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Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Telomere length is considered as a clock mirroring aging and is influenced by oxidative stress and inflammation. Both conditions are highly prevalent in patients with chronic kidney disease and other degenerative disorders, such as cardiovascular disease. However, it is discussed controversially whether short telomeres are causally associated with chronic kidney disease or whether chronic kidney disease is contributing to an attrition of telomere length. Park et al., in this issue of Kidney International, use an extended 2-sample Mendelian randomization analysis with large data sets to shed new light on this research question., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m 2 /year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m 2 at follow-up among those with eGFRcrea 60 mL/min/1.73m 2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., (Copyright © 2020 International Society of Nephrology. All rights reserved.)

Telomere length is known to be inversely associated with aging and has been proposed as a marker for aging-related diseases. Telomere attrition can be accelerated by oxidative stress and inflammation, both commonly present in patients with chronic kidney disease. Here, we investigated whether relative telomere length is associated with mortality in a large cohort of patients with chronic kidney disease stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. Relative telomere length was quantified in peripheral blood by a quantitative PCR method in 4,955 patients from the GCKD study, an ongoing prospective observational cohort. Complete four-year follow-up was available from 4,926 patients in whom we recorded 354 deaths. Relative telomere length was a strong and independent predictor of all-cause mortality. Each decrease of 0.1 relative telomere length unit was highly associated with a 14% increased risk of death (hazard ratio1.14 [95% confidence interval 1.06-1.22]) in a model adjusted for age, sex, baseline eGFR, urine albumin/creatinine ratio, diabetes mellitus, prevalent cardiovascular disease, LDL-cholesterol, HDL-cholesterol, smoking, body mass index, systolic and diastolic blood pressure, C-reactive protein and serum albumin. This translated to a 75% higher risk for those in the lowest compared to the highest quartile of relative telomere length. The association was mainly driven by 117 cardiovascular deaths (1.20 [1.05-1.35]) as well as 67 deaths due to infections (1.27 [1.07-1.50]). Thus, our findings support an association of shorter telomere length with all-cause mortality, cardiovascular mortality and death due to infections in patients with moderate chronic kidney disease., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Recently, 4 new risk scores for the prediction of mortality and cardiovascular events were especially tailored for hemodialysis patients; these scores performed much better than previous scores. Tripepi et al. found that these risk scores were even more predictive for all-cause and cardiovascular death than the measurement of the left ventricular mass index was. Nevertheless, the investigation of left ventricular mass and function has its own place for other reasons., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Bowe et al. report an association between low high-density lipoprotein cholesterol concentrations and various incident chronic kidney disease end points in a cohort of almost 2 million US veterans followed for 9 years. These impressive data should be a starting point for further investigations including genetic epidemiologic investigations as well as post hoc analyses of interventional trials that target high-density lipoprotein cholesterol and, finally, studies that focus on the functionality of high-density lipoprotein particles., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The KDIGO guideline on lipid management in adult patients with chronic kidney disease (CKD) reflects a paradigm shift as proposals for statin use are based on cardiovascular risk rather than cholesterol levels. Statin use is now universally recommended in CKD patients 50 years and older, assuming a 10-year risk of coronary heart disease (CHD) of over 10%. Specific comorbidities or formal risk calculation are required for younger patients. It is unknown to which extent these new guidelines differ from previous practice. Here we analyzed statin use in the German Chronic Kidney Disease study of 5217 adult patients with moderately severe CKD under nephrological care enrolled shortly before publication of the new guideline. Accordingly, 407 patients younger than 50 years would be eligible for statins compared with the 277 patients treated so far, and all 4224 patients 50 years and older would be eligible compared with the 2196 already treated. Overall, guideline implementation would almost double statin prescription from 47 to 88%. Among patients 50 years and older currently not on a statin, an estimated 10-year CHD and atherosclerotic event risks over 10% were present in 68% and 82%, respectively. Thus, implementation of the new lipid guideline requires a substantial change in prescription practice, even in CKD patients under nephrological care. Based on comorbidities and risk estimates, the universal recommendation for statin use in CKD patients 50 years and older appears justified.

Early mortality is high in hemodialysis (HD) patients, but little is known about early cardiovascular event (CVE) rates after HD initiation. To study this we analyzed data in the AROii cohort of incident HD patients from over 300 European Fresenius Medical Care dialysis centers. Weekly rates of a composite of CVEs during the first year and monthly rates of the composite and its constituents (coronary artery, cerebrovascular, peripheral arterial, congestive heart failure, and sudden cardiac death) during the first 2 years after HD initiation were assessed. Of 6308 patients that started dialysis within 7 days, 1449 patients experienced 2405 CVEs over the next 2 years. The first-year CVE rate (30.2/100 person-years; 95% CI, 28.7-31.7) greatly exceeded the second-year rate (19.4/100; 95% CI, 18.1-20.8). Composite CVEs were highest during the first week with increased risk compared with the second year, persisting until the fifth month. Except for sudden cardiac death, temporal patterns of rates for all CVE categories were very similar, with highest rates during the first month and a high-risk period extending to 4 months. Higher or lower cumulative weekly dialysis dose, lower blood flow, and lower net ultrafiltration during dialysis were associated with CVE during the high-risk period, but not during the post high-risk period. Thus, the incidence of CVE in the first weeks after HD initiation is much higher than during subsequent periods which raises concerns that HD initiation may trigger CVEs.

Although mortality risk scores for chronic hemodialysis (HD) patients should have an important role in clinical decision-making, those currently available have limited applicability, robustness, and generalizability. Here we applied a modified Framingham Heart Study approach to derive 1- and 2-year all-cause mortality risk scores using a 11,508 European incident HD patient database (AROii) recruited between 2007 and 2009. This scoring model was validated externally using similar-sized Dialysis Outcomes and Practice Patterns Survey (DOPPS) data. For AROii, the observed 1- and 2-year mortality rates were 13.0 (95% confidence interval (CI; 12.3-13.8)) and 11.2 (10.4-12.1)/100 patient years, respectively. Increasing age, low body mass index, history of cardiovascular disease or cancer, and use of a vascular access catheter during baseline were consistent predictors of mortality. Among baseline laboratory markers, hemoglobin, ferritin, C-reactive protein, serum albumin, and creatinine predicted death within 1 and 2 years. When applied to the DOPPS population, the predictive risk score models were highly discriminatory, and generalizability remained high when restricted by incidence/prevalence and geographic location (C-statistics 0.68-0.79). This new model offers improved predictive power over age/comorbidity-based models and also predicted early mortality (C-statistic 0.71). Our new model delivers a robust and reproducible mortality risk score, based on readily available clinical and laboratory data.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

In this issue of Kidney International, the Dialysis Outcomes and Practice Patterns Study reports that hemodialysis patients with monthly intravenous iron supplementation of 300-399 mg or ⩾400 mg had a 13 or 18% higher risk of dying, respectively, compared with those receiving 100-199 mg per month, with no obvious differences in cause-specific mortalities. This study supports that randomized controlled trials are urgently needed to identify optimized iron supplementation strategies for anemic dialysis patients.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

A-type natriuretic peptide (ANP) and adrenomedullin (ADM) are potent hypotensive, diuretic, and natriuretic peptides involved in maintaining cardiovascular and renal homeostasis. We conducted a prospective 7-year study of 177 nondiabetic patients with primary chronic kidney disease to see if ANP and ADM plasma concentrations predict the progression of their disease, using novel sandwich immunoassays covering the midregional epitopes of the stable prohormones (MRproANP and MR-proADM). Progression of chronic kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure, which occurred in 65 patients. Analysis of the receiver operating characteristic curve for the prediction of renal endpoints showed similar areas under the curve for the glomerular filtration rate (GFR) (0.838), MR-proANP (0.810), and MRproADM (0.876), respectively, as did the Kaplan-Meier curve analyses of the patients stratified according to the median of the respective markers. In separate multiple Cox-proportional hazard regression analyses, increased plasma concentrations of both peptides were each strongly predictive of the progression of chronic kidney disease after adjustments for age, gender, GFR, proteinuria and amino-terminal pro-B-type natriuretic peptide. Our study suggests that MR-proANP and MR-proADM are useful new markers of progression of primary nondiabetic chronic kidney disease.

Progressive renal vascular sclerosis is a key feature of chronic kidney disease (CKD). Adiponectin, an adipokine with potent anti-inflammatory and antiatherosclerotic properties, is associated with insulin resistance, type II diabetes and cardiovascular disease. In this study, we evaluated the predictive value of adiponectin for the progression of CKD in patients enrolled in the Mild to Moderate Kidney Disease Study. The primary end point was defined as a doubling of the baseline serum creatinine and/or terminal renal failure in 177 patients who completed a prospective follow-up of 7 years. Patients who reached a progression endpoint (n=65) were significantly older, had higher baseline serum creatinine, proteinuria and adiponectin concentrations and more components of the metabolic syndrome. A gender-stratified Cox model revealed adiponectin in men as a significant predictor of progression after adjustment for age, glomerular filtration rate, and proteinuria. Male patients with adiponectin levels above their ROC analysis-derived optimal cutoff of 4 microg/ml had a significantly faster progression than patients below this point. This prospective long-term study in patients with CKD indicates high adiponectin as a novel independent predictor of disease progression in men but not in women. Our observation may be relevant for other conditions of progressive vascular sclerosis and diabetic nephropathy.

Lipoprotein(a) (Lp(a)) consists of a low-density lipoprotein-like particle and a covalently linked highly glycosylated protein, called apolipoprotein(a) (apo(a)). Lp(a) derives from the liver but its catabolism is still poorly understood. Plasma concentrations of this highly atherogenic lipoprotein are elevated in hemodialysis (HD) patients, suggesting the kidney to be involved in Lp(a) catabolism. We therefore compared the in vivo turnover rates of both protein components from Lp(a) (i.e. apo(a) and apoB) determined by stable-isotope technology in seven HD patients with those of nine healthy controls. The fractional catabolic rate (FCR) of Lp(a)-apo(a) was significantly lower in HD patients compared with controls (0.164+/-0.114 vs 0.246+/-0.067 days(-1), P=0.042). The same was true for the FCR of Lp(a)-apoB (0.129+/-0.097 vs 0.299+/-0.142 days(-1), P=0.005). This resulted in a much longer residence time of 8.9 days for Lp(a)-apo(a) and 12.9 days for Lp(a)-apoB in HD patients compared with controls (4.4 and 3.9 days, respectively). The production rates of apo(a) and apoB from Lp(a) did not differ significantly between patients and controls and were even lower for patients when compared with controls with similar Lp(a) plasma concentrations. This in vivo turnover study is a further crucial step in understanding the mechanism of Lp(a) catabolism: the loss of renal function in HD patients causes elevated Lp(a) plasma levels because of decreased clearance but not increased production of Lp(a). The prolonged retention time of Lp(a) in HD patients might importantly contribute to the high risk of atherosclerosis in these 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.

Background: Apolipoprotein A-IV (ApoA-IV) is a 46 kD glycoprotein thought to protect against atherosclerosis. It is synthesized primarily in epithelial cells of the small intestine. Elevated plasma concentrations of ApoA-IV in patients with chronic kidney disease suggest that the human kidney is involved in ApoA-IV metabolism., Methods: To investigate whether the human kidney directly metabolizes ApoA-IV and which kidney tissue compartment is involved therein, ApoA-IV was localized by immunohistochemistry in 28 healthy kidney tissue samples obtained from patients undergoing nephrectomy. ApoA-IV mRNA expression was analyzed by real-time polymerase chain reaction (PCR) to exclude de novo synthesis in the kidney., Results: ApoA-IV immunostaining was detected in proximal and distal tubular cells, capillaries and blood vessels but not inside glomeruli. ApoA-IV was predominantly found in the brush border of proximal tubules and in intracellular granules and various plasma membrane domains of both proximal and distal tubules. mRNA expression analysis revealed that no ApoA-IV was produced in the kidney., Conclusion: The immunoreactivity of ApoA-IV observed in kidney tubular cells suggests a direct role of the human kidney in ApoA-IV metabolism. The granular staining pattern probably represents lysosomes degrading ApoA-IV. The additional ApoA-IV localization in distal tubules suggests a rescue function to reabsorb otherwise escaping ApoA-IV in case proximal tubules cannot reabsorb all ApoA-IV. Since no mRNA expression could be detected in any kidney cells, the observed ApoA-IV immunoreactivity represents uptake and not de novo synthesis of ApoA-IV.

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.

Background: The atherogenic serum lipoprotein(a) [Lp(a)] is significantly elevated in patients with nephrotic syndrome. The underlying mechanism for this elevation is poorly understood., Methods: We investigated in 207 patients with nondiabetic nephrotic syndrome and 274 controls whether the apolipoprotein(a) [apo(a)] kringle-IV repeat polymorphism explains the elevated Lp(a) levels in these patients., Results: Patients showed a tremendous elevation of Lp(a) concentrations when compared to controls (mean 60.4 vs. 20.0 mg/dL and median 29.8 vs. 6.4 mg/dL, P < 0.0001). Primary and secondary causes contributed to this elevation. The primary causes became apparent by a markedly elevated number of low-molecular-weight apo(a) phenotypes which are usually associated with high Lp(a) levels. This frequency was 35.7% in patients compared to only 24.8% in controls (P= 0.009). In addition, secondary causes by the pathogenetic mechanisms of the nephrotic syndrome itself resulted in a different increase of Lp(a) in the various apo(a) isoform groups. Based on the measured Lp(a) concentrations in each subject, we calculated separately the Lp(a) concentrations arising from the two expressed isoforms by estimating the relative proportion of the two serum isoforms in the sodium dodecyl sulfate (SDS) agarose gel electrophoresis. Low-molecular-weight isoforms were associated with 40% to 75% elevated Lp(a) concentrations when compared to matched isoforms from controls. High-molecular-weight apo(a) isoforms showed 100% to 500% elevated Lp(a) levels compared to matched isoforms from controls. The severity of the nephrotic syndrome as well as the degree of renal impairment did not influence the Lp(a) concentrations., Conclusion: The tremendously increased Lp(a) levels in nephrotic syndrome ar caused by primary genetic as well as disease-related mechanisms.

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.

Background: The measurement of many parameters of human blood is usually performed in plasma or serum. Since lipoproteins or apolipoproteins, for example, are found almost exclusively in the plasma fraction after low-speed centrifugation, these parameters can be expected to be distributed in a different plasma volume depending on the hematocrit value. Therefore, the measured plasma levels might be relatively too low or too high in comparison to the whole blood concentrations in the case of abnormal hematocrit levels. The aim of our experiments was to evaluate the extent of differences between whole blood and plasma concentrations, taking as an example lipoprotein(a) [Lp(a)] in hemodialysis patients with documented decreased hematocrit values., Methods: Lp(a) was measured in plasma as well as whole blood of 15 hemodialysis patients with low hematocrit values (0.29 +/- 0.02) in comparison to 11 control subjects (0.45 +/- 0.04)., Results: Plasma concentrations were 27% higher in patients than in controls (19.7 vs. 15.5 mg/dl). The relative difference was twice as high (59%) when measured in whole blood (13.5 vs. 8.5 mg/dl). Similar relative differences were observed when whole blood concentrations of 125 hemodialysis patients and 256 controls were calculated with the formula [Lp(a)plasma * (1-hematocrit)]., Conclusions: Our findings clearly demonstrate that hematocrit is a strong confounding variable of lipoprotein measurement in epidemiological studies when concentrations are measured in plasma, especially in cases of abnormal hematocrit values. Furthermore, studies investigating the longitudinal changes of lipoproteins should consider potential hematocrit changes.

Hemodialysis with cuprophane dialyzer membranes promotes rapid activation of the complement system, which is thought to be mediated by the alternative pathway. Complete hereditary deficiency of complement C4, a classical pathway component, in two hemodialysis patients provided the opportunity to investigate a possible role of the classical pathway. In two hemodialysis patients with both C4 isotypes, C4A and C4B, and in one patient with C4B deficiency complement activation occurred immediately after the onset of hemodialysis, with peak levels of C3a and terminal complement complex (TCC) after ten to fifteen minutes. In patients with complete C4 deficiency, C3a and TCC remained unchanged for fifteen minutes and increased thereafter, reaching the highest level after thirty minutes. The leukocyte nadir was also delayed from fifteen to thirty minutes. In vitro incubation of normal, C4A- or C4B-deficient serum with cuprophane caused complement activation after fifteen minutes. In contrast, no activation was observed in sera of four C4-deficient patients. The addition of normal serum or purified human C4 restored the capacity for rapid complement activation. In one patient with severe immunoglobulin deficiency, C3a and TCC levels increased only moderately after 25 minutes of cuprophane dialysis. This patient's serum also exhibited delayed complement activation in vitro, which was normalized after pretreatment of cuprophane with immunoglobulins. Preincubation of normal serum with MgEGTA, a blocker of the classical pathway, inhibited rapid complement activation through cuprophane. As basal levels of C4a are markedly increased in hemodialysis patients (3450 +/- 850 ng/ml) compared to healthy controls (224 +/- 81 ng/ml), no further elevation of C4a was detectable during cuprophane hemodialysis. Incubation of normal serum with cuprophane, however, caused a slight increase in C4a after five minutes. These results indicate that the initial deposition of complement C3b on the cuprophane membrane, necessary for activation of the amplification loop of the alternative pathway, is mediated by the classical pathway C3-convertase C4b2a. We propose an extended concept of complement activation through cuprophane, which is based on four steps: (a) binding of anti-polysaccharide antibodies, (b) classical pathway activation, (c) alternative pathway activation and (d) terminal pathway activation.

Lipoprotein(a) [Lp(a)] and its characteristic glycoprotein apolipoprotein(a) [apo(a)] are risk factors for atherosclerosis in the general population. Patients with renal disease show an elevation of Lp(a). Recent studies have described an arteriovenous difference of Lp(a) in the renovascular bed as well as the plasma-derived fragmented LDL-unbound apo(a) in urine, suggesting that the kidney is involved in the metabolism of Lp(a). We therefore investigated whether patients with chronic renal failure have higher levels of LDL-unbound apo(a) and whether this could account for the increased Lp(a) concentrations in these patients. In addition, we studied the possible generation of apo(a) fragments in vitro by mimicking uremic plasma conditions and by investigating the assembly of Lp(a) in cell culture experiments. Patients treated by hemodialysis (N = 185) and by continuous ambulatory peritoneal dialysis (CAPD; N = 20) had markedly elevated absolute (1.22 +/- 1.55 mg/dl and 2.14 +/- 2.86 mg/dl) as well as relative (7.5% and 7.3%) amounts of LDL-unbound apo(a) in comparison to controls (0.46 +/- 0.48 mg/dl or 4.5%). Following renal transplantation the absolute amount decreased significantly. Lp(a) plasma concentration was the most important determining variable for the absolute amount of LDL-unbound apo(a) and showed a positive correlation in both hemodialysis patients (r = 0.85) and controls (r = 0.92). In vitro experiments demonstrated that "uremization" of plasma samples did not generate a higher amount of LDL-unbound apo(a). Although LDL of renal patients has different chemical and structural properties as compared to control LDL, the extracellular assembly of Lp(a) did not differ between patients and controls. Therefore, the higher amounts of LDL-unbound apo(a) found in renal disease are not caused by an impaired assembly of Lp(a), but rather indicate a catabolic role of the kidney for LDL-unbound apo(a) as was already shown for Lp(a). Despite a small contribution, these elevated levels cannot explain the higher Lp(a) values found in patients with end-stage renal disease.