First-line cyclosporin A monotherapy in cadaveric renal transplantation.
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Azathioprine↗
Biomedical subjects
J M Bone
Publications and source records attributed to J M Bone.
Cyclosporin monotherapy in pancreaticorenal transplantation.
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Actuarial Analysis↗
Observations on the early renal uptake and later tubular metabolism of radiolabelled aprotinin (Trasylol) in man: theoretical and practical considerations.
1. The novel method recently developed to measure renal tubular degradation of filtered proteins in man using radiolabelled aprotinin (Trasylol) has been modified to allow the fate and the significance of the renal catabolism of radiolabelled aprotinin to be determined beyond 24h. 2. Ten renal patients with normal kidney function and variable proteinuria each received two separate intravenous injections of radiolabelled aprotinin, 5.0 mg of 99mTc-labelled aprotinin (40MBq) and 0.5mg of 131I-labelled aprotinin (5MBq). Chromatography (Sephadex-G-25-M) was used to separate undegraded radiolabelled aprotinin from the free isotope in urine and plasma. Renal uptake from gamma-camera images (24h for 99mTc-labelled aprotinin and up to 96h for 131I-labelled aprotinin) and urinary activity (48 and 96h, respectively) were measured. 3. The renal handling of radiolabelled aprotinin was similar with the two isotopes. Chromatography showed that all plasma activity was undegraded radiolabelled aprotinin, and urine activity was only the free isotopic label. 4. Kidney uptake of 131I-labelled aprotinin was prompt, reaching a cumulative maximum of 37.1 +/- 3.0% of dose at 24h, but falling exponentially thereafter to 5.6 +/- 1.0% of dose at 96h. 5. The rate of excretion of the free label in urine, i.e. the metabolic rate of radiolabelled aprotinin, was relatively constant over the first 24h (1.6 +/- 0.09% of dose/h), but then fell in parallel with the diminishing activity over the kidney, i.e. to 1.0 +/- 0.1% of dose/h over 24-48h and to only 0.4 +/- 0.08% of dose/h over 72-96h.(ABSTRACT TRUNCATED AT 250 WORDS)
Aprotinin↗
Renal tubular protein degradation of radiolabelled aprotinin (Trasylol) in patients with chronic renal failure.
1. The new method developed to measure renal tubular degradation of small filtered proteins in patients with normal renal function, using radiolabelled aprotinin (Trasylol) (R. Rustom, J. S. Grime, P. Maltby, H. R. Stockdale, M. Critchley, J. M. Bone. Clin Sci 1992; 83, 289-94), was evaluated in patients with chronic renal failure. 2. Aprotinin was labelled with either 99mTc (40 MBq) or 131I (0.1 MBq), and injected intravenously in nine patients, with different renal pathologies. 51Cr-EDTA clearance (corrected for height and weight) was 40 +/- 5.4 (range 11.2-81) ml min-1 1.73 m-2. Activity in plasma and urine was measured over 24-48 h, and chromatography on Sephadex-G-25-M was used to separate labelled aprotinin from free 99mTcO4- or 131I-. Renal uptake was measured for 99mTc-labelled aprotinin only. 3. The volume of distribution was 20.2 +/- 2.3 litres. Chromatography showed all plasma activity as undegraded aprotinin, and urine activity only as the free labels (99mTcO4- or 131I-). 4. As in patients with normal renal function, activity in the kidney appeared promptly, with 5.7 +/- 2.5% of the dose detected even at 5 min. Activity rose rapidly to 9.4 +/- 1.6% of dose after 1.5 h, then more slowly to 15.0 +/- 0.5% of dose at 4.5 h, and even more slowly thereafter, reaching 24.1 +/- 2.8% of dose at 24 h. Extra-renal uptake was again insignificant, and both 99mTcO4- and 131I- appeared promptly in the urine, with similar and uniform rates of excretion over 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Aprotinin↗
A new method to measure renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol).
1. A method has been developed to measure the renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol), a 6500 Da cationic polypeptide. 2. Aprotinin (0.5 or 5.0 mg) was labelled with either 99mTc (40 MBq) or 131I (1 MBq) and injected intravenously in 19 renal patients (10 with normal renal function and nine on haemodialysis). Activity in plasma and urine was measured over 48 h, and chromatography with Sephadex-G-25-M was used to separate labelled aprotinin from free 99mTcO4- or 131I-. Renal uptake was measured for 99mTc-labelled aprotinin only. 3. The volumes of distribution were similar in all patients: 18.2 +/- 0.4 litres in those with normal renal function and 20.2 +/- 0.1 litres in the others. Chromatography showed all plasma activity as undegraded aprotinin and urine activity only as the free labels (99mTcO4- or 131I-). 4. In patients with normal renal function, activity in the kidneys rose rapidly to 24.2 +/- 2.8% of dose after 90 min and to 42.2 +/- 3.4% of dose after 24 h. In the dialysis patients, activity over the kidneys was only 2.7 +/- 0.8% of dose at 24 h. Extra-renal uptake was insignificant in all patients with normal kidney function. 5. Both 99mTcO4- and 131I- appeared in the urine promptly after injection, and the rates of excretion of the two isotopes were similar, varying little over 24 h (1.8 +/- 0.04% of dose/h and 1.7 +/- 0.04% of dose/h for 99mTc and 131I, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Aprotinin↗
Effects of lysine infusion on the renal metabolism of aprotinin (Trasylol) in man.
1. Aprotinin (Trasylol) is a cationic 6500 Da polypeptide that inhibits proteolytic enzymes, and when labelled with 99mTc it is a reproducible marker for the renal tubular turnover of small filtered proteins in man. Lysine potently inhibits tubular peptide uptake, and may thus depress the uptake and metabolism of aprotinin. This was investigated in 14 glomerulonephritic patients with normal renal function and variable proteinuria and in one healthy subject. 2. 99mTc-labelled aprotinin was given intravenously alone, and again 3 days later, immediately after the intravenous administration of 3-6 g of lysine, followed by an infusion over 1 h of 0.3-1.9 g of lysine/kg in individual patients. Activity over kidneys and in urine was measured over 24 h and chromatography was used to separate the undegraded peptide from free isotope. 3. At the low dosage of lysine (< 0.8 g/kg) given to six patients, kidney activity (representing tubular uptake) was unchanged, but early urine samples contained some undegraded aprotinin. Urinary excretion of free isotope, representing tubular metabolism, fell from 1.6 +/- 0.2% of dose/h with no lysine to 0.9 +/- 0.1% of dose/h in the 24 h after lysine, suggesting suppression of tubular aprotinin degradation. Corrected fractional degradation was calculated from the mean urinary excretion of free isotope over a given interval, determined by chromatography, divided by the mean cumulative kidney counts over this same interval, and this also fell after lysine from 0.06 +/- 0.006 to 0.03 +/- 0.006 h-1 (P < 0.005) between 3.75 and 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Aprotinin↗
Urinary dopamine excretion in chronic renal disease.
We have measured unconjugated urinary dopamine and investigated its relationship to glomerular filtration rate in two groups of 22 patients with chronic renal failure matched for age and sex, one group with primary glomerular disease, the other with tubulo-interstitial disease. Urine dopamine excretion was similar in both glomerular and tubulo-interstitial disease groups, and correlated significantly with creatinine clearance. Although urinary protein excretion was significantly higher in glomerular disease, urinary sodium excretion, fractional sodium excretion, urine flow rate and free water clearance were similar in both groups and did not correlate with dopamine excretion. These results suggest that in patients with chronic renal disease, urinary dopamine excretion is mainly under the influence of the glomerular filtration rate, irrespective of the underlying pathology, and therefore interpretation of urinary dopamine excretion requires a knowledge of the patients' renal function.
Adult↗
Tubular metabolism of aprotinin 99mTc and urinary ammonia: effects of proteinuria.
Increased renal ammoniagenesis is pathogenic in animals. Thus, tubular degradation of filtered proteins to ammonia might link proteinuria to disease progression. The tubular uptake, metabolism and fractional degradation of aprotinin 99mTc (Trasylol), were measured in 26 glomerulonephritic patients with normal renal function, 10 with proteinuria > 5 g/24 h. In addition, urinary ammonia pH, and titratable acidity were measured. Patients with heavy proteinuria had a higher tubular metabolism, a lower uptake and a higher fractional degradation of aprotinin. Urinary ammonia and titratable acidity were also increased. Fractional degradation and urinary ammonia were strongly correlated as were urinary ammonia and proteinuria.
Acids↗
Prevention of bacterial infection and sepsis in acute severe pancreatitis.
Between 1984 and 1986 six patients with acute respiratory failure (requiring ventilation for at least 3 days) complicating acute pancreatitis were managed on the intensive care unit (median ventilation period 6 days; range 3-41 days). Between 1987 and 1989 nine similar patients were managed (median ventilation period 35 days, range 4-69 days), and a regimen of enteral tobramycin, polymyxin and amphotericin to selectively decontaminate the digestive tract (SDD) was introduced. Five of six patients treated before 1987 had serious infections (three Gram-negative, one fungal), compared with only one of nine patients treated with SDD (P < 0.05). Clinical signs of sepsis were evident for 62% of the pre-SDD period, compared with 39% of the period during SDD therapy (P < 0.001). Systemic antibiotic prescribing was reduced in the SDD group; however, mortality remained unaffected with only two patients surviving pre-SDD and three during SDD treatment. SDD reduces infection rates and sepsis in patients with acute pancreatitis and may help to improve the prognosis of this life-threatening condition.
Acute Disease↗
Necrotizing myopathy in critically-ill patients.
Skeletal muscle wasting is commonly observed in critically-ill patients and has been attributed to catabolic fibre atrophy and to neuropathy. This study describes the occurrence of a necrotizing myopathy in 15 out of 31 critically-ill patients who had percutaneous biopsies taken from the tibialis anterior muscles. While most cases showed necrosis of isolated fibres, 5 of the 12 patients who had serial biopsies showed progressive necrosis of up to 95 per cent of the fibres. One other case showed infarction and one case had staphylococcal vasculitis. Atrophy of type 1 and/or type 2 fibres was documented by morphometry in 12 cases. Myoglobin-containing casts were demonstrated immunohistochemically in renal tubules on either biopsy or necropsy material in 5 out of 7 cases. The presence of muscle necrosis was a clinically unexpected finding which may contribute to weakness, complicate the interpretation of tissue biochemistry and energy balance studies, and potentiate renal failure. The necrosis is probably multifactorial in origin, with ischaemia and sepsis contributing factors.
Acetaminophen↗
Failure of dietary protein and phosphate restriction to retard the rate of progression of chronic renal failure: a prospective, randomized, controlled trial.
Ninety-five patients (63 male, 32 female), age 45 +/- 2 years (mean +/- SEM) with chronic renal failure of varied aetiology were randomized to receive either a conventional low protein diet (0.6 g/kg/day protein, 800 mg phosphate; n = 33), a low phosphate diet (providing approximately 1000 mg phosphate plus an orally administered phosphate binder, minimum protein intake 0.8 g/kg/day; n = 30) or to control (minimum protein intake 0.8 g/kg/day, no phosphate restriction; n = 32). Patients were reviewed for a minimum of 6 months before randomization and were withdrawn from the study if plasma creatinine exceeded 900 mumol/l, plasma phosphate was greater than 2.0 mmol/l or at the onset of uraemic symptoms. Following randomization patients were studied for an average of 19 +/- 3 months. Mean plasma creatinine rose from 398 +/- 33 to 600 +/- 50 mumol/l. Dietary protein intake was estimated at 0.69 +/- 0.02 g/kg/day in the low protein group, 1.02 +/- 0.05 in the low phosphate and 1.14 +/- 0.05 in the controls, phosphate intake was 815 +/- 43, 1000 +/- 47, and 1315 +/- 57 mg/day, respectively. Urinary urea excretion and protein catabolic rates were significantly reduced (p less than 0.01) only in those on protein restriction, at 213 +/- 9 mmol/24 hours and 0.71 g/kg/day, respectively. Phosphate excretion was significantly lower (p less than 0.05) in both the low protein group (17.9 +/- 0.8 mmol/24 hours) and the low phosphate group (18.6 +/- 1.0 mmol/24 hours) compared to controls. Changes in body weight, muscle mass and serum transferrin, albumin and immunoglobulins were comparable between the groups. Mean blood pressure following randomization was 150/89 +/- 3/1 (low protein), 148/87 +/- 3/1 (low phosphate) and 146/87 +/- 3/1 (controls). Progression of renal failure was analysed by rate of all of creatinine clearance (ml/min/1.73 m2/month), by rate of deterioration derived from reciprocal plasma creatinine against time plots (1/mmol/year) and to assess individual patient's response to treatment by two phase linear regression ('breakpoint') analysis of reciprocal plasma creatinine/time plots. Progression was analysed only in patients seen for at least 3 months following randomization. The rate of fall of creatinine clearance was not significantly different between the groups (ANOVA): 0.56 +/- 0.08 ml/min/1.73 m2/month (low protein, n = 28), 0.44 +/- 0.07 (low phosphate, n = 23) and 0.69 +/- 0.11 (control, n = 27).(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Multiple organ failure--a role for plasma exchange?
Two patients with multiple organ failure, septicaemia and a deteriorating clinical course were treated by plasma exchange in addition to standard supportive measures. Dramatic improvements were seen in cardio-respiratory (patient 1), neurological and renal parameters (patient 2) which were attributable to the exchanges. Plasma exchange might be of value as adjunctive therapy where overwhelming septicaemia occurs with multiple organ failure.
Adult↗
Reducing sepsis in severe combined acute renal and respiratory failure by selective decontamination of the digestive tract.
Fifteen patients with severe combined acute renal and respiratory failure (SCARRF), who required mechanical ventilation and renal replacement therapy for at least 5 days, were treated with a regimen to selectively decontaminate the digestive tract (SDD). In these patients the incidence of significant infection was compared with the infection rate in 12 similar patients with SCARRF who had not received SDD, treated over the preceding 12 months. Both groups were comparable for age, study period, sepsis score, and therapeutic intervention scoring system on admission, although the Acute Physiology and Chronic Health Evaluation score was higher (p less than .05) in the SDD-treated group. Ten (83%) of 12 control patients developed definable infections compared with five (33%) of 15 in the SDD group (p less than .05). Gram-negative bacteria and fungi were responsible for 14 of the 17 infections affecting ten control patients, compared with six of the seven infections in only four SDD patients (p less than .05). The most notable site to benefit was the respiratory tract, with only one patient in the SDD group developing a pulmonary infection compared with five in the control patients (p less than .05). Urine infections may have been reduced from six (50%) of the 12 control patients to two (13%) of the 15 SDD patients, but this difference was not significant. Although survival in the control and SDD group was comparable (42% vs. 40%), mortality overall seemed related to infection. Eleven (73%) of 15 patients with definite infection died, in contrast with five (42%) of 12 who had no infections, although this was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Kidney Injury↗
Red cell antigens and renal transplantation.
Donor-specific transfusion was performed with and without cyclosporine between haplomismatched relatives prior to living-donor renal transplantation. Red cell antigen mismatching was not taken as a contraindication to DST. Of 80 patients included in the trial; eleven were ABO-mismatched, 15 were Rh(D)-mismatched, and a further 11 were transfused in the presence of atypical red cell antibodies (anti-D, -C, -Fya, -Kell -N, -H/I -I, -P1, -Wra). Patients were randomized to receive cyclosporine (10 mg/kg) daily during DST or not (control group). The presence of atypical red cell antibodies, with the exception of Rh anti-D, did not appear to influence DST or renal transplantation. DST did not act as a primary stimulus to Rh anti-D production but stimulated preexisting anti D levels. ABO mismatching did not appear to influence DST or subsequent renal transplantation except in one group A [corrected] patient who received group O [corrected] blood and cyclosporine. This patient developed a severe, but self-limiting, autoimmune hemolytic anemia due to auto-anti A antibodies. A similar group A patient in the control group developed an auto-antibody with no clinical sequelae. The influence of cyclosporine on the development of this auto-antibody is uncertain. We conclude that, with the exception of preexisting anti-D antibodies, minor red cell antigen disparities should not preclude pretransplant conditioning with donor-specific transfusions.
ABO Blood-Group System↗
Renal transplantation: cyclosporin A and antibody development after donor-specific transfusion.
The survival of a one haplotype, mismatched living-related renal allograft is improved by donor specific transfusion (DST) before transplantation although the mechanism is unclear. The major risk of DST is sensitization of the recipient to donor lymphocytes precluding transplantation. Fifty prospective recipients of a living related transplant received either DST with cyclosporin A (group I) or DST alone (group II). Persistent donor sensitization precluding transplantation occurred in no patients in group I but in six in group II (P less than 0.05). Ten of 14 of those who developed donor cytotoxicity had previously been pregnant or received greater than or equal to 10 third party transfusions compared with 11 of 36 without such a history (P less than 0.05). Alloantibodies detected by a cellular ELISA developed following DST in 29% patients and antiidiotypic antibodies detected by the short antiidiotypic assay (SAA) in 36%; antiidiotypic activity occurred more frequently in those given cyclosporin A (P less than 0.02). Potentiating activity in the SAA which occurred in sera from six patients after DST had no influence on transplant outcome. Persistent sensitization, particularly in potential transplant recipients who have been pregnant or received many transfusions, can be prevented by giving cyclosporin A with DST; the mechanisms of this effect may be the induction of antiidiotypic antibodies. Both alloantibodies and antiidiotypic antibodies are induced by DST and may protect a subsequent renal allograft from the specific donor.
Antibodies↗
Aggressive immunosuppression in glomerulonephritis.
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Acute Disease↗
Immunosuppression can arrest progressive renal failure due to idiopathic membranous glomerulonephritis.
The effect of pulse intravenous methylprednisolone therapy followed by oral immunosuppression was evaluated in ten patients with idiopathic membranous glomerulonephritis who had developed progressive renal failure--a group generally considered to have a poor prognosis. The patients (six male, four female, mean age 50 years) were monitored over 9-30 months during which time creatinine clearance reduced from (mean +/- SEM) 83 +/- 10 to 29 +/- 6 ml/min, and plasma creatinine increased from 135 +/- 22 to 297 +/- 35 mumol/l. All patient were nephrotic with mean 24-h urinary protein excretion ranging from 5.8 to 19.6 g. Treatment administered was pulse intravenous methyl-prednisolone 1 g X 3 then oral prednisolone 30 mg and azathioprine 50 mg (nine patients) or cyclophosphamide 50 mg (one patient). Mean prednisolone dosage was 25 mg at 3 months, 16 mg at 6, and 10 mg at 12 months. Patients have been followed up for between 12 and 57 months on therapy. Creatinine clearance increased to 39 +/- 6, 47 +/- 5 and 48 +/- 18 ml/min after 3, 6 and 12 months treatment with a fall in proteinuria to 6.2 +/- 1.7, 5.7 +/- 1.4, and 3.1 +/- 1.1 g/24h. The deterioration of renal function was reversed in six patients (associated with a reduction in proteinuria to less than 1 g/24 hours in five), slowed in three (with a significant reduction in proteinuria in two), and only one patient with more advanced renal failure before treatment progressed to end-stage failure without any retardation of the rate of deterioration or change in proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Varicella in an immunocompromised patient an electron microscopic study.
We report the electron-microscopic appearances of tissues from an immunocompromised patient who died of chickenpox. We observed structures consistent with some of the reported appearances of Varicella-Zoster virus in cultured cells, and tubular structures that have not to our knowledge been previously described.
Adult↗