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.

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.

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.

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.