Multiple-dose study of imipenem/cilastatin in patients with end-stage renal disease undergoing long-term hemodialysis.

Multiple doses of imipenem/cilastatin were administered to patients with end-stage renal disease undergoing long-term hemodialysis. Schedules of 250 mg every six hours, 500 mg every six hours, and 500 mg every 12 hours were studied. Five hundred mg every 12 hours was the most efficient schedule that maintained effective trough antibiotic activity. Twelve volunteers including two patients with clinical infections using the dose schedule of 500 mg every 12 hours received imipenem/cilastatin for two to 14 days without any notable clinical side effects. Imipenem peak and trough concentrations averaged 29 +/- 5 micrograms/ml and 10 +/- 3 micrograms/ml, respectively. No accumulation of imipenem occurred during the trial. Cilastatin peak and trough concentrations were 89 +/- 38 micrograms/ml and 70 +/- 27 micrograms/ml, respectively. The plasma concentration of cilastatin increased with each dose until the next hemodialysis session.

Ceftriaxone pharmacokinetics in patients with various degrees of renal impairment.

The effects of renal impairment on the pharmacokinetics of ceftriaxone in humans were examined after intravenous infusion of a 1-g dose over 15 min to 30 renally impaired patients. The study included 12 dialysis patients and 18 patients with severe, moderate, or mild renal impairment. Plasma and, where appropriate, urine and dialysate samples were collected at predetermined times and analyzed for ceftriaxone by high-pressure liquid chromatography. The elimination half-life (group mean ranged from 11.7 to 17.3 h) and plasma clearance (group mean ranged from 529 to 705 ml/h) did not correlate linearly with creatinine clearance. The renal clearance and fraction of dose excreted unchanged in urine were related linearly, however weakly, with creatinine clearance. Ceftriaxone was not removed from plasma to a significant extent during hemodialysis. The half-life was prolonged twofold, the plasma clearance was lowered less than 50%, and the volume of distribution was relatively unchanged in renally impaired patients compared with young or elderly healthy subjects with normal renal function at an equivalent dose. Since these changes are moderate, adjustment in the dosage regimen of ceftriaxone for patients with impaired renal function should not be necessary when ceftriaxone dosage is 2 g or less per day (2 g every 24 h or 1 g every 12 h). It was reported that the elimination half-life of ceftriaxone is substantially prolonged in a small percentage of patients with end-stage renal disease maintained on hemodialysis. Therefore, plasma concentrations of ceftriaxone should be monitored in dialysis patients to determine whether dosage adjustments are necessary.

Coping with transplant failure: grief vs. denial.

A major drawback to kidney transplantation as a treatment for end stage renal disease is the common occurrence of rejection and failure of the transplanted kidney. We evaluated twenty-five dialysis patients, all of whom had suffered transplant failure during a ten year period. Of these, twenty-four had good psychological readjustment to chronic dialysis. Fourteen patients successfully grieved the loss of their kidneys. Ten denied any psychological difficulty in returning to dialysis and did not manifest the usual signs of grief. We suggest that the effectiveness of denial as a coping mechanism should be recognized and supported when present; in contrast, "grievers" should be helped through the grieving process and followed up to ensure resolution and proper readjustment to dialysis.

Denial in dialysis patients: relationship to compliance and other variables.

Denial has been documented as an important defense mechanism to helping the chronically ill cope with their disease. With respect to a dialysis population, however, the role of denial has been ambiguous. The purpose of this study were 1) to examine the physiological and psychological correlates of denial in a dialysis population and 2)( to examine the relationship between use of denial and compliance to fluid restrictions. Subjects were 46 self- and limited-care dialysis patients. From this subject pool two groups were derived, based upon weight gains between treatments: complies (N=15) and noncompliers(N=16). Both physiological and psychological data were correlated with denial as measured by the Marlow-Crowne Social Desirability Scale. Results indicated that denial is used a great deal in dialysis patients, but there was no difference in denial scores between compliers and noncompliers. For compliers, however, denial was correlated with more adaptive attitudes toward illness. The results have implication for the clinical management of dialysis patients.

Pharmacokinetics of ceforanide in patients with end stage renal disease on hemodialysis.

The pharmacokinetics of ceforanide were evaluated in 11 patients with end stage renal disease (creatinine clearance less than 5 ml/min). A single intravenous dose of 750 mg/m2 produced peak plasma concentrations of 123 +/- 29 microgram/ml. The plasma half-life (T 1/2) of the drug was 19.1 +/- 2.5 h. A 5.5 h hemodialysis session removed 53% of the drug and reduced the T 1/2 to 5 +/- 0.7 h. Plasma concentrations greater than 10 microgram/m2 were maintained without adverse effects with a 1.5-g/m2 dose administered three times a week for 2 weeks.

Interactions between treatment with 1,25(OH)2D3 and glucocorticoids in uremic patients after kidney transplantation.

3 patients undergoing maintenance hemodialysis and receiving 1,25(OH)2D3 for osteomalacic bone disease received cadaveric kidney grafts and concomitant glucocorticoid therapy. The administration of pharmacological doses of glucocorticoids increased the dosage of 1,25(OH)2D3 needed to maintain a normal serum calcium level 7- to 10-fold in 2 patients whose renal grafts failed to function, but there was no decrease in sensitivity to 1,25(OH)2D3 in 1 patient whose renal graft functioned normally. These data suggest that steroids given to a uremic patient may block certain effects normally produced by 1,25(OH)2D3. An end-organ defect due to the combined effects of steroids and uremia is possible.

Pharmacokinetics of cefaclor in patients with end stage renal disease and during hemodialysis.

A single 1.0-g dose of cefaclor administered to patients with stable end stage renal disease whose creatinine clearances were <5 ml/min produced a mean peak serum concentration of 48.3 +/- 19.8 mug/ml. The half-life was 2.3 +/- 0.3 h. Hemodialysis shortened the half-life of a similar dose to 1.6 +/- 0.3 h. Approximately one-third (340 mg) of the administered drug was recovered in the dialysate. Multiple doses of 500 mg every 6 h between hemodialysis sessions produced effective serum concentrations and no bioassay evidence of drug accumulation.

Antibodies to nuclear antigens in patients with renal failure.

Nuclear material, presumably from damaged leukocytes, adheres to hemodialysis membranes. Previous studies have shown an increased prevalence of antibodies to nuclear antigens in chronic dialysis patients. Present studies verify the increased prevalence of antibodies to nuclear antigens in 52 of 243 chronic dialysis patients (21.4%). Because antibodies are present only intermittently, prevalence increases with repetitive blood sampling. In patients tested every 3 months over several years on chronic dialysis, the prevalence of antinuclear antibodies approaches 100%. The present studies also demonstrate, however, that the prevalence of antibodies is increased in patients with renal failure who have never undergone hemodialysis (10 of 86, 11.6%). Thus the tendency to form antibodies to nuclear antigens may be associated with renal failure rather than dialysis per se. Higher prevalences with increased time on dialysis and transplantation failure may accordingly reflect the greater duration of renal failure. The prevalence of antibodies to nuclear antigens was not significantly influenced by age, sex, type of kidney disease, major blood group, HLA tissue type, or coil reuse. Significantly lower hematocrits and white blood counts were noted when antibodies were present.

Charcoal hemoperfusion for chronic renal failure.

16 patients with end-stage renal disease were treated with a fixed-bed, uncoated-charcoal hemoperfusion device, used either alone or in series with a hemodialyzer. 3 patients had one of their thrice weekly dialyses replaced by one 3 hour combined treatment for up to 6 months, and 3 patients had 150-min combined treatments thrice weekly for up to 5 months. The procedure was well tolerated. Transient hypotension occurred and interfered with fluid removal by ultrafiltration. Platelet counts were reduced, but there was no clinical bleeding. Pretreatment of the device with albumin provided no advantage over heparinized saline, and dextran caused a more severe reduction in the platelet count. The changes in platelets, white blood cells, and hematocrit were transient and noncumulative. Considerable amounts of creatinine and uric acid were removed. Regular charcoal hemoperfusion appears to be safe, and long-term studies of clinical efficacy are indicated.

Hemodialysis-associated infections: treatment with cephapirin.

Large doses of cephapirin (50 mg/kg) administered during the first and last half hours of routine hemodialysis produced effective antimicrobial serum concentrations for 48 h. Repetitive administration during five successive hemodialysis sessions did not result in accumulation or accelerated metabolism of cephapirin. Ten infectious episodes in nine patients were treated in this manner with good clinical results and no toxicity.

Antibodies to nuclear antigens in patients undergoing long-term hemodialysis.

Free nuclei of damaged leukocytes adhere to hemodialysis membranes. To see if the incidence of antibodies to nuclear antigens is increased in patients receiving hemodialysis, serums from 77 patients undergoing long-term dialysis for one to 66 months were assayed for antibodies to extractable nuclear antigen and native deoxyribonucleic acid (DNA) by hemagglutination technics. Serums from 300 other hospital patients (who did not have diseases known to be associated with antibodies to nuclear antigens) were assayed concurrently. Of the 77 dialysis patients, serums from 19 (25 per cent) were positive for one or both antibodies. Serums from only three (1 per cent) of the 300 other patients had detectable antibodies. The incidence was significantly higher (p less than 0.001) in dialysis patients suggesting the possibility of sensitization to nuclear antigens during hemodialysis.