Predialysis Samples Research Articles

Oxidative Stress Influences CC-Chemokine Levels in Hemodialyzed Patients

Background: Increased oxidative stress (SOX) has been reported in hemodialyzed (HD) patients, but its influence on CC-chemokine levels remains unknown. Methods: The levels of 3 distinct SOX markers (Cu/Zn superoxide dismutase (Cu/Zn SOD), total lipid peroxide, and autoantibodies against oxidized LDL (OxLDL-Ab)), as well as those of 4 CC-chemokines (monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1α, MIP-1β), regulated upon activation, normal T cell expressed and secreted (RANTES), and tumor necrosis factor-α (TNF-α)) were measured pre- and post-HD session in 15 HD patients with cardiovascular disease (CVD) and 12 HD patients without CVD (pre- and post-HD session) and 17 controls. Results: Cu/Zn SOD levels were elevated in HD patients (both before and after HD) compared to controls (p < 0.001). Total lipid peroxide levels were similar in the controls in pre-dialysis samples, but were increased after a HD session (p < 0.001). Pre-dialysis OxLDL-Ab levels were increased only in the HD group with CVD compared to controls (p < 0.05). The pre-dialysis plasma levels of TNF-α (p < 0.001), MCP-1 (p < 0.001) and MIP-1β (p < 0.01) were increased both in all HD patients and subgroups with CVD when compared to the controls, and remained significantly elevated when measured after HD. Dialysis increased MCP-1 (p < 0.05) and MIP-1β (p < 0.001) levels as compared to the controls as well as in patients without CVD. Plasma RANTES was significantly lower before HD (p < 0.05) and after HD (p < 0.001) in patients with CVD. Patients without CVD and all HD patients also had lower RANTES before and after HD when compared to controls (all p < 0.001). A positive correlation was observed between plasma pre-dialysis Cu/Zn SOD levels and the other SOX markers (all p < 0.05), age (p < 0.05) and duration of hemodialysis (p < 0.001). A positive relationship existed between plasma Cu/Zn SOD levels and those of MCP-1, MIP-1β and TNF-α (all p < 0.001). RANTES levels negatively correlated with Cu/Zn SOD (p < 0.0001).TNF-α positively correlated with age (p < 0.05), total lipid peroxide (p = 0.010), MCP-1 (p < 0.01) and MIP-1β levels (p < 0.01). An identifiable association exists between MCP-1 and MIP-1β levels (p < 0.01), whereas both MCP-1 and MIP-1β were inversely correlated with RANTES (both p < 0.05). Conclusion: Our data indicate for the first time a probable functional relationship between oxidative stress and CC-chemokine levels in hemodialyzed patients, particularly in those with cardiovascular disease. This relationship may represent one of the mechanisms involved in the progression of atherosclerosis in these patients.

Comparison of the Humoral Markers of Bone Turnover and Bone Mineral Density in Patients on Haemodialysis and Continuous Ambulatory Peritoneal Dialysis

Renal osteodystrophy is an important complication in patients with end-stage renal disease on maintenance dialysis. The aim of this study was to compare the biochemical markers of bone formation (serum collagen type I C-terminal propeptide) and resorption (serum deoxypyridinoline – DPD – and pyridinoline – PYR) with the bone mineral density (BMD) at lumbar spine, femoral neck, and forearm in patients with end-stage renal disease on haemodialysis (HD) versus continuous ambulatory peritoneal dialysis (CAPD). Fifty-nine adult patients, 45 on CAPD (18 females, 27 males) and 14 on HD (2 females, 12 males), were studied. The mean age was 44 ± SEM 1.6 and 54.4 ± 4.8 years, respectively. No significant differences in serum calcium, phosphorus, creatinine, and parathyroid hormone were found between patients on HD and CAPD in predialysis samples. Serum urea was significantly lower (p = 0.02) in the CAPD group. Serum PYR (nmol/l) and DPD (nmol/l) were significantly higher in patients on HD as compared with those on CAPD: 105 ± 23.3 versus 43.7 ± 3.47 (p = 0.007) and 31.0 ± 2.4 versus 24.4 ± 1.4 (p = 0.027), respectively. The results were still significantly higher in the HD patients following correction for serum creatinine and body mass index. There was a close correlation between dialysate DPD and creatinine in both dialysis modalities (HD r = 0.9, CAPD r = 0.76). The clearance of DPD did not differ significantly between the CAPD membrane and the HD membrane (p = 0.22). Serum collagen type I C-terminal propeptide was not significantly different between the HD and CAPD patients. The results were unaffected following correction for age and gender. The BMD was measured in 38 (65%) of the patients (HD n = 8, CAPD n = 30) by dual-energy X-ray absorptiometry and expressed as ‘Z’ scores. This was reduced at all sites in the patients with end-stage renal disease. The BMD was significantly lower at the ultradistal forearm (mostly trabecular bone) in HD patients as compared with CAPD patients (n = 0.02). A similar trend was observed at the lumbar spine, although the results failed to reach significance. In the whole population (n = 38), linear regression analysis revealed a significant negative correlation between BMD at the ultradistal forearm and serum PYR (r = –0.35, p = 0.04) and DPD (r = –0.33, p = 0.049). Combined measurements of BMD and biochemical markers of bone resorption may have potential in the identification of patients at high risk of bone loss who may require further evaluation of bone remodeling by bone histomorphometry.

Predialysis versus postdialysis hematocrit evaluation during erythropoietin therapy

American guidelines for the management of renal anemia by recombinant human erythropoietin (rHuEPO) recommend collecting a predialysis blood sample to evaluate hemoglobin (Hb) and hematocrit (Hct) levels in hemodialysis patients. Although a predialysis blood sample is appropriate for evaluating when to start rHuEPO treatment, the same sample would not be appropriate for evaluating the target Hb/Hct to be maintained, particularly when normal or near-normal values are pursued. We measured the degree of intradialytic and extradialytic variation of Hb, Hct, and body weight in 68 stable hemodialysis patients on maintenance subcutaneous rHuEPO treatment. Hb and Hct concentrations were determined before and after dialysis. In 16 patients, Hb and Hct concentrations also were assessed 24 hours after the end of dialysis. Predialysis versus postdialysis Hb and Hct concentrations for all patients were 10.5 ± 1.3 g/dL versus 11.5 ± 1.3 g/dL (P < 0.0001) and 32 ± 4% versus 35 ± 4% (P < 0.0001). The intradialytic percent variation (%Δ) of Hct and body weight were 10 ± 6% and −6.3 ± 3.5%. There was a close inverse correlation between %Δ of Hct and Hb and %Δ of body weight (P < 0.0001). In patients with body weight losses 2.5 kg or more per session, the mean %Δ of Hct was 12 ± 7%. In the 16 patients studied 24 hours after the end of the dialysis session, Hct and Hb values remained significantly higher compared with the predialysis levels (P < 0.001), suggesting a slow reequilibration of the intravascular volume in the first 24 hours after hemodialysis. For these reasons, predialysis samples for monitoring the target Hb and Hct levels in patients treated by rHuEPO should be considered with caution. © 2002 by the National Kidney Foundation, Inc.

Cardiac Troponin T Predicts Long-Term Outcomes in Hemodialysis Patients

Increased plasma troponin T (cTnT), but not troponin I (cTnI), is frequently observed in end-stage renal failure patients. Although generally considered spurious, we previously reported an associated increased mortality at 12 months. We studied long-term outcomes in 244 patients on chronic hemodialysis for up to 34 months, correlating the outcomes to plasma cTnT in routine predialysis samples. In addition, subsequent plasma samples at least 1 year later and within 6 months of data analysis were available in 97 patients and were used to identify patients with increasing plasma cTnT. The endpoints used were death and new or worsening coronary, cerebro-, and peripheral vascular disease and neuropathy. Transplantation occurred more frequently in patients with low initial cTnT: 31%, 13%, and 3% in the groups with cTnT < 0.010, 0.010-0.099, and > or = 0.100 microg/L, respectively. In the same groups, total deaths occurred in 6%, 43%, and 59% and cardiac deaths in 0%, 14%, and 24% of patients. In patients with follow-up samples, the group with increasing cTnT had a significantly increased death (relative risk, 2.0; P = 0.028). The increase was mainly in cardiac and sudden deaths. Higher plasma cTnT predicts long-term all-cause mortality in hemodialysis patients, even at concentrations < 0.100 microg/L, as does an increasing cTnT concentration over time.

Plasma concentrations of alpha-melanocyte-stimulating hormone are elevated in patients on chronic haemodialysis.

Clinical and/or laboratory signs of systemic inflammation occur frequently in patients undergoing long-term haemodialysis. It is likely, therefore, that a compensatory release of endogenous anti-inflammatory molecules occurs to limit host reactions. The aim of the present research was to determine if the potent anti-inflammatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH), a pro-opiomelanocortin derivative, is increased in plasma of haemodialysis patients. Because endotoxin and cytokines induce alpha-MSH in vivo and in vitro, we also measured plasma concentrations of endotoxin, interleukin-6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), and the two circulating products of activated monocytes, nitric oxide (NO) and neopterin. Thirty-five chronic haemodialysis patients, 20 patients with chronic renal failure not yet on dialysis, and 35 normal controls were included in the study. In the haemodialysis group, blood samples were obtained before and at the end of a dialysis session. Plasma alpha-MSH was measured using a double antibody radioimmunoassay, and IL-6, TNF-alpha, and neopterin using specific enzyme-linked immunosorbent assays. Plasma nitrites were determined by a colorimetric method, and endotoxin with the quantitative chromogenic LAL (limulus amoebocyte lysate) method. Mean plasma alpha-MSH was higher in haemodialysis patients than in control subjects, with the peptide concentrations being particularly elevated in dialysed patients with detectable endotoxin. High alpha-MSH concentrations were observed in the pre-dialysis samples, with no substantial change at the end of the dialysis session. Plasma concentrations of IL-6, TNF-alpha, neopterin, and NO were generally elevated in chronic haemodialysis patients and there was a negative correlation between circulating alpha-MSH and IL-6. In patients with renal failure not yet on dialysis, mean plasma alpha-MSH was similar to that of normal subjects. alpha-MSH is increased in the circulation of chronic haemodialysis patients and particularly so in case of detectable endotoxaemia. Reduction of renal clearance is unlikely to contribute to the observed rise of the peptide because alpha-MSH concentration is not increased in patients with chronic renal failure who are not yet on dialysis. It is likely that dialysis-associated endotoxaemia, directly and/or through cytokine release, enhances the production of the anti-inflammatory mediator alpha-MSH that limits host reactions.

The Ferroxidase Activity of Caeruloplasmin Is Reduced in Haemodialysis Patients

Increased free-radical production leading to oxidative stress may contribute to the development of cardiovascular complications in haemodialysis patients. The ferroxidase activity of caeruloplasmin forms an important component of antioxidant defences in body fluids. The aim of this study was to assess ferroxidase activity in haemodialysis patients. Venous blood was collected from 83 haemodialysis patients immediately prior to and after dialysis and from 52 healthy controls. Immunoreactive caeruloplasmin was measured by rate nephelometry, and ferroxidase activity determined by measuring loading of ferrous iron onto iron-free transferrin. A significant reduction in ferroxidase activity was observed in dialysis patients when compared with controls (37 ± 1.20 and 46 ± 1.14 mU/l, respectively; p < 0.001). Following dialysis, ferroxidase activity rose significantly to 41 ± 1.16 mU/l, with a significant difference still remaining between control and patient ferroxidase activity (p < 0.005). Immunoreactive caeruloplasmin was found to be similar in all groups (before dialysis 0.40 ± 0.07 g/l, after dialysis 0.39 ± 0.07 g/l, control 0.42 ± 0.09 g/l: p = NS). A significant difference in caeruloplasmin-specific activity was therefore observed between predialysis, postdialysis and control samples (97 ± 2.31, 105 ± 1.74 and 112 ± 1.51 mU/g; p < 0.001, p < 0.01, respectively). Ferroxidase activity of caeruloplasmin is impaired in renal failure. Inhibition of caeruloplasmin ferroxidase activity in dialysis patients may contribute to increased oxidative stress in these patients.

Modulation of Neutrophil Apoptosis by Uremic Plasma during Hemodialysis

During hemodialysis (HD), blood-membrane interactions lead to activation of several circulating cells and plasma proteins. The resultant activation and/or release of mediators can modulate the structure, function and survival of circulating neutrophils. Little is known of plasma factors that influence apoptosis of neutrophils in hemodialyzed patients. Hence, we investigated the effect of uremic plasma obtained during HD on the survival of neutrophils obtained from healthy volunteers. Neutrophils harvested from healthy volunteers were incubated in ultrafiltered culture medium supplemented with either 50% heterologous normal plasma obtained from healthy volunteers (n = 15) or 50% uremic plasma collected from long-term HD patients dialyzed with cuprophan (CU) (n = 8), cellulose triacetate (CTA) (n = 8) or polysulfone (PS) (n = 8) dialyzers. Plasma samples were drawn predialysis, 15 min after starting dialysis, and postdialysis. After 24-hour incubation, neutrophil aliquots were processed for quantification of apoptosis by flow cytometry, using propidium iodide DNA staining. In addition, tumor necrosis factor α (TNFα) and interleukin-10 (IL-10) were measured in normal and predialysis uremic plasma samples. Neutrophils from healthy volunteers exposed to heterologous normal plasma samples exhibited 10.3 ± 1.2% apoptosis. In contrast, the proportion of apoptosis was significantly higher among neutrophils exposed to predialysis (28.5 ± 2.3%, p < 0.0001), 15 min (23.0 ± 2.4%, p < 0.0001), or postdialysis uremic plasma samples (25.7 ± 2.3%, p < 0.0001). Compared to neutrophils exposed to predialysis uremic plasma samples, a significantly lower proportion of apoptosis was observed in neutrophils exposed to the 15-min plasma samples among patients dialyzed with CU (26.4 ± 2.9 vs. 18.2 ± 3.5%; p < 0.001) but not with CTA or PS dialyzers. Futher, CU membranes induced the greatest percentage decrease in neutrophil apoptosis at 15 min. There was a direct correlation between neutrophil apoptosis and plasma levels of TNFα (r = 0.424, p = 0.02) and IL-10 (r = 0.744, p < 0.0001). The results of the study suggest that normal neutrophils exposed to uremic plasma undergo accelerated in vitro apoptosis compared to those incubated with normal plasma. Further, during HD, the apoptosis-inducing activity of uremic plasma is modulated by the use of dialyzers with different degrees of biocompatibility. The identification of soluble factors that are responsible for the increased apoptosis-inducing activity of uremic plasma needs to be further investigated.

High-performance liquid chromatographic determination of pyridinium crosslinks in serum, urine and dialysate of patients in chronic renal failure.

This study describes an isocratic reversed phase high-performance liquid chromatographic method for the analysis of pyridinium crosslinks in serum, urine and dialysates obtained from patients with chronic renal failure on haemodialysis. The mean (SD) urine pyridinoline (PYD) and deoxypyridinoline (DPD) to creatinine (Cr) ratio in 19 healthy volunteers was 28.9 (6.3) and 9.1 (3.6) mumol/mol, respectively. In the 22 patients the PYD/Cr and DPD/Cr ratio was 244.6 (436.5) and 66.5 (116.8) mumol/mol, respectively. The mean serum PYD concentration in 29 patients of 268.5 (334.4) nmol/L was significantly higher than that of 5.9 (1.5) nmol/L found in normal volunteers: the mean DPD concentration was 82.9 (93.7) nmol/L in the patients but was undetectable in the serum from the normal volunteers. The concentration of crosslinks in pre-dialysis serum samples was higher than those found post-dialysis reflecting a significant removal of the crosslinks during dialysis. The assay of pyridinium crosslinks in serum, urine and dialyses fluid could potentially provide evidence of bone collagen turnover in patients in renal failure. Their measurement in serum and dialysate could be particularly useful in anuric patients.

Effects of Hemodialysis on Plasma Protein Binding of Bepridil

The effects of end-stage renal disease (ESRD) and hemodialysis on the in vitro plasma protein binding of bepridil hydrochloride were investigated. The possible influence of bepridil metabolites on bepridil-protein binding in ESRD patients was also examined. Plasma samples were obtained from six patients with ESRD. Bepridil-plasma protein binding was measured by microequilibrium dialysis after addition of freshly prepared bepridil-14C (239 microCi/mg) at a final concentration of 2 micrograms/mL. The percentage of free bepridil in peripheral venous samples drawn on a nondialysis day was lower (i.e., binding was greater) in the patients with ESRD relative to previous observations in healthy subjects (0.15% +/- 0.04% versus 0.31% +/- 0.05% (mean +/- SD). The plasma concentrations of alpha-1-acid glycoprotein (AAG), the principal bepridil binding protein, were also higher in ESRD patients (110 +/- 32 mg/dL) than previously reported in healthy subjects. Although hemodialysis resulted in significant increases in AAG, total protein, and albumin concentrations, no significant difference in bepridil-plasma protein binding was detected between predialysis and postdialysis peripheral venous samples in the presence (0.16 versus 0.18) or absence (0.20 versus 0.17) of bepridil metabolites. The percentage of free bepridil in plasma from both the arterial and venous limbs of the dialyzer during hemodialysis (means of free bepridil ranged from 0.24-0.28%) was higher than in samples drawn from a peripheral vein. This displacement of bepridil from its binding sites as blood passes through the dialyzer may have been owing to the presence of high local concentrations of plasticizers. Confirmation of this hypothesis will require further investigation.

Neutrophil adhesion molecules in chronic hemodialysis patients.

The expression of the adhesion molecules LFA-1 (CD11a-CD18), Mac-1 (CD11b-CD18), and LAM-1 on predialysis and intradialysis neutrophils (PMN) was analyzed by flow cytometry in 10 chronic hemodialysis patients (CHD) and compared with age-matched normal controls. All patients were dialyzed either with a polyacrylonitrile, or a polysulfone membrane. To appreciate the influence of the interdialytic time, we compared the samples of Monday (3 days without dialysis), with those of Wednesday (2 days without dialysis). A patient group not treated with recombinant human erythropoietin (rHuEPO) was also included to analyze the influence of r-HuEPO. We found on the predialysis and intradialysis samples that the expression of CD11a was not different in the CHD patients and in the normal controls. Hemodialysis was associated with a rapid and significant reduction in LAM-1 on the 15- and 30-min samples (p < 0.05). This reduction was only transient, and returned to near predialysis levels after 120 min dialysis. The MAC-1 increased significantly after 30 min dialysis (p < 0.01), and remained at the end of the dialysis procedure still substantially above the predialysis levels (p < 0.01). On the other hand, we have found a significant (p < 0.005) up-regulating of the MAC-1, and a down-regulating of the LAM-1 in the predialysis samples. We noticed further a significantly lower expression (82 +/- 9.6%) for LAM-1 in these predialysis samples (p < 0.005). These results demonstrate that 'high MAC-1, low LAM-1' neutrophils were not only a dialysis-related phenomenon, but that they were already present before the hemodialysis session, nor was there any difference between the interdialytic times or compared with the r-HuEPO treatment.

Depressed phagocytosis in hemodialyzed patients: in vivo and in vitro mechanisms.

Infection is a frequent complication and the major cause of death among end-stage renal patients. Polymorphonuclear phagocytes (PMNL) are important in host defense mainly because of bacterial destruction by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-related free radical production following phagocytosis. In this study, hexose monophosphate pathway glycolytic activity, delivering energy to NADPH oxidase, is evaluated in vivo and in vitro, in healthy controls and in dialyzed renal failure patients. Our results show a marked parallel and correlated inhibition in the response to three stimuli for phagocytic activity (Staphylococcus aureus, formyl-methionine-leucine-phenylalanine, phorbol myristic acid) in predialysis samples. These data point to a main suppression of metabolic pathways, possibly beyond protein kinase C. This response is further suppressed at the 15th minute of cuprophane dialysis, for all stimuli studied (-40 to -94%; p < 0.001) except PMA. PMNL response remains intact during dialysis with non-complement-activating dialyzers. In vitro experiments confirm decreased PMNL glycolytic activity after the suspension of cuprophane fragments in normal whole blood. We conclude that polymorphonuclear cell energy delivery to NADPH oxidase is impaired in patients with end-stage renal failure. The impaired response against various stimuli is different in predialysis blood samples compared to samples collected during cuprophane dialysis, and may be related to two different conditions. These events probably contribute to the acquired immune suppression of uremia and the high incidence of infection among dialysis patients.

Plasma profiles and removal rates of inorganic sulphate, and their influence on serum ionized calcium, in patients on maintenance haemodialysis

1. Regular dialysis treatment is reported to remove inorganic sulphate, but not to restore its level to normal. To evaluate the adequacy of modern dialysis techniques in maintaining the sulphate balance, intra- and interdialysis plasma profiles and removal rates of sulphate were studied in 20 stable patients on maintenance haemodialysis. The influence of sulphate levels on the distribution of calcium-complex species was also investigated. 2. Sulphate was determined by ion-exchange chromatography of both serum ultrafiltrates, taken at the start of, during, at the end of, and at 24 h and 48 h after a dialysis session, and whole diffusate collections. Dialyser clearances of sulphate were assessed by two independent procedures and compared with those of urea and creatinine, on two different methods of dialysis, i.e. traditional haemodialysis with Cuprophan hollow fibre filters, and haemodiafiltration with high-flux Polysulphone or polyacrylonitrile dialysers. Concentrations of the main serum ions were determined before and after dialysis and used to solve a multiple mass balance equation system by which concentrations of the calcium-complex species were calculated. 3. Before dialysis, sulphate levels were eight times those determined in 17 control subjects and remained higher than normal at the end of dialysis. These changes were independent of the dialysis procedure. There was a close correlation between serum levels of sulphate and creatinine. Dialyser clearances of sulphate were comparable with those of creatinine, but lower than those of urea. Clearances of all solutes were higher on haemodiafiltration.(ABSTRACT TRUNCATED AT 250 WORDS)

Phagocytosis in uremic and hemodialysis patients: A prospective and cross sectional study

Leukocyte response to phagocytic challenge was assessed in uremic and hemodialysis patients in a prospective and cross sectional study. Using latex, zymosan and staphylococcus as phagocytic challenge, the utilization of glucose-I-C14 and the generation of reactive oxygen species was measured in these patients. In uremic, non-dialysis dependent patients, the response to phagocytosis was significantly reduced when creatinine exceeded 6 mg/dl and prior to initiation of dialysis (mean serum creatinine 9.3 +/- 0.3 mg/dl) was less than half that of patients with normal renal function (P less than 0.01). In a prospective study of 15 patients initiated on dialysis, the metabolic response of their leukocytes was assessed sequentially. In eight patients, initiation of dialysis with cuprophane (Cu) membrane lead to a further decline (60%) in their metabolic response to phagocytosis at the end of four weeks of dialysis compared to pre-initiation of dialysis (P less than 0.01), whereas in seven other patients, dialysis with non-complement activating membranes did not result in a significant decline. Prospective cross-over studies of chronic hemodialysis patients corroborated these findings; eight patients dialyzed with new CU membranes had a significant decline of their metabolic response to phagocytic challenge acutely at the end of each dialysis and in pre-dialysis samples after two weeks of Cu dialysis, whereas their response returned back to baseline after two weeks of dialysis with non-complement activating membrane. In prospective and cross sectional studies, a decreased response to phagocytic stimulus was a predictor of hospitalization, primarily for infectious reasons.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of phagocytosis in patients on complement activating dialyzers

A defect of NAD(P)H oxidase related glycolysis has been described in polymorphonuclear cells of hemodialysis patients resulting in the suppression of free radical production and bacterial killing. The present study compares polymorphonuclear glycolytic activity in controls and equilibrated hemodialysis patients after challange with two different stimuli affecting polymorphonuclear activation in different ways: latex (L) and zymosan (Z). On pre-dialysis samples, an important decrease in polymorphonuclear activity was found, versus healthy controls (latex: from 158±7 to 80±5; zymosan : from 339±15 to 192±14 DPM/ 10 3 Phag, p < 0·05). Evaluation of the intra-dialysis polymorphonuclear function revealed a further parallel suppression, for both stimuli, after 15 min of dialysis with the complement activating cuprophan membrane (pre-dialysis versus intradialysis, latex: from 55±9 to 0·4±0·3, zymosan, from 181±32 to 74±20 DPM/10 3 Phag, p < 0·05). A similar suppression was absent during hemodialysis with non-complement activating cellulosic and synthetic dialysis membranes (hemophan, reused cuprophan, polysulfone, polymethylmethacrylate, AN69S). In conclusion, a profound polymorphonuclear dysfunction, parallel in response to latex and zymosan, is observed in hemodialyzed patients, pointing to a metabolic defect of the glycolytic energy delivery to NAD(P)H-oxidase. The disturbance is further accentuated intra-dialysis with complement activating cuprophan membranes, and might explain the immunologic anergy and susceptibility to infection of hemodialyzed patients. Polymer composition of dialysis membranes and especially their capacity to activate complement, are determinants affecting the immune system of patients treated by these membranes.

Glucocorticoid activity in cord serum: Comparison of hydrocortisone and betamethasone regimens

Our patients had surprisingly high concentrations of unbound PHT in their predialysis samples, levels which might ordinarily be associated with clinical evidence of PHT toxicity. None of our patients, however, had overt or subtle evidence of phenytoin toxicity. Atypical neurotoxicity, such as movement disorders and pseudodementia, have been caused by PHT, and is found most often in patients who are neurologically abnormal. TM 12 Very high concentrations ~0f. phenytoin may cause seizures. ~ Because these symptoms also may occur in uremic encepha!opathy, it is important to rule out PHT toxicity caused by high concentrations of unbound PHT in patients who are suspected of having uremic encephal0pathy. Although PHT is relatively nondialyzable, dialysis can reduce the effective PHT concentration. No seizures occurred following dialysi s during our studies. It is possible, however, that when patients' unbound PHT concentrations are lowered during dialysis, subtherapeutic concentrations might result and allow seizures to recur. According to our findings, this would be most likely in patients with significant weight loss during dialysis or if albumin is given. In these instances, or if PHT-induced neurotoxicity were suspected, the unbound PHT concentration should be measured and the dosage adjusted accordingly. The therapeutic range of unbound phenytoin is 1.0 to 2.0 ~zg/ml.

Radioimmunoassay for somatomedin C: comparison with radioreceptor assay in patients with growth-hormone disorders, hypothyroidism, and renal failure.

We raised an antiserum (Tr4) in rabbits against a basic somatomedin C-like peptide preparation. Using high-immunoreactivity somatomedin C tracer, we compared the performance of radioimmunoassays in which we used the Tr4 antiserum and a well-characterized somatomedin C antiserum distributed by the National Pituitary Agency (NPA) with that of the human placental-membrane somatomedin radioreceptor assay (RRA). In their cross reactivity toward various somatomedin-like and unrelated peptides, the two radioimmunoassay methods were almost identical, although NPA antiserum, with about fourfold higher titer than Tr4 antiserum, showed a slightly greater sensitivity for most peptides tested. Radioimmunoassay of acid-ethanol-extracted plasma samples from normal persons and acromegalic, hypopituitary, hypothyroid, and renal-failure patients revealed no analytical differences between the antisera (for 122 samples, r = 0.979 between methods). Somatomedin values for acromegalic and hypopituitary samples showed no overlap with normals. Values for hypothyroid and pre-dialysis renal-failure samples were significantly lower than normal. By comparison, the RRA showed greater cross reactivity toward some somatomedin-like peptides and gave significantly lower values than radioimmunoassay for acromegalic and hypothyroid plasma extracts, and significantly higher value for hypopituitary and renal-failure samples. We conclude that the radioimmunoassay methods clearly are of greater diagnostic value than RRA for clinical somatomedin measurement.

Chloramphenicol Hemodialysis Clearance

Summary: The purpose of this study was to evaluate the dialysis clearance and plasma protein binding of chloramphenicol in a chronic renal failure patient and an acute renal/hepatic failure patient undergoing hemodialysis. Predialysis, dialysis and postdialysis plasma samples were collected and analyzed. Plasma chloramphenicol levels declined slowly during hemodialysis with measured dialysis clearance rates of 21.2 ml/min (patient C.W.) and 24.2 ml/min (patient S.T.). The protein binding of chloramphenicol, determined before and 30 min after hemodialysis, was 40 and 25% (patient C.W.) and 44 and 35% (patient S.T.), respectively. The extent to which hemodialysis removes chloramphenicol from the plasma does not appear significant enough to warrant routine dosage adjustment. The clinical significance of protein binding alterations is discussed.

Hemodialysis clearance and total body elimination of carbamazepine during chronic hemodialysis.

The effect of the artificial kidney on the removal of carbamazepine was studied in four uremic patients undergoing chronic hemodialysis. Each patient received 500 mg of carbamazepine PO 8 hr prior to hemodialysis. Predialysis and postdialysis blood samples as well as dialysate samples were collected at various time intervals during a 4-hr hemodialysis. Samples were analyzed for carbamazepine content by HPLC. Dialysis clearance calculated from dialysate measurements averaged 53.6 +/- 10.0 mL/min which is double the reported mean plasma clearance of 27.5 mL/min. Since drug clearance by the dialyzer is twice the endogenous plasma clearance, we conclude that carbamazepine is dialyzable. Despite the significant dialysis clearance, a dosage regimen adjustment may not be necessary because of the long elimination half-life of carbamazepine of 35 hr compared to the short length of the usual hemodialysis treatment of 3-5 hr.

Chloramphenicol Hemodialysis Clearance

The purpose of this study was to evaluate the dialysis clearance and plasma protein binding of chloramphenicol in a chronic renal failure patient and an acute renal/hepatic failure patient undergoing hemodialysis. Predialysis, dialysis and postdialysis plasma samples were collected and analyzed. Plasma chloramphenicol levels declined slowly during hemodialysis with measured dialysis clearance rates of 21.2 ml/min (patient C.W.) and 24.2 ml/min (patient S.T.). The protein binding of chloramphenicol, determined before and 30 min after hemodialysis, was 40 and 25% (patient C.W.) and 44 and 35% (patient S.T.), respectively. The extent to which hemodialysis removes chloramphenicol from the plasma does not appear significant enough to warrant routine dosage adjustment. The clinical significance of protein binding alterations is discussed.

Studies of Plasma Aldosterone in Anephric People: Evidence for the Fundamental Role of the Renin System in Maintaining Aldosterone Secretion*

When plasma aldosterone (PA) was measured in 32 predialysis samples from 18 anephric subjects more than 3 months postnephrectomy, all but two values were subnormal, 16 measurements were undetectable, i.e. below 0.35 ng/100 ml, and PA averaged only 1.7 ng/100 ml +/- 0.5 (SE) in the remaining 16. In contrast, PA averaged 29.7 +/- 5.6 ng/100 ml in 12 dialysis patients with kidneys. Plasma renin activity was undetectable in 15 assays of anephric subjects and averaged 0.5 +/- 0.1 ng/ml/h in the remaining 17. However, these latter measurements appeared to be an artifact caused by the presence of plasma prorenin. Serum potassium fell during dialysis and appeared responsible for the concurrent 75% fall in PA observed in six nephric patients (delta 14 ng/100 ml), and in three anephric patients (delta 3.3 ng/100 ml) with low but measurable PA values. Overt hyperkalemia was required for potassium to stimulate aldosterone into the normal range in anephric subjects. The angiotensin II analog, saralasin, also increased PA slightly in five studies. Renin and PA fell after nephrectomy and increased after transplantation. Decreases and increases in renin always preceded those of aldosterone. Usually it took several weeks for aldosterone to fall to undetectable levels and several days to return to normal levels after renal transplantation. These observations suggest that the baseline plasma level of angiotensin determines both the baseline level of aldosterone secretion and its capacity to respond either to more angiotensin or to other stimuli. In the absence of renin, the adrenal almost loses its capacity to generate aldosterone. The data support the view that the renin system plays a fundamental role in maintaining aldosterone secretion in man.