Sodium pump isoform specificity for the digitalis-like factor isolated from human peritoneal dialysate

We have isolated a labile, specific sodium pump inhibitor or digitalis-like factor from the peritoneal dialysate of volume-expanded renal failure patients whose levels correlated closely with volume status and blood pressure. This study characterizes the inhibitory profile of this agent compared with that of ouabain against the three alpha-isoforms of the sodium pump. We prepared microsomal Na,K-ATPase from rat tissues representing the highest proportion of one of the alpha-isoforms. Both Northern and Western blot analyses confirmed that kidney had predominantly the alpha1-isoform, skeletal muscle the alpha2-isoform, and fetal brain the alpha3-isoform. Ouabain (5 x 10(-6) mol/L) produced little inhibition of kidney Na,K-ATPase (3.4+/-2.0%) but significant inhibition of skeletal muscle (37.2+/-3.7%, P<.001) and fetal brain (38.8+/-3.5%, P<.001) activity. In contrast, the labile digitalis-like factor, causing comparable inhibition of fetal brain Na,K-ATPase activity (33.3+/-4.7%), produced markedly greater inhibition of kidney (42.5+/-5.6%, P<.001) and moderately greater inhibition of skeletal muscle pump activity (57.7+/-6.3%, P<.05). In addition, the labile digitalis-like factor produced a marked concentration-dependent inhibition of the alpha2- and alpha3-isoforms (r=.79, P=.00005). Experiments combining the labile digitalis-like factor and ouabain confirmed that digitalis-like factor, unlike ouabain, was an effective inhibitor of all three isoforms in rat, in particular alpha2. The different pattern of isoform sensitivity displayed by the labile digitalis-like factor and ouabain further differentiates the two agents and raises some interesting possibilities about the functional implications of the endogenous factor.     

Pharmacokinetics of cefdinir and its transfer to dialysate in patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis

Cefdinir (CAS 91832-40-5) was administered orally as a 100-mg capsule (Cefzon) to a total of 12 patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis (CAPD) to investigate changes in the serum concentrations, excretion rate into the dialysate and serum-protein binding of cefdinir. Cmax values were 1.64-4.34 micrograms/ml, t1/2 values were 10.8-21.9 h., and AUC values were 31.1-73.1 micrograms.h/ml (0-30 h) in four patients given a single oral dose of 100 mg of cefdinir as a capsule. About 1 microgram/ml of cefdinir had still remained in the blood of all the patients 24 h after administration. The serum concentrations of cefdinir were dose-dependent in four patients of each group who were given an oral daily dose of 100 mg for 3 to 8 days and 200 mg (2 capsules) for 4 to 14 consecutive days. No marked change in laboratory test values or clinical symptoms before and after administration were observed in these dose regimes. Protein levels of 5.17-5.71 g/day were eliminated from the peritoneal dialysate and urine. Cefdinir inhibited 90 to 100% of the clinical isolates such as Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and other enteric bacteria causing catheter infection and peritonitis, and its antibacterial activity was stronger than that of amoxicillin (CAS 26787-78-0) or cefaclor (CAS 53944-73-3) against these clinical isolates.     

Echocardiographic evaluation of left ventricular function in patients with chronic renal failure treated with intermittent peritoneal dialysis

As a result of preclinical data demonstrating the antitumour and antimetastatic efficiency of indomethacin in murine models, and the clinical observation of occasional tumour regression in patients with advanced melanoma treated with indomethacin together with ranitidine, a Phase II study was performed of prolonged administration of these two oral agents in combination. Seventeen patients were entered into the study and commenced on indomethacin 50 mg three times daily; the dose was escalated to a maximum of 75 mg three times daily in patients who tolerated the starting dose. Ranitidine was administered concurrently at a dose of 150 mg twice daily. One patient with uveal melanoma metastatic to the liver achieved a partial response, with slow shrinkage of a biopsy-proved liver metastasis (objective response rate 6 percent; 95 percent CI0-29). Another patient demonstrated a minor response in pelvic lymph nodes. The combination of indomethacin and ranitidine has negligible activity in advanced malignant melanoma; a response may require months to be achieved.     

The use of an indwelling peritoneal catheter in the treatment of chronic renal failure

Thirty-seven patients with end-stage renal failure were treated by dialysis by the peritoneal route, with a Tenckoff catheter. The basic regime was 30 2-litre exchanges twice a week. Two patients died while receiving peritoneal therapy, and 7 patients were transferred to haemodialysis because of catheter failure. Four patients received transplants directly from peritoneal dialysis, 22 were transferred electively to haemodialysis, and 2 are still being treated by peritoneal dialysis. Fourteen (1-2%) of the 1,161 dialyses were complicated by peritoneal infection. This was controlled in 13 instances by the addition of gentamicin to the dialysate, but removal of the catheter was required in one case. The mean duration of peritoneal dialysis was 14-4 weeks; 4 patients underwent this type of therapy for 78, 63, 41 and 40 weeks respectively.     

A comparative study of the outcome of renal transplantation in peritoneal dialysis and hemodialysis patients

Fifty-four cases of renal transplantation performed in peritoneal dialysis (PD) patients were compared with 48 cases in hemodialysis (HD) patients. Three immunosuppressive treatments were used: prednisolone, azathioprine and cyclosporine. Methylprednisolone was used to treat rejection, and polyclonal Atgem or monoclonal OKT3 antibodies were used if there was no response. There was no difference in sex, age, donor source, immunosuppressive regime, duration of dialysis before transplantation, or duration of follow-up between the two groups. Following transplantation, there was no significant difference in patient mortality and survival or graft survival between the groups. The incidences of infections were also similar in the two groups. PD is commonly used in developing countries as an alternative to hemodialysis for the treatment of chronic renal failure. This study has shown that renal transplantation can be successfully performed in patients treated by this method.     

What is the place of peritoneal dialysis in the integrated treatment of renal failure?

The role of peritoneal dialysis (PD) in renal replacement therapy (RRT) remains unclear. There are no controlled trials to provide hard evidence of its efficacy. Comparative studies with haemodialysis from different centres and countries have given conflicting results even when allowing for case mix. Data from the United States on patients starting or receiving treatment in the late 1980s suggested a worse prognosis for older patients, particularly diabetics receiving PD as compared to HD. Analysis of the USRDS data base for patients starting in the early 1990s shows an improvement in outcome but with no difference in overall mortality. The Canadian registry has recently published data showing a better survival with PD than with HD in the first two years of RRT. Morbidity is similar with both therapies, although hospitalization is increased with PD. Unfortunately long-term technique survival is not as good with PD. However, PD has certain medical advantages, particularly the maintenance of residual renal function that contributes to solute and fluid removal. It may also postpone the onset of amyloidosis. Patients transplanted after previous PD have a decreased risk of early acute renal failure and equally good long-term results when compared to those patients who were on HD before transplantation. The quality of life is as good with PD as with center HD, and there are social advantages to PD including an increased chance of employment, more flexible holidays and avoidance of thrice weekly travel to a dialysis center. PD also has logistical advantages and can be utilized by the majority of new patients. We therefore conclude that PD has potential advantages early in the course of RRT, and should therefore be offered as a first option to all suitable new patients. Whether PD has a major or minor role in later years (> 5) remains unclear.     

A flux ratio analysis of the Post-Albers mechanism of the sodium pump

A thermodynamically constrained method of flux ratio analysis has been applied to the Post-Albers mechanism of the sodium pump to establish a relationship between the thermodynamic "boundary conditions" for the overall pump reaction and the unidirectional flux ratios for the pump-mediated fluxes of sodium and potassium. This relationship provides an experimental criterion for assessing whether or not the reactions associated with ion binding and dissociation to and from the pump, respectively, are close to equilibrium. Examination of experimental data from the current body of literature indicates that the above criterion is not satisfied for the sodium pump of human red blood cells under normal physiological conditions. On the basis of this result, it is concluded that within the context of a Post-Albers mechanism one or more of the ion binding and dissociation steps are not in rapid equilibrium with other such steps, at least not for the sodium pump of human red blood cells under normal physiological conditions.     

The pharmacokinetics and protein-binding of fusidic acid in patients with severe renal failure requiring either haemodialysis or continuous ambulatory peritoneal dialysis

Antibiotic treatment options for Burkholderia cepacia infection are limited because of high intrinsic resistance. The problem is complicated by development of cross-resistance between antibiotics of different classes. We isolated antibiotic-resistant mutants by stepwise exposure to chloramphenicol (Chlor) and to trimethoprim/sulphamethoxazole (T/S) for four B. cepacia strains: ATCC13945, Per (clinical isolate), Cas and D4 (environmental isolates). Chlor(r) mutants did not produce chloramphenicol acetyl-transferase. Cross-resistance, defined as greater than four-fold increase in MIC by microtitre dilution method, was consistently seen in both types of mutants. For chloramphenicol-resistant (Chlor[r]) and trimethoprim/sulphamethoxazole-resistant (Tr/Sr) mutants of B. cepacia ATCC13945 and Cas, no MIC change was seen for piperacillin, ceftazidime, rifampicin, gentamicin, tobramycin, polymyxin B or azithromycin. B. cepacia-Per and -D4 mutants showed cross-resistance to ceftazidime and to piperacillin. Comparison of outer membrane protein (OMP) profiles of B. cepacia and their mutants by SDS-PAGE revealed Tr/Sr) mutants to be deficient in a major OMP (molecular weight 39-47 kDa). Tr/Sr mutants also expressed additional OMPs not found in wild type strains at 75-77 kDa for B. cepacia-ATCC13945 and -Cas, and 20-21 kDa in B. cepacia-D4 and -Per. No OMP changes occurred in Chlor(r) mutants. Lipopolysaccharide (LPS) profiles of each type of mutant showed new high and low molecular weight LPS bands. Cross-resistance seems to be mediated by alterations in porin and LPS for Tr/Sr mutants, but only by LPS in Chlor(r) mutants.     

A new approach to the treatment of renal failure

There is an apparent need for an alternative form of treatment for renal failure. This study, therefore, sought to determine the feasibility of dialysing across an isolated loop of colon and its possible application to augment failing renal function in chronic uraemic patients. Haemodialysis and renal transplantation are undisputedly effective in treating renal failure but have many drawbacks. They are unavailable in the underdeveloped world, extremely expensive to institute and maintain, and their need and expense are compounded every year by the discovery of new cases. Colonic loops were isolated in sheep and studies performed to find an effective solution in terms of urea clearance. The best solution was then used in animals in which acute or chronic uraemia was induced and, compared with controls, prolonged life significantly (P less than 0-05). Once it had been established that urea could be removed across the colonic mocosa, it was used in patients with established isolated loops of colon. Even though they had normal blood levels, urea was recovered in the dialysate. Results indicate that colonic dialysis, which is simple and inexpensive, may have a place as an adjunctive therapy in the treatment of chronic renal failure.     

Should dialysate calcium be varied in proportion to the amount of ultrafiltration in peritoneal dialysis dwells? Directions from a computer simulation

Patellar metastases are very rare. There have been approximately 20 cases reported in the literature. We have also noted two other reports of patellar metastasis from lung carcinoma as the first manifestation of lung cancer in our literature review. We present a case of patellar metastasis as the first manifestation of lung epidermoid carcinoma in a patient who was a smoker for 33 years.     

Elevated SCF levels in the serum of patients with chronic renal failure

Exposing neonatal rat heart myocytes to the redox cycling quinone naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) for 15 to 45 minutes led to a time-dependent release of cathepsin D from many secondary lysosomes to the cytosol, as analyzed by morphometry. Cathepsin D was detected electron microscopically using a pre-embedding immunostaining technique that utilizes antibodies conjugated to ultra-small (0.8-nm) gold particles and subsequent silver enhancement. The exposure to naphthazarin also caused a decrease in both the pH and the ATP level of the cells within the same time frame. Lipid peroxidation was, however, not detected. Pretreatment of the cultures with alpha-tocopherol succinate prevented cathepsin D relocation, as shown by immunofluorescence. After exposure to naphthazarin, cells were washed, and normal culture conditions were re-established for 18 hours. Many cells then showed apoptotic morphology (ie, cellular shrinkage and chromatin condensation) as analyzed by Giemsa staining. Also, 41% of the cells stained positive with the TUNEL technique, and DNA fragmentation was detected by separation of intact and fragmented DNA. Apoptosis was significantly decreased in cultures pretreated with alpha-tocopherol succinate.     

Dialysis in the treatment of renal failure in patients with liver disease

The value and effects of treating renal failure by dialysis are analyzed in a series of 84 patients with various types of liver disease. Although none of the 25 patients with cirrhosis survived, six of 50 with fulminant hepatic failure recovered completely as did seven of nine patients with renal failure secondary to extrahepatic biliary tract obstruction or with liver and renal damage following episodes of severe hypotension. Dialysis was required for seven weeks before diuresis occurred in one patient in the latter group. Both peritoneal and hemodialysis satisfactorily controlled plasma urea and creatinine levels, except in patients with fulminant hepatic failure in whom this was only achieved by hemodialysis. Complications of dialysis were most common in patients with cirrhosis and fulminant hepatic failure and included hypotension, gastrointestinal bleeding, and intraperitoneal sepsis. Overall, the results show that dialysis is only worth attempting in those patients in whom recovery of the underlying liver lesion is possible, and even then treatment for prolonged periods may be necessary.     

Geographical variation in the referral of patients with chronic end stage renal failure for renal replacement therapy

The translocation of t(8;16)(p11;p13) has been demonstrated in the blasts of a phenotypically normal newborn baby with acute monoblastic leukemia. No antileukemic therapy was administered and spontaneous, complete remission was observed at 2 months of age. The patient remains well 18 months after the diagnosis and continues to have a normal hemogram.