Renal artery thromboembolism and immunosuppressive therapy.
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Azathioprine↗
Biomedical subjects
F Kronenberg
Publications and source records attributed to F Kronenberg.
Complement C4 phenotypes in patients with end-stage renal disease.
The phenotypes of complement C4 were determined by agarose gel electrophoresis in 130 patients with end-stage renal failure of various causes and compared with those of 140 healthy controls. C4 allotype frequencies did not differ between patients and controls. Null alleles of both isotypes C4A and C4B were increased, but also without reaching significance. In type 1 diabetics an increased frequency of C4AQ0 (25 vs. 11.8%, p < 0.05) was found. Patients with two null alleles were far more frequent in the group with insulin-dependent diabetes mellitus (25 vs. 3.6%, p < 0.01). We confirmed the presence of a previously described uremic variant of C4B1. Additional uremic variants of C4 were detected in uremic patients homozygous for C4A3, B2 and B3. The relative electrophoretic migration values of the uremic variants of C4A3, B1, B2 and B3 were 132.1 +/- 2.9, 35.8 +/- 1.5, 70.4 and 73.9. These variants appear early in the course of chronic renal failure and disappear after successful renal transplantation. Uremic variants are the only acquired C4 phenotypes known so far. How uremia causes these variants remains unclear, but probably involves carbamylation of the C4 molecule.
Alleles↗
Lp(a) levels and atherosclerotic vascular disease in a sample of patients with familial hypercholesterolemia sharing the same gene defect.
There is considerable variation in the severity of cardiovascular disease among patients with familial hypercholesterolemia (FH). Some reports have suggested that plasma lipoprotein(a) [Lp(a)] levels may explain such variation and that FH subjects deficient in LDL receptors, especially those with coronary heart disease, tend to have elevated Lp(a) levels. We have investigated the possible role of the LDL receptor in determining plasma Lp(a) levels in genetically homogeneous FH population and the contribution of Lp(a) to cardiovascular risk. A total of 98 FH subjects and 66 healthy first- and second-degree relatives from 30 families with FH due to the French-Canadian > 10-kilobase deletion of the LDL receptor gene were studied. A reference group of 392 normolipidemic French-Canadian participants in a Heart Health Survey was used for comparison. FH subjects were subdivided into subsets of 63 individuals free from atherosclerotic vascular disease (AVD) and 35 individuals with AVD. A complete cardiovascular evaluation was performed, and plasma lipid, lipoprotein, and Lp(a) levels were measured in all subjects in the absence of medication. Apolipoprotein (a) [apo(a)] phenotype was determined in 112 of FH and non-FH subjects. The log-transformed values for plasma Lp(a) were not significantly different among the three groups: 0.98 +/- 0.54 (mean +/- SD) in FH subjects with AVD, 0.89 +/- 0.51 in FH subjects without AVD, and 0.82 +/- 0.64 in their relatives. The distribution of the apo(a) phenotypes did not differ between the FH and non-FH groups. Comparison of two age- and sex-matched subgroups of FH subjects, with and without AVD, failed to show any differences in Lp(a) level. However, mean Lp(a) log values in the reference group (n = 392) were significantly lower than values obtained for the total FH group (0.79 +/- 0.57 versus 0.92 +/- 0.52, respectively; P < .05) but were not different from those of the unaffected family members. Thus, in our sample, the LDL receptor appears not to influence plasma Lp(a) levels; rather, these levels reflect shared apo(a) genes. The cardiovascular risk in this group of subjects with FH was related to age, male sex, total and LDL cholesterol, and higher apoB but not Lp(a) levels.
Adolescent↗
Lipoprotein(a) in stored plasma samples and the ravages of time. Why epidemiological studies might fail.
Prospective case-control studies investigating lipoprotein(a) [Lp(a)] as a risk factor for atherosclerosis have measured Lp(a) in samples stored frozen up to nearly 20 years. We therefore prospectively examined the influence of long-term plasma sample storage on measured values, depending on the molecular weight of apolipoprotein(a) [apo(a)] isoforms. Apo(a) phenotyping was performed in 310 plasma samples, and Lp(a) was measured after 3 and 28 months of storage at -80 degrees C. The values of both measurements correlated significantly for both low- and high-molecular-weight apo(a) phenotypes (r = .97 and r = .98, respectively, P < .001). Nevertheless, we detected on average a small decrease of 4.83% from mean +/- SD (median) 21.24 +/- 23.54 (11.10) mg/dL to 20.02 +/- 21.72 (10.55) mg/dL, which was statistically significant (P < .001). The absolute and relative Lp(a) decrease over time became larger with a decreasing number of kringle IV repeats of apo(a) (P < .05), and Lp(a) decreased markedly more in subjects with low-molecular-weight compared with those with high-molecular-weight apo(a) isoforms (-3.26 versus -0.46 mg/dL, P < .05). More than 70% of the absolute Lp(a) decrease in the total sample was caused by samples with low-molecular-weight apo(a) isoforms, which represented only 27% of the sample. Low-molecular-weight apo(a) isoforms are reportedly more frequent in patients with atherothrombotic disease compared with control subjects. Measurement of Lp(a) in several-year-old frozen samples is therefore likely to result in a preferential decrease and false lower Lp(a) concentrations in patient groups compared with control groups. The negative results of some prospective studies with retrospective measurement of Lp(a) may be caused by such an artifact.
Arteriosclerosis↗
Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease.
A high plasma concentration of lipoprotein(a) [Lp(a)] has been suggested as a risk factor for coronary heart disease (CHD), but some recent prospective studies have questioned the significance of Lp(a). Lp(a) concentrations are determined to a large extent by the hypervariable apo(a) gene locus on chromosome 6q2.7, which contains a variable number of identical tandemly arranged transcribed kringle IV type 2 repeats. The number of these repeats correlates inversely with plasma Lp(a) concentration. We analyzed whether apo(a) gene variation (kringle IV repeat number) is associated with CHD. Apo(a) genotypes were determined by pulsed-field gel electrophoresis/genomic blotting in CHD patients who had undergone angiography (n = 69) and control subjects matched for age, sex, and ethnicity (n = 69) and were related to Lp(a) concentration, apo(a) isoform in plasma, and disease status. Apo(a) alleles with a low kringle IV copy number ( < 22) and high Lp(a) concentration were significantly more frequent in the CHD group (P < .001), whereas large nonexpressed alleles were more frequent in control subjects. The odds ratio for CHD increased continuously with a decreasing number of kringle IV repeats and ranged from 0.3 in individuals with > 25 kringle IV repeats on both alleles to 4.6 in those with < 20 repeats on at least one allele. This provides direct genetic evidence that variation at the apo(a) gene locus, which determines Lp(a) levels, is also a determinant of CHD risk.
Alleles↗
Polymorphism of complement C4 and susceptibility to IDDM and microvascular complications.
OBJECTIVE: The aim of this study was to investigate whether or not the inherited polymorphism of complement C4 is associated with genetic susceptibility to microvascular complications in IDDM as previously reported. RESEARCH DESIGN AND METHODS: We determined C4 phenotypes in 241 patients with IDDM and 140 healthy control subjects by agarose gel electrophoresis and immunoprecipitation. C4 allotype frequencies were compared between patients and healthy control subjects. In addition, we compared allotype frequencies of 83 patients with nephropathy with those of 80 patients without nephropathy and compared those of 50 patients with proliferative retinopathy with those of 68 patients without retinopathy or background retinopathy. Duration of IDDM in control patients was at least 21 years. RESULTS: Patients and healthy control subjects differed at both the C4A (P < 0.00001) and C4B (P < 0.0005) loci. The C4 null allele C4AQ0 was significantly increased in IDDM patients (26.8 vs. 11.8%, P < 0.005). C4B2 was more frequently observed in patients (14.5 vs. 6.8%, P < 0.05) compared with healthy control subjects. No differences were observed in C4 allotype distribution between patients with and without nephropathy or retinopathy. CONCLUSIONS: These data confirm previous reports of an association between the C4 null allele C4AQ0 and IDDM. Our results do not support an association of the inherited polymorphism of complement C4 with genetic susceptibility to microvascular complications in patients with IDDM.
Adolescent↗
Lipoprotein(a) in health and disease.
Lipoprotein(a) [Lp(a)] represents an LDL-like particle to which the Lp(a)-specific apolipoprotein(a) is linked via a disulfide bridge. It has gained considerable interest as a genetically determined risk factor for atherosclerotic vascular disease. Several studies have described a correlation between elevated Lp(a) plasma levels and coronary heart disease, stroke, and peripheral atherosclerosis. In healthy individuals, Lp(a) plasma concentrations are almost exclusively controlled by the apo(a) gene locus on chromosome 6q2.6-q2.7. More than 30 alleles at this highly polymorphic gene locus determine a size polymorphism of apo(a). There exists an inverse correlation between the size (molecular weight) of apo(a) isoforms and Lp(a) plasma concentrations. The standardization of Lp(a) quantification is still an unresolved task due to the large particle size of Lp(a), the presence of two different apoproteins [apoB and apo(a)], and the large size polymorphism of apo(a) and its homology with plasminogen. A working group sponsored by the IFCC is currently establishing a stable reference standard for Lp(a) as well as a reference method for quantitative analysis. Aside from genetic reasons, abnormal Lp(a) plasma concentrations are observed as secondary to various diseases. Lp(a) plasma levels are elevated over controls in patients with nephrotic syndrome and patients with end-stage renal disease. Following renal transplantation, Lp(a) concentrations decrease to values observed in controls matched for apo(a) type. Controversial data on Lp(a) in diabetes mellitus result mainly from insufficient sample sizes of numerous studies. Large studies and those including apo(a) phenotype analysis came to the conclusion that Lp(a) levels are not or only moderately elevated in insulin-dependent patients. In noninsulin-dependent diabetics, Lp(a) is not elevated. Conflicting data also exist from studies in patients with familial hypercholesterolemia. Several case-control studies reported elevated Lp(a) levels in those patients, suggesting a role of the LDL-receptor pathway for degradation of Lp(a). However, recent turnover studies rejected that concept. Moreover, family studies also revealed data arguing against an influence of the LDL receptor for Lp(a) concentrations. Several rare diseases or disorders, such as LCAT- and LPL-deficiency as well as liver diseases, are associated with low plasma levels or lack of Lp(a).
Animals↗
Glomerular deposition of the complement C4 isotypes C4A and C4B in glomeruonephritis.
BACKGROUND: Complement C4 is a component of the classical complement pathway, which is a major mediator of inflammation in many forms of glomerulonephritis. The two isoforms of C4-C4A and C4B-differ in their physicochemical and functional properties. METHODS: The glomerular deposition of C4A and C4B was investigated in 39 cases of glomerulonephritis with classical pathway activation using isotype-specific monoclonal antibodies 99H7 (C4A) and 1288 (C4B) and indirect immunofluorescence. Complement C4 phenotypes of all patients were determined by agarose gel electrophoresis and immunoprecipitation. RESULTS: Three biopsies contained only the isotype C4B. C4 phenotyping revealed complete C4A deficiency in these three patients. Both isotypes C4A and C4B were detected in 36 biopsies. In 19 (53%) thereof staining for both isotypes was identical. In the remaining 17 (47%), staining intensity of C4A predominated over C4B. The distribution of these two staining patterns did not differ between membranous glomerulonephritis and lupus nephritis. They were also independent of C4A and C4B allotypes including the presence or absence of null alleles at either gene locus. In no case was C4B staining stronger than C4A staining. Serum creatinine and proteinuria did not differ between patients with identical and C4A-dominant C4 deposition. CONCLUSIONS: The most likely but still hypothetical explanation for predominance in glomerular deposition of C4A over C4B in many cases of immune complex-mediated glomerulonephritis is the greater affinity of C4A to protein-containing immune complexes as compared to C4B.
Adolescent↗
Lipoprotein metabolism in renal replacement therapy: a review.
Lipoprotein disorders are considered an important cause for the high cardiovascular morbidity and mortality in patients with end-stage renal disease and following renal transplantation. This article reviews the disease-associated changes of lipids and lipoproteins in these patients and, where known, the underlying causes and mechanisms. Further, we discuss the perturbed lipoprotein system in relation to the cardiovascular risk of patients on renal replacement therapy. Patients treated by hemodialysis are often hypertriglyceridemic with increased very low density lipoprotein (VLDL) levels and a type IV Frederickson pattern of hyperlipidemia. Total and LDL cholesterol concentrations are usually normal or subnormal. Treatment of end-stage renal disease by peritoneal dialysis results in increased total, VLDL and LDL cholesterol concentrations. Both treatment modalities are accompanied by a decrease of high density lipoprotein (HDL) cholesterol and apolipoprotein AI, whereas lipoprotein(a) [Lp(a)] concentrations are significantly elevated in both groups. Following renal transplantation a high incidence of hypercholesterolemia and hypertrigylceridemia is observed, which is attributed, at least in part, to the immunosuppressive therapy. Most patients normalize HDL cholesterol values and Lp(a) decreases to pre-disease plasma concentrations. Several studies have described elevated levels of cholesterol, triglycerides and Lp(a) in patients with cardiovascular complications during different phases of renal replacement therapy, which indicates a predictive (causative) role of these parameters for atherosclerotic diseases.
Humans↗
Conversion from cyclosporin to azathioprine after kidney transplantation.
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Apolipoproteins A↗
Sequence polymorphism in kringle IV 37 in linkage disequilibrium with the apolipoprotein (a) size polymorphism.
Apolipoprotein(a) [apo(a)] contains a variable number of identical (K-IV A/B) or nearly identical (K-IV 1, K-IV 30-37) kringle repeats that are homologous to K-IV from plasminogen. The sizes of 414 apo(a) alleles were determined by pulsed-field gel electrophoresis (PFGE) of KpnI-digested DNA. Furthermore, sequence variation in the apo(a) K-IV 30-37 domain was analysed. Reverse transcription/polymerase chain reaction (RT-PCR) cloning of human liver poly A+ RNA followed by sequencing revealed a single nucleotide exchange in the ultimate K-IV (K-IV 37) of apo(a) (codon 4168); this results in an ATG (Met) to ACG (Thr) substitution. A PCR-based restriction assay of genomic DNA demonstrated that this substitution represents a common polymorphism. In 231 unrelated Tyroleans, the frequencies for the K-IV 37 Thr and K-IV 37 Met alleles were 0.66 and 0.34, respectively. The phase between the K-IV 37 Met/Thr and the KpnI size polymorphism was determined for 224 alleles. A significant linkage disequilibrium was detected between the sequence and size polymorphisms of apo(a). K-IV 37 Met was significantly associated with KpnI allele no. 18 (DAB = 0.0267 +/- 0.0101; chi 2 = 10.09, df = 1). The Met/Thr polymorphism was further used to test whether deletions or duplications of K-IV 37 occur frequently in the apo(a) gene. Some 40 apo(a) alleles, 22 of which were from subjects that appeared to be double heterozygotes for K-IV repeat number and the Met/Thr variation were separated by PFGE and analysed for the 4168 Met/Thr polymorphism. The Met and Thr sequences were always present on different size alleles and no evidence for a duplication or deletion of K-IV 37 was obtained. This suggests that the copy number of K-IV 37 is invariable, in contrast to the highly variable K-IV A/B domain of the gene. The 4168 Met/Thr polymorphism had no effect on Lp(a) concentration, neither did it influence the lysine-binding property of the Lp(a) particle.
Adult↗
A pentanucleotide repeat polymorphism in the 5' control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians.
The enormous interindividual variation in the plasma concentrations of the atherogenic lipoprotein(a) [Lp(a)] is almost entirely controlled by the apo(a) locus on chromosome 6q26-q27. A variable number of transcribed kringle4 repeats (K4-VNTR) in the gene explains a large fraction of this variation, whereas the rest is presently unexplained. We here have analyzed the effect of the K4-VNTR and of a pentanucleotide repeat polymorphism (TTTTA)n (n = 6-11) in the 5' control region of the apo(a) gene on plasma Lp(a) levels in unrelated healthy Tyroleans (n = 130), Danes (n = 154), and Black South Africans (n = 112). The K4-VNTR had a significant effect on plasma Lp(a) levels in Caucasians and explained 41 and 45% of the variation in Lp(a) plasma concentration in Tyroleans and Danes, respectively. Both, the pentanucleotide repeat (PNR) allele frequencies and their effects on Lp(a) concentrations were heterogeneous among populations. A significant negative correlation between the number of pentanucleotide repeats and the plasma Lp(a) concentration was observed in Tyroleans and Danes. The effect of the 5' PNRP on plasma Lp(a) concentrations was independent from the K4-VNTR and explained from 10 to 14% of the variation in Lp(a) concentrations in Caucasians. No significant effect of the PNRP was present in Black Africans. This suggests allelic association between PNR alleles and sequences affecting Lp(a) levels in Caucasians. Thus, in Caucasians but not in Blacks, concentrations of the atherogenic Lp(a) particle are strongly associated with two repeat polymorphisms in the apo(a) gene.
Adult↗
Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
Numerous studies have investigated lipoprotein(a) (Lp(a)) plasma concentrations in patients with ESRD, a patient group with an enormous risk for atherosclerosis. The reported differences in Lp(a) between controls and patients vary from a decrease of 49% to an increase of more than 1,000%. However, data are not consistent, mostly because of problems with statistical analysis, and only limited data are available for patients treated by continuous ambulatory peritoneal dialysis (CAPD). To estimate the significance of Lp(a) in ESRD and to demonstrate the statistical pitfalls concerning Lp(a) in case-control studies, a large multicenter study including 702 patients treated by either hemodialysis (HD) (N = 534) or CAPD (N = 168) was conducted, and results were compared with results from 256 healthy controls. Both patient groups showed significantly elevated Lp(a) levels in comparison with controls: 23.4 +/- 25.0 mg/dL (P < 0.005; HD) and 34.6 +/- 38.4 mg/dL (P < 0.0001; CAPD) versus 18.4 +/- 22.8 mg/dL (controls). CAPD patients showed significantly higher Lp(a) values than did patients treated by HD (P < 0.001). The difference between the two treatment groups possibly reflects an overproduction of Lp(a) to compensate for protein losses in CAPD patients. Both treatment groups included significantly more patients with Lp(a) values greater than the 75th percentile (25.6 mg/dL) of the control group (33.9 and 41.7% for HD and CAPD, respectively; P < 0.005). The higher Lp(a) values in patients were not explained by differences in isoform frequencies and the increase in Lp(a) was apolipoprotein(a) type specific: only patients with high-molecular-weight apolipoprotein(a) isoforms showed a significant elevation in Lp(a) levels. The increased plasma concentrations of Lp(a) may contribute to the high risk for atherosclerosis in ESRD, especially in patients treated by CAPD. Finally, it is believed that small sample sizes are responsible for the diverging results in Lp(a) literature.
Adult↗
Low molecular weight heparin does not necessarily reduce lipids and lipoproteins in hemodialysis patients.
Recent studies have indicated a beneficial effect of one particular low molecular weight heparin preparation (Fragmin) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin. We conducted a prospective crossover study with paired comparison of two different anticoagulant agents to examine the effects of a recently released new low molecular weight heparin (Sandoparin) on lipid and lipoprotein parameters in 24 patients starting hemodialysis. During the first six months of observation patients received Sandoparin. Then patients were switched to unfractionated heparin and observed for further six months. After switching from Sandoparin to unfractionated heparin we observed significant decreases in total cholesterol (from 168.6 +/- 42.2 to 154.4 +/- 41.9 mg/dl, p < 0.02), LDL cholesterol (from 106.4 +/- 35.2 to 89.9 +/- 32.3 mg/dl, p < 0.005), triglycerides (from 148.7 +/- 85.0 to 121.4 +/- 88.8 mg/dl, p < 0.05) and apolipoprotein B (from 100.0 +/- 35.3 to 89.9 +/- 30.4 mg/dl, p < 0.05) and a significant increase in HDL cholesterol (from 32.8 +/- 12.5 to 37.7 +/- 17.5 mg/dl, p < 0.02). This is in contrast to earlier results and can possibly be explained by a higher percentage of fractions with high M(r) in the investigated Sandoparin, which results in a more pronounced depletion of lipoprotein lipase. Together with the enhanced hepatic clearance of lipoprotein lipase induced by low molecular weight heparins, this may decrease lipoprotein lipase activity with a subsequent increase in plasma triglycerides, total and LDL cholesterol. We conclude from our data that a general recommendation for clinical use of low molecular weight heparin in hemodialysis patients cannot be given.
Adult↗
Lipoprotein(a) in renal disease: what we have, what we need, what we can forget.
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Arteriosclerosis↗
Influence of various heparin preparations on lipoproteins in hemodialysis patients: a multicentre study.
Recent studies have indicated controversial effects of low molecular weight heparin (LMWH) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin (UFH). We therefore conducted a cross-sectional multicentre study comparing 153 patients treated with LMWH and 153 patients with UFH, matched for sex, age and diabetes mellitus. Both groups have been treated with LMWH or UFH for six months or longer (14.9 vs. 23.4 months). We observed no differences between the UFH and LMWH treatment groups for total cholesterol, LDL cholesterol, triglycerides, apoB, apoA-IV or Lp(a). The only significant differences were seen for HDL cholesterol and the corresponding apolipoprotein apoA-I, which were significantly higher in the UFH group (HDL cholesterol: 0.97 +/- 0.35 mM/l vs. 0.87 +/- 0.37 mM/l, p < 0.05; apoA-I 1.23 +/- 0.27 g/l vs. 1.15 +/- 0.27 g/l, p < 0.05). We conclude that the results of studies investigating the influence of LMWH on lipid metabolism are as heterogeneous as the substances themselves. This challenges the beneficial influence supposedly had by LMWH preparations on lipid metabolism.
Adult↗
Rehabilitation medicine and alternative therapies: new words, old practices.
"Alternative" medicine is receiving increased interest from the public, the media, government, and academic medical centers. Although currently being defined as encompassing practices outside of the medical mainstream, what are now being called "alternative" therapies have long been used by practitioners of physical medicine and rehabilitation. Recently identified by the National Institutes of Health as a legitimate area for research, alternative medicine is now receiving new sources of funding. Physical medicine and rehabilitation (PM&R) expertise encompasses many of the therapies and health care issues that are being categorized as alternative. Practitioners and researchers in PM&R should seize the opportunity to provide leadership in this emerging area in American medicine.
Complementary Therapies↗
Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.
High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. In the general population, Lp(a) levels are primarily determined by allelic variation at the apolipoprotein(a) [apo(a)] gene locus. Apo(a) isoforms of various sizes are associated with different Lp(a) concentrations. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by the size variation at the apo(a) gene locus. To further investigate the origin of the elevated Lp(a) plasma concentrations, we examined Lp(a) concentrations and apo(a) phenotypes in 154 ESRD patients undergoing renal transplantation. In a prospective longitudinal study we observed a rapid normalization of Lp(a) levels from an average concentration of 25.9 +/- 28.7 mg/dL before to 17.9 +/- 25.5 mg/dL 3 weeks after renal transplantation (P < .0001). Only patients with high-molecular-weight phenotypes had a significant decrease in Lp(a) plasma concentrations. This study demonstrates the nongenetic origin of elevated Lp(a) concentrations in ESRD patients, which is obviously caused by the disease. It further confirms a phenotype-associated elevation of Lp(a) concentrations in ESRD.
Adolescent↗