Optimal EPO dosing in hemodialysis patients using a non-linear model predictive control approach.

Anemia management with erythropoiesis stimulating agents is a challenging task in hemodialysis patients since their response to treatment varies highly. In general, it is difficult to achieve and maintain the predefined hemoglobin (Hgb) target levels in clinical practice. The aim of this study is to develop a fully personalizable controller scheme to stabilize Hgb levels within a narrow target window while keeping drug doses low to mitigate side effects. First in-silico results of this framework are presented in this paper. Based on a model of erythropoiesis we formulate a non-linear model predictive control (NMPC) algorithm for the individualized optimization of epoetin alfa (EPO) doses. Previous to this work, model parameters were estimated for individual patients using clinical data. The optimal control problem is formulated for a continuous drug administration. This is currently a hypothetical form of drug administration for EPO as it would require a programmable EPO pump similar to insulin pumps used to treat patients with diabetes mellitus. In each step of the NMPC method the open-loop problem is solved with a projected quasi-Newton method. The controller is successfully tested in-silico on several patient parameter sets. An appropriate control is feasible in the tested patients under the assumption that the controlled quantity is measured regularly and that continuous EPO administration is adjusted on a daily, weekly or monthly basis. Further, the controller satisfactorily handles the following challenging problems in simulations: bleedings, missed administrations and dosing errors.

Saliva urea dipstick test: application in chronic kidney disease.

BACKGROUND: A noninvasive test for determining elevated levels of blood urea nitrogen (BUN) may be useful under circumstances in which there is limited access to laboratories. Because saliva urea nitrogen (SUN) parallels BUN, we investigated the diagnostic performance of a semiquantitative SUN dipstick to test for elevated BUN levels in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: Patients with CKD Stages 1 to 5D were studied. 50 µl of saliva were transferred onto the SUN test strip (Integrated Biomedical Technology, Elkhart, Indiana, IN, USA). SUN was determined after 1 minute by visual comparison of the color of the moistened test pad with 6 calibrated color blocks. Interobserver reproducibility was evaluated by independent observers, masked to urea concentrations of 6 calibrated urea solutions. Correlation between SUN and BUN was quantified by Spearman's rank correlation coefficient (RS), Kappa Statistic was employed to evaluate within-sample reproducibility of duplicates. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance of SUN. RESULTS: 68 patients (31 females, 60 ± 14 years; 34 hemodialysis patients, 34 patients CKD Stages 1 - 4) were studied. Interobserver coefficient of variation was 4.9% at SUN levels > 50 mg/dl; within-sample reproducibility was 90%. SUN and BUN were correlated significantly (RS = 0.63; p < 0.01). Elevated BUN was diagnosed with high accuracy by SUN determination (area under the ROC curve: 0.90 (95% CI 0.85 - 0.95)). CONCLUSION: Semiquantitative dipstick measurements of SUN can reliably identify CKD patients with elevated BUN levels.

Significance of self-reported sleep quality (SQ) in chronic kidney disease (CKD): the Renal Research Institute (RRI)-CKD study.

BACKGROUND: There has been limited research on sleep quality (SQ) in CKD. METHODS: This prospective cohort study of adults with CKD Stages 3 - 5 at four US centers collected self-reported SQ information from the Kidney Disease Quality of Life (KDQOL) instrument, including an estimated SQ score (0 - 100), and 3 SQ-related questions. "Poor" SQ was defined as SQ score < or = 60. Logistic and multiple linear regression assessed associations between SQ and its potential predictors. Times to death and end stage renal disease (ESRD) were examined using Cox regression. A comparison with SQ in ESRD patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS), was additionally performed. RESULTS: Mean SQ score was 59.4 +/- 23.6 (n = 689), and "poor" SQ was reported by 57%. Mean estimated glomerular filtration rate (eGFR) was 24.9 +/- 10.6 ml/min/1.73 m2. Higher SQ significantly correlated with KDQOL mental and physical component summary scales. Significant predictors of lower SQ score included--younger age, presence of dyspnea, self-reported depression, pain, and itchness. There were no significant pairwise differences in SQ from CKD Stage 3 through ESRD. Self-reported daytime sleepiness was significantly associated with higher risk of mortality prior to ESRD (HR = 1.85, p = 0.02). CONCLUSION: Self-reported "poor" SQ was common in a CKD cohort (Stages 3 - 5) and was not only associated with lower quality of life scores and several modifiable symptoms, but also with higher risk of pre-ESRD mortality. Greater attention to this clinical problem is highly recommended in this high-risk population.

Quantification and classification of potassium and calcium disorders with the electrocardiogram: What do clinical studies, modeling, and reconstruction tell us?

Diseases caused by alterations of ionic concentrations are frequently observed challenges and play an important role in clinical practice. The clinically established method for the diagnosis of electrolyte concentration imbalance is blood tests. A rapid and non-invasive point-of-care method is yet needed. The electrocardiogram (ECG) could meet this need and becomes an established diagnostic tool allowing home monitoring of the electrolyte concentration also by wearable devices. In this review, we present the current state of potassium and calcium concentration monitoring using the ECG and summarize results from previous work. Selected clinical studies are presented, supporting or questioning the use of the ECG for the monitoring of electrolyte concentration imbalances. Differences in the findings from automatic monitoring studies are discussed, and current studies utilizing machine learning are presented demonstrating the potential of the deep learning approach. Furthermore, we demonstrate the potential of computational modeling approaches to gain insight into the mechanisms of relevant clinical findings and as a tool to obtain synthetic data for methodical improvements in monitoring approaches.

Assessment of body composition in dialysis patients by arm bioimpedance compared to MRI and 40K measurements.

This study used multi-frequency bioimpedance spectroscopy (BIS) of the arm and whole body to estimate muscle mass (MM) and subcutaneous adipose tissue (SAT) in 31 hemodialysis (HD) patients comparing these results with magnetic resonance imaging (MRI) and body potassium ((40)K) as gold standards. Total body and arm MM (MM(MRI)) and SAT (SAT(MRI)) were measured by MRI. All measurements were made before dialysis treatment. Regression models with the arm (aBIS) and whole body (wBIS) resistances were established. Correlations between gold standards and the BIS model were high for the arm SAT (r(2) = 0.93, standard error of estimate (SEE) = 3.6 kg), and whole body SAT (r(2) = 0.92, SEE = 3.5 kg), and for arm MM (r(2) = 0.84, SEE = 2.28 kg) and whole body MM (r(2) = 0.86, SEE = 2.28 kg). Total body MM and SAT can be accurately predicted by arm BIS models with advantages of convenience and portability, and it should be useful to assess nutritional status in HD patients.

A method for the estimation of hydration state during hemodialysis using a calf bioimpedance technique.

Although many methods have been utilized to measure degrees of body hydration, and in particular to estimate normal hydration states (dry weight, DW) in hemodialysis (HD) patients, no accurate methods are currently available for clinical use. Biochemcial measurements are not sufficiently precise and vena cava diameter estimation is impractical. Several bioimpedance methods have been suggested to provide information to estimate clinical hydration and nutritional status, such as phase angle measurement and ratio of body fluid compartment volumes to body weight. In this study, we present a calf bioimpedance spectroscopy (cBIS) technique to monitor calf resistance and resistivity continuously during HD. Attainment of DW is defined by two criteria: (1) the primary criterion is flattening of the change in the resistance curve during dialysis so that at DW little further change is observed and (2) normalized resistivity is in the range of observation of healthy subjects. Twenty maintenance HD patients (12 M/8 F) were studied on 220 occasions. After three baseline (BL) measurements, with patients at their DW prescribed on clinical grounds (DW(Clin)), the target post-dialysis weight was gradually decreased in the course of several treatments until the two dry weight criteria outlined above were met (DW(cBIS)). Post-dialysis weight was reduced from 78.3 +/- 28 to 77.1 +/- 27 kg (p < 0.01), normalized resistivity increased from 17.9 +/- 3 to 19.1 +/- 2.3 x 10(-2) Omega m(3) kg(-1) (p < 0.01). The average coefficient of variation (CV) in three repeat measurements of DW(cBIS) was 0.3 +/- 0.2%. The results indicate that cBIS utilizing a dynamic technique continuously during dialysis is an accurate and precise approach to specific end points for the estimation of body hydration status. Since no current techniques have been developed to detect DW as precisely, it is suggested as a standard to be evaluated clinically.

The impact of visceral mass on survival in chronic hemodialysis patients.

In chronic hemodialysis, patient survival is positively correlated with body weight and body mass index (BMI). This relationship extends even to obese patients with a BMI >30 kg/m2. We have put forward the hypothesis that this survival benefit may be due to a lower average synthesis rate of uremic toxins (expressed as amount per time per unit of body weight) in larger patients, because the relative contribution of the high metabolic rate organs (HMRO) to body weight in these patients is lower and HMRO are most likely to be the prime source of uremic toxins. In addition, the average uremic toxin concentration in larger patients may be lower because of the larger distribution volume. Based on these assumptions, a better survival in patients with a lower HMRO to body weight fraction (HMRO%BW) can be predicted. To test this hypothesis we estimated gender- and race-specific HMRO mass by means of recently published regression models in 2,004 incident hemodialysis patients. Cox proportional hazards models were used to assess the association between age, serum albumin concentration, eKt/V, and HMRO% BW and mortality. High HMRO%BW was significantly associated with increased mortality (hazard ratio 1.323 [95% CI: 1.186 to 1.477]). Mean survival time was longest in the low HMRO%BW tertile (1,031 days [95%CI: 974 to 1,087]), 935 days [95%CI: 886 to 984] in the middle, and 876 days [95%CI: 825 to 926] in the high HMRO%BW tertile (p<0.0001; log rank test). These results support the hypothesis predicting that a low HMRO mass per unit of weight confers a beneficial effect on survival.

A mathematical model comparing solute kinetics in low- and high-BMI hemodialysis patients.

BACKGROUND: Patients with low Body Mass Index (BMI) on maintenance hemodialysis have a higher mortality risk than patients with elevated BMI. We investigated the use of kinetic modeling to test different hypotheses which have been advanced to explain this relationship. METHODS: Equations from a three-pool urea-kinetic mathematical model (hepatic mass, extracellular fluid, muscle mass and adipose tissue) were solved to yield predictive profiles of solute and putative toxin concentrations versus time for patients of different body weights. RESULTS: For the interdialytic interval, our mathematic model suggests that extracellular solute/toxin concentration increases more rapidly in small patients. Additionally, time average concentration (TAC) is higher for this cohort. A lower value of the muscle mass and adipose tissue mass-transfer coefficient (K(MMAT)), which determines the rate of solute release into the extracellular fluid, exacerbates this difference. CONCLUSION: These results suggest that higher mortality for smaller dialysis patients may be mediated by higher time average toxin concentration, especially for solutes with a low mass-transfer coefficient value.

Unraveling the relationship between mortality, hyponatremia, inflammation and malnutrition in hemodialysis patients: results from the international MONDO initiative.

BACKGROUND/OBJECTIVES: Hyponatremia is a risk factor for mortality in hemodialysis (HD) patients. It is not well known to which extent the comorbidities, malnutrition, fluid status imbalance and inflammation are related to hyponatremia and affect outcomes. SUBJECTS/METHODS: We studied 8883 patients from the European subset of the international MONitoring Dialysis Outcomes initiative. Nutritional and fluid statuses were assessed by bioimpedance spectroscopy. Fluid depletion was defined as overhydration⩽-1.1 l and fluid overload as overhydration>+1.1 l, respectively. Malnutrition was defined as a lean tissue index below the 10th percentile of age- and gender-matched healthy controls. Hyponatremia and inflammation were defined as serum sodium levels <135 mEq/l and C-reactive protein levels>6.0 mg/l, respectively. We used logistic regression to test for predictors of hyponatremia and Cox proportional hazards analysis to assess the association with all-cause mortality. RESULTS: Hyponatremia was predicted by the presence of malnutrition (odds ratio (OR)=1.49 (95% confidence interval (CI)=1.30-1.70), inflammation (OR=1.44 (95% CI=1.26-1.64)) and fluid overload ((>+1.1 l to +2.5 l) OR=0.73 (95% CI=0.62-0.85)) but not by fluid depletion (OR=1.34 (95% CI=0.92-1.96)). Malnutrition, inflammation, fluid overload, fluid depletion and hyponatremia (hazard ratio=1.70 (95% CI=1.46-1.99)) were independent predictors for all-cause mortality. CONCLUSIONS: In HD patients, hyponatremia is associated with malnutrition, inflammation and fluid overload. Hyponatremia maintained predictive for all-cause mortality after adjustment for malnutrition, inflammation and fluid status abnormalities. The presence of hyponatremia may assist in identifying HD patients at increased risk of death.

Association between pre hemodialysis serum sodium concentration and blood pressure: results from a retrospective analysis from the international monitoring dialysis outcomes (MONDO) initiative.

A recent study from the United Kingdom indicates an association between pre hemodialysis (HD) serum sodium (SNa(+)) and systolic and diastolic blood pressure (SBP and DBP) in chronic HD patients. We extend this analysis to an international cohort of incident HD patients. The Monitoring Dialysis Outcomes initiative encompasses patients from 41 countries. Over 2 years monthly pre-HD SNa(+) levels were used as predictors of pre-HD SBP and DBP in a linear mixed model (LMM) adjusted for age, gender, interdialytic weight gain, diabetes, serum albumin and calcium. Similar models were constructed with DBP as outcome. Analyses were carried out stratified by continent (North and South America; Europe and Asia). LMMs were also constructed for the entire observation period of 2 years, and separately the first and the second year after HD initiation. We studied 17 050 incident patients and found SNa(+) to have a significant slope estimate in the LMM predicting pre-HD SBP and DBP (ranging from 0.22 to 0.29 and 0.10 to 0.21 mm Hg per mEq l(-1), respectively, between the continents). The findings were similar in subsets of SBP and SNa(+) tertiles, and separately analyzed for the first and second year. Our analysis shows an independent association between SNa, SBP and DBP in a large intercontinental database, indicating that this relation is a profound biological phenomenon in incident and prevalent HD patients, generalizable to an international level and independent of SBP and DBP magnitude.

Compartmentation of ATP within renal proximal tubular cells.

Studies on the relations between active solute transport and cell metabolism require not only knowledge of the total cellular ATP, but also of the separate mitochondrial and cytosolic ATP levels. For this purpose, mitochondrial and cytosolic fractions were separated from isolated proximal tubular suspensions by the digitonin technique and the amount of ATP analyzed separately for each compartment. In a parallel series of experiments, the absolute volumes of mitochondrial and extramitochondrial spaces were determined in rat renal cortical tubular suspension utilizing electron microscopic morphometry. When referring ATP measurements to the morphometrically determined absolute volumes, the ATP concentrations were calculated to be 4.33 mmol/l for the cytosolic and 2.62 mmol/l for the mitochondrial space. The cytosolic and mitochondrial ATP, thus, represent 70 and 30% of the total cellular ATP, respectively.

Open-flow microperfusion of subcutaneous adipose tissue for on-line continuous ex vivo measurement of glucose concentration.

OBJECTIVE: To evaluate a novel technique for on-line continuous glucose measurement in subcutaneous adipose tissue, and to investigate its accuracy for detection of hypoglycemia. RESEARCH DESIGN AND METHODS: The method combined an open-flow microperfusion of subcutaneous adipose tissue using a double lumen catheter and an extracorporeal sensor cell. An isotonic ion-free solution was perfused through the inner lumen of the catheter, equilibrated with the subcutaneous tissue fluid, and sampled through the outer lumen. The recovery was continuously monitored as the ratio between the measured sampled fluid conductivity and the subcutaneous tissue fluid conductivity (assumed to have a constant value of 1.28 S/m at 25 degrees C). Glucose concentration was calculated on-line from the measured glucose in the sampled fluid and the measured recovery in healthy volunteers during hyperglycemic glucose loads (n = 8), hypoglycemic hyperinsulinemic clamp (n = 6), and a 24-h monitoring period (n = 7). RESULTS: Subcutaneous glucose concentrations in the fasting state were 94% of the plasma glucose concentrations in arterialized venous samples. According to the error grid analysis, 96.9% of the on-line measured subcutaneous glucose concentrations during hyperglycemia and 96.3% during hypoglycemia were in accurate or acceptable zones. The mean differences between the measured subcutaneous glucose and the actual plasma glucose concentration were -0.06-3.3 mmol/l (hyperglycemia), and -0.6-1.1 mmol/l (hypoglycemia). CONCLUSIONS: By combining open-flow microperfusion, glucose sensor, and conductivity measurement, glucose concentration in the subcutaneous adipose tissue can be monitored on-line, extracorporeally, and continuously without any in vivo calibration, and gives accurate measurements during hyper- and hypoglycemia.

UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.

Gout, which is commonly associated with hyperuricemia, affects 0.2% of the population. Hyperuricemia has a heterogeneous etiology that may be due to either over production and/or reduced renal clearance, of urate. In order to identify the mechanisms underlying reduced excretion of urate, we undertook positional cloning studies of familial juvenile hyperuricaemic nephropathy (FJHN), which is an autosomal dominant disorder characterized by hyperuricaemia, a low fractional renal excretion of urate, and chronic renal failure that is associated with interstitial fibrosis. The FJHN locus has been previously localized to a 22 centiMorgan interval flanked centromerically by D16S401 and telomerically by D16S3069, on chromosome 16p11-p13. This interval contains over 120 genes and we selected 13 renal expressed sequences to search for mutations in 5 unrelated FJHN families that contained 21 affected and 24 unaffected members. This revealed 5 heterozygous missense mutations (Cys77Tyr, Cys126Arg, Asn128Ser, Cys255Tyr and Cys300Gly) that altered evolutionary conserved residues in the gene encoding UROMODULIN. UROMODULIN, which is an 85 Kda glycoprotein, has roles in renal stone formation, the modulation of immune responses, and urothelial cytoprotection. The results of our studies, which have identified the gene causing FJHN, now indicate a further, novel role for UROMODULIN in urate metabolism.

beta-2 Adrenergic receptor variants affect resting blood pressure and agonist-induced vasodilation in young adult Caucasians.

Recent evidence suggests that the prodownregulatory Gly16 allele of the beta-2 adrenergic receptor (beta-2 AR) is associated with essential hypertension in African Caribbeans. To further investigate the effect of the glycine (Gly)16 and arginine (Arg)16 beta-2 AR variants on hemodynamics, we investigated the agonist-mediated in vivo vasodilation in normotensive Austrian Caucasians and analyzed the results with respect to the Gly16/Arg16 polymorphism. Fifty-seven normotensive men, 20 to 32 years of age with body mass index of 18.7 to 29.9 kg/m2, were genotyped for the Arg16/Gly16 beta-2 AR alleles. All 15 Gly16/Gly16 subjects, all 12 Arg16/Arg/16 subjects, and 27 of 30 heterozygous subjects underwent hemodynamic measurements while supine after an overnight fast. The observers were unaware of the subjects' genotypes. The subjects received a graded infusion of the selective beta-2 AR agonist salbutamol (0.07, 0.14, and 0.21 microgram/kg per minute, respectively), each dose over 8 minutes. Stroke volume and blood pressure were determined continuously by means of impedance cardiography and oscillometry, respectively. The last 4 minutes of each infusion were evaluated statistically. Basal mean blood pressure was higher in the Gly16/Gly16 subjects compared with Arg16/Arg16 subjects (mean+/-SD: 81.6+/-6.14 versus 75.2+/-4.93 mm Hg, P<0.01). Homozygous Gly16 subjects showed a significantly decreased vasodilation during the first dose of salbutamol infusion compared with Arg16/Arg16 subjects (Deltatotal peripheral resistance index -17.9+/-14.4 versus -30. 6+/-8.3%, P<0.01) despite increased sympathetic counterregulation in the Arg16/Arg16 group (Deltaheart rate +16.9+/-7.0% versus +8.6+/-7. 0%, P<0.01; Deltacardiac index +39.5+/-18.5% versus 21.4+/-18.8%, P<0.05). Our results provide additional evidence that the Gly16/Arg16 alleles of the beta-2 AR are intimately related to blood pressure regulation and deserve further studies in the pathogenesis of essential hypertension.

Essential hypertension in African Caribbeans associates with a variant of the beta2-adrenoceptor.

Populations of West African ancestry dwelling in Western communities exhibit greater prevalence of human essential hypertension and higher rates of end-organ damage. The sympathetic nervous system influences cardiac output, vascular tone, renal sodium reabsorption, and renin release and could be implicated in enhanced vascular responsiveness observed in African hypertensives. Such an effect could arise from genetic variants that alter agonist response of alpha-adrenoceptors, leading to enhanced vasoconstriction, or attenuate beta2-adrenoceptor-mediated vasodilatation. Indeed, there is evidence of a blunted vasodilator response to the beta-agonist isoprenaline in African Americans. A variant of the beta2-adrenoceptor gene that encodes glycine rather than arginine at position 16 (Arg16-->Gly) has been shown to confer exaggerated agonist-mediated receptor downregulation, which might attenuate vasodilator response. One hundred thirty-six unrelated hypertensives and 81 unrelated normotensives of African Caribbean origin were identified from primary care on the island of St Vincent. Genomic DNA from these subjects was analyzed for the presence of the Gly16 and Arg16 alleles by using an allele-specific polymerase chain reaction method. We report strong support for association of the prodownregulatory glycine 16 variant of the beta2-adrenoceptor gene with hypertension in African Caribbeans from St Vincent and the Grenadines (chi2=18.9, P=.000014, 1 df). This observation, coupled with reports of attenuated vasodilator responses to beta-agonists among people of West African ancestry, may provide a mechanism for enhanced vascular reactivity and identify a candidate gene for hypertension in this ethnic group.

Reduced renal allograft survival is related to low urinary N-acetyl-beta-D-glucosaminidase excretion during the first posttransplant month.

The excretion of urinary N-acetyl-beta-D-glucosaminidase (NAG) was measured daily between day 7 and day 28 in 33 renal allograft recipients enjoying an entirely uncomplicated first postoperative month. Graft status was evaluated after 4 and 6 years and related to NAG excretion. After 4 years, 6 patients had experienced graft loss due to chronic rejection. Posttransplant urinary NAG excretion in the group of patients with failing grafts was significantly lower (9.4 +/- 6.3 vs. 17.2 +/- 8.5 U/g urinary creatinine, P = 0.036). Univariant analysis of recipient and donor characteristics revealed urinary NAG excretion to be the only parameter significantly differing between the groups. After 6 years, a total of 8 patients had lost their grafts. The posttransplant urinary NAG excretion in this group was 10.8 +/- 6.2 U/g; in the 25 patients with functioning grafts NAG excretion was 17.4 +/- 8.8 U/g (P = 0.064). A very low urinary NAG excretion ( < 7 U/g) was seen in 5 patients and associated with poor graft survival after 4 and 6 years (odds ratios 12.5 (1.9-82.1) and 6.9 (1.1-44.8), respectively. Kaplan-Meier analysis showed a reduced graft survival in this subgroup (P = 0.031). Receiver operating characteristics (ROC) analysis demonstrated an association between low NAG excretion and graft survival rates both at 4 and 6 years (area under the ROC curve 0.799 +/- 0.115, P, 0.05, and 0.747 +/- 0.104, P < 0.05, respectively). Cox proportional hazards analysis identified a low urinary NAG excretion as an independent prognostic risk factor. Urinary NAG excretion was expressed as unit per gram of urinary creatinine; as the amount of NAG excreted depends on the graft mass, and the amount of urinary creatinine depends on the recipient body mass, a low NAG excretion (in terms of U/g urinary creatinine) could be a surrogate marker of an unfavorable low graft to body weight ratio, which, in turn, might be associated with a reduced graft survival.

Evidence of accelerated gastric emptying in longstanding diabetic patients after ingestion of a semisolid meal.

UNLABELLED: This study investigated the prevalence of accelerated gastric emptying in 40 consecutive nonselected patients with longstanding insulin-dependent diabetes mellitus (range 11-54 yr; mean 27 yr). METHODS: The gastric emptying of a semisolid meal labeled with 99mTc was continuously recorded with a dual-head gamma camera for 90 min in patients who were supine. RESULTS: Eleven patients demonstrated delayed gastric emptying, but three male diabetics showed accelerated gastric emptying with retention values that were different from controls already after 10 min of recording (89% +/- 3% versus 96% +/- 4%; p < 0.02). During the 90-min segment, accelerated gastric emptying reduced initial gastric contents to 11% +/- 8% (p < 0.001) as compared to 50% +/- 10% in control subjects and 78% +/- 6% (p < 0.001) in patients with delayed gastric emptyings. Accelerated gastric emptying was characterized by an almost equal initial meal distribution in proximal and distal compartments of stomach, both emptying approximately 90% of their contents within 90 min. Normal and delayed gastric emptying was characterized by a 60%-40% initial ratio of meal distribution between gastric compartments. During normal emptying, both compartments reduced contents with approximately 50%, but delayed gastric emptying was caused by only a 15% reduction of proximal contents accompanied by a 34% reduction in distal contents. CONCLUSION: Recording in the supine position to abolish gravitational influences demonstrated accelerated gastric emptying of a firm semisolid meal with a prevalence of 8%. However, delayed gastric emptying was shown as the predominant gastric manifestation of longstanding insulin-dependent diabetes mellitus with a prevalence of 28%.

Glutathione depletion and in vitro lipid peroxidation in mercury or maleate induced acute renal failure.

Nephrotoxic acute renal failure was experimentally induced in male rats by s.c. application of mercuric chloride and i.p. administration of maleate, respectively. Mercuric chloride and maleate are known to enhance the formation of free radicals and peroxides, which presumably overload the cell's natural elimination mechanisms for these highly reactive intermediates. In addition, a reduction in activities of superoxide dismutase, catalase and glutathione-peroxidase, enzymes responsible for the protection of cells against peroxidative action of superoxide anions and hyperperoxides was found. In both models of acute renal failure, enhanced lipid peroxidation in kidney homogenates in vitro, monitored as malondialdehyde production, was observed. Furthermore, HgCl2 and maleate may react with free SH-groups and thus lead to a depletion of glutathione in tubular cells. Indeed, renal cortical contents of reduced and oxidized glutathione were drastically diminished. These results suggest that alterations in membrane integrity, possibly caused by peroxidative processes, can be considered the cause underlying the well-known disturbances in renal function commonly observed during the initiation phase of HgCl2 and maleate induced acute renal failure.

Portable device for continuous fractionated blood sampling and continuous ex vivo blood glucose monitoring.

The objective of the study was to develop and evaluate a portable device for continuous fractionated blood sampling and continuous ex vivo monitoring of blood glucose. The inner lumen of a double lumen catheter (18 gauge x 45 mm) was placed in a peripheral vein and perfused with heparin solution (1.4 U min-1). The outer lumen was used to collect heparinized blood into 48 vacuum tubes at programmable sample volumes and time intervals (0.2-2 ml in 2.5-30 min). A sensor flow chamber with an internal volume of 1 mm3 incorporating a miniaturized thin-film amperometric glucose sensor was placed in the sampling line for continuous ex vivo blood glucose monitoring. Blood glucose and plasma insulin were measured during a frequently sampled intravenous glucose tolerance test (250 mg kg-1) and a subsequent oral glucose tolerance test (150 g) over 6 h in eight healthy volunteers (BMI 24.5 +/- 3.2 kg m-2). Additionally, in four experiments blood glucose was measured on-line using the glucose sensors. The overall correlation coefficients for whole blood glucose and plasma insulin between the manually drawn samples and the vacuum tubes were 0.73 and 0.87, respectively (p < 0.001). The miniaturized glucose sensor exhibited a linear measuring range of 25 mmol-1 glucose concentration and 95% response times of less than 30 s. Sensor readings and laboratory analyser results for the blood glucose measurement correlated between 0.93 and 0.98 (p < 0.001). In summary, continuous fractionated blood sampling and ex vivo blood glucose monitoring in ambulatory subjects is possible with a portable device.

Urinary enzyme analysis in renal allograft transplantation.

The urinary excretion of four enzymes (fructose-1,6-bisphosphatase, glutathione S-transferase, N-acetyl-beta-D-glucosaminidase and pyruvate kinase) was assayed daily in 59 patients following renal cadaveric allografting. 51 patients were given cyclosporin A (CyA group) as an immunosuppressive, 8 patients were treated conventionally with azathioprine and prednisolone (CON-group). Urinary enzyme output was evaluated by two different mathematical models. Model A follows single enzyme excretion, whereas model B also analyzes enzyme patterns. The best results were obtained by a combined analysis of all four enzymes with model B. In the CON-group the sensitivity was 1.00, the specificity 0.85, the predictive values of positive test 0.45 and all 12 graft rejections were diagnosed correctly. In the CyA group the sensitivity was 0.40, the specificity 0.99, the predictive value of positive test 0.33, and 6 out of 9 rejections were recognized. The evaluation of the single enzymes did not produce similarly good results with either model.