Gerald A. Coles

Clinical Pharmacokinetics of Epoetin (Recombinant Human Erythropoietin)

SummaryEpoetin (recombinant human erythropoietin, EPO) is of proven benefit in the treatment of renal anaemia, and preliminary reports suggest that it may have a role in the management of other anaemic conditions. Pharmacokinetic and therapeutic studies have examined the use of epoetin administered intravenously, intraperitoneally and subcutaneously, and there is accumulating evidence that the last route has several advantages. After intravenous administration, epoetin is distributed in a volume comparable to the plasma volume, and plasma concentrations decay monoexponentially with a half-life of between 4 and 12 hours. Administration of epoetin in peritoneal dialysis fluid results in detectable concentrations in the bloodstream after 1 to 2 hours, and peak concentrations of the order of 2 to 4% of those obtained with the same intravenous dose are found after approximately 12 hours. The bioavailability of epoetin administered intraperitoneally in dialysis fluid is about 3 to 8%, but this may be increased by injecting the drug into a dry peritoneal cavity. Subcutaneous administration results in peak concentrations at about 18 hours which are 5 to 10% of those found after the same intravenous dose. The bioavailability of subcutaneous epoetin is about 20 to 30%, and detectable serum concentrations are still present 4 days after administration, in contrast to intravenous administration after which concentrations have returned to baseline within 2 to 3 days.Remarkably little is known about the metabolic fate of either erythropoietin or epoetin. In addition, there is much controversy surrounding the relative roles of the kidney and liver in the catabolism of epoetin. About 3 to 10% of epoetin is excreted unchanged in the urine. In common with other glycoproteins, the carbohydrate residues which constitute 40% of its molecular size are essential for maintaining the stability of epoetin in circulation. Desialated epoetin, although biologically active in vitro, is cleared very rapidly from plasma with resultant loss of activity. Further work is required, however, in identifying the pathways of metabolism and elimination of this glycoprotein hormone.

In vivo exposure to bicarbonate/lactate- and bicarbonate-buffered peritoneal dialysis fluids improves ex vivo peritoneal macrophage function

The impact on peritoneal macrophage (PMO) function of acidic lactate-buffered (Lac-PDF [PD4]; 40 mmol/L of lactate; pH 5.2) and neutral-pH, bicarbonate-buffered (TB; 38 mmol/L of bicarbonate; pH 7. 3) and bicarbonate/lactate-buffered (TBL; 25 mmol/L of bicarbonate/15 mmol/L of lactate; pH 7.3) peritoneal dialysis fluids (PDFs) was compared during a study of continuous therapy with PD4, TB, or TBL. During a run-in phase of 6 weeks when all patients (n = 15) were treated with their regular dialysis regimen with Lac-PDF, median PMO tumor necrosis factor alpha (TNFalpha) release values were 203.6, 89.9, and 115.5 pg TNFalpha/10(6) PMO in the patients subsequently randomized to the PD4, TB, and TBL treatment groups, respectively. Median stimulated TNFalpha values (serum-treated zymosan [STZ], 10 microgram/mL) were 1,894.6, 567.3, and 554.5 pg TNFalpha/10(6) PMO in the same groups, respectively. During the trial phase of 12 weeks, when the three groups of patients (n = 5 per group) were randomized to continuous treatment with PD4, TB, or TBL, median constitutive TNFalpha release values were 204.7, 131.4, and 155.4 pg TNFalpha/10(6) PMO, respectively. Stimulated TNFalpha values (STZ, 10 microgram/mL) were 1,911, 1,832, and 1,378 pg TNFalpha/10(6) PMO in the same groups, respectively. Repeated-measures analysis of variance comparing the run-in phase with the trial phase showed that PMO TNFalpha release was significantly elevated in patients treated with both TB (P = 0.040) and TBL (P = 0.014) but not in patients treated with Lac-PDF (P = 0. 795). These data suggest that patients continuously exposed to bicarbonate- and bicarbonate/lactate-buffered PDFs might have better preserved PMO function and thus improved host defense status.

Enalapril Can Treat the Proteinuria of Membranous Glomerulonephritis Without Detriment to Systemic or Renal Hemodynamics

The effect of enalapril on renal hemodynamics and glomerular permselectivity was studied in eight patients with nephrotic syndrome secondary to biopsy-proven membranous glomerulonephritis. The patients received the drug in incremental doses (median, 5 mg) until 24-hour urinary protein excretion had decreased persistently by 30%. Median treatment duration was 6 weeks. Patients were studied three times: (I) after a 4-week run-in period, (II) on the final day of treatment, and (III) after a 4-week wash-out. Median 24-hour urinary protein excretion decreased on treatment from 10.45 g/d to 5.25 g/d and increased to pretreatment levels after the drug was stopped (P less than 0.05 for both changes). Fractional clearance of dextrans greater than 4.1 nm decreased on treatment, indicating both a reduction of macromolecules passing through the shunt pathway of the glomerular basement membrane (GBM) and a possible decrease in ultrafiltration coefficient. There were no significant changes in glomerular filtration rate (GFR), effective renal plasma flow (ERPF), or mean arterial blood pressure (MAP) throughout the study. The effect of enalapril in treating proteinuria appears therefore to be due to a specific intraglomerular action.

Treating renal anaemia with recombinant human erythropoietin: practical guidelines and a clinical algorithm.

Treatment with erythropoietin is highly effective and beneficial if given with care. In view of its cost, however, it is essential to exclude and treat other causes of anaemia before considering using this hormone. After treatment is started the important points for success are regular review of iron availability state combined with a slow correction of the anaemia. Failure of response requires a thorough search for a possible cause, which should be corrected before considering an increased dose of the hormone. Regular monitoring for potential complications, particularly a rise in blood pressure, is required.

Proteinases and the glomerulus: Their role in glomerular diseases

SummaryDegradation of matrix in normal glomeruli occurs through the action of neutral metalloproteinases which are in turn regulated by specific inhibitors. Both of these proteins are secreted by mesangial cells. Macrophages and IL-1 enhance the secretion of the proteinase. Decreased production of the metalloproteinase and for increased secretion of its inhibitor may lead to matrix accumulation. Neutrophil serine paternases degrade glomerular basement membrane (GBM)in vitro. In both animal and human disease urine excretion of these enzymes is accompanied by proteinuria and the presence of GBM-fragments. Further knowledge of the processes involved in matrix degradation may lead to improved therapy of glomerular disease.

Rheological studies during treatment of renal anaemia with recombinant human erythropoietin

Summary. Whole blood, plasma, and serum viscosity together with red cell deformability were measured before and during treatment of renal anaemia with recombinant human erythropoietin (EPO). Whole blood viscosity (WBV) progressively increased during the first 4 months of treatment in association with the rise in haemoglobin concentration. When the WBV was corrected to a standard haemoglobin concentration no change in blood viscosity was observed, neither was there any alteration in a derived index of red cell deformability, or in the plasma and serum viscosities. In addition, a direct measurement of red cell deformability using a filtration technique before EPO therapy was similar to that obtained in 30 healthy volunteers. There was no significant change in this parameter over the first 9 months of treatment. The rheological changes which occur with correction of anzemia with EPO can be explained solely by the increase in circulating haemoglobin mass rather than to any change in the properties of the plasma or red cells themselves.

The use of erythropoietin in renal failure.

The treatment of renal anaemia by recombinant human erythropoietin (EPO) is now well established. Several studies have examined the pharmacokinetics and efficacy of the drug given intravenously, intraperitoneally and subcutaneously and there is increasing evidence that the subcutaneous route has several advantages including the requirement for a lower dose. It is also important to stress the need for careful determination of baseline iron status of all patients before commencing EPO therapy. In the long term the extremely high iron stores of transfusion dependent patients will disappear. In the short term, however, the majority of the patients whose serum ferritin is less than 100 micrograms/l will require iron supplementation to allow an appropriate haemoglobin response. Alternatively, a fall in transferrin saturation to less than 20% is certainly an indication for iron supplementation and if oral iron therapy is not adequate then intravenous preparations may have to be considered. Although the anaemia of renal failure can be fully corrected by EPO, partial correction may be sufficient to reverse the problems of reduced exercise capacity, myocardial ischaemia and cardiomegaly which are frequently associated with end-stage renal disease. Partial correction will also result in a lesser rise in whole blood viscosity and, in turn, possibly reduce hypertension, thrombosis and increased peripheral resistance and thus lessen the side effects of EPO therapy.

The significance of monocytes in glomeruli of human renal transplants.

A total of 50 biopsies from 42 renal transplants obtained during a 30-month period were studied for the presence of monocytes in the glomeruli using the nonspecific esterase reaction. Eleven biopsies from ten grafts were positive. Immune deposition was light or absent. The prognosis for the grafts containing glomerular monocytes was significantly worse during the six months after the biopsy than for those without such cells present.

Host defence and effects of solutions on peritoneal cells

It is general experience that some patients receiving long-term peritoneal dialysis suffer from repeated episodes of peritonitis while others remain relatively free of this complication. It has been suggested that differences in the ability of individual subjects to resist infection, i.e., their host defence, are at least partly responsible for this clinical observation. This hypothesis was strengthened by the report by Verbrugh et al. on the potential efficacy of peritoneal macrophages and opsonins in the antibacterial defence of such patients [1]. In this chapter we review the available evidence on the various components of host defences of peritoneal dialysis patients including the effect of the dialysate.

Permselectivity in thin membrane nephropathy.

The glomerular permselectivity to polydisperse neutral dextrans was compared in 6 patients with thin membrane nephropathy (TMN) and 10 healthy controls. Despite having normal renal hemodynamics and minimal proteinuria, the patients with TMN had significantly increased fractional clearance of neutral molecules with Stokes radius > 42 A. Conventional theories of glomerular barrier size selectivity cannot fully explain these data since they would predict that our patients would have had nephrotic range proteinuria.