The PTH (1-84)/non-PTH (1-84) ratio is a risk factor for cardiovascular events in hemodialysis patients.

BACKGROUND: We hypothesized that the PTH (1-84)/non-PTH (1-84) ratio (PTH ratio) might help to assess cardiovascular risk in hemodialysis patients. METHODS: In this prospective cohort study 70 prevalent hemodialysis patients were followed up to 4 years. The PTH ratio was determined at baseline. Primary outcomes were cardiovascular events (CVE) and all-cause mortality. Cumulative event-free survival was compared between patients with a ratio < 1 and those with a ratio > 1. The risk-association of the PTH ratio with CVE was examined using an adjusted Multiple Cox Proportional Hazards model. RESULTS: A PTH ratio > 1 was found in 34 patients (49%). During follow-up 26 patients suffered a CVE. Patients with a CVE showed a higher ratio than patients with event-free survival (p = 0.033). In patients with a ratio > 1 a significantly higher number of CVE occurred (53 vs. 22%; p = 0.013), and these patients showed a significantly shorter event-free survival (p = 0.032). In an adjusted Cox-proportional hazards model a higher PTH ratio was found to be independently associated with an elevated risk for CVE (HR = 3.2; 95% CI 1.06 - 13.63; p = 0.04). CONCLUSIONS: A higher PTH (1-84)/non-PTH (1-84) ratio is associated with an increased risk for CVE in hemodialysis patients and might therefore be useful for cardiovascular risk estimation in this population.

A simple score predicts future cardiovascular events in an inception cohort of dialysis patients.

Vascular calcifications are very common in dialysis patients and have been shown to be associated independently with outcome. However, all of these studies used prevalent patients on dialysis since many years. We investigated vascular calcifications in an inception cohort of dialysis patients and followed them for cardiovascular disease outcomes during an average observation period of 66 months. One hundred and fifty-four Caucasian dialysis patients were enrolled in one Austrian dialysis center. Standardized plain radiographs from the pelvis and calves were carried out in all patients at the start of dialysis therapy. Vascular calcifications were assessed by a single radiologist. At the start of renal replacement therapy, 67.5% of the patients showed vascular calcifications. During follow-up, 29.9% of patients suffered a cardiovascular event. An additive 'vascular risk score', constructed from the presence of vascular calcifications and/or previous cardiovascular events before the start of dialysis treatment, showed the strongest independent association with cardiovascular events in the Cox regression model adjusted for various risk factors. The presence of each of these two conditions was associated with a hazard ratio of 2.03 (95% confidence interval 1.19-3.46) and a hazard ratio twice as high if both conditions were present. In summary, vascular calcifications on plain X-rays of pelvis and calves are largely present in incident dialysis patients. A history of a cardiovascular event in the predialysis period together with vascular calcifications at the beginning of dialysis therapy is a more powerful predictor of a cardiovascular event than age, smoking, diabetes, or other traditional risk factors.

Variable parathyroid hormone(1-84)/carboxylterminal PTH ratios detected by 4 novel parathyroid hormone assays.

AIM: Parathyroidhormone (PTH) measurement is important in the evaluation of bone disease in patients with chronic renal failure. Large carboxyl-terminal PTH fragments (C-PTH) cross-react with second-generation PTH assays, lead to an overestimation of biologically active PTH, and are evaluated by a combination of second- and third-generation PTH assays. The aim of our study was to examine whether the use of 4 different PTH assays of putatively same specificity leads to comparable results detecting C-PTH fragments. SUBJECTS AND METHODS: In 70 chronic dialysis patients, total PTH and PTH(1-84) were measured in parallel by 4 novel PTH assays (Nichols Advantage Intact PTH and Bio-Intact PTH Chemiluminescence Assay, Nichols Institute Diagnostics, USA, DUO Total and CAP PTH IRMA, Scantibodies Laboratory, USA). The C-PTH concentration was quantitated by subtracting PTH(1-84) from total PTH. Consecutively, the PTH(1-84)/C-PTH ratio was calculated. RESULTS: Nichols Intact PTH and DUO Total PTH assays were highly correlated (r = 0.985), as well as Nichols Bio-Intact and DUO CAP assays (r = 0.984). However, total PTH values measured by the Nichols assay were 30% higher (median (range): 185 (9.9 - 2,332) versus 130 (2.3 - 1,271.1) pg/ml, p < 0.01). PTH(1-84) values, measured by the Nichols Bio-Intact PTH assay were 8% higher compared to the Scantibodies CAP assay (median (range): 79.6 (7.5 - 1,060.9) versus 73.7 (4.4 - 918.9) pg/ml, p = NS). Thirty-six patients had a ratio < 1 measured by the Nichols assays, whereas only 8 patients showed the same ratio when measured by the Scantibodies assays. In 28 patients (40%), contradictory PTH(1-84)/C-PTH ratios were found, showing a ratio < 1 when measured by the Nichols assays, but > 1 when the Scantibodies assays were used. CONCLUSION: In conclusion, our results suggest that the PTH(1-84)/C-PTH ratio cannot be equally used as a predictor of bone turnover when different PTH assays are used. Depending on those assays, differences in total PTH values mathematically lead to varying amounts of C-PTH fragments resulting in variable, even contradictory PTH(1-84)/C-PTH ratios.

Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.

BACKGROUND: The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown. METHODS: We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups. RESULTS: Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS. For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups. CONCLUSION: FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.

Proteinuria and plasma total homocysteine levels in chronic renal disease patients with a normal range serum creatinine: critical impact of true glomerular filtration rate.

Conflicting data have been reported concerning the independent association between proteinuria and plasma total homocysteine (tHcy) levels, particularly among chronic renal disease (CRD) patients with a normal range serum creatinine. Studies of this potential relationship have been limited by failure to assess true GFR, failure to assess proteinuria in a quantitative manner, or arbitrary restriction of the range of proteinuria examined. We examined the potential independent relationship between plasma tHcy levels and a wide range of quantitatively determined proteinuria (i.e., 0.000-8.340 g/day), among 109 CRD patients with a normal range serum creatinine (range; 0.8-1.5 mg/dl; median=1.2 mg/dl). Glomerular filtration rate (GFR) was directly assessed by iohexol clearance, and plasma status of folate, pyridoxal 5'-phosphate, and B12, along with serum albumin, were also determined. Linear modeling with ANCOVA revealed that proteinuria was not independently associated with tHcy levels (partial R=0.127; P=0.201), after adjustment for potential confounding by GFR (partial R=0.408; P<0.001), age, sex, plasma B-vitamin status, and serum albumin. Moreover, descending across quartiles (Q) [from Q4 to Q1] of GFR, ANCOVA-adjusted (i.e., for age, sex, and folate status) geometric mean tHcy levels (micromol/l) were significantly increased: tHcy Q4 GFR=9.6; tHcy Q3 GFR=10.5; tHcy Q2 GFR=11.9; tHcy Q4 GFR=14.5; P<0.001 for overall Q difference. We conclude that across a broad spectrum of quantitatively determined proteinuria, after adjustment for true GFR, in particular, there is no independent relationship between proteinuria and tHcy levels among CRD patients with a normal range serum creatinine.

Chronic renal transplantation: a model for the hyperhomocysteinemia of renal insufficiency.

Renal transplant recipients (RTR) are considered representative of patients with chronic renal insufficiency (CRI) in general with respect to both reduced, progressively declining renal function, and increased risk for cardiovascular disease (CVD). In accord with this argument, we hypothesized that total (t) plasma concentrations of the putatively atherothrombotic amino acid homocysteine (Hcy) would be equivalent in RTR and CRI patients with comparable renal function. We determined plasma tHcy, folate, pyridoxal 5'-phosphate, and B12 concentrations, in addition to serum creatinine and albumin concentrations, in 86 chronic, stable RTR, and 238 patients with CRI. Within comparable ranges of serum creatinine (i.e. RTR=0.6-4.2 mg/dl; CRI=0.7-4.1 mg/dl), tHcy concentrations did not differ between the two groups (RTR=15.0 micromol/l; CRI=14.9 micromol/l, P=0.899). ANCOVA revealed that renal function, gauged as a simple creatinine measurement, was the major independent determinant of plasma tHcy concentrations, accounting for approximately 80-90% of the total variability in tHcy predicted by the full model (i.e. full model R(2)) containing, in addition to creatinine, the seven other potential explanatory variables. If controlled trials confirm that tHcy-lowering treatment reduces CVD events rates in RTR, these results should be applicable to CRI patients in general.

[Focal proliferation in reactive hyperplastic parathyroid tissue in end-stage renal failure--implication for autotransplantation after total parathyroidectomy]. / Fokale Proliferationen in reaktiv hyperplastischen Nebenschilddrüsen bei terminaler Niereninsuffizienz-Implikation für die Autotransplantation nach totaler Parathyreoidektomie.

Total parathyroidectomy with simultaneous autotransplantation may be associated with recurrence of graft-dependent hyperfunction due to excessive proliferation. We performed macroscopic tissue selection with a stereomicroscope prior to autotransplantation, which resulted in very low recurrence rates. As this technique greatly depends on experience, we investigated the possibility of additionally using proliferation staining (PCNA, MIB-1) for the detection of dysfunctional tissue. Selected tissue from 26 patients was investigated. Serial sections of freshly removed parathyroid tissue were correlated with their macroscopic appearance, HE and immunohistochemically stained paraffin sections, and with semithin Epon sections. The asymptotic growth mode of clonal proliferating regions was reflected by highest staining intensity (1-5%) in small to medium sized foci (diffuse, up to 3 mm in diameter) and very low staining in large areas (diffuse or nodular, 5-15 mm in diameter, from 0.03 to 0.003% positive cells). Thus, very large dysfunctional regions with (almost) no proliferation could not be detected by this method. However, they were very evident on macroscopic investigation. In conclusion, multiple fulminant recurrence after parathyroidectomy can be prevented by selecting tissue after proliferation staining. This may allow a delayed autotransplantation after total parathyoidectomy for those surgeons lacking experience in macroscopic tissue classification.

[Leptospirosis (Weil's syndrome) with renal failure, severe jaundice, disseminated hemorrhages and xanthopsia]. / Leptospirose mit akutem Nierenversagen, schwerem lkterus, disseminierten Blutungen und Xanthopsie.

We report a case of a 48-year-old man from western Austria with severe leptospirosis. This disease occurs worldwide but predominates in the tropics. The infectious urine of a wide variety of domestic and wild animals mediates transmission of the infection, which characteristically has a biphasic pattern. It begins with the "leptospiraemic phase" with high fever, conjunctival suffusion, muscle pain and headache. Hepatitis, nephritis and haemorrhages may follow. The second "immune phase" has a greater variety of clinical manifestations. Fever and the initial symptoms may recur and the central and peripheral nervous system may be involved. The patient reported showed all major characteristics except conjunctival suffusion. The outcome was favourable despite some conditions with a poor prognosis (jaundice, renal failure, haemorrhages). The extreme severity of jaundice and the xanthopsia (yellow vision) make the case unique.

Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.

The highly atherogenic lipoprotein(a) [Lp(a)] is significantly elevated in patients with renal disease. It is discussed controversially whether Lp(a) concentrations decrease after renal transplantation and whether the mode of immunosuppressive therapy influences the Lp(a) concentrations. In a prospective study the Lp(a) concentrations before and on average 48 months after renal transplantation were measured in 145 patients. The determinants of the relative changes of Lp(a) concentrations were investigated in a multivariate analysis. Patients treated by CAPD showed a larger decrease of Lp(a) than hemodialysis patients, reflecting their markedly higher Lp(a) levels before transplantation. The relative decrease of Lp(a) was higher with increasing Lp(a) concentrations before transplantation in combination with an increasing molecular weight of apolipoprotein(a) [apo(a)]. That means that the relative decrease of Lp(a) is related to the Lp(a) concentration and the apo(a) size polymorphism. With increasing proteinuria and decreasing glomerular filtration rate, the relative decrease of Lp(a) became less pronounced. Neither prednisolone nor cyclosporine (CsA) had a significant impact on the Lp(a) concentration changes. Azathioprine (Aza) was the only immunosuppressive drug which had a dose-dependent influence on the relative decrease of Lp(a) levels. These data clearly demonstrate a decrease of Lp(a) following renal transplantation which is caused by the restoration of kidney function. The relative decrease is influenced by Aza but not by CsA or prednisolone.

The low molecular weight apo(a) phenotype is an independent predictor for coronary artery disease in hemodialysis patients: a prospective follow-up.

Patients with end-stage renal disease treated by hemodialysis have a tremendous risk for cardiovascular complications that cannot be explained by traditional atherosclerosis risk factors. Lipoprotein(a) (Lp(a)), a risk factor for these complications in the general population, is significantly elevated in these patients. In this study, it was determined whether Lp(a) and/or the genetically determined apo(a) phenotype are risk predictors for the development of coronary artery disease in these patients. A cohort of 440 unselected hemodialysis patients were followed for a period of 5 yr independent of the cause of renal disease, duration of preceding treatment, and the preexistence of coronary artery disease at study entry. Coronary events defined as definite myocardial infarction, percutaneous transluminal coronary angioplasty, aortocoronary bypass, or a stenosis >50% in the coronary angiography were the main outcome measure. Sixty-six (15%) of the 440 patients suffered a coronary event during follow-up. In univariate analysis, patients with events were significantly older and showed a trend to lower HDL cholesterol concentrations, and higher apolipoprotein B and Lp(a) concentrations without reaching significance. Apo(a) phenotypes of low molecular weight, however, were significantly more frequent in patients with compared to those without events (43.9% versus 21.9%, P<0.001). The other lipids, lipoproteins, and apolipoproteins were similar in both groups. Multiple Cox proportional hazards regression analysis found age and the apo(a) phenotype to be the best predictors for coronary events during the observation period, independent of whether patients with a preexisting coronary artery disease or an age >65 yr at the study entry or both were excluded from the analysis. Diabetes mellitus was a risk factor only in presence of a low molecular weight apo(a) phenotype. The genetically determined apo(a) phenotype is a strong and independent predictor for coronary events in hemodialysis patients. Apo(a) phenotyping might be helpful to identify hemodialysis patients at high risk for coronary artery disease.

[Intraoperative blood sampling for parathyroid hormone measurement during total parathyroidectomy and autotransplantation in patients with renal hyperparathyroidism]. / Stellenwert der intraoperativen Blutabnahme zur Parathormonbestimmung während totaler Parathyreoidektomie mit Autotransplantation bei Patienten mit renalem Hyperparathyreoidismus.

Normalisation of intact parathyroid hormone serum level confirms sufficient resection of parathyroid tissue after total parathyroidectomy in patients with secondary hyperparathyroidism. The short half-life of the intact parathyroid hormone is such that complete resection may even be confirmed by intraoperative monitoring of the hormone, and operative exploration thus reduced. We tested intact parathyroid hormone serum levels in 9 patients during total parathyroidectomy, preoperatively, after the removal of each gland, after autotransplantation and 1 month postoperatively. The serum levels of the intact parathyroid hormone were significantly reduced after removal of each gland. The total percentage decrement after parathyroidectomy with autotransplantation was 77%. However intact parathyroid hormone levels had normalised in all patients one month after the operation. The absence of perioperative normalisation of intact parathyroid hormone serum levels in our patients cannot be defined as a predictor of incomplete resection in total parathyroidectomy. The definition of an intraoperative cut-off-level concerning the decrement of intact parathyroid hormone levels remains to be proven in further studies.

Angiotensin-converting enzyme gene polymorphism determines the antiproteinuric and systemic hemodynamic effect of enalapril in patients with proteinuric renal disease. Austrian Study Group of the Effects of Enalapril Treatment in Proteinuric Renal Disease.

Angiotensin-converting enzyme (ACE) inhibitors are known to reduce blood pressure and proteinuria in a variety of different glomerular diseases. Nonetheless, a marked interindividual difference in the efficacy of these agents exists. The activity of the ACE and therefore of the renin-angiotensin-aldosterone system (RAAS) has been shown to be under genetic influence. Patients with a deletion genotype at the intron 16 of the ACE gene have been shown to exhibit higher activity of plasmatic ACE when compared to patients with the insertion genotype. We therefore studied prospectively the hemodynamic and antiproteinuric effect of a 6-month therapy with enalapril in patients with biopsy-proven proteinuric glomerular diseases and the DD (n = 10) and ID/II (n = 26) genotype. Although patients with the DD genotype received a slightly higher dose of enalapril, blood pressure and proteinuria did not change significantly. However, both were significantly reduced in the II/ID group after 10 weeks and 6 months of therapy. Creatinine clearance decreased steadily in DD patients. In II/ID patients, creatinine clearance was reduced significantly after 10 weeks of therapy but increased again thereafter and the value at 6 months was again comparable to the one obtained in the DD patients. We conclude from our study that the ACE genotype influences the blood pressure-lowering and antiproteinuric effect of enalapril in patients with proteinuric glomerular disease.

LDL-unbound apolipoprotein(a) and carotid atherosclerosis in hemodialysis patients.

High lipoprotein(a) [Lp(a)] plasma concentrations, which are genetically determined by apo(a) size polymorphism, are directly associated with an increased risk for atherosclerosis. Patients with end-stage renal disease (ESRD), who show an enormous prevalence of cardiovascular disease, have elevated plasma concentrations of Lp(a). In recent studies we were able to show that apo(a) size polymorphism is a better predictor for carotid atherosclerosis and coronary artery disease in hemodialysis patients than concentrations of Lp(a) and other lipoproteins. Less than 5% of apo(a) in plasma exists in a low-density lipoprotein (LDL)-unbound form. This "free" apo(a) consists mainly of disintegrated apo(a) molecules of different molecular weight, ranging from about 125 to 360 kDa. LDL-unbound apo(a) molecules are elevated in patients with ESRD. The aim of this study was therefore to investigate whether the LDL-unbound form of apo(a) contributes to the prediction of carotid atherosclerosis in a group of 153 hemodialysis patients. The absolute amount of LDL-unbound apo(a) showed a trend to increasing values with the degree of carotid atherosclerosis, but the correlation of Lp(a) plasma concentrations with atherosclerosis was more pronounced. In multivariate analysis the two variables were related to neither the presence nor the degree of atherosclerosis. Instead, the apo(a) phenotype took the place of Lp(a) and LDL-unbound apo(a). After adjustment for other variables, the odds ratio for carotid atherosclerosis in patients with a low molecular weight apo(a) phenotype was about 5 (p<0.01). This indicates a strong association between the apo(a) phenotype and the prevalence of carotid atherosclerosis. Finally, multivariate regression analysis revealed age, angina pectoris and the apo(a) phenotype as the only significant predictors of the degree of atherosclerosis in these patients. In summary, it seems that LDL-unbound apo(a) levels do not contribute to the prediction of carotid atherosclerosis in hemodialysis patients. However, this does not mean that "free", mainly disintegrated, apo(a) has no atherogenic potential.

Effect of cyclosporin A in a patient with refractory nephrotic syndrome associated with B chronic lymphocytic leukemia.

We report on a patient with an almost 20-year history of B chronic lymphocytic leukemia (B-CLL). During the last 2 years, the patient developed nephrotic syndrome (NS) due to membranous glomerulonephritis (MN), refractory to standard therapeutic regimens. Neither NS nor B-CLL responded objectively to systemic administration of two different combinations of corticosteroids and alkylating agents (chlorambucil, cyclophosphamide). Third-line therapy with cyclosporin A resulted in reduction of proteinuria and improvement of leukemia. Withdrawal of the drug led to an increase in leukocyte count.

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.

MR imaging in graft-dependent recurrent hyperparathyroidism after parathyroidectomy and autotransplantation.

The purpose of this study was to compare the value of MR imaging versus sonography in the detection of hyperfunctioning transplanted parathyroid tissue. After parathyroidectomy and autotransplantation of parathyroid tissue to the forearm, 14 patients were examined with sonography and MR imaging. Five of these patients had recurrent hyperparathyroidism. In three of these five, sonography found one echolucent nodule. MR imaging in all three patients detected, in addition to this nodule, other small nodules of hyperplastic parathyroid tissue, which were confirmed intraoperatively. In the other two patients, sonographic and MR imaging findings were negative. Further investigations showed that both patients had a fifth parathyroid gland. In the patients without recurrent hyperparathyroidism, sonography showed scar tissue only, whereas MR imaging found some tiny, contrast-enhancing structures in two patients, probably autograft material. MR imaging seems to be more sensitive than sonography in detecting hyperfunctioning autotransplanted parathyroid tissue.

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.

Alpha 1-antitrypsin phenotypes in patients with anti-neutrophil cytoplasmic antibody-positive vasculitis.

1. The genetic background of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis remains largely unknown. Recently a very high prevalence of medium and severe deficiency of alpha 1-antitrypsin was described in a small group of patients with Wegener's granulomatosis and c-ANCA. c-ANCAs are autoantibodies against proteinase 3, and alpha 1-antitrypsin is the main inhibitor of this enzyme. 2. alpha 1-Antitrypsin phenotypic polymorphism was determined by isoelectric focusing in 32 patients with c-ANCA-associated systemic vasculitis. Twenty-nine patients had Wegener's disease, two had microscopic polyarteritis and one suffered from idiopathic rapidly progressive glomerulonephritis. 3. Two patients were homozygous PiZZ and three were heterozygous PiMZ. These phenotype frequencies differed significantly from expected values, assuming Hardy-Weinberg equilibrium (P < 0.01). Compared with a control group of 868 healthy blood donors, these results meant a significant increase in the PiZ allele (0.0138 versus 0.1094, P < 0.001). 4. Furthermore, the serum of 47 patients with severe alpha 1-antitrypsin deficiency (PiZZ) was tested for the presence of ANCA. All sera were negative for c-ANCA and p-ANCA. None of the patients showed clinical signs of systemic vasculitis. 5. In conclusion, these data indicate that alpha 1-antitrypsin deficiency, despite being significantly more common in patients with c-ANCA-associated systemic vasculitis, is only a minor genetic risk factor for the development of this disease.

Apolipoprotein(a) phenotypes predict the risk for carotid atherosclerosis in patients with end-stage renal disease.

Several studies have demonstrated that atherosclerotic complications are the major cause of morbidity and mortality in hemodialysis patients. High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by size variation at the apolipoprotein(a) [apo(a)] gene locus. The aim of our study was to investigate whether Lp(a) concentrations and/or apo(a) phenotypes are predictive of the degree of atherosclerosis in the extracranial carotid arteries in ESRD patients. Of 167 patients, 108 showed atherosclerotic plaques (65%). Univariate analysis showed that the plaque-affected group was significantly older and had a higher frequency of angina pectoris, previous myocardial infarction, or cerebrovascular accident. Furthermore, this group included significantly more patients with low-molecular-weight apo(a) isoforms (26.9% versus 8.5%, P < .005) and had significantly higher mean Lp(a) plasma concentrations (29.3 +/- 31.0 versus 19.7 +/- 25.7 mg/dL, P < .05). Lp(a) plasma concentration increased significantly with the number of affected arterial sites, from 19.7 mg/dL in patients without plaques to 40.1 mg/dL in patients with seven or eight affected sites. In patients with low-molecular-weight phenotypes, significantly more arterial sites were affected (3.62 versus 2.08, P < .001). Multivariate regression analysis showed that age, angina pectoris, and the apo(a) phenotype were the only significant predictors of the degree of atherosclerosis. We conclude that, besides age, the apo(a) phenotype is the best predictor of carotid atherosclerosis in ESRD patients and may be used for assessment of general atherosclerosis risk in this patient group.