Chronic kidney disease (CKD) is a risk factor for development and progression of heart failure (HF). CKD and HF share common risk factors, but few data exist on the prevalence, signs and symptoms as ...well as correlates of HF in populations with CKD of moderate severity. We therefore aimed to examine the prevalence and correlates of HF in the German Chronic Kidney Disease (GCKD) study, a large observational prospective study.
We analyzed data from 5,015 GCKD patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73m² or with an eGFR ≥60 and overt proteinuria (>500 mg/d). We evaluated a definition of HF based on the Gothenburg score, a clinical HF score used in epidemiological studies (Gothenburg HF), and self-reported HF. Factors associated with HF were identified using multivariable adjusted logistic regression. The prevalence of Gothenburg HF was 43% (ranging from 24% in those with eGFR >90 to 59% in those with eGFR<30 ml/min/1.73m2). The corresponding estimate for self-reported HF was 18% (range 5%-24%). Lower eGFR was significantly and independently associated with the Gothenburg definition of HF (p-trend <0.001). Additional significantly associated correlates included older age, female gender, higher BMI, hypertension, diabetes mellitus, valvular heart disease, anemia, sleep apnea, and lower educational status.
The burden of self-reported and Gothenburg HF among patients with CKD is high. The proportion of patients who meet the criteria for Gothenburg HF in a European cohort of patients with moderate CKD is more than twice as high as the prevalence of self-reported HF. However, because of the shared signs, symptoms and medications of HF and CKD, the Gothenburg score cannot be used to reliably define HF in CKD patients. Our results emphasize the need for early screening for HF in patients with CKD.
Physical and chemical irritation of the peritoneum through glucose-based hyperosmolar dialysis solutions results in a nonbacterial serositis with fibrinous exudation. Thereby, human peritoneal ...mesothelial cells (HMC) play an important role in maintaining the balance between the peritoneal generation and degradation of fibrin by expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) as well as the specific plasminogen activator inhibitor-1 (PAI-1). In this study, we analyzed the effect of D-glucose and metabolically inert monosaccharides on the synthesis of t-PA and PAI-1 in cultured HMC. Incubation of HMC with D-glucose or the metabolically inert monosaccharides mannitol and L-glucose (5-90 mM) resulted in a time- and concentration-dependent increase in t-PA mRNA expression and antigen secretion without affecting PAI-1 synthesis. A similar effect was evident when HMC were first exposed sequentially to pooled spent peritoneal dialysis effluent for up to 4 hours, and subsequently incubated for 20 hours in control medium. The stimulating effect of high D-glucose on t-PA expression in HMC was prevented by treating the cells with different protein kinase C (PKC) inhibitors (Ro 31-8220, Gö 6976), but could not be mimicked by the PKC-activating phorbol ester PMA, indicating that this effect of high glucose is dependent on PKC activity, but not mediated through PKC activation. Also, using specific inhibitors (PD 98059, SB 203580) and activators (PMA, anisomycin, IL-1alpha) of the major routes of the mitogen-activated protein kinases (MAPKs) cascade, we found no evidence for a role of this cascade in regulating t-PA expression in HMC. We conclude that hyperosmolarity induces t-PA (but not PAI-1) in HMC via a regulatory mechanism that requires active PKC, but that does not involve a major pathway in the MAPK cascade.
Telomere length is considered as a biological marker for aging. It is expected that telomeres shorten with age and with conditions associated with oxidative stress and inflammation. Both are present ...in patients with chronic kidney disease (CKD) who have a very high cardiovascular risk. We investigated whether CKD duration is associated with relative telomere length (RTL) in 4802 patients from the German Chronic Kidney Disease (GCKD) study. We measured RTL in each sample in quadruplicates using a quantitative polymerase chain reaction (qPCR). We observed a U-shaped association of RTL with CKD duration: the longest RTL was found in those 339 patients who reported the shortest disease duration (<6months) and shorter RTL in 2108 patients with duration between 6months and less than 5years. Most importantly, those 2331 patients who reported a CKD duration of 5years and more had significantly longer RTL compared to those with intermediate CKD duration (6months to less than 5years): mean 0.954, 95%CI 0.946–0.961 versus 0.937, 95%CI 0.929–0.944, p=0.002). Due to the cross-sectional nature of the study these surprising results have to be considered with caution and as hypothesis-generating. Whether the longer RTL in patients with long-lasting disease is caused by an activation of telomerase to counteract the shortening of RTL due to oxidative stress and inflammation or whether they are caused by a survival bias needs to be investigated in longitudinal studies. Our data are in support of a higher plasticity of shortening and elongations of RTL as until recently anticipated.
•Relative telomere length (RTL) is considered as a biological marker for aging.•We investigated RTL in 4802 patients from the German Chronic Kidney Disease study.•We observed a U-shaped association of RTL with chronic kidney disease duration.•RTL was longer in patients with short and long versus intermediate disease duration.•Our data support a higher plasticity of RTL as until recently anticipated.
Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the ...associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD.
The German Chronic Kidney Disease study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate : 30-60 mL/min/1.73 m2, or >60 mL/min/1.73 m2 in the presence of overt proteinuria. Associations of NC, WC, and BMI with all-cause death, major adverse cardiovascular events (MACE: a composite of nonfatal stroke, nonfatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), and kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria were calculated. Models included sex interactions with adiposity measures.
A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (hazard ratio 1.080 per cm; 95% CI 1.009-1.155) but not in men. Irrespective of sex, WC was associated with all-cause death (hazard ratio 1.014 per cm; 95% CI 1.005-1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death, including WC offered the best (lowest) Akaike information criteria.
In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause but BMI was not.
Human peritoneal mesothelial cells (HMC) contribute to the activation and control of inflammatory processes in the peritoneum by their potential to produce various inflammatory mediators. The present ...study was designed to assess the effect of glucose, the osmotic active compound in most commercially available peritoneal dialysis fluids, on the synthesis of the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured HMC. The MCP-1 concentration in the cell supernatants was determined by enzyme-linked immunosorbent assay and the MCP-1 mRNA expression was examined using Northern blot analysis. Incubation of HMC with glucose (30-120 mM) resulted in a time- and concentration-dependent increase in MCP-1 protein secretion and mRNA expression. After 24 h the MCP-1 synthesis was increased from 2.8 +/- 0.46 to 4.2 +/- 0.32 ng/10(5) cells (n = 5, p < 0.05) in HMC treated with 60 mM glucose. In contrast, osmotic control media containing either the metabolically inert monosaccharide mannitol or NaCl did not influence MCP-1 production. The stimulating effect of high glucose on MCP-1 expression in HMC was mimicked by activation of protein kinase C (PKC) with the phorbol ester PMA (20 nM). Coincubation of the cells with glucose and the specific PKC inhibitor Ro 31-8220 completely blunted glucose-mediated MCP-1 expression. In summary, our results indicate that glucose induces MCP-1 synthesis by a PKC-dependent pathway. Since osmotic control media did not increase MCP-1 release, it is suggested that the effect of glucose is mainly related to metabolism and not to hyperosmolarity. These data may in part explain elevated steady-state levels of MCP-1 found in the dialysis effluent of continuous ambulatory peritoneal dialysis patients.
Extracellular matrix (ECM) not only provides molecular and spatial information that influence cell proliferation, differentiation and apoptosis but also has the potential to bind and present or ...release cytokines and cytotactic factors. Synthesis and degradation of extracellular matrix components are balanced by matrix metalloproteinases (MMP) and their inhibitors. In the pericardium as well as in the pleural and peritoneal cavities a multitude of clinically relevant disease states ranging from inflammation to fibrosis and tumor invasion result from altered regulation of MMP activity and are known to be associated with viral disease.
Therefore, the functional linkage between viral receptors of the innate immune system, the toll-like receptors (TLR), and control of MMP activity was exemplarily analyzed by stimulating human mesothelial cells with poly (I:C) RNA.
We hereby show that human mesothelial cells (MC) express TLR3. After stimulation of MC with the cytokines TNF-α, IL-1β and IFN-γ alone or in combination to simulate a proinflammatory milieu as would occur during immune-mediated inflammatory disease, an upregulation of TLR3 is seen. Furthermore, a selectively TLR3 mediated, time- and dose-dependent upregulation of MMP-9 and TIMP-1 is found, whereas MMP-2 expression is not significantly affected by TLR3 stimulation.
With these results we provide evidence for a mechanism by which infectious agents can mediate processes of the final common path of inflammation as fibrosis via regulation of MMP and TIMP.
Hyaluronan (HA) is a ubiquitous extracellular matrix glycosaminoglycan composed of repeated disaccharide units of alternating D-glucuronic acid and D-N-acetylglucosamine residues linked via ...alternating β-1,4 and β-1,3 glycosidic bonds. HA is synthesized in humans by HA synthase (HAS) enzymes 1, 2, and 3, which are encoded by the corresponding HAS genes. Previous in vitro studies have shown characteristic changes in HAS expression and increased HA synthesis in response to wounding and proinflammatory cytokines in human peritoneal mesothelial cells. In addition, in vivo models and human peritoneal biopsy samples have provided evidence of changes in HA metabolism in the fibrosis that at present accompanies peritoneal dialysis treatment. This review discusses these published observations and how they might contribute to improvement in peritoneal dialysis.
Soluble urokinase plasminogen activation receptor (suPAR) is an immune-derived pathogenic factor for kidney and atherosclerotic disease. Whether the association between suPAR and cardiovascular (CV) ...outcomes is dependent on the severity of underlying kidney disease is unclear.
We measured serum suPAR levels in 4994 participants (mean age 60 years; 60% men; 36% with diabetes mellitus; mean estimated glomerular filtration rate (eGFR) 49 ml/min per 1.73 m2, SD 18) of the German Chronic Kidney Disease (GCKD) cohort and examined its association with all-cause death, CV death, and major CV events (MACE) across the range of eGFR and urine albumin-to-creatinine ratio (UACR).
The median suPAR level was 1771 pg/ml (interquartile range IQR 1447–2254 pg/ml). SuPAR levels were positively and independently correlated with age, eGFR, UACR, and parathyroid hormone levels. There were 573 deaths, including 190 CV deaths and 683 MACE events at a follow-up time of 6.5 years. In multivariable analyses, suPAR levels (log2) were associated with all-cause death (hazard ratio HR 1.36, 95% confidence interval CI 1.21–1.53), CV death (HR 1.27, 95% CI 1.03–1.57), and MACE (HR 1.13, 95% CI 1.00–1.28), and were not found to differ according to diabetes mellitus status, baseline eGFR, UACR, or parathyroid hormone levels. In mediation analysis, suPAR’s direct effect on all-cause death, CV death, and MACE accounted for 77%, 67%, and 60% of the total effect, respectively; whereas the effect mediated through eGFR accounted for 23%, 34%, and 40%, respectively.
In a large cohort of individuals with chronic kidney disease (CKD), suPAR levels were associated with mortality and CV outcomes independently of indices of kidney function, consistent with its independent role in the pathogenesis of atherosclerosis.
Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-ANP) are associated with outcomes independently of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with heart failure ...(HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied.
Prospective cohort study.
A total of 4,417 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60mL/min/1.73m2 or overt proteinuria (urinary albumin-creatinine ratio>300mg/g or equivalent).
Copeptin, MR-pro-ANP, and NT-pro-BNP levels were measured in baseline samples.
Noncardiovascular death, cardiovascular (CV) death, major adverse CV event (MACE), and hospitalization for HF.
HRs for associations of Copeptin, MR-pro-ANP, and NT-pro-BNP with outcomes were estimated using Cox regression analyses adjusted for established risk factors.
During a maximum follow-up of 6.5 years, 413 non-CV deaths, 179 CV deaths, 519 MACE, and 388 hospitalizations for HF were observed. In Cox regression analyses adjusted for established risk factors, each one of the 3 markers were associated with all the 4 outcomes, albeit the highest HRs were found for NT-pro-BNP. When models were extended to include all the 3 markers, NT-pro-BNP remained associated with all 4 outcomes. Conversely, from the 2 novel markers, associations remained only for Copeptin with non-CV death (HR, 1.62; 95% CI, 1.04-2.54 for highest vs lowest quintile) and with hospitalizations for HF (HR, 1.73; 95% CI, 1.08-2.75).
Single-point measurements of Copeptin, MR-pro-ANP, and NT-pro-BNP.
In patients with moderately severe CKD, we confirm NT-pro-BNP to be strongly associated with all outcomes examined. As the main finding, the novel marker Copeptin demonstrated independent associations with non-CV death and hospitalizations for HF, and should therefore be evaluated further for risk assessment in CKD.
A blood sample–based biomarker that indicates high cardiovascular risk in a patient with kidney disease would help to guide interventions and has the potential to improve outcomes. In 4,417 patients of the German Chronic Kidney Disease study, we assessed the relationship of Copeptin, pro-atrial natriuretic peptide, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) with important outcomes over a follow-up period of 6.5 years. NT-pro-BNP was strongly associated with all of the 4 outcomes, including death unrelated to cardiovascular disease, death because of cardiovascular disease, a major cardiovascular event, and hospitalization for heart failure. Copeptin was associated with death unrelated to cardiovascular disease and hospitalization for heart failure. NT-pro-BNP and Copeptin are, therefore, promising candidates for a blood sample–based strategy to identify patients with kidney disease at high cardiovascular risk.
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