Introduction. Renal replacement therapy remains the treatment of option for
patients in end stage renal disease. The most frequent cause of late allograft loss is
cardiovascular disease, which constitutes the leading cause of death of renal transplant
recipients (RTR). When compared with the general population, RTR show a four-fold
greater risk for CVD, and a two-fold higher risk for cardiovascular death. Renal
transplant dysfunction can be considered as a traditional risk factor, while high
sympathetic activity and accumulation of the endogenous inhibitor of endothelial NO
synthase (eNOS), asymmetric dimethylarginine (ADMA) are factors peculiar to chronic
renal failure. eNOS can be strongly inhibited by ADMA, whose accumulation in plasma
may play an important role in endothelial dysfunction.
ADMA is an uremic toxin that can be considered as parameter of endothelial
dysfunction. ADMA, also, causes local vasoconstriction when infused intra-arterially.
Symmetric dimethylagini...ne (SDMA) does not inhibit NOS directly, and is also elevated
in patients with renal failure, its levels, better than ADMA, correlate with glomerular
filtration rate (GFR). ADMA was proposed to be a marker for atherosclerotic changes,
and for the assessment of cardiovascular morbidity and mortality.
Atherosclerosis is today described as a disease where inflammation is the
dominant pathological and biochemical alteration. The development of the atherosclerotic
plaque is closely linked to expression of different cellular adhesion molecules (CAMs),
that are essential mediators, playing a central role in the recruitment of inflammatory
cells to the site development. Many factors were demonstrated to increase concentration
of cellular adhesion molecules: hypertension, immunosuppressive therapy, autoimmune
disease and cell mediated allograft rejection. These CAMs can be measured in plasma
and therefore may represent promising biomarkers that may reflect underlying
endothelial activation and vascular inflammation.
Besides inflammation many studies have generally suggested a positive
association between dyslipidemia and end stage renal disease and advanced chronic
kidney failure. Renal disease is associated with profound abnormalities in lipids and
lipoprotein metabolism and in renal transplant recipients hyperlipidemia is a well known
feature. It has been suggested that dyslipoproteinemia observed in kidney disease
contributes to the progression of glomerular and tubular lesions, with deterioration to end
stage renal disease. Factors that induce post-transplant dyslipidemia include age, body
weight, pre-transplant lipid levels, presence of proteinuria and allograft dysfunction.
Standard immunosuppressive therapy usually consists of triple drug therapy of
three drug classes: calcineurin inhibitors, anti-proliferative agents and corticosteroids.
Corticosteroids and cyclosporine, besides the nephrotoxic effect, seem to be one of the
main contributing factors that influence the post-transplant lipidemic profile.
Cyclosporine plays an independent role in elevating cholesterol levels by modulating the
low density lipoprotein (LDL) receptors. Corticosteroids, cyclosporine and tacrolimus (to
a lesser degree than cyclosporine) increase post-transplant cholesterol and triglycerides
levels, usually in dose dependent fashion. Elevated total and LDL cholesterol occur in
about 60% and hypertriglyceridemia in about 35%, whereas low high density (HDL)
cholesterol is present in only 15% of renal transplant recipients.
Enhanced sympathetic activity is frequently reported in end stage renal disease,
and such activation declines, but does not normalize, after successful kidney
transplantation.
Renalase is a new flavoprotein that regulates sympathetic tone and blood pressure.
It is secreted by the kidney and is reported that has monoamine oxidase (MAO) activity,
therefore may metabolize catecholamines. Cardiomyocytes, liver and skeletal muscles
also secrete renalase, and it was found in peripheral nerves, central nervous system,
adrenals, adipose tissue, 12.5-day-old embryo and endothelium. It circulates in the blood
as a proenzyme waiting for elevated catecholamines for activation.
The purpose of the study was to observe parameters of endothelial dysfunction
(parameters of chronic inlammation and nitrosative stress), lipid profile disturbances and
the level of sympathetic activity in the stable renal transplant recipients, to assess
correlations between renal dysfunction and inflammatory biomarkers, lipid profile
disturbances, nitrosative stress and sympathetic activity, as well as potential differences
in these parameters in regard to immunosuppressive protocol, and among them to
hypothesize the best independent predictor, and predictors of early renal dysfunction after
multivariate modeling (adjustment for age, body mass index, hypertension, smoking and
diabetes mellitus).
Methods. We enrolled 73 renal transplant recipients, who were greater than 12
months post-renal transplant surgery, had a stable graft function, no clinically present
cardiovascular disease and were on standard immunosuppression. The study was
conducted between March and November 2012 at the Clinic for Nephrology, Dialysis
and Transplantation, Clinical Centre Nis. Ethics Committee of Medical Faculty Nis
approved the study and fully informed written consent was obtained from each patient.
Results. Significant differences were found between clinical and control group in
sistolic blood pressure, (p<0.001), diastolic blood pressure, (p<0.001), urea (p<0.001),
creatinine (p<0.001), creatinine clearance (p<0.001), hemoglobin (p=0.003), white blood
cells, (p=0.003), total cholesterol (p<0.001), non-HDL (p<0.001) and Tg (p<0.001).
Plasma concentration of nitrates (p<0.001), eNOS (p<0.001), ADMA (p=0.001), SDMA
(p<0.001), renalase (p<0.0001), ICAM-1 (p<0.001), and VCAM-1 (p<0.001), were
statistically increased with regard to controls. Non-adjusted OR showed that there was a
significant risk of reduced GFR in patients with total cholesterol higher than 5.19
mmol/L, LDL cholesterol≥4.1 mmol/L, non-HDL≥4.2 mmol/L and higher VCAM-1
concentration. After adjustment for age and in multivariable model OR showed a
significant risk for reduced GFR in patients with total cholesterol ≥5.2 mmol/L, LDL≥4.1
mmol/L, non-HDL≥4.2 mmol/L and higher VCAM-1 concentration. HDL, triglycerides,
CRP and lipoprotein ratios did not have any significance as predictors of renal
dysfunction. Finally, there were no differences in all evaluated parameters between
groups in regard to immunosuppressive therapy. Total cholesterol, LDL, non-HDL and
VCAM-1 are strong and independent predictors of renal dysfunction in stable renal
transplant recipients. In contrast HDL, CRP, triglycerides and ICAM-1 did not seem to
have any impact on renal dysfunction.
Non-adjusted OR showed that there was a significant risk of reduced eGFR in
transplant recipients with increased renalase activity (p=0.026); age-adjusted OR showed
a significant risk of reduced eGFR with increased renalase activity (p=0.042), also after
multivariable adjustment (p=0.032). Increased plasma eNOS activity was protective
factor for eGFR (p=0.011), also after adjustment for age (p=0.045), and after multivariate
modeling, eNOS was shown to be protective factor for eGFR (p=0.014). Significant
differences with respect to immunosuppression were in plasma renalase in patients
maintained on cyclosporine (p=0.027), as well as differences in eGFR (p=0.034).
We found statistically significant inverse correlation between renalase and eGFR
(p<0.001), positive correlation between renalase and creatinine (p=0.003), total
cholesterol (p<0.001), LDL-cholesterol (p=0.046), and non-HDL cholesterol (p=0.01).
There was a significant difference in plasma renalase with regard to chronic kidney
disease stages (p<0.001). Renalase correlated with leukocytes, but did not correlate with
C-reactive protein. Renalase did not correlate with any of parameters of endothelial
dysfunction, neither with some demographic data (gender, age, time or type of
transplantation, risk factors). There were no differences in renalase activity with regard to
antihypertensive therapy.
Conclusion. Renalase was shown to be strong predictor for decreased eGFR in
stable renal recipients. eNOS was identified as a strong protective factor for eGFR.
Renalase strongly and inversely correlated with eGFR, positively with creatinine and
lipid disturbances, but did not correlate with endothelial dysfunction parameters, and is
most probably determined by kidney function. Total cholesterol, LDL, non-HDL and
VCAM-1 strongly and inversely correlated with glomerular filtration rate and were
shown to be independent predictors for decreased GFR, as well as predictors by
multivariate modeling. In contrast there was no correlation of HDL, CRP, triglycerides
and ICAM-1 with glomerular filtration rate. All evaluated lipid and inflammation
parameters did not differ between the groups in respect to immunosuppression therapy
protocol. Renalase was significantly higher in the group of patients on cyclosporine.
