Mark Rohrscheib

Changing Relationship of Blood Pressure with Mortality over Time among Hemodialysis Patients

High BP is a major risk factor for atherosclerotic cardiovascular disease mortality in the general population. Surprising, studies that have been conducted among hemodialysis (HD) patients have yielded conflicting data on the relationship between BP and mortality. This study explores two hypotheses among HD patients: (1) The relationship between BP and mortality changes over time, and (2) mild to moderate hypertension is well tolerated. Incident HD patients who were treated at Dialysis Clinic Inc. facilities between 1993 and 2003 were studied. Primary end points were atherosclerotic cardiovascular disease and all-cause mortality. The relationship between BP and mortality was analyzed in two sets of Cox proportional hazards models. Model-B explored the relationship between baseline BP and mortality in sequential time periods. Model-TV assessed the relationship between BP, treated as time-varying, and mortality. The study sample (n = 16,959) was similar in characteristics to the United States Renal Data Systems population, although black patients were slightly overrepresented. Model-B demonstrated that the relationship between baseline BP and mortality changes over time. Low systolic BP (<120 mmHg) was associated with increased mortality in years 1 and 2. High systolic BP (> or =150 mmHg) was associated with increased mortality among patients who survived > or =3 yr. Low pulse pressure was associated with increased mortality. Model-TV demonstrated that mild to moderate systolic hypertension may be relatively well tolerated. In conclusion, the relationship between baseline BP and mortality changes over time. Mild to moderate systolic hypertension was associated with only modest increases in mortality.

Which Targets in Clinical Practice Guidelines Are Associated with Improved Survival in a Large Dialysis Organization

Professional organizations have developed practice guidelines in the hope of improving clinical outcomes. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has set targets for dialysis dosage (single-pool Kt/V), hematocrit, serum albumin, calcium, phosphorus, parathyroid hormone, and BP for hemodialysis (HD) patients. Several guidelines are largely based on results from observational studies. In contrast to other parameters, BP values within the KDOQI guidelines have been associated with increased mortality. Therefore, it was postulated that having multiple parameters that satisfy the current guidelines, except those for BP, is associated with improved survival among HD patients. A retrospective analysis was conducted of incident HD patients who were treated at facilities operated by Dialysis Clinic Inc., a not-for-profit dialysis provider, between January 1, 1998, and December 31, 2004 (n = 13,792). Cox proportional hazards models were used to assess the association between satisfying guidelines and mortality. Values within guidelines for single-pool Kt/V, hematocrit, serum albumin, calcium, phosphorus, and parathyroid hormone were associated with decreased mortality (P < or = 0.0001). The largest survival benefit was found for serum albumin (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.24 to 0.31). Satisfying these six guidelines simultaneously was associated with an 89% reduction in mortality (HR 0.11; 95% CI 0.06 to 0.19]). Conversely, BP values satisfying the guideline were associated with increased mortality (HR 1.90; 95% CI 1.73 to 2.10). Because this target was largely extrapolated from the general population, a randomized, controlled trial is needed to identify the optimal BP for HD patients.

Age, Race, Diabetes, Blood Pressure, and Mortality among Hemodialysis Patients

Observational studies involving hemodialysis patients suggest a U-shaped relationship between BP and mortality, but the majority of these studies followed large, heterogeneous cohorts. To examine whether age, race, and diabetes status affect the association between systolic BP (SBP; predialysis) and mortality, we studied a cohort of 16,283 incident hemodialysis patients. We constructed a series of multivariate proportional hazards models, adding age and BP to the analyses as cubic polynomial splines to model potential nonlinear relationships with mortality. Overall, low SBP associated with increased mortality, and the association was more pronounced among older patients and those with diabetes. Higher SBP associated with increased mortality among younger patients, regardless of race or diabetes status. We observed a survival advantage for black patients primarily among older patients. Diabetes associated with increased mortality mainly among older patients with low BP. In conclusion, the design of randomized clinical trials to identify optimal BP targets for patients with ESRD should take age and diabetes status into consideration.

Noninvasive Type 2 Diabetes Screening Superior sensitivity to fasting plasma glucose and A1C

OBJECTIVE—This study compared the performance of a novel noninvasive technology to fasting plasma glucose (FPG) and A1C tests for detecting undiagnosed diabetes and impaired glucose tolerance. RESEARCH DESIGN AND METHODS—The design was a head-to-head evaluation in a naïve population. Consented subjects received FPG and A1C tests and an oral glucose tolerance test (OGTT). Subjects were also measured by a noninvasive device that detects the fluorescence of skin advanced glycation end products. A total of 351 subjects participated. RESULTS—Subjects with 2-h OGTT values ≥140 mg/dl defined the positive screening class. A total of 84 subjects (23.9% prevalence) screened positive. The performances of the noninvasive device, FPG, and A1C were evaluated for sensitivity and specificity against this classification. At the impaired fasting glucose threshold (FPG =100 mg/dl), the FPG testing sensitivity was 58% and the specificity was 77.4%. At that same specificity, the sensitivity for A1C testing was 63.8%, while the noninvasive testing sensitivity was 74.7%. The sensitivity advantage of the noninvasive device over both blood tests for detecting diabetes and precursors was statistically significant (P < 0.05). CONCLUSIONS—The noninvasive technology showed clinical performance advantages over both FPG and A1C testing. The sensitivity differential indicated that the noninvasive device is capable of identifying 28.8% more individuals in the OGTT-defined positive screening class than FPG testing and 17.1% more than A1C testing. The combination of higher sensitivity and greater convenience—rapid results with no fasting or blood draws—makes the device well suited for opportunistic screening.

Noninvasive Type 2 Diabetes Screening: Superior Sensitivity to Fasting Plasma Glucose and Glycosylated Hemoglobin

OBJECTIVE—This study compared the performance of a novel noninvasive technology to fasting plasma glucose (FPG) and A1C tests for detecting undiagnosed diabetes and impaired glucose tolerance. RESEARCH DESIGN AND METHODS—The design was a head-to-head evaluation in a naïve population. Consented subjects received FPG and A1C tests and an oral glucose tolerance test (OGTT). Subjects were also measured by a noninvasive device that detects the fluorescence of skin advanced glycation end products. A total of 351 subjects participated. RESULTS—Subjects with 2-h OGTT values ≥140 mg/dl defined the positive screening class. A total of 84 subjects (23.9% prevalence) screened positive. The performances of the noninvasive device, FPG, and A1C were evaluated for sensitivity and specificity against this classification. At the impaired fasting glucose threshold (FPG =100 mg/dl), the FPG testing sensitivity was 58% and the specificity was 77.4%. At that same specificity, the sensitivity for A1C testing was 63.8%, while the noninvasive testing sensitivity was 74.7%. The sensitivity advantage of the noninvasive device over both blood tests for detecting diabetes and precursors was statistically significant (P < 0.05). CONCLUSIONS—The noninvasive technology showed clinical performance advantages over both FPG and A1C testing. The sensitivity differential indicated that the noninvasive device is capable of identifying 28.8% more individuals in the OGTT-defined positive screening class than FPG testing and 17.1% more than A1C testing. The combination of higher sensitivity and greater convenience—rapid results with no fasting or blood draws—makes the device well suited for opportunistic screening.

Anemia Management and Association of Race With Mortality and Hospitalization in a Large Not-for-Profit Dialysis Organization

BACKGROUND The optimal hemoglobin target and possible toxicity of epoetin therapy in hemodialysis patients are controversial. Previous studies suggest that African American patients use higher doses of epoetin and have better survival compared with white hemodialysis patients. STUDY DESIGN Retrospective longitudinal cohort. SETTING & PARTICIPANTS Epoetin-exposed incident hemodialysis patients (N = 12,733; African Americans, n = 4,801; white, n = 7,386) treated in Dialysis Clinic Inc facilities during 2000 to 2006. PREDICTORS Hemoglobin, epoetin, iron. OUTCOMES Mortality, hospitalization. MEASUREMENTS Proportional hazards models with time-varying covariates. RESULTS Hemoglobin concentrations less than 10 g/dL in whites and less than 11 g/dL in African Americans were associated with increased mortality and hospitalization versus the referent hemoglobin level of 11 to 11.9 g/dL. Hemoglobin levels of 13 g/dL or greater in whites were associated with decreased noncardiovascular mortality. Six-month cumulative epoetin doses of 20,000 U/wk or greater were associated with increased mortality and hospitalization versus the referent group (8,000 to 12,499 U/wk). Epoetin doses less than 8,000 U/wk were associated with decreased risk. Higher epoetin doses were associated with increased mortality at hemoglobin concentrations of 10 to 12.9 g/dL and with increased hospitalization at all hemoglobin concentrations of 10 g/dL or greater. Higher epoetin doses were associated with increased mortality and hospitalization within each tertile of serum albumin concentration. These patterns did not differ by race. LIMITATIONS Treatment-by-indication bias and unidentified confounders cannot be excluded. Small sample sizes in the highest and lowest hemoglobin strata decrease statistical power. CONCLUSIONS Relationships between hemoglobin concentration and mortality differed between African Americans and whites. Additionally, the relationship of lower mortality with greater achieved hemoglobin concentration seen in white patients was observed for all-cause, but not cardiovascular, mortality. A higher cumulative epoetin dose was associated with worse outcomes, even in patients with albumin levels greater than 4 g/dL. There were no statistically significant interactions between race and epoetin dose. Further studies are needed to confirm and to define the mechanism of these findings.

Body fluid abnormalities in severe hyperglycemia in patients on chronic dialysis: review of published reports

Reports of dialysis-associated hyperglycemia (DH) were compared to reports of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) in patients with preserved renal function. Average serum values in DH (491 observations), DKA (1036 observations), and NKH (403 observations) were as follows, respectively: glucose, 772, 649, and 961 mg/dl; sodium, 127, 134, and 149, mmol/l; and tonicity, 298, 304, and 355 mOsm/kg. Assuming that euglycemic (serum glucose, 90 mg/dl) values were the same (sodium, 140 mmol/l; tonicity, 285 mOsm/kg) for all three states, the hyperglycemic rise in the average serum tonicity value per 100-mg/dl rise in serum glucose concentration was 1.9 mOsm/kg in DH, 3.5 mOsm/kg in DKA, and 8.1 mOsm/kg in NKH. Neurological manifestations in DH patients were caused by coexisting conditions (ketoacidosis, sepsis, and neurological disease) in most instances, and by severe hypertonicity (>320 mOsm/kg), with clearing after insulin administration, in a few instances. In 148 episodes of DH corrected with insulin only, the mean increase in serum sodium per 100-mg/dl decrease in serum glucose (Delta[Na]/Delta[Glu]) was -1.61 mmol/l. In agreement with theoretical predictions, Delta[Na]/Delta[Glu] was numerically smaller in patients with edema than in those with euvolemia. The average hyperglycemic increase in extracellular volume, calculated from changes in serum sodium concentration during correction of DH using insulin alone, was 0.013 l/l per 100-mg/dl increase in serum glucose concentration. A small number of DH patients presented with pulmonary edema rectified by insulin alone. DH causes modest hypertonicity, with few patients having neurological manifestations caused usually by other coexisting conditions. In contrast to DKA or NKH, which usually presents with hypovolemia, DH causes hypervolemia manifested occasionally by pulmonary edema. Insulin is adequate treatment for DH.

Characterization of pH variation in lysed blood by near-infrared spectroscopy

Near-infrared spectra (1300–2500 nm) collected from lysed blood solutions were shown to correlate with the pH of the solutions measured potentiometrically. Cross-validated partial least-squares (PLS) models were developed from these spectral data, which provided standard error of prediction (SEP) values below 0.05 pH units for a pH range of 1.0 (6.8–7.8). Experiments were designed to eliminate possible correlation between pH and other components in the blood in order to ensure that variations in the spectral data correlated to pH were due to hydrogen ion changes only. Further work was performed to discern the primary source of pH information in the lysed blood spectra by using spectra collected from plasma and histidine solutions. The blood, plasma, and histidine data sets were compared with the use of loading vectors from principal component analysis (PCA). These loading vectors show that variations in the spectra of the titrated amino acid histidine mimic those seen in lysed blood, but not those seen in plasma. These results suggest that histidine residues of hemoglobin are providing the spectral variation necessary for pH modeling in the lysed blood solutions. It is further shown that the observed pH-sensitive histidine bands do not arise from the exchangeable proton on the imidazole ring of histidine; rather they arise from the variation in the C–H bonds of the C2 and/or the C4 carbons of the imidazole ring as they are influenced by the titration of the nitrogen-bound proton of the imidazole ring.

Non-invasive glucose sensors and improved informatics – the future of diabetes management

Modern diabetes care algorithms require the patient to take a very active role in day-to-day blood glucose management. Reduction of morbidity and mortality over the last 30 years in the population with type 1 diabetes are partially the result of improvements of insulin therapy based on capillary blood self-monitoring. Home glucose monitoring technology has made this clinical evolution possible. Enzyme-based ‘strip monitors’ provide the patient with the ability to determine capillary blood glucose level on demand. With proper training and a means to accurately determine blood glucose concentration, the patient with diabetes can effectively manage insulin or oral hypoglycaemic agent therapy. This approach has been validated on the basis of multiple outcome evaluations and linked to improvement of long-term objective markers of glucose concentration such as percentage haemoglobin A1c. The recent multicentre Diabetes Control and Complications Trial demonstrated that intensive insulin therapy based on multiple daily, self-administered capillary blood glucose measurements combined with periodic review by a health professional team resulted in better glycaemic control and improved outcomes. Patients with type 1 diabetes randomized to the intensive therapy group had lower mean blood glucose concentrations as evidenced by lower percentage glycosylated haemoglobin. More importantly, the incidence of chronic complications of diabetes associated with microvascular disease was significantly reduced [1]. Given the labile nature of blood glucose concentration, frequent sampling is required to detect hypo or hyperglycaemia and to effectively base insulin therapy. Unfortunately, blood collection by finger lancet is painful, inconvenient and messy. Consequently, patients with diabetes frequently fail to obtain data critical to their management. This observation coupled with the potential for blood glucose levels to rapidly fluctuate has led to extensive efforts in the biomedical industry to develop alternatives to the ‘finger puncture’ approach to selfblood glucose monitoring. These have included a variety of bioengineering efforts directed at minimally invasive, continuous in situ invasive and non-invasive instrumentation (table1) as well as alternate site blood testing. In each case, the objective has been to provide the patient with the means to make a higher frequency of daily glucose measurements with less personal discomfort. As the technology approaches this objective, four observations bear on the way new non-invasive monitoring and web-based informatics will impact diabetes care. First, it has become clear that the developing alternate site, non-invasive and minimally invasive technologies inherently sample glucose in tissue compartments other than the accepted standard of fingertip whole blood. The relationship of glucose concentration in compartments, such as the interstitial fluid, to glucose in the plasma compartment must be well understood to ensure that pharmacological and caloric therapy can be safely and effectively based on such measurements. Second, non-invasive monitoring techniques promise the possibility of easy access to glucose level monitoring away from home. As there is no risk of transmission of infection by blood or other bodily fluid, single centralized units would accommodate multiple users. Third,

Measurement of pH in Whole Blood by Near-Infrared Spectroscopy

Whole blood pH has been determined in vitro by using near-infrared spectroscopy over the wavelength range of 1500 to 1785 nm with multivariate calibration modeling of the spectral data obtained from two different sample sets. In the first sample set, the pH of whole blood was varied without controlling cell size and oxygen saturation (O2 Sat) variation. The result was that the red blood cell (RBC) size and O2 Sat correlated with pH. Although the partial least-squares (PLS) multivariate calibration of these data produced a good pH prediction cross-validation standard error of prediction (CVSEP) = 0.046, R2 = 0.982, the spectral data were dominated by scattering changes due to changing RBC size that correlated with the pH changes. A second experiment was carried out where the RBC size and O2 Sat were varied orthogonally to the pH variation. A PLS calibration of the spectral data obtained from these samples produced a pH prediction with an R2 of 0.954 and a cross-validated standard error of prediction of 0.064 pH units. The robustness of the PLS calibration models was tested by predicting the data obtained from the other sets. The predicted pH values obtained from both data sets yielded R2 values greater than 0.9 once the data were corrected for differences in hemoglobin concentration. For example, with the use of the calibration produced from the second sample set, the pH values from the first sample set were predicted with an R2 of 0.92 after the predictions were corrected for bias and slope. It is shown that spectral information specific to pH-induced chemical changes in the hemoglobin molecule is contained within the PLS loading vectors developed for both the first and second data sets. It is this pH specific information that allows the spectra dominated by pH-correlated scattering changes to provide robust pH predictive ability in the uncorrelated data, and visa versa.