G. A. Verpooten

The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation

Mycophenolate mofetil, a pro‐drug for mycophenolic acid, reduces the likelihood of allograft rejection after renal transplantation. We studied the relationship between mycophenolic acid pharmacokinetics and the likelihood of rejection in a randomized concentration‐controlled trial.

Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients

BACKGROUNDnAdynamic bone disease was recently described to be increasingly prevalent in the dialysis population. At present the diagnosis of this type of renal osteodystrophy can only be made by bone histomorphometry. We assessed the value of different biochemical serum markers in the diagnosis of adynamic bone disease.nnnMETHODSnIn 103 haemodialysis patients a bone biopsy was performed after double tetracycline labelling, and the serum levels of intact PTH, osteocalcin, and the bone isoenzyme of alkaline phosphatase were determined. Bone alkaline phosphatase was measured by an optimized agarose gel electrophoretic method, recently shown to have a high accuracy, precision and reproducibility, also in the lower range.nnnRESULTSnIn 38 (37%) of the patients the diagnosis of adynamic bone disease was histologically established. Constructing receiver operator curves optimal cut-off levels for the diagnosis of adynamic bone disease were determined, being <=27 U/litre for the bone isoenzyme of alkaline phosphatase, <=14 microg/litre for osteocalcin and <=150 pg/ml for intact PTH. Concentrations of bone alkaline phosphatase or intact PTH below these cut-off levels, were shown to be the best performing tests in the detection of adynamic bone disease as indicated by a sensitivity of 78.1 and 80.6% and a specificity of 86.4 and 76.2% respectively. Applying Bayes theorema, it was calculated that in the current haemodialysis population in which a prevalence of adynamic bone disease up to 35% has been described, the positive predictive values for the proposed cut-off values are 75% for bone alkaline phosphatase, 65% for intact PTH and 55% for osteocalcin. Moreover, in this population, levels of bone alkaline phosphatase and intact PTH below the optimal cut-off excluded hyperparathyroid bone disease.nnnCONCLUSIONnIn view of the relative easy and accurate methodology for bone alkaline phosphatase determination, the closer physiological link with osteoblast function and the lesser expense for its determination we suggest that this marker is a useful tool in the non-invasive diagnosis of the adynamic type of bone disease in the individual patient.

Once‐daily dosing decreases renal accumulation of gentamicin and netilmicin

The pathogenesis of aminoglycoside nephrotoxicity is intimately related to the extent of drug accumulated in the renal cortex. In the framework of searching for preventive measures of aminoglycoside‐induced nephrotoxicity, we investigated the influence of dosage regimen on the renal cortical accumulation of gentamicin and netilmicin in humans. Patients with a tumor partly involving one kidney, with normal renal function, and scheduled for nephrectomy received one dose of either gentamicin (4.5 mg/kg) or netilmicin (5 mg/kg) as a single short‐term infusion or as 24‐hour continuous infusion. Treatment started 24 hours before surgery. Serum aminoglycoside pharmacokinetics were examined during treatment and renal cortical tissue was sampled at the moment of operation for drug determination. The short‐term infusion schedule yielded cortical concentrations of 103.2 ± 36.3 and 137.4 ± 34.6 µg/gm for gentamicin and netilmicin, respectively. Tissue levels after continuous infusion were 158.1 ± 52.9 and 178.5 ± 21.8 µg/gm for gentamicin and netilmicin, respectively. For each aminoglycoside, a single short‐term infusion resulted in significantly lower renal drug levels than did a continuous infusion of the same dose. From the nephrotoxicity point of view, these data support the administration of gentamicin and netilmicin as once‐daily injections. This also supports the appropriateness of further studies to determine clinical efficacy of once‐a‐day dosing for aminoglycosides.

Fibrous intimal thickening at implantation as a risk factor for the outcome of cadaveric renal allografts.

BACKGROUNDnDuring the past decade, the donor age of cadaveric renal allografts steadily increased. Because cerebrovascular injury is the main cause of death in this donor population, an increased prevalence of atherosclerotic lesions in the retrieved grafts could be anticipated. In a prospective study, we investigated the predictive value of morphologic lesions at implantation for the functional and morphologic outcome of cadaveric renal allografts at 1 1/2 years.nnnMETHODSnIn 50 consecutive adult recipients of a cadaveric renal allograft, under cyclosporine-based regimen, implantation biopsies and subsequent protocol biopsies at 18 months were performed, and morphometrically analyzed for the extent of glomerulosclerosis, interstitial fibrosis, and atherosclerosis. Risk factors were assessed at implantation and during the subsequent observation period of 18 months. Endpoints for this study were: the 24-hr creatinine clearance (normalized for body surface area) and the fractional interstitial volume at 1 1/2 years.nnnRESULTSnIn multivariate analysis, fibrous intimal thickening at implantation (FIT) was the main determinant of the functional and morphologic outcome at 1 1/2 years. FIT represented a relative risk of 4.55 for interstitial fibrosis (95% CI=1.855-11.138), and 1.89 for impaired renal function (95% CI=1.185-3.007) at 1 1/2 years. FIT adversely affected fractional interstitial volume at 1 1/2 years (34.3 vs. 27.7%, P=0.004), as well as renal function (54 vs. 68 ml/min/1.73 m2, P=0.028).nnnCONCLUSIONSnFibrous intimal thickening at implantation is a determinant risk factor for the functional and morphologic outcome of cadaveric renal allografts at 1 1/2 years.

Elevated plasminogen activator inhibitor levels in cyclosporin-treated renal allograft recipients

Atherosclerosis and thrombosis, two major causes of morbidity and mortality in renal transplant recipients, share the same clinical risk factors including decreased fibrinolysis and lipid disturbances. In a cross-sectional study we have determined parameters of fibrinolysis in control subjects (n = 23) and stable renal allograft recipients without cyclosporin (CsA) (n = 10) and with CsA (n = 87) in their immunosuppressive treatment. In CsA-treated patients, tissue-type plasminogen activator was moderately increased compared to patients without CsA (8.4+/-3.3 vs 5.5+/-2.8 ng/ml). The plasminogen activator inhibitor (PAI) activity in plasma was clearly increased in CsA-treated patients: 14.5+/-8.8 vs 7.2+/-3.2 in normal controls and 8.5+/-2.4 AU/ml in patients without CsA. Total cholesterol and LDL cholesterol levels were higher in CsA-treated patients (256+/-62 and 169+/-60 mg/dl) than in patients without CsA (209+/-45 and 136+/-44 mg/dl). The two groups did not differ in HDL cholesterol, triglycerides, and lipoprotein(a). Hypercholesterolaemia, obesity, and steroid-induced diabetes could be identified as risk factors for elevated plasma PAI activity in CsA-treated patients. Hypofibrinolysis induced by elevated PAI levels and increased LDL cholesterol may contribute to the increased thrombogenicity and accelerated atherosclerosis observed in cyclosporin-treated patients.

Combined hemoperfusion-hemodialysis in severe poisoning: Kinetics of drug extraction

We studied the kinetics of drug extraction during a combined hemoperfusion-hemodialysis procedure for treatment of severely poisoned patients. In most drugs studied an overall clearance of 120-180 ml/min (at a blood flow of 200 ml/min) was obtained, the relative contribution of hemoperfusion and hemodialysis being variable. A one-compartment pharmacokinetic model is presented that allows calculation of the optimal treatment time as a function of the extracorporeal clearance and the distribution volume of the toxic agent. For some drugs two-compartment kinetics were observed during treatment. The behaviour during treatment of these drugs is illustrated with computer simulation.

Improved procedure for extracting aminoglycosides from renal cortical tissue.

An efficient and reproducible procedure was developed for extracting aminoglycosides from renal cortical tissue. It involves a double homogenization and two rinsings with trichloroacetic acid. A higher recovery is obtained compared with that of other previously reported methods.

Renal cortical kinetics of gentamicin after implantation of gentamicin-polymethylmethacrylate beads in rats.

Beads of gentamicin-polymethylmethacrylate (Septopal), each containing 4.5 mg of gentamicin base, were implanted intraperitoneally in rats. Each rat received one bead. Serum levels and urinary excretion of gentamicin were maximal in the first day of treatment (0.6 micrograms/ml in serum 3 h after implantation of the bead and 525 micrograms per 24-h urine sample) and decreased thereafter. Kidney cortical concentrations of gentamicin progressively increased and peaked after 4 days, reaching 117 micrograms/g. Tissue levels decreased thereafter in spite of the persistence of the drug in urine, and this occurred in the absence of cell damage leading to cell death. Release of gentamicin from intact proximal tubular cells, despite continuous uptake, prevented intracellular drug concentrations from reaching a nephrotoxic level. This experimental study provides a rational basis for the previous clinical observation that nephrotoxicity due to treatment with gentamicin-polymethylmethacrylate beads is improbable.

Functional Acute Renal Failure in a Patient with Carcinoid Syndrome

Acute renal failure occurred in a patient with a carcinoid syndrome whenever he developed a flushing episode. Renal biopsy performed during one of these oliguric episodes did not reveal any lesions which could explain this reversible form of renal insufficiency. Urinary indices were not conclusive. Alteration of intrarenal hemodynamics by vasoactive compounds is proposed to be the causative mechanism of this relapsing acute oliguric renal failure.

Pharmacokinetics of neoral before and after total gastrectomy in a renal transplant patient

ABUNDANT information is available about improved gastrointestinal absorption of the newer form of Cyclosporine CsA, Neoral, compared with the older formulation, Sandimmun. However, no studies have investigated the possibility that an abnormal gastrointestinal tract could influence the absorption of Neoral (N). Because N absorption and pharmacokinetic profiles after a gastrectomy (Gx) have not yet been described, we present a case of altered absorption of N in the early post-Gx period with an even more remarkable restoration of absorption at 1 year post-Gx.