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Karl Lhotta

Publications and source records attributed to Karl Lhotta.

31 records · Page 2Linked to original sources
PubMed2004

Lipoprotein(a)- and low-density lipoprotein-derived cholesterol in nephrotic syndrome: Impact on lipid-lowering therapy?

BACKGROUND: Patients with nephrotic syndrome have the highest lipoprotein(a) [Lp(a)] concentrations known. Lp(a) is an low-density lipoprotein (LDL)-like particle consisting of 45% cholesterol. The usual methods to determine LDL cholesterol do not distinguish between cholesterol derived from LDL and Lp(a) and are thus the net result of cholesterol levels from both lipoproteins. High Lp(a) concentrations therefore significantly contribute to the measured or calculated LDL cholesterol levels. Since statins have no influence on Lp(a) levels, it can be expected that the LDL cholesterol-lowering effect of statins may be diminished in patients who have a pronounced elevation of Lp(a) levels accompanied by only moderate elevations of LDL cholesterol. METHODS: We investigated 207 patients with nondiabetic nephrotic syndrome in whom Lp(a) concentrations were strikingly elevated when compared to 274 controls (60.4 +/- 85.4 mg/dL vs. 20.0 +/- 32.8 mg/dL, P < 0.0001). RESULTS: According to National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Managing Dyslipidemias, almost 95% of these patients are candidates for a therapeutic intervention to lower LDL cholesterol. LDL cholesterol levels corrected for Lp(a)-derived cholesterol, however, were 27 mg/dL lower than uncorrected concentrations (compared to only 9 mg/dL in controls). If Lp(a)-corrected levels instead of total LDL cholesterol levels were used, 25.7% of patients with low-molecular-weight (LMW) apolipoprotein(a) [apo(a)] isoforms were classified no longer to be in need of LDL cholesterol-lowering therapeutic intervention compared to only 2.3% of patients with high-molecular-weight (HMW) apo(a) phenotypes (P < 0.00001). This ("pseudo") pharmacogenetic effect results in incorrect determination of LDL cholesterol. CONCLUSION: Our observation has an impact on the indication for, and assessment of efficacy of intervention. This potential artifact should be investigated in ongoing large trials in renal patients as well as in nonrenal African American subjects who have on average markedly higher Lp(a) levels. In nonrenal Caucasian subjects with much lower Lp(a) concentrations, this issue will be less relevant.

Adult↗
PubMed2004

The intricate role of complement component C4 in human systemic lupus erythematosus.

It was observed about 50 years ago that low serum complement activity or low protein concentrations of complement C4 concurred with disease activities of systemic lupus erythematosus (SLE). Complete deficiencies of complement components C4A and C4B, albeit rare in human populations, are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds. However, whether heterozygous or partial deficiency of C4A (C4AQ0) or C4B (C4BQ0) is a predisposing factor for SLE has been a highly controversial topic. In this review we critically analyzed past epidemiologic studies on deficiency of C4A or C4B in human SLE. Cumulative results from more than 35 different studies revealed that heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from almost all ethnic groups or races investigated, which included northern and central Europeans, Anglo-Saxons, Caucasians in the US, African Americans, Asian Chinese, Koreans and Japanese. In addition, French SLE and control populations had relatively low frequencies of C4AQ0, but the difference between the patient and control groups was statistically significant. The relative risk of C4AQ0 in SLE varied between 2.3 and 5.3 among different ethnic groups. In Caucasian and African SLE patients, the two major causes for C4AQ0 are (1) the presence of a mono-S RCCX (RP-C4-CYP21-TNX) module with a single, short C4B gene in the major histocompatibility complex; and (2) a 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant C4A gene. Both mono-S structures and 2-bp insertion in exon 29 are absent or extremely rare in the C4AQ0 of Oriental SLE patients. The highly significant association of C4AQ0 with SLE across multiple HLA haplotypes and ethnic groups, and the presence of different mechanisms leading to a C4A protein deficiency among SLE patients suggested that deficiency or low expression level of C4A protein is a primary risk factor for SLE disease susceptibility per se. On the other hand, Spanish, Mexican, Australian Aborigine SLE patients had increased frequencies of C4B deficiency instead of C4A deficiency. Such observations underscore the importance of both C4A and C4B proteins in the fine control of autoimmunity. Different racial and genetic backgrounds could change the thresholds for the requirement of C4A or C4B protein levels in immune tolerance and immune regulation. Most past epidemiological studies of C4 in human SLE did not consider the polygenic and gene size variations of C4A and C4B. In addition, many studies were overly dependent on phenotypic observations or methods that did not distinguish differential C4A and C4B protein expression caused by unequal gene number or different gene size from the absence of a functional C4A or C4B gene. For further longitudinal studies on clinical manifestations of SLE, it would be informative to stratify the patients with accurately defined C4A and C4B genotypes. Likewise, elucidation of epistatic genetic factors interacting with C4AQ0 would provide important insights into the intricate roles of C4 in SLE disease susceptibility and pathogenesis.

Alleles↗
PubMed2004

Neutrophil transmigration in renal proximal tubular LLC-PK1 cells.

BACKGROUND/AIMS: Adhesion of intratubular leukocytes to proximal tubules in biopsies of patients with rapidly progressive glomerulonephritis and the appearance of leukocytes in the urine in interstitial nephritis suggest interactions between leukocytes and tubular epithelia in renal disease. The present study was performed to investigate whether incubation of tubular epithelia with cytokines or endotoxin (LPS) does stimulate adhesion and migration of leukocytes through these epithelia in vitro. METHODS: Experiments determined adhesion of PMN to LLC-PK cells cultured on tissue culture plates and transepithelial migration (TEM) through LLC-PK monolayers cultured on microporous membranes. Measurements of transepithelial electrical resistance (TER), cytokine release into apical or basolateral compartments and chemotactic activities of apical and basolateral supernatants were performed. RESULTS: Preincubation of LLC-PK cells with either TNFalpha or LPS resulted in stimulation of PMN adhesion and consequently PMN migration through LLC-PK monolayers in both apical-to-basolateral and basolateral-to-apical direction. TEM was not associated with a reduction of TER. Although largely apical IL-8 secretion by LLC-PK cells was found, apical-to-basolateral migration occurred against a concentration gradient of IL-8 and could not be inhibited by IL-8 antibodies. Chemotactic activities of supernatants were slightly increased by TEM but did not show any significant differences between apical and basolateral compartments independent of the direction of PMN migration. TEM in basolateral-to-apical direction was about twice as efficient as in apical-to-basolateral direction (Transmigration Index = 3,92 +/- 0,55 and 2,28 +/-,21, respectively). Only basolateral-to-apical TEM could be partly inhibited by preincubation of basolateral membrane with IL-8 antibodies. CONCLUSION: Inflammatory mediators stimulate PMN adherence to LLC-PK cells and subsequently TEM. The mechanisms involved in TEM stimulated by cytokines or endotoxin appear to be rather changes in surface receptor properties of LLC-PK cells than chemotactic stimuli. Basolateral-to-apical TEM appears to be the favored direction most likely augmented by IL-8 associated haptotactic PMN stimulation.

Animals↗
PubMed2003

Flow cytometry based detection of HLA alloantibody mediated classical complement activation.

Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) testing is used to assess recipient presensitization and post-transplant alloantibody formation in transplant recipients. However, CDC test results can be affected by false-positive reactions brought about by autoantibodies or antilymphocyte reagents. As an alternative to the CDC-PRA assay, detection of HLA alloantibodies using HLA antigen-coated microbeads (FlowPRA test) was recently established. FlowPRA testing, however, does not distinguish between (presumably more harmful) complement-fixing and noncomplement-fixing alloantibodies. In this study, we established a novel assay allowing flow cytometric detection of HLA alloantibody dependent classical complement activation using the FlowPRA test. For the detection of complement activation, FlowPRA beads were incubated with sera from highly sensitized dialysis patients (CDC-PRA reactivity >60%) and then stained for C4 (C4d, C4c) and C3 (C3d, C3c) fragments, as well as C1q deposition using indirect immunofluorescence. We demonstrate alloantibody induced induction of C4 fragment, and in parallel C1q deposition to HLA class I or class II beads. As shown by immunoblotting, C4 staining was not due to the presence of preformed C4 fragment-IgG/M complexes. Indeed, C4 fragment deposition in our in vitro system was demonstrated to result from de novo complement activation. First, inactivation of C4 by treatment of sera with methylamine, which inhibits cleavage of the internal thioester, completely abolished C4 fragment deposition. Second, C4 fragment deposition was not observed in the evaluation of C4-free immunoadsorption eluates obtained from highly sensitized dialysis patients. After supplementation with complement, however, eluates induced C4 deposition. Deposition of C4 split products and C1q was temperature-dependent with maximum binding after incubation at 4 degrees C for 60 min. In contrast, maximum C3 fragment deposition was found at 37 degrees C. At this temperature, C3 deposition occurred in an alloantibody and C4-independent fashion, presumably as a result of alternative complement activation. In summary, we describe a novel cell-independent and easy-to-perform PRA test that permits flow cytometry based detection of alloantibody induced classical complement activation. Future studies will have to evaluate its possible relevance as an alternative to CDC-PRA testing in clinical transplantation.

Case-Control Studies↗
PubMed2003

Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation.

The atherogenic lipoprotein(a) (Lp(a)) is significantly increased in patients with kidney disease. Some studies in hemodialysis patients described this increase to be dependent on the genetic apolipoprotein(a) (apo(a)) isoforms. Only patients who express high molecular weight (HMW) apo(a) isoforms but not those with low molecular weight (LMW) isoforms show a relative increase of Lp(a) when compared to healthy controls matched for apo(a) isoforms. However, this was not confirmed by all studies. We therefore prospectively investigated the changes of Lp(a) deriving from each apo(a) isoform in heterozygotes following kidney transplantation. Lp(a) concentrations were measured by ELISA. To calculate the isoform-specific concentrations and the changes of Lp(a) deriving from each isoform, we densitometrically scanned the apo(a) bands from immunoblots before and after transplantation in 20 patients expressing two apo(a) isoforms. Of these, 10 patients expressed both an LMW and an HMW apo(a) isoform. The other 10 patients expressed only HMW isoforms. Densitometric scanning of apo(a) bands and calculation of isoform-derived Lp(a) concentrations clearly demonstrated that the decrease of Lp(a) following kidney transplantation is caused by changes in the expression of HMW apo(a) isoforms. In some patients, we observed an almost complete disappearance of the HMW apo(a) isoform after transplantation. This study clearly demonstrates that the changes of Lp(a) plasma concentrations in kidney disease depend on the genetically determined size of apo(a). This provides evidence for an interaction of apo(a) genetic variability and kidney function on Lp(a) concentrations.

Adult↗
PubMed2003

Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients.

BACKGROUND: Dyslipidemic factors obviously contribute to the high cardiovascular risk in dialysis patients but are often an underestimated problem. Therefore, we determined the prevalence of dyslipidemic factors in a large group of unselected hemodialysis (N = 564) and CAPD (N = 168) patients. METHODS: We used the recently published recommendations of the Medical Experts Group concerning cardiovascular risk factors for the categorization of dyslipidemic factors. These were total cholesterol>200 mg/dL, low-density lipoprotein (LDL) cholesterol>100 mg/dL, high-density lipoprotein (HDL) cholesterol <40 mg/dL, triglycerides>180 mg/dL, and Lp(a)>30 mg/dL. RESULTS: CAPD patients had, in sum, a markedly worse lipid profile when compared with HD patients. They had higher frequencies of elevated total cholesterol (67% vs. 34%), triglycerides (47% vs. 28%), and Lp(a) concentrations (37% vs. 30%) when compared with HD patients. In both patient groups, about two thirds of the patients had LDL cholesterol above 100 mg/dL and HDL cholesterol below 40 mg/dL. When we analyzed the total frequency of dyslipidemic factors, we observed that the CAPD group included a markedly higher number of patients with three or four concurrent dyslipidemic factors than HD patients (P < 0.001). Furthermore, we analyzed apolipoprotein A-IV (apoA-IV), which was recently shown to be associated with cardiovascular disease, and which was about twice as high in both patient groups when compared with controls (P < 0.001). CONCLUSIONS: Dyslipidemic risk factors are highly prevalent in dialysis patients, and the concomitant occurrence of several risk factors in a given patient is more often observed in CAPD than HD patients.

Adult↗
PubMed2003

Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.

Familial juvenile hyperuricemic nephropathy (FJHN), which is inherited as an autosomal dominant disorder, is characterized by hyperuricemia, a low fractional renal excretion of urate, and chronic renal failure that is associated with interstitial fibrosis. Studies in 4 families (3 European and 1 Japanese) have mapped the gene causing autosomal dominant FJHN to chromosome 16p11-p13. To refine this location we have pursued linkage studies in 7 European families with autosomal dominant FJHN and used 11 chromosome 16p11-p13 polymorphic loci whose order has been established as 16pter-D16S3069-D16S3060-D16S3041-D16S3036-D16S3046-[D16S403,D16S417]-D16S420-D16S3113-D16S401-D16S3133-16cen. Cosegregation between these polymorphic loci and FJHN was observed in 5 of the families, and linkage was established between FJHN and 6 loci (peak LOD score, 5.32 with D16S417, at 0% recombination), with the most likely location of FJHN being within a 22-centimorgan interval flanked centromerically by D16S401 and telomerically by D16S3069. Furthermore, FJHN in 2 families was found not to be linked to chromosome 16p11-p13, thereby demonstrating genetic heterogeneity. Thus, 5 additional families with FJHN showing linkage to chromosome 16p11-p13 loci have been identified, and genetic heterogeneity has been demonstrated in more than 25% of FJHN families. These results will facilitate the characterization of this gene regulating urate metabolism.

Child↗
PubMed2002

Cigarette smoking and vascular pathology in renal biopsies.

BACKGROUND: In recent years cigarette smoking has been identified as a progression factor in chronic nephropathies such as glomerulonephritis or diabetic nephropathy. The exact pathomechanism of nicotine-induced renal damage is, however, unknown. Autopsy studies and functional investigations suggest that the renal vasculature is primarily affected by smoking. METHODS: Renal vascular pathology, that is, glomerulosclerosis, hyalinosis of arterioles and myointimal hyperplasia of small arteries, was determined in 135 biopsies of patients over thirty years of age. A questionnaire about smoking habits was returned by 107 of the patients. For glomerular sclerosis the percentage of sclerotic glomeruli was determined, whereas arteriolar hyalinosis and myointimal hyperplasia of small arteries were described as present or absent without further quantification. A univariate analysis was performed for existence of vascular changes and ever-smoking status. In addition, a multivariate analysis for glomerular sclerosis and logistic regression analysis for arteriolar hyalinosis and myointimal hyperplasia and the variables ever-smoking, age, body mass index, creatinine clearance, blood pressure and lipids were performed. RESULTS: Creatinine clearance was comparable for nonsmokers, ex-smokers and smokers. Frequency of myointimal hyperplasia of small arteries was twice as high in ever-smokers as compared to nonsmokers (50% vs. 25.5%, P < 0.01). Arteriolar hyalinosis was detected in 23.5% of nonsmokers and in 35.7% of smokers, showing a trend toward hyalinosis in ever-smokers (P=0.20). Glomerular sclerosis was found in 62.7% of nonsmokers and in 69.6% of ever-smokers. Logistic regression analysis confirmed an association between ever-smoking and myointimal hyperplasia (P < 0.01). This association also was present in males and patients over fifty years of age, but not in younger patients and females. CONCLUSION: In patients with renal, especially glomerular disease, cigarette smoking exhibits its deleterious effect on the kidneys primarily through damage of small interlobular arteries.

Adult↗
PubMed2002

Apolipoprotein A-IV serum concentrations are elevated in patients with mild and moderate renal failure.

Cell culture studies and investigations in mice that overexpress either human or mouse apolipoprotein A-IV (apoA-IV) revealed anti-atherogenic properties of apoA-IV. An association between low apoA-IV concentrations and coronary artery disease in humans was demonstrated; therefore, apoA-IV may also play an antiatherogenic role in humans. Because apoA-IV is markedly elevated in dialysis patients, patients with the earliest and modest stages of renal impairment were studied to assess the association of apoA-IV with GFR and atherosclerotic complications. GFR was measured by the use of iohexol in 227 non-nephrotic patients with different degrees of renal impairment. ApoA-IV increased significantly with decreasing GFR and was already elevated in earliest stages of renal disease (GFR > 90 ml/min per 1.73 m2). Multiple linear regression analysis identified renal function parameters (GFR, creatinine, and urea) as the most important determinants of apoA-IV levels in serum of these patients. Twenty-six patients had already experienced 36 atherosclerotic events. Logistic regression analysis identified three variables associated with atherosclerotic complications: age, apoA-IV, and gender. Each 1 mg/dl increase of apoA-IV decreased the odds ratio for an atherosclerotic complication by 8% (P = 0.011). The data clearly show that the anti-atherogenic apoA-IV starts to increase during the earliest phases of renal insufficiency, which makes apoA-IV an early marker of renal impairment.

Adult↗
PubMed2002

Beyond hepatorenal syndrome: glomerulonephritis in patients with liver disease.

Liver disease is frequently associated with renal abnormalities. In liver cirrhosis, impaired hepatic clearance of immune complexes leads to their trapping in the kidney, causing the lesions of hepatic immunoglobulin A (IgA) nephropathy and hepatic glomerulosclerosis. Chronic hepatitis C virus (HCV) infection can induce cryoglobulinemia type II with membranoproliferative glomerulonephritis, whereas chronic hepatitis B virus (HBV) infection may cause membranous nephropathy, or, more rarely, polyarteritis nodosa. Treatment aims at eliminating the viral infection, in HCV infection with interferon alfa and ribavirin and in HBV infection with interferon alfa or lamivudine. Short-term immunosuppressive treatment may be indicated in patients with severe inflammation. In alpha1-antitrypsin deficiency with liver disease a membranoproliferative type of glomerulonephritis can occur. In addition, partial or complete deficiency is frequently observed in patients with c-ANCA-positive systemic vasculitis.

Glomerulonephritis↗
PubMed2000

Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.

High lipoprotein(a) (Lp(a)) serum concentrations and the underlying apolipoprotein(a) (apo(a)) phenotypes are risk factors for cardiovascular disease in the general population as well as in patients with renal disease. Lp(a) concentrations are markedly elevated in patients with end-stage renal disease. However, nothing is known about the changes of Lp(a) depending on apo(a) size polymorphism in the earliest stages of renal impairment. In this study, GFR was measured by iohexol technique in 227 non-nephrotic patients with different degrees of renal impairment and was then correlated with Lp(a) serum concentrations stratified according to low (LMW) and high (HMW) molecular weight apo(a) phenotypes. Lp(a) increased significantly with decreasing GFR. Such an increase was dependent on apo(a) phenotype. Only renal patients with HMW apo(a) phenotypes expressed higher median Lp(a) concentrations, i.e., 6.2 mg/dl at GFR >90 ml/min per 1.73 m2, 14.2 at GFR 45 to 90 ml/min per 1.73 m2, and 18.0 mg/dl at GFR <45 ml/min per 1.73 m2. These values were markedly different when compared with apo(a) phenotype-matched control subjects who had a median level of 4.4 mg/dl (ANOVA, linear relationship, P < 0.001). In contrast, no significant differences were observed at different stages of renal function in patients with LMW apo(a) phenotypes when compared with phenotype-matched control subjects. The elevation of Lp(a) was independent of the type of primary renal disease and was not related to the concentration of C-reactive protein. Multiple linear regression analysis found that the apo(a) phenotype and GFR were significantly associated with Lp(a) levels. Non-nephrotic-range proteinuria modified the association between GFR and Lp(a) levels. In summary, an increase of Lp(a) concentrations, compared with apo(a) phenotype-matched control subjects, is seen in non-nephrotic patients with primary renal disease even in the earliest stage when GFR is not yet subnormal. This change is found only in subjects with HMW apo(a) phenotypes, however.

Adult↗
PubMedDate not supplied

Late referral defined by renal function: association with morbidity and mortality.

BACKGROUND: Many patients with chronic renal failure are referred very late to nephrology units. Late referral (LR) is reported to be associated with increased morbidity and mortality. METHODS: We used glomerular filtration rate (GFR) at the first visit to a nephrologist to define early referral (ER) and LR in a retrospective analysis. Patients admitted with a GFR < 20 mL/min/1.73 m2 were classified as LR. The 75 patients with chronic renal failure beginning renal replacement therapy (RRT) at Innsbruck University Hospital between January 1999 and October 2000 were included. Patient characteristics were compared between the two groups. Survival analysis until the end of 2002 was carried out using Cox's proportional hazard model. To identify the influence of comorbidity on mortality a comorbidity score was applied. RESULTS: Thirty-three patients were classified as ER and 42 patients as LR. Diabetic nephropathy was more frequent in the LR group (18 vs. 6 patients, p = 0.005). ER patients were significantly younger (53 +/- 16 yrs) as compared to LR patients (62 +/- 14 yrs, p = 0.012). Comorbid conditions were more frequent in the LR group (comorbidity score 1.5 +/- 1.3 for LR and 0.7 +/- 1.1 for ER, p = 0.003). During follow-up, 27 patients died, 19 from the LR group and 8 from the ER group. In the univariate analysis, comorbidity score (p < 0.001) and age (p = 0.017) were significantly associated with mortality, whereas LR patients demonstrated higher mortality (p = 0.076). By multivariate analysis the comorbidity score (p < 0.001) only was associated with mortality within at least 2 yrs of RRT. CONCLUSION: Over half of the patients with end-stage renal disease (ESRD) were referred too late, with a GFR < 20 mL/min/1.73 m2. Mortality during the 1st 2 yrs on RRT was mainly determined by comorbidity, acquired during the course of chronic renal failure. In comparison, the negative impact of LR seems to be minor and requires a larger sample size to be demonstrated.

Diabetic Nephropathies↗