-3): 293-301.
26.Bostom AG, Culleton BF: Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol 1999, 10(4): 891-900.
27.Parsons DS, Reaveley DA, Pavitt DV, Brown EA: Relationship of renal function to homocysteine and lipoprotein(a) levels: the frequency of the combination of both risk factors in chronic renal impairment. Am J Kidney Dis 2002, 40(5): 916-923.
28.Ghorbanihaghjo A, Argani H, Rahbaninoubar M, Rashtchizadeh N: Effect of nandrolone decanonate on paraoxonase activity in hemodialysis patients. Clin Biochem 2005, 38(12): 1076-1080.
Corresponding author:
A Ghorbanihaghjo
Address: Drug Applied Research center.
Biotechnology Research center
Tabriz University of Medical Sciences,
Tabriz, Iran.
E-mail:Ghorbaniamir@hotmail.com
Tel: 0098-411-3363234
Fax: 0098-411-3363231