The role of tenofovir alafenamide in future HIV management.

HIV infection has become a chronic condition rather than an acute life-threatening disease in developed countries, thanks to consistent innovation and evolution of effective interventions. This has altered HIV management and created new challenges. People living with HIV (PLWHIV) are living longer and so encounter comorbidities linked not only with their disease, but also with ageing, lifestyle and chronic exposure to antiretroviral therapy (ART). Although longevity, viral suppression and the prevention of viral transmission remain key goals, more needs to be achieved to encompass the vision of attaining an optimum level of overall health. Treatment choices and management practices should ensure patients' long-term health with minimal comorbidity. Treatments that balance optimal efficacy with the potential for improved long-term safety are needed for all patients. In this review, we consider the evolution and development of tenofovir alafenamide (TAF), a novel prodrug of tenofovir which offers high antiviral efficacy at doses over ten times lower than that of tenofovir disoproxil fumarate (TDF). Emerging clinical data suggest that elvitegravir, cobicistat, emtricitabine and TAF (E/C/F/TAF) as a single-tablet regimen offers highly effective viral suppression in treatment-naïve and treatment-experienced patients with an improved renal and bone safety profile compared with TDF, this having been demonstrated in diverse groups including patients with existing renal impairment and adolescents. The profile of TAF identifies it as an agent with a promising role within future ART regimens that aim to deliver the vision of undetectable viral load, while requiring less monitoring and having a safety profile designed to minimize comorbid risks while supporting good long-term health.

Spectrum of chronic kidney disease in HIV-infected patients.

OBJECTIVES: The aim of the study was to investigate the prevalence and aetiology of chronic kidney disease (CKD) and trends in estimated glomerular filtration rate (eGFR) in HIV-infected patients. METHODS: Ascertainment and review of CKD cases among patients attending King's College and Brighton Hospitals, UK were carried out. CKD was defined as eGFR <60 mL/min for > or =3 months. Longitudinal eGFR slopes were produced to examine trends in renal function before, during and after exposure to indinavir (IDV) or tenofovir (TFV). RESULTS: CKD prevalence was 2.4%. While HIV-associated nephropathy accounted for 62% of CKD in black patients, 95% of CKD in white/other patients was associated with diabetes mellitus, hypertension, atherosclerosis and/or drug toxicity. Exposure to IDV or TFV was associated with an accelerated decline in renal function (4.6-fold and 3.7-fold, respectively) in patients with CKD. In patients initiating IDV, age > or =50 years increased the odds of CKD [odds ratio (OR) 4.9], while in patients initiating TFV, age > or =50 years (OR 5.4) and eGFR 60-75 mL/min (OR 17.2) were associated with developing CKD. CONCLUSION: This study highlights the importance of metabolic and vascular disease to the burden of CKD in an ageing HIV-infected cohort. In patients who developed CKD, treatment with IDV or TFV was associated with an accelerated decline in renal function.

Treatment-limiting renal tubulopathy in patients treated with tenofovir disoproxil fumarate.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is widely used in the treatment or prevention of HIV and hepatitis B infection. TDF may cause renal tubulopathy in a small proportion of recipients. We aimed to study the risk factors for developing severe renal tubulopathy. METHODS: We conducted an observational cohort study with retrospective identification of cases of treatment-limiting tubulopathy during TDF exposure. We used multivariate Poisson regression analysis to identify risk factors for tubulopathy, and mixed effects models to analyse adjusted estimated glomerular filtration rate (eGFR) slopes. RESULTS: Between October 2002 and June 2013, 60 (0.4%) of 15,983 patients who had received TDF developed tubulopathy after a median exposure of 44.1 (IQR 20.4, 64.4) months. Tubulopathy cases were predominantly male (92%), of white ethnicity (93%), and exposed to antiretroviral regimens that contained boosted protease inhibitors (PI, 90%). In multivariate analysis, age, ethnicity, CD4 cell count and use of didanosine or PI were significantly associated with tubulopathy. Tubulopathy cases experienced significantly greater eGFR decline while receiving TDF than the comparator group (-6.60 [-7.70, -5.50] vs. -0.34 [-0.43, -0.26] mL/min/1.73 m2/year, p < 0.0001). CONCLUSIONS: Older age, white ethnicity, immunodeficiency and co-administration of ddI and PI were risk factors for tubulopathy in patients who received TDF-containing antiretroviral therapy. The presence of rapid eGFR decline identified TDF recipients at increased risk of tubulopathy.

The blockage of the electrical conductance in a pore-containing membrane by the n-alkanes.

1. In monooelein bilayers made highly conducting by the addition of a fixed amount of o-pyromellitylgramicidin, the membrane conductance has been shown to be strongly dependent on the chain length of the n-alkane with which the membrane is in equilibrium. Thus for n-hexadecane, the conductance is larger by approx. 10(4) times than it is for n-octane. This result is independent of whether the polypeptide is introduced via the aqueous or lipid phases. 2. The observed conductance variations have been accounted for in terms of a mechanism (outlined in earlier publications) which is based on the thickness and tension changes produced in bilayers by the adsorption of n-alkanes. Essentially quantitative agreement between theory and experiment is found.

Transplant renal artery stenosis in 77 patients--does it have an immunological cause?

Transplant renal artery stenosis (TRAS) is a common complication after transplantation and is an important cause of graft dysfunction. Damage from graft rejection, trauma, and atherosclerosis have been implicated as possible causes. We reviewed all 917 patients transplanted in our unit since 1978 to study the prevalence, clinical features, and possible causes of TRAS. Seventy-seven patients with TRAS were identified. The detected incidence was 2.4% before the introduction of color doppler ultrasonography (CDU) and rose to 12.4% after CDU was introduced in 1985, giving an overall incidence of 8.4% during a mean follow-up period of 6.9 years. The TRAS group was compared with a control group of 77 transplanted patients matched for age, year of transplant, sex, and number of previous grafts. Mean ages for the study and control groups were 43.6 +/- 15 and 44.8 +/- 13.7 yr. A total of 25% of cases of TRAS were diagnosed within the first 8 wk of transplantation and in 60% within the first 30 wk (median = 23 wk). All patients were treated with angioplasty, 28 patients had recurrence of TRAS requiring multiple angioplasties (maximum 5) and 1 went on to have surgery. Angioplasty resulted in a significant fall in plasma creatinine. Patient and graft survival were significantly worse in the TRAS group: 69% vs. 83% (P < 0.05) and 56% vs. 74% (P < 0.05) (TRAS vs. Control), respectively. There was a significantly higher incidence of rejection, especially cellular rejection in the TRAS group, 0.67 vs. 0.35 episodes per patient (P < 0.01) (TRAS vs. Control). Recurrence but not occurrence of TRAS was associated with the use of cyclosporine.

The effects of external and internal application of disopyramide on the ionic currents of the squid giant axon.

1 The actions of the class I anti-arrythmic agent, disopyramide, on the ionic currents of the voltage-clamped squid axon have been investigated, by use of both extra-axonal and intra-axonal routes of application. 2 Extra-axonal application of 0.1 mM disopyramide produced no significant effects on the membrane currents. External disopyramide at 1.0 mM caused small, poorly reversible inhibition of both sodium and potassium currents. This block was use-dependent and was enhanced by use of test stimuli to more positive membrane potentials. 3 Intra-axonal application of 0.1 mM disopyramide caused a 40% reduction in the first-pulse sodium current (tonic block) and an additional use-dependent block. Analysis of first-pulse currents in terms of the Hodgkin-Huxley formalism indicated that the block resulted mainly from a reduction in the maximum available sodium conductance (gNa); there were no effects on the voltage dependence of the steady-state activation and inactivation parameters, m infinity and h infinity. 4 The use-dependent actions of disopyramide were investigated with a double voltage-clamp pulse protocol. The significant use-dependent effects of the drug were a further reduction in gNa and an increase in the time constant of inactivation (tau h). 5 Disopyramide appears to enter a blocking site in the sodium channel which is only readily accessible from the axoplasmic phase. Partition to the site depends on membrane voltage and on the state of the channel gates. Disopyramide binds at a significant rate to both open and inactivated forms of the sodium channel.

Effects of anesthetics and convulsants on the resting potassium conductance in squid nerve.

The effects of some fluorinated anesthetics and convulsants on the ionic conductances of the axon membrane of the squid Loligo forbesi are described. The substances studied were the inhalation anesthetics enflurane (CF2HOCF2CClFH) and isoflurane (CF2HOCClHCF3) and the convulsants flurothyl (CF3CH2OCH2CF3) and trichlorofluormethane (CCl3F). At low concentrations (0.4-0.8 mM), none of these substances significantly affected the voltage-dependent Na and K channels of the nerve. However, at these concentrations each substance produced a depolarization of the resting potential and reduced the potassium conductance of the resting membrane. This was associated with a tendency to cause axonal hyperexcitability. The potassium conductance of the resting membrane was separated into a component arising from residual open Hodgkin-Huxley delayed rectifier K channels and another voltage-independent component (g'k). The former component was insensitive to the test substances at 0.4-0.8 mM, while g'k was inhibited by 40-80%. It is suggested that the convulsant activity of certain small fluorinated molecules, and the proconvulsant actions of certain clinical anesthetics at low concentrations, may be related to the inhibition of a resting, voltage-independent potassium conductance system in the nerve membrane.

HIV-associated renal disease in London hospitals.

We report experience from London hospitals which further illustrates the heterogeneous nature of HIV-associated nephropathy (HIVAN). Nineteen HIV-positive patients underwent renal biopsy from 1992 to 1994. Fourteen were male, five female. Eleven were Afro-Caribbean, 7 Caucasian and 1 Asian. Eleven patients had classical HIVAN with proteinuria, rapidly progressive renal failure and features of focal and segmental glomerulosclerosis (FSGS) on renal biopsy, and three of these had associated tubulo-interstitial nephritis (TIN). One further patient had TIN and tubular changes suggestive of HIVAN but no glomeruli were present in the biopsy. Other biopsy findings were of focal proliferative glomerulonephritis and TIN (1 patient), pauci-immune crescentic glomerulonephritis and TIN (1 patient), membranous nephropathy (1 patient), membranoproliferative nephropathy (1 patient) and haemolytic uraemic syndrome (2 patients). Of 11 patients with FSGS, seven died with median survival of 8 months (range 23 days-46 months) and five are still alive after median follow-up of 18 months (range 10-22 months). Of patients with glomerular disease other than FSGS, five died, with median survival of 3 months (range 1-27 months) and two have survived (10 and 27 months, respectively). Thirteen patients had renal failure, 10 of whom had FSGS. In 10 cases renal failure was acute and in two was the presenting feature of HIV infection. Thirteen patients underwent renal replacement therapy. Four received haemodialysis, and all died within one month. Nine patients received CAPD. Two were able to discontinue dialysis. Of the remaining seven, five died with median survival of 8 months (range 1.3-40 months) and two are alive 1 and 10 months after beginning dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

CMV infection is associated with transplant renal artery stenosis.

Transplant renal artery stenosis (TRAS) is a significant cause of graft dysfunction, with no clearly defined aetiology. Evidence suggests a role for cytomegalovirus (CMV) infection in cardiac transplant vasculopathy and in native coronary artery restenosis after angioplasty. We investigated the relationship between CMV infection after renal transplantation and subsequent development of TRAS. Of 917 patients receiving renal transplants at a single centre from 1978 to 1994, 75 had TRAS diagnosed by angiography. Each was paired with a control transplanted patient with no TRAS, matched for age, sex, year of transplant and number of grafts. Incidence of CMV infection between transplantation and the time of diagnosis of TRAS was assessed in both groups, using clinical and serological criteria to assign patients to three groups: definite CMV infection (CMV-DEF), possible infection (CMV-POSS) and no evidence of infection (CMV-NUL). CMV-DEF was significantly more common in TRAS than in controls (36 vs. 12, respectively, p < 0.001) and CMV-NUL was less common (TRAS 15, controls 33). We have previously reported an increased incidence of acute rejection in patients with TRAS. The subset of patients with no rejection episodes also had significantly more CMV-DEF cases in the TRAS group (54%) than in controls (10%) (p = 0.002). The data are consistent with the hypothesis that CMV infection can contribute to the development of TRAS. The relationship between CMV and TRAS did not arise from an excess of anti-rejection treatment in the TRAS group. CMV-induced large-vessel damage in immunosuppressed patients may occur through local infection and the mitogenic actions of viral gene products within cells of the vessel wall.

Modelling and costing the consequences of using an ACE inhibitor to slow the progression of renal failure in type I diabetic patients.

Antihypertensive drugs slow the progressive decline in renal function seen in patients with insulin-dependent diabetes and nephropathy. In a recent study, the ACE inhibitor captopril protected against this deterioration in renal function. We developed an economic model to analyse the cost impact of ACE inhibitor treatment on progression to endstage renal failure (ESRF) in diabetic patients over 4 years. Two scenarios were compared: one describing the progression of a cohort of 1000 patients receiving 25 mg captopril three times daily, and the other for an equivalent cohort without such prophylactic treatment. Previously published data were used to estimate the transition rates for each stage from the onset of renal failure until death. All direct costs were discounted by an annual rate of 6%, and were subjected to sensitivity analysis. The discounted cost saving of ACE inhibitor treatment for a cohort of 1000 patients was estimated as 0.95 million pounds over 4 years. Under sensitivity analysis, these results were very robust to variations in the costs of ESRF treatment. Prophylactic treatment with ACE inhibitors was predicted to provide substantial increases in life expectancy and reduction in the incidence of ESRF, while also providing significant economic savings.

Presentation, clinical features and outcome in different patterns of atherosclerotic renovascular disease.

Atherosclerotic renovascular disease (ARD) is an increasingly important cause of renal failure. However, important features of the clinical presentation are not fully described, and the outcome after intervention by angioplasty remains controversial. Ninety-four patients with ARD diagnosed at angiography were reviewed. Twenty-four patients were diabetic. Thirty-nine patients had unilateral renal artery stenosis or occlusion (group A), 28 had bilateral stenosis (group B), and 27 had unilateral occlusion plus contralateral occlusion or stenosis (group C). Two years after presentation, actuarial patient survival was 96%, 74.3% and 47.1% in groups A, B and C, respectively (p < 0.001 for all differences); actuarial renal survival in surviving patients was 97.3%, 82.4% and 44.7%, respectively (p < 0.001 for all differences). Percutaneous transluminal balloon angioplasty (PCTA) was performed in 74 patients. Renal function improved in only a minority of cases, but was stable in 73% of nondiabetic patients 12 months after PCTA. Angioplasty was less effective in diabetic subjects, with only 53.3% having stable renal function at 12 months follow-up. Renal and patient survival were strongly related to the initial angiographic findings. In non-diabetic subjects, PCTA resulted in stabilization of renal function for at least one year in nearly three-quarters of cases, which suggests a benefit from intervention in this disease whose natural history is otherwise of progression.

Actions of arachidonic acid on erythrocyte membrane Rb permeability.

The effects of non-esterified arachidonic acid (AA) on erythrocyte membrane ion permeability have been studied using 86Rb flux measurements. [14C]AA was used to quantify membrane incorporation of AA and to show AA removal by albumin washing. The actions of vitamin E and other antioxidants on the effects of AA were examined. Reversible membrane incorporation of 700-2000 nmol AA per ml cells was achieved without significant haemolysis or morphological change. AA incorporation caused a reversible mean increase in bumetanide-sensitive Rb influx of 34% (S.E.M. 4.5, n = 23). This action could be partially prevented by co-incubation with vitamin E, but not by Trolox or dithioerythritol. AA incorporation caused an irreversible mean increase in residual Rb permeability (bumetanide and ouabain insensitive) of 130% (S.E.M. 22, n = 20), associated with a rise in intracellular Na and a fall in intracellular K concentrations. This action was also partially prevented by co-incubation with vitamin E. The effects of AA incorporation on Na,K-ATPase function were difficult to quantify because of the concomitant rises in intracellular Na but the data are consistent with approximately 20% inhibition of activity. Modulation of membrane ion permeability by AA appears to be partially mediated by lipid peroxidation and may have pathophysiological significance.

Effects of membrane incorporation of short-chain phospholipids on sodium pump function in human erthrocytes.

Erythrocyte membrane incorporation of exogenous short-chain diacyl phosphatidylcholines (PC) has been quantified by gas chromatography of fatty acid methyl esters of extracted membrane lipids after incubation of cells with sonicated aqueous suspensions of PC. The PCs studied included didecanoyl PC (C10-PC), dilauroyl PC (C12-PC), dimyristoyl PC (C14-PC) and dipalmitoyl PC (C16-PC). PC incorporation of 10-15 mol% was achieved by incubation at 37 degrees C for 0.5-24 h. Control cells incubated in saline alone showed a progressive reduction in endogenous polyunsaturated acyl chain content. Incubation with C10-PC and C16-PC was associated with reductions in membrane cholesterol. Experiments were performed with mixtures of PC and cholesterol in order to minimise this effect. Short-chain PC incorporation was associated with increases in intracellular Na+ and reduced intracellular K+ concentrations. Sodium pump activity was measured as the ouabain-sensitive rate of 86Rb+ influx and was significantly reduced by all PCs tested; mean reductions were 13-30%. These results confirm that the sodium pump in situ is sensitive to lipid acyl chain composition.

The effects of tert-butyl hydroperoxide on human erythrocyte membrane ion transport and the protective actions of antioxidants.

The oxidising actions of tert-butyl hydroperoxide (tBH) (0-3 mmol/l) on human erythrocyte membrane ion transport have been studied using measurements of 86Rb+ influx. Ouabain and bumetanide were used to distinguish Rb+ flux via the sodium pump (Na,K-ATPase), Na,K,2Cl cotransporter and through residual membrane permeability. The protective actions of antioxidants and related molecules (vitamin E, vitamin E acetate, Trolox, butylated hydroxytoluene (BHT) and dithioerythritol (DTE) were studied. The effects of tBH were concentration dependent and the mean residual (ouabain and bumetanide insensitive) Rb+ permeability was increased by a factor of 8.5 (S.E.M. 2.2, n = 15) by a 5-min exposure to 2 mmol/l tBH. This action was almost completely prevented by co-incubation with Trolox or BHT, and partially prevented by the presence of vitamin E or DTE. Incubation with 2 mmol/l tBH for 5 min increased intracellular Na+ by a factor of 1.8 (S.E.M. 0.1, n = 8) and reduced intracellular K+ by a factor of 0.93 (S.E.M. 0.03, n = 8). These effects were prevented by Trolox and partially prevented by vitamin E, whereas DTE and vitamin E acetate were ineffective. Incubation with 2 mmol/l tBH for 5 min reduced the mean apparent sodium pump Vmax by 43% (S.E.M. 4, n = 8). This effect was completely prevented by Trolox and partially prevented by vitamin E. Vitamin E acetate had no effect. The mean bumetanide-sensitive Rb+ influx via the Na,K,2Cl cotransporter was reduced by 30% (S.E.M. 8.7, n = 25) by a 5-min exposure to 2 mmol/l tBH. This action was variable and no significant actions of the antioxidants studied could be demonstrated. This study suggests that tBH-mediated oxidative damage occurs from a hydrophilic site and involves increased non-selective membrane cation permeability and inhibition of specific transport systems.

Effects of HMG-CoA reductase inhibition on erythrocyte membrane cholesterol and acyl chain composition.

The effects of 2 months treatment with simvastatin (40 mg, 20 mg p.o. daily) or placebo on erythrocyte membrane cholesterol content and acyl chain composition have been studied in 36 patients with a clinical history of atherosclerosis enrolled in the Oxford Cholesterol Study. All patients received advice corresponding to a standard phase 1 cholesterol-lowering diet. As expected the mean serum total cholesterol fell substantially (-26.5%, 20 mg simvastatin, P < 0.05; -32.7%, 40 mg simvastatin, P < 0.05) compared to placebo (-6.3%, ns). However, mean erythrocyte cholesterol content did not change significantly in any group (2 months therapy: 20 mg simvastatin, -0.62%; 40 mg simvastatin, +2.2%; placebo, -4.2%). Erythrocyte cholesterol was also unaltered after 5 months of therapy. Erythrocyte osmotic fragility was unchanged in the treatment and placebo groups. In the placebo group dietary advice alone was associated with a significant increase in the linoleic acid content of erythrocytes from 9.4 mole% of total acyl chains to 11.8 mole% (P < 0.05). Treatment with simvastatin was associated with an increase in the arachidonic acid content of the erythrocyte membrane from 12.2 to 15.3 mole% (P < 0.05). Treatment with simvastatin does not alter erythrocyte cholesterol content, but does alter acyl chain distribution. These results suggest that the chemical potential of cholesterol in serum is not markedly altered by HMG-CoA reductase inhibition.

Heterogeneous calcium responses to extracellular ATP in cultured rat renal tubule cells.

There is increasing evidence that extracellular ATP acting on purinoceptors may play an important signalling role in renal epithelial cells, often through alterations in cellular Ca(2+). In this paper effects of extracellular ATP and related purinoceptor agonists and antagonists on [Ca(2+)](i) have been studied in single cells from primary cultures of rat proximal tubule cells. Responses to 1--100 micromol/l ATP were heterogeneous; 55% of cells showed a transient rise in [Ca(2+)](i), 20% of cells showed a transient fall; in 25% there was no response. ATP actions on [Ca(2+)](i) were abolished by pre-treatment with thapsigargin. The P(2) receptor antagonist suramin unexpectedly increased the [Ca(2+)](i) response to ATP; the related antagonist XAMR 0721 did not significantly alter ATP responses. This difference is likely to arise from the inhibition of ATP hydrolysis by suramin. UTP, ADP and the non-hydrolyzable ATP analogue adenosine-5'-O-(3-thio)-triphosphate (ATP gamma S)produced similar increases in [Ca(2+)](i). The magnitude of the [Ca(2+)](i) responses to 100 micromol/l agonist gave an agonist potency order of ATP> or =ADP> or =UTP approximately ATP gamma S. Desensitisation experiments demonstrated the presence of more than one P2Y ATP receptor subtype on a single cell. These results are consistent with the expression of purinoceptors of both P2Y(1) and P2Y(2) subclasses on individual rat proximal tubule cells coupled to inositol trisphosphate-mediated release of intracellular calcium stores.

Haemodialyser biocompatibility and erythrocyte structure and function.

There is controversy as to the clinical importance of providing haemodialysis (HD) with biocompatible versus non-biocompatible membranes. The effects of both acute and chronic dialysis with a biocompatible membrane (polyacrylonitrile, PAN) and a non-biocompatible membrane (cuprophane, CU) on the structural and functional properties of human erythrocytes have been examined. All 27 studied HD patients had increased erythrocyte osmotic fragility (OF) compared to controls; a single CU HD decreased mean OF (% lysis) by 13% without altering cell cholesterol. A single PAN HD decreased OF by a significantly greater amount (24%) and was associated with a 20% reduction in cell cholesterol. Chronic PAN HD for 6 months was associated with a sustained reduction in osmotic fragility compared to chronic CU HD (mean lysis 16% vs 45%) with no differences in mean pre-HD cell cholesterol. A single CU HD was associated with increased mean erythrocyte malonyldialdehyde (MDA) and reduced membrane content of spectrin and band 3 and this was significantly different from the effects of PAN. A single CU or PAN HD had no significant action on reduced glutathione (GSH), ankyrin, actin or sodium pump activity. Chronic HD was associated with increased GSH, and decreased ankyrin and band 3 protein compared with controls but the results for CU and PAN were not different. There was a non-significant tendency for higher MDA levels after chronic CU HD compared to PAN. These results indicate that the structural integrity of erythrocytes is improved by PAN HD with respect to CU but this difference cannot easily be ascribed to gross changes in structural proteins, ionic homeostasis or oxidation status.

Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient.

We report the case of a man who took two overdoses of aspirin, on each occasion suffering a grand mal fit with blood levels of salicylate of over 5 mmol/l. The first event was treated with hemodialysis but without effective alkalinization, and the second with alkalinization but without hemodialysis. The rate of decline in salicylate concentration was faster with alkalinization in the first 4 hours. Similar salicylate levels were achieved with both techniques by 24 hours post-overdose. If a case of salicylate poisoning is to be treated with hemodialysis, treatment with alkalinization should still be given without delay, in order to prevent acidemia and to promote elimination of as much salicylate as possible via the kidneys.

The influence of recipient and donor age on the outcome of renal transplantation.

This paper assesses the impact of age on the outcome of cadaveric renal transplantation. Data are presented on 99 consecutive patients undergoing first renal allografts at one unit. Patients are divided into those aged less than 50 (n = 53), patients between 50 and 60 (n = 16), and those aged 60 years and over (n = 30). There was no significant difference in graft survival at one year between the three groups. There was however an increased mortality with increasing recipient age (1.9%, 12.5% and 20.0% respectively for each age group). The effect of increasing donor age on graft survival was also studied. Graft survival at two years for first grafts was not influenced by donor age. We conclude that age alone is not a criterion for exclusion of patients from transplant programs. In addition we provide data to support the use of elderly donors as a potential source of cadaveric renal grafts for certain patients.

The pharmacokinetics of anti-thymocyte globulin (ATG) following intravenous infusion in man.

The pharmacokinetics of the distribution and elimination of polyclonal rabbit antithymocyte globulin (ATG) following intravenous infusion was studied in patients who had received renal allografts. ATG concentration was measured using a new enzyme-linked immunoabsorbent assay (ELISA) for the Fc portion of rabbit IgG. Eleven patients received 14 courses of ATG supplied either by Fresenius (F-ATG) or Merieux (M-ATG) as a daily infusion of 2-6 mg/kg body weight for a therapeutic course lasting 5-10 days. The washout phase of ATG elimination was analysed over 0-300 days; results were well-fitted by a single exponential decay (r2 > 0.95) giving a mean elimination half-life (t0.5e) of 29.8 days (range 14.3-45.0, n = 9). Data for the first 4 days of treatment were analysed with linear regression to obtain a mean value for the apparent volume of distribution of ATG (Vd) of 0.12 l/kg body weight (range 0.07 to 0.17, n = 5). These results demonstrate that rabbit ATG has a long half-life in human plasma and an apparent volume of distribution of about twice plasma volume. The relationship between the concentration of ATG measured by this Fc receptor assay and its biological activity requires further study.