Body composition in patients treated with peritoneal dialysis

Background: Malnutrition is a common complication in uremia and during maintenance dialysis. Several factors contribute to its development. Different modes of dialysis treatment may differ in their effects on nutritional status. Methods: In order to analyse the nutritional consequences of peritoneal dialysis (PD), body composition analyses were performed in PD patients between February 1993 and March 1996. Body cell mass (BCM) was estimated from measurements of total body potassium (TBK) in a whole-body counter. Total body water (TBW) was determined by measurement of tritiated water. Body fat (BF) was calculated from body weight (BW), TBK and TBW. Observed values were related to predicted (o/p) derived from local population studies. Results: Sixty patients were repeatedly investigated during the study period. Of these, 34 were investigated during the first year of PD. At the start of dialysis, TBK o/p was 0.94 and BF o/p 0.76. No change in body composition was seen during the observation period in the group as a whole. However, within the group individual changes in BW were strongly correlated with individual changes in BF (r=0.66, P=0.0001). Twenty-six patients were examined during the second and third year of PD. In this group, BW o/p remained constant over time. However, there was a small but significant decline of TBK o/p and a concomitant increase of BF o/p (P<0.05). No correlation was observed between changes in TBK and changes in serum albumin. Conclusions: The results of this study indicate, that there may be a risk for further reduction of body cell mass during long-term PD treatment, while body energy stores are maintained or even increased.     

Calcium dependence of histamine-induced increases in capillary permeability in isolated perfused rat hindquarters

Experiments were performed on isolated maximally vasodilated perfused rat hindquarters to evaluate the role of calcium and magnesium for the capillary permeability increase(s) elicited by histamine. Changes in capillary permeability were quantified by determinations of capillary filtration coefficient (CFC) with gravimetric technique, and capillary diffusion capacity (PS) for vitamin B12 (MW = 1,355) with a single injection indicator dilution technique. During control, vascular resistance was 2.2 PRU100 at a flow of 9.4 ml min-1 per 100 g, and PS for B12 was 3.7 +/- 0.1 ml min-1 per 100 g, while CFC was 0.0377 +/- 0.0004 ml min-1 mmHg-1 per 100 g. Perfusion with 'Mg-free' solution for 1 h caused a 24% increase in CFC, while neither 'Ca-free' perfusion nor perfusion with verapamil (5 X 10(-5) M) nor felodipine (1 X 10(-6) M) induced any changes in CFC. Histamine (100-200 microM) caused in all preparations a 150-200% increase in CFC with only small changes in PS for B12. This histamine effect was absent after 1 h of 'Ca-free' perfusion and was partially blocked after 1 h of perfusion with 0.1 mM calcium, while the calcium antagonists verapamil and felodipine had no effects on the histamine-induced changes. The results imply that histamine exerts its action on the endothelial cells through a calcium-dependent process, probably involving low affinity calcium sites but this process could not be inhibited by the calcium antagonists used. Thus, endothelial cell contractility, which probably is responsible for the histamine-induced increase in capillary permeability, exhibits unique characteristics, differing from those of vascular smooth muscle.     

Genetic basis for individual variations in pain perception and the development of a chronic pain condition

Pain sensitivity varies substantially among humans. A significantpart of the human population develops chronic pain conditionsthat are characterized by heightened pain sensitivity. We identifiedthree genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase(COMT) that we designated as low pain sensitivity (LPS), averagepain sensitivity (APS) and high pain sensitivity (HPS). We showthat these haplotypes encompass 96% of the human population,and five combinations of these haplotypes are strongly associated(P=0.0004) with variation in the sensitivity to experimentalpain. The presence of even a single LPS haplotype diminishes,by as much as 2.3 times, the risk of developing myogenous temporomandibularjoint disorder (TMD), a common musculoskeletal pain condition.The LPS haplotype produces much higher levels of COMT enzymaticactivity when compared with the APS or HPS haplotypes. Inhibitionof COMT in the rat results in a profound increase in pain sensitivity.Thus, COMT activity substantially influences pain sensitivity,and the three major haplotypes determine COMT activity in humansthat inversely correlates with pain sensitivity and the riskof developing TMD.     

Higher Kt/V is needed for adequate dialysis if the treatment time is reduced

The widely used Kt/V concept for quantitating haemodialysis(HD) and ensuring adequate dialysis is based on several assumptions.In order to simplify the urea kinetic modelling, the body isassumed to be a single well-mixed compartment. Previously, morephysiological two-compartment or blood flow distribution modelshave been used to explain the phenomenon of blood urea reboundafter dialysis. This study attempts to evaluate the effectsof a multi compartment model on the removal of urea, i.e. onthe adequacy of dialysis. Four different tissue compartmentsof similar size are used, with flow rates between 40 and 3600ml/min for a bodyweight around 70 kg, allowing for blood flowheterogeneity within and between skeletal muscles. Dialysisis simulated by removing blood containing urea and replacingit with blood free of urea, during isovolumetric conditionsand assuming no diffusion barriers for urea. Several importantconclusions can be drawn from the model. Firstly the removalof urea is dependent both on the time of dialysis and on thenumber of HD treatments per week despite constant Kt/V. Secondlythe blood urea concentration is increased after dialysis—‘urearebound’—in accordance with clinical data. Thirdlythe concept of blood flow distribution can fully explain thedifference between haemodialysis and peritoneal dialysis interms of Kt/V needed for adequate dialysis. Thus a weekly Kt/Vof 3.6 for HD 4 h 3 times per week removes the same amount ofurea as CAPD and a Kt/V of 2.1. Also, nightly intermittent PDrequires similar Kt/Vs (0.1 higher) as CAPD to obtain equivalentremoval of urea. Finally the crucial point is that the Kt/Vrequired for adequate dialysis must be increased if the dialysistreatment time is reduced. If not, the patient with renal insufficiencysuffers the risk of being under-dialysed.     

Diacyl glyceryl ester prodrugs for slow release in the skin: synthesis and in vitro degradation and absorption studies for naproxen derivatives

Diacyl glyceryl ester derivatives of naproxen were synthesized and tested for transdermal and dermal administration. Diacyl derivatives of aliphatic acids of various chain length were compared. The pharmaceutical properties of these compounds, such as lipophilicity, hydrolysis in a buffer solution at various pH values and degradation in human serum and hairless mouse skin homogenate, were investigated. All the diacyl derivatives were relatively stable in a neutral buffer solution, but were rapidly degraded to release naproxen in human serum and hairless mouse skin homogenate. The diacyl compounds could not penetrate hairless mouse skin in vitro. However, significant absorption into the skin could be measured, and this increased with increasing lipophilicity. A more than 100-fold difference in absorption was observed. The prodrugs were slowly hydrolyzed to naproxen inside the skin. The release of naproxen to the receptor compartment of diffusion cells showed that this type of prodrug could be used for controlled drug delivery.     

Computer simulations of peritoneal fluid transport in CAPD

To model the changes in intraperitoneal dialysate volume (IPV) occurring over dwell time under various conditions in continuous ambulatory peritoneal dialysis (CAPD), we have, using a personal computer (PC), numerically integrated the phenomenological equations that describe the net ultrafiltration (UF) flow existing across the peritoneal membrane in every moment of a dwell. Computer modelling was performed according to a three-pore model of membrane selectivity as based on current concepts in capillary physiology. This model comprises small "paracellular" pores (radius approximately 47 A) and "large" pores (radius approximately 250 A), together accounting for approximately 98% of the total UF-coefficient (LpS), and also "transcellular" pores (pore radius approximately 4 to 5 A) accounting for 1.5% of LpS. Simulated curves made a good fit to IPV versus time data obtained experimentally in adult patients, using either 1.36 or 3.86% glucose dialysis solutions, under control conditions; when the peritoneal UF-coefficient was set to 0.082 ml/min/mm Hg, the glucose reflection coefficient was 0.043 and the peritoneal lymph flow was set to 0.3 ml/min. Also, theoretical predictions regarding the IPV versus time curves agreed well with the computer simulated results for perturbed values of effective peritoneal surface area, LpS, glucose permeability-surface area product (PS or "MTAC"), intraperitoneal dialysate volume and dialysate glucose concentration. Thus, increasing the peritoneal surface area caused the IPV versus time curves to peak earlier than during control, while the maximal volume ultrafiltered was not markedly affected. However, increasing the glucose PS caused both a reduction in the IPV versus time curve "peak time" and in the "peak height" of the curves. The latter pattern was also seen when the dialysate volume was reduced. It is suggested that computer modelling based on a three-pore model of membrane selectivity may be a useful tool for describing the IPV versus time relationships under various conditions in CAPD.     

Unrestricted pore area (A0/Deltax) is a better indicator of peritoneal membrane function than PET

BACKGROUND: How to measure the peritoneal exchange in uremic patients treated with peritoneal dialysis (PD) is still a matter of controversy. Most clinics use the peritoneal equilibration test (PET), but from a theoretical point of view, it would be more appropriate to determine the "area" parameter, A0/Deltax. The latter reflects the total unrestricted pore area per centimeter diffusion distance and can be obtained by three-pore analysis using, for example, the PD capacity test (PDC). To evaluate the different estimates of peritoneal function, PET data and the A0/Deltax parameters were compared with the independently determined uptake of a small diffusible tracer, iohexol (molecular weight of 821 D), from the abdominal cavity to blood. METHODS: Fourteen patients on routine PD underwent determinations of PET and A0/Deltax using PDC. Within a month, the two-hour uptake of iohexol (6 mg/mL) was also determined from the plasma iohexol concentration following abdominal filling. RESULTS: A strong correlation was found between the rate of iohexol plasma concentration increase (k30-120) and A0/Deltax (A0/Deltax = 76,300. k30-120 - 1.56; r2 = 0.799; N = 14) for the 2 L dwell, while the PET data were far less related to iohexol uptake (D/DPurea, r2 = 0.409; D/Pcreatinine, r2 = 0.436; and D/D0glucose, r2 = 0.015, respectively). CONCLUSION: The "area" parameter, A0/Deltax, is superior to the more widely used routine PET as an indicator of peritoneal membrane function. In addition, the concept of A0/Deltax has the virtue of supplying quantitative information about the peritoneal pathophysiology and physiology.