Assessment of Hyperglycemia, Hypoglycemia and Inter-Day Glucose Variability Using Continuous Glucose Monitoring among Diabetic Patients on Chronic Hemodialysis.

Continuous glucose monitoring (CGM) facilitates the assessment of short-term glucose variability and identification of acute excursions of hyper- and hypo-glycemia. Among 37 diabetic hemodialysis patients who underwent 7-day CGM with the iPRO2 device (Medtronic Diabetes, Northridge, CA, USA), we explored the accuracy of glycated albumin (GA) and hemoglobin A1c (HbA1c) in assessing glycemic control, using CGM-derived metrics as the reference standard. In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) in diagnosing a time in the target glucose range of 70-180 mg/dL (TIR70-180) in <50% of readings was higher for GA (AUC: 0.878; 95% confidence interval (CI): 0.728-0.962) as compared to HbA1c (AUC: 0.682; 95% CI: 0.508-0.825) (p < 0.01). The accuracy of GA (AUC: 0.939; 95% CI: 0.808-0.991) in detecting a time above the target glucose range > 250 mg/dL (TAR>250) in >10% of readings did not differ from that of HbA1c (AUC: 0.854; 95% CI: 0.699-0.948) (p = 0.16). GA (AUC: 0.712; 95% CI: 0.539-0.848) and HbA1c (AUC: 0.740; 95% CI: 0.570-0.870) had a similarly lower efficiency in detecting a time below target glucose range < 70 mg/dL (TBR<70) in >1% of readings (p = 0.71). Although the mean glucose levels were similar, the coefficient of variation of glucose recordings (39.2 ± 17.3% vs. 32.0 ± 7.8%, p < 0.001) and TBR<70 (median (range): 5.6% (0, 25.8) vs. 2.8% (0, 17.9)) were higher during the dialysis-on than during the dialysis-off day. In conclusion, the present study shows that among diabetic hemodialysis patients, GA had higher accuracy than HbA1c in detecting a 7-day CGM-derived TIR70-180 < 50%. However, both biomarkers provided an imprecise reflection of acute excursions of hypoglycemia and inter-day glucose variability.

Comparison of Glycemic Markers in Chronic Hemodialysis Using Continuous Glucose Monitoring.

BACKGROUND: Glycated hemoglobin A1c (HbA1c) among diabetic hemodialysis patients continues to be the standard of care, although its limitations are well recognized. This study evaluated glycated albumin (GA) and glycated serum protein (GSP) as alternatives to HbA1c in detecting glycemic control among diabetic hemodialysis patients using continuous-glucose-monitoring (CGM)-derived glucose as reference standard. METHODS: A CGM system (iPRO) was applied for 7 days in 37 diabetic hemodialysis patients to determine glycemic control. The accuracy of GA and GSP versus HbA1c in detecting a 7-day average glucose ≥184 mg/dL was evaluated via receiver-operating-characteristic (ROC) analysis. RESULTS: CGM-derived glucose exhibited strong correlation (r = 0.970, p < 0.001) and acceptable agreement with corresponding capillary glucose measurements obtained by the patients themselves in 1,169 time-points over the 7-day-long CGM. The area under ROC curve (AUC) for GA, GSP, and HbA1c to detect poor glycemic control was 0.976 (0.862-1.000), 0.682 (0.502-0.862), and 0.776 (0.629-0.923) respectively. GA levels >20.3% had 90.9% sensitivity and 96.1% specificity in detecting a 7-day average glucose ≥184 mg/dL. The AUC for GA was significantly higher than the AUC for GSP (difference between areas: 0.294, p < 0.001) and the AUC for HbA1c (difference between areas: 0.199, p < 0.01). CONCLUSION: Among diabetic hemodialysis patients, GA is a stronger indicator of poor glycemic control assessed with 7-day-long CGM when compared to GSP and HbA1c.

Matrix Gelatinases in Atherosclerosis and Diabetic Nephropathy: Progress and Challenges.

BACKGROUND: Matrix metalloproteinases (MMPs) are zinc-dependent proteases that degrade components of the extracellular matrix (ECM). In glomerular disease, MMPs are major regulators of ECM degradation as well as structural and functional integrity in the glomerulus. In altered matrix composition diseases, glomerular damage is due to increased degradation of kidney and vessel basement membranes (BMs) by MMPs. MMP -2 and -9 are both considered as the main enzymes that degrade collagen type-IV (coll-IV), which represents the key collagenous component of ECM and constitutes the architectural structure of vessels and glomerular BM. There is growing evidence implicating MMPs in atherosclerosis as well as in cardiovascular disease (CVD) and chronic kidney disease (CKD). Specific endogenous tissue inhibitors of MMPs (TIMPs) are also implicated in CKD, CVD and diabetic nephropathy (DN). CONCLUSION: The present review discusses the role of MMPs -2 and -9 in DN, as a leading cause of endstage renal disease and as a model of the link between progressive glomerulosclerosis and MMP expression.

Role of asymmetrical dimethylarginine in the progression of renal disease.

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.

Elevated asymmetric dimethylarginine is associated with oxidant stress aggravation in patients with early stage autosomal dominant polycystic kidney disease.

BACKGROUND/AIMS: In experimental models of polycystic kidney disease impaired bioavailability of nitric oxide (NO) and elevated mRNA expression of oxidative stress markers at the kidney level was noted. However, clinical studies investigating the potential role of endothelial dysfunction and oxidative stress in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) are limited. We evaluated asymmetric dimethylarginine (ADMA) as marker of NO synthase inhibitor as well as 15-F2t-Isoprostane and oxidized-low density lipoprotein (oxidized-LDL) as measures of oxidative stress in patients with early stages ADPKD. METHODS: We recruited 26 ADPKD patients (Group A) with modestly impaired renal function (eGFR 45-70 ml/min/1.73 m(2)), 26 age- and sex-matched ADPKD patients (Group B) with relatively preserved renal function (eGFR)>70 ml/min/1.73 m(2)), and 26 age- and sex-matched controls (Group C). Determination of circulating levels of ADMA, 15-F2t-Isoprostane, oxidized-LDL and routine biochemistry was performed. RESULTS: Group A and B had significantly higher ADMA levels as compared to controls (1.68 ± 0.7 vs 0.51 ± 0.2 µmol/l, P<0.001 and 1.26 ± 0.7 vs 0.51 ± 0.2 µmol/l, P<0.001, respectively). 15-F2t-IsoP and oxidized-LDL levels were also significantly higher in Group B relative to controls (788.8 ± 185.0 vs 383.1 ± 86.0 pgr/ml, P<0.001 and 11.4 ± 6.6 vs 6.4 ± 2.6 EU/ml, P<0.05 respectively) and were further elevated in Group A. In correlation analysis, ADMA levels exhibited strong associations with levels of 15-F2t-Isoprostane (r=0.811, P<0.001) and oxidized-LDL (r=0.788, P<0.001), whereas an inverse correlation was evident between ADMA and eGFR (r=-0.460, P<0.001). CONCLUSION: This study shows elevation in circulating levels of ADMA along with aggravation of oxidative stress from the early stages of ADPKD. © 2014 S. Karger AG, Basel.

Aggressive systemic mastocytosis associated with mesangioproliferative glomerulonephritis.

BACKGROUND/AIMS/METHODS: Aggressive systemic mastocytosis (ASM) is a subtype of systemic mastocytosis, which comprises a heterogenous group of disorders characterized by infiltration of bone marrow, skin, liver, spleen, lymph nodes and gastrointestinal tract by neoplastic mast cells. There is lack of data on the association of ASM with renal involvement, as kidney is not among the known organs affected by ASM. RESULTS/CONCLUSIONS: To the best of our knowledge, this is the first case of ASM associated with mesangioproliferative glomerulonephritis and monoclonal gammopathy of undetermined significance, without the presence of nephrotic syndrome. The patient's clinical course and the intriguing family history, along with the treatment selection are described. Finally, the proposed possible pathophysiological mechanisms explaining the renal involvement of our patient are discussed.

Depression, heart rate variability, and exercise training in dialysis patients.

BACKGROUND: Functional limitations, altered cardiac autonomic activity, and psychological distress are known disorders in chronic hemodialysis (HD) patients, relating to increased morbidity and mortality. The aim of this study was to examine the influence of an exercise training program on emotional parameters and heart rate variability (HRV) indices, as well as to determine whether emotional stress contributes to autonomic dysfunction in these patients. METHODS: Forty-four HD patients were randomly assigned into group A (24 patients, aged 46.3+/-11.2 years), who participated in a 1-year intradialytic exercise training program and group B (20 patients, aged 45.8+/-10.8 years), who were used as controls. At baseline and a year after, measures of HRV were obtained for the estimation of standard deviation of RR intervals, the mean square successive differences, percentage of RR intervals differing by more than 50 ms from the preceding RR interval (pNN50), and low to high frequency components. Emotional parameters (Beck Depression Inventory - BDI and Hospital Anxiety and Depression Scale - HADS) were also assessed by validated questionnaires. Moreover, all patients performed a spiroergometric study for the estimation of VO2peak. RESULTS: At baseline, all measurements were similar in the two groups and remained almost unchanged after a year in group B. After a year of training, VO2peak increased from 16.79+/-5.24 to 22.33+/-4.90 ml/kg per min (P<0.001) in group A. Trained patients also showed an increase in standard deviation of RR intervals by 58.8% (P<0.001), the mean square successive differences by 68.1% (P<0.001), pNN50 by 23.5% (P<0.001), and a low to high frequency ratio by 17.3% (P<0.001). Finally, at the end of the study, group A showed a decrease in BDI score by 34.5% (P<0.001) and HADS by 23.9% (P<0.001). Canonical correlation revealed significant inverse correlation among depression (in BDI and HADS) and HRV indices before and after exercise training. CONCLUSION: Cardiac autonomic modulation seemed to be sensitive to the experience of persistent depression in HD patients. Significantly, exercise training reduced emotional distress and concomitantly improved HRV.

The effect of folic acid supplementation on carotid intima-media thickness in patients with cardiovascular risk: a randomized, placebo-controlled trial.

INTRODUCTION: Observational studies have suggested a causal relationship between hyperhomocysteinemia and cardiovascular complications such as stroke and ischemic heart disease. The Homocysteine Lowering Trialists' Collaboration has shown that daily administration of folic acid can significantly decrease homocysteine levels up to 25%. Aim of this study was to investigate the effect of daily supplementation of folic acid (5 mg) on IMT after 18 months of treatment in patients with at least one cardiovascular risk factor. METHODS: We enrolled 103 patients with at least one cardiovascular risk factor who were randomized to receive either a daily dose of 5 mg folic acid (group I, n=53) or placebo (group II, n=50) for 18 months. RESULTS: After 18 months of folic acid supplementation, homocysteine levels were significantly reduced in the active treatment group compared to a non-significant increase in the placebo group. Folic acid levels were markedly increased in the former group and non-significantly reduced in the latter. Significant regression of carotid IMT was observed (0.961+/-0.092 to 0.933+/-0.077 mm, p<0.001) compared to significant IMT progression in the placebo group (0.964+/-0.099 to 0.984+/-0.094 mm). CONCLUSION: Folic acid supplementation results in significant IMT reduction after 18 months in patients with at least one cardiovascular risk.

The controversial role of B-vitamins in cardiovascular risk: An update.

Cardiovascular disease is the leading cause of death in Western countries. Since 1969, homocysteine has been implicated in the atherosclerotic process, and numerous observational studies have suggested that hyperhomocysteinaemia should be considered as an independent cardiovascular risk factor. B-vitamins, particularly folic acid, reduce homocysteine levels effectively; it was suggested, therefore, that supplementation with these vitamins might decrease cardiovascular risk and reduce the morbidity and mortality associated with stroke, coronary heart disease and peripheral artery disease. However, the results of clinical trials conducted to investigate this issue have been inconsistent. This review discusses the findings of these trials and provides an updated overview on the 'homocysteine hypothesis'.

Effects of exercise training on noninvasive cardiac measures in patients undergoing long-term hemodialysis: a randomized controlled trial.

BACKGROUND: Noninvasive screening studies may identify hemodialysis (HD) patients at increased risk of sudden cardiac death. Interventions that improve the findings of such screening studies may reduce sudden cardiac death. STUDY DESIGN: Randomized and controlled clinical trial. SETTING & PARTICIPANTS: 59 HD patients were randomly assigned to an exercise training group (group A; 30 patients) or control group (group B; 29 patients). INTERVENTION: Group A participated in a 10-month supervised exercise training program during the HD sessions (3 times weekly). OUTCOMES: Each risk factor separately and the composite risk score. Patients were considered high risk according to the criteria (aerobic capacity: peak oxygen consumption [Vo(2)peak] < or = 14 mL/kg/min, left ventricular ejection fraction < or = 30%, SD of normal RR intervals [SDNN] < or = 70 milliseconds, positive T-wave alternans, or positive late potentials). Statistical analysis included a 2-group comparison of change scores and analysis of covariance adjusting for baseline. MEASUREMENTS: At entry and end of the study, Vo(2)peak and left ventricular ejection fraction were estimated, heart rate variability was calculated (measurement of SDNN, mean RR intervals), and the ratio between low- (LF) to high-frequency (HF) components (LF/HF) and late potentials and T-wave alternans were detected. RESULTS: Baseline measurements were similar between the 2 groups. At follow-up, 9 patients from group A and 20 from group B (P = 0.003) were considered high risk. The change in number of risk markers over time was significantly different between groups (-0.5 +/- 0.7 in group A versus 0.07 +/- 0.3 in group B; P < 0.001). Additionally, the change in Vo(2)peak over time was 3.5 +/- 3.2 in group A and -0.2 +/- 3.5 mL/kg/min in group B (P < 0.001), left ventricular ejection fractions were 3.4% +/- 3.9% and 0.2% +/- 7.7% (P < 0.05), SDNNs were 12.6 +/- 16.3 and -1.1 +/- 10.2 milliseconds (P < 0.001), and LF/HF ratios were 0.3 +/- 0.4 and -0.1 +/- 0.3 (P < 0.001), respectively. Change in numerical score of the signal-averaged electrocardiogram also was found to be statistically different (P < 0.05) between groups. LIMITATIONS: Clinical outcomes, including survival, were not assessed. CONCLUSIONS: Exercise training improves aerobic capacity and ameliorates some indicators of risk of sudden cardiac death in HD patients.

Physical training in patients on hemodialysis has a beneficial effect on the levels of eicosanoid hormone-like substances.

OBJECTIVE: The aim of this study was to evaluate the changes in the levels of vasoactive eicosanoid hormone-like substances PGE2, PGI2 and TXA2 in hemodialysis (HD)patients who were following a long-term physical training program during the hemodialysis session. DESIGN: A total of 50 patients with Chronic Kidney Disease (CKD) (stage 5)on hemodialysis and 35 healthy individuals who served as controls (C) were evaluated. The 50 CKD patients were divided into two groups: the HD group consisted of 31 patients who received usual care without any physical activity during the hemodialysis sessions, while group HD/Exer included 19 patients who followed a program of physical exercise for six months. Plasma levels of PGE2, 6-Keto-PGF1alpha (the stable derivative of PGI2) and TXB2 (the stable derivative of TXA2) were measured by reliable enzymo-immunoassay methods (EIA) in HD and HD/Exer patients before and after the hemodialysis sessions as well as in the group of C. RESULTS: The plasma levels of PGE2 and 6-keto-PGF1alpha in group HD Exer/before patients were higher than those in group HDbefore (20.39+/-5.82 and 1449.19+/-553.41 vs 17.68+/-5.36 and 1295.10+/-384.43 pg/ml, p=0.044 and p=0.067, respectively), while the plasma levels of TXB2 were lower in HD Exer/before patients compared to HDbefore(499.76+/-67.51 vs 608.01+/-80.23 pg/ml, p=0.041). The plasma levels of PGE2 and 6-keto-PGF1alpha in group HD Exer/after patients were significantly higher compared to those in HDafter patients (23.01+/-5.70 and 1618.19+/-435.07 vs 16.57+/-4.97 and 1005.44+/-317.16 pg/ml, p<0.001 and p<0.040, respectively). However, significantly lower values in the plasma levels of TXB2 in HD Exer/after compared to HDafter patients (363.10+/-51.91 vs 439.75+/-62.34 pg/ml, p=0.030) were detected. As expected, PGE2 and 6-keto-PGF1alpha values were lower in C than in the groups of patients with CKD. CONCLUSIONS: The data indicate that exercise training during HD exerts a beneficial effect on the levels of the vasoactive eicosanoid hormone-like substances in patients on HD.

Effects of intradialytic exercise training on health-related quality of life indices in haemodialysis patients.

OBJECTIVE: To assess the effects of intradialytic exercise training on health-related quality of life indices in haemodialysis patients. SUBJECTS/PATIENTS: Thirty-five patients on haemodialysis, with a mean (SD) age of 48.8 (13.9) years, volunteered to participate in the study. They were randomized either to rehabilitation group (group A: 19 patients), following a 10-month intradialytic exercise training programme or to control group (group B: 14 patients). After the randomization, two of the patients, one of each group, withdrew from the study for reasons unrelated to exercise training. METHOD: All patients at the beginning and the end of the study underwent clinical examination, laboratory tests and a treadmill exercise testing with spiroergometric study for the evaluation of their aerobic capacity (Vo(2peak)). A formal psychosocial assessment, which included affective (Beck Depression Inventory), health-related quality of life (Quality of Life Index, Living Questionnaire of Minnesota, Life Satisfaction Index and Short Form-36 questionnaire) and personality (Eysenck Personality Questionnaire) parameters, was evaluated at beginning and end of the study. The dose of erythropoietin was changed as needed, according to the level of the haemoglobin, aiming to keep it at 11 (2) g/dL during the study. RESULTS: Baseline values were similar between the two groups. After training in group A, Vo(2peak) was increased by 21.1% (P<0.05) and exercise time by 23.6% (P<0.05). Moreover, group A showed a decrease in self-reported depression (Beck Depression Index) of 39.4% (P<0.001). In addition, trained patients demonstrated a significant improvement in Quality of Life Index (from 6.5 (1.8) to 9.0 (1.3), P<0.001) and Life Satisfaction Index (from 44.8 (8.6) to 53.0 (5.6), P<0.001), and an increase in the Physical Component Scale of the SF-36 (from 40.5 (5.6) to 44.5 (5.5), P<0.05), while the Mental Component Scale remained unchanged. Multiple regression analysis indicated that the improvement in quality of life depended on the participation in exercise programmes, the effects of training and the reduction in the level of depression. No changes were observed in Eysenck Personality Questionnaire by the end of the study, while all the above parameters remained almost unchanged in the controls. CONCLUSION: The results demonstrated that intradialytic exercise training improves both physical functioning and psychological status in haemodialysis patients, leading to an improvement of patients' quality of life.

Enhanced oxidative stress with a gradient between plasma and muscle interstitial fluid in patients with end stage renal failure on hemodialysis.

OBJECTIVE: The concentration of 8-iso-prostaglandin-F2 alpha (8-iso-PGF2 alpha in biological fluids has been considered as the most reliable biochemical index of the lipid peroxidation and oxidative stress in patients with several pathological conditions including end stage renal failure. However, there is no reference regarding the influence of Hemodialysis (HD) on the values of 8-iso-PGF2 alpha in the muscle Interstitial Fluid (IF) of patients with end stage renal failure. The aim of our study was to determine 8-iso-PGF2 alpha concentration in the IF during hemodialysis and the gradient between plasma and IF in patients with end stage renal failure. DESIGN: In this study, two microdialysis probes were inserted into the vastus lateralis muscle of the right leg of six male patients with end stage renal failure who were on hemodialysis, and in six healthy males (controls). The samples of IF (12 dialysate fluids) were collected after an equilibration of 30 min: a) during the 1st hour preceding hemodialysis (group CRF0), b) during the 1st, 2nd, 3rd and 4th hour while on hemodialysis (groups CRF1, CRF2, CRF3 and CRF4) and c) during the 1st hour following hemodialysis (group CRF5). At the end of the above periods and simultaneously, blood samples were drawn from the arteriovenous fistula. In the controls, the IF samples (twelve dialysate fluids) were collected during a period of one hour and the blood samples at the end of this period. The levels of 8-iso-PGF2 alpha were measured with an enzyme-immunoassay method. Statistical evaluation was carried out with the statistical program NCSS 2000 and the ANOVA test. RESULTS: Plasma and IF levels of 8-iso-PGF2 alpha in the patients were significantly higher than in controls at base line. During hemodialysis, the 8-iso-PGF2 alpha rose progressively both in plasma and IF but remained higher in plasma than in IF. CONCLUSIONS: Lipid peroxidation is higher in patients on hemodialysis than in controls but it is lower in the IF compared to plasma. The mechanism for this gradient is speculative.

Increase in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease.

BACKGROUND/AIMS: Increased oxidative stress in chronic kidney disease (CKD) was suggested to be both a cause and an effect of renal injury. However, the evolution of oxidant stress from early stages of renal function decline is not fully clear. This study aimed to determine the oxidant-antioxidant balance across the whole range of renal function. METHODS: A total of 116 patients with CKD (85 predialysis patients divided into groups according to CKD stage, and 31 patients with end-stage renal disease (ESRD) on hemodialysis treatment), as well as 29 healthy subjects were evaluated. Plasma levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP), a valid marker of oxidant stress, as well as total antioxidant capacity (TAC) and serum levels of vitamin E were measured in all participants. RESULTS: Plasma 15-F(2t)-IsoP levels were higher in predialysis and ESRD patients compared to healthy subjects and were progressively increasing with advancing CKD stages (p < 0.001). In contrast, plasma TAC was similar between healthy subjects and predialysis patients, and presented a small reduction in ESRD patients (p < 0.001). Vitamin E levels were higher in healthy subjects compared to any other group (p < 0.001) and slightly higher in ESRD patients compared to predialysis patients (p < 0.01), but did not differ significantly between the groups of predialysis patients. Plasma 15-F(2t)-IsoP levels were inversely correlated with estimated glomerular filtration rate in predialysis patients (r = -0.65, p < 0.001). CONCLUSIONS: This study shows that 15-F(2t)-IsoP levels increase progressively with advancing CKD stages, whereas TAC and vitamin E levels remain rather stable with the loss of renal function and change only in patients with ESRD.

A cost-effectiveness analysis of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in diabetic nephropathy.

The aim of this study was to estimate the cost-effectiveness of renin-angiotensin-aldosterone system blockers in patients with diabetic nephropathy. A cost-effectiveness analysis was performed based on a meta-analysis of studies investigating the effect of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) as part of a treatment regimen on the incidence of end-stage renal disease (ESRD) in patients with diabetic nephropathy. The primary outcome was the cost to prevent 1 patient from developing ESRD. Cost analysis was performed from a third-party payer perspective in 2006 US dollars. As part of a treatment regimen, ARBs significantly reduced the incidence of ESRD and doubling of serum creatinine concentration (P<.05) but not total mortality. The cost to prevent 1 patient from developing ESRD was $31,729 (95% confidence interval, $19,443-$85,442; P<.01), $189,190 (P=.13) and $51,585 (P=.068) for patients receiving ARBs, ACE inhibitors, or either of them, respectively. This study demonstrates that blocking the RAAS, which delays the progression to ESRD, appears to be cost-effective. The current analysis favors ARBs in terms of cost-effectiveness.

Insulin resistance and oxidant stress: an interrelation with deleterious renal consequences?

Within the past years, several epidemiologic studies have shown that insulin resistance and hyperinsulinemia are associated with chronic kidney disease, and experimental data suggest that a number of background mechanisms could connect insulin resistance with renal injury. Moreover, the acute sodium-retaining action of insulin at the kidney level has been proposed to participate in the development of salt sensitivity in essential hypertension. Current knowledge suggests that oxidative stress can be involved in the development of renal injury and can also promote primary salt retention at the kidney level. Insulin resistance and hyperinsulinemia seem to be closely connected with oxidative stress in the form of a vicious circle. This article discusses the potential role of oxidative stress as a mediator of the renal effects of insulin resistance/hyperinsulinemia.

Digital clubbing as an unusual complication associated with severe secondary hyperparathyroidism: report of two cases.

Digital clubbing due to secondary hyperparathyroidism has been described as an unusual complication among patients with chronic kidney disease undergoing maintenance hemodialysis therapy. Although the pathogenesis of digital clubbing is unknown, certain growth factors such as platelet-derived growth factor and hepatocyte growth factor have been associated with this clinical syndrome. Two patients of our renal unit population presented this unique clinical feature bilaterally, among the other clinical findings of severe secondary hyperparathyroidism. Both patients were subjected to parathyroidectomy. Histological examination revealed diffuse hyperplasia of parathyroid glands. Despite the improvement of clinical symptoms and laboratory findings of secondary hyperparathyroism after parathyroidectomy, digital clubbing remained unchanged.

Association between hyperhomocysteinemia and ultrasonographic atherosclerotic indices of carotid arteries in chronic hemodialysis patients.

BACKGROUND: Atherosclerotic cardiovascular events are a major cause of morbidity and the main cause of mortality in hemodialysis patients. Hyperhomocysteinemia--which is a consistent finding in uremic patients--is considered an independent risk factor for cardiovascular disease (CVD). However, the relationship between plasma homocysteine (Hcy) concentrations and atherosclerotic CVD has not been extensively investigated. PATIENTS AND METHODS: 37 patients undergoing chronic hemodialysis and 30 healthy individuals (control group), sex- and age-matched, were included in this study. Both healthy controls and hemodialysis patients underwent echo-Doppler carotid artery examination. The right and left carotid arteries were assessed separately. Our observation included measurements of the ultrasound images of the intimal wall thickness, the lumen diameter and the atherosclerotic plaques. We determined plasma Hcy, vitamin B12 and folic acid levels and serum cholesterol, triglycerides, HDL, ApoA-I, ApoB-100, Lp(a), CRP, albumin and creatinine levels in blood samples from both studied groups. We also determined the urea reduction ratio in the patient groups. The epidemiological as well as the biochemical data were correlated with the findings of the carotid artery examination. RESULTS: Plasma Hcy levels were significantly increased in hemodialysis patients compared to controls (33 +/- 12.3 vs. 12.27 +/- 7.47 micromol/l, p < 0.001). Intimal wall thickness, lumen diameter and number of atherosclerotic plaques of both carotid arteries were significantly higher (p < 0.01 or p < 0.001) in patients compared to controls. There was a significant positive correlation between plasma Hcy levels and the number of the atherosclerotic plaques (r = 0.41, p < 0.01 in the right and r = 0.49, p < 0.001 in the left carotid artery). Lumen diameter was significantly (p < 0.01) associated with age, MAP and CRP levels. Significant correlations (p = 0.05-0.01) were also found between the number of the plaques and age as well as the duration of hemodialysis, while folic acid levels were inversely correlated with the number of the plaques. CONCLUSIONS: Both hyperhomocysteinemia and atherosclerotic indices of the carotid arteries are more prevalent in hemodialysis patients compared to healthy controls. Elevated plasma Hcy levels were associated with the carotid artery atherosclerotic indices in chronic hemodialysis patients.

Unit dosing of darbepoetin alfa for thetreatment of anemia in patients with end-stage renal disease being switched from recombinant human erythropoietin: Results of a phase IIIb, 27-week, multicenter, open-label study in Greek patients.

BACKGROUND: Darbepoetin alfa is an erythropoietis-stimulating glycoprotein with a ∼3-fold longer t1/2 and greater biological activity compared with recombinant human erythropoietin (rHuEPO). OBJECTIVE: The objective of this study was to evaluate the efficacy andtolerability of long-term (24-week) darbepoetin alfa treatment in maintaining hemoglobin (Hb) concentrations in the target range of 10 to 13 g/dL in patients undergoing dialysis; the patients were switched from rHuEPO to a less-frequent dosing regimen of darbepoetin alfa without an increase in dose. METHODS: In this Phase IIlb, open-label, multicenter study, patients withend-stage renal disease (ESRD) undergoing dialysis who were receiving rHuEPO BIW or TIW at baseline were switched to darbepoetin alfa QW; patients receiving rHuEPO QW were switched to darbepoetin alfa Q2W Administration of darbepoetin alfa was by the same route as previous rHuEPO administration (IV or SC). Patients received darbepoetin alfa for 24 weeks, including a 20-week drug titration period followed by a 4-week, stable-dose evaluation period. The mode, dose, and frequency of administration of darbepoetin alfa were compared with those of baseline rHuEPO. Tolerability assessment was based on spontaneous reporting and laboratory tests (hematology, vital sign measurement, iron status, and biochemistry). RESULTS: The study comprised 173 patients who were divided into 2 groups by route of administration (IV group, n = 146; SC group, n = 27). Mean (SE) adjusted increases in Hb concentration from baseline to the evaluation period for patients receiving darbepoetin alfa QW were 0.94 (0.32) g/dL and 0.38 (0.30) g/dL for the IV or SC routes, respectively (P = 0.004 and NS, respectively). For patients receiving darbepoetin alfa Q2W the mean (SE) adjusted increases in Hb concentration were 0.08 (0.53) g/dL and 0.48 (0.35) g/dL for the IV and SC routes, respectively (both, P = NS). No significant differences in IV/SC dose ratio were observed between the 2 routes of administration. In addition, no increases in darbepoetin alfa dose were observed. The most commonly reported adverse events were hypertension (8 patients [5%]) and vascular access thrombosis (4 [2%]). The incidence of treatment-related adverse events was 6 (3%). CONCLUSIONS: Darbepoetin alfa effectively maintained Hb concentrations within the target range without an increase in dose, even at a reduced dosing frequency. Overall, darbepoetin alfa was well tolerated.