Safety and efficacy of total dose iron dextran administration in patients on home renal replacement therapies.

OBJECTIVE: To determine the safety and efficacy of intravenous total dose iron (TDI) replacement in patients treated with home renal replacement therapy. DESIGN: Prospective open-label study on end points in the population studied. SETTING: Institutional outpatient home dialysis program. PATIENTS: The study included 20 end-stage renal disease (ESRD) patients, performing chronic peritoneal or home hemodialysis, with iron deficiency defined as ferritin < 100 ng/mL and/or an iron saturation < 20%. INTERVENTION: The total dose of iron dextran was calculated and infused at a rate not exceeding 6 mg/min. Hemoglobin, hematocrit, iron studies, and liver function tests (LFTs) were obtained before and 3 to 4 weeks after TDI infusion. Hematocrit of patients failing to achieve an increase in Hct over this period was re-examined 2 to 4 weeks later looking for a delayed response. MAIN OUTCOME MEASURES: Primary end points for efficacy were changes in Hct, ferritin, and iron saturation. Toxicity was measured as reported immediate and delayed symptoms and elevated transaminases and/or alkaline phosphatase levels. RESULTS: A median iron dose of 1000 mg (range, 325-1500 mg) was administered. The infusions were generally well tolerated. Clinical adverse effects were seen in 2 patients weighing less than 50 kg. No increase in LFT results was seen. Hematocrit increased 2.2% (95% CI, 0.5%-3.9%) from 29.0% to 31.2% (p = 0.01) within 4 weeks of infusion. Significant increases also occurred in iron saturation (from 13% to 22%, p = 0.001) and ferritin (from 234 to 305 ng/mL, p = 0.008). Among the 9 patients who did not respond with a significant increase in Hct, 2 had a delayed response, increasing the overall response from 63% at 4 weeks to 71%, 8 weeks after TDI. Inadequate erythropoietin dosing and low-grade infectious/inflammatory disorders may have contributed to a poor response in several patients. CONCLUSION: Total dose iron is a safe and effective means of restoring iron and erythropoietic response in ESRD patients weighing more than 50 kg who receive their renal replacement therapy at home.

Studies on platelet membrane glycoproteins and platelet function during hemodialysis.

Hemodialysis only partially corrects the defects in platelet function associated with uremia. Platelet contact with the artificial surfaces of the dialysis filter during hemodialysis can itself cause platelet activation, degranulation, and loss of platelet membrane glycoproteins. Although the transient platelet dysfunction that occurs after platelet contact with foreign surfaces during cardiopulmonary bypass has been well characterized, there has been no such investigation of hemodialysis. In this study of hemodialysis patients, bleeding times (BT) and the response of their platelets to thrombin, ristocetin, and collagen were measured before, immediately after, and in some patients, the day after hemodialysis. In addition, membrane glycoproteins in platelets obtained at these time intervals were studied using fluorescein isothiocyanate (FITC) conjugated monoclonal antibodies (mAb) CD42b (anti-GPIb), CD41a (anti-GPIIb/IIIa), and CD62 (anti-P-selectin), with flow cytometry. BT was significantly prolonged, and response to thrombin and ristocetin was significantly decreased immediately after hemodialysis (P < 0.01). Binding of CD42b mAb to the platelet membrane was decreased in platelets obtained immediately after hemodialysis. Most patients had shortened BT and demonstrated increased response of their platelets to thrombin and increased CD42b binding to their platelets the day after hemodialysis. These findings suggest that in uremic patients, hemodialysis is associated with transient platelet dysfunction and decreased membrane expression of GPIb.

Beneficial effect of low-dose transdermal estrogen on bleeding time and clinical bleeding in uremia.

Patients with renal failure frequently manifest a hemorrhagic diathesis characterized by prolonged bleeding time (BT). Oral and intravenous estrogens have been shown to correct this abnormality, but both estrogens have real and potential disadvantages, especially for long-term use. We examined the effectiveness of transdermally applied 17 beta-estradiol on clinical bleeding and BT in renal failure patients. Six patients with renal insufficiency and prolonged BT were included in the study. Four patients had recurring gastrointestinal bleeding from telangiectasias. Two patients anticipated percutaneous renal biopsy. Transdermal estradiol 50 or 100 micrograms/24 hr was applied every 3.5 days for a period of 2 months. Bleeding times were measured just prior to estrogen administration (pre-estradiol) and again on cessation of clinical bleeding or prior to renal biopsy (post-estradiol). Differences were analyzed using a paired t-test. Erythrocyte transfusion requirement 2 months before and 2 months after estradiol application also was observed. Hemorrhage in all four actively bleeding patients ceased or improved, as reflected by the reduced need for transfusion. Bleeding time improved significantly (P = 0.008) when comparing before (day 0) with after (days 1 to 17) estradiol application. No adverse reactions associated with estradiol occurred over 2 months of therapy. In conclusion, transdermal application of 17 beta-estradiol is a safe and effective means to reduce BT and clinical hemorrhage in patients with renal failure and prolonged BT.

Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients.

A study was undertaken to ascertain the effects of recombinant human erythropoietin (r-HuEPO) on renal function in chronic renal failure predialysis patients. The effect of improvement of anemia by r-HuEPO on the rate of decline in renal function in predialysis patients has not been previously studied prospectively in a large number of patients using reliable measures of glomerular filtration rate (GFR). To investigate the efficacy, safety, and impact of r-HuEPO therapy in chronic renal insufficiency patients, a 48-week, randomized, open-label, multicenter study was initiated in 83 anemic, predialysis (serum creatinine 3 to 8 mg/dL) patients. Serial GFRs were measured using 125I-iothalamate clearance. Forty patients were randomized to the untreated arm and 43 patients to the treatment arm (50 U/kg r-HuEPO subcutaneously three times weekly). Baseline characteristics were comparable for the r-HuEPO-treated and untreated groups. During this 48-week study, GFR, mean arterial blood pressure, and daily protein intake were not significantly different between the two groups. There was a statistically significant increase in hematocrit for the r-HuEPO-treated group that was not associated with acceleration of deterioration in residual renal function. This was demonstrated by the lack of a significant (P = 0.376) between-group difference in mean change in GFR from baseline to last available value for the r-HuEPO-treated (-2.1 +/- 3.2 mL/min) and untreated (-2.8 +/- 3.5 mL/min) groups. This study concludes that r-HuEPO therapy improves anemia in predialysis patients and does not accelerate the rate of progression to end-stage renal disease.

Reduction of platelet glycoprotein Ib in uraemia.

Patients with uraemia have abnormal platelet function that may be partially corrected by haemodialysis, cryoprecipitate or 1-desamino-8-D-arginine vasopressin (DDAVP). We studied the platelet von Willebrand factor receptor, glycoprotein Ib (GPIb), and plasma von Willebrand factor (vWF) in uraemic patients undergoing chronic haemodialysis. Using the slope of agglutination of formalin-fixed platelets as an index of response to ristocetin (with a constant amount of normal plasma as a source of vWF), we found the response of platelets from uraemic patients, both before (2.7 +/- 1.5, n = 40) and after dialysis (1.2 +/- 1.2, n = 40) to be significantly less than that for normal controls (14.1 +/- 10.2, n = 20; P less than 0.001). In addition, the agglutination response of platelets obtained after dialysis was less than that of platelets obtained before dialysis (P less than 0.001). Immunoblotting demonstrated decreased or absent staining of glycocalicin, a subunit of GPIb, in platelet lysates from 25 patients. All platelet samples with reduced glycocalicin also had decreased responses to ristocetin. Tritium-labelled platelets from seven patients showed decreased labelling of a protein with an electrophoretic mobility equivalent to that of GPIb (140,000 daltons). In addition, platelets with the lowest levels of surface GPIb, as demonstrated by flow cytometry, also had decreased ristocetin agglutination and decreased staining on immunoblot. Levels of von Willebrand factor antigen and ristocetin cofactor in plasma from 10 patients were generally within the normal range, although postdialysis levels tended to be higher than pre-dialysis levels. The pre- and post-dialysis plasma vWF multimeric patterns were normal.

Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis.

PURPOSE: To determine if the natural anticoagulant protein C plays a role in the pathogenesis of systemic calciphylaxis, a syndrome characterized by extensive vascular and soft tissue calcification and skin necrosis, which is similar to that seen in warfarin-induced skin necrosis. PATIENTS AND METHODS: The study population included five patients with end-stage renal disease and systemic calciphylaxis undergoing hemodialysis, 12 patients without evidence of calciphylaxis undergoing dialysis, eight patients with nephrotic syndrome, and eight normal healthy volunteers. Protein C antigen levels were measured by rocket immunoelectrophoresis, and functional activity was quantitated by a chromogenic assay and an anticoagulant assay utilizing the venom of Agkistrodon contortrix. RESULTS: Skin biopsy specimens of involved areas in three patients showed thrombotic occlusion of venules identical to that seen in warfarin-induced skin necrosis. Protein C antigen levels were normal in all groups. However, protein C activity was significantly reduced as measured by chromogenic (p less than 0.01) or anticoagulant assays (p less than 0.01) in patients with calciphylaxis compared with the other three groups. CONCLUSION: These findings suggest that hypercoagulability due to functional protein C deficiency may contribute to thrombosis, resulting in skin necrosis and digital gangrene in systemic calciphylaxis.

Captopril reduces urinary cystine excretion in cystinuria.

Cystinuria is characterized by cystine stone formation and loss of renal function. Conservative therapy is generally ineffective and penicillamine therapy can be complicated by serious side effects. To our knowledge, we report the first clinical use of captopril in the treatment of homozygous cystinuria in two siblings. In the first patient, a 70% reduction in cystine excretion was observed after 26 weeks of therapy with 150 mg/d of captopril. Discontinuation of use of the drug resulted in a return to baseline cystine excretion, further loss of renal function, and nephrotic range proteinuria. Repeated treatment with captopril stabilized renal function, reduced proteinuria, and returned cystine excretion to near normal levels. In the second patient, cystine excretion was reduced by 93% after nine weeks of therapy with 75 mg/d of captopril. No adverse side effects were observed in either patient. Formation of the captopril-cysteine disulfide accounts for part of the reduction in cystine excretion but other mechanisms probably contribute. Because captopril-cysteine disulfide is 200 times more soluble than cystine, long-term captopril therapy may be useful in the treatment of cystinuria.