Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure.

BACKGROUND: Atherosclerotic diseases are a major cause of death in patients with renal failure. Increased serum concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases and have been demonstrated in patients with moderate renal failure, suggesting that this lipoprotein contributes to the increased cardiovascular risk seen in these patients. Variable alleles at the apolipoprotein(a) [apo(a)] gene locus are the main determinants of the serum Lp(a) level in the general population. The purpose of this study was to investigate apo(a) isoforms in patients with moderate renal failure and mild proteinuria (less than 1.0 g/day). METHODS: In 250 consecutive subjects recruited at a hypertension clinic, we assessed the renal function by 24-hour creatinine clearance, proteinuria, and microalbuminuria, as well as the prevalence of atherosclerotic disease, and we also measured apo(a) isoforms, serum albumin, and Lp(a) concentrations. RESULTS: Moderate impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) was found in 97 patients. Lp(a) levels were significantly greater in patients with moderate renal failure (21.7+/-23.9 mg/dl) as compared with patients with normal renal function (15.6+/-16.4 mg/dl, P<0.001), and an inverse correlation was observed between log Lp(a) and creatinine clearance (r = -0.181, P <0.01). However, no difference was found in the frequency of low molecular weight apo(a) isoforms between patients with normal (25.5%) and impaired (27.8%) renal function. Only patients with the smallest size apo(a) isoforms exhibited significantly elevated levels of Lp(a), whereas the large-size isoforms had similar concentrations in patients with normal and impaired renal function. No significant relationship was found between serum Lp(a) and proteinuria. Clinical and laboratory evidence of one or more events attributed to atherosclerosis was found in 9.8% of patients with normal renal function and 25.8% of patients with moderate renal failure (P<0.001). CONCLUSIONS: These results indicate that renal failure per se or other genes beside the apo(a) gene locus are responsible for the elevation of serum Lp(a) levels in patients with moderate impairment of renal function. The elevation of Lp(a) levels occurs independently of the level of proteinuria and may contribute to the risk for atherosclerotic disease in these patients.     

Lipoprotein (a) in patients with aortic aneurysmal disease

OBJECTIVE: Lipoprotein (a) is an independent risk factor for atherosclerosis. Atherosclerotic degeneration is usually found in abdominal aortic aneurysms (AAAs), whereas thoracic aortic aneurysms (TAAs) caused by aortic dissection are not suggested to be linked pathogenetically to atherosclerosis. Lipoprotein (a) was analyzed in patients with AAA and TAA and in healthy individuals in relation to the extent of atherosclerosis. METHODS: Included in the case control study were patients with AAA (n = 75) and TAA with dissection (n = 39) and healthy control subjects (n = 43), for a total of 157 participants. Serum lipoprotein (a) was measured with nephelometry. Lipoprotein (a) levels were compared between age-matched and gender-matched paired samples of the three groups, and an association of lipoprotein (a), aortic aneurysm, and the extent of atherosclerosis was determined in multivariate analysis. RESULTS: Median lipoprotein (a) levels of patients with AAA and TAA and of control subjects were 18.9 mg/dL (interquartile range [IQR], <9.6 to 40.5), less than 9.6 mg/dL (IQR, <9.6 to 16.7), and less than 9.6 mg/dL (IQR, <9.6 to 16.3), respectively. Lipoprotein (a) was positively associated with the extent of atherosclerosis in patients and control subjects (P <.0001). Lipoprotein (a) levels of patients with AAA were significantly higher compared with patients with TAA (P <.0001) and control subjects (P <.0001). Multivariate analysis confirmed an independent association between lipoprotein (a) and AAA (P =.009). No significant differences of lipoprotein (a) were found between patients with TAA and control subjects (P =.3). CONCLUSION: The lipoprotein (a) serum level, an indicator of atherosclerosis, is significantly elevated in patients with abdominal aneurysms independently of cardiovascular risk factors and the extent of atherosclerosis. Patients with TAAs caused by dissection have lipoprotein (a) levels comparable with healthy individuals.     

Lipoprotein (a) level and mortality in patients with critical lower limb ischaemia.

OBJECTIVE: to investigate if serum lipoprotein (a) level is a predictor of survival in patients with lower limb atherosclerotic occlusive disease. DESIGN: prospective follow up study. METHODS: demographic, biochemical and disease variables were collected prospectively in 441 patients with lower limb arterial occlusive disease. Survival data were obtained at a mean follow up of 44 months, and significant risk factors identified by the life table method and multivariate Cox regression analysis. RESULTS: the cumulative survival for all patients at three and five years was 79% and 63%. Lipoprotein (a) level was the only significant independent biochemical predictor for all deaths and cardiorespiratory deaths on multivariate analysis, along with age, diabetes mellitus, renal impairment, cardiac diseases and major amputation. An elevated Lipoprotein(a) level of >24 mg/dl incurred a 107% and 45% increase in mortality at three and five years respectively. The higher mortality associated with elevated Lipoprotein (a) was particularly evident in patients with critical ischemia, in whom three and five year survival was reduced from 85% to 63% and 67% to 53% (p=0.0064). In claudicants a survival discrepancy was manifested only after five years (73% vs 62%), and the overall association did not reach statistic significance (p=0.52). CONCLUSIONS: lipoprotein (a) level is a reliable biochemical marker for survival in patients with critical ischemia where traditional atherosclerosis risk factors were prevalent.     

Lipoprotein(a)-associated atherothrombotic risk in hemodialysis patients

BACKGROUND: Hemodialysis patients show a considerably higher risk of atherothrombotic disease than the general population. We investigated both lipoprotein(a) [Lp(a)] plasma levels and apolipoprotein(a) [apo(a)] phenotypes in relation to occurrence of atherothrombotic events in hemodialysis patients compared with subjects showing a normal kidney function. Methods: Lp(a) levels and apo(a) isoforms were determined in 118 hemodialysis patients, including 59 with prior atherothrombotic events, and in 182 subjects with normal creatinine clearance, including 82 who experienced a prior atherothrombotic event. Results: Lp(a) levels in hemodialysis patients (median; 20 mg/dl) were higher (p < 0.01) than in age- and sex-matched subjects with normal renal function without a history of atherothrombosis (11.3 mg/dl). Among hemodialysis patients, median Lp(a) levels were higher in subjects with than in those without prior atherothrombosis (34 vs. 15 mg/dl, p < 0.05). In hemodialysis patients and in subjects without nephropathy, the percentage of low-molecular-weight apo(a) phenotypes were significantly higher in patients with than in those without a history of prior atherothrombotic events (56.9% vs. 33.9%, p < 0.05; 62.2% vs. 25%, p < 0.00001,respectively). Stepwise regression analysis indicated that the presence of at least one apo(a) isoform of low molecular weight was an independent predictor of atherothrombosis in hemodialysis patients (p < 0.05). Conclusions: Elevated Lp(a) plasma levels appear to be associated with atherothrombosis, independent of their origin due to genetic factors or related to the impaired kidney function. Low-molecular-weight apo(a) isoforms are reliable genetic markers of atherothrombosis both in patients with impaired kidney function and in subjects without nephropathy.     

Symptomatic antiproteinuric treatment decreases serum lipoprotein (a) concentration in patients with glomerular proteinuria

Elevated serum levels of the atherogenic and thrombogenic lipoprotein(a) (Lp(a)) have been recognized as a feature of the nephroticsyndrome associated hyperlipidaemia. To examine a possible relationshipbetween serum Lp(a) concentration and proteinuria, serum albumin,or blood pressure, we studied nine patients with nephrotic-rangeproteinuria both at baseline and after various forms of antihypertensiveand antiproteinuric treatment. In fixed order, patients receivedconventional antihypertensive treatment (either -methyldopaor clonidine), subsequently ACE-inhibition therapy (lisinopril),ACE inhibition combined with an NSAID (indomethacin), and finallyNSAID plus conventional antihypertensive therapy. Measurementswere performed at the end of each 2-month study period. When compared to controls (n = 29), proteinuric patients beforetreatment showed increased levels of total cholesterol, very-lowand low-density lipoprotein (VLDL + LDL) cholesterol, triglyceridesand apolipo-protein B (apoB), while high-density lipoprotein(HDL) HDL cholesterol was lower. Lp(a) was significantly higherin patients (107 (95% CI: 55–208) mg/l) as compared tocontrols (25 (13–49) mg/l, P<0.01). Conventional antihypertensivetreatment did not reduce proteinuria, while Lp(a) remained unaffected.ACE-inhibitor treatment lowered proteinuria, raised serum albumin,while La(a) tended to fall (– 11 ±8%). Additionof an NSAID induced a further fall in proteinuria and a risein serum albumin. Lp(a) now fell by 40±5% from baselinevalues (P<0.01). Both serum total, HDL and VLDL + LDL cholesterolfell significantly. Finally, during subsequent single therapywith NSAID most parameters, including proteinuria and Lp(a),returned towards values obtained during single therapy withACE inhibition. Multiple regression analysis showed a strongrelation of Lp(a) with the amount of proteinuria (P = 0.001),while serum albu-min did not independently contribute to Lp(a)levels (P = 0.2). In conclusion, effective symptomatic antiproteinuric treatmentdecreases serum Lp(a) levels in patients with glomerular proteinuria.Our data suggests that renal protein leakage plays a more importantrole in the metabolic regulation of this lipoprotein than serumalbumin level, and that antiproteinuric treatment may be ofbenefit in reducing the increased risk of thrombosis and atherosclerosisobserved in this patient category.     

Lipoprotein(a) determination and risk of cardiovascular disease in South African patients with familial hypercholesterolaemia.

OBJECTIVE: A raised plasma level of lipoprotein(a) (Lp(a)) is an established genetic risk factor for coronary heart disease (CHD), particularly in patients with concomitant elevation of low-density lipoprotein (LDL) cholesterol. The current study focused on the comparison of two commercially available Lp(a) assay kits to determine whether differences observed in measured Lp(a) levels could be deemed negligible in CHD risk assessment in familial hypercholesterolaemic (FH) patients. DESIGN: To compare results obtained on duplicate plasma samples using two commercially available Lp(a) measuring kits, the immunoradiometric assay (RIA) and the enzyme-linked immunoabsorbent assay (ELISA). SETTING: Division of Human Genetics, Department of Obstetrics and Gynaecology, University of Stellenbosch, Tygerberg, South Africa and the Institute for Medical Biology and Human Genetics, University of Innsbruck, Austria. SUBJECTS: Plasma samples were obtained from 146 family members of 65 molecularly characterised South African FH families for comparative analysis. RESULTS: Using the RIA method, 34 samples (23%) considered to be in the normal range by the ELISA technique, were placed in the high-risk group (> 30 mg/dl). Only one sample, considered to have a normal Lp(a) level with the RIA method, was categorised by the ELISA technique as high risk. CONCLUSION: Our data demonstrate that measurements of Lp(a) using the RIA method (the only assay available in South Africa at the time of this study) differ significantly from those obtained by the reference ELISA technique, suggesting that misclassification could lead to inaccurate CHD risk assessment. This is an important consideration in Afrikaner FH families, where plasma levels of Lp(a) have been shown to be elevated significantly in FH patients compared with non-FH individuals.     

Lipoprotein (a) levels in those with high molecular weight apo (a) isoforms may remain low in a significant proportion of patients with end-stage renal disease.

BACKGROUND: Studies have reported an increase in median Lipoprotein (Lp) (a) in patients with high molecular weight (HMW) apolipoprotein (apo) (a) isoforms and renal impairment. Some studies identify Lp (a) levels as a risk factor for vascular disease in renal failure whilst others have demonstrated an association with apo (a) isoform type and vascular disease. METHODS: A total of 239 patients at end-stage renal failure (ESRF) were studied prior to the initiation of dialysis. Blood was taken for Lp (a) levels and apo (a) isoforms. Clinical vascular disease (CVD) was assessed on the basis of clinical history and Rose questionnaire. The control group for Lp (a) levels consisted of 228 healthy volunteers. RESULTS: Despite a higher median Lp (a) level in those with HMW isoforms, 30% of patients had Lp (a) levels <10 mg/dl. Overall, 49% patients were identified as having CVD. Diabetes, smoking history and Lp (a) levels were significantly associated with CVD in logistic regression analysis, although when patients with low molecular weight (LMW) and HMW isoforms were analysed separately, Lp (a) levels were not significantly associated with CVD in those with LMW isoforms. The rates of CVD in those with HMW isoform and low Lp (a) levels were significantly lower than those with HMW isoforms and elevated Lp (a) levels, 34 vs 57% (P < 0.01). CONCLUSIONS: Although median Lp (a) levels in those patients at ESRF with HMW isoforms are higher than controls, in a third of such patients Lp (a) levels remain relatively low. These patients have lower rates of CVD than those with high levels of Lp (a).     

Lipoprotein(a) and its role in occlusive vascular disease.

An increased serum level of lipoprotein(a) (LP(a)) is acknowledged as an independent risk factor for occlusive vascular disease, especially atherosclerosis. Recently, a considerable amount of data has been produced on the structure and functional relationships between Lp(a) and the primary cellular interactions of atherosclerosis. In this review we discuss the structure and function of Lp(a) with specific reference to its role in the proposed mechanisms of atherosclerosis.     

Increased Lipoprotein (a) concentrations in patients with chronic venous leg ulcers: a study on patients with or without postthrombotic syndrome

Chronic venous leg ulcers are common and cause considerable burden of disease for affected patients with significant costs for health care systems worldwide. The complex pathophysiology of chronic venous leg ulcers is still not entirely understood. In addition, reliable pathogenic and/or prognostic parameters are not known. Published data suggest that patients with chronic venous leg ulcers reveal congenital or acquired thrombophilia. We examined the serum Lipoprotein (a) [Lp(a)] level, a proatherogenic and prothrombotic risk factor, in patients with chronic venous leg ulcers (n=210, stratified into patients with postthrombotic syndrome or without) and in a healthy control group (n=341). Forty‐two percent of all patients, compared with 20% of healthy controls, revealed significantly increased Lp(a) serum concentrations above 0.3 g/L. Furthermore, 49% without postthrombotic syndrome but only 35% with postthrombotic syndrome showed increased Lp(a) levels. The increase of Lp(a) level was significantly different between all three groups (p<0.001). There was no correlation of Lp(a) levels and CRP values in all groups. Based on these data, it is conceivable that Lp(a) plasma level is a novel pathogenic parameter for chronic venous leg ulcers. Elevated concentrations may contribute to the pathogenesis through induction of thrombogenic microcirculatory dysregulations, impaired extravascular fibrinolysis, or other mechanisms like proinflammatory effects.     

Lipoprotein (a) and the kidney

Summary: Cardiovascular disease is the main cause of death in chronic renal failure patients. Lipoprotein (a) [Lp(a)] is an independent risk factor for development of vascular disease in non-renal and renal populations. the atherogenicity of Lp(a) is thought to relate to the structural homology between its apolipoprotein moiety [apo(a)] and plasminogen. Raised low-density-lipoprotein (LDL) cholesterol concentrations increase the atherogenic potential of Lp(a). Normally Lp(a) level is genetically determined but in renal disease positive correlations with urinary protein loss and peritoneal dialysate protein loss have been found. Levels are highest in nephrotic patients and chronic renal failure patients treated with peritoneal dialysis but are also increased in pre-dialysis and haemodialysis patients. Lipoprotein (a) falls following renal transplantation but cyclosporine therapy may adversely affect post transplant cardiovascular risk profile. Treatment with antiproteinuric drugs (converting enzyme inhibitors or non-steroidal anti-inflammatory agents) has been shown to reduce Lp(a) (and total cholesterol) concentrations. Most lipid-lowering drugs do not affect Lp(a) concentration but lowering LDL-cholesterol alone may significantly reduce the atherogenic effect of Lp(a). Routine measurement of Lp(a) concentration is not recommended but antiproteinuric therapy should have favourable effects on cardiovascular risk profile.     

Lipoprotein (a) in patients on maintenance haemodialysis and continuous ambulatory peritoneal dialysis

Lipoprotein (a) concentrations and apoprotein (a) isoforms weremeasured in 99 haemodialysis and 79 peritoneal dialysis patientsand compared with a normal population. Peritoneal dialysis patientsdemonstrated a threefold and haemodialysis a twofold increasein median Lp(a) values compared to controls (P0.001). The peritonealdialysis group had significantly more patients with Lp(a) valuesgreater than 30 mg/dl compared to controls, (53% versus 22%P0.001). In addition both patient groups demonstrated significanthypertriglyceridaemia (P0.001), reduction in HDL (P0.001) andelevation of the cholesterol/HDL ratio (P0.001) compared withcontrols. Peritoneal dialysis patients also demonstrated significanthypercholesterolaemia (P0.003). Lipoprotein (a) concentrations are considerably elevated inpatients on maintenance dialysis and this occurs in additionto the typical lipoprotein disturbances. This elevation mayincrease vascular risk, particularly in the peritoneal dialysisgroup who also have hypercholesterolaemia and reduced HDL.     

Transforming growth factor-beta(1) in the kidney and urine of patients with glomerular disease and proteinuria.

BACKGROUND: Transforming growth factor-beta(1) (TGF-beta(1)) is the major fibrogenic growth factor implicated in the pathogenesis of renal scarring. Proteinuria is a poor prognostic feature for various types of glomerular disease and its toxic action may be related to the activation of tubular epithelial cells towards increased production of cytokines and chemoattractant peptides. In this work we studied the site of synthesis and expression profile of TGF-beta(1) in the renal tissue of patients with heavy proteinuria and examined the relation of this expression with the urinary excretion of TGF-beta(1). METHODS: Twenty-five patients with heavy proteinuria (8.4+/-3.0 g/24 h) were included in the study. All patients underwent a diagnostic kidney biopsy and were commenced on immunosuppressive therapy with corticosteroids and cyclosporin. The sites of synthesis and expression profile of TGF-beta(1) mRNA and protein in the kidney were examined by in situ hybridization and immunohistochemistry. Urinary and plasma TGF-beta(1) levels were determined by ELISA before the initiation of treatment and 6 months later and compared with those of normal subjects and of patients with IgA nephropathy and normal urinary protein excretion. RESULTS: The site of synthesis and expression of TGF-beta(1) in the renal tissue of patients with heavy proteinuria was mainly localized within the cytoplasm of tubular epithelial cells. Interstitial expression was also present but glomerular TGF-beta(1) expression was found only in patients with mesangial proliferation. Urinary TGF-beta(1) excretion was significantly higher in nephrotic patients compared with normal subjects and with patients with IgA nephropathy and normal urinary protein excretion (783+/-280 vs 310+/-140 and 375+/-90 ng/24 h, respectively; P<0.01). In patients with remission of proteinuria after immunosuppressive therapy, urinary TGF-beta(1) excretion was significantly reduced (from 749+/-290 to 495+/-130 ng/24 h; P<0.01), while in patients with persistent nephrotic syndrome, it remained elevated. CONCLUSIONS: The localization of TGF-beta(1) mRNA and protein within tubular epithelial cells, along with its increased urinary excretion in patients with nephrotic syndrome, suggest the activation of these cells by filtered protein towards increased TGF-beta(1) production.     

Lovastatin in glomerulonephritis patients with hyperlipidaemia and heavy proteinuria.

Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, was given to 14 patients with unremittent nephrotic syndrome (heavy proteinuria with hyperlipidaemia) for 6 months. Treatment was started at an initial dose of 20 mg/day, increasing to a maximum of 80 mg/day. Treatment was well tolerated except in two patients: one developed rhabdomyolysis and one severe hypertriglyceridaemia requiring an additional antihyperlipidaemic agent. Lovastatin was effective in reducing serum cholesterol, LDL-C and apolipoprotein B in the remaining 12 patients. Cholesterol was reduced by 31% from 8.24 +/- 0.49 mmol/l (mean +/- SEM) to 5.7 +/- 0.18 mmol/l after 6 months (P less than 0.001). LDL-C was normalized to 3.26 +/- 0.21 mmol/l from a pretreatment value of 5.76 +/- 0.48 mmol/l (P less than 0.001), a decrease of 43%. Serum apolipoprotein B was also normalized to 1.11 +/- 0.09 g/l from a basal level of 1.51 +/- 0.10 g/l (P less than 0.05). Triglyceride, HDL-C and apolipoprotein A1 concentrations were unchanged. Proteinuria as well as renal albumin clearance were unchanged. GFR by plasma radioisotope Cr-EDTA clearance for the whole group was unaltered by treatment. However, among those with relatively good pretreatment renal function (GFR greater than 70 ml/min per 1.73 m2), GFR increased at the end of 6 months' treatment (118.2 +/- 15 ml/min per 1.73 m2 versus 77.6 +/- 8.4 ml/min per 1.73 m2 in wash-out phase).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prednisone-induced fluctuations of proteinuria in patients with a nephrotic syndrome

We studied the effect of prednisone on urinary protein excretion in 19 patients with a nephrotic syndrome, who were treated with prednisone (125-150 mg) on alternate days. We found a typical, fluctuating pattern of proteinuria resulting from an increased protein excretion rate on prednisone days and a decreased protein excretion rate on nonprednisone days. The urinary protein excretion on prednisone days was 9.9 +/- 3.3 g/24 h, as compared to 5.7 +/- 3.8 g/24 h on nonprednisone days (mean +/- SD). In the whole group of patients the percentual change in proteinuria was significantly correlated with the endogenous creatinine clearance. However, systematic differences between creatinine excretion rates on prednisone and nonprednisone days were not found in individual patients. In 6 patients, renal hemodynamics were studied more precisely, using a single injection technique. Only a slight and nonsignificant decrease in glomerular filtration rate was found on nonprednisone days (delta = -9.6 +/- 16.3%; mean +/- SD). Filtration fraction remained unchanged. It is therefore suggested that the effects of prednisone on proteinuria are not simply mediated by overall changes in renal hemodynamics.     

Lipoprotein(a) is not associated with venous thromboembolism risk

Objectives. Evidence from case-control studies as well as meta-analyses of these study designs suggest elevated lipoprotein(a) [Lp(a)] to be associated with an increased risk of venous thromboembolism (VTE). Prospective evidence on the association is limited, uncertain, and could be attributed to regression dilution bias. We aimed to assess the prospective association of Lp(a) with risk of VTE and correct for regression dilution. Design. We related plasma Lp(a) concentrations to the incidence of VTE in 2,180 men of the Kuopio Ischemic Heart Disease cohort study. Hazard ratios (HRs) (95% confidence intervals [CI]) were assessed and repeat measurements of Lp(a) at 4 and 11 years from baseline, were used to correct for within-person variability. Results. After a median follow-up of 24.9 years, 110 validated VTE cases were recorded. The regression dilution ratio of log_e Lp(a) adjusted for age was 0.85 (95% CI: 0.82–0.89). In analyses adjusted for several established risk factors and potential confounders, the HR (95% CI) for VTE per 1 SD (equivalent to 3.56-fold) higher baseline log_e Lp(a) was 1.06 (0.87–1.30). In pooled analysis of five population-based cohort studies (including the current study) comprising 66,583 participants and 1314 VTE cases, the fully-adjusted corresponding HR for VTE was 1.00 (95% CI: 0.94–1.07), with no evidence of heterogeneity between studies. Conclusions. Primary analysis as well as pooled evidence from previous studies suggest circulating Lp(a) is not prospectively associated with future VTE risk, indicating that evidence of associations demonstrated in case-control designs may be driven by biases such as selection bias.     

Effect of cyclosporin a on proteinuria in patients with Alport's syndrome

Eight patients with Alport's syndrome and massive proteinuria (129±60.57 mg/m² per hour) were treated with cyclosporin A (CyA) for 8 months. The average dose of CyA administered to all patients was 4.21±0.26 mg/kg per day and blood CyA levels of 63.4±4.1 ng/ml were attained. In five patients, proteinuria abated during the 3rd week of treatment. In the remaining three, all of whom had low creatinine clearance (82.0, 46.0 and 43.2 ml/min per 1.73 m² respectively), proteinuria persisted but at levels lower than before treatment: 32.5±15.9 mg/m² per hour versus 183.3±29.7 mg/m² per hour. No permanent decrease in creatinine clearance was observed in any of these patients throughout treatment. In those patients in whom proteinuria abated, it reappeared 2 weeks after discontinuation of CyA treatment. We observed no significant increases in angiotensin II plasma levels in our patients during CyA administration. Although we have shown that CyA will reduce massive proteinuria in patients with Alport's syndrome, we cannot yet recommend its use as a therapeutic measure.