Intracellular acidification associated with changes in free cytosolic calcium. Evidence for Ca2+/H+ exchange via a plasma membrane Ca(2+)-ATPase in vascular smooth muscle cells.

The purpose of this study was to define the mechanism whereby agonists that increase free cytosolic calcium (Cai2+) affect intracellular pH (pHi) in smooth muscle. Rat aortic vascular smooth muscle cells grown on coverslips were loaded with BCECF/AM or fura-2/AM for continuous monitoring of pHi or Cai2+, respectively, in a HCO3-/CO2- containing medium. Recovery from rapid increases in Cai2+ produced by 1 microM angiotensin (Ang) II (delta Cai2+ -229 +/- 43 nM) or 1 microM ionomycin (delta Cai2+ -148 +/- 19 nM) was accompanied by a fall in pHi (delta pHi, -0.064 +/- 0.0085 P < 0.01, and -0.05 +/- 0.012 pH units, P < 0.01, respectively). Neither the fall in pHi nor the rise in Cai2+ elicited by Ang II was prevented by pretreatment with agents which block the action of this agonist on pHi via the stimulation of the Cl/HCo3 exchangers (DIDS, 50 microM) or the Na+/H+ antiporter (EIPA, 50 microM). In the presence of DIDS and EIPA, Ang II produced a fall in pHi (delta pHi, -0.050 +/- 0.014, P < 0.01) and a rise in Cai2+ (delta Ca2+ 252 +/- 157 nM, P < 0.01). That the change in pHi was secondary to changes in Cai2+ was inferred from the finding that, when the rise in Cai2+ elicited by Ang II was prevented by preincubation with a Ca2+ buffer, BAPTA (60 microM), the fall in pHi was abolished as well (delta pHi, 0.0014 +/- 0.0046). The pHi fall produced by Ang II and ionomycin was prevented by cadmium at a very low concentration (20 nM) which is known to inhibit plasma membrane Ca(2+)-ATPase activity (delta pHi -0.002 +/- 0.0006 and -0.0016 pH units, respectively). Cadmium also blunted Cai2+ recovery after Ang II and ionomycin. These findings suggest that the fall in pHi produced by these agents is due to H+ entry coupled to Ca2+ extrusion via the plasma membrane Ca(2+)-ATPase. Our results indicate that agonists that increase Cai2+ cause intracellular acidification as a result of Ca2+/H+ exchange across the plasma membrane. This process appears to be mediated by a plasma membrane Ca(2+)-ATPase which, in the process of extruding Ca2+ from the cell, brings in [H+] and thus acidifies the cell.

Transdermal clonidine in mild hypertension. A randomized, double-blind, placebo-controlled trial.

In 30 patients with mild essential hypertension, clonidine hydrochloride was delivered from a skin patch reservoir designed to release medication at a constant rate for seven days. After a four-week washout period, patients were randomized (double-blind) into a clonidine- or a placebo-treated group. Clonidine or placebo was then given for five weeks, followed by a two-week washout period to assess withdrawal from treatment. Blood pressure was controlled in 11 of 15 clonidine-treated patients but in only four of 15 placebo-treated patients. The clonidine-treated group evidenced larger decreases in both systolic and diastolic blood pressures. In the clonidine-treated group, blood pressures and plasma clonidine levels were stable throughout a representative seven-day period. Besides mild skin irritation with both clonidine and placebo patches, few side effects were observed. After discontinuation of clonidine administration, plasma levels declined in a non-log linear manner. There was no rebound hypertension. The results suggest that clonidine delivered transdermally is safe and effective for control of mild essential hypertension.

Spurious hyperphosphatemia due to hyperlipidemia.

A patient had hyperlipidemia associated with apparent hyperphosphatemia. Further tests on his serum and on the lipemic sera from 15 additional patients revealed a method-dependent overestimation of inorganic phosphorus values. The degree of overestimation was found to correlate positively with the serum triglyceride concentration. Unexplained elevation of the serum phosphorus level should alert the physician to the possibility of spurious hyperphosphatemia due to hyperlipidemia.

Sclerotic thickening of the peritoneal membrane in maintenance peritoneal dialysis patients.

Five patients receiving maintenance peritoneal dialysis (duration, three months to four years) required surgical exploration of the abdomen for various reasons. Four had a prior history of bacterial peritonitis, and four of aseptic peritonitis. At laparotomy, the peritoneal membrane was found to be markedly thickened and sclerotic in all patients, and loops of bowel were bound together in a dense, opaque casing. On microscopic examination, an increase in fibroconnective tissue in the peritoneum was observed.

Peritoneal fluid eosinophilia in patients undergoing maintenance peritoneal dialysis.

In ten patients undergoing maintenance peritoneal dialysis, large numbers of eosinophils were found in the peritoneal fluid. A few of the affected patients complained of episodic abdominal pains, but there was no correlation between abdominal symptoms and the number of peritoneal fluid eosinophils. Microorganisms failed to grow on cultures of the peritoneal fluids, and results of tests for endotoxin were negative. The cause of eosinophilia could not be determined. Peritoneal fluid eosinophil counts were noted to be elevated soon after catheter insertion and initiation of peritoneal dialysis. In some patients, peritoneal fluid eosinophil counts spontaneously returned to normal despite continued peritoneal dialysis.

Asymptomatic, nonketotic, severe hyperglycemia with hyponatremia.

We describe five patients with asymptomatic, nonketotic, severe hyperglycemia (serum glucose concentrations between 45.8 and 92 mmol/L) in the face of renal insufficiency are described. As opposed to most of the previously described patients with hyperglycemic, nonketotic, hyperosmolar coma, our patients were hyponatremic. The lack of symptoms in our patients may be related to the absence of cerebral cellular dehydration. Aggressive treatment of hyperglycemia in such patients is unnecessary. Attention to the serum sodium level as well as to the serum glucose concentration will allow recognition of this clinical entity.

Subxiphoid pericardiostomy for hemodialysis-associated pericardial effusion.

Sixteen patients receiving maintenance hemodialysis in whom moderate-to-large pericardial effusions developed were treated with short-term drainage via a large-bore tube implanted into the pericardial sac. Drainage tubes were implanted using a subxiphoid approach (subxiphoid pericardiostomy) while the patient was under local anesthesia. In seven patients, triamcinolone hexacetonide was instilled into the pericardial sac through the drainage tube at regular intervals. In all patients, a drainage period of two to four days, with or without instillation of nonabsorbable steroids, was associated with resolution of the pericardial effusion. Only one recurrence of effusion was demonstrable over a follow-up period extending from three months to eight years (median, 4.2 years). Complications of subxiphoid pericardiostomy were minor (incisional hernia, wound infection, and small pneumothorax) and easily treatable. Our results suggest that short-term drainage via a surgically implanted drainage tube is an effective and safe treatment of moderate-to-large hemodialysis-associated pericardial effusion.

Blood eosinophilia in patients undergoing maintenance peritoneal dialysis.

To determine the prevalence of blood eosinophilia in patients receiving maintenance peritoneal dialysis, routine peripheral WBC counts of 49 such patients were reviewed. In 29 patients, blood eosinophilia was noted. Elevations in blood eosinophil counts tended to be mild and episodic. They were often associated with concomitant elevation of peritoneal fluid eosinophil counts. Possible predisposing factors included recent peritoneal catheter insertion and antibiotic therapy for peritonitis.

Severe anaphylactoid reactions to cuprammonium cellulose hemodialyzers.

Twenty-one severe reactions to hemodialysis occurred in approximately 260,000 dialysis treatments at three centers within a 10 1/2-year period. Reactions typically appeared within minutes of initiating dialysis, and were characterized by cardiopulmonary, mucocutaneous, and/or gastrointestinal tract symptoms highly suggestive of anaphylaxis. Four respiratory arrests and one death resulted. Analysis of dialyzer use patterns and of each patient's dialyzer exposure history strongly implicated hollow-fiber dialyzers made of cuprammonium cellulose (CC) as a cause of these reactions. No obvious factors could be found to identify predisposed patients. Less than optimal rinsing of the CC hollow-fiber dialyzers prior to use may have been responsible for some, but not all, of these reactions.

Depressant effect of acetate in isolated cardiac tissue.

Because acetate may have cardiodepressant properties in vitro, but previous studies have not separated out effects of acetate from possible effects of osmolality, sodium concentration, or calcium complexing, the effects of isosmotic acetate substitution (at a constant calcium concentration) on contractility were studied in isolated rat atrial tissue and in an isolated perfused non-working whole heart preparation. In spontaneously contracting right atrial tissue acetate induced dose dependent inhibition of isometric tension in the clinically important dose range of 4 to 16 mmol.litre-1. Bath acetate concentrations of 4, 16, or 64 mmol.litre-1 reduced peak tension (mean(SEM] to 78(2.7)%, 56(2.5)%, or 61(4.6)% respectively of control values. Because the calcium concentrations of the acetate baths were set equal to that of the control bath, calcium complexing by acetate could not have accounted for acetate's cardiodepressant effect. The inhibitory action was demonstrable with both isosmotic and hyperosmotic acetate solutions. Acetate had no effect on the spontaneous rate of atrial contraction. Inhibition of contractility (+dP/dt) by acetate in the whole heart preparation was also demonstrable at bath acetate concentrations of 8 and 16 mmol.litre-1. The results suggest that acetate has a myocardial depressant effect in vitro at concentrations achievable in the plasma during haemodialysis. The myocardial depressant action is not dependent on calcium complexing or on changes in bath osmolality or sodium concentration.

Fanconi syndrome associated with a non-ossifying fibroma of bone.

A 20-year-old man presenting with osteomalacia was found to have the Fanconi syndrome, as evidenced by hypophosphatemia with hyperphosphaturia, glycosuria in the presence of normoglycemia, and generalized aminoaciduria. After removal of a non-ossifying fibroma of the left tibia, the renal tubular abnormalities promptly resolved with subsequent healing of the osteomalacia. A humoral factor released from the tumor may have caused the disorder in proximal renal tubular cell transport.

Pathophysiology of dialysis hypotension: an update.

Dialysis hypotension occurs because a large volume of blood water and solutes are removed over a short period of time, overwhelming normal compensatory mechanisms, including plasma refilling and reduction of venous capacity, due to reduction of pressure transmission to veins. In some patients, seemingly paradoxical and inappropriate reduction of sympathetic tone may occur, causing reduction of arteriolar resistance, increased transmission of pressure to veins, and corresponding increase in venous capacity. Increased sequestration of blood in veins under conditions of hypovolemia reduces cardiac filling, cardiac output, and, ultimately, blood pressure. Adenosine release due to tissue ischemia may participate in reducing norepinephrine release locally, and activation of the Bezold-Jarisch reflex, perhaps in patients with certain but as yet undefined cardiac pathology, may be responsible for sudden dialysis hypotension. Patients with diastolic dysfunction may be more sensitive to the effects of reduced cardiac filling. The ultimate solution is reducing the ultrafiltration rate by use of longer dialysis sessions, more frequent dialysis, or reduction in salt intake. Increasing dialysis solution sodium chloride levels helps maintain blood volume and refilling but ultimately increases thirst and interdialytic weight gain, with a possible adverse effect on hypertension. Blood volume monitoring with ultrafiltration or dialysis solution sodium feedback loops are promising new strategies. Maintaining tissue oxygenation via an adequate blood hemoglobin level seems to be important. Use of adenosine antagonists remains experimental. Given the importance of sympathetic withdrawal, the use of pharmacologic sympathetic agonists is theoretically an attractive therapeutic strategy.

Variation in blood sample collection for determination of hemodialysis adequacy. Council on Renal Nutrition National Research Question Collaborative Study Group.

Inadequate dialysis has been associated with high morbidity and mortality in end-stage renal disease (ESRD) patients receiving maintenance hemodialysis. The accurate estimation of dialysis adequacy, measured either as a calculated urea kinetics (Kt/V) or a simple urea reduction ratio (URR) is dependent on the proper collection of blood samples for predialysis and postdialysis blood urea nitrogen (BUN) determination. Because no established protocol exists for blood sampling, we surveyed the study cohort of dialysis centers participating in the National Kidney Foundation Council on Renal Nutrition National Research Question Collaborative Study to determine the comparability of BUN data that were collected to calculate URR to determine adequacy of dialysis. Surveys were completed by 100% of the 202 units participating: 195 in the United States (from 43 states) and seven from Canada, treating approximately 15,000 hemodialysis patients in total. The distribution of the sample by the type of facility mirrored that of 1996 United States Renal Data System (USRDS) Annual Report facilities data. Results showed a 5.0% error in predialysis blood draw and an 8.4% to 41.6% error in the postdialysis counterpart. There was a large variability in the observed postdialysis methods in general. Dilution of predialysis sample with either heparin or saline will falsely underestimate Kt/V and URR. The presence of access-derived, recirculated blood in the postdialysis sample will falsely overestimate Kt/V and URR. Excessive delay in drawing postdialysis sample will reduce Kt/V and URR because of urea rebound. Adoption by all dialysis providers of a uniform blood sample draw procedure will result in a consistency necessary to allow reliable and valid comparison of adequacy of dialysis parameters within and between ESRD patients, units, and clinical trials.

Body size, dose of hemodialysis, and mortality.

This study investigates the role of body size on the mortality risk associated with dialysis dose in chronic hemodialysis patients. A national US random sample from the US Renal Data System was used for this observational longitudinal study of 2-year mortality. Prevalent hemodialysis patients treated between 1990 and 1995 were included (n = 9,165). A Cox proportional hazards model, adjusting for patient characteristics, was used to calculate the relative risk (RR) for mortality. Both dialysis dose (equilibrated Kt/V [eKt/V]) and body size (body weight, body volume, and body mass index) were independently and significantly (P < 0.01 for each measure) inversely related to mortality when adjusted for age and diabetes. Mortality was less among larger patients and those receiving greater eKt/V. The overall association of mortality risk with eKt/V was negative and significant in all patient subgroups defined by body size and by race-sex categories in the range 0.6 < eKt/V < 1.6. The association was negative in the restricted range 0.9 < eKt/V < 1.6 (although not generally significant) for all body-size subgroups and for three of four race-by-sex subgroups, excepting black men (RR = 1. 003/0.1 eKt/V; P > 0.95). These findings suggest that dose of dialysis and several measures of body size are important and independent correlates of mortality. These results suggest that patient management protocols should attempt to ensure both good patient nutrition and adequate dose of dialysis, in addition to managing coexisting medical conditions.

Mortality risk by hemodialyzer reuse practice and dialyzer membrane characteristics: results from the usrds dialysis morbidity and mortality study.

Hemodialyzer reuse is commonly practiced in the United States. Recent studies have raised concerns about the mortality risk associated with certain reuse practices. We evaluated adjusted mortality risk during 1- to 2-year follow-up in a representative sample of 12,791 chronic hemodialysis patients treated in 1,394 dialysis facilities from 1994 through 1995. Medical record abstraction provided data on reuse practice, use of bleach, dialyzer membrane, dialysis dose, and patient characteristics and comorbidity. Mortality risk was analyzed by bootstrapped Cox models by (1) no reuse versus reuse, (2) reuse agent, and (3) dialyzer membrane with and without the use of bleach, while considering dialysis and patient factors. The relative risk (RR) for mortality did not differ for patients in reuse versus no-reuse units (RR = 0.96; 95% confidence interval [CI], 0.86 to 1.08; P > 0.50), and similar results were found with different levels of adjustment and subgroups (RR = 1.01 to 1.05; 95% CI, lower bound > 0.90, upper bound < 1.19 each; each P > 0.40). The RR for peracetic acid mixture versus formalin varied significantly by membrane type and use of bleach during reprocessing, achieving borderline significance for synthetic membranes. Among synthetic membranes, mortality was greater with low-flux than high-flux membranes (RR = 1.24; 95% CI, 1.02 to 1.52; P = 0.04) and without than with bleach during reprocessing (RR = 1.24; 95% CI, 1.01 to 1.48; P = 0.04). Among all membranes, mortality was lowest for patients treated with high-flux synthetic membranes (RR = 0.82; 95% CI, 0.72 to 0.93; P = 0.002). Although mortality was not greater in reuse than no-reuse units overall, differences may exist in mortality risk by reuse agent. Use of high-flux synthetic membrane dialyzers was associated with lower mortality risk, particularly when exposed to bleach. Clearance of larger molecules may have a role.

First-use reactions during hemodialysis: a definition of subtypes.

We believe that it is worthwhile to separate out two distinct types of first-use reactions: a hypersensitivity type (type A) characterized by anaphylactic signs and symptoms and a non-specific type (type B) characterized primarily by chest pain and back pain. Further research is needed to better define the etiology, the epidemiology, and the pathogenesis of these two subgroups of the first-use syndrome.

Transdermal clonidine for hypertensive patients.

Seventeen moderately hypertensive patients, whose blood pressure was previously controlled with hydrochlorothiazide and oral clonidine (blood pressure 129 +/- 8/85 +/- 5 mmHg during therapy), were treated with a transdermal system involving application of one or more clonidine-containing patches (3 mg per patch) to the skin once a week. The patients continued to take 50 mg of oral hydrochlorothiazide daily. By four to eight weeks, 15 of 17 patients using the transdermal system had achieved baseline blood pressure levels (130 +/- 10/84 +/- 6 mmHg, NS). During the maintenance phase of transdermal therapy, plasma clonidine levels measured four hours (0.78 +/- 0.43 ng/ml), four days (0.89 +/- 0.48 ng/ml), and seven days (0.78 +/- 0.41 ng/ml) after patch application did not differ significantly from one another or from trough plasma clonidine levels (0.86 +/- 0.54 ng/ml) measured during oral clonidine therapy. The results suggest that, in moderately hypertensive patients, blood pressure can be controlled with a once-weekly application of clonidine-containing skin patches as effectively as with oral clonidine.

In vitro binding of amantadine to plasma proteins.

In vitro binding of amantadine to plasma protein was assessed by ultrafiltration of plasma samples (from a blood bank) to which amantadine hydrochloride had been added. Approximately two-thirds of the amantadine was found to be protein-bound. The degree of protein binding was constant over a plasma amantadine concentration range of 100-2,000 ng/ml.

Hemodialysis ascites in anephric patients.

Six maintenance hemodialysis patients are described in whom ascites was encountered at a time when they were anephric. No etiology for ascites could be found, and it was presumed that these patients were manifesting so-called "hemodialysis ascites". Our findings suggest that the use of bilateral nephrectomy in the treatment of hemodialysis ascites should be re-evaluated.

Hematologic studies during isolated ultrafiltration.

The effect of negative-pressure isolated ultrafiltration on leucocytes, platelets, and clotting factors was evaluated in maintenance hemodialysis patients. A significant decrease in the number of leucocytes was observed during the first 45 minutes of ultrafiltration. However, by one hour, leucocyte counts had returned to pre-ultrafiltration values. A slight, of haptoglobin, free hemoglobin, or fibrinogen after one hour of isolated ultrafiltration. Levels of fibrin degradation products and fibrin monomers similarly showed no change. Heparin administration alone had no effect on the above hematologic values. We suggest that isolated ultrafiltration, as clinically practised, has little acute effect on the coagulation system, and does not cause detectable hemolysis. The transient decrease in leucocyte count, and the modest fall in platelet count that were found are in keeping with changes previously reported to occur during hemodialysis.