Cardiovascular Disease in Kidney Transplantation and Its Association With Blood Concentrations of Cyclosporine and Cyclosporine Metabolites

doi:10.1016/j.transproceed.2018.03.115

Transplantation Proceedings

Volume 50, Issue 6, July–August 2018, Pages 1850-1854

https://doi.org/10.1016/j.transproceed.2018.03.115 Get rights and content

Highlights

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Cyclosporine metabolites' ratios is associated with increased diastolic blood pressure.
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There is a lower AM9/cyclosporine A ratio in obesity and diabetes mellitus.
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No associations were found between cyclosporine metabolites' ratios and coronary disease.

Abstract

Cyclosporine A (CsA) is the first calcineurin inhibitor used as immunosuppressive agent. Its administration is associated with multiple adverse effects including cardiovascular diseases (CVDs), but their mechanisms have not been fully elucidated. Cyclosporine metabolites are not well studied in this context. This study was aimed at analysis of the incidence of CVDs and their association with concentrations of cyclosporine and its metabolites.

Sixty patients after kidney transplantation (KTX) taking an immunosuppressive regimen including CsA participated in the study. There were 22 women (36.67%) and 38 men (63.33%), mean age 51.73 years, mean 109.38 months after KTX.

We observed a correlation between mean diastolic blood pressure and concentrations of metabolite to parent drug ratios of AM1-CsA/CsA (r = 0.35, P = .006), dihydroxy-CsA/CsA (r = 0.42, P = .001), trihydroxy-CsA/CsA (r = 0.42; P = .003) and desmethyl-carboxy-CsA/CsA (r = 0.65, P = .003). There were no significant associations of other CsA metabolites' parameters with CVDs (coronary disease, hypertension, stroke, arrhythmia, diabetes mellitus, obesity).

Study results suggest that blood pressure increases associated with CsA therapy could be caused by CsA metabolites that influence mainly diastolic blood pressure levels. A lack of such differences in relation with other CVDs may suggest that more complex mechanisms are involved in the development of cardiovascular injury and disease after kidney transplantation.

Section snippets

Methods

This was an open trans-sectional one-center study including kidney transplant patients taking cyclosporine as an element of their immunosuppressive regimen. Sixty consecutive KTX patients attending the outpatient clinic from May 2014 to April 2016 who agreed to participate in the study were included. Blood samples for CsA and its metabolites were drawn in occasions of routine blood testing 12 hours after administration of the evening dose of CsA (through levels). Graft function was assessed by

Results

Among the patients, 36.67% (22) were women, median age 51.73 (12.05) years, 109.38 (68.26) months after kidney transplantation. Table 1 shows the patients' clinical data. In univariate analyses, we have observed significant positive correlations of diastolic blood pressure with metabolite to parent drug (M/D) cyclosporine ratios of AM1, DiH-CsA, TriH-CsA, and dMC-CsA (Fig 1). There were no such correlations with systolic blood pressure and eGFR values, nor correlation of DBP with CsA blood

Discussion

It is hypothesized that approximately 65% of cyclosporine may be present in the blood in the form of various metabolites [10]. The search for causes of cyclosporine toxicity has led to increased interest in CsA metabolites [11], [12], [13], [14], [15]. In the early 1990s the immunosuppressive and toxic actions of cyclosporine metabolites were studied extensively, but the results were mostly inconclusive or contradictory [4], [14], [16], [17], [18], [19]. It should also be emphasized that

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For example, cyclosporine, by binding to hepatic LDLR and inhibiting LDL uptake by hepatocytes, induces a dose-dependent significant increase in serum total cholesterol and LDL-C levels and a drop in serum HDL-C levels. Corticoids have also been confirmed to induce dyslipidemia by promoting the hepatic synthesis of lipids, especially facilitating VLDL production as well as diminishing the hepatic uptake of LDL-C [66]. Noticeably, two novel medicines, tacrolimus and azathioprine, have been recently provided to induce less important alterations of the lipid profiles, which could be considered for replacement of the more harmful cyclosporine [67].
Dyslipidemia is correlated with a series of health problems, such as obesity, insulin resistance, and the development of cardiovascular disease (CVD). Currently, accumulating evidence sheds light on the fact that β-hydroxy β-methylglutaryl-CoA reductase inhibitors, named statins, could lower circulating lipid-density lipoprotein cholesterol (LDL-C) and represent a revolution for the prevention of metabolic disorder diseases. In addition, statins remain the cornerstone of LDL-C-lowering treatments, together with ezetimibe and bile acid sequestrants, which are used either in combination with statins or as monotherapies in the case of statin intolerance or side effects. On the other hand, other medicines that reduce circulating LDL-C have also been researched, including inhibitors of protein convertase subtilisin/kexin type 9 (PCSK9). More recently, PCSK9 inhibitors have been approved for the secondary prevention of CVD and for the atherogenic dyslipidemia therapy. Here, we summarize the latest guidelines for the management of dyslipidemia and its relation to CVD, focusing on LDL-C-lowering medicines that are either available in daily clinical practice or under investigation. In addition, we also discuss the “who, when, and how” with respect to treating patients with dyslipidemia according to LDL-C reduction as an individualized clinical precision medicine.
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CsA derivatives were also studied in the context of cardiovascular diseases in kidney transplant recipients. It has been found that higher AM1/CsA, DiHCsA/CsA, TriHCsA/CsA, and DemCarbCsA/CsA ratios correlate with elevated arterial blood pressure, coronary disease/myocardial infarction, supraventricular arrhythmia, hypertriglyceridemia, and overweight/obesity [16,17]. We discovered relationships between CsA metabolites and infections.
Infection remains a serious clinical problem in liver transplant (LTX) recipients. A higher risk of infection is connected with immunosuppression therapy. The aim of the study was to assess the relationships between infections’ incidence and concentrations of cyclosporine (CsA) metabolites after LTX.
Forty-three liver transplant recipients receiving CsA were included in the study. With the use of liquid chromatography combined with tandem mass spectrometry, concentrations of CsA and its metabolites were measured: dihydroxylated cyclosporine metabolites (DiHCsA), trihydroxylated cyclosporine metabolites (TriHCsA), demethylcarboxylated cyclosporine metabolites (DemCarbCsA), AM1, AM9, and AM4N. The study protocol conformed with the Declaration of Helsinki.
Patients with a history of Epstein-Barr virus (EBV) infection had higher DiHCsA, TriHCsA, DemCarbCsA, AM1/CsA, DiHCsA/CsA, TriHCsA/CsA i DemCarbCsA/CsA in comparison with group without such infection (P = .049, P = .037, P = .006, P = .018, P = .005, P = .027, and P = .026, respectively). LTX recipients with a history of all viral infections had higher DiHCsA, TriHCsA, DiHCsA/CsA, TriHCsA/CsA than patients without viral infections (P = .013, P = .021, P = .013, and P = .048, respectively). Multivariable analysis showed that AM1, DiHCsA, TriHCsA, DemCarbCsA, AM4N/CsA had positively influence on the incidence of all viral infections (β = 0.0302, P = .0328; β = 0.0699, P = .0453; β = 0.6781, P = .0382; β = 0.6767, P = .0414; and β = 0.8307, P = .0267, respectively). In multivariable analysis, patients with a history of all bacterial infections had higher AM1 and higher AM1/CsA in comparison with LTX recipients without such infections (β = 0.0118, P = .0279; and β = 0.0099, P = .036, respectively).
In liver transplant recipients with a history of viral or bacterial infections higher concentrations of CsA metabolites were found. Possibly CsA metabolites could be used to assess the risk of infection in patients after liver transplantation. It should be confirmed in further investigations.
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: This work was supported by the Polish National Science Centre (grant 2013/09/B/NZ2/00275) and the Polish National Centre of Research and Development (grant NR13014410).

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13th Congress of the Polish Society of Transplantation: Part IKidney transplantationCardiovascular Disease in Kidney Transplantation and Its Association With Blood Concentrations of Cyclosporine and Cyclosporine Metabolites

Highlights

Abstract

Section snippets

Methods

Results

Discussion

Lancet

Kidney Int

Transplant Proc

Clin Biochem

Transplant Proc

Transplant Proc

Cyclosporine immunosuppression mitigates immunologic risk factors in renal allotransplantation

Transplant Proc

A randomized clinical trial of cyclosporine in cadaveric renal transplantation

N Eng J Med

Cyclosporine clinical pharmacokinetics

Clin Pharmacokinet

Review: metabolism of immunosuppressant drugs

Curr Drug Metab

Microscale high-performance liquid chromatography-electrospray tandem mass spectrometry assay for cyclosporin A in blood

J Chromatogr B Biomed Sci Appl

Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate

Ann Intern Med

13th Congress of the Polish Society of Transplantation: Part I
Kidney transplantation
Cardiovascular Disease in Kidney Transplantation and Its Association With Blood Concentrations of Cyclosporine and Cyclosporine Metabolites