Dissociation between progression of coronary artery calcification and endothelial function in hemodialysis patients: a prospective pilot study.

UNLABELLED: Chronic kidney disease profoundly disturbs calcium-phosphate metabolism and predisposes to premature atherosclerosis. Both coronary artery calcification (CAC) and endothelial dysfunction are common in hemodialysis (HD) patients. We hypothesized that a calcium-free phosphate binder would improve endothelial function and delay progression of vascular calcification in HD patients. METHODS: This was a randomized parallel-group trial in HD patients comparing lanthanum carbonate (LC) with a non-LC phosphorus binders control group (non-LC) at a 1 : 1 randomization. CAC was obtained at baseline, 6, and 12 months, and endothelial function (brachial artery flow-mediated dilation - FMD) at baseline and 6 months. RESULTS: 13 patients were randomized (LC n = 7 and non-LC n = 6). CAC scores (Log ± SE) at baseline were 7.21 ± 0.62 (LC) and 6.07 ± 0.73 (control). CAC increased in the non-LC group (33 ± 17% and 77 ± 22% at 6 and 12 months), but tended to decrease in the LC group (-10 ± 11% and -2 ± 11% at 6 and 12 months). There was statistically less progression in CAC in the LC group compared to control at 6 (p = 0.002) and 12 months (p = 0.003). There was no difference between groups in FMD (p = 0.7). Markers of inflammation did not change significantly. CONCLUSION: A slower rate of progression of CAC occurred in the LC group, independent of changes in FMD. This is the first study showing dissociation between progression of CAC and FMD in HD patients. Larger studies are warranted to elucidate the impact of different phosphate sequestration therapies on atherosclerosis in HD patients.

On-line near-infrared spectrometer to monitor urea removal in real time during hemodialysis.

The ex vivo removal of urea during hemodialysis treatments is monitored in real time with a noninvasive near-infrared spectrometer. The spectrometer uses a temperature-controlled acousto optical tunable filter (AOFT) in conjunction with a thermoelectrically cooled extended wavelength InGaAs detector to provide spectra with a 20 cm(-1) resolution over the combination region (4000-5000 cm(-1)) of the near-infrared spectrum. Spectra are signal averaged over 15 seconds to provide root mean square noise levels of 24 micro-absorbance units for 100% lines generated over the 4600-4500 cm(-1) spectral range. Combination spectra of the spent dialysate stream are collected in real-time as a portion of this stream passes through a sample holder constructed from a 1.1 mm inner diameter tube of Teflon. Real-time spectra are collected during 17 individual dialysis sessions over a period of 10 days. Reference samples were extracted periodically during each session to generate 87 unique samples with corresponding reference concentrations for urea, glucose, lactate, and creatinine. A series of calibration models are generated for urea by using the partial least squares (PLS) algorithm and each model is optimized in terms of number of factors and spectral range. The best calibration model gives a standard error of prediction (SEP) of 0.30 mM based on a random splitting of spectra generated from all 87 reference samples collected across the 17 dialysis sessions. PLS models were also developed by using spectra collected in early sessions to predict urea concentrations from spectra collected in subsequent sessions. SEP values for these prospective models range from 0.37 mM to 0.52 mM. Although higher than when spectra are pooled from all 17 sessions, these prospective SEP values are acceptable for monitoring the hemodialysis process. Selectivity for urea is demonstrated and the selectivity properties of the PLS calibration models are characterized with a pure component selectivity analysis.

Physician access and early nephrology care in elderly patients with end-stage renal disease.

Early nephrology care may improve treatment outcomes of patients with end-stage renal disease. We sought to examine if physician access affects early nephrology care defined as visiting a nephrologist 12 to 4 months before initiating dialysis. The study population consisted of elderly patients starting hemodialysis whose demographic characteristics and initial dialysis therapy were derived from form 2728 files of the Centers for Medicare & Medicaid Services. Early nephrology care, chronic kidney disease and co-morbidities along with access to local non-nephrologist physicians and nephrologists were identified based on Medicare claims and/or United States 2000 Census data. About one-third of elderly patients received early nephrology care prior to initiating dialysis. Patients living in an area with a large number of non-nephrologist physicians or living relatively far away from a nephrologist had a lower likelihood of getting early nephrology care prior to initiating dialysis while those in an area with more practicing nephrologists were more likely to get early nephrology care. The study shows that physician access significantly influences the use of early nephrology care among elderly patients progressing to end-stage renal disease in the United States.

Effect of dialysis center profit-status on patient survival: a comparison of risk-adjustment and instrumental variable approaches.

OBJECTIVE: To compare the estimated effects of dialysis center profit status on patient survival using alternative estimation strategies with retrospective data. DATA SOURCES/STUDY SETTING: Patient and provider-level retrospective data from the United States Renal Data System (USRDS), 1996-1999. STUDY DESIGN: Observational risk adjustment and instrumental variable methods. DATA COLLECTION/EXTRACTION METHODS: Study collected measures from various USRDS files describing clinical characteristics, survival, and the profit status of the initial dialysis center for incident end-stage renal disease (ESRD) patients aged 67+. USRDS facility files were used to assess dialysis center profit status and measure patient distances to dialysis centers. PRINCIPAL FINDINGS: Found survival effect related to profit status in the range of previous research using risk-adjusting covariates similar to those used in previous models. Adding further risk-adjusting covariates halved this effect. The relative proximity of for-profit and nonprofit dialysis centers to the patient residence was the strongest determinant of the profit status of the patient's initial dialysis center. The effect of profit status on survival was eliminated using the two-stage least squares variant of instrumental variable estimation with the relative proximity of for-profit and nonprofit dialysis centers to the patient's residence as the instrument. CONCLUSIONS: Using only the variation in initial dialysis center profit status that was related to the relative proximity of for-profit and nonprofit dialysis centers to the patient, we found no relationship between dialysis center profit status and patient survival. These results are in contrast to results obtained using risk-adjustment methods with a limited set of risk-adjusting covariates.

Technology in clinical practice.

Salt and water are the major components of extracellular fluid, and each patient on dialysis has a unique serum sodium activity that is defended to ensure homeostasis. Dialysate use that does not restore extracellular composition to its equilibrium value results in disequilibrium and affects dialysis discomfort, blood pressure, thirst, and weight gain. When dialysate sodium activity exceeds the dialyzable plasma sodium activity, sodium diffuses from the dialysate into the patient. This results in hypertonicity, cellular dehydration, plasma volume expansion, and hypertension. A dialysate sodium activity below the patient's dialyzable plasma sodium reverses this process. Neither of these situations is desirable. Rather, dialysis should restore homeostasis by reconstituting the extracellular fluid to its desired salt and water content. Because each patient has a unique serum sodium activity, this goal can only be realized by using individualized dialysate sodium prescriptions. Further, because a patient's dialyzable sodium is dynamic and determined by serum chemistry plus dialyzer membrane behavior, the dialysate sodium needed to achieve isonatemic dialysis can only be defined by measuring the dialyzable serum sodium activity during dialysis. Achieving balanced salt and water removal to preserve homeostasis and intracellular tonicity requires automated sensors and feed-back control of dialysate conductivity.

Peritoneal catheters and exit-site practices toward optimum peritoneal access: a review of current developments.

OBJECTIVE: This review updates the 1998 International Society for Peritoneal Dialysis (ISPD) recommendations for peritoneal dialysis catheters and exit-site practices (Gokal R, et al. Peritoneal catheters and exit-site practices toward optimum peritonealaccess: 1998 update. Perit Dial Int 1998; 18:11-33.) DATA SOURCES: The Ovid and PubMed search engines were used to review the Medline databases of January 1980 through June 2003. Searches were restricted to human data; primary key word searches included dialysis, peritoneal dialysis, and continuous ambulatory peritoneal dialysis cross referenced with access, catheter, dialysis catheter, peritoneal dialysis catheter, and Tenckhoff catheter. Related searches were provided via the PubMed related articles link. STUDY SELECTION: Reports were selected if they provided identifiable information on catheter design, catheter placement technique, and survival or placement complications. Reports without such data were excluded from review. Each study was then categorized by its characteristics: single-center or multicenter; retrospective or prospective; controlled trial, with or without random patient assignment; or review article. MAIN RESULTS: There are few randomized controlled evaluations testing how catheter design and/or placement influence long-term survival and function, and these are typically conducted at a single center. The majority of reports represent retrospective single-center experiences, and these are supplemented by occasional multicenter data registries. CONCLUSIONS: There is substantial variability in catheter outcomes between centers, and this variability is more closely correlated with operator and center characteristics than with catheter design. Some catheter designs appear to impact long-term catheter success, and, in some cases, specific patient characteristics and dialysis formats combine with specific catheter designs to influence catheter survival. Most reporters prefer two-cuff designs and placement of the deep cuff at an intramuscular location. Intramuscular cuff placement results in fewer pericatheter leaks and hernias, but makes catheter removal more difficult. High-risk patients (those with previous pelvic surgery) benefit from visual inspection of the peritoneum during catheter placement, and in randomized controlled trials, catheters with pre-shaped arcuate subcutaneous segments ("swan neck" designs) reduce the risk of early drainage failure via "migration."

Does hemodialysis increase protein breakdown? Dissociation between whole-body amino acid turnover and regional muscle kinetics.

Hemodialysis (HD) is a protein catabolic procedure. Whole-body amino acid turnover studies identify dialysate amino acid loss and reduced protein synthesis as the catabolic events; proteolysis is not increased. Regional amino acid kinetics, however, document enhanced muscle protein breakdown as the cause of the catabolism; muscle protein synthesis also increased but to a lesser magnitude than the increment in protein breakdown. This discordance between whole-body and regional kinetics is best explained by the contrasting physiology between the muscle and the liver. During HD, muscle releases amino acids, which then are taken up by the liver for de novo protein synthesis. There seems to be a somatic to visceral recycling of amino acids. Evidence supporting this concept includes the increased fractional synthesis of albumin and fibrinogen during HD. It should be emphasized that region- or organ-specific kinetics vary, and whole-body turnover is a composite of all of the visceral and somatic compartments taken together. Reduced whole-body protein synthesis may be a compensatory adaptation to dialysate amino acid loss with a consequent reduction in plasma amino acid concentration. Notwithstanding the protein catabolic nature of HD, evidence is accumulating that intradialytic nutritional supplementation may blunt its catabolic effect.

Hormonal responses to fasting and refeeding in chronic renal failure patients.

To study anorexia in chronic renal failure (CRF) patients, we measured appetite-related hormones in seven CRF patients and four controls. Plasma concentrations and fractional changes from baseline (values from day 1, 0800) are listed as control vs. CRF (means +/- SE). Leptin, although higher in CRF (5.6 +/- 1.7 and 34 +/- 17 ng/ml), was suppressed after fasting; decrements were -51 +/- 9 and -55 +/- 8%. Nocturnal surge present during feeding was abolished upon fasting in both groups. Neuropeptide Y (NPY) was elevated in CRF (72 +/- 12 vs. 304 +/- 28 pg/ml, P = 0.0002). NPY rhythm, reciprocal to that of leptin, was muted in CRF. Basal cortisol was similar in both groups (17 +/- 3 and 17 +/- 2 microg/dl). In the controls, cortisol peaked in the morning and declined in the evening. CRF showed blunted cortisol suppression. Decrements were -61 +/- 3 and -20 +/- 9% at 1800 on day 1 (P = 0.008) and -61 +/- 8 and -26 +/- 8% at 2000 on day 2 (P = 0.02). Basal ACTH (25 +/- 5 and 54 +/- 16 pg/ml) as well as diurnal pattern was not statistically different between the groups. Baseline insulin was 6 +/- 1 and 20 +/- 9 microU/ml. During fasting, insulin was suppressed to -64 +/- 10 and -51 +/- 9%, respectively. Upon refeeding, increments were 277 +/- 96 and 397 +/- 75%. Thus, in our CRF patients, anorexia was not due to excess leptin or deficient NPY. Impaired cortisol suppression should favor eating. Insulin suppression during fasting and secretion after feeding should enhance both eating and anabolism. The constant high NPY suggests increased tonic hypersecretion.

Dialysate composition and hemodialysis hypertension.

Dialysis prescriptions have evolved to take advantage of new technology and serve a burgeoning patient population. High-sodium bicarbonate-based dialysate was first formulated in 1982 to enable short, safe, comfortable, high-efficiency hemodialysis (HD). Near-universal adaptation of these high-sodium formulas has virtually eliminated profound dialysis disequilibrium and greatly reduced dialysis discomfort, but has created a syndrome of dialysis salt loading with accentuated postdialysis thirst, interdialytic weight gain, and hypertension. Available technology will soon permit individuals to receive isonatremic dialysis with dialysate customized to the patient's serum sodium activity. Then, rather than choosing between comfortable, safe, high-efficiency dialysis with salt loading; cramps, asthenia, and symptomatic hypotension using low-sodium, high-efficiency rapid HD to control blood pressure (BP) and weight gain; or comfortable, slow, low-efficiency HD with BP control, physicians may be able to minimize symptoms and avoid dialysis salt loading while providing maximum time for rehabilitative activities. The current use of a single sodium activity for all patients ignores the inter- and intraindividual variability in serum sodium activity in our patients. This results in undesired consequences for 20-40% of patients. The application of even more severe salt loading through high-salt sodium modeling only accentuates the long-term problems of excessive thirst, weight gain, and hypertension.

Whole-genome shotgun assembly and comparison of human genome assemblies.

We report a whole-genome shotgun assembly (called WGSA) of the human genome generated at Celera in 2001. The Celera-generated shotgun data set consisted of 27 million sequencing reads organized in pairs by virtue of end-sequencing 2-kbp, 10-kbp, and 50-kbp inserts from shotgun clone libraries. The quality-trimmed reads covered the genome 5.3 times, and the inserts from which pairs of reads were obtained covered the genome 39 times. With the nearly complete human DNA sequence [National Center for Biotechnology Information (NCBI) Build 34] now available, it is possible to directly assess the quality, accuracy, and completeness of WGSA and of the first reconstructions of the human genome reported in two landmark papers in February 2001 [Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., et al. (2001) Science 291, 1304-1351; International Human Genome Sequencing Consortium (2001) Nature 409, 860-921]. The analysis of WGSA shows 97% order and orientation agreement with NCBI Build 34, where most of the 3% of sequence out of order is due to scaffold placement problems as opposed to assembly errors within the scaffolds themselves. In addition, WGSA fills some of the remaining gaps in NCBI Build 34. The early genome sequences all covered about the same amount of the genome, but they did so in different ways. The Celera results provide more order and orientation, and the consortium sequence provides better coverage of exact and nearly exact repeats.

Online measurement of urea concentration in spent dialysate during hemodialysis.

BACKGROUND: We describe online optical measurements of urea in the effluent dialysate line during regular hemodialysis treatment of several patients. Monitoring urea removal can provide valuable information about dialysis efficiency. METHODS: Spectral measurements were performed with a Fourier-transform infrared spectrometer equipped with a flow-through cell. Spectra were recorded across the 5000-4000 cm(-1) (2.0-2.5 microm) wavelength range at 1-min intervals. Savitzky-Golay filtering was used to remove baseline variations attributable to the temperature dependence of the water absorption spectrum. Urea concentrations were extracted from the filtered spectra by use of partial least-squares regression and the net analyte signal of urea. RESULTS: Urea concentrations predicted by partial least-squares regression matched concentrations obtained from standard chemical assays with a root mean square error of 0.30 mmol/L (0.84 mg/dL urea nitrogen) over an observed concentration range of 0-11 mmol/L. The root mean square error obtained with the net analyte signal of urea was 0.43 mmol/L with a calibration based only on a set of pure-component spectra. The error decreased to 0.23 mmol/L when a slope and offset correction were used. CONCLUSIONS: Urea concentrations can be continuously monitored during hemodialysis by near-infrared spectroscopy. Calibrations based on the net analyte signal of urea are particularly appealing because they do not require a training step, as do statistical multivariate calibration procedures such as partial least-squares regression.

ThurGood: evaluating assembly-to-assembly mapping.

The alignment and mapping of large genomic sequences is the focus of much recent research. However, relatively little has been done so far about testing and validating alignment methods. We introduce criteria and new tools we have developed for alignment evaluation. These tools have already proved useful in the evaluation and ranking of several methods for assembly-to-assembly mapping, which were recently used to map multiple versions of the human genome to each other (Istrail et aL, 2004).

Near-infrared spectroscopic measurement of urea in dialysate samples collected during hemodialysis treatments.

Single-beam spectra were collected over the combination region of the near-infrared spectrum for 80 samples collected from 15 people over a two-week period. Partial least-squares (PLS) regression was used to generate an optimized calibration model for urea. PLS calibration models accurately measure urea in the spent dialysate matrix. Prediction errors are on the order of 0.15 mM, which is sufficient for the clinical assessment of the dialysis process. In addition, the feasibility of a global calibration model is demonstrated by generating a calibration model from samples and spectra obtained from 12 people to predict the level of urea in samples collected from 3 different people. In this case, the standard error of prediction is 0.09 mM. Spectra were modified in order to systematically examine the impact of resolution and noise. Little impact is observed by altering the spectral resolution from 4 to 32 cm-1. Spectral noise, however, plays an important role in the accuracy of these calibration models. Increasing the magnitude of the spectral noise increases the prediction errors and increases the width of the spectral range necessary for extracting the analytical information. The utility of the method is demonstrated by analyzing dialysate samples collected during actual dialysis treatments. In addition, the necessary resolution and spectral quality necessary for reliable on-line urea monitoring is identified. These findings indicate that a dedicated, on-line urea spectrometer must posses a resolution of 16 cm-1 coupled with a sample thickness of 1.5 mm and spectral noise levels on the order of 25 micro-absorbance units when measured as the root-mean-square (RMS) noise of 100% lines.

Insulin is protein-anabolic in chronic renal failure patients.

To examine the protein anabolic actions of insulin in chronic renal failure, the authors measured four sets of whole body leucine fluxes during insulin alone and insulin with amino acid infusion in nine uremic patients before hemodialysis (B-HD). Seven were restudied 8 wk after initiation of maintenance hemodialysis (HD). Six normal subjects served as control (N). All values ( micro mol/kg/h, mean +/- SEM) are presented in the sequence of B-HD, HD, and N, and only P < 0.05 are listed. During Flux 1 (baseline), D (leucine release from body protein degradation) were 114 +/- 7, 126 +/- 4, and 116 +/- 6, respectively. C (leucine oxidation rates) were 18 +/- 2, 17 +/- 2, and 21 +/- 3, respectively. S (leucine disappearance into body protein [index of protein synthesis]) were 96 +/- 6, 107 +/- 4, and 94 +/- 4, respectively, and balances (net leucine flux into protein [values were negative during fasting]) were -18 +/- 2, -17 +/- 2, and -21 +/- 3, respectively. During Flux 2 (low-dose insulin infusion), D were 89 +/- 3, 98 +/- 6, and 94 +/- 5, respectively; C were 12 +/- 1, 11 +/- 2, and 18 +/- 1, respectively (P = 0.02); S were 77 +/- 4, 87 +/- 5, and 76 +/- 5, respectively, and balances were -12 +/- 1, -11 +/- 2, and -18 +/- 1, respectively (P = 0.02). During Flux 3 (high-dose insulin infusion): D were 77 +/- 3, 82 +/- 7, and 84 +/- 5, respectively; C were 9 +/- 1, 8 +/- 1, and 14 +/- 1, respectively (P = 0.005); S were 68 +/- 4, 74 +/- 6, and 70 +/- 5, respectively, and balances were -9 +/- 1, -8 +/- 1, and -14 +/- 1, respectively (P = 0.005). In Flux 4 (insulin infused with amino acids): D were 73 +/- 3, 107 +/- 18, and 85 +/- 7, respectively; C were 35 +/- 4, 29 +/- 5, and 39 +/- 3, respectively; S were 105 +/- 5, 145 +/- 15, and 113 +/- 6, respectively (P = 0.02), and balances were 32 +/- 4, 38 +/- 5, and 27 +/- 3, respectively. These data show that B-HD and HD patients were as sensitive as normal subjects to the protein anabolic actions of insulin. Insulin alone reduced proteolysis and leucine oxidation, and insulin given with amino acids increased net protein synthesis.

Sources of Staphylococcus aureus for patients on continuous ambulatory peritoneal dialysis.

OBJECTIVE: This study was designed to determine whether family members and health care workers are a source of Staphylococcus aureus for patients on peritoneal dialysis. DESIGN: Over 36 months, cultures were obtained from the nares of patients, family members that cared for the patients' catheters, and health care workers in a dialysis unit. Pulsed-field gel electrophoresis was performed on all S. aureus isolates. SETTING: A university-based peritoneal dialysis program. PARTICIPANTS: 74 patients, 32 family members, and 17 health care workers. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The number of patients that acquired S. aureus strains during the study period. RESULTS: Of the 48 patients whose initial nares cultures were negative, 7 (15%) acquired S. aureus strains. Overall, 24 of 53 (45%) patients that had 2 or more cultures obtained during the study gained strains. Potential sources were not identified for strains gained by 11 (46%) patients. Five patients appeared to acquire their strains from family members; however, other patients also shared related strains; 8 patients acquired strains shared by other patients. CONCLUSIONS: Family members and other patients appeared to be important sources of S. aureus for patients on peritoneal dialysis. Health care workers that carry S. aureus transiently may be important intermediaries. Good hand hygiene is essential to prevent transmission of S. aureus to these susceptible patients.

Response to inadequate dialysis in chronic peritoneal dialysis patients. Results from the 2000 Centers for Medicare and Medicaid (CMS) ESRD Peritoneal Dialysis Clinical Performance Measures (PD-CPM) Project.

BACKGROUND: It is not known if patient prescriptions are being changed if patients are receiving an inadequate dose of peritoneal dialysis. METHODS: Data from the 2000 Centers for Medicare and Medicaid were used to obtain data on dialysis adequacy and dialysis prescriptions. RESULTS: A total of 359 of 1,268 (28%) adult peritoneal dialysis patients had a total weekly Kt/V urea (twKt/V) less than 2.0 and 436 of 1,245 (35%) patients had a total weekly creatinine clearance (twCrCl) less than 60 L/wk/1.73 m2, defined as "inadequate dialysis." Among chronic ambulatory peritoneal dialysis (CAPD) patients, 81 of 188 (43%) patients had inadequate dialysis and a change in the peritoneal dialysis prescription within 6 months of the initial adequacy value. Among cycler patients, 106 of 197 (54%) patients had inadequate dialysis and a change in the prescription. Thirty-six of 46 (78%) CAPD patients and 48 of 56 (86%) cycler patients had an improvement in twKt/V after the prescription was revised. Thirty-two of 42 (76%) CAPD patients and 45 of 57 (79%) cycler patients had an improvement in twCrCl after the prescription was changed. For these patients, twKt/V increased from 1.6 +/- 0.3 to 2.1 +/- 0.5, with an increase in the peritoneal Kt/V urea from 1.5 +/- 0.3 to 1.9 +/- 0.4. Similarly, twCrCl increased from 46.3 +/- 7.5 to 59.1 +/- 10.6 L/wk/1.73 m2 with an increase in the peritoneal CrCl dose from 42.0 +/- 9.1 to 52.7 +/- 9.9 L/wk/1.73 m2. CONCLUSION: About half of peritoneal dialysis patients with inadequate dialysis did not have a prescription change and could benefit from modifications in their dialysis prescription.

The genome sequence of the malaria mosquito Anopheles gambiae.

Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91% of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency ("dual haplotypes") in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.