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Increased plasma concentrations of LDL-unbound apo(a) in patients with end-stage renal disease
E Trenkwalder1, A Gruber, P König
1Institute of Medical Biology and Human Genetics, University of Innsbruck, Austria.
Insights
Patients with kidney disease have higher levels of LDL-unbound apolipoprotein(a) [apo(a)], indicating the kidney
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Biochemistry
Background:
- Lipoprotein(a) [Lp(a)] and apolipoprotein(a) [apo(a)] are established risk factors for atherosclerosis.
- Patients with renal disease exhibit elevated Lp(a) levels.
- Previous studies suggest kidney involvement in Lp(a) metabolism, noting arteriovenous differences and urinary apo(a) fragments.
Purpose of the Study:
- To investigate elevated LDL-unbound apo(a) levels in chronic renal failure patients.
- To determine if higher LDL-unbound apo(a) accounts for increased Lp(a) in renal disease.
- To explore apo(a) fragment generation in vitro under uremic conditions and Lp(a) assembly in cell cultures.
Main Methods:
- Comparison of LDL-unbound apo(a) levels in hemodialysis and CAPD patients versus controls.
- Assessment of changes in LDL-unbound apo(a) post-renal transplantation.
- In vitro experiments mimicking uremic plasma and cell culture studies on Lp(a) assembly.
Main Results:
- Hemodialysis and CAPD patients showed significantly higher absolute and relative amounts of LDL-unbound apo(a) compared to controls.
- Renal transplantation led to a significant decrease in absolute LDL-unbound apo(a) amounts.
- Lp(a) plasma concentration was the primary determinant of absolute LDL-unbound apo(a), with strong positive correlations observed.
- In vitro uremization did not increase LDL-unbound apo(a); Lp(a) assembly was similar in patients and controls.
- Elevated LDL-unbound apo(a) levels in renal disease are not due to impaired Lp(a) assembly but suggest a kidney catabolic role.
Conclusions:
- The kidney plays a catabolic role in the clearance of LDL-unbound apo(a).
- Elevated LDL-unbound apo(a) in renal disease does not fully explain the higher Lp(a) concentrations observed in end-stage renal disease.
Abstract:
Lipoprotein(a) [Lp(a)] and its characteristic glycoprotein apolipoprotein(a) [apo(a)] are risk factors for atherosclerosis in the general population. Patients with renal disease show an elevation of Lp(a). Recent studies have described an arteriovenous difference of Lp(a) in the renovascular bed as well as the plasma-derived fragmented LDL-unbound apo(a) in urine, suggesting that the kidney is involved in the metabolism of Lp(a). We therefore investigated whether patients with chronic renal failure have higher levels of LDL-unbound apo(a) and whether this could account for the increased Lp(a) concentrations in these patients. In addition, we studied the possible generation of apo(a) fragments in vitro by mimicking uremic plasma conditions and by investigating the assembly of Lp(a) in cell culture experiments. Patients treated by hemodialysis (N = 185) and by continuous ambulatory peritoneal dialysis (CAPD; N = 20) had markedly elevated absolute (1.22 +/- 1.55 mg/dl and 2.14 +/- 2.86 mg/dl) as well as relative (7.5% and 7.3%) amounts of LDL-unbound apo(a) in comparison to controls (0.46 +/- 0.48 mg/dl or 4.5%). Following renal transplantation the absolute amount decreased significantly. Lp(a) plasma concentration was the most important determining variable for the absolute amount of LDL-unbound apo(a) and showed a positive correlation in both hemodialysis patients (r = 0.85) and controls (r = 0.92). In vitro experiments demonstrated that "uremization" of plasma samples did not generate a higher amount of LDL-unbound apo(a). Although LDL of renal patients has different chemical and structural properties as compared to control LDL, the extracellular assembly of Lp(a) did not differ between patients and controls. Therefore, the higher amounts of LDL-unbound apo(a) found in renal disease are not caused by an impaired assembly of Lp(a), but rather indicate a catabolic role of the kidney for LDL-unbound apo(a) as was already shown for Lp(a). Despite a small contribution, these elevated levels cannot explain the higher Lp(a) values found in patients with end-stage renal disease.