The distribution of sodium-potassium--activated adenosine triphosphatase in medulla and cortex of the kidney.

The activity of sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) is considerably higher in homogenates of outer medulla than in the cortex or papilla of the kidney. The enzyme has similar kinetic characteristics in both cortex and medulla, and binds ouabain in the same proportion. The discrepancy in enzymatic activity is not paralleled by similar change in the activity of adenyl cyclase, 5'nucleotidase, glucose-6-phosphatase, or succinic dehydrogenase. Na-K-ATPase is also higher in distal convoluted tubules (ventral slices) than in the proximal tubules (dorsal slices) of the kidney of Amphiuma. The high concentration of Na-K-ATPase in the red medulla of the kidney is probably related to the presence here of the thick ascending limb of the loop of Henle, and this has important implications with regard to the mechanism of sodium reabsorption by different portions of the nephron.

Pharmacokinetics of digoxin and digitoxin in patients undergoing hemodialysis.

The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population. Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dialyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin. When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (plus or minus SE) of 0.84 plus or minus 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 plus or minus 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the parmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.

Leukocyte responses to acute renal transplant rejection.

A retrospective study of the response of the leukocyte count to renal transplant rejection was performed in 159 rejection episodes. Results of the study showed that 1. contrary to what is commonly thought leukocytosis is the least common response to acute rejection and a decrease in leukocyte count is far more common, 2. a sudden decrease in leukocyte count in a previously stable patient can be an early sign of rejection, 3. there is a significantly greater incidence of graft loss in rejection episodes characterized by leukopenia and 4. the risk of infection following rejection is greatest in patients with rejection characterized by leukopenia.

Prospective controlled study of androgen therapy in the anemia of chronic renal disease: effects on iron kinetics.

Ferrokinetic and RBC mass determinations were made at 3-month intervals in iron-replete hemodialysis patients randomized to a control group or to nandrolone decanoate therapy. After 3 months, RBC mass increased in two of 4 androgen-treated patients. Erythron iron turnover, an index of RBC production, increased in the one responder studied but not in the two nonresponders. Similarly, in a fifth subject, who was not restudied until 6 months of androgen therapy were completed, an increase in RBC mass was associated with an increase in erythron iron turnover. However, between 3 and 6 months, RBC mass increased in all 4 androgen-treated patients studied even though erythron iron turnovers remained unchanged and dialysis-associated blood losses did not decrease. Thus, at least two androgen-treated patients had increases in RBC mass without ever increasing their erythron iron turnover. Two of three control subjects also had increased erythron iron turnovers, which in one case was related to increased dialysis-associated blood losses. Changes in RBC mass were not consistently paralleled by changes in Hb. These findings suggest that increases in RBC mass during nandrolone decanoate therapy result from two mechanisms: increased erythropoiesis (shown by simultaneous increases in RBC mass and erythron iron turnover) and increased RBC survival (indirectly shown by increases in RBC mass without increases in erythron iron turnover). The importance of control groups, RBC mass determinations and the monitoring of dialysis-associated blood losses in studying the effects of androgens on erythropoiesis in chronic hemodialysis patients is also demonstrated.

Androgen therapy in haemodialysis patients. II. Effects on red cell metabolism.

Activities of the red cell enzymes hexokinase, glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, lactic dehydrogenase and aspartate aminotransferase were measured in 17 chronic haemodialysis patients receiving androgen therapy, 15 untreated chronic haemodialysis patients and 15 normal subjects. Compared to normal subjects, untreated haemodialysis patients had similar reticulocyte counts but significantly increased levels of all five enzymes studied. This finding suggests the presence of a younger red cell population in the peripheral blood and is consistent with the shortened red cell survival known to occur in this clinical setting. Red cell enzyme activities in untreated haemodialysis patients were significantly correlated with one another and with the serum phosphate level. Moreover, in this population, red cell DPG content was directly related to hexokinase and glucose 6-phosphate dehydrogenase activities while haemoglobin-oxygen affinity (P50) was inversely related to all five enzyme activities. In contrast, in androgen-treated haemodialysis patients, despite higher reticulocyte counts, red cell enzyme activities were the same or lower than those in the untreated haemodialysis group and only slightly higher than those in normal subjects, suggesting an overall older red cell population. Moreover, relationships of red cell enzymes to one another, to serum phosphate levels and to both red cell DPG content and haemoglobin-oxygen affinity were significantly different in androgen-treated subjects than in the untreated haemodialysis group. These changes are consistent with a direct effect of androgens on red cell metabolism and an improved red cell survival during androgen therapy.

Prospective controlled study of androgen effects on red cell oxygen transport and work capacity in chronic hemodialysis patients.

Effects of androgens on red blood cell (RBC) oxygen transport, RBC metabolism and work capacity in chronic hemodialysis patients were evaluated in a prospective controlled study. Compared to control subjects, patients given nandrolone decanoate had a sustained fall in RBC ATP and a transient rise in RBC DPG but P50 values were unchanged. Despite increases in RBC mass of 16-44% on androgen therapy, exercise on the treadmill improved in only 1 patient and actually declined in 3 others. Thus, these preliminary observations suggest that androgens may not improve hemoglobin-oxygen transport and that androgen-induced increases in red cell mass may only balance increased tissue oxygen requirements produced by these anabolic hormones.

Androgen therapy in hemodialysis patients: I. Effects on red cell oxygen transport.

Measures related to red cell oxygen transport were evaluated in 17 hemodialysis patients receiving androgen therapy, 15 untreated hemodialysis patients and 15 normal subjects. Hemoglobin levels were higher in androgen-treated patients than in the untreated population and were directly related to the reticulocyte index. Hill coefficients were normal, and in vivo P5O values were increased to the same degree in both dialysis groups. However, DPG and serum phosphate explained 70% and 12%, respectively, of the variance in P5O in untreated patients but only 2% and 5% in androgen-treated subjects. In contrast, sample pH explained 34% of the variance in P5O in the androgen-treated group and less than 1% in the untreated dialysis population. Despite the relative importance of pH as a determinant of P5O in patients on androgen therapy, the Bohr coefficient in this group was only about half of that in untreated dialysis subjects. Androgen-treated patients also had lower red cell ATP levels. Finally, the expected correlation of MCHC with pH was noted in untreated dialysis subjects but not in patients receiving androgens. We conclude that androgen therapy in hemodialysis patients in addition to increasing red cell production, directly alters red cell metabolism. Moreover, although the androgen regimens used did not change the net oxygen transport characteristics of hemoglobin, they decreased the responsiveness of hemoglobin-oxygen affinity to changes in pH, DPG and phosphate. Thus, red cell adaptation to changes in oxygen supply and/or demand may be limited in androgen treated patients, and the improvement in clinical performance expected from androgen-stimulated erythropoiesis may not be realized.

Immune defects in chronic renal impairment: evidence for defective regulation of lymphocyte response by macrophages from patients with chronic renal impairment on haemodialysis.

Cellular mechanisms contributing to impaired lymphocyte proliferative responses in chronic renal impairment (CRI) were investigated using peripheral blood mononuclear cells (PBMC) from 25 patients receiving haemodialysis. Impaired T cell proliferative responses to phytohaemagglutinin were demonstrated. The hyporeactive PBMC from patients with CRI suppressed the responses of PBMC from normals to a greater degree than did control PBMC. This immunosuppression was reversed significantly by depleting adherent monocytes (M phi). To further determine if these impairments might be critically dependent on cell-cell contact, M phi from an additional 10 patients on haemodialysis were examined for ability to support B and T cell colony formation in semi-solid cultures stimulated by Staphylococcus protein A (SpA). When compared to normal controls, significantly fewer B and T cell colonies were observed with M phi from CRI patients than when autologous M phi were used. Also, T cells from patients were significantly less effective than controls in supporting B cell colony growth. Decreased T and B cell colony responses in patients were not due to a primary abnormality of these cells, since allogeneic mixing experiments showed that B and T cells from patients were able to form a sufficient number of colonies when control M phi or T cells from normals were used as accessory and helper cells. These findings suggest that although M phi-mediated suppressor activity is an important mechanism contributing to impaired lymphocyte responsiveness in patients with chronic renal impairment on haemodialysis, additional or related abnormalities in M phi 'accessory' function may also exist.