The compositional abnormalities of lipoproteins in diabetic renal failure.

Per-Ola Attman 0 1 Carolyn Knight-Gibson 0 1 Marcelo Tavella 0 1 Ola Samuelsson 0 1 Petar Alaupovic 0 1 0 of Nephrology, Sahlgrenska University Hospital , S-41345 Go teborg , Sweden 1 Department of Nephrology, Sahlgrenska University Hospital, University of Go teborg, Go teborg, Sweden, and Lipid and Lipoprotein Laboratory, Oklahoma Medical Research Foundation , Oklahoma City, Oklahoma , USA Background. Diabetic nephropathy (DN ) is a common cause of chronic renal failure (CRF ). Patients with DN have abnormal lipoprotein metabolism that can be influenced by both the impairment of renal function and the metabolic control of diabetes. The aim of the study was to explore the specific compositional lipoprotein abnormalities in patients with insulin-dependent DN in comparison with diabetic patients without nephropathy and non-diabetic CRF patients. Methods. The lipid and apolipoprotein (apo) composition of major lipoprotein density classes was determined in 20 patients with insulin-dependent diabetes mellitus and nephropathy and compared with that in seven diabetic patients without nephropathy, 20 patients with non-diabetic CRF, and nine healthy control subjects. Lipoproteins isolated by preparative ultracentrifugation were very-low-density lipoproteins ( VLDL), intermediate-density lipoproteins ( IDL), low-density lipoproteins (LDL), and high-density lipoproteins ( HDL). Results. Patients with DN had a plasma lipid and apolipoprotein profile characteristic of renal dyslipoproteinaemia with increased concentrations of triglycerides and cholesterol, reduced levels of apoA-I and apoA-II and increased levels of apoB, apoC-II, apoC-III and apoE. These changes were more pronounced in diabetic than in non-diabetic patients with comparable degrees of renal failure. All density classes were characterized by abnormal concentration and composition of some lipid and apolipoprotein constituents. DN patients had a more than four-fold increase of VLDL mass, a three-fold increase of IDL mass, and a significant reduction of HDL mass compared to control subjects. They also had significantly higher concentrations of apoB, apoC-peptides and apoE particularly in VLDL and IDL, and to some extent in LDL. In HDL, DN patients had lower cholesterol, apoA-I, apoA-II and apoC-II levels than controls. The major compositional change in DN patients was a significant increase in the relative content of apoC-peptides in IDL and LDL. - The lipoprotein abnormalities were more pronounced in patients with high HbA1c values. In addition, lower GFR and increased proteinuria were associated with higher concentrations of triglycerides and apoC peptides in VLDL, IDL, and LDL in DN patients. Conclusions. The results indicate that patients with DN share the characteristic features of dyslipidaemia of CRF with accumulation of intact or partially delipidized apoB-containing lipoproteins enriched in apoC-peptides and apoE, which are present not only in VLDL and IDL but also in LDL density range. The alterations are more marked in DN than in nondiabetic CRF patients reflecting the additional impact of metabolic control. Increased levels of these lipoproteins may represent risk factors for the accelerated development of atherosclerotic vascular disease in these patients. Patients with diabetic nephropathy ( DN ) constitute a major proportion of patients with chronic renal failure (CRF ) treated with dialysis and transplantation [1,2]. During the course of the disease these patients frequently develop severe atherosclerotic complications and vascular disease resulting in a significantly higher morbidity and mortality rate than in their non-diabetic counterparts [13]. Renal failure is inherently associated with specific alterations of lipoprotein metabolism and these alterations also aVect the diabetic patients [4]. The diabetic state is by itself also characterized by abnormal lipoprotein metabolism [5]. These two factors may contribute in concert to the dyslipoproteinaemia of diabetic renal failure with development of atherosclerosis and progressive renal failure as possible clinical consequences. We have shown earlier that the determination of protein moieties of lipoproteins, the apolipoproteins, provides important means for identifying dyslipidaemias [ 6 ]. We have established that insulin-dependent diabetic patients with progressive nephropathy and moderately to severely impaired renal function have altered lipid and apolipoprotein profiles that were in many respects similar to those of non-diabetic patients with comparable degree of renal insuYciency, and that the diabetic state could further accentuate these changes [ 7 ]. The purpose of the present study was to determine lipoprotein composition in insulin-dependent diabetic patients with moderate to severe renal failure and to compare it with that in non-diabetic patients with CRF. The specific aim was to determine the changes in lipid and apolipoprotein concentrations and composition of major lipoprotein density classes in patients with DN. Subjects and methods Study subjects Patients and control subjects were recruited from a larger group of subjects described previously [7]. All patients were treated at the Department of Nephrology and Medicine, University of Go teborg. Diabetic patients Twenty-seven patients (17 men, 10 women) with insulindependent diabetes mellitus (type I ) were studied. The clinical characteristics of patients are shown in Table 1. Seven of the patients (5 men, 2 women) had no clinical signs of nephropathy; they had normal serum creatinine and urinary albumin excretion did not exceed 6 mg/l in any patient. Their mean age was 45.5 years (range 2763 years) and they had a mean duration of diabetes of 26.211.7 years. The selection of diabetic patients without nephropathy was based on a similar duration of disease as patients with renal disease. The patients were in good physical condition without signs of major vascular complications. They were treated with combinations of long- and short-acting insulin regimens or, in one case, with an insulin pump. One patient was treated for hypertension with a cardioselective betablocking agent. Twenty patients had renal insuYciency judged to be caused by DN. There were 12 men and eight women with a mean age 43.4 years (range 2662 years). The mean duration of diabetes was 28.05.7 years. All patients had reduced renal function as measured by the glomerular filtration rate (GFR) [8] with a mean value of 19.512.2 ml/1.73 m2 body surface area. The mean concentration of glycated haemoglobin ( HbA1c) was 9.51.3%, significantly higher than that in the diabetic controls without nephropathy (P<0.05). Eighteen patients were treated for hypertension, mostly with cardioselective beta-blocking drugs and furosemide. Macrovascular complications in coronary, cerebral and major peripheral vessels were present in 12 patients. The patients had increased 24 h urinary protein excretion with a mean value of 2.41.8 g (...truncated)