Relationship between dialysis adequacy and sleep quality in haemodialysis patients.

AIM AND OBJECTIVES: The aim of this study is to examine the relationship between dialysis adequacy and sleep quality in haemodialysis patients. BACKGROUND: Sleep problems are common in haemodialysis patients. Dialysis adequacy is one of the factors associated with sleep quality. Studies evaluating the association between dialysis adequacy and sleep quality in haemodialysis patients present different results. DESIGN: Descriptive and cross-sectional study. METHODS: This study was performed with a total of 119 patients who had applied to dialysis centres for haemodialysis treatment between January and March 2014. The data collection form consists of socio-demographic and medical characteristics as well as laboratory parameters. A modified Post-Sleep Inventory was used to examine sleep quality in the research. RESULTS: There were no statistically significant relationship between sleep quality and dialysis adequacy (p > 0·05). When the Post-Sleep Inventory scores were evaluated according to sleep quality, 63·0% of patients had poor sleep quality, and 37·0% had good sleep quality. Sleep quality was worse in unemployed patients (X(2) = 4·852; p = 0·025) and patients who smoked heavily (Z = 2·289; p = 0·022). CONCLUSIONS: In this study, there is no statistically significant relationship between dialysis adequacy and sleep quality. However, it was found that the majority of haemodialysis patients had poor sleep quality. RELEVANCE TO CLINICAL PRACTICE: Even if the dialysis adequacy of patients is at the recommended level, their sleep qualities may be poor. Therefore, evaluations of the sleep quality of haemodialysis patients during the clinical practice must be taken into consideration.

Neutrophil to lymphocyte ratio independently predicts cardiovascular events in patients with chronic kidney disease.

BACKGROUND: Increased inflammation is common in patients with chronic kidney disease (CKD) and is associated with increased adverse cardiovascular events (CVE). Neutrophil-to-lymphocyte ratio (NLR) was used to predict survival in patients with acute coronary syndrome. We aimed to evaluate predictive ability of NLR in CKD patients. METHODS: 225 subjects with stage 3-5 CKD were followed for a mean of 39 months. Fatal and nonfatal CVE were recorded during this period. NLR at baseline was determined from complete blood count differential. Endothelial dysfunction (flow-mediated dilation, FMD), hsCRP and insulin resistance were determined. We investigated if NLR could predict development of fatal and nonfatal CVE. We also looked at how NLR and its individual components change across CKD stages and whether NLR is related to CRP, insulin resistance and endothelial dysfunction. RESULTS: There were 70, 74 and 81 patients in groups of CKD stage-3, stage-4 and stage-5, respectively. Median NLR was 2.81. NLR showed a significant increase from stage 3 to stage 5. NLR was inversely associated with FMD independent of hsCRP. 14 fatal and 52 nonfatal CVE occurred during follow-up period. NLR could predict composite CVE independent of insulin resistance and hsCRP. Increased NLR over 2.81 was related to a significantly decreased survival time (log-rank Chi-square = 14.833, P < 0.0001). A cutoff value for NLR ≥3.76 could predict development of composite CVE with 80.3 % sensitivity and 91.8 % specificity. CONCLUSIONS: NLR is independently related to endothelial dysfunction and could predict composite cardiovascular endpoints independent of traditional confounding factors in patients with moderate to severe CKD.

Comparison of calcium acetate and sevelamer on vascular function and fibroblast growth factor 23 in CKD patients: a randomized clinical trial.

BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a marker of endothelial dysfunction and atherosclerotic complications in patients with chronic kidney disease (CKD). Because previous studies suggested that sevelamer may exert effects on FGF-23 level and endothelial function independently of its phosphate-lowering action, we tested the effect of sevelamer versus calcium acetate on vascular function and FGF-23 levels. STUDY DESIGN: Randomized prospective open-label trial. SETTING & PARTICIPANTS: Patients with stage 4 CKD with hyperphosphatemia (n = 100). INTERVENTION: An 8-week intervention with sevelamer (n = 47) and calcium acetate (n = 53). OUTCOMES: The primary study outcome was change in flow-mediated vasodilatation in the forearm. The secondary outcome was change in FGF-23 levels. RESULTS: Serum phosphate levels decreased in both treatment arms (P < 0.001), but more markedly in the sevelamer group (P < 0.001). Flow-mediated vasodilatation increased from 6.1% to 7.1% (P < 0.001) in sevelamer-treated patients, whereas it was unchanged in the calcium-acetate group (6.0% vs 6.0%). In a combined analysis, treatment-induced changes in flow-mediated vasodilatation were (P < 0.001) associated with simultaneous changes in FGF-23 levels (-27.1% [-33.2% to -8.8%] for the sevelamer group; 3.5% [-8.4% to 12.1%] for the calcium acetate group), as well as with C-reactive protein and fetuin A levels. These relationships were confirmed in multiple regression analysis adjusting for changes in serum phosphate levels and other factors. LIMITATIONS: Unblinded randomized controlled study that cannot establish mechanisms of effect. CONCLUSIONS: In hyperphosphatemic patients with stage 4 CKD, treatment with phosphate lowering induces measurable improvements in flow-mediated vasodilatation. Furthermore, independently of serum phosphate level, FGF-23 level changes induced by phosphate binders are associated with simultaneous changes in flow-mediated vasodilatation. These observations are compatible with the hypothesis that FGF-23 may contribute to vascular dysfunction in this population.

Relationship between serum magnesium levels and cardiovascular events in chronic kidney disease patients.

BACKGROUND: Magnesium is an essential ion for all living cells because over 300 enzymes require the presence of magnesium for their catalytic action. To date, no group has evaluated magnesium as a cardiovascular risk factor in chronic kidney disease (CKD) subjects, in which closely interrelated factors and potential confounders such as endothelial dysfunction, insulin resistance (the homeostasis model assessment (HOMA) index) and inflammation (expressed as serum C-reactive protein (CRP) levels) were also considered. METHODS: Between March 2006 and December 2010, 283 CKD patients were followed up for time-to-event analysis until the occurrence of fatal or nonfatal cardiovascular events. Endothelium-dependent vasodilatation (flow-mediated dilatation; FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation) of the brachial artery were assessed noninvasively using high-resolution ultrasound. RESULTS: From the univariate analysis of FMD, it appears that a higher magnesium level is associated with less endothelial dysfunction. When a multivariate analysis was performed, magnesium and estimated glomerular filtration rates (eGFR) maintained a strong positive correlation with FMD, supporting the hypothesis that higher levels of magnesium may protect against endothelial damage. In univariate Cox proportional hazards models, FMD, magnesium, high sensitivity CRP, the HOMA index, eGFR, comorbid diabetes, hypertension, smoking status, systolic blood pressure, serum phosphate and intact parathormone emerged as significant predictors for cardiovascular outcomes. Kaplan-Meier curves showed significantly higher cardiovascular mortality rates in CKD patients whose serum magnesium levels were below 2.05 mg/dl. CONCLUSIONS: This observational cohort study showed that magnesium may be an independent predictor of future cardiovascular outcomes and is the first study demonstrating such a role in etiologically diagnosed CKD patients, across different stages.

Testosterone deficiency is a cause of anaemia and reduced responsiveness to erythropoiesis-stimulating agents in men with chronic kidney disease.

BACKGROUND: Hypogonadism or testosterone deficiency is a prevalent condition in men with chronic kidney disease (CKD). Testosterone stimulates erythropoiesis via production of haematopoietic growth factors and possible improvement of iron bioavailability. We hypothesized that testosterone deficiency predisposes to anaemia and reduced responsiveness to erythropoiesis-stimulating agents (ESAs) in CKD men. Materials and methods. We studied associations between endogenous testosterone and haemoglobin in 239 ESA-naïve nondialysed CKD Stages 1-5 male patients. Additionally, we studied associations between endogenous testosterone levels and ESA dose (U/kg/week) in 126 ESA-treated men undergoing haemodialysis (HD). RESULTS: Among ESA-naïve males, patients with anaemia presented lower testosterone values. Endogenous testosterone was negatively associated with haemoglobin levels in uni- and multivariate models. Testosterone-deficient patients (total testosterone <10 nmol/L) were 5.3 (95% confidence interval 2.2-12.5) times more likely to be anaemic (Hb < 13.0 g/dL) than testosterone-sufficient patients. In ESA-treated men undergoing HD, higher ESA doses (above the median value of 121 IU/kg body weight/week) are associated with lower testosterone levels and higher percentage of hypochromic red blood cells (RBC). The inverse association between testosterone levels and ESA doses persisted after multivariate adjustment for age, sex hormone-binding globulin, comorbidities, C-reactive protein and s-albumin but was lost after further adjustment for iron medication and hypochromic RBC. CONCLUSIONS: Hypogonadism may be an additional cause of anaemia and reduced ESA responsiveness in men with CKD. Our results raise the possibility that restoration of testosterone levels in hypogonadal CKD males may translate into lower prevalence of anaemia and better ESA responsiveness.

Serum uric acid level and endothelial dysfunction in patients with nondiabetic chronic kidney disease.

BACKGROUND: An elevated serum uric acid level is strongly associated with endothelial dysfunction and inflammation, both of which are common in chronic kidney disease (CKD). We hypothesized that endothelial dysfunction in subjects with CKD would correlate with uric acid levels. MATERIALS AND METHODS: We evaluated the association between serum uric acid level and ultrasonographic flow-mediated dilatation (FMD) in 263 of 486 patients with recently diagnosed CKD (stage 3-5) (48% male, age 52 ± 12 years). To minimize confounding, 233 patients were excluded because they were diabetic, had established cardiovascular complications or were taking drugs (renin-angiotensin system blockers, statins) interfering with vascular function. RESULTS: Serum uric acid level was significantly increased in all stages of CKD and strongly correlated with estimated glomerular filtration rate (eGFR-MDRD); FMD was inversely associated with serum uric acid (r = -0.49, p < 0.001). The association of serum uric acid with FMD remained after adjustment for age, gender, smoking, LDL cholesterol, eGFR, high-sensitivity C-reactive protein, systolic blood pressure, proteinuria, and homeostatic model assessment index (ß = -0.27, p < 0.001). CONCLUSION: Increased serum uric acid is an independent predictor of endothelial dysfunction in subjects with CKD.

Low triiodothyronine alters flow-mediated vasodilatation in advanced nondiabetic kidney disease.

BACKGROUND/AIMS: Subclinical or frank hypothyroidism is causally implicated in endothelial dysfunction. Since the plasma concentration of the active form of thyroid hormone, triiodothyronine (T3), is reduced in chronic kidney disease (CKD), where endothelial function is frequently altered, low T3 may be a factor implicated in this disturbance in CKD patients. METHODS: We investigated the relationship between flow-mediated vasodilatation (FMD) and thyroid hormones in a series of 217 nondiabetic patients with stage 3-4 CKD. RESULTS: The plasma concentration of free T3 (fT3) was closely associated with FMD (r = 0.38; p < 0.001). fT3 was also inversely associated with hemoglobin (r = -0.41; p < 0.001), systolic pressure (r = -0.28; p < 0.001) and the plasma concentration of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA; r = -0.18; p = 0.007). However, adjustment for ADMA markedly attenuated the fT3-FMD link, a phenomenon suggesting that raised plasma ADMA, possibly driven by low fT3, at least in part mediates the adverse effects of low T3 on endothelial function in CKD. CONCLUSIONS: Low T3 in patients with moderate-to-severe CKD is a marker of endothelial dysfunction. This study sets a solid rationale for designing specific intervention studies aimed at clarifying the nature (causal or not causal) of the endothelial function-T3 link in CKD.

Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes.

INTRODUCTION: Systemic inflammation, endothelial dysfunction and arterial thickening contribute to the elevated cardiovascular risk of dialysis patients. However, the course of these derangements and their relative contribution to the cardiovascular risk of nondialysed chronic kidney disease (CKD) are scarcely investigated. METHODS: Flow-mediated dilatation (FMD) and intima-media thickness (IMT) were assessed in 304 nondialysed CKD patients Stages 1-5 (mean age 46 ± 12 years, 158 men), together with routine biochemical measurements, C-reactive protein (CRP) and insulin resistance. Patients were then followed for time-to-event analysis of cardiovascular outcomes (fatal and nonfatal). RESULTS: CRP and IMT increased, while FMD decreased in parallel with estimated glomerular filtration rate (eGFR) decline (P < 0.001 for all). CRP and intact parathormone, as well as eGFR, appeared as strong determinants of FMD and IMT in multivariate analyses. After a median follow-up of 41 (range 6-46) months, 30 fatal and 59 nonfatal cardiovascular events occurred. In univariate analysis, FMD, IMT and CRP were significant predictors of outcome. In a multivariate Cox model excluding IMT, both FMD [hazard ratios 0.52 (95% confidence intervals 0.37-0.73) per %] and CRP [1.07 (1.03-1.11) per mg/L] predicted cardiovascular outcomes independently of confounders. In a model excluding FMD, only CRP (and not IMT) was a significant predictor. CONCLUSIONS: Endothelial dysfunction, arterial thickening and inflammation occur in parallel with the decline in eGFR, contributing to the increased cardiovascular risk of nondialysed CKD. Our results support the use of FMD over IMT measurements to monitor nondialysed CKD patients at risk.

The relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy.

OBJECTIVES: Diabetic nephropathy (DN) is a major manifestation of microangiopathy in patients with Diabetes Mellitus (DM). Inflammation is one of the major factors in the formation of endothelial dysfunction. Endothelial dysfunction is a major contributor to the complications of DM. The aim of the present study was to investigate the possible relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy. MATERIALS AND METHODS: Plasma TNF-α and IL-6, pro-inflammatory cytokines, concentrations were measured in 25 patients with DN and in 30 diabetic control subjects. Also, we evaluated the markers of endothelial dysfunction such as flow mediated dilatation (FMD), nitrate-mediated dilatation (NMD) and carotid intima-media thickness (CIMT). RESULTS: TNF-α, IL-6 and high-sensitivity C-reactive protein concentrations were significantly higher (p = 0.012, p = 0.006 and p < 0.001, respectively) in the patients with DN than the controls. And, urinary protein concentrations were significantly higher (p < 0.001) but eGFR levels were significantly lower (p < 0.001) in the patients with DN. FMD was significantly lower in DN patients (p < 0.001). We have observed that FMD correlated negatively with body mass index (r = -0.424, p < 0.05). And there was also a positive correlation between TNF-α and urinary protein concentrations in the patients with DN (p < 0.05). CONCLUSION: TNF-α, IL-6, hsCRP and urinary protein concentrations are higher in the DN patients. There were no correlations among pro-inflammatory cytokines concentrations and markers of vascular endotelial disfunction. These findings did not show vascular endothelial dysfunction, but may indicate glomerular endothelial dysfunction.

Diffuse alveolar hemorrhage as an unusual presentation of systemic lupus erythematosus.

Diffuse alveolar hemorrhage (DAH) is rarely seen in patients with systemic lupus erythematosus (SLE), often associated with a poor outcome. It almost affects young women and it is an unusual initial manifestation of SLE. We report a case of SLE presenting with DAH. The patient was a male. He had no history of photosensitivity, malar rash, discoid rash, arthritis, and oral ulcer. Antinuclear antibody, and anti-double stranded DNA (dsDNA) were positive with very high titers, and serum complement levels (C3, C4) were low. He also had renal dysfunction and pericardial effusion. He was diagnosed as DAH due to SLE. He had to undergo hemodialysis for several weeks. DAH and renal dysfunction were improved with intensive treatment including corticosteroid, cyclophosphamide, and mycophenolate mophetil.

FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease.

Studies in animals show that fibroblast growth factor (FGF)-23 interferes with vascular reactivity induced by the nitric oxide (NO) system. To investigate the relationship between circulating FGF-23 levels and the response of forearm blood flow to ischemia (flow-mediated vasodilatation, FMD) and nitroglycerin, we tested 183 patients with stage 3-4 chronic kidney disease (CKD). None of them had cardiovascular complications or were taking drugs interfering with vascular function. Patients with FGF-23 levels above the median had significantly lower glomerular filtration rate, FMD, and fetuin-A levels (an anti-inflammatory molecule and potent inhibitor of calcification). They also had higher proteinuria and phosphate levels when compared to patients whose FGF-23 levels were below the median. The response to nitroglycerin was not different between the two groups. Multiple regression analysis showed that the relationship between FGF-23 and FMD was only modestly sensitive to adjustment for classical risk factors, biomarkers of bone mineral metabolism, high-sensitivity C-reactive protein, and homeostatic model assessment index. Adjustment for asymmetrical dimethyl arginine (ADMA) weakened the strength of this link; however, it remained highly significant. There was no independent association between FGF-23 and nitroglycerin. Thus, attenuation of FMD by ADMA suggests that this endogenous inhibitor of NO synthase may, in part, mediate the vascular effects of FGF-23 in patients with CKD.

Predictors of carotid artery intima-media thickness in chronic kidney disease and kidney transplant patients without overt cardiovascular disease.

BACKGROUND/AIMS: Carotid intima-media thickness (IMT) assessed using ultrasonography is a widely used marker of atherosclerosis. In the largest study to date of IMT and chronic kidney disease (CKD), we assessed correlates of IMT in CKD patients with a wide range of renal dysfunction, and also investigated what happens to IMT following renal transplantation. METHODS: We studied 406 patients with different stages of nondiabetic CKD (50% males, 46 +/- 12 years), and 58 kidney transplant recipients (27 +/- 6 years), testing relationships between IMT, assessed by ultrasonography, and selected biomarkers. RESULTS: Despite a lack of overt CVD, patients had significantly higher IMT as compared to controls (0.9 [0.7-1.0] vs. 0.6 [0.4-0.7] mm; p > 0.001). Furthermore, in multivariate analysis IMT was independently associated with CKD stage, mean arterial pressure (MAP) and calcium-phosphate product, but not with Framingham risk factors. Following kidney transplantation, IMT decreased rapidly, reaching levels comparable to those in the controls within 90 days. In a time-dependent multivariate analysis, this decrease was predicted by changes in GFR, MAP, and uric acid levels. CONCLUSION: Our data does not exclude IMT as a predictor of mortality in CKD, but suggests that other etiologies than atherosclerosis may be more important in determining IMT levels in the population with CKD.

Reduced proteinuria using ramipril in diabetic CKD stage 1 decreases circulating cell death receptor activators concurrently with ADMA. A novel pathophysiological pathway?

BACKGROUND: Renin-angiotensin system (RAS) blockade improves proteinuria and the endothelial functions in diabetic nephropathy. Plasma asymmetric dimethylarginine (ADMA), abundant in the cell than in the plasma, is also improved by RAS blockage. We hypothesized that RAS blockade may reduce ADMA by reducing injurious cell death. METHODS: In a hypothesis-generating study, we assessed circulating levels of apoptotic signalling peptides in incident chronic kidney disease (CKD) stage 1 patients (aged >18 years with diabetes mellitus type 2 as the only cause of nephropathy) not previously prescribed statins or RAS blockade. Ninety-three (29 M, 47 ± 5 years) patients with CKD 1 diabetic nephropathy and 38 healthy subjects (20 M, 47 ± 5 years) were enrolled. Ramipril was given (5 mg daily for 12 weeks), and circulating ADMA, soluble Fas (sFas), myostatin and endothelial function [flow-mediated vasodilation (FMD); ultrasound)] were measured. RESULTS: After the study, ADMA, sFas, myostatin, insulin resistance, high-sensitive C-reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), blood pressure and proteinuria levels were decreased, and FMD and serum albumin levels increased (P < 0.05 for all). ADMA and sFas levels were independently related to FMD levels both before (rho = -0.33; P < 0.005 and rho = -0.26; P < 0.02, respectively) and after (rho = -0.39; P < 0.001 and rho = -0.28; P < 0.002, respectively) ramipril treatment. Changes in sFas and ADMA were related to the change in FMD (-0.32; P > 0.004 and -0.31; P < 0.004, respectively). CONCLUSION: A reduction of proteinuria in CKD 1 diabetic kidney disease is accompanied by lower circulating sFas, myostatin and ADMA, suggesting that increased cell death may contribute to ADMA formation and endothelial dysfunction in diabetic CKD.

No regression of renal amyloid mass despite remission of nephrotic syndrome in a patient with TRAPS following etanercept therapy.

Reactive systemic (AA) amyloidosis leading to renal failure is the most severe complication of tumor necrosis factor receptor-associated periodic syndrome (TRAPS). There is now growing evidence to suggest that anti-tumor necrosis factor (anti-TNF) agents may be an attractive treatment option for amyloidosis not only in TRAPS but in several forms of secondary amyloidosis complicating inflammatory rheumatic diseases. In most of the reported cases, anti-TNF agents were deemed successful on the basis of regression of proteinuria and either improvement or stabilization of creatinine clearance, while objective proof of renal amyloid regression either by serum amyloid P scintigraphy or biopsy is limited. We herein report a case of TRAPS complicated with nephrotic syndrome due to AA amyloidosis in which treatment with etanercept was associated with remission of the nephrotic syndrome but no regression of amyloid mass on the follow-up renal biopsy. Indeed, amyloid deposition was noted to be more pronounced on the second renal biopsy, particularly at tubular basement membranes. Although the variable relation between reduction in amyloid load and changes in organ function is well-known, the basis for renal recovery in association with stable or even progressive amyloid deposition is challenging. We suggest that in patients with secondary AA amyloidosis, mechanisms other than the reduction of amyloid mass could have contributed to the observed improvement of renal function with anti-TNF agents.

Irritable bowel syndrome in haemodialysis: Prevalence, link with quality of life and depression.

AIM: Health-related quality of life (HRQOL) is decreased in haemodialysis (HD) patients. Irritable bowel syndrome (IBS) is highly prevalent in general population. This study evaluated the prevalence of IBS and its association with HRQOL and depression in HD. METHODS: Sociodemographic and laboratory variables were recorded. Severity of depressive symptoms and HRQOL were assessed by the Beck Depression Inventory (BDI) and Short Form 36 (SF-36), respectively. Diagnosis of IBS was based on Rome II criteria. RESULTS: Among 236 patients 69 (29.2%) had IBS. Patients with IBS had lower SF-36 scores and had higher depressive symptoms than patients without IBS. Presence of IBS was associated with sleep disturbance (odds ratio (OR) = 2.012; P = 0.045), physical component summary score (OR = 0.963, P = 0.029), mental component summary score (OR = 0.962, P = 0.023), BDI score (OR = 1.040, P = 0.021) and albumin (OR = 0.437, P = 0.01). CONCLUSION: IBS is highly prevalent in HD patients. Presence of IBS is closely related with HRQOL and depression.

Effect of renin-angiotensin-aldosterone system (RAAS) blockade on visfatin levels in diabetic nephropathy.

AIM: Plasma visfatin levels are elevated in diabetic nephropathy in parallel to the severity of proteinuria and glomerular filtration rate. The aim of this study was to find out whether the renin-angiotensin-aldosterone system (RAAS) blockage has any effect on the plasma visfatin levels. METHODS: Thirty-two patients with diabetic proteinuria (>500 mg/day) with a normal glomerular filtration rate (GFR) and 33 healthy subjects were enrolled. Patients were treated with ramipril 5 mg daily for 2 months. Proteinuria, GFR, high-sensitivity C-reactive protein (hsCRP), visfatin, flow-mediated dilatation (FMD) and homeostasis model assessment of insulin resistance (HOMA-IR) index measurements were performed both before and after the treatment. RESULTS: The plasma visfatin, and hsCRP levels of the patients were significantly higher and the FMD was significantly lower (P < 0.001 for all). The visfatin levels were significantly correlated to FMD, systolic and diastolic blood pressures, proteinuria, eGFR, HOMA-IR and hsCRP. Ramipril treatment resulted in a significant decrease in plasma visfatin, proteinuria, hsCRP, HOMA-IR and increase in FMD (P < 0.001) in patients (P < 0.001 for all). CONCLUSION: The present study suggests that plasma visfatin levels are related to the endothelial functions, inflammation and the severity of proteinuria in diabetic nephropathy. Treatment with ramipril causes a significant decrease in visfatin levels along with the improvement of proteinuria, endothelial dysfunction and inflammatory state in diabetic nephropathy.

Hemoglobin is inversely related to flow-mediated dilatation in chronic kidney disease.

The microcirculation is regulated by oxygen gradients and by endothelial release of nitric oxide, which can react with hemoglobin to form S-nitroso derivatives. Here we induced flow-mediated dilatation of the brachial artery in response to ischemia in 141 non-diabetic patients with stage 3-4 chronic kidney disease who had no history of smoking, cardiovascular events or use of erythropoietin-based agents. Patients with hemoglobin concentrations above the cohort median of 11.6 g/dl were found to have significant reductions in flow-mediated dilatation compared to those below the median. This inverse relationship remained significant after adjustment for potential confounders, including insulin sensitivity, glomerular filtration rate, proteinuria, body mass index, serum urate, etiology of underlying renal disease, treatment with anti-hypertensive drugs, and traditional Framingham risk factors. Given that hemoglobin can act as an important nitric oxide carrier and buffer, our studies suggest that the mechanism by which hemoglobin influences the endothelium-dependent microcirculation requires its nitrosylation; however, more direct studies need to be performed.

Normalization of endothelial dysfunction following renal transplantation is accompanied by a reduction of circulating visfatin/NAMPT. A novel marker of endothelial damage?

Endothelial dysfunction is strongly linked to cardiovascular disease and outcome of patients with chronic kidney disease. We hypothesized that decreased inflammatory activity and increased adiponectin following transplantation could be one mechanism for a better endothelial health. Fifty-eight living donor kidney transplant non-diabetic recipients, 31 (23 male, 29 +/- 5 yr) on cyclosporine A and 27 (10 male, 26 +/- 5 yr) on tacrolimus immunsupression, were studied longitudinally. Visfatin, adiponectin, high sensitive C-reactive protein (hsCRP) levels, brachial artery flow mediated dilatation (FMD) and nitroglycerine mediated dilatation were measured before transplantation and on the 30th and 90th day after transplantation. Pre-transplantation visfatin, adiponectin and FMD values of patients were significantly higher than those of the controls (p < 0.001 for all). All values decreased significantly 30 and 90 d post-transplantation. Plasma visfatin and adiponectin, correlated negatively with FMD levels 90 d both before and after kidney transplantation (p < 0.001 for both). Endothelial function improved during the first month after transplantation, and the degree of improvement correlated to reductions in circulating visfatin, adiponectin and hsCRP levels. Of interest, the intracellular enzyme visfatin was the strongest predictor of FMD both before and after kidney transplantation and may thus reflect endothelial cell damage directly.

ADMA levels correlate with proteinuria, secondary amyloidosis, and endothelial dysfunction.

Asymmetric dimethyl-arginine (ADMA), a residue of the proteolysis of arginine-methylated proteins, is a potent inhibitor of nitric oxide synthesis. The increased protein turnover that accompanies proteinuric secondary amyloidosis may increase circulating levels of ADMA, and this may contribute to endothelial dysfunction. We performed a cross-sectional study of 121 nondiabetic proteinuric patients with normal GFR (including 39 patients with nephrotic-range proteinuria and secondary amyloidosis) and 50 age-, sex-, and BMI-matched healthy controls. The proteinuric patients had higher levels of serum ADMA, symmetric dimethyl-arginine (SDMA), high-sensitivity C-reactive protein (hsCRP), and insulin resistance (homeostasis model assessment index) than controls. Compared with controls, brachial artery flow-mediated dilatation (FMD), serum L-Arginine, and the L-Arginine/ADMA ratio were significantly lower among proteinuric patients, suggesting greater endothelial dysfunction. When patients with secondary amyloidosis were compared with patients with glomerulonephritis who had similar levels of proteinuria, those with amyloidosis had higher ADMA and SDMA levels and lower L-Arginine/ADMA ratios and FMD measurements (P < 0.001 for all). Finally, even after adjusting for confounders, ADMA level correlated with both proteinuria and the presence of secondary amyloidosis, and was an independent predictor of FMD. We propose that ADMA synthesis may be increased in chronic kidney disease, especially in secondary amyloidosis, and this may explain part of the mechanism by which proteinuria increases cardiovascular morbidity and mortality.

The relationship between adiponectin levels and degree of proteinuria in patients with nephrotic and non-nephrotic proteinuria.

Adipose tissue appears to be a modulator of vascular injury and systemic inflammation. The aim of this study was to establish the relationship between plasma adiponectin concentration and severity of proteinuria in patients with proteinuria. We enrolled 77 patients with nephrotic and non-nephrotic proteinuria with normal renal function along with 38 matched controls in a cross-sectional study. These patients were divided into group 1 (n = 44, non-nephrotic proteinuria, <3.5 g/day) and group 2 (n = 43, nephrotic proteinuria, >3.5 g/day) by severity of proteinuria. Circulating adiponectin and high-sensitivity C-reactive protein (hsCRP) levels were measured using commercial ELISA. HOMA index and hsCRP levels were all significantly higher in proteinuric patients than in control subjects, while plasma adiponectin levels were significantly lower (p < 0.001). When compared to patients with non-nephrotic proteinuria, patients with nephrotic proteinuria had significantly higher plasma hsCRP and HOMA index (p < 0.001). According to the multiple regression analysis, proteinuria levels were independently related to adiponectin levels. Decreases in adiponectin levels were more prominent in patients with nephrotic proteinuria than in patients with non-nephrotic proteinuria. These results show that the reduction of plasma adiponectin concentrations depend on insulin resistance and inflammation rather than directly severity of proteinuria in patients with proteinuria.