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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2006  |  Volume : 17  |  Issue : 2  |  Page : 129-136
Management of Dyslipidemia in Renal Disease and Transplantation


School of Pharmacy, University of Auckland, Auckland, NewZealand

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How to cite this article:
Zolezzi M. Management of Dyslipidemia in Renal Disease and Transplantation. Saudi J Kidney Dis Transpl 2006;17:129-36

How to cite this URL:
Zolezzi M. Management of Dyslipidemia in Renal Disease and Transplantation. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2019 Jul 22];17:129-36. Available from: http://www.sjkdt.org/text.asp?2006/17/2/129/35780

   Introduction Top


Cardiovascular disease (CVD) is the leading cause of death among patients with chronic and end-stage renal disease (ESRD). [1],[2] There is growing evidence that cardiovascular damage begins as soon as the kidney loses function and increases in severity during the pro­gression of kidney disease. [3],[4] Hypertension and diabetes mellitus, known risk factors for the development of CVD in the general population, are also the most common causes for the development of CVD in patients with chronic and ESRD. It is known that patients with type 2 diabetes who require dialysis are about 30 times more likely to die of CVD, [5] including heart attacks and strokes, than the general population.

There are several other important risk factors, such as smoking, proteinuria and dyslipidemia that independently or in combination with elevated blood pressure, can cause deterio­ration in renal function. Abnormalities in lipid metabolism and dyslipidemia are known to contribute to glomerulosclerosis and are common in renal disease. [6],[7] In addition, post-transplant dyslipidemias have been associated with an increased risk of ischemic heart disease and have been shown to increase risk of chronic rejection, altered graft function and mortality. [8],[9] However, only recently, trials are starting to evaluate if reversal of dyslipidemia can actually lead to a decreased risk of CVD in patients with chronic renal conditions.

This article will review the role of lipids in the progression of renal disease and the current recommendations for the pharmaco­logical management of dyslipidemia in patients at different stages of renal disease, and after renal transplantation.


   Dyslipidemia and Renal Disease Top


The impact of lipid abnormalities on renal function has been evaluated in various studies. [6],[7],[10],[11] In these studies, unfavorable lipoprotein profiles interacted as risk factors for progressive renal decline. The patterns of dyslipidemia and the factors contributing to these abnormalities are different among patients with renal insufficiency, severe renal failure, those on hemodialysis and peritoneal dialysis, and those with renal transplants. [12]

Abnormal lipid profiles start to appear soon after renal function begins to deteriorate. [11] Common characteristics of the lipid profile include an elevation of serum triglycerides, a decrease in the high-density lipoprotein (HDL) cholesterol, and some elevation in the low-density lipoprotein (LDL) cholesterol. Patients with progressive renal failure, but without significant proteinuria, have been shown to also have abnormalities in circu­lating lipoproteins [13] , including low ApoA1 and APO A 2 , elevated Apo B and Apo C 3 , high lipoprotein (a), lipoprotein remnants, and marked oxidation of LDL cholesterol, [14] all of which have been associated with increased atherosclerotic risk. [7],[15] Epidemio­logical studies have also suggested a role for hyperlipidemia in the progression of diabetic nephropathy. [16],[17]

Dyslipidemia in Patients on Dialysis

The distinctive features of the lipid profile in dialysis patients appear to be the presence of low concentrations of HDL cholesterol and increased triglycerides, but without, or slight elevations of LDL cholesterol. The risks associated with this lipid profile are still not quite clear, due to the relative lack of research in the dialysis population. However, there is growing evidence that a low HDL cholesterol concentration imparts additional risk of coronary heart disease. [18]

Analyses and prevalence reports have estimated that about 45-50% of hemodialysis and peritoneal dialysis patients have lipid abnormalities. [12],[19],[20] [Table - 1] shows a summary of the prevalence of lipoprotein abnormal­ities in dialysis patients as reported on one of these analyses. [19]

Dyslipidemia after Renal Transplantation

Patients with renal transplants have a different lipid profile than do patients on dialysis, with higher values of total cholesterol, LDL cholesterol, very-low density lipoprotein (VLDL), and triglycerides. Other changes that occur in the lipid profile of renal transplant recipients may include variable effects on HDL cholesterol and lipoprotein (a) and the accumulation of atherogenic remnants such as intermediate LDL. [21] These changes are estimated to occur in up to 60% of renal transplant patients. [Table - 2] lists those factors that are associated with post­transplant dyslipidemias.

Because renal transplant patients use immunosuppressive agents, which themselves may alter lipids and complicate the use of antihyperlipidemic agents, it appears important to briefly review each of this class of medi­cations. Typical alterations will include increases of up to 30% in total cholesterol, 69% in triglycerides, 57% in LDL cholesterol, and 61% in HDL cholesterol levels from pre-transplant baseline values.

a. Calcineurin inhibitors can produce alterations in lipid profiles within one month of the start of therapy; studies suggest that cyclosporine has an increased propensity to promote dyslipidemia compared with tacrolimus. [22],[23]

b. Antiproliferative agents, such as sirolimus, can produce changes in the lipid profile that may be even more pronounced than with the calcineurin inhibitors. [22],[24]

c. Corticosteroids may also induce increases in total cholesterol with variable effects on triglyceride values, the combination of corticosteroids with other immuno­suppressive agents may have additive effects. [22]

d. Azathioprine and mycophenolate mofetil do not appear to produce dyslipidemic effects.

Other non-traditional CVD risk factors can arise from the transplant, such as acute rejection episodes, which cause endothelial damage, requiring even higher doses of immunosuppressants and more complex combination regimens. [21] A number of studies and reports have also determined that hyper­lipidemia may contribute to the high incidence of allograft dysfunction and subsequent rejection. [8],[9],[21] A study by Wissing et al identified hypercholesterolemia as an independent risk factor for graft loss. [25] In another study, hypertriglyceridemia was associated with a greater probability of doubling serum creatinine, often recognized as a major contributor to renal allograft dysfunction. [26] [Table - 3] shows three common factors that have been reported in one study to significantly increase the relative risk for developing ischemic heart disease in renal transplant recipients during the first year after transplantation. [27]


   Management of Dyslipidemia in Renal Disease Top


The appropriate management of dyslipidemia plays an important role in the overall care of the patient with chronic and ESRD, and renal transplantation. Unfortunately, patients with different stages of renal disease have often been excluded from major studies examining the benefits of lipid-lowering agents on improved cardiovascular-related survival and morbidity. Additionally, most international guidelines on the management of cardio­vascular risk, do not distinguish patients with chronic and ESRD, or renal transplantation, from the general population in terms of treatment goals and methods for achieving them. [12],[28],[29] Studies have also suggested that many patients with chronic renal disease who are candidates for lipid-lowering therapy do not receive it. [30]

It is important to recognize that dyslipidemia in the patient with chronic and ESRD, and renal transplantation require a different screening and management approach than other populations, [31],[32] as dyslipidemia may be secondary to different conditions, such as proteinuria, diabetic hyperlgycemia, or drug-induced, all of which require a distinctive management approach. [32] Additionally, patients who have progressed to advanced renal disease may have altered metabolism and elimination of lipid lowering medications, which would increase their risk for adverse effects to these agents. [31]

The United States (US) National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease provide guidance for the management of dyslipidemias in chronic and ESRD, and in renal transplant patients, with the recognition that these patients are in the highest risk category for the development of cardiovascular events. [32] [Table - 4] provides a summary of these guideline recommendations, and outlines some differences in the K/DOQI guidelines versus the US National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) guidelines. [28],[32]

Cardiovascular risk screening for patients with chronic and ESRD usually follow similar recommendations as those provided in CVD risk assessment guidelines set for the general population. However, it has been suggested that, based on the high prevalence and mortality induced by CVD in patients with chronic and ESRD, they might benefit from a more systematic and more frequent assessment, primarily due to proteinuria, dialysis-induced alterations in lipoprotein concentrations, nutritional supplementation, dietary modifi­cation, and the use of immunosuppressive drugs. [31],[33]

Pharmacotherapy Recommendations

Several options for managing dyslipidemias in patients with chronic and ESRD, or after transplantation have been investigated, including diet, pharmacotherapy and modification of immunosuppressive regimens (for post­transplant dyslipidemias). According to the K/DOQI guidelines, chronic kidney disease is considered a CVD risk equivalent; [32] thus, target lipid levels for these patients should follow the recommendations summarized in [Table - 5]. It is important to point out, however, that specific data showing the benefits with this degree of lowering LDL cholesterol are lacking. [31]

If LDL cholesterol goals are not achieved after 3 months of lifestyle modification, the K/DOQI guidelines also recommend that statins should be the drugs of first choice. [32]

Starting at a low dose and then titrating the dose of the statin upward to the goal minimizes adverse effects. Elevated transaminases occur in some patients on statin therapy and baseline values should be obtained. The risk of rhabdo­myolysis from statins is low in general but it is increased in patients with chronic renal disease and those taking immunosuppressive agents, macrolide antibiotics, and fibric acid derivatives. [34]

For patients with elevated triglycerides (>500 mg/dL), fibric acid derivatives and niacian may be used. Fibrates may increase the levels of stains; when used in combination an increased risk of rhabdomyolysis has been reported. [34] Blood levels of a number of fibrates are increased in renal patients (e.g., bezafibrate, and fenofibrate), but levels of gemfibrozil are not increased. Elevations of BUN and creatinine have been reported with many fibrates. Since this occurs only rarely with gemfibrozil, it has been recommended by some as the fibrate of choice in renal disease. [31] Niacin reduces lipids only to a moderate degree and may be associated with flushing and other untoward side effects. Bile acid sequestrants are effective in cholesterol lowering, but may interfere with the absorption of other medications. The potential benefit of combination therapy must be closely weighed against the increased risk of adverse effects. [31],[34]

The pharmacotherapy management of post­transplant dyslipidemia is similar; however, another alternative which must be considered is the modification of the immunosuppressive regimen. [22] Examples of such modifications include switching from cyclosporine to tacrolimus, lowering doses of sirolimus, and corticosteroid withdrawal. Although studies that have examined these approaches have found no increased risk of graft rejection or dysfunction, it is important to keep in mind that many of these studies were not powered to detect such risk, and any modification in immunosuppressive therapy must be under­taken carefully and monitored closely. [22]

Another important consideration in the pharmacotherapy management of post­transplant dyslipidemia is the potential drug interactions of lipid-lowering agents with immunosuppressants. Overall, statins have little effect on cyclosporine concentrations; however, cyclosporine has been shown to inhibit the metabolism of statins and a resultant increase in the risk of myopathy or rhabdomyolysis. [22],[34] It has been suggested that fluvastatin, simvastatin and atorvastatin are the safest statins to be used with cyclo­sporine. Whereas fibrates may be especially valuable in patients treated with sirolimus, but should be carefully used in renal transplant patients taking cyclosporine or tacrolimus. [22]

The Role of Statins

Statin therapy has been found to rapidly improve vasomotor response, enhance coronary blood flow, and reduce the levels of adhesion molecules. This is due in part to the ability of the statins to increase endothelial nitric oxide production. [35] The antioxidant effects of statins may also contribute to their ability to improve endothelial function. [36] In addition, statins have been shown to exert positive effects on the fibrinolytic profile in the vascular endothelium [37] and anti-inflam­matory effects by several pathways, including the reduction of inflammatory markers such as C-reactive protein, modification of fibrosing factors such as TGF-beta, and a favorable effect on coagulation and plaque stability. [12],[35],[36] Thus, theoretically, statins' anti-inflam­matory and immunomodulatory effects and also their effects on endothelial function may be beneficial in renal hemodynamics. In addition, many large clinical trials have demonstrated the benefits of lowering lipid levels in both medium- and high-risk patient populations. [38],[39],[40]

A meta-analysis of 13 controlled trials in 404 subjects confirmed the beneficial effect of lipid-lowering agents on preservation of kidney function. [39] Most of these trials were conducted with the use of statins. When the outcomes were pooled it was shown that the use of lipid-lowering therapy was associated with a protective effect on loss of renal function amounting to 1.9 ml/min/year in comparison with controls (95% confidence interval 0.3-3.4), an effect whose magnitude was related to length of treatment. The authors also concluded that therapy with newer lipid­lowering agents, such as the statins, is relatively safe in patients with chronic renal disease.

The role of statins in the management of dyslipidemia after renal transplantation has also been investigated by numerous authors. [22],[41],[42] Although some findings have been controversial, authors have speculated that statins may have an additional benefit in the prevention of acute and chronic rejection. [7],[21] In the placebo-controlled ALERT (Assessment of Lescol in Renal Transplantation) study, 41 a total of 1050 patients were followed up for a mean of 5.1 years to evaluate the effect of fluvastatin on cardiovascular events. Fluvastatin proved to reduce the combined endpoint of cardiac death and nonfatal myo­cardial infarction by 35% ( p =0.005). How­ever, fluvastatin did not show a significant effect on noncardiovascualr death or graft loss.


   Conclusions Top


There is sufficient evidence that cardio­vascular diseases contribute to the mortality of patients with renal disease, and after renal transplantation. There is also evidence support­ing a role for dyslipidemia in the progression of renal disease. Therefore, appropriate manage­ment of dyslipidemia plays an important role in the overall care of the patient with chronic and ESRD, and after renal transplantation.

Evidence on the value of using lipid-lowering medications in patients with chronic renal disease is beginning to emerge. Specific guide­lines for the management of dyslipidemia in patients with chronic renal disease have also recently been released, and have recommended that statins should be used as first-line treatment. Currently, fluvastatin is the only statin with docu­mented benefits on cardiovascular endpoints and appears to be the least likely to produce myopathy or rhabdomyolysis in this patient population.

Unfortunately, a clear role for lowering lipid levels and renoprotection cannot be discerned until large, randomized controlled trials are conducted. As such, prevention of cardio­ vascular disease remains the primary goal of lipid management in patients with chronic renal disease and after renal transplantation.

 
   References Top

1.Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32:S112-9.  Back to cited text no. 1    
2.Rayner HC, Pisoni RL, Bommer J, et al. Mortality and hospitalization in haemodialysis patients in five European countries: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2004;19:108-20.  Back to cited text no. 2    
3.Jungers P, Massy ZA, Khoa T, et al. Incidence and risk factors of atherosclerotic cardiovascular accidents in pre-dialysis chronic renal failure patients: a prospective study. Nephrol Dial Transpalnt 1997;12:2597-602.  Back to cited text no. 3    
4.Fried LP, Kronmal RA, Newman AB, et al. Risk factors for 5-year mortality in older adults: The Cardiovascular Health Study. J Am Med Assoc 1998;279:585-92.  Back to cited text no. 4    
5.Rischen-Vos J, van der Woude FJ, Tegzess AM, et al. Increased morbidity and mortality in patients with diabetes mellitus after kidney transplantation as compared with non-diabetic patients. Nephrol Dial Transplant 1992;7:433-7.  Back to cited text no. 5    
6.Moorhead JF, Chan MK, El-Nahas M, et al. Lipid nephrotoxicity in chronic progressive glomerular and tubulo-intersticial disease. Lancet 1982;2:1309-11.  Back to cited text no. 6    
7.Wanner C, Quaschning T. Dyslipideamia and renal disease: pathogenesis and clinical consequences. Curr Opin Nephrol Hyprtens 2001;10:195-201.  Back to cited text no. 7    
8.Massy ZA, Kasiske BL. Post-transplant hyperlipidemia: mechanisms and management. J Am Soc Nephrol 1996;7:971-7.  Back to cited text no. 8    
9.Wanner C, Quaschning T, Weingarnter K. Impact of dyslipideamia in renal transplant recipients. Curr Opin Urol 2000;10:77-80.  Back to cited text no. 9    
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11.Schaeffner ES, Kurth T, Curhan GC, et al. Cholesterol and the risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol 2003;14:2084-91  Back to cited text no. 11    
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14.Massy Z, Jungers P, Roullet J, Drueke T, Lacour B. Disturbances of apolipoprotein distribution in lipoproteins of uremic patients. J Nephrol 1993;6:153-8.  Back to cited text no. 14    
15.Freedman DS, Otvos JD, Jeyarajah EJ, et al. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease. Arterioscler Thromb Vasc Biol 1998;18:1046-53.  Back to cited text no. 15    
16.Krolewski AS, Warram JH, Christlieb AR. Hypercholesterolemia - a determinant of renal function loss and deaths in IDDM patients with nephropathy. Kidney Int 1994;45(Suppl 45):S125-31.  Back to cited text no. 16    
17.Coonrod BA, Ellis D, Becker DJ, et al. Predictors of microalbuminuria in individuals with IDDM: Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 1993;16:1276-83.  Back to cited text no. 17    
18.Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977; 62:707-14.  Back to cited text no. 18    
19.Kasiske BL. Hyperlipidemia in patients with chronic renal disease. Am J Kidney Dis 1998;32:S142-56.  Back to cited text no. 19    
20.Parra HJ, Cachera C, Equagoo K, et al. Quantitative abnormalities of lipoprotein particles in chronic hemodialysis patients. Edv Exp Med Biol 1988;243:283-7.  Back to cited text no. 20    
21.Katznelson S, Superdock K, Wilkinson A. Reducing cardiovascular risk in renal transplant patients. Medscape®. Available online. URL: http://www.medscape.comviewprogram /3037_pnt. Accessed December 2005.  Back to cited text no. 21    
22.Mathis AS, Dave N, Knipp GT, Friedman GS. Drug related dyslipidemia after renal transplantation. Am J Health Syst Pharm 2004;61:565-85.  Back to cited text no. 22    
23.Hohage H, Arlt M, Bruckner D, et al. Effects of cyclosporine A and FK 506 on lipid metabolism and fibrinogen in kidney transplant recipients. Clin Transplant. 1997;11:225-30.  Back to cited text no. 23    
24.Legendre C, Campistol JM, Squifflet JP, et al. Cardiovascular risk factors of sirolimus compared with cyclosporine: early experience from two randomized trials in renal trans­plantation. Transplant Proc 2003;35:151S-3S.  Back to cited text no. 24    
25.Wissing KM, Abramowicz D, Broeders N, Vereerstraeten P. Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection. Transplantation 2000;70:464-72.  Back to cited text no. 25    
26.Carvalho MF, Soares V. Hyperlipidemia as a risk factor of renal allograft function impairment. Clin Transplant 2001;15:48-52.  Back to cited text no. 26    
27.Kasiske BL. Epidemiology of cardiovascular disease after renal transplantation. Trans­plantation 2001;72(6 suppl):S5-8.  Back to cited text no. 27    
28.Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). J Am Med Assoc 2001;285:2486-97.  Back to cited text no. 28    
29.New Zealand Guidelines Group. The Assess­ment and Management of Cardiovascular Risk. 2003. Available online. URL: http://www.nzgg.org.nz/guidelines/0035/CV D_ Risk_Full.pdf. Accessed December 2005.  Back to cited text no. 29    
30.Tonelli M, Bohm C, Pandeya S, Gill J, Levin A, Kiberd BA. Cardiac risk factors and the use of cardioprotective mediations in patients with chronic renal insufficiency. Am J Kidney Dis 2001;37:484-9.  Back to cited text no. 30    
31.Zillich AJ, Saseen JJ, DeHart RM, et al. Caring for patients with chronic kidney disease: a joint opinion of the ambulatory care and the nephrology practice and research networks of the American College of Clinical Pharmacy. Pharmacotherapy 2005;25(1):123-43.  Back to cited text no. 31    
32.National Kidney Foundation. K/DOQI clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J Kidney Dis 2003;41(suppl 3):S1-92.  Back to cited text no. 32    
33.Iliou MC, Fumeron C. Cardiovascular disease in chronic renal failure patients. Saudi J Kidney Dis Transplant 2005;16(2):129-39.  Back to cited text no. 33    
34.Farmer JA,Torre-Amione G . Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Saf 2000;23:197-213.  Back to cited text no. 34    
35.Sheffield MC. Multiple effects of statins in non­lipid disease states. US Pharm 2004;6:38-54.  Back to cited text no. 35    
36.Wolfrum S, Jensen KS, Liao JK. Endothelium­dependent effects of statins. Arterioscler Thromb Vasc Biol 2003;23(5):729-36.  Back to cited text no. 36    
37.Ikeda U, Shimada K. Pleiotropic effects of statins on the vascular tissue. Curr Drug Targets Cario Haema Disord 2001;1(1):51-8.  Back to cited text no. 37    
38.Bianchi S, Bigazzi R, Caiazza A, et al. A controlled prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003; 41:565-70.  Back to cited text no. 38    
39.Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001;59:260-9.  Back to cited text no. 39    
40.Konstadinidou I, Boletis JN, Perrea D, et al. Beneficial effects of fluvastatin on progre­ssive renal allograft dysfunction. Transplant Proc 2003;35:1364-7.  Back to cited text no. 40    
41.Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024-31.  Back to cited text no. 41    
42.Kosch M, Barenbrock M, Suwelack B, et al. Effect of a 3-year therapy with the 3­hydroxy-3-methylglutaryl coenzyme a reductase-inhibitor fluvastatin on endothelial function and distensibility of large arteries in hypercholesterolemic renal transplant recipient. Am J Kidney Dis 2003;41:1088-96.  Back to cited text no. 42    

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Correspondence Address:
Monica Zolezzi
Lecturer in Pharmacotherapy, School of Pharmacy, University of Auckland, Auckland
NewZealand
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PMID: 16903617

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    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]

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