Increased circulating levels of natriuretic peptides predict future cardiac event in patients with chronic hemodialysis

BACKGROUND/AIMS: Cardiovascular events are the major determinant of the prognosis in patients with chronic hemodialysis. The present study was designed to investigate whether increased plasma levels of atrial or brain natriuretic peptides (ANP or BNP) predict future cardiac events in such patients. METHODS: Fifty-three patients undergoing chronic hemodialysis without clinical symptoms suggestive of cardiac disorders were enrolled and their blood was sampled for ANP and BNP measurements. Electrocardiograms demonstrated left ventricular hypertrophy in 28 patients but no other abnormal findings. We followed them up for 11.3 +/- 0.2 months. The endpoint was cardiac events. RESULTS: Cardiac events occurred in 13 patients (CE group). Both ANP and BNP levels were higher in CE group than in patients without cardiac events (ANP: 118 +/- 21 vs. 56 +/- 5 pg/ml, BNP: 769 +/- 204 vs. 193 +/- 25 pg/ml, respectively). Receiver operating characteristics curve revealed that the cut-off levels of ANP and BNP were 58 and 390 pg/ml, respectively. Using the Kaplan-Meier method, the incidence of cardiac events was significantly greater in patients with higher levels of ANP (50.0 vs. 0.0%) or BNP (72.7 vs. 11.9%) than in those with lower levels of the peptides. CONCLUSIONS: Elevated levels of ANP or BNP indicate an increased risk of cardiac events and these peptides are clinically useful to predict cardiac events in patients with hemodialysis.     

The utility of circulating levels of human pancreatic polypeptide as a marker for islet cell tumors

The measurement of plasma levels of human pancreatic polypeptide (hPP) has been reported to be clinically useful in predicting the existence of pancreatic islet cell neoplasms in patients with familial multiple endocrine neoplasia type 1 (FMEN-I) and the possible presence of metastatic disease in patients with islet cell tumors. However, these studies have not been prospective and involve small numbers of patients. In this study, fasting plasma samples from 36 patients with biopsy-proved islet cell tumors were analyzed for hPP by radioimmunoassay and compared with age-matched control subjects. Of 13 patients with FMEN-I who had islet cell tumors, 7 (54%) had elevated plasma hPP levels before surgery. After resection of all islet cell tumors, 4 of 12 patients evaluated after surgery still had elevated levels. Fifteen patients had islet cell tumors that were localized (seven insulinomas and eight gastrinomas), but none of these patients had elevated hPP levels, either before or after surgery. Nine patients, including one with FMEN-I, with metastatic islet cell tumors to the liver were studied; three with more advanced disease had elevated hPP levels before surgery. Each of the nine patients underwent resection of all gross disease and the three patients with elevated preoperative levels had normal postoperative hPP levels. Our results indicate that basal plasma levels of hPP were not clinically useful. The hPP levels did not reliably predict the presence of islet cell tumors in patients with FMEN-I, because 46% of patients with tumors did not have elevated plasma levels, and in those with elevated values hPP levels did not reliably predict the resection of all tumor. Plasma levels of hPP have no utility in patients with localized sporadically occurring islet cell tumors and limited utility (33%) in predicting the presence of metastatic islet cell tumors to the liver.     

Relative lymphocyte count as a marker of progression of chronic kidney disease

Background

Although low relative lymphocyte count (RLC) is associated with poor outcomes in patients with chronic kidney disease (CKD), the relationship between low RLC and progression of CKD is poorly defined. The aim of this study was to determine the association between low RLC and the progression of CKD.

Methods

Between January 2003 and December 2009, 288 CKD patients were analyzed. RLC was calculated as the ratio between lymphocyte and total white blood cell counts.

Results

The median RLC was 29.1 % [interquartile range (IQR) 24.1–34.1]. When the patients were compared according to a level below or above the median value for RLC, the rate of CKD progression to end-stage renal disease (ESRD) was greater in patients with low RLC count than in patients with high RLC (48 vs. 25 %, p < 0.001) during the median follow-up of 5.5 years (IQR 3.5–7.6). The variables found to be predictive of progression to the ESRD included younger age, smoking, diabetes, higher systolic blood pressure, no use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), lower hemoglobin and serum albumin levels, higher low-density lipoprotein cholesterol concentration, presence of proteinuria, and low RLC in the univariate Cox proportional hazards regression analysis. However, after adjustment, younger age, male, higher systolic blood pressure, no use of ACEIs or ARBs, lower hemoglobin and serum albumin concentrations, higher proteinuria, and lower RLC were significantly associated with progression to ESRD in multivariate analysis.

Conclusions

Low RLC is independently associated with increased rate of progression in patients with CKD.     

Skin autofluorescence as a marker of cardiovascular risk in children with chronic kidney disease

Background

We examined skin autofluorescence (sAF) in chronic kidney disease children (CKD) in relation to renal function and dialysis modality.

Methods

Twenty children on hemodialysis (HD), 20 on peritoneal dialysis (PD), 36 treated conservatively, and 26 healthy subjects were enrolled into the study. In all children sAF, pulse-wave velocity indexed to height (PWV/ht), left ventricular mass index (LVMI), blood pressure (BP), serum lipid profile, phosphate (P), calcium (Ca), and homocysteine were measured.

Results

sAF was significantly elevated in CKD groups vs. controls and was significantly associated with PWV/ht, LVMI, BP, P, Ca?×?P product and homocysteine. sAF in HD and PD groups was positively correlated with dialysis vintage, and in the predialysis group negatively correlated with glomerular filtration rate (eGFR). Multiple regression analysis showed significant association of sAF with LVMI and P in the CKD patient group, and with dialysis treatment duration and BP in dialyzed children.

Conclusions

In CKD children, tissue accumulation of advanced glycation end-products (AGEs) was observed. This was aggravated as eGFR declined and was related to early cardiovascular changes and some biochemical cardiovascular disease (CVD) risk markers. sAF as a non-invasive method may be a useful tool for identification of a clinical risk factors of cardiovascular disease in CKD children.     

Increased mast cells of the bladder in suspected cases of interstitial cystitis: a possible disease marker

Mast cells reportedly have been increased in the detrusor muscle bundles of the bladder in patients with interstitial cystitis. In 30 patients with suspected interstitial cystitis quantification of mast cells within the muscularis and submucosa was done. The results were compared to those obtained from a variety of normal bladder specimens removed surgically (16 specimens) and at autopsy (15), and from bladders with a variety of miscellaneous inflammatory conditions (20). In patients with suspected interstitial cystitis the number of mast cells was increased significantly (p less than 0.001) compared to the 3 control groups. This finding suggests that quantification of mast cells in the muscularis may be a useful marker in the histopathological evaluation of bladder biopsies in patients with suspected interstitial cystitis.     

以SSX基因mRNA作为肿瘤标志物检测循环中的肝癌细胞

目的　探讨检测肝细胞癌 (HCC)患者外周血中SSX基因mRNA的临床意义。方法　以简易“降落”PCR(stepdownRT PCR)方法检测HCC患者外周血中SSX基因mRNA的表达 ,并对SSX基因的表达与临床指标和预后的关系进行了分析。结果　 4 2例肝癌患者肝癌组织中SSX基因mRNA阳性率为 85 7% (36 4 2 ) ,而癌旁组织、肝硬化组织和正常肝组织均未发现有SSX基因的表达。外周血标本中 ,有 17例可检测到SSX基因的表达 ,占 4 0 5 %。肝癌组织不表达SSX基因者以及健康志愿者的外周血中未检测到其表达。外周血中SSX基因的表达与年龄、性别、肿瘤分化程度、TNM分期、肿瘤大小、血清AFP水平和HBV感染无显著相关性 (P >0 0 5 )。除肝组织不表达SSX和死于并发症的 7例患者外 ,在随访 7 7± 5 4月的过程中 ,16例外周血中表达SSX基因mRNA者有 8例出现了复发和 或转移 ,其中 7例已经死亡 ,另 1例带瘤生存 ,而 19例阴性者仅 2例出现了复发和 或转移 ,二者相比差异有显著性 (P =0 0 2 8)。结论　外周血中SSX基因表达与复发、转移密切相关 ,SSX基因可作为检测HCC患者循环肿瘤细胞的标志基因。     

Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease

Background

Chronic renal failure on dialysis can reduce the number of circulating endothelial progenitor cells (EPCs), but this biomarker has not been fully investigated in patients with chronic kidney disease (CKD). A link between CKD and increased mononuclear cell apoptosis (MCA) in circulation has been reported but the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α, two angiogenesis factors, on circulating EPC levels in CKD has not been clarified. This study examined the relationships between the numbers of circulating EPCs and the severity of CKD, degree of MCA and serum levels of VEGF and SDF-1α in CKD patients.

Methods

The numbers of circulating EPCs (CD31/CD34+, CD62E/CD34+, KDR/CD34+, CXCR4/CD34+) were measured in 166 patients with varying degrees of CKD under regular treatment at an outpatient department and in 30 volunteer control subjects.

Results

CKD patients had significantly lower numbers of EPCs (p < 0.007), higher MCA in circulation and higher serum levels of VEGF and SDF-1 compared with the control subjects (all p < 0.001). Compared with patients with early CKD (stages I–III), patients with late CKD [stage IV–V or end-stage renal disease (ESRD)] had significantly lower numbers of EPCs (CXCR4/CD34+), higher MCA, and elevated serum levels of VEGF and SDF-1α (all p < 0.01). Serum VEGF level but not MCA or SDF-1α was strongly correlated with increased numbers of circulating EPCs. Multivariate analysis showed that ESRD along with lower serum albumin was independently predictive of lower numbers of circulating EPCs (p < 0.04).

Conclusion

Circulating EPCs were markedly reduced in CKD patients. ESRD was strongly and independently predictive of decreased numbers of circulating EPCs.     

Increased coated-platelet levels in chronic haemodialysis patients

Aim: To determine if levels of coated‐platelets, which are potentially pro‐thrombotic, are increased in end‐stage renal disease patients on haemodialysis, a condition associated with high cardiovascular disease risk. Methods: In a cross‐sectional observational study, coated‐platelet levels were measured by flow cytometry in 25 end‐stage renal failure haemodialysis patients and 25 controls without renal disease. Associations between coated‐platelet levels and clinical and biochemical factors relevant to renal and cardiovascular disease were evaluated. Results: Mean ± SD coated‐platelet levels were higher in the dialysis group than in the control group (39.3 ± 14.3% vs 30.9 ± 10.3%, P = 0.02). The number of subjects with high coated‐platelet levels (>40%) was larger in the dialysis than in the control group (13/25 vs 4/25, χ² test, P = 0.007). On univariate analysis, coated‐platelet levels correlated with serum C‐reactive protein levels in renal failure (r = 0.47, P = 0.02) and inversely with white cell count in the control group (r = ?0.60, P = 0.001). Coated‐platelet levels were higher in dialysis patients reporting alcohol abstinence than among those reporting ‘social’ drinking (44.3 ± 12.6 vs 28.8 ± 13.5%, P = 0.01). Age, gender, body weight, smoking, diabetes, lipid levels and lipid‐lowering drugs were not associated with coated‐platelet levels (all P > 0.05). Conclusion: Coated‐platelet levels are increased in haemodialysis patients relative to subjects with normal renal function, and are related to inflammation and alcohol abstinence. Other vascular risk factors, such as smoking, lipids and diabetes, were not related to coated‐platelet levels. Coated‐platelets may be implicated in the increased thrombosis and vascular risk in end‐stage renal disease.     

Serum gamma-glutamyltransferase levels are inversely related to endothelial function in chronic kidney disease

Backgrounds

Gamma-glutamyltransferase (GGT) is an enzyme responsible for the extracellular catabolism of the antioxidant glutathione and recently implicated in the pathogenesis of atherosclerosis. Endothelial dysfunction is a prodromal feature of atherogenesis. Since oxidative stress is highly present in uremia and causally linked to endothelial dysfunction, we hypothesized that GGT may be a factor implicated in this process.

Methods

Serum GGT and C-reactive protein (CRP) levels, estimated glomerular filtration rate (eGFR), and 24-h proteinuria were measured in 214 nondiabetic stages 3–5 CKD patients. The endothelium-dependent vasodilatation (FMD) of the brachial artery was assessed by using high-resolution ultrasound. We investigated the relationship between FMD and circulating serum GGT.

Results

Serum GGT levels were negatively associated with FMD (r = ?0.41, p < 0.001) and eGFR (r = ?0.34, p < 0.001) in univariate analysis. Multivariate regression analysis showed that the association between GGT and FMD persisted after adjustment for age, sex, smoking, renal function (eGFR), inflammation (CRP), proteinuria, and homeostatic model assessment index.

Conclusion

Circulating GGT levels significantly associate with endothelial dysfunction, an important early feature of the atherogenic process. GGT might be an early marker of oxidative or other cellular stress that it is possibly directly related to the pathogenesis of endothelial dysfunction.     

Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in children with chronic kidney disease

Very few biomarkers exist for monitoring chronic kidney disease (CKD). We have recently shown that serum neutrophil gelatinase-associated lipocalin (NGAL) represents a novel biomarker for early identification of acute kidney injury. In this study, we hypothesized that serum NGAL may also represent a biomarker for the quantitation of CKD. Forty-five children with CKD stages 2–4 were prospectively recruited for measurement of serum NGAL, serum cystatin C, glomerular filtration rate (GFR) by Ioversol clearance, and estimated GFR (eGFR) by Schwartz formula. Serum NGAL significantly correlated with cystatin C (r=0.74, P<0.000). Both NGAL and cystatin C significantly correlated with measured GFR (r=0.62, P<0.000; and r=0.71, P<0.000, respectively) as well as with eGFR (r=0.66, P<0.000 and r=0.59, P<0.000, respectively). At GFR levels of ≥30 ml/min per 1.73 m², serum NGAL, cystatin C, and eGFR were all significantly correlated with measured GFR. However, in subjects with lower GFRs (<30 ml/min per 1.73 m²), serum NGAL levels correlated best with measured GFR (r=0.62), followed by cystatin C (r=0.41). We conclude that (a) both serum NGAL and cystatin C may prove useful in the quantitation of CKD, and (b) by correlation analysis, NGAL outperforms cystatin C and eGFR at lower levels of measured GFR.     

Increased circulating endothelial progenitor cells in patients with bacterial pneumonia: evidence that bone marrow derived cells contribute to lung repair

Background: Tissue repair often occurs in organs damaged by various inflammatory diseases including pneumonia. Inflammatory stimuli induce a rapid and massive release of inflammatory cells from the bone marrow. Recent studies have suggested that bone marrow cells have the potential to differentiate into a variety of cell types. It has been shown that administration of lipopolysaccharide (LPS) to murine lungs induces a rapid release of endothelial progenitor cells (EPCs) into the circulation, and that bone marrow derived progenitor cells including EPCs contribute to lung repair after lung injury in mice. This study was undertaken to investigate the mobilisation of EPCs in humans following acute pneumonia.

Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood taken from 23 patients with pneumonia during both the acute and convalescent phase. 1x10⁶ PBMCs were plated on fibronectin coated culture slides and cultured in culture medium for endothelium. The numbers of EPCs were counted 8 days after plating.

Results: The number of circulating EPCs significantly increased in patients with pneumonia (p<0.0001). Patients with low EPC counts tended to have persistent fibrotic changes in their lungs even after their recovery from pneumonia.

Conclusions: Inflammatory stimuli induce a rapid release of EPCs into the circulation in humans. A sufficient number of EPCs is necessary for proper lung repair following bacterial pneumonia.

     

Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress

BACKGROUND: Bronchiectasis is a chronic inflammatory lung disease associated with increased production of oxidants due mostly to neutrophilic inflammation. Induction of heme oxygenase (HO-1) by reactive oxygen species is a general cytoprotective mechanism against oxidative stress. HO-1 catabolises heme to bilirubin, free iron and carbon monoxide (CO). Exhaled CO measurements may therefore reflect an oxidative stress and be clinically useful in the detection and management of inflammatory lung disorders. METHODS: The levels of exhaled CO of 42 non-smoking patients with bronchiectasis treated or not treated with inhaled corticosteroids were compared with CO levels in 37 normal non-smoking subjects. RESULTS: Levels of exhaled CO were raised in patients with bronchiectasis, both those treated with inhaled corticosteroids (n = 27, median 5.5 ppm, 95% CI 5.16 to 7.76) and those not treated with inhaled corticosteroids (n = 15, median 6.0 ppm. 95% CI 4.74 to 11.8), compared with normal subjects (n = 37, median 3.0 ppm, 95% CI 2.79 to 3.81, p = 0.0024). There was no correlation between exhaled CO and HbCO levels (r = 0.42, p = 0.12) in normal subjects (n = 7), nor between the urine cotinine concentration and exhaled CO levels (r = 0.2, p = 0.12). CONCLUSIONS: Increased levels of exhaled CO may reflect induction of HO-1 and oxidative stress in bronchiectasis. Measurement of exhaled CO may be useful in the management of bronchiectasis and possibly other chronic inflammatory lung disorders.     

Increased plasma S-nitrosothiol levels in chronic haemodialysis patients

Nephrol Dial Transplant 2003; 18: 153–157     

Increased plasma malondialdehyde levels in glomerular disease as determined by a fully validated HPLC method.

BACKGROUND: Reactive oxygen species and particularly free radical induced lipid peroxidative tissue damage have been implicated in the pathogenesis of various renal diseases. Lipid peroxidation is assessed indirectly by the measurement of secondary products, such as malondialdehyde (MDA), using the widely employed thiobarbituric acid reactive substances (TBARS) method. However, this method lacks sensitivity and specificity. We have therefore developed and validated an HPLC (high-performance liquid chromatography) method for measurement of MDA and applied this to a variety of plasma samples in renal patients. METHODS: The optimized method involves antioxidant treatment of the plasma sample, followed by a protein precipitation step using trichloroacetic acid, acid hydrolysis and formation of an MDA thiobarbituric acid complex. The MDA-(TBA)2 adduct is separated from other interfering compounds by C18 reverse-phase HPLC techniques, with visible detection at 532 nm. RESULTS: The assay was linear over the ranges 0.25-1.0 microM MDA and the detection limit was 0.06 microM MDA. Within-run precision was <4.5% and between-run precision was <10.0%. MDA plasma concentrations (mean+/-SD) were higher in ESRF diabetic patients (0.32 +/- 0.14 microM, n=20), non-diabetic ESRF patients (0.32 +/- 0.09 microM, n=20), and CRF patients (0.14 +/- 0.06 microM, n=40) compared to healthy controls (0.11 +/- 0.03 microM, n=40), (P < 0.001, P < 0.001 and P = 0.008). Levels were similar in healthy controls with normal renal function and transplanted patients (0.12 +/- 0.03 microM MDA, n=40), (P=NS). No correlation was observed between MDA and creatinine levels (r2 = 0.05, n=80), which suggests that MDA does not correlate with the degree of renal impairment. We matched CRF patients with glomerular and non-glomerular causes of renal failure for creatinine levels and found that MDA levels were higher in patients with glomerulonephritis (0.16 +/- 0.06 microM) than in those with CRF from non-glomerular causes (0.12 +/- 0.04 microM, P = 0.002). CONCLUSIONS: We have introduced a reliable and sensitive HPLC technique to enhance the specificity of MDA-(TBA)2 measurement, with a significant improvement in HPLC column life. Using this method, picomole quantities of MDA can be detected in plasma. We have shown that MDA levels are significantly raised in patients with CRF due to glomerulonephritis, regardless of serum creatinine, which suggests that there is oxidative injury independent of any possible MDA retention due to renal impairment.     

Increased plasma levels of mature adrenomedullin in chronic glomerulonephritis

Adrenomedullin (AM) is a potent vasodilative and natriuretic peptide that is processed from its precursor as the intermediate form, AM-glycine-COOH (iAM). Subsequently, iAM is converted to the biologically active mature form, AM(1-52)-CONH(2) (mAM), by enzymatic amidation. Using immunoradiometric assays that recognize total AM (tAM) and only mAM, we determined the plasma and urinary levels of mAM and iAM in patients with chronic glomerulonephritis (CGN). The plasma mAM concentration was significantly higher in the patients than in the controls (1.8 +/- 0.1 vs. 1.3 +/- 0.1 fmol/ml, p < 0.01), whereas the plasma iAM concentration of the CGN patients did not significantly differ from that of the controls (9.4 +/- 0.5 vs. 8.9 +/- 0.5 fmol/ml). Levels of urinary mAM excretion in the patients did not statistically differ from those of the controls (1. 6 +/- 0.4 vs. 2.0 +/- 0.3 fmol/mg creatinine), whereas urinary iAM excretion was significantly lower in the CGN patients (3.7 +/- 0.7 vs. 5.6 +/- 0.8 fmol/mg creatinine, p < 0.05). Urinary excretion levels of mAM significantly correlated with those of sodium (r = 0. 47, p < 0.05), whereas those of iAM did not. In conclusion, the plasma ratio of mAM to iAM is augmented in CGN patients, and mAM appears to be involved in the regulation of sodium. Therefore, determination of the mAM in addition to the tAM concentration is essential in CGN patients.