Dennis A. Diederich

Regional Citrate Anticoagulation for Hemodialysis in the Patient at High Risk for Bleeding

CONVENTIONAL hemodialysis requires heparin anticoagulation to prevent clotting in the dialysis assembly. Hemodialysis of the patient who is at high risk for hemorrhage is complicated by a 10 to 30 ...

Cyclosporine produces endothelial dysfunction by increased production of superoxide.

Vasoconstriction and hypertension are major side effects of cyclosporine therapy. The mechanism or mechanisms responsible for the vascular effects of cyclosporine are unclear. The vascular effects of cyclosporine may arise as a consequence of endothelial dysfunction induced by the agent. To test this possibility, we compared in vessels prepared in myographs endothelium-mediated relaxations of mesenteric resistance arteries of Wistar-Kyoto rats treated for 21 to 28 days with subcutaneous injections of cyclosporine (25 mg/kg per day), or vehicle. Endothelium-dependent relaxations in response to acetylcholine were impaired in arteries from cyclosporine-treated rats; the concentrations of acetylcholine required to produce 50% relaxation of norepinephrine activation (pD2) were 31.6 +/- 0.1 versus 5 +/- 0.1 nmol/L in control arteries (P < .05). Nitro-L-arginine produced comparable 10-fold decreases in sensitivity to acetylcholine in arteries from both rat groups, indicating that the relaxations were mediated by endothelium-derived nitric oxide. Acetylcholine-induced relaxations in cyclosporine-treated arteries were normalized by pretreatment of the arteries with superoxide dismutase (150 IU/mL; pD2, 3.6 +/- 0.1; P < .05); superoxide dismutase had no effect on relaxations in control arteries. SQ 29,548, an inhibitor of prostaglandin H2/thromboxane A2 receptors; H-7, an inhibitor of protein kinase C; and indomethacin did not alter relaxations in response to acetylcholine in either group of arteries. Cyclosporine-treated arteries were more sensitive than control arteries to nitroprusside, an agent that induces relaxation via nitric oxide (pD2, 1.3 and 6.2 mumol/L, respectively; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin H2 and thromboxane A2 are contractile factors in intrarenal arteries of spontaneously hypertensive rats.

Vascular resistance is increased in the kidneys of spontaneously hypertensive rats (SHR). Previous studies have demonstrated impaired vascular relaxations of mesenteric resistance arteries of SHR because of increased production of a cyclooxygenase-dependent endothelium-derived contracting factor. To test the hypothesis that altered endothelial function contributes to the enhanced constriction in kidneys of SHR, endothelium-mediated relaxations of renal resistance arteries from 5–6-week-old prehypertensive SHR and Wistar-Kyoto rats were compared in arteriographs. Acetylcholine induced endothelium-dependent contractions in SHR arteries, while potent endothelium-dependent relaxations were noted in renal arteries from Wistar-Kyoto rats. Inhibition of cyclooxygenase (indomethacin) or blockade of prostaglandin H2-thromboxane A2 receptors (SQ 29,548) blocked acetylcholine-induced contractions in SHR renal arteries; relaxations in SHR renal arteries after either treatment were similar to those observed in renal arteries from Wistar-Kyoto rats. NG-Nitro-L-arginine inhibited acetylcholinemediated relaxations in both SHR and Wistar-Kyoto arteries. Endothelium-independent relaxations induced by verapamil were comparable in SHR and Wistar-Kyoto arteries. Thus, the impaired response to acetylcholine in SHR renal resistance arteries may result from the release of endothelium-derived cyclooxygenase products (prostaglandin H2 or thromboxane A2), which oppose endothelium-derived nitric oxide–mediated relaxation.

pH-Dependent Accumulation of Clindamycin in a Polycystic Kidney

We determined the concentrations of clindamycin and gentamicin in fluid aspirated from 16 cysts of a surgically excised polycystic kidney. The patient had received both drugs intravenously for seven days before nephrectomy. The cysts were grouped into proximal (pH greater than 6.5) and distal (pH less than 6.5) types according to the pH of the fluid. In nine proximal cysts the mean concentration of gentamicin was 1.3 +/- 0.2 and that of clindamycin was 9.2 +/- 2.3 micrograms/mL. In seven distal cysts the gentamicin concentration was 0.7 +/- 0.2 micrograms/mL and the clindamycin concentration was 34.0 +/- 5.2 micrograms/mL. Plasma gentamicin was 3.8 (peak) and 1.9 (trough) micrograms/mL, and clindamycin was 3.9 micrograms/mL (random). Clindamycin cyst concentrations showed an inverse correlation with cyst fluid pH (r2 = 0.78). These studies confirm that in autosomal dominant polycystic kidney disease (ADPKD), certain cysts develop steep pH gradients between fluid and plasma and indicate that intracystic pH determines the extent to which basic lipophilic antibiotics accumulate in the fluid. Lipid-soluble antibiotics with relatively alkaline pKaS may be useful in the treatment of infected renal cysts.

Safety of Regional Citrate Hemodialysis in Acute Renal Failure

Regional citrate anticoagulation is an alternative to heparin anticoagulation for hemodialysis of patients at increased risk of bleeding. We report the successful use of this technique in 326 dialyses in 49 high bleeding risk patients with acute renal failure. Systemic anticoagulation did not occur as a result of any dialysis procedure, and in no instance was bleeding observed. Dialysis was effective, as judged by removal of creatinine. The safety of this procedure is demonstrated by the lack of bleeding complications and the small incidence of electrolyte and acid-base abnormalities. In addition we document the absence of citrate intoxication by serial measurements of serum citrate levels. Regional citrate anticoagulation is a safe and effective method of performing hemodialysis in patients with acute renal failure at increased risk of bleeding.

Binding of 2,3-diphosphoglycerate to oxyhemoglobin☆

Abstract Extensive binding of 2,3 diphosphoglycerate to oxyhemoglobin is demonstrated both by diafiltration and by Sephadex gel filtration. The average concentration of both 2,3 DPGA and hemoglobin in human erythrocytes is about 5 mM; a portion of the 2,3 DPGA remains bound to oxyhemoglobin and cannot be removed by Sephadex gel filtration.

Relationship between the oxygen affinity and in vitro sickling propensity of carbamylated sickle erythrocytes.

Summary Incubation of Hb SS blood in vitro with NaCNO produces an increase in red cell oxygen affinity and a decrease in the propensity of the cells to sickle. The increase in oxygen affinity is dependent upon the extent of hemoglobin carbamylation. Carbamylated (2 moles of 14 C cyanate incorporated per mole of hemoglobin) and control Hb SS cells sickle in vitro to an equal extent when the hemoglobin is deoxygenated to the same degree. Inhibition of the in vitro sickling phenomenon by hemoglobin carbamylation is in major part a result of the increased affinity of hemoglobin for oxygen.

Dialysis Leukopenia, Hypoxemia, and Anaphylatoxin Formation: Effect of Membrane, Bath, and Citrate Anticoagulation

The goal of these prospective studies was to determine the effect of different dialyzer membranes and dialysate composition on leukopenia and hypoxemia during hemodialysis with citrate anticoagulation. Significant early leukopenia was found with a cuprophane membrane, while a cellulose acetate membrane was associated with mild early leukopenia. Bath composition had no effect. Bicarbonate dialysate, compared with acetate, eliminated hypoxemia in cellulose acetate membranes and reduced its degree and duration with cuprophane. Membrane composition had no effect on hypoxemia during acetate dialysis. The findings indicate that leukopenia is directly and exclusively related to membrane composition while hypoxemia only relates in part to membrane effects. Serial determinations of complement components C3a and C5a showed significant increases in parallel with leukopenia during heparin anticoagulation, but the anaphylatoxin concentration changes were dissociated during dialysis with citrate anticoagulation. The concentrations of anaphylatoxins C3a and C5a appear not to be directly related to dialysis-induced leukopenia. The dissociation between anaphylatoxin concentrations and leukopenia may be related to changes in generation or unmasked changes in leukocyte response. Citrate anticoagulation may provide a useful probe for further studies on membrane-leukocyte interactions in vivo.

Long-Term Comparisons of Citrate and Heparin as Anticoagulants for Hemodialysis

Citrate was compared to heparin as an anticoagulant during chronic hemodialysis. A randomized crossover design was used in six stable male dialysis patients. There were no measurable crossover effects. Use of citrate as the sole anticoagulant for periods of 2 months was easily accomplished, free of complications, and resulted in comparable clearance of solutes. Major laboratory parameters were similar with both anticoagulants. Importantly, there was no significant citrate accumulation. The results also indicate that recurrent use of heparin during dialysis has no measurable effect on lipid metabolism in stable patients.

Effective Use of Streptokinase for Peritoneal Catheter Failure

The fibrinolytic enzyme streptokinase (streptase) was infused into the peritoneal catheter in 19 episodes of catheter failure in 16 patients. Intraabdominal bleeding prior to infusion was seen in seven of these episodes. Fibrin strands and clots were present in four additional successful cases. Streptokinase successfully relieved the obstruction in 13 episodes in 11 patients. The procedure failed in two cases of omental ingrowth and in another with catheter malposition. Streptokinase infusion also failed in two patients with Pseudomonas aeruginosa and one patient with Staphylococcus epidermidis peritonitis. Intraperitoneal streptokinase infusion is simple and free of side effects. Its use should be considered in peritoneal catheter failure, particularly in cases where bleeding or fibrin accumulation may play a role.