Metabolic responses during hemodialysis determined by quantitative (1)H NMR spectroscopy.

A large proportion of patients with end-stage renal disease have lifelong hemodialysis (HD) treatment. HD rapidly and indiscriminately removes necessary small metabolites together with uremic toxins from plasma into dialysate. To investigate metabolic responses to HD, we determined the levels of metabolites through time-course monitoring of (1)H NMR spectroscopy of dialysate during HD. The dialysate sample is stable for analysis because it contains only small metabolites without proteins. It was collected non-invasively from 9 HD patients with chronic glomerular nephropathy, at 6 time points during 4h of HD in 5 sessions. Creatinine, alanine, lactate, pyruvate and valine were simultaneously quantified on a one-dimensional single-pulse spectrum with a single standard compound. The concentration of creatinine exhibited monotonous decay with time, while that of valine decreased slowly and then maintained its levels throughout an HD. Lactate, alanine and pyruvate increased at 2-3h after the initiation of HD. They exhibited remarkable responses to HD with production from the body. The time-course of change in the 4 metabolites of lactate, pyruvate, alanine, and valine had reproducible behavior unique to each patient during the HD. This finding may be applied to distinguish metabolic status in HD patients.

¹H NMR spectroscopic quantification of plasma metabolites in dialysate during hemodialysis.

We used ¹H nuclear magnetic resonance (NMR) spectroscopy to assess metabolic responses in patients undergoing hemodialysis (HD). We collected 71 samples of plasma and dialysate from 10 patients before, during, and after HD. We used the dialysate as a possible substitute for blood plasma to quantify small metabolites by ¹H NMR. We confirmed TSP (sodium 3-(trimethylsilyl) propionate 2, 2, 3, 3-d4) as a reference of NMR intensity in dialysate. We examined TSP sensitivities in various dialysate spectra and the correlation between signal intensities and added quantities of TSP. We used integrations of signal areas on ¹H NMR spectra of plasma and dialysate to quantify concentrations of creatinine, lactate, alanine, and valine and calculate their ratios between plasma and dialysate. The ratios of metabolites in plasma to dialysate were 3.2±0.4 (creatinine), 3.6±0.5 (valine), 3.8±0.7 (alanine), and 4.0±0.8 (lactate) mM (mean±standard deviation [SD]). The broader distributions of ratios in levels of lactate and alanine suggested their de novo production during the HD session. Estimation of blood metabolite levels using dialysate is useful for quantitative analysis of metabolic status in blood during HD.

Three-year follow-up of lanthanum carbonate therapy in hemodialysis patients.

For 3 years following the start of lanthanum carbonate therapy, effects on other pharmaceutical treatment with sevelamer hydrochloride (SH), calcium carbonate (CC), and vitamin D, and those on clinical condition were examined. Dialysis patients with hyperphosphatemia (89 cases; average age 55.2 years; dialysis history of 10 years; 50 male and 39 female), who agreed to start lanthanum carbonate (LC) administration, were observed for a mean period of 32.6 ± 6.2 months. Mean daily dosages of CC and SH before starting LC were 2.68 g and 0.73 g; mean daily dosage amounts of LC, CC, and SH at the time of final evaluation were 0.87 g, 2.30 g, and 0.99 g, respectively. After the application of LC, serum phosphate as well as serum calcium controls were significantly improved, and the amounts of active vitamin D agents applied was significantly increased. In conclusion, LC is useful in managing serum phosphorus levels (P levels), and little incidence of hypercalcemia suggests favorable concomitant use with active vitamin D agents in LC therapy.

Cinacalcet for hemodialyzed patients with or without a high PTH level to control serum calcium and phosphorus: ECO (evaluation of cinacalcet HCl outcome) study.

BACKGROUND: We investigated the influence of cinacalcet on serum Ca and P in hemodialyzed patients with or without a high PTH level, according to K/DOQI guideline, to control serum Ca and P levels. METHODS: We recruited 130 patients in this prospective cohort study and classified them into Group A (iPTH > 300 pg/ml), Group B (iPTH = 181 - 300 pg/ml), and Group C (iPTH ≤ 180 pg/ml). After 24 weeks on cinacalcet, serum Ca, P and iPTH were measured. RESULTS: The achievement rate of the target iPTH level in JSDT guideline was significantly higher in Group B compared with Group A. The achievement rate of serum Ca and P target levels in the Japanese Society for Dialysis Therapy (JSDT) guideline was higher in Group C. In Group A and Group C, the simultaneous achievement rates (Ca, P, and iPTH) in KDOQI guideline increased after treatment with cinacalcet (p < 0.01). There was no difference in the reduction of Ca and P among the groups, while the iPTH reduction was significantly lower in groups B and C compared with that in A. CONCLUSION: Administration of cinacalcet to patients with or without high PTH levels, according to the K/DOQI guideline, facilitates the control of Ca and P levels.

Biotin ameliorates muscle cramps of hemodialysis patients: a prospective trial.

Patients with renal failure undergoing hemodialysis often have muscle cramps during and after the dialysis therapy. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied with severe pain, resulting in early termination of a HD session and inadequate dialysis. The etiology of the cramps is unknown and effective anti-cramp medicine is not available. We have hypothesized that water-soluble vitamins are deficient in HD patients. Accordingly, we administrated biotin to 14 patients who had frequent muscle cramps during HD sessions. Oral administration of 1 mg/day biotin promptly reduced the onset and the severity of cramps in 12 patients both during and after HD. Then, the plasma biotin levels were measured by an enzyme-linked immunosorbent assay method (ELISA) in HD patients, including 14 patients with cramps and 13 patients without cramps, and 11 healthy volunteers. Plasma biotin levels were elevated in 27 HD patients at baseline compared with healthy volunteers [451 (377 - 649) vs. 224 (148 - 308) ng/l, median (lower-upper quartiles); p < 0.0001]. Unexpectedly, among the 14 cramp patients, the biotin levels were significantly higher in biotin-ineffective 7 patients than biotin-effective 7 patients [1,064 (710 - 1,187) vs. 445 (359 - 476) ng/l; p < 0.001]. Thus, the biotins measured by ELISA may consist of not only intact biotin but also its metabolites that do not function as a vitamin. In conclusion, biotin administration is one choice to relieve HD patients from muscle cramps regardless of their elevated plasma biotin levels.

Serum soluble α-klotho in hemodialysis patients.

BACKGROUND: The extracellular domain of klotho is cleaved and released into various extracellular fluids, such as blood, urine, and cerebrospinal fluid, as soluble α-klotho (sαKl). METHODS: We measured sαKl in 53 hemodialysis patients and 20 healthy controls to examine its role in mineral metabolism. RESULTS: The sαKl level of the hemodialysis patients was 430 pg/ml (386 - 540 pg/ml, which was lower than that of healthy controls 740 pg/ml (550 - 913 pg/ml, p < 0.01). The serum sαKl level showed a positive correlation with serum phosphorus (P) (σ = 0.33, p = 0.014), while serum corrected Ca tended to be negatively correlated with sαKl (σ = -0.26, p = 0.06). Both parameters showed the same trends in healthy subjects. However, there was no significant association between serum sαKl and age (σ= 0.21, p = 0.14), intact PTH (σ = -0.08, p= 0.55), whole PTH (σ = -0.08, p = 0.59), or FGF23 (σ = -0.07, p = 0.62). Multiple regression analysis showed that P was independently associated with the serum sαKl levels (total adjusted R2 = 0.18, p = 0.02). CONCLUSIONS: The sαKl level was lower in hemodialysis patients than in healthy persons. Serum P level was independently associated with the serum sαKl level.

Blood pressure and sympathetic nerve tone relation during hemodialysis may reflect cardiovascular dysfunction.

BACKGROUND: The blood pressure response to the rapid removal of fluid during hemodialysis is complex and the pathophysiological mechanisms underlying intradialytic hypotension are not clear and sometimes these mechanisms render dialysis difficult to continue. PURPOSE: We analyzed the changes in blood pressure and sympathetic nerve tone and attempted to clarify whether the dynamic pattern of this relationship reflects cardiovascular dysfunction. METHODS: The dynamic pattern of sympathetic nerve activity throughout dialysis was analyzed by frequency analysis of RR intervals recorded by 24 hours Holter electrocardiography in 64 patients and 3 minutes ECG every 15 minutes during dialysis in 121 stable end-stage renal failure patients who underwent maintenance hemodialysis. Blood pressure and fluid volume removed was measured every 15-30 minutes during dialysis and the average value of the ratio of low to high frequency components (LF/HF) was calculated as an index of sympathetic nerve tone. The relationship between removed fluid volume, systolic blood pressure (Bp) and LF/HF was analyzed. RESULTS: The patients were classified into 3 groups based on the correlation between the LF/HF and Bp as follows: positive (52 cases), inverse (54 cases), and not significant (NS; 61 cases). Eighteen patients who showed multiple arrhythmias, atrial fibrillation and other artifacts or noises were eliminated as they were inadequate for frequency analysis of RR intervals. The positive group was characterized by a hypotension-resistant response with a low LF/HF, whereas the inverse group was characterized by a hypotension-prone response with high LF/HF. These results suggest that cardiovascular dysfunction is responsible for the inverse correlation. CONCLUSION: Analysis of the relationship between sympathetic nerve tone and Bp is effective in predicting the existing of cardiovascular dysfunction.

Attempt of quantitative analysis of visual evaluation for (123)I-BMIPP myocardial scintigraphy images.

We developed a new technique to quantitatively analyze visual evaluation single photon emission computed tomography (SPECT). Short axis tomograms and color scales were computer scanned. The scales were divided into 25 parts; numbers of each hue pixel were scored 0-100%. Short-axis images were divided into eight equal partitions, numbers of hue pixels distributed in each partition were scored, and total scores were obtained. Each partition's radio-isotope (RI) accumulation index was calculated as partition score/highest score. For method validation, scintigrams from each left ventricular phantom part were divided into eight partitions and filled with (123)I-BMPP (10-100%). The error between theoretical and calculated concentrations was within 20% in the concentration range of ≥50%, suggesting a good correlation and indicating the method's validity.

Pattern recognition analysis for 1H NMR spectra of plasma from hemodialysis patients.

1H NMR spectroscopic and pattern recognition-based methods (NMR-PR) were applied to the metabolic profiling studies on hemodialysis (HD). Plasma samples were collected from 37 patients before and after HD and measured by 600 MHz NMR spectroscopy. Each spectrum was data-processed and subjected to principal component analysis for pattern recognition. Spectral patterns of plasma between pre- and post-dialyses were clearly discriminated, together with significant fluctuations in the levels of creatinine, trimethylamine-N-oxide, glucose, lactate, and acetate, which were quantitated. We have first observed the significant elevation of lactate levels in post-dialysis plasma. The present study has demonstrated the high feasibility of NMR-PR method for monitoring the dialysis condition and comprehensive profiling of the change of low-molecular-weight metabolites in HD.

Evaluation of carotid atherosclerosis from the perspective of blood flow reflection.

Detection and prevention of atherosclerosis at an early stage is important for its prevention. The aim of this study was to propose a valid and highly reliable index for the evaluation of carotid atherosclerosis or carotid function. Images of carotid Doppler wave profiles were processed using an image processing software, and the relative fluctuation in blood flow was calculated from the luminance in one cardiac cycle. Frequency analysis was performed and up to 10 time components of basic frequency (f1) were indicated. The evaluation function alpha was estimated by calculating the ratio of the sum of components f3-f10 against the f1 + f2 components. Blood pressure of the finger was continuously measured using Finapress during passive postural change from the supine to the standing position, the baroreceptor function was evaluated by the frequency method, and the plaque score was measured by ultrasound tomography. The influence of factors such as arterial compliance, blood vessel resistance, and heart rate on this index was studied using electric circuit model simulation. The subjects were 33 patients (18 men, 15 women) who had various types of atherosclerotic disease and hypertension. The average age was 67.3 + 12.2 years. The results showed that index alpha had a strong negative correlation with age and plaque score, and a weak positive correlation with baroreceptor function. Simulation results supported the clinical result. We proposed a new index to evaluate carotid atherosclerosis without blood pressure measurement using the carotid Doppler method. It is a potential index for detecting atherosclerosis of local arteries such as the carotid.

Effects of daily physical activity level on the degree of sympathetic tone.

BACKGROUND: Exercise is recommended for the treatment and prevention of cardiac disorders. Relaxation of the sympathetic nervous system has been considered to be one of the therapeutic mechanisms. However, the means by which the level of daily physical activity affects sympathetic activity remains unclear. OBJECTIVE: To evaluate the effects of daily physical activity on autonomic nervous tone. METHODS: Daily physical activity was measured for 5 or more days in 26 patients with various cardiac disorders of NYHA class 1 or 2 and in 6 healthy individuals using an intelligent calorie counter. Recumbent resting ECG was recorded for 3 minutes immediately before waking up and after going to bed using a digital ECG. Low- (Lf, 0.03-0.15 Hz) and high- (Hf, 0.15-0.45 Hz) frequency components were calculated by frequency analysis of the R-R interval, and Lf/Hf ratio was calculated as an index of sympathetic tone. RESULTS: The average values of energy expenditure and time were 145+/-93.6 kcal/day and 47.8+/-24.3 min/day, respectively. The morning Lf/Hf ratio decreased following an increased physical activity level the day before, but increased with subsequent increase in the activity level in 65.6% of subjects. A negative correlation was observed in 34.4% of subjects, which suggested that an appropriate level of physical activity led to relaxation of sympathetic tone. CONCLUSION: The daily level of physical activity affects sympathetic tone, and an appropriate level results in sympathetic relaxation. The results of this study provide a useful index to enable patients with cardiac disorder to perform exercise without overloading.

Involvement of carotid baroreceptor function in blood pressure control in the chronic phase: effect on 24-hour ambulatory blood pressure.

BACKGROUND: It is generally thought that the sole function of baroreceptors is for the regulation of rapid blood pressure fluctuations caused by postural changes and other motion. However, recent studies have suggested that baroreceptors may also be involved in blood pressure control in the chronic phase. PURPOSE: The study was performed to examine the involvement of carotid baroreceptors in blood pressure control in the chronic phase, through determination of the relationship between 24-hour blood pressure data and carotid baroreceptor function. METHODS: Ambulatory blood pressure, ECG, and the number of steps during exercise were measured every 15 minutes with an ambulatory blood pressure monitor and a 24-hour Holter ECG fitted with an accelerometer (Cardy-II-p, Suzuken KK, Japan). In addition, the dependence of blood pressure on autonomic nerve activity and exercise was analyzed based on the frequency of the RR interval. Patients were divided into three groups based on different blood-pressure types: autonomic nerve-dependent, exercise-dependent, and independent types. Carotid baroreceptor function was evaluated using the sequence method; subjects adopted a supine position on a tilt table and their arterial pressure was monitored continuously using a Finapress finger cuff (Finapress, Ohmeda, Louisville, Colorado, USA). The study was performed in 90 patients, including 42 with essential hypertension whose blood pressure was well controlled. RESULTS AND CONCLUSIONS: A significant negative correlation was found between the mean 24-hour blood pressure and baroreceptor function for both systolic and diastolic pressure. Systolic pressure in patients of the independent type was significantly higher than that in patients of the exercise-dependent type. Furthermore, non-dipper hypertension was noted more frequently and baroreceptor function was significantly lower in independent-type patients, compared with autonomic nerve-dependent and exercise-dependent types, suggesting that independent-type blood pressure may be due to baroreceptor dysfunction. In conclusion, our results suggest that baroreceptor function might be involved in blood pressure control in the chronic phase, and baroreceptor dysfunction may contribute to the development of essential hypertension.

Circadian variation of the myocardial ischemic threshold in patients with ischemic heart disease.

PURPOSE: Circadian variation of the heart rate (HR) at the myocardial ischemic threshold was compared with that of the HR at the sympathetic tone threshold in 16 cases of effort angina pectoris. METHODS: The high (0.15-0.40 Hz, Hf) and low (0.03-0.15 Hz, Lf) frequency spectral components were extracted every twenty seconds, using frequency domain analysis of the RR interval recorded by a 24-hour Holter ECG with an accelerometer. HR-Hf data collected every five minutes were plotted as the X-Y coordinates, and a two-compartment analysis was performed. The HR at the autonomic tone threshold was then determined at the intersection point of the lines. A loop of the HR-ST segment was drawn during walking to determine the ischemic threshold at which heart rate ischemic ST segment depression began and circadian variation was observed. RESULTS: The circadian rhythm at the sympathetic tone threshold and the HR at the ischemic threshold were high during the day and low at night. The HR at the ischemic threshold was 15-20% higher than that at the sympathetic tone threshold at night but only 9-13% higher during the day. Also, there was a period during which there was no significant difference between the HR at the two thresholds. CONCLUSION: In comparing circadian variation between HR at the sympathetic tone threshold and HR at the ischemic threshold, there was a period during which there was no significant difference between the HRs. This might suggest a period in which a high incidence of cardiac ischemic attack is likely. This information could provide a feasible indicator for appropriate exercise training for patients with ischemic heart disease.

Evaluation of the severity of dementia using expectation control function.

The results of an animal experiment without anesthesia suggested the presence of expectation control in which sympathetic nerve tone increases at rest immediately before behaviors to prepare for the subsequent behavior. We investigated whether such function is present in humans in their daily living and whether patients with dementia could be differentiated from healthy adults based on this finding. Using a Holter electrocardiograph with an acceleration sensor, electrocardiograms (ECG) and behavioral states were recorded. The total recorded ECG was divided by 20 sec, and high (HF, 0. 15-0.4 Hz) and low (LF, 0.03-0.15 Hz) frequency components were extracted by frequency analysis of the RR interval. We used the HF component, L/H ratio, and RR interval as the index grade of parasympathetic/sympathetic nerve tone. The mean value of each parameter was calculated and compared between the time zone during which resting persisted for 1 min or more (3 intervals) and that during which behaviors occurred immediately after a 1-min rest., In 32 patients with dementia, Holter ECG and behaviors were serially recorded, and the time zone during which intentional behaviors occurred was detected. RR interval and HF component decreased and L/H increased. Increasing in sympathetic nerve tone was observed at rest condition immediately before intentional behaviors, suggesting a presence of expectation control function. The expectation control mechanism will present in humans and involved in this function by severity of dementia. This parameter may be useful for objectively evaluating the severity of dementia.

The effects of physical activity and autonomic nerve tone on the daily fluctuation of blood pressure.

The effects of daily activity and autonomic nerve tone on the fluctuation of ambulatory blood pressure were studied in hypertensive patients. The autonomic nerve tone was measured by frequency domain analysis of the RR interval. Physical activity was evaluated by a walk count, converted to a walk rate (WR), recorded using a digital Holter ECG fitted with an accelerometer, with simultaneous monitoring of blood pressure (Bp). Average values of the WR, H and L/H components were calculated for the 15 min. period just prior to Bp monitoring. The relationship between the average WR, H and L/H values and the Bp was determined by a linear regression analysis. Hypertension was classified into three types, autonomic nerve dominant (AN), exercise dominant (EX), and irregular (IR), based on a high correlation coefficient between Bp and either H or L/H (AN type), between Bp and WR (EX type), or no significant correlation between Bp and any of the parameters (IR type). Of the thirty hypertensive patients studied 11 were classified as AN, 12 as EX, and 7 as IR. Patients of the EX type had significantly lower Bp than patients in the other two classes. Furthermore, all of the IR type patients showed non-dipper type hypertension, suggesting that the Bp regulation mechanisms were impaired. The results suggest the significance of simultaneous monitoring of physical activity and autonomic nerve function at the time of Bp monitoring.