[Coronavirus disease 2019 pandemic from a nephrological perspective]. / "Coronavirus-disease-2019"-Pandemie aus nephrologischer Perspektive.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has also resulted in substantial challenges for nephrology worldwide. Patients with chronic kidney diseases are a particularly vulnerable patient group in this context and in severe courses of COVID-19 the kidneys are most frequently affected by organ failure after the lungs. MATERIAL AND METHODS: In order to reliably evaluate the prevalence and mortality of dialysis patients in Germany with respect to COVID-19, during the first wave in spring 2020 the German Society of Nephrology implemented a registry for dialysis patients. Weekly data on the number and course of dialysis patients affected by COVID-19 were recorded and analyzed. RESULTS: The prevalence of COVID-19 in dialysis patients in Germany developed in two waves, similar to the course of the pandemic in the general population. In spring the prevalence in dialysis patients reached 1.4% and considerably declined during the summer. In December during the second wave of the pandemic the prevalence again rose to 1.9%, despite comprehensively implemented hygiene measures in dialysis centers. Similar to other industrial nations, dialysis patients in Germany also showed a very high lethality of COVID-19 of up to 20%. CONCLUSION: Immediate consequences for hygiene measures in dialysis institutions as well as vaccination strategies and vaccination prioritization for this patient group and the personnel treating them can be derived from the high mortality in dialysis patients. A consequence of the frequent involvement of the kidneys during infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients who had not previously suffered from advanced kidney disease should be the consistent nephrological aftercare.

Exofacial phospholipids at the plasma membrane: ill-defined targets for early infection processes.

The eukaryotic plasma membrane (PM) consists largely of phospholipids and proteins, and separates the intracellular compartments from the extracellular space. It also serves as a signaling platform for cell-to-cell communication and an interaction platform for the molecular crosstalk between pathogens and their target cells. Much research has been done to elucidate the interactions between pathogens and host membrane proteins. However, little is known about the interactions between pathogens and membrane phospholipids, although reports have described a contribution of phospholipids to cell recognition and/or invasion during early infection by diverse pathogens. Thus, during adhesion to the host cell, the obligate intracellular bacterial pathogens Chlamydia spp., the facultative intracellular pathogen Helicobacter pylori and the facultative aerobic pathogen Vibrio parahaemolyticus, interact with exofacial phospholipids. This review focuses on several prominent instances of pathogen interaction with host-cell phospholipids.

The novel chlamydial adhesin CPn0473 mediates the lipid raft-dependent uptake of Chlamydia pneumoniae.

Chlamydiae are Gram-negative, obligate intracellular pathogens that pose a serious threat to public health worldwide. Chlamydial surface molecules are essential for host cell invasion. The first interaction with the host cell is thereby accomplished by the Outer membrane complex protein B (OmcB) binding to heparan sulfate moieties on the host cell surface, followed by the interaction of the chlamydial polymorphic membrane proteins (Pmps) with host cell receptors. Specifically, the interaction of the Pmp21 adhesin and invasin with its human interaction partner, the epidermal growth factor receptor, results in receptor activation, down-stream signalling and finally internalization of the bacteria. Blocking both, the OmcB and Pmp21 adhesion pathways, did not completely abolish infection, suggesting the presence of additional factors relevant for host cell invasion. Here, we show that the novel surface protein CPn0473 of Chlamydia pneumoniae contributes to the binding and invasion of infectious chlamydial particles. CPn0473 is expressed late in the infection cycle and located on the infectious chlamydial cell surface. Soluble recombinant CPn0473 as well as rCPn0473-coupled fluorescent latex beads adhere to human epithelial HEp-2 cells. Interestingly, in classical infection blocking experiments pretreatment of HEp-2 cells with rCPn0473 does not attenuate adhesion but promotes dose-dependently internalization by C. pneumoniae suggesting an unusual mode of action for this adhesin. This CPn0473-dependent promotion of infection by C. pneumoniae depends on two different domains within the protein and requires intact lipid rafts. Thus, inhibition of the interaction of CPn0473 with the host cell could provide a way to reduce the virulence of C. pneumoniae.

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

BACKGROUND: Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. METHODS: Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. RESULTS: Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. CONCLUSIONS: Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients.

Effects of citrate dialysate in chronic dialysis: a multicentre randomized crossover study.

BACKGROUND: Although citrate dialysate (CiDi) is regarded to be safe, dialysis modalities using higher dialysate volumes, like haemodiafiltration (HDF), may expose patients to higher citrate load and thus increase the risk of complications. We investigated the residual risk of CiDi compared with standard dialysate (StDi) in patients on different dialysis modalities and its effect on dialysis dose. METHODS: In a multicentre randomized crossover study, 92 dialysis patients (HDF post-dilution: n = 44, HDF pre-dilution: n = 26, haemodialysis: n = 25) were treated for 4 weeks with each dialysate (StDi and CiDi). Hypocalcaemia (ionized calcium ≤0.9 mmol/L), alkalosis (pH ≥7.55), post-treatment bicarbonate ≥32 mmol/L, pre-treatment bicarbonate ≥27 mmol/L, intra-dialytic events (IEs) and adverse events (AEs) between dialysis sessions were investigated as primary end points. The secondary objective was dialysis efficacy, i.e. dose and removal ratios of urea, creatinine, phosphate and ß-2-microglobulin. RESULTS: Post-dialysis overcorrection of bicarbonate (>32 mmol/L) was less frequent with CiDi (P = 0.008). Other predefined calcium and acid-base disturbances did not vary. There was no significant difference in IE. However, more patients developed AEs such as fatigue, muscle spasms or pain using CiDi (StDi: 41 versus CiDi: 55 patients, P = 0.02), particularly in the first 2 weeks of exposure. Dialysis efficacy was comparable with both dialysates. CONCLUSIONS: It can be confirmed that CiDi is not associated with the development of severe calcium and acid-base disorders, even when dialysis modalities with higher citrate loads are used. However, a refinement of the CiDi composition to minimize AEs is necessary.

Escalation Therapy of Steroid Refractory Multiple Sclerosis Relapse with Tryptophan Immunoadsorption - Observational Multicenter Study with 147 Patients.

BACKGROUND: A marked proportion of multiple sclerosis (MS) relapses is followed by incomplete recovery. Our aim was to considerably increase the evidence of the clinical use of immunoadsorption (IA) as escalation therapy for patients with MS relapse. METHODS: A retrospective multicenter study was performed in MS patients with steroid refractory relapse who were treated with tryptophan IA. The main outcome parameter was change of acute relapse-related disability assessed by Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). IA treatments were performed using single-use tryptophan adsorbers. RESULTS: Data of 147 MS patients and 786 single IA treatments were analyzed. Treatment with IA was commenced in mean 32 ± 35 days after the onset of relapse. One hundred and five out of 147 patients (71.4%) improved functionally after mean 5.4 IA treatments within 7-10 days. EDSS improved from median 5 (interquartile range, IQR 3.5) to 4 (IQR 2.5) (p < 0.001). In patients with ON (n = 32), VA improved after the IA series in 84% of cases from median 0.2 (IQR 0.6) to 0.6 (IQR 0.66) (p < 0.001). In 98.9% of IA treatments, no clinically relevant side effect was reported. CONCLUSION: Tryptophan IA was found to be effective and well tolerated as escalation therapy for MS relapse.

Global Alliance for the Promotion of Physical Activity: the Hamburg Declaration.

Non-communicable diseases (NCDs), including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression and cancers, are on the rise worldwide and are often associated with a lack of physical activity (PA). Globally, the levels of PA among individuals are below WHO recommendations. A lack of PA can increase morbidity and mortality, worsen the quality of life and increase the economic burden on individuals and society. In response to this trend, numerous organisations came together under one umbrella in Hamburg, Germany, in April 2021 and signed the 'Hamburg Declaration'. This represented an international commitment to take all necessary actions to increase PA and improve the health of individuals to entire communities. Individuals and organisations are working together as the 'Global Alliance for the Promotion of Physical Activity' to drive long-term individual and population-wide behaviour change by collaborating with all stakeholders in the community: active hospitals, physical activity specialists, community services and healthcare providers, all achieving sustainable health goals for their patients/clients. The 'Hamburg Declaration' calls on national and international policymakers to take concrete action to promote daily PA and exercise at a population level and in healthcare settings.

An observational cohort study of extended dosing (once every 2 weeks or once monthly) regimens with darbepoetin alfa in patients with chronic kidney disease not on dialysis: the EXTEND study.

BACKGROUND: Darbepoetin alfa (DA) has been shown to be an effective treatment of anaemia in patients with chronic kidney disease (CKD) not on dialysis (NoD). EXTEND is an observational study assessing the effectiveness of DA administered once biweekly (Q2W) or monthly (QM) in a general CKD-NoD population. METHODS: Adult CKD-NoD patients starting DA Q2W/QM treatment in June 2006 or later were eligible. Retrospective and/or prospective data including haemoglobin levels and erythropoiesis-stimulating agent (ESA) dosing were collected for 6 months before and 12 months after DA initiation. Mean Hb levels were calculated every 3 months, and ESA dose was converted to a geometric mean weekly DA equivalent dose and summarized monthly. RESULTS: Data from 4278 patients showed that patients receiving ESA treatment before DA Q2W/QM initiation had a mean (95% confidence interval) Hb level of 11.9 g/dL (11.8-12.0 g/dL) at initiation and 11.6 g/dL (11.6-11.7 g/dL) at Months 10-12, with mean ESA dose of 22 µg/week (21-23 µg/week) prior to initiation, 16 µg/week (15-16 µg/week) at initiation and 16 µg/week (15-16 µg/week) at Month 12. In ESA-naive patients, Hb levels increased from 10.3 g/dL (10.2-10.3 g/dL) at initiation to 11.7 g/dL at Months 4-6 and were maintained at a mean level of 11.7 g/dL (11.7-11.8 g/dL) at Months 10-12, with mean ESA dose of 16 µg/week (16-17 µg/week) at initiation and 16 µg/week (16-17 µg/week) at Month 12. In the 85% of patients receiving DA at extended intervals (Q2W or less frequently) at Month 12, 12 patients (0.3%) experienced DA-related adverse reactions. CONCLUSION: DA Q2W/QM was an effective treatment of anaemia in the general CKD-NoD patient population and a dose increase was not required in patients switching from a previous ESA regimen.

[Nomenclature for kidney function and kidney diseases - Improving assessment and prognosis through precision and comprehensibility]. / Nomenklatur für Nierenfunktion und Nierenkrankheiten ­ Durch Präzision und Verständlichkeit zu besserer Erfassung und Prognose.

Kidney disease represents an increasing global health problem. Its mitigation requires effective communication between all stakeholders involved in assessment, diagnosis and therapy and individuals affected by kidney disease. However, as of today the nomenclature for kidney function and kidney disease is far from uniform. In 2019, the international non-profit organization Kidney Disease: Improving Global Outcomes (KDIGO) has implemented a consensus process to develop a glossary in English language to standardize the nomenclature for kidney function, kidney structure and kidney disease. Guiding principles for this process were (1) precision, (2) patient-centeredness and (3) consistency with KDIGO guidelines. The current position paper includes a translation of this nomenclature into German that was developed on behalf of the national societies for nephrology in Germany, Austria and Switzerland.

[Kidney as pacemaker for cardiovascular aging]. / Die Niere als Schrittmacher kardiovaskulärer Alterung.

Kidney patients age faster and vascular risk factors intensify the process. Lifetime is reduced up to 16 years in patients with diabetes mellitus type 2 and kidney disease. SGLT2 inhibitors play a significant role in maintaining organ function. By inhibiting the SGLT2 transporter in the proximal tubule of the kidneys, energy and water are continuously excreted and metabolic processes that are counter-regulated are set in motion. This hypometabolic adaptation supports organ functions and induces longevity. Kidney protection extends life expectancy of patients with diabetes mellitus type 2.Also patients with heart failure benefit and a 3-stage therapy is newly being discussed. The beta blocker is combined with an SGLT2 inhibitor in the first stage. In the second stage, the angiotensin receptor/neprilysin inhibitor and then a mineralocorticoid receptor antagonist (MRA) is used. These therapies have a complementary effect.

Monomeric C-reactive protein decreases acetylated LDL uptake in human endothelial cells.

BACKGROUND: C-reactive protein (CRP) is a risk marker for cardiovascular disease and has been implicated in atherogenesis. In atherosclerotic plaques, it colocalizes with oxidized LDL (oxLDL) and promotes oxLDL uptake by macrophages, suggesting an important cross-talk between CRP and lipid processing. A growing body of evidence indicates the existence of distinct configurations of human CRP, native pentameric (nCRP) and structurally modified monomeric (mCRP), that elicit opposing bioactivities in vitro and in vivo. Here, we tested the impact of mCRP and nCRP on the uptake of acetylated LDL (acLDL), which is internalized by receptors similar to those of oxLDL in human endothelial cells. METHODS: We cultured human umbilical vein endothelial cells (HUVECs) for 8 h with mCRP or nCRP (10-100 mg/L) and measured the uptake of acLDL (10-100 mg/L) over a 20-h period by FACS analysis. To assess the receptors involved, we used function-blocking antibodies against Fc gamma receptor CD16 (FcgammaRIII) and CD32 (FcgammaRII), and RT-PCR analysis of CD16, CD32, and the receptor for oxidized LDL (LOX-1). Uptake of acLDL and CRP isoforms was visualized by immunofluorescence. RESULTS: Culture of HUVECs with mCRP, but not nCRP, decreased uptake of acLDL, which was not prevented by anti-CD16 or anti-CD32 antibodies. LOX-1, CD16, and CD32 were undetectable by RT-PCR. Immunofluorescence showed decreased cytoplasmic acLDL staining in human umbilical vein endothelial cells (HUVECs) treated with mCRP, but not with nCRP. CONCLUSIONS: Monomeric CRP, but not nCRP, decreased acLDL uptake in human endothelial cells independent of CD16, CD32, or LOX-1. Our data support a protective role of mCRP in cardiovascular disease.

A Chlamydia pneumoniae adhesin induces phosphatidylserine exposure on host cells.

In mammalian cells, the internal and external leaflets of the plasma membrane (PM) possess different phospholipids. Phosphatidylserine (PS) is normally confined to the inner (cytoplasmic) membrane leaflet. Here we report that the adhesin CPn0473 of the human pathogenic bacterium Chlamydia pneumoniae (Cpn) binds to the PM of human cells and induces PS externalization but unexpectedly not apoptosis. PS externalization is increased in human cells exposed to infectious Cpn cells expressing increased CPn0473 and reduced in exposure to Cpn expressing decreased CPn0473. CPn0473 binds specifically to synthetic membranes carrying PS and stimulates pore formation. Asymmetric giant unilamellar vesicles (GUVs) in which PS is restricted to the inner leaflet reveal that CPn0473 induces PS externalization in the absence of other proteins. Thus our identification of CPn0473 as a bacterial PS translocator capable of specific and apoptosis-independent PS externalization during infection extends the spectrum of mechanisms intracellular pathogens use to enter host cells.

Antiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathy.

BACKGROUND: Renin-angiotensin system blockade reduces proteinuria and prevents nephropathy progression in patients with type 2 diabetes mellitus (T2D). Experimental evidence demonstrates that angiotensin receptor blockers (ARBs) possess anti-inflammatory potential, which might contribute to reducing proteinuria and providing renoprotection. METHODS: We conducted a multicentre, double-blind, prospective, parallel-group non-inferiority study of 885 hypertensive [systolic blood pressure/diastolic blood pressure (SBP/DBP) >130/80 mmHg] patients with T2D, proteinuria (> or =900 mg/24 h) and serum creatinine (< or =3.0 mg/dl) who were randomized to once-daily telmisartan 80 mg or valsartan 160 mg; additional antihypertensive therapy was permitted. The primary endpoint was the change from baseline in the 24-h proteinuria after 12 months. Secondary endpoints included changes in 24-h albuminuria, estimated glomerular filtration rate (eGFR) and inflammatory parameters asymmetrical dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)). RESULTS: Telmisartan and valsartan produced comparable reductions in 24-h urinary protein excretion rates: geometric mean reduction (95% confidence interval) [telmisartan, 33% (27-39%); valsartan, 33% (27-38%)]. No significant differences between treatments were seen in changes from baseline in 24-h urinary albumin excretion rate and eGFR at 12 months. With both treatments, greater renoprotection was seen among patients with better blood pressure control. No significant changes in ADMA or CRP were noted in either group after 12 months, but urinary 8-iso-PGF(2alpha) levels decreased by 14% with telmisartan and by 7% with valsartan (P = 0.040). CONCLUSIONS: In patients with T2D, hypertension and overt nephropathy, the renoprotection afforded by telmisartan and valsartan appears similar, and the study was unable to show any effect beyond that due to blood pressure control. At doses used to treat hypertension, there is no evidence of inflammatory parameters being modified by ARBs in patients with more advanced kidney disease due to T2D.

Lack of iNOS impairs endothelial function in endothelin-1 transgenic mice.

BACKGROUND: Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice overexpressing ET-1 exhibit normal blood pressure. We hypothesized that in states of ET-1 overproduction, the lack of counterregulatory mediators such as nitric oxide (NO), produced by the inducible NO synthase (iNOS), may critically impair endothelial function and may result in blood pressure elevation. METHODS: We generated crossbred animals of ET transgenic mice (ET+/+) and iNOS knockout mice (iNOS-/-) and evaluated blood pressure and endothelial function in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine, sodium nitroprusside, and ET-1, alone or in the presence of BQ123 or BQ788. RESULTS: Systolic blood pressure was similar in ET+/+, iNOS-/- and wild-type mice, but was significantly elevated in ET+/+ iNOS-/- crossbred animals versus ET+/+ mice. Maximum endothelium-dependent relaxation was enhanced in ET+/+ mice (95 +/- 5 vs. 78 +/- 5% of preconstriction in wild-type littermates; p < 0.05). Additional knockout of iNOS led to a significant decrease of endothelium-dependent relaxation in combined ET+/+ iNOS-/- animals (75 +/- 6%; p < 0.05 vs. ET+/+ mice). Endothelium-independent relaxation was comparable among all groups. Maximum vascular contraction to ET-1 was reduced in ET+/+ mice (33 +/- 4%), iNOS-/- mice (38 +/- 5%) and ET+/+ iNOS-/- mice (44 +/- 4%) to a similar extent as compared with wild-type littermates (66 +/- 4%; p < 0.05). CONCLUSIONS: Our data show for the first time that in transgenic mice overexpressing human ET-1, additional knockout of iNOS results in impaired endothelium-dependent vasodilatation thus contributing to elevated blood pressure in ET+/+ iNOS-/- animals.

[Renal Replacement Procedure: Information, Education, Documentation]. / Nierenersatzverfahren: Information, Aufklärung, Dokumentation.

In renal replacement therapy, different methods are available: hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KTx). In addition, variants can be used: HD as a home HD or center HD, PD as a conventional PD or automated (cycler) PD, KTx as a potentially short-term predictable living donation or conventional donor kidney donation. The patient and his familiar or caring environment must be informed accordingly. This means first of all: information about which procedures of kidney replacement therapy are possible and can be offered. Then the specific risks associated with each procedure should be elucidated (e. g. HD and shunt bleeding, PD and peritonitis, KTx and infections/neoplasias). This necessarily includes a structured documentation of the educating center/doctor about the communicated information and decisions taken.

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica.

BACKGROUND: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce. METHODS: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). RESULTS: A total of 24 patients were analyzed, 23 with relapsing-remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7-10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments. CONCLUSIONS: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.

[How to develop Choosing Wisely recommendations for internal medicine]. / Praktisches Vorgehen bei der Entwicklung von "Klug-entscheiden"-Empfehlungen.

"Choosing Wisely" is an initiative of the German Society of Internal Medicine with the aim to provide recommendations for diagnostic and therapeutic procedures that are of clear medical and scientifically proven benefit, but are rather underused in daily practice. As such, these positive recommendations are indicative of an undersupply. On the other hand, the German Society of Internal Medicine also developed "negative recommendations", pointing out diagnostic and therapeutic procedures that are frequently used but for which there is little or no scientific evidence. They indicate oversupply. So far, the various internal medicine societies have each developed five positive and five negative recommendations, and there are more to come.

Native C-reactive protein increases whereas modified C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice.

BACKGROUND: C-reactive protein (CRP) may have proatherogenic but also vasoprotective properties. We tested the hypothesis that the configuration of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) determines these different characteristics in an in vivo model. METHODS AND RESULTS: We investigated the effects of human nCRP and mCRP on the development of atherosclerosis in apolipoprotein E-knockout (ApoE(-/-)) mice. Treatment with nCRP for 8 weeks (2.5 mg/kg SC weekly) resulted in a 4-fold-higher mean aortic plaque area in 14-week-old female ApoE(-/-) mice compared with the saline controls. In contrast, mean plaque size was decreased by approximately 50% in mCRP-treated ApoE(-/-) mice (2.5 mg/kg SC weekly). Using immunohistochemistry, we report the natural presence of the mCRP antigen in saline controls. mCRP antigen was expressed in smooth muscle cells and extracellularly in the vicinity of the plaques to a similar level in both CRP-treated groups and saline controls. mCRP and ApoB colocalized with macrophages and were equally upregulated in all aortic plaques. Vascular cell adhesion molecule expression was increased, and CD154 and intercellular adhesion molecule showed a trend for higher expression in nCRP-treated compared with mCRP-treated mice. CD154 expression in the vessel wall and plaque size correlated significantly. mCRP-treated ApoE(-/-) exhibited higher serum levels of the antiinflammatory interleukin-10 compared with the other 2 groups. CONCLUSIONS: Here, we show that mCRP and nCRP have opposite effects on atherosclerosis in ApoE(-/-) mice. These data may explain in part the conflicting activities previously reported for CRP in models of atherogenesis.

Impact of oxidized low density lipoprotein on vascular cells.

Oxidized LDL (OxLDL) is a proatherogenic lipoprotein, accumulating in the vascular wall and contributing to the pathogenesis of vascular dysfunction early in the development of atherosclerosis. Enhanced serum levels of OxLDL, as well as antibodies against its epitopes, are predictive for endothelial dysfunction and coronary heart disease. While enhanced oxidative stress is one factor triggering formation of OxLDL, OxLDL itself has been identified as a potent stimulus for vascular oxygen radical formation, causing a vicious circle. OxLDL-induced O(2)(-) formation, largely through activation of NADPH oxidase, but also through uncoupling of endothelial NO-synthase and through direct O(2)(-) release, leads to endothelial dysfunction. Furthermore, OxLDL-induced O(2)(-) formation has a strong impact on tissue remodeling, resulting in either cell growth - proliferation or hyperplasia - or apoptotic cell death. The effect of OxLDL on cell cycle regulation is mediated by activation of the small GTPase RhoA and consequent regulation of p27(KIP1), a key enzyme of the cell cycle. In addition, OxLDL-induced activation of RhoA sensitizes the contractile apparatus of the vessel wall, enhancing the contractile tonus and favoring vasospasm. Thus, through a variety of mechanisms, OxLDL importantly contributes to vascular dysfunction and remodeling.

C-reactive protein: a family of proteins to regulate cardiovascular function.

Based on a multitude of clinical studies, C-reactive protein (CRP) has emerged as a risk marker for the development of cardiovascular disease, leading to recently published recommendations for screening the general population for plasma CRP level as a predictor for future cardiovascular events. However, uncertainties exist in how to apply these recommendations to populations with very high serum CRP levels and a high prevalence of cardiovascular disease, such as patients with end-stage renal disease. Furthermore, in vitro results are conflicting concerning the role of CRP in the vessel wall. Although many data are in favor of a proinflammatory effect of CRP, evidence is accumulating that CRP also exerts anti-inflammatory actions, mainly in neutrophils and platelets. Many of the apparently contradictory actions of CRP may be attributed to method issues, but, of interest, also may be explained by the existence of 2 distinct conformations of CRP, the native pentamer (nCRP) and modified CRP (mCRP) forms. nCRP is the classical acute-phase reactant detected in serum, whereas mCRP represents a predominantly tissue-bound form. It is detected immunohistochemically, mainly in and around endothelial and vascular smooth muscle cells. Although mCRP activates endothelial cells and neutrophils, induces neutrophil adhesion to the endothelium, and delays apoptosis of neutrophils in vitro, these effects were absent using nCRP. Clearly defined CRP conformers thus may provide a tool for how to reconcile the reported proinflammatory and anti-inflammatory properties of CRP. There is good evidence to believe that CRP is more than just a "bad guy," and further experiments are needed to determine how these 2 configurations contribute to atherogenesis, development of cardiovascular disease, and acute coronary events.