Renal replacement in the deployed setting.

We present a case of a UK soldier suffering multiple injuries in Afghanistan including a lacerated liver, complicated by acute anuric renal failure. His condition was stabilised prior to transfer to the UK using continuous venovenous haemofiltration. This is the first deployed use of renal replacement therapy by UK forces for several decades, and raises questions regarding the provision of this high level capability in the deployed setting.

Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD.

BACKGROUND: Azithromycin is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity. Azithromycin displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin. This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis. OBJECTIVE: This study aimed to define the potential role of azithromycin in treating CAPD peritonitis. DESIGN: The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin were studied following a single 500-mg oral dose of azithromycin. Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography. SETTING: The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom. PATIENTS: Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day). RESULTS: Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75). The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour. This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers. After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr. CONCLUSION: Azithromycin is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present. However, the successful use of azithromycin in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported. Future research should address this possibility.

A survey of CAPD peritonitis management and outcomes in North and South Thames NHS regions (U.K.): support for the ISPD guidelines. International Society for Peritoneal Dialysis.

OBJECTIVE: This survey examined the current management of continuous ambulatory peritoneal dialysis (CAPD) peritonitis and the effectiveness of the various antibiotic protocols in use. DESIGN: The information required was elicited via a postal questionnaire. SETTING: The questionnaire was posted to each renal dialysis unit offering CAPD throughout the North and South Thames National Health Service regions. PATIENTS: All patients using CAPD at each responding unit were eligible for inclusion. MAIN OUTCOME MEASURES: Each unit provided details of their CAPD peritonitis episodes for 1997. Each unit's empirical treatment regimen for CAPD peritonitis was sought in addition to response rates. Also requested were numbers for peritonitis episodes, recurrences, and negative cultures, plus the peritonitis rate per patient-month. RESULTS: Thirteen units returned the questionnaire (87% of the survey population). Nine of the 13 units were using vancomycin regimens, with the remainder using cephalosporin regimens. The results were compared to the audit standards of the British Renal Association. Seventy percent of units reached the 80% mark for response rate; similar results were achieved with both the vancomycin and cephalosporin regimens. Ninety-two percent achieved the suggested peritonitis rate of 1 episode every 18 patient-months; 30% achieved the culture-negative rate of 10%. The average recurrence rate was 19%. CONCLUSION: The units contacted achieved most of the standards suggested by the British Renal Association; however, wide variations did exist. Recent guidelines have suggested avoiding vancomycin-based regimens in order to reduce the incidence of vancomycin resistance. The suggested regimen of a cephalosporin with an aminoglycoside seems to represent a suitable alternative.

Pamidronate therapy as prevention of bone loss following renal transplantation.

BACKGROUND: Very rapid bone loss, osteopenia and skeletal morbidity after renal transplantation have been well documented and found to occur in a sex dependent fashion. Glucocorticoids, cyclosporine and pre-existing uremic osteodystrophy have been implicated in the pathogenesis of the skeletal lesions. Glucocorticoid induced osteopenia is also a serious clinical problem in patients with various nonrenal diseases and can be prevented, or at least attenuated, by pamidronate and other bisphosphonates. METHOD: We prospectively studied 26 male patients undergoing renal transplantation, and randomized them to receive either placebo or intravenous pamidronate (0.5 mg/kg) at the time of transplantation and again one month later. All patients received immunosuppression comprising prednisolone, cyclosporine and azathioprine. The bone mineral density (BMD) of the second, third and fourth lumbar vertebrae and of the femoral neck was measured at the time of transplantation and at three months and 12 months after transplantation using dual energy X-ray absorptiometry (DXA). RESULTS: Twelve months after transplantation, the mean (+/- SEM) BMD of the lumbar vertebrae in patients who received placebo had decreased 6.4% (P < 0.05). In contrast, patients who received pamidronate experienced no significant reduction of BMD at the lumbar vertebrae. At the femoral neck, placebo-treated patients showed a reduction of BMD of 9% (P < 0.005), whereas there was no significant change in the pamidronate treated group. The two study groups had similar patient profiles, serum parathyroid hormone (PTH) and aluminium concentrations. After transplantation, comparable falls in the serum creatinine and PTH concentration were found in the two groups. Apart from transient hypocalcemia in two patients, no significant adverse effects of pamidronate were noted. CONCLUSION: This study has shown that the early rapid bone loss that occurs in men during the first 12 months after renal transplantation can be prevented by two intravenous doses of pamidronate given at transplantation and one month later. The regimen was simple to administer, well tolerated and potentially applicable to other clinical groups of glucocorticoid treatment patients.

Polyarteritis nodosa and the antiphospholipid syndrome.

We describe a case of classical polyarteritis nodosa (PAN) with visceral aneurysms presenting with renal infarction and hypertension. The female patient also had all the laboratory features of the antiphospholipid syndrome (APS) and 2 months into her illness developed a large iliofemoral thrombosis. She responded well to immunosuppressive therapy and anti-coagulation. Repeat arteriogram showed regression of the visceral aneurysms. The link between PAN and APS, and the therapeutic dilemma posed by this association, are discussed.

Clinical pharmacokinetics of oral acyclovir in patients on continuous ambulatory peritoneal dialysis.

It is increasingly recognised that dose adjustment of oral acyclovir in continuous ambulatory peritoneal dialysis (CAPD) patients is necessary to avoid neurotoxicity. A single 800-mg oral dose of acyclovir was administered to 10 uninfected anuric patients who were treated by CAPD. Serial blood and CAPD bag samples were analysed for acyclovir during the 31 h after dosing. Serum acyclovir levels were measured using radioimmunoassay and the pharmacokinetic parameters were estimated by linear regression using the STRIPE computer programme. Peak plasma levels of 8.95 +/- 3.95 microM were achieved at 4.1 +/- 1.85 h with the T1/2 calculated to be 14.52 +/- 3 h. The mean predicted serum acyclovir levels at steady state after 1,600-, 800- and 600-mg daily doses were 13.76, 6.88 and 5.16 microM, respectively. The present recommended daily doses of acyclovir (1,600 mg) for end-stage renal disease patients leads to supratherapeutic levels therefore increasing the risk and incidence of neurotoxicity. Computer modelling of various dosage simulations suggests that daily doses of 800 and 600 mg will achieve therapeutic levels (4-8 microM).

Avoiding acyclovir neurotoxicity in patients with chronic renal failure undergoing haemodialysis.

Acute neurotoxicity following the administration of the recommended oral dose of acyclovir (800 mg twice daily) to dialysis-dependent patients is increasingly recognised. This suggests that the recommended dose is too high. Little is known of the pharmacokinetics of oral acyclovir in dialysis patients. We studied 7 patients with oliguric end stage renal failure receiving haemodialysis. Following haemodialysis, each patient received a single 800-mg tablet of acyclovir. Plasma acyclovir levels were monitored over the next 48 h as well as before and after the next routine dialysis. Peak plasma levels were achieved at 3 h (12.54 +/- 1.76 microM, range 8.5-17.5 microM) with the half-life calculated to be 20.2 +/- 4.6 h. Mean plasma level of 6.29 +/- 0.94 microM were within the quoted range to inhibit herpes zoster virus (4-8 microM) at 18 h. Haemodialysis (4-5 h) eliminated 51 +/- 11.5% of the acyclovir which remained at 48 h. Computer modelling of various dose modifications suggests that a loading dose of 400 mg and a maintenance dose of 200 mg twice daily is sufficient to maintain a mean plasma acyclovir level of 6.4 +/- 0.8 microM. A further loading dose (400 mg) after dialysis would raise the residual acyclovir concentration by 6.1 +/- 1.0 microM. Such a dose modification should prevent neurotoxicity, whilst the rapid elimination of acyclovir by a single haemodialysis treatment provides both a diagnostic and therapeutic tool when toxicity is suspected.

Ketone bodies promote a rapid rise in glutamate efflux from the isolated perfused rat liver without altering the rate of glutamine production.

Livers of starved (48 hr) male Wistar rats were perfused in a non recirculating manner with a near physiological mix of ammonium, lactate, ornithine and pyruvate in Krebs buffer. The addition of ketone bodies (3-DL-hydroxybutyrate [B OHB] 2-30 mM or lithium-acetoacetate (15 mM) to the perfusate resulted in a rapid rise in the efflux of glutamate from the liver (five times above basal). This was not seen with control solutions (sodium chloride or lithium chloride). The increased efflux was sustained for the duration of the addition of the ketone bodies (7 min), was rapidly reversible and dose dependant. Glutamine export rates were not altered, suggesting that either the glutamate originated from cells not responsible for glutamine synthesis or that this glutamate was superfulous to the requirement of glutamine synthesis. There was no evidence that the lactate transporter was involved in the entry of lactate into perivenous hepatocytes for glutamine synthesis; lactate presumably entering the hepatocyte by an alternative pathway, probably nonionic diffusion.

Increased erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme.

The response to erythropoietin (Epo) is dose dependent but, for various poorly understood reasons, variable. In a cross-sectional study we determined the Epo requirement of 60 patients in a dialysis population to identify those patients requiring a high dose of Epo, and ascertained the reasons for higher requirements, paying particular attention to the effect of previous transplantation. All 289 patients attending a single centre were surveyed. Of these, 164 were receiving renal replacement therapy by continuous ambulatory peritoneal dialysis (CAPD) and 125 were on haemodialysis (HD). Patients on HD needed more Epo than those on CAPD (129.0 +/- 14.9 U/kg/week versus 86.9 +/- 10.7 U/kg/week, P < 0.05). However, this difference was accounted for by a subgroup of patients who had a previously failed transplant. The Epo requirement in those patients on HD with a failed transplant was significantly greater than those on HD who had never been transplanted (164.0 +/- 24.5 U/kg/week versus 96.6 +/- 11.9 U/kg/week, P < 0.05). The seven patients who retain their transplanted kidney had the highest Epo requirement of all (213.4 +/- 46.6 U/kg/week). These studies have shown that previous transplantation is a significant determinant of Epo requirement upon return to dialysis. They also show that it is necessary to 'correct' for the effect of previous transplantation when investigating generally accepted determinants of Epo need. Interpretation of previously published studies needs to take account of this.

Loss of regional bone mineral density in the first 12 months following renal transplantation.

A high incidence of osteopenia is likely in renal transplant recipients in whom pre-existing uraemic osteodystrophy, persisting hyperparathyroidism and glucocorticoids constitute a formidable array of risk factors. The correction of some biochemical and hormonal abnormalities, an increase in body weight and an increase in physical activity following transplantation could favour improvements in skeletal integrity. Using dual energy X-ray absorptiometry (DEXA), we studied prospectively the regional bone mineral density (BMD) of 34 consecutive cadaveric renal allograft recipients who were already established on dialysis. BMD of these patients was measured at the time of transplantation and was repeated at 3, 6 and 12 months following the transplantation. Immunosuppression was achieved using triple therapy: azathioprine, cyclosporin-A and prednisolone. At baseline, total BMD and BMD at the lumbar spine and femoral neck did not differ from age- and sex-matched controls. Females experienced marked and progressive bone loss at the lumbar spine, with less marked changes at the femoral neck. Males, in contrast, experienced substantial reduction of BMD at the femoral neck at 6 months and a recovery at 12 months without significant change at the lumbar spine. Whole body bone mineral content fell transiently in males, with partial recovery by 6 months. No significant correlation was found with the cumulative doses of either corticosteroids or cyclosporin-A, the duration of hospitalisation, the function of the transplant, patient age or menopausal status.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced bone mineral density in long-term survivors of medulloblastoma.

Bone mineral density (BMD) reaches a peak at approximately 30 years of age, and may be influenced by radiotherapy before completion of skeletal maturation. Regional BMD has been measured using dual energy X-Ray absorptiometry (DEXA) in adults following craniospinal irradiation for medulloblastoma between ages 4 and 19 years, receiving doses of 3500-4000 cGy to the brain and spinal cord. Lumbar spine (LS) and was failure to achieve normal adult BMD at both LS and FN, with a mean reduction at LS of 12.1% +/- 2.4% (p < 0.01) and a mean reduction at FN of 14.3% +/- 3.4% (p < 0.01). The mean body mass index (BMI) was also less than that of a standard population (21.8 +/- 1.5), as were mean standing and sitting heights. No relationship was found between reduction in BMD at either site and age at irradiation, time elapsed since irradiation or BMI at time of scanning. Biochemical and endocrine markers including corrected calcium, alkaline phosphatase, sex hormones and IGF-1 were normal in all seven patients. The reduction in BMD outside the irradiated area suggests that indirect factors may be important in this effect.

'Pulse' oral calcitriol in uraemic patients: rapid modification of parathyroid response to calcium.

We performed dynamic parathyroid function tests, with generation of parathyroid hormone/ionized calcium (PTH/iCa) response curves, obtained during sequential hypercalcaemic and hypocalcaemic dialysis, on six haemodialysis patients before and after 4-weekly 'pulse' doses of oral calcitriol. There were no significant changes in the pretreatment, 2-week and 4-week values of blood ionized calcium, serum total calcium, phosphate, and alkaline phosphatase. PTH decreased significantly after 4 weeks of treatment with calcitriol (P less than 0.03), and the post-treatment PTH/iCa curves were all displaced leftwards and downwards, indicating a marked inhibitory effect of calcitriol on parathyroid responsiveness across and beyond the physiological range of calcaemia. The mean shift of the PTH/iCa relationship was equivalent to a reduction of iCa of 0.2 mM for any given concentration of PTH, and conversely to a 70% reduction of PTH for any given blood iCa. The results suggest that wide spacing of oral 'pulse' doses of calcitriol can achieve favourable modification of the PTH/iCa relationship, and that dosing interval and dose size, rather than route of administration, may be the major determinants of the previously reported superiority of intravenous over daily oral calcitriol regimens.

Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation.

We performed serial measurements of total body bone mineral content (BMC) and bone mineral density (BMD), and of regional BMD at the lumbar spine and femoral neck using dual energy X-ray absorptiometry. Twenty-six patients (15 females and 11 males) were studied at the time of transplantation, and 3 and 6 months post-transplant. At baseline, the total body BMC and regional BMD values of the patients did not differ significantly from age- and sex-matched controls. Total body BMC had fallen progressively at 3 months, followed by partial recovery at 6 months. Significant decreases of BMD were seen in the lumbar spine and femoral neck at 3 months with no evidence of recovery at 6 months. The changes in these indices correlated well with the duration of hospital stay in the first 3 post-transplant months. This preliminary study demonstrated rapid deterioration of skeletal integrity following renal transplantation and that this might be progressive. Preventative strategies to avoid this early bone loss may need to be investigated.

Hepatic glutamine metabolism and acid-base regulation.

Switching of hepatic nitrogen disposal from urea synthesis to glutamine production has been proposed as a mechanism for countering acidosis, with glutamine synthesis providing a route for the detoxification of ammonium not incorporated into urea. Isolated livers from starved rats were perfused with ammonium (0.8 mM); increasing perfusate lactate concentration 0-2 mM raised glutamine synthesis threefold whilst increasing perfusate glucose concentration 0-20 mM did not. This was true under normal and acidotic conditions. In the presence of both substrates plus either 14C-glucose or 14C-lactate, the mean specific activity of glutamine synthesised was greater for 14C-lactate. Thus, the preferred substrate for hepatic glutamine synthesis is lactate, a proton neutral reaction. Perfusion with lactate and glutamine over the pH range 6.9-7.5 with or without the glutamine synthase inhibitor L-methionine-s-sulphoxime showed that the switch in acidosis to net glutamine production is entirely due to inhibition of glutamine removal by periportal hepatocytes.