John A. D’Elia

Effect of Glycemic Control on Heart Rate Variability in Type I Diabetic Patients With Cardiac Autonomic Neuropathy

Diabetic cardiac autonomic neuropathy (CAN) is associated with a high risk of cardiovascular events. Previous studies have shown that strict glycemic control slows the deterioration of CAN as assessed by standard autonomic function tests but fails to show reversibility. The aim of this study was to evaluate the effect of glycemic control on early and advanced CAN in type I diabetic patients using power spectral analysis of heart rate variability (HRV). Ten patients with early and 13 patients with advanced CAN were enrolled in a program of intensified insulin treatment. Standard autonomic function tests and 24-hour time and frequency domain HRV parameters were obtained at baseline, 3, 6, and 12 months. Hemoglobin A1C decreased from 9.5 +/- 0.4% to 8.4 +/- 0.5% (p = 0.02) in the early CAN group, and from 9.3 +/- 0.4% to 8.2 +/- 0.5% (p = 0.006) in the advanced CAN group. In general, both time and frequency domain HRV indexes tended to improve in patients with early CAN but continued to deteriorate in patients with advanced CAN. The low- and high-frequency power increased in patients with early CAN (229 +/- 95 to 626 +/- 563 ms2 and 62 +/- 30 to 183 +/- 168 ms2, respectively). The high-frequency power significantly improved at 12 months over baseline (p = 0.04), indicating increased parasympathetic tone. By contrast, these parameters continued to deteriorate in patients with advanced CAN (65 +/- 32 to 46 +/- 8 ms2 and 193 +/- 75 to 144 +/- 33 ms2, respectively). Autonomic function tests showed no significant change in both groups. These data show that a reversible metabolic component of CAN exists in patients with early CAN. Power spectral analysis of HRV allows early identification of potential reversibility as early as 1 year after the institution of strict glycemic control.

Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus

Heart rate variability (HRV) has been used to assess cardiac autonomic function noninvasively, understand the pathophysiologic mechanisms of heart disease, evaluate therapy, and assess long-term prognosis. We examined both the short- and long-term reproducibility of the time and frequency domain HRV parameters in 23 type I diabetics over a 12-month interval. Entry criteria included juvenile onset diabetes before age 35 years, >24-year duration of diabetes, diabetes difficult to control, and albuminuria. Standardized noninvasive autonomic testing and 24-hour ambulatory electrocardiographic recordings were obtained. Fifteen men and 8 women (mean age 36.7 years) were enrolled. Fifty-three percent of the men and 75% of the women were smokers, and women had higher cholesterol than men. All HRV parameters were markedly decreased when compared with normal persons. Using Pearson correlation, the time domain indicators of parasympathetic activity demonstrated very strong correlations at 3 and 6 months compared with baseline, with good correlations at 1 year. The average SD of all 5-minute RR intervals maintained a very strong correlation for the entire year (r >0.94). In the frequency domain, the measures of parasympathetic and sympathetic activity maintained a solid correlation for the entire study period. Reproducibility of HRV was also examined using repeated-measures analysis of variance. The time and frequency domain parameters demonstrated very little variation over the study period of 12 months. Thus, our investigation demonstrated that HRV in long-term diabetics using 24-hour ambulatory recordings is abnormal and reproducible over a 12-month interval; very little variation in all HRV parameters, especially in parameters of parasympathetic activity, occurred during the study period.

Circadian patterns of heart rate variability, fibrinolytic activity, and hemostatic factors in type I diabetes mellitus with cardiac autonomic neuropathy.

Diabetes mellitus is associated with a marked increase in the risk of coronary events but with an altered circadian distribution that demonstrates an absent morning peak and higher infarction rate during the evening hours. To elucidate the mechanism of this phenomenon, the circadian pattern of heart rate variability was evaluated in 22 type I diabetic patients with diabetic autonomic neuropathy in conjunction with circadian changes of fibrinolytic and hemostatic factors. The circadian pattern (6 A.M. to 10 P.M. vs 10 P.M. to 6 A.M.) of 3 indexes of parasympathetic tone was evaluated using 24-hour heart rate variability analysis. The high-frequency power (3.0 +/- 0.2 vs 3.3 +/- 0.2 ms2, p = 0.08) and the percentage of RR intervals with >50 ms variation (0.47 +/- 0.18 vs 0.69 +/- 0.33 ms, p = 0.52) demonstrated no significant circadian variation. The square root of mean squared differences of successive RR intervals showed a small but significant increase during nighttime (8.5 +/- 0.7 vs 9.7 +/- 1.1 ms, p = 0.02). Fibrinolytic activity was significantly lower at 8 A.M. than at 4 P.M. (166.4 +/- 12.5 to 200.2 +/- 9.3 mm2, p = 0.0003), but with a low amplitude. Plasminogen activator inhibitor 1 showed no circadian variation. Factor VII and fibrinogen demonstrated a significant reduction from 8 A.M. to 4 P.M., but both peak and nadir values were elevated. The von Willebrand factor was markedly elevated with no circadian variation. Thus, diabetic autonomic neuropathy is associated with a loss of both the nocturnal predominance of parasympathetic activity and a prothrombotic state that persists throughout the day. These abnormalities may attenuate the relative protection from coronary events during the afternoon and nighttime.

Diagnosis of Protein Calorie Malnutrition in Diabetic Patients on Hemodialysis and Peritoneal Dialysis

43 diabetic patients on hemodialysis (n = 26) and peritoneal dialysis (n = 17) underwent nutritional assessment by weight, midarm muscle circumference (MAMC), serum albumin, transferrin, prealbumin (P

Marked abnormalities in heart rate variability are associated with progressive deterioration of renal function in type I diabetic patients with overt nephropathy.

BACKGROUND Cardiac autonomic neuropathy is a common complication of long-standing, type 1 diabetes and is associated with increased morbidity and mortality. Impaired heart rate variability is a sensitive and reproducible marker of cardiac autonomic neuropathy. We sought to examine the relationship between cardiac autonomic neuropathy as assessed by heart rate variability and overt nephropathy, with emphasis on the progression of renal dysfunction over 1 year. METHOD Baseline and 12 month clinical and biochemical characteristics, as well as autonomic function tests, were analyzed in 23, type 1 diabetic patients (mean age 37+/-10 years, 65% males), who were prospectively enrolled as a part of a multi-center investigation. In addition, ambulatory, 24-h, 3-channel electrocardiograms were recorded, and heart rate variability indices were assessed in the time and frequency domains over the same period. RESULTS All heart rate variability indices were markedly decreased in our study population. On univariate analysis, heart rate variability was associated with creatinine clearance, and to a lesser extent, mean 24-h blood pressures and cholesterol. On multivariate analysis, only heart rate variability was a significant and independent predictor of abnormalities in creatinine clearance. Severe reduction in heart rate variability at baseline was also significantly associated with the further deterioration in renal function at 1 year. CONCLUSION Heart rate variability is significantly reduced in long-standing, type 1 diabetics with proteinuria or overt nephropathy. Marked abnormalities in heart rate variability are significantly associated with and predictive of progressive renal deterioration at 1 year. These findings may have implications for aggressive medical intervention to improve prognosis and survival in this population.

Pathophysiology of Obesity-Related Renal Dysfunction Contributes to Diabetic Nephropathy

Recent studies have demonstrated the role of insulin resistance in renal injury related to obesity, with hyperfiltration leading to glomerulomegaly in a pattern similar to that found in diabetic nephropathy. Similarities in the histologic patterns of damage from obesity and diabetes point to overlapping mechanisms of injury. In this review, we will examine the hormonal mechanisms, signaling pathways and injury patterns in renal injury resulting from obesity and attempt to draw conclusions on the reasons for these similarities.

Diabetic Renal Transplantation

Fifty-three juvenile onset diabetics have received 59 renal allografts: 31 from living related donors and 27 from cadaveric donors. The average patient age was 34 years and the duration of diabetes was 27 years at the time of transplantation. Patient survival rates for living related recipients at 1 and 2 years were 97 and 94 per cent, respectively. Patient survival rates for cadaveric recipients at 1 and 2 years were 85 and 66 per cent, respectively. Renal allograft survival rates for living related recipients were 81 per cent at 1 year and 71 per cent at 2 years. Cadaveric renal allograft survival rates were 22 per cent at 1 year and 20 per cent at 2 years. The role of pre-transplant coronary angiography relative to patient selection and a recent decrease in our perioperative mortality are discussed.

Protein-Restricted Diets in Diabetic Nephropathy

Low-protein diets in nondiabetic renal failure may slow the progressive loss of renal function in some patients, but few studies have detailed the nutritional consequences of these diets in patients with diabetic nephropathy. We studied 7 patients with insulin-dependent diabetes mellitus and chronic renal insufficiency [mean +/- SEM creatinine clearance (S, U): 28.3 +/- 6.5 ml/min (0.47 +/- 0.11 ml/s x 1.73/A)] for 15 weeks who were prescribed a diet of 0.6 g protein/kg ideal body weight. Midarm muscle circumference (24.1 +/- 1.8 at onset vs. 24.5 +/- 1.5 cm at completion), triceps skinfold thickness (21.6 +/- 3.1 vs. 21.0 +/- 1.5 mm), body weight (71.8 +/- 4.1 vs. 71.2 +/- 4.6 kg), and serum albumin [3.0 +/- 0.1 vs. 3.2 +/- 0.1 g/dl (30 +/- 1 vs. 32 +/- 1 g/l)] remained stable. Based on urinary nitrogen excretion, diet diaries overestimated the degree of dietary protein restriction; there was good adherence to the diet as evidenced by a reduction in urinary urea nitrogen (average 32%). Blood glucose control was maintained despite increased carbohydrate intake. On average, creatinine clearance did not change significantly, but proteinuria diminished slightly (1.8 +/- 0.2 vs. 1.5 +/- 0.6 g/day). These results indicate that 0.6 g/kg/day protein diets did not cause protein depletion in insulin-dependent diabetic patients. Longer-term studies are indicated to assess more fully the efficacy of these dietary regimens in reducing proteinuria or benefiting diabetic nephropathy.

RENAL ARTERY STENOSIS IN HYPERTENSIVE DIABETICS

The incidence of atherosclerotic renal artery stenosis was compared in consecutive renal angiography of 28 hypertensive diabetics and 104 hypertensive non-diabetics. Mean age and sex distribution were comparable. Angiographic evidence of atherosclerotic renal artery stenosis was present in 10 diabetics (36 per cent) and 50 non-diabetics (48 per cent). Stenosis was considered hemodynamically significant if the renal vein renin ratio of the involved to uninvolved side was 1.4:1.0 or more. A renal vein renin ratio equal to or more than 1.4 was observed in 4 of 7 diabetics (57 per cent) and 31 of 47 non-diabetics (67 per cent). Fibromuscular hyperplasia was not seen in diabetics but was present in 12 per cent of the non-diabetics. Hypertension was treated surgically and improved in 2 of 3 diabetics (67 per cent) and in 17 of 19 non-diabetics (89 per cent) with angiographic and hemodynamic evidence of renal artery stenosis. In this series the incidence of atherosclerotic renal artery stenosis of physiologic consequence was not significantly different in hypertensive diabetics when compared to hypertensive non-diabetics.

Manifestation of renal disease in obesity: pathophysiology of obesity-related dysfunction of the kidney.

Albuminuria in individuals whose body mass index exceeds 40 kg/m2 is associated with the presence of large glomeruli, thickened basement membrane and epithelial cellular (podocyte) distortion. Obstructive sleep apnea magnifies glomerular injury as well, probably through a vasoconstrictive mechanism. Insulin resistance from excess fatty acids is exacerbated by decreased secretion of high molecular weight adiponectin from adipose cells in the obese state. Adiponectin potentiates insulin in its post-receptor signaling resulting in glucose oxidation in mitochondria. Recent studies of podocyte physiology have concentrated on the structural and functional requirements that prevent glomerular albumin leakage. The architecture of the podocyte involves nephrin and podocin, proteins that cooperate to keep slit pores between foot processes competent to retain albumin. Insulin and adiponectin are necessary for high-energy phosphate generation. When fatty acids bind to albumin, the toxicity to proximal renal tubules is magnified. Albumin and fatty acids are elevated in urine of individuals with obesity related nephrotic syndrome. Fatty acid accumulation and resistin inhibit insulin and adiponectin. Study of cytokines produced by adipose tissue (adiponectin and leptin) and macrophages (resistin) has led to a better understanding of the relationship between weight and hypertension. Leptin, is presumably secreted after food intake to inhibit the midbrain/hypothalamic appetite centers. Resistance to leptin results in excess signaling to hypothalamic sympathetics leading to hypertension. Demonstration of the existence of a cerebral receptor mutation provide evidence for a role in hypertension of a central nervous reflex arc in humans. Further understanding of obesity-related renal dysfunction has been accomplished recently using experimental models. Rapid weight loss following bariatric surgery may reverse renal pathology of obesity with restoration of normal blood pressure.