Hyperlipidemias: Wanner C

Wanner C, Ritz E. · Department of Internal Medicine, University of Würzburg, Würzburg, Germany. · Kidney Int Suppl. · Pubmed #19034322 No free full text.

Abstract: Lipid parameters are altered in the earliest stages of primary kidney disease, some even when measured glomerular filtration rate (GFR) is still normal. The main problem is that routinely measured lipid parameters are deceivingly normal except low high-density lipoprotein (HDL) and moderately elevated triglycerides (TGs) (>150 mg per 100 ml). Behind this unimpressive spectrum, serious anomalies are hidden: increased very low-density lipoprotein (VLDL) and chylomicron remnants, accumulation of delipidated small dense low-density lipoprotein (LDL), post translational modification of lipoproteins, abnormal concentrations of Lp(a) and nonprotective HDL. A routine parameter with some predictive value is the concentration of non-HDL cholesterol. Several of these abnormal lipoprotein particles stimulate cellular free oxygen radical formation which in turn induce inflammation and impact on endothelial function.A bone of contention is the indication for treatment with statins in endstage renal disease. Poor survival is paradoxically predicted by low cholesterol. This appears to be the result of confounding by microinflammation. One controlled interventional study in hemodialysed type 2 diabetics, the 4-D study, failed to show a significant benefit on the primary cardiovascular endpoint. We discuss potential explanations for this 'negative' outcome and the implications for statin treatment.

Holdaas H, Wanner C, Abletshauser C, Gimpelewicz C, Isaacsohn J. · Medical Department, National Hospital, University of Oslo, 0027 Oslo, Norway. · Int J Cardiol. · Pubmed #16889855 No free full text.

Abstract: BACKGROUND: Individuals with chronic kidney disease are at high risk for cardiovascular disease and have a high prevalence of hyperlipidemia. Lipid-lowering therapy may help patients with renal disease reduce their risk for cardiovascular events. METHODS: A pooled analysis of 30 completed clinical trials compared the efficacy and safety profiles of fluvastatin in subgroups of patients with moderate to severe renal insufficiency (creatinine clearance < 50 ml/min) and patients with normal renal function or mild renal insufficiency (creatinine clearance > or = 50 ml/min). RESULTS: Changes in lipid parameters with fluvastatin treatment were similar for the compared patient subgroups. Fluvastatin treatment reduced combined cardiac death and myocardial infarction by 41% compared with placebo among patients with moderate to severe renal insufficiency (hazard ratio, 0.59; p=0.007) and by 30% among patients with normal renal function or mild renal insufficiency (hazard ratio, 0.70; p=0.009). The relative reduction in the risk of major adverse cardiac events, a composite endpoint comprising cardiac death, nonfatal myocardial infarction, and coronary intervention procedures, with fluvastatin treatment was not significant for patients with moderate to severe renal insufficiency (hazard ratio, 0.83; p=0.18); in this patient subgroup, the incidence of coronary intervention procedures was similar between treatment groups. The safety profiles were similar for fluvastatin- and placebo-treated patients. CONCLUSIONS: The results of this pooled analysis indicate that fluvastatin is safe and effective for reducing cardiac death and nonfatal myocardial infarction in patients with moderate to severe renal insufficiency. Fluvastatin did not reduce the rate of coronary intervention procedures.

Wanner C, Krane V. · Department of Medicine, Division of Nephrology, University of Würzburg, Germany. · Am J Kidney Dis. · Pubmed #12612957 No free full text.

Abstract: BACKGROUND: The finding of an increased prevalence and levels of atherogenic lipoproteins in the context of normal plasma total and low-density lipoprotein (LDL) cholesterol (LDL-C) levels in hemodialysis (HD) patients highlights the need to look beyond the basic assessment of plasma concentrations of total cholesterol and LDL-C. Measurement of atherogenic lipoproteins (remnant lipoprotein particles [RLPs], particularly intermediate-density lipoprotein [IDL]), is not routinely performed at the present time. METHODS: The National Cholesterol Education Program guidelines indicate that the secondary goal in persons with triglyceride levels greater than 200 mg/dL is non-high-density lipoprotein cholesterol (HDL-C). Non-HDL-C comprises all RLPs, including IDL, as well as atherogenic small dense LDL. RESULTS: We propose, for practical reasons, that non-HDL-C be used as a primary target in HD patients when lipid-lowering therapy is indicated. However, it remains unclear whether and how effective statins are in lowering remnant particle levels in dialysis patients. Recent data show that both simvastatin and atorvastatin reduce non-HDL-C levels effectively. Atorvastatin preferentially reduces RLP levels in patients with combined hyperlipidemia. CONCLUSION: The safety profile of statins predisposes prescription of this class of drugs to correct dyslipidemia or modulate lipoprotein particle composition in uremic patients. Whether atorvastatin influences myocardial infarction or all-cause mortality by adequately correcting dyslipidemia should be seen fairly quickly in the 1,252 dialysis patients with diabetes randomly assigned in the ongoing Die Deutsche Diabetes Dialyse study.

Krane V, Wanner C. · Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany. · Nephrol Dial Transplant. · Pubmed #12386253 links to  free full text

Abstract: Hyperglycaemia induces mitochondrial superoxide production, increases oxidative stress, and leads to activation of the acute-phase response. Hyperglycaemia, impaired renal function, and uraemia cause inflammatory and oxidative processes. Advanced oxidation protein products and advanced glycation end products are formed, leading to subsequent cytokine release. This promotes alterations in lipoprotein metabolism, composition, and function. These changes result in a highly atherogenic environment, perpetuating the vicious cycle of accelerated atherogenesis. The terminal pathway is an elevation of C-reactive protein, a biomarker of both overall and cardiovascular outcome.

Wanner C, Krane V. · Department of Medicine, Division of Nephrology, University of Würzburg, Germany. · Blood Purif. · Pubmed #12207090 No free full text.

Abstract: Uremic patients suffer from a secondary form of complex dyslipidemia consisting of quantitative and qualitative abnormalities in serum lipoproteins resulting in altered lipoprotein composition and metabolism. The most prominent are an increase in serum triglyceride levels (due to elevated very-low-density lipoprotein remnants and intermediate-density lipoprotein) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol is often normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass. The apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide modification of the enzymatic and advanced glycation end-product, oxidation or glycosylation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. HDL particles are structurally altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is at present unclear. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Since it is also still unclear whether we have therapeutics available with a sufficient impact on LDL size, remnant lipoprotein lowering and restoration of HDL function, we urgently need specific intervention trials.

Wanner C. · Department of Medicine, University of Würzburg, Germany. · J Nephrol. · Pubmed #12018641 No free full text.

This publication has no abstract.

Wanner C, Quaschning T. · Department of Medicine, Division of Nephrology, University Hospital Wurzburg, Germany. · Ann Transplant. · Pubmed #11803608 No free full text.

Abstract: The evidence that lipid disorders in patients following renal transplantation play a major role in the pathogenesis of atherosclerosis and chronic renal allograft rejection is circumstantial. The high rate of clinical vascular disease and cardiovascular complications in renal transplant recipients, the high prevalence of an atherogenic dyslipidemia and the evidence from the statin regression trials in the general population suggest that lipid lowering treatment is beneficial in patients after renal transplantation. In addition, animal models and observational studies in patients have demonstrated correlations between plasma lipid levels and both acute and chronic rejection. Animal transplant models and clinical trials in heart transplant patients also suggest that statin treatment decreases the incidence of chronic rejection. However, the mechanisms behind this protective effect remain unsolved and no conclusive data exist proving that statins directly inhibit the development of chronic rejection. However, sufficient evidence exists to consider the use of these agents in the posttransplant setting for their possible effects on cardiovascular complications.

Wanner C, Krane V, Metzger T, Quaschning T. · Department of Medicine, Division of Nephrology, University of Würzburg, Germany. · J Nephrol. · Pubmed #11798151 No free full text.

Abstract: Chronic renal failure patients suffer from a secondary form of complex dyslipidemia, similar to the so-called atherogenic dyslipidemia in insulin resistant patients or to diabetic dyslipidemia. The most important abnormalities are an increase in the serum level of triglyceride (elevated VLDL-remnants/IDL), small LDL particles and a low HDL cholesterol. The highly atherogenic LDL subclass, namely LDL-6 or small dense LDL, accumulates in hypertriglyceridemic diabetic hemodialysis patients. All these lipoprotein particles contain apoB, thus much of this complex disorder can be summarized as an elevation of triglyceride-rich apoB containing complex lipoprotein particles. Growing evidence suggests that all of the components of this type of dyslipidemia are independently atherogenic. Further disturbances exist in the dynamics of cholesterol exchange between the various lipoprotein particles and in transport from cells to catabolic sites. The European Joint Task Force and the US National Cholesterol Education Program expert panel have issued guidelines for the general population to lower the cardiovascular risk in hyper- and dyslipidemias. There is preliminary consensus that these guidelines should be applied to dialysis patients. However, the genesis of atherosclerosis in the dialysis population may be different and real benefit from lipid-lowering has not yet been demonstrated in this population. Large-scale, prospective randomized trials (4D-trial, HARP) are underway to determine whether statins reduce cardiovascular complications in diabetic and non-diabetic patients with end-stage renal disease (ESRD) and on hemodialysis treatment.

Quaschning T, Krane V, Metzger T, Wanner C. · Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany. · Am J Kidney Dis. · Pubmed #11576915 No free full text.

Abstract: Patients with end-stage renal disease (ESRD) suffer from a secondary form of complex dyslipidemia consisting of both quantitative and qualitative abnormalities in serum lipoproteins resulting from alterations in lipoprotein metabolism and composition. The prominant features of uremic dyslipidemia are an increase in serum triglyceride levels (due to elevated very low density lipoprotein [VLDL]-remnants and intermediate-density lipoprotein [IDL]) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol often is normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass (sdLDL). The apolipoprotein B (apoB)-containing part of the lipoprotein may undergo modifications (enzymatic- and advanced glycation end-product [AGE]-peptide modification, oxidation, or glycosilation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. While LDL particles undergo a vicious cycle of accumulation and modification, reverse cholesterol transport is also impaired due to low lecithin:cholesterol acyltransferase (LCAT) and paraoxonase activity. Therefore, discoid HDL particles are structurally altered and hepatic cholesterol clearance is limited. The composition of HDL may also be altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is unclear at present. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Nevertheless, patients with renal disease belong to a very high cardiovascular risk group and dyslipidemia should most likely be subjected to sufficient lipid-lowering therapy in most patients. Because it is also still unclear whether we have available therapies with sufficient impact on LDL size, remnant lipoprotein-lowering, and restoration of HDL function, we urgently need the results from large scale intervention trials such as the 4D-trial and the CHORUS study.

Locatelli F, Bommer J, London GM, Martín-Malo A, Wanner C, Yaqoob M, Zoccali C. · Azienda Ospedale di Lecco, Ospedale A. Manzoni, Lecco, Italy, and. University Hospital, Heidelberg, Germany. · Nephrol Dial Transplant. · Pubmed #11239016 links to  free full text

Abstract: INTRODUCTION: Cardiovascular disease (CVD), as the leading cause of morbidity and mortality in patients on renal replacement therapy (RRT), has a central role in everyday nephrological practice. METHODS: Consensus was reached on key points relating to the clinical approach and treatment of the main cardiovascular risk factors in RRT patients (hypertension, anaemia, hyperparathyroidism, dyslipidaemia, new emerging risk factors). In addition, the role of convective treatments on cardiovascular outcomes was examined. RESULTS: Hypertension should be managed by aiming at blood pressure values of < or =140/90 mmHg (< or =160/90 mmHg in the elderly), firstly by ensuring target dry body weight is achieved. No single class of drug has proved superior to others in RRT patients, provided that the blood pressure target is achieved, although ACE inhibitors have shown specific organ protection in high-risk patients (HOPE study) and are well tolerated. Anaemia should be managed by using erythropoietin and iron supplements, aiming at haemoglobin levels of 12 g/dl and keeping serum ferritin levels < 500 ng/ml. The management of hyperparathyroidism is currently unsatisfactory, as calcium supplements have the potential to increase cardiovascular calcification. While awaiting new calcium- and aluminium-free phosphate binders, it is essential to ensure dialysis adequacy. Clinical studies are in progress to assess the real impact of lipid-lowering drugs in RRT. In the meantime, serum LDL-cholesterol < 160 mg/dl and triglycerides < 500 mg/dl may be desirable targets. The impact of new emerging risk factors (inflammation and chronic infection, hyperhomocysteinaemia, metabolic waste-product accumulation) and their proper management are still under research. Convective dialysis treatments may confer some degree of protection from dialysis-related amyloidosis and mortality, but clinical data on this important issue are still controversial and no definitive conclusions can be drawn at present. CONCLUSION: CVD prevention and treatment is a great challenge for the nephrologist. Achieving evidence-based consensus can help in encouraging the implementation of best clinical practice in line with the progress of current knowledge.

Wanner C, Quaschning T. · Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany. · Curr Opin Nephrol Hypertens. · Pubmed #11224694 No free full text.

Abstract: Patients with chronic renal disease suffer from a secondary form of complex dyslipidemia. The most important abnormalities are an increase in serum triglyceride levels (elevated VLDL-remnants/IDL), small LDL particles and a low HDL cholesterol level. The highly atherogenic LDL subclass, namely LDL-6 or small dense LDL, accumulates preferentially in hypertriglyceridemic diabetic patients with nephropathy or on hemodialysis treatment. All these lipoprotein particles contain apolipoprotein B, thus the complex disorder can be summarized as an elevation of triglyceride-rich apolipoprotein B-containing complex lipoprotein particles. Growing evidence suggests that all of the components of this type of dyslipidemia are independently atherogenic. These particles, specifically the apolipoprotein B moiety, are predominantly prone to modification such as oxidation and glycosilation, which contributes to impaired clearance by the LDL receptor. These complex alterations in lipoprotein composition not only passively accompany chronic renal disease but on the contrary also promote its progression and the development of atherosclerosis. Therefore, renal patients with dyslipidemia should be subjected to lipid-lowering therapy. The effectiveness of lipid lowering on the reduction of cardiovascular endpoints or the progression of renal disease is under investigation or remains to be studied.

Wanner C. · Department of Medicine, Division of Nephrology, University of Würzburg, Germany. · Nephrol Dial Transplant. · Pubmed #11073280 links to  free full text

This publication has no abstract.

Wanner C, Quaschning T, Weingärnter K. · Department of Medicine, University Hospital, Würzburg, Germany. · Curr Opin Urol. · Pubmed #10785846 No free full text.

Abstract: The evidence that lipid disorders in patients following renal transplantation play a major role in the pathogenesis of atherosclerosis and chronic renal allograft rejection is circumstantial. The absolute rate of clinical vascular disease and cardiovascular complications in transplant patients, the high prevalence of an atherogenic lipid profile and the evidence from the large HMG-CoA reductase inhibitor (statin) regression trials in the general population suggest that lipid lowering treatment is necessary in most patients after renal transplantation. Furthermore, animal models and observational studies in patients have found correlations between plasma lipid levels and both acute and chronic rejection. Animal transplant models and clinical trials in heart transplant patients also suggest that statin treatment decrease the incidence of chronic rejection in a manner that may also be independent of lipid lowering. Although the mechanisms behind this protective effect remains unclear, statins may be the first agents to be effective in preventing chronic rejection and in reducing the rate of cardiovascular complication in renal transplant recipients.

Kasiske B, Cosio FG, Beto J, Bolton K, Chavers BM, Grimm R, Levin A, Masri B, Parekh R, Wanner C, Wheeler DC, Wilson PW, Anonymous00362. · No affiliation provided · Am J Transplant. · Pubmed #15027968 No free full text.

Abstract: The incidence of cardiovascular disease (CVD) is very high in patients with chronic kidney (CKD) disease and in kidney transplant recipients. Indeed, available evidence for these patients suggests that the 10-year cumulative risk of coronary heart disease is at least 20%, or roughly equivalent to the risk seen in patients with previous CVD. Recently, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) published guidelines for the diagnosis and treatment of dyslipidemias in patients with CKD, including transplant patients. It was the conclusion of this Work Group that the National Cholesterol Education Program Guidelines are generally applicable to patients with CKD, but that there are significant differences in the approach and treatment of dyslipidemias in patients with CKD compared with the general population. In the present document we present the guidelines generated by this workgroup as they apply to kidney transplant recipients. Evidence from the general population indicates that treatment of dyslipidemias reduces CVD, and evidence in kidney transplant patients suggests that judicious treatment can be safe and effective in improving dyslipidemias. Dyslipidemias are very common in CKD and in transplant patients. However, until recently there have been no adequately powered, randomized, controlled trials examining the effects of dyslipidemia treatment on CVD in patients with CKD. Since completion of the K/DOQI guidelines on dyslipidemia in CKD, the results of the Assessment of Lescol in Renal Transplantation (ALERT) Study have been presented and published. Based on information from randomized trials conducted in the general population and the single study conducted in kidney transplant patients, these guidelines, which are a modified version of the K/DOQI dyslipidemia guidelines, were developed to aid clinicians in the management of dyslipidemias in kidney transplant patients. These guidelines are divided into four sections. The first section (Introduction) provides the rationale for the guidelines, and describes the target population, scope, intended users, and methods. The second section presents guidelines on the assessment of dyslipidemias (guidelines 1-3), while the third section offers guidelines for the treatment of dyslipidemias (guidelines 4-5). The key guideline statements are supported mainly by data from studies in the general population, but there is an urgent need for additional studies in CKD and in transplant patients. Therefore, the last section outlines recommendations for research.

Wanner C, Bahner U, Mattern R, Lang D, Passlick-Deetjen J. · Department of Medicine, Division of Nephrology, University Clinic of Würzburg, Germany. · Nephrol Dial Transplant. · Pubmed #15280524 links to  free full text

Abstract: BACKGROUND: Dyslipidaemia, inflammation and oxidative stress are prominent risk factors that potentially cause vascular disease in haemodialysis patients. Dialysis modalities affect uraemic dyslipidaemia, possibly by modifying oxidative stress, but the effects of dialyser flux and membrane material on atherogenic remnant particles and oxidized low-density lipoproteins (LDL) are unknown. METHODS: We performed a randomized crossover study in 36 patients on haemodialysis to analyse the effect of dialyser flux and membrane material on plasma lipids, apolipoproteins and markers of inflammation and oxidative stress. Stable patients on low-flux dialysis with polysulphone for >/=6 weeks were assigned to high-flux polysulphone or high-flux modified cellulose with similar dialyser surface area and permeability characteristics and crossed over twice every 6 weeks. RESULTS: Thirty patients completed the study per protocol. Treatments with high-flux polysulphone and modified cellulose lowered serum triglyceride (by 20% and 10%, respectively; P<0.05) and remnant-like particle cholesterol by 32% (P<0.001) and 11% (NS) after the first 6 weeks of treatment. Oxidized LDL decreased significantly with high-flux polysulphone, but not with modified cellulose. Apolipoproteins CII and CIII were reduced, whereas the ratio CII/CIII was increased (all P<0.05). Acute-phase proteins and LDL and high-density lipoprotein cholesterol remained unaffected. CONCLUSIONS: This randomized crossover study demonstrates a potent effect of high-flux haemodialysis on uraemic dyslipidaemia. Polysulphone membrane material showed superiority on oxidatively modified LDL, an indicator of oxidative stress in haemodialysis patients.

Quaschning T, Mainka T, Nauck M, Rump LC, Wanner C, Krämer-Guth A. · Department of Medicine, University of Würzburg, Germany. · Kidney Int Suppl. · Pubmed #10412786 No free full text.

Abstract: BACKGROUND: Patients after renal transplantation exhibit high cardiovascular morbidity and mortality because of the accumulation of cardiovascular risk factors such as hypertension or dyslipidemia. To elucidate the influence of immunosuppressive therapy on hyperlipidemia, we studied serum lipids and lipoproteins in renal transplant patients who received prednisone and either azathioprine or cyclosporine or triple immunosuppressive therapy. METHODS: Serum lipids and lipoprotein levels were measured in 216 renal transplant patients (81 female and 135 male) with stable graft function of 4.8 +/- 2.3 years (range six months to eight years) after transplantation. Patients were divided into three groups according to one of the following immunosuppressive regimens: (a) prednisone and azathioprine, (b) prednisone and cyclosporine, or (c) prednisone, azathioprine, and cyclosporine. Healthy, age- and sex-matched subjects served as controls. In addition to measurement of total serum lipids, lipoproteins were isolated by preparative ultracentrifugation, and lipids were determined in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) density classes. RESULTS: Total serum triglycerides, VLDL, and LDL triglycerides, as well as VLDL cholesterol were elevated in all renal transplant patients, but elevation was pronounced in female patients. In contrast to total serum cholesterol, which was significantly increased in only female patients, elevation of LDL-triglyceride/apo B ratio was more marked in male patients. Patients in group A exhibited only mild hypertriglyceridemia, whereas triglyceride enrichment in VLDL and LDL was more distinct in group B and was most pronounced in patients of group C. Furthermore, hypertriglyceridemia increased with the dose of administered prednisone. CONCLUSIONS: Immunosuppressive therapy in renal transplant patients leads to accumulation of triglyceride-enriched VLDL and LDL. Triglyceride enrichment in LDL indicates the accumulation of small, dense LDLs, which are known to bear enhanced atherosclerotic risk. This study provides data that underline the use of individually adjusted immunosuppressive therapy and steroid-sparing protocols in renal transplant patients to improve their atherogenic lipoprotein profile.

Krane V, Wanner C. · Medizinische Klinik und Poliklinik I der Universität Würzburg. · MMW Fortschr Med. · Pubmed #16669278 No free full text.

Abstract: In patients with chronic kidney disease, treatment with statins presumably not only has an influence on cardiovascular endpoints, but also delays the progression of the renal disease. Recommendations for the treatment of lipid metabolism disorders in the general population with normal renal function are based on numerous prospective, randomized and placebo-controlled studies. In contrast, recommendations for patients with pathological renal function can merely be extrapolated from the results of those studies. Post hoc analyses from the large pravastatin studies confirm a significant risk reduction of primary cardiovascular and cerebrovascular end points for the CDK stages 2 and 3. For CKD stages 4 and 5, available data are merely rudimentary, so that the results of ongoing studies will have to be awaited.

Königer M, Quaschning T, Wanner C, Schollmeyer P, Krämer-Guth A. · Department of Medicine, University of Freiburg, Germany. · Kidney Int Suppl. · Pubmed #10412790 No free full text.

Abstract: BACKGROUND: Patients on chronic hemodialysis treatment are at elevated atherogenic risk, and dyslipidemia appears to be one of the major risk factors. However, most of these patients exhibit elevated serum triglycerides, whereas serum cholesterol and low-density lipoprotein (LDL) cholesterol levels are in the normal range. This study was therefore designed to examine the influence of hypertriglyceridemia under the condition of hemodialysis and diabetes mellitus on LDL metabolism. METHODS: LDL was isolated from healthy controls, hypertriglyceridemic diabetic patients, and nondiabetic hemodialysis patients (N = 30, 10 in each group), which were separated into six subfractions by density gradient ultracentrifugation and were characterized concerning lipid/protein composition, degree of glycation, and oxidation. Uptake of 125I-labeled LDL was examined via LDL receptors of HepG2 cells and scavenger receptors of mouse peritoneal macrophages. RESULTS: In hemodialysis patients, serum triglycerides were significantly elevated, whereas cholesterol levels were within the normal range. Triglyceride enrichment occurred in the very low-density lipoprotein (VLDL) class and LDL class, and an accumulation of a highly atherogenic small dense LDL subfraction could be detected predominantly in patients with non-insulin-dependent diabetes mellitus. LDL of hemodialysis patients also contained elevated levels of lipid peroxidation products, which were even higher in diabetic patients. Alterations in composition, size, and configuration of LDL from diabetic and nondiabetic patients on hemodialysis impaired LDL receptor-mediated degradation and enhanced the uptake of these modified LDL particles via nonsaturable scavenger receptors. CONCLUSION: Diminished LDL receptor-mediated uptake of modified, triglyceride-rich, small dense LDL most likely leads to accumulation of these lipoproteins in vivo, favoring the development of atherosclerotic lesions. Future clinical studies must demonstrate whether patients will benefit from reducing these atherogenic particles by lipid-lowering intervention.

Olbricht CJ, Wanner C, Thiery J, Basten A. · Klinik für Nieren- und Hochdruckkrankheiten, Katharinenhospital, Stuttgart, Germany. · Kidney Int Suppl. · Pubmed #10412752 No free full text.

Abstract: BACKGROUND: Hyperlipidemia of the nephrotic syndrome is a risk factor for the development of systemic atherosclerosis, but it also may aggravate glomerulosclerosis and enhance the progression of glomerular disease. HMG-CoA reductase inhibitors are effective in reducing cardiovascular morbidity and mortality. Whether they may influence the progression of glomerular disease is not clear. The Simvastatin in Nephrotic Syndrome Study addressed the question of whether or not cholesterol lowering by the HMG-CoA reductase inhibitor simvastatin was superior to placebo treatment in limiting the decline of GFR and reducing proteinuria in nephrotic patients with primary glomerulonephritis. METHODS: This was a prospective, two-year, double-blind trial that included 56 patients with primary glomerulonephritis, hypercholesterolemia due to the nephrotic syndrome (proteinuria > 3 g/24 hr), and a creatinine clearance > 40 ml/min/1.73 m2. They were randomly assigned to treatment with simvastatin or placebo targeted to achieve low density lipoprotein (LDL) cholesterol levels below 120 mg/dl. The objectives were to determine the efficacy and safety of simvastatin, the rate of GFR decline as measured by inulin clearance, and the change in proteinuria over a two-year treatment period. RESULTS: Simvastatin produced a mean change in cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides of -39% -47%, +1%, and -30%, respectively. Serum lipoprotein(a) [Lp(a)] was not affected. No major simvastatin related events occurred. Minor events included elevations in serum creatine kinase without clinical symptoms. The course of renal function and of proteinuria during the study are still under evaluation and are not given here. CONCLUSIONS: Long-term treatment with simvastatin in nephrotic patients with hypercholesterolemia is effective and safe.

Quaschning T, Schömig M, Keller M, Thiery J, Nauck M, Schollmeyer P, Wanner C, Krämer-Guth A. · Department of Medicine, University of Würzburg, Germany. · J Am Soc Nephrol. · Pubmed #10215333 links to  free full text

Abstract: Patients with diabetes mellitus undergoing chronic hemodialysis treatment have the worst outcome on dialysis due to an increased rate of cardiovascular complications. Nearly all patients present with dyslipidemia, a prominent vascular risk factor, probably responsible for the high rate of vascular injury. Since both uremia and diabetes predispose to hypertriglyceridemia, the present study was conducted to investigate the influence of diabetes mellitus and/or hypertriglyceridemia on lipoprotein metabolism in hemodialysis patients. LDL was isolated and characterized from hyper- and normotriglyceridemic diabetic and nondiabetic hemodialysis patients (n = 40; 10 in each group); also, LDL-receptor-dependent uptake and intracellular cholesterol metabolism were studied in HepG2 cells. In addition, scavenger-receptor-mediated uptake was examined in mouse peritoneal macrophages. LDL isolated from nondiabetic normotriglyceridemic hemodialysis patients exhibited impaired cellular uptake via the LDL receptor. Additionally, intracellular sterol synthesis was less inhibited and cholesterol esterification was reduced compared with LDL from healthy control subjects. Reduction of catabolic capacities was more marked in hemodialysis patients who were either diabetic or hypertriglyceridemic and even more pronounced in patients presenting with a combination of both diabetes and hypertriglyceridemia. Hypertriglyceridemic and diabetic patients showed reduced lipase activity and increased LDL oxidation. Furthermore, they accumulated a fraction of small, dense LDL, and LDL was predominantly taken up via the scavenger-receptor pathway in peritoneal macrophages. This study elucidates the distinct influence of diabetes and/or hypertriglyceridemia in hemodialysis patients on cellular LDL metabolism via specific and nonspecific metabolic pathways. Furthermore, it underscores the cumulative impact of these pathologic entities on impairment of lipoprotein metabolism and increase of cardiovascular risk.