The use of new concepts in vascular physiology and pharmacology to improve hemodialysis access outcomes.

Greater insight into vascular pathophysiology and intimal hyperplasia has resulted in observational studies that suggest that interventions which decrease inflammatory mediators, improve endothelial function and inhibit smooth muscle migration and proliferation may be of benefit in improving hemodialysis vascular access survival. Longer dialysis times may also reduce inflammatory mediators and restore vascular sensitivity to endothelium dependent relaxation factor. In contrast, the common procedure of angioplasty is the experimental model to develop intimal hyperplasia and stenosis, while the efficacy of stents to prevent that stenosis in hemodialysis accesses remains controversial. Common drugs that interfere with metalloproteinases may prevent aneurysm formation while avoiding drugs that aid quorum sensing and using drugs that interfere with it may prevent biofilm infection in hemodialysis vascular catheters. Large prospective randomized studies will be needed to determine the true benefit.

Minidose heparin therapy. Treatment of chronic intravascular coagulation syndrome.

An elderly patient had multiple life-threatening episodes of disseminated intravascular coagulation (DIC). There was no apparent cause other than an abdominal aortic aneurysm. Her condition was maintained with minidoses of subcutaneously administered heparin sodium in the acute stages and as an outpatient for seven months, which proved to be an effective therapy. We suggest that minidoses of heparin can be used in the treatment of DIC and that this is a safe, easily administered mode of therapy, especially in the outpatient setting.

Long-term selenium exposure.

Metabolic pathways and toxic effects of long-term selenium exposure in animal models and humans have both similarities and significant differences. In animal models the target organ is the liver, in which chronic cirrhosis develops. In man the target organ appears to be the lung, which manifests acute "rose cold," or, as in our patient, a chronic granulomatous hypersensitivity. Our data indicate not only a different target organ than would have been predicted from animal models, but also a difference in the distribution of selenium in human tissues. Long-term use of selenium favors production of dimethylselenide, which is excreted by the lungs and should be considered a pulmonary toxin. The ramifications of these findings may require a change in the monitoring techniques of long-term industrial exposure and mandate a close follow-up of selenium as a health fad.

Pharmacokinetics and dialyzability of sulindac and metabolites in patients with end-stage renal failure.

Sulindac was administered as a single 300-mg oral dose to six patients with end-stage renal failure and six normal subjects. Plasma concentrations of sulindac and its sulfide and sulfone metabolites were examined over a 48-hour period. As determined by ultrafiltration methods at 37 degrees C, the percentage free of sulindac and sulindac sulfide in plasma was greater, respectively, in the patients with renal failure (10.50 +/- 2.42 and 9.96 +/- 1.21) than in the normal subjects (6.78 +/- 0.45 and 6.01 +/- 0.37). Free sulindac plasma concentrations were not different between the two groups. However, sulindac sulfide, total and free, plasma concentrations were substantially decreased in the group with renal failure. Total area under the curve (AUC) of the sulfide metabolite was 18% in the normal subjects and the free AUC was 29%. In patients with renal failure, the apparent half-lives of sulindac (1.98 +/- 0.76 hours) and sulindac sulfide (15.6 +/- 5.8 hours) were not different from those of normal subjects. Sulindac sulfone half-life was highly variable and longer in the patient group. Studies of dialysis clearance showed that sulindac and its metabolites are poorly dialyzed. A 4-hour dialysis period increased the plasma binding of both sulindac and sulindac sulfide in the patient group. Based on the decreased plasma concentration of the active sulindac sulfide metabolite in the patient group, dosage adjustments may be required in patients with end-stage renal failure.

Effect of cholestyramine resin on single dose valproate pharmacokinetics.

Cholestyramine, a nonabsorbable anion exchange resin, has been reported to bind concomitantly administered drugs and decrease their bioavailability. The objective of the study was to determine the effect of cholestyramine on the plasma concentrations of valproic acid (VPA) following concurrent and staggered (VPA 3 hours before cholestyramine) dosing. Six healthy volunteers participated in an open-label, 3-way crossover study. In each phase fasting subjects received 250 mg of VPA followed by serial blood sampling for VPA plasma concentrations over a 37-hour period. In the concurrent and staggered phase the subjects received 4 g of cholestyramine (CHOL) twice daily 24 hours prior to and following the VPA dose. During the concurrent phase the coadministration of CHOL resulted in a decrease (p < 0.05) in the area under the curve (AUC) for VPA compared to VPA alone (415.2 +/- 113.2 mg*hr/l vs 489.2 +/- 153.0 mg*hr/l, respectively). When the same dose of each drug was administered 3 hours apart, the AUC for VPA (454.8 +/- 123.1 mg*hr/l) was not significantly decreased when compared to VPA alone (489.2 +/- 153.0 mg*hr/l). Also, the bioavailability relative to VPA alone was 86.2% +/- 7.1 for the concurrent phase and 95.3% +/- 13.6 for the staggered phase. Based on the AUC of VPA concurrent administration of CHOL significantly decreases VPA absorption and separating the doses of the 2 drugs by 3 hours may lessen the interaction.

Effects of hand dominance and sleep side preference on hemodialysis vascular access survival.

We examined the effects of hand dominance and the patients' stated preference of the sleeping position on the survival of vascular accesses for hemodialysis in different locations. Analysis was made of vascular access survival times after 1, 126 vascular access surgeries performed between January 1, 1989, and December 31, 1994. We found that hand dominance and access site were not related to any survival differences in patients with autogenous fistulas, but thigh grafts on both sides had greater survival than arm grafts. The preferential side for sleeping similarly did not seem to affect access survival, but patients who stated a sleep preference on the side opposite their vascular graft tended to have longer access survival time.

Surface tension, proteinuria, and the urine bubbles of Hippocrates.

Hippocrates noted that bubbles in urine were associated with kidney disease. We examined changes in surface tension responsible for bubble formation in urine, to investigate whether surface tension could be a more accurate and continuous linear predictor of 24-h proteinuria than currently available tests on spot urine.

The periodicity of vascular access thrombosis.

A periodicity has been observed in thrombotic events that occur in a variety of vascular beds. There also has been a recent suggestion that there is an increased failure of hemodialysis vascular accesses due to thrombosis during the summer months. We reviewed the last 949 episodes of vascular access thrombosis and found no seasonal pattern, but a weekly pattern was noted that corresponded to the patients' dialysis schedule. That pattern was apparently due to our technique of observation and not due to any intrinsic periodicity in the thrombosis itself. We find no evidence to support the belief in any intrinsic periodicity in hemodialysis vascular access thrombosis and since the thrombotic event itself is usually asymptomatic, any accurate assessment of a diurnal or circumseptan pattern is not possible under ordinary clinical conditions.

The importance of timing of surgery for hemodialysis vascular access thrombectomy.

The effect of delay in thrombectomy of occluded hemodialysis accesses was examined to determine whether a critical period exists during which a salvage procedure was more likely to be successful. A total of 1,126 vascular access surgeries between January 1, 1989, and December 31, 1994, were analyzed. No period of delay in thrombectomy was found when it was possible to say with certainty that an access could not be salvaged, although success was greatest in the first 48 h. Autogenous fistulas were less likely to be salvaged and surgery was unlikely to be successful if performed later than the day of thrombosis. However, grafts were likely to undergo successful thrombectomy even 3 days after thrombosis. Overall when the delay was more than 3 weeks after thrombosis, a new access was more likely to be constructed than the thrombosed access was to be successfully declotted.

The long-term clinical course of systemic lupus erythematosus in end-stage renal disease.

In an attempt to define the long-term clinical course of systemic lupus erythematosus followed by end-stage renal disease, we studied 28 patients with lupus nephritis at Stanford University between January 1969 and December 1980. The clinical and serologic manifestations of both renal and nonrenal disease improved with long-term hemodialysis despite the withdrawal of immunosuppressive drugs in almost all the patients. Rehabilitation was excellent, and a return to normal physical activity was generally the rule. The mortality rate was low (6 of the 28 patients died), but death occurred primarily in patients receiving high doses of prednisone. Recovery from renal failure and discontinuation of dialysis were not rare (eight patients recovered) despite the reduction in immunosuppressive drugs. Renal transplantation was also well tolerated. We found the long-term clinical course of these patients to be comparable to that of patients with end-stage renal disease associated with disorders other than systemic lupus erythematosus.

Electrocardiographic changes following dialysis.

We investigated electrocardiographic changes occurring after hemodialysis in 20 male patients with chronic renal failure. Changes in the configuration of T wave, ST segment and R wave consistent with ischemia were found in 30, 45, and 75%, respectively. Contrary to prior speculation the R wave height did not vary with the volume changes of body fluid occurring in dialysis. It is concluded that ischemic-appearing changes of uncertain significance are common in the postdialysis population.

Edema, oncotic pressure, and free entropy: novel considerations for the treatment of edema through attention to thermodynamics.

Over 170 years after Richard Bright and a century after Ernest H. Starling, the development, location, and severity of edema in patients with renal impairment continue to baffle the predictions of most nephrologists. While much of the phenomenon can be explained by levels of serum proteins, or hydrostatic pressures, there are stunning exceptions well known to any practicing nephrologist. Some of the derangement is undoubtedly due to unmeasured but well-known variables, such as membrane permeability; however, other factors such as free entropy of plasma are also clearly involved. The study of other polyelectrolyte colloids, similar to plasma proteins, for industrial purposes has led to the identification of various phenomena such as counterion condensation that can result in loss of entropy and consequently osmotic pressure. Variables known to result in a loss of free entropy, such as pH, oxidation products and ligand binding, are discussed. Older equations developed by van't Hoff and Donnan might require replacement by newer mathematical models such as the nonlinear Poisson-Boltzmann equation or the Monte Carlo simulator. Attempts to restore free entropy to plasma would be a more physiological treatment of edema than diuretic use. Implications are noted for future drug development to treat edema.

Thallium-201 myocardial imaging in patients on chronic hemodialysis.

10 long-term hemodialysis patients had immediate and redistribution thallium-201 myocardial imaging performed after a course of hemodialysis. Subjects had EKGs done on the same day before and after dialysis. 3 of the 10 subjects had resting thallium-201 myocardial imaging obtained on non-dialysis days. 60% of the electrocardiograms showed changes with dialysis. All 13 thallium studies were abnormal, showing multiple transient filling defects at rest. Most subjects had permanent filling defects as well. It is concluded that hemodialysis patients have a high frequency of abnormal thallium-201 myocardial images at rest. The cause of these abnormal studies is uncertain.