[Autoimmune diagnostics in nephrology and rheumatology]. / Autoimmundiagnostik in der Nephrologie und Rheumatologie.

Autoimmune diagnostics plays a central role in the detection of various acute and/or chronic diseases in both nephrology and rheumatology, which are associated with high morbidity and mortality if left untreated or not detected in time. Patients are threatened with significant limitations in everyday skills and quality of life due to loss of kidney function and dialysis, immobilizing and destructive joint processes or also significant damage of organ systems. In all of these autoimmune diseases, early diagnosis and treatment is of central importance for the further course and prognosis of disease.Antibodies play an essential role in the pathogenesis of autoimmune diseases. Antibodies are either directed against organ or tissue-specific antigens, such as in primary membranous glomerulonephritis or Goodpasture's syndrome, or they lead to a systemic disease such as systemic lupus erythematosus (SLE) or rheumatoid arthritis.Knowledge of the sensitivity and specificity of antibodies is crucial for the interpretation of antibody diagnostics results. Antibody detection can precede the clinical onset of the disease, and antibody titers often reflect disease activity. However, there are also false positive results. Detection of antibodies in the absence of disease symptoms often leads to uncertainty and unnecessary further diagnostics. Therefore, an unfounded "antibody screening" is not recommended.A rational antibody diagnostics is an integral part of the diagnostics and during treatment of nephrological and rheumatological diseases like glomerulonephrititis, pulmorenal syndrome, SLE and other collagenosis, thrombotic microangiopathy (HUS/TTP) and rheumatoid arthritis.

Impact of first-line use of caplacizumab on treatment outcomes in immune thrombotic thrombocytopenic purpura.

BACKGROUND: The von Willebrand factor-directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety. OBJECTIVES: This study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting. METHODS: We report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls). RESULTS: Caplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%. CONCLUSION: Caplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www. CLINICALTRIALS: gov as #NCT04985318.

Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation.

The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the "calcification blocking factor" (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.

Novel plasma peptide markers involved in the pathology of CKD identified using mass spectrometric approach.

Chronic kidney disease (CKD) may progress to end-stage renal disease (ESRD) at different pace. Early markers of disease progression could facilitate and improve patient management. However, conventional blood and urine chemistry have proven unable to predict the progression of disease at early stages. Therefore, we performed untargeted plasma peptidome analysis to select the peptides involved in progression, which are suitable for long prospective studies in future. The study consists of non-CKD (n = 66) and CKD (n = 106) patients with different stages. We performed plasma peptidomics on these subjects using chromatography and mass spectrometric approaches. Initially, we performed LC-ESI-MS and applied least absolute shrinkage and selection operator logistic regressions to select the peptides that are differentially expressed and we generated a peptidomic score for each subject. Later, we identified and sequenced the peptides with MALDI-MS/MS and also performed univariate and multivariate analyses with the clinical variables and peptidomic score to reveal their association with progression of renal disease. A logistic regression model selected 14 substances showing different concentrations according to renal function, of which seven substances were most likely occur in CKD patients. The peptidomic model had a global P value of < 0.01 with R2 of 0.466, and the area under the curve was 0.87 (95% CI, 0.8149-0.9186; P < 0.0001). The predicted score was significantly higher in CKD than in non-CKD patients (2.539 ± 0.2637 vs - 0.9382 ± 0.1691). The model was also able to predict stages of CKD: the Spearman correlation coefficient of the linear predictor with CKD stages was 0.83 with concordance indices of 0.899 (95% CI 0.863-0.927). In univariate analysis, the most consistent association of peptidomic score in CKD patients was with C-reactive protein, sodium level, and uric acid, which are unanticipated substances. Peptidomic analysis enabled to list some unanticipated substances that have not been extensively studied in the context of CKD but were associated with CKD progression, thus revealing interesting candidate markers or mediators of CKD of potential use in CKD progression management. KEY MESSAGES: • Conventional blood and urine chemistry have proven unable to predict the progression of disease at early stages of chronic kidney disease (CKD). • We performed untargeted plasma peptidome analysis to select the peptides involved in progression. • A logistic regression model selected 14 substances showing different concentrations according to renal function. • These peptides are unanticipated substances that have not been extensively studied in the context of CKD but were associated with CKD progression, thus revealing markers or mediators of CKD of potential use in CKD progression management.

Association of Plasma ß-Amyloid with Cognitive Performance and Decline in Chronic Kidney Disease.

Decreased ß-amyloid (Aß) clearance from the brain has been suggested to contribute to cerebral Aß accumulation in Alzheimer's disease. Based on the idea of a dynamic Aß equilibrium in different body compartments, plasma Aß levels have been investigated as biomarker candidates for preclinical Alzheimer's pathology, yet with inconsistent results. Since the kidneys are involved in Aß elimination from the blood, we evaluated how chronic kidney disease (CKD) affects the association between plasma Aß and cognitive deficits and cognitive decline. In 28 CKD patients, stages 3-5D, and 26 control subjects with comparable vascular risk profile from the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, plasma total Aß was determined with a highly sensitive electrochemiluminescence immunoassay. Cognition was evaluated using a comprehensive battery of ten neuropsychological tests at baseline and 2-year follow-up. Subjects with high plasma Aß level (above median) demonstrated a significantly worse baseline cognitive performance than subjects exhibiting low Aß level (summary score of global cognitive performance at baseline z = -0.46 ± 0.76 vs z = -0.08 ± 0.57, p = 0.045). Cognitive performance moderately decreased over the 2-year follow-up in subjects with high plasma Aß level (Δz = -0.13 ± 0.51), but increased in subjects with low plasma Aß level (Δz = 0.16 ± 0.41, p = 0.023). In linear regression analyses, baseline plasma Aß was significantly associated with cognitive decline both in unadjusted analyses (ß = -0.28, 95% CI = -0.55 to -0.01) and analyses adjusted for age (ß = -0.27, 95% CI = -0.54 to -0.01). Our results suggest the utility of plasma Aß level in predicting cognitive decline in patients suffering from CKD.

Cognitive Performance Is Highly Stable over a 2-Year-Follow-Up in Chronic Kidney Disease Patients in a Dedicated Medical Environment.

BACKGROUND: As kidney and brain functions decline with aging, chronic kidney disease (CKD) and dementia are becoming increasing health burdens worldwide. Among the risk factors for cognitive impairment, CKD is increasingly recognized. The precise impact of CKD on the development of cognitive impairment is poorly understood. METHODS: In the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, which was recruited in a dedicated nephrology department, we examined the 2-year course of cognitive performance in 120 patients (73 patients with CKD stages 3-5D, 47 control patients without CKD with similar vascular risk profile) using a comprehensive battery of 10 neuropsychological tests. RESULTS: Kidney function, vascular risk factors and cognitive performance were highly stable both in CKD and control patients. The summary score of cognitive performance in CKD patients was very similar at baseline (z = -0.63±0.76) and follow-up (z = -0.54±0.79, p = 0.113), as was cognitive performance in control patients (z = -0.01±0.59 and 0.01±0.70, p = 0.862, at baseline and follow-up, respectively). Total serum cholesterol (199.6±36.0 and 186.0±32.9, p = 0.005 in controls; 194.4±46.1 and 181.2±41.2, p = 0.008 in CKD) and common carotid intima-media thickness (0.87±0.18 and 0.84±0.17, p = 0.351 in controls; 0.88±0.21 and 0.82±0.16, p = 0.002 in CKD) moderately but significantly decreased during the follow-up. In multivariable regression analyses, high age (ß = -0.28, 95%CI = -0.48 to 0.08, p = 0.007) predicted decrease in cognitive performance. CONCLUSIONS: In this well-defined cohort receiving state-of-the-art therapy, cognitive performance did not decrease over 2 years. Our data emphasize the aspect of risk factor control, suggesting that dedicated medical care might prevent cognitive decline in CKD patients.

Factors Responsible for Plasma ß-Amyloid Accumulation in Chronic Kidney Disease.

Disturbed brain-to-blood elimination of ß-amyloid (Aß) promotes cerebral Aß accumulation in Alzheimer's disease. Considering that the kidneys are involved in Aß elimination from the blood, we evaluated how chronic kidney disease (CKD) affects plasma Aß. In 106 CKD patients stages 3-5 (including 19 patients on hemodialysis and 15 kidney recipients), 53 control subjects with comparable vascular risk profile and 10 kidney donors, plasma Aß was determined using electrochemiluminescence immunoassay and gel electrophoresis followed by Western blotting. Plasma Aß increased with CKD stage (control = 182.98 ± 76.73 pg/ml; CKD3A = 248.34 ± 103.77 pg/ml; CKD3B = 259.25 ± 97.74 pg/ml; CKD4 = 489.16 ± 154.16 pg/ml; CKD5 = 721.19 ± 291.69 pg/ml) and was not influenced by hemodialysis (CKD5D = 697.97 ± 265.91 pg/ml). Renal transplantation reduced plasma Aß (332.57 ± 162.82 pg/ml), whereas kidney donation increased it (251.51 ± 34.34 pg/ml). Gel electrophoresis confirmed stage-dependent elevation namely of Aß1-40, the most abundant Aß peptide. In a multivariable regression including age, sex, estimated glomerular filtration rate (eGFR), potassium, hemoglobin, urine urea, and urine total protein, the factors eGFR (ß = -0.42, p < 0.001), hemoglobin (ß = -0.17, p = 0.020), and urine protein (ß = 0.26, p = 0.008) were associated with plasma Aß. In a regression including age, sex, eGFR, potassium, hemoglobin and the vascular risk factors systolic blood pressure, smoking, LDL, HDL, HbA1c, body mass index, brain-derived natriuretic peptide and fibrinogen, the factors eGFR (ß = -0.53, p < 0.001), body mass index (ß = -0.17, p = 0.022), and fibrinogen (ß = 0.18, p = 0.024) were associated with plasma Aß. Our results demonstrate a stage-dependent plasma Aß increase that is augmented by loss of glomerulotubular integrity, low body weight, and inflammation, demonstrating a multifaceted role of renal dysfunction in Aß retention.

Identification of the Vasoconstriction-Inhibiting Factor (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the Angiotensin II Type 2 Receptor.

BACKGROUND: The renin-angiotensin system and especially the angiotensin peptides play a central role in blood pressure regulation. Here, we hypothesize that an as-yet unknown peptide is involved in the action of angiotensin II modulating the vasoregulatory effects as a cofactor. METHODS AND RESULTS: The peptide with vasodilatory properties was isolated from adrenal glands chromatographically. The effects of this peptide were evaluated in vitro and in vivo, and the receptor affinity was analyzed. The plasma concentration in humans was quantified in patients with chronic kidney disease, patients with heart failure, and healthy control subjects. The amino acid sequence of the peptide from bovine adrenal glands was HSSYEDELSEVL EKPNDQAE PKEVTEEVSSKDAAE, which is a degradation product of chromogranin A. The sequence of the peptide isolated from human plasma was HSGFEDELSEVLENQSSQAELKEAVEEPSSKDVME. Both peptides diminished significantly the vasoconstrictive effect of angiotensin II in vitro. Therefore, we named the peptide vasoconstriction-inhibiting factor (VIF). The vasoregulatory effects of VIF are mediated by the angiotensin II type 2 receptor. VIF impairs angiotensin II-induced phosphorylation of the p38 mitogen-activated protein kinase pathway but not of extracellular-regulated kinase 1/2. The vasodilatory effects were confirmed in vivo. The plasma concentration was significantly increased in renal patients and patients with heart failure. CONCLUSIONS: VIF is a vasoregulatory peptide that modulates the vasoconstrictive effects of angiotensin II by acting on the angiotensin II type 2 receptor. It is likely that the increase in VIF may serve as a counterregulatory effect to defend against hypertension. The identification of this target may help us to understand the pathophysiology of renal and heart failure and may form a basis for the development of new strategies for the prevention and treatment of cardiovascular disease.

Physical, cognitive and emotional factors contributing to quality of life, functional health and participation in community dwelling in chronic kidney disease.

BACKGROUND: Quality of life (QoL) impairment is a well-known consequence of chronic kidney disease (CKD). The factors influencing QoL and late life functional health are poorly examined. METHODS: Using questionnaires combined with neuropsychological examinations, we prospectively evaluated physical, cognitive, and emotional factors influencing QoL, functional health and participation in community dwelling in 119 patients with CKD stages 3-5 including hemodialysis (61.5±15.7years; 63% men) and 54 control patients of the same age without CKD but with similar cardiovascular risk profile. RESULTS: Compared with control patients, CKD patients showed impairment of the physical component of QoL and overall function, assessed by the SF-36 and LLFDI, whereas disability, assessed by LLFDI, was selectively impaired in CKD patients on hemodialysis. Multivariable linear regressions (forced entry) confirmed earlier findings that CKD stage (ß = -0.24; p = 0.012) and depression (ß = -0.30; p = 0.009) predicted the QoL physical component. Hitherto unknown, CKD stage (ß = -0.23; p = 0.007), cognition (ß = 0.20; p = 0.018), and depression (ß = -0.51; <0.001) predicted disability assessed by the LLFDI, while age (ß = -0.20; p = 0.023), male gender (B = 5.01; p = 0.004), CKD stage (ß = -0.23; p = 0.005), stroke history (B = -9.00; p = 0.034), and depression (ß = -0.41; p<0.001) predicted overall function. Interestingly, functional health deficits, cognitive disturbances, depression, and anxiety were evident almost only in CKD patients with coronary heart disease (found in 34.2% of CKD patients). The physical component of QoL and functional health decreased with age and depressive symptoms, and increased with cognitive abilities. CONCLUSIONS: In CKD, QoL, functional health, and participation in community dwelling are influenced by physical, cognitive, and emotional factors, most prominently in coronary heart disease patients.

Cognitive impairment in chronic kidney disease: clinical findings, risk factors and consequences for patient care.

Cognitive deficits have a high prevalence in elderly patients with chronic kidney disease (CKD). The clinical picture consists of cognitive slowing, executive, memory and language deficits, and is attributed to cerebral white matter disease and clinically often silent brain infarcts. In the meantime, robust evidence exists that low estimated glomerular filtration rate, a measure of CKD severity, predisposes to cognitive deficits, cerebral white matter lesions, and ischemic brain infarcts in addition to demographic factors, vascular risk factors and diseases which also contribute to CKD-related cognitive deficits. In terminal CKD, cerebral blood flow is compromized during hemodialysis sessions, resulting in oxygen desaturation, cognitive deterioration and-in the longer run-brain atrophy. Kidney transplantation improves cognitive deficits in terminal CKD. At all stages, vascular risk factors and associated diseases should stringently be treated according to therapeutic guidelines.

The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease.

Cognitive impairment is a frequent finding in patients with chronic kidney disease (CKD). We examined cognitive performance in a prospective study of 119 patients with CKD stages 3-5 (including dialysis) and 54 control patients of the same age without CKD but with similar vascular risk profiles. Analysis included a comprehensive test battery evaluating memory, information processing speed, executive function, language, and visuoconstructive function, in addition to depression and anxiety. Thirty percent of patients with CKD had cognitive deficits (one or more s.d. below control patient performance). Cognitive deficits (T-value related to published norm values) were mild but significantly decreased to 48.8 in patients with stage 3-5 CKD not requiring hemodialysis and 47.2 in patients with stage 5D disease requiring hemodialysis, compared with 51.5 in control patients. Linear regressions among patients with CKD (forced entry strategy) showed that age (ß=-0.50 per s.d.), HbA1c (ß=-0.18 per s.d.), and fibrinogen (ß=-0.18 per s.d.) predicted cognitive performance. Interestingly, HbA1c discriminated cognition in all age groups, while fibrinogen differentiated cognition particularly in patients over 70 years of age. Thus, our cross-sectional study suggests the severity of cognitive impairment in CKD is mild. As such, longitudinal studies are required to further characterize the role of cognitive deficits in CKD.

Associations of smoking with alterations in renal hemodynamics may depend on sex--investigations in potential kidney donors.

BACKGROUND/AIMS: Cigarette smoking is a risk factor for renal damage, but little is known about subclinical effects of smoking on renal hemodynamics and parameters of renal function in humans. We examined the associations of smoking with systemic and renal hemodynamics and renal function parameters in healthy individuals. METHODS: Data from 196 potential living kidney donors were analysed retrospectively. Mean arterial blood pressure (MAP), effective renal plasma flow (ERPF) and creatinine clearance had been measured. We additionally calculated parameters of renal hemodynamics. Data were analyzed for the effects of smoking and sex dependent on age and MAP. RESULTS: Systemic and renal hemodynamic parameters did not differ between smokers and non-smokers. In non-smokers of both sexes MAP was negatively correlated with ERPF, and higher MAP was associated with increased renal vascular resistance and with afferent arteriolar resistance, with glomerular pressure (PG) remaining constant. However, in male, but not in female smokers, ERPF and PG increased with MAP. A correlation of age with a steeper decline in ERPF in male smokers was lost in multiple regression analysis. CONCLUSIONS: As compared to women, smoking men may exhibit an increased glomerular hydrostatic pressure, which is a known promoter of kidney damage.

Membranoproliferative glomerulonephritis complicating Waldenström's macroglobulinemia.

BACKGROUND: Lymphoproliferative disorders causing paraproteinemia can be associated with various kidney injuries including the deposition of monoclonal immunoglobulins (Ig). A known glomerular manifestation of Waldenström's macroglobulinemia is characterized by prominent intracapillary hyaline thrombi and lack of conspicuous glomerular proliferation. The present case was special in 2 aspects: 1. the diagnosis of glomerulonephritis was unexpected before renal biopsy, 2. the prominent glomerular proliferation paired with large intracapillary hyaline thrombi is uncommon in Waldenström's macroglobulinemia-associated glomerulonephritis. CASE PRESENTATION: A 73-year-old Caucasian woman with a long-standing history of rheumatoid arthritis and Waldenström's macroglobulinemia was admitted for acute renal failure (ARF), which initially was presumed to be the consequence of extrarenal causes. Proteinuria and hematuria were only mild. In renal core biopsy, a membranoproliferative glomerulonephritis (MPGN) and prominent intracapillary hyaline monoclonal IgM thrombi were found in addition to acute tubular necrosis. Of note, the patient's history was positive for purpuric skin changes, suspicious for cryoglobulinemia. However, serological tests for cryoglobulins were repeatedly negative. The ARF resolved before the start of immunomodulatory therapy for Waldenström's macroglobulinemia. CONCLUSION: The presence of MPGN with prominent hyaline thrombi in the context of Waldenström's macroglobulinemia is uncommon and can be oligosymptomatic. We discuss this case in the context of previous literature and classifications suggested for monoclonal Ig-related renal pathologies.

Relationship between magnesium and clinical biomarkers on inhibition of vascular calcification.

BACKGROUND: Arteriosclerosis and cardiovascular disease are strongly associated with vascular calcification. Hyperphosphatemia is an essential risk factor for increased vascular calcification. End-stage renal disease (ESRD) patients could serve as an in vivo model for accelerated calcification. This study focuses on the most likely protective effects of magnesium ion (Mg(2+)) on phosphate-induced vascular calcification ex vivo/in vitro. Furthermore, plasma Mg(2+) concentrations of ESRD and healthy controls were investigated for association with surrogate parameters of vascular calcification in vivo. METHODS: Aortic segments of male Wistar-Kyoto rats were incubated and the phosphate concentration of the medium was elevated. The aortic segments were incubated in the absence and presence of MgCl(2); tissue calcification was quantified by different methods. Serum Mg(2+) concentrations of patients with chronic kidney disease (CKD stage 5; ESRD) and patients without CKD (controls) were associated with carotid intima media thickness (IMT) and aortic pulse wave velocity (PWV) as surrogate parameter for arteriosclerosis and arterial stiffening. RESULTS: Incubation of aortic segments in the presence of ß-glycerophosphate and NaH(2)PO(4) caused an increased tissue Ca(2+) deposition compared to control conditions. This increased amount of Ca(2+) in the aortic rings was significantly decreased in the presence of Mg(2+). In CKD patients, but not in controls, magnesium serum concentration was associated with the IMT of the carotid arteries. In addition, CKD patients with higher magnesium serum concentration had a significantly lower PWV. DISCUSSION AND CONCLUSION: Elevated phosphate concentrations in the culture media induce ex vivo/in vitro medial calcification in intact rat aortic rings in the presence of alkaline phosphatase. Mg(2+) ions reduced ex vivo/in vitro vascular calcification despite increased phosphate concentration. This hypothesis is additionally based on the fact that CKD patients with high Mg(2) serum levels had significantly lower IMT and PWV values, which may result in a lower risk for cardiovascular events and mortality in these patients. Therefore, Mg(2+) supplementation may be an option for treatment and prevention of vascular calcification resulting in a reduction of cardiovascular events in CKD patients.

Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor.

AIM: This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor. METHODS: Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) ). RESULTS: Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONS: Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

Iterative cardiac output measurement for optimizing cardiac resynchronization therapy: a randomized, blinded, crossover study.

BACKGROUND: Many invasive and noninvasive methods have been proposed for guiding optimal programming of cardiac resynchronization therapy (CRT) devices. However, results are not satisfying. Preliminary results suggest that cardiac output (CO) measurements using inert gas rebreathing (IGR) might be an eligible method to tailor atrioventricular (AV) and ventriculo-ventricular (VV) programming. The aims of the present study were: (1) to evaluate whether an optimization of CRT can be obtained by noninvasive CO measurements and (2) to evaluate whether acute hemodynamic improvements obtained by this approach relate into increase in cardiac exercise capacity. METHODS: In 24 patients on CRT, iterative VV- and AV-delay optimization was done using the IGR method. This blinded, randomized, crossover study compared the responses to optimization during two periods: a 4-week optimized and a 4-week standard programming. Exercise capacity after optimization was assessed after each period by New York Heart Association (NYHA) classification, a 6-minute walking test, and quality of life (QoL) questionnaire. RESULTS: CO could be determined by IGR in all patients. The NYHA class decreased by 17.8% (2.8 ± 0.3 vs 2.3 ± 0.4, P < 0.001), the mean (± standard deviation) distance walked in 6 minutes was 9.3% greater after optimization (456 ± 140 m vs 417 ± 134 m, P < 0.001), and the QoL improved by 14.5% (41.8 ± 10.4 vs 36.5 ± 9.5, P < 0.001). The portion of responders to CRT increased from 66.5% to 87.5%. CONCLUSION: CRT optimization by iterative CO measurements leads to an increase in CO and an improvement of exercise capacity. Our results suggest that this method might become an important additive tool to adjust CRT programming.

Avosentan reduces albumin excretion in diabetics with macroalbuminuria.

Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory, antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER 0.2 to 5.6 mg/min), and BP <180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo, in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean relative UAER (-16.3 to -29.9%) compared with placebo (35.5%). Median relative UAER decreased with all avosentan dosages (-28.7 to -44.8%) compared with placebo (12.1%). Creatinine clearance and BP were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (>/=25 mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%) patients experienced adverse events that led to withdrawal from study medication. In summary, the endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER in patients with diabetic nephropathy and macroalbuminuria.

Cardiac adrenoceptors: physiological and pathophysiological relevance.

At present, nine adrenoceptor (AR) subtypes have been identified: alpha(1A)-, alpha(1B)-, alpha(1D)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, beta(2)-, and beta(3)AR. In the human heart, beta(1)- and beta(2)AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in betaAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, betaAR are chronically (over)stimulated, and that results in beta(1)AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of beta(2)AR in CHF? What is the role of increases in cardiac G(i)-protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does betaAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of beta(1)- and beta(2)AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, betaAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and/or might influence progression of disease. Furthermore, betaAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a beta(1)AR polymorphism (the Arg389Gly beta(1)AR) may affect the response to betaAR-blocker treatment.