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Biomedical subjects

A B Dawnay

Publications and source records attributed to A B Dawnay.

18 recordsLinked to original sources
PubMed1997

Acute reversal of cyclosporine nephrotoxicity by neutral endopeptidase inhibition in stable renal transplant recipients.

BACKGROUND: Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function. METHODS: Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study. Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation. RESULTS: After administration of candoxatrilat, plasma atrial natriuretic factor rose from 12.8+/-1.6 (mean +/- SEM) to 44.1+/-6.8 pmol/L (P<0.001) in association with a threefold increase in urine cGMP excretion (573+/-195 pmol/min baseline to 1823+/-545 pmol/ min; P<0.001), marked natriuresis (207+/-34 micromol/min baseline to 416+/-62 micromol/min; P<0.001), fractional sodium excretion (3.3+/-0.5% baseline to 5.6+/-0.7%; P<0.01), and diuresis (3.4+/-0.5 ml/min baseline to 7.4+/-1 ml/min; P<0.001). All parameters remained elevated above baseline for the remaining 7-hr study period. In response to candoxatrilat, the glomerular filtration rate rose by 19% (P=0.01), renal plasma flow by 7% (P=0.04), renal blood flow by 13% (P=0.03) in association with an increase in filtration fraction from 24+/-2% to 28+/-2% (P=0.002) and small fall in renal vascular resistance from 0.38+/-0.04 to 0.30+/-0.04 mmHg x min x 1.73 m2 x ml(-1) (P=0.02). There was a fall in plasma angiotensin II without a change in plasma renin concentration or plasma aldosterone. Median urinary albumin excretion increased after candoxatrilat administration from 48 (3-131) to 114 (32-641) microg/min (P<0.01). CONCLUSIONS: Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclosporine in stable renal transplant recipients.

Adult↗
PubMed1997

Enhanced natriuretic response to neutral endopeptidase inhibition in patients with moderate chronic renal failure.

Atrial natriuretic factor (ANF) has natriuretic, renin-suppressing and chronic hypotensive actions that may be utilized by inhibition of ANF degradation by neutral endopeptidase, E.C.24.11 (NEP). Three groups of 8 male patients [GFR 103 +/- 8 (Normal), 64 +/- 6 (Moderate CRF), and 16 +/- 2 ml/min (Severe CRF)] received 100 mg i.v. bolus of the NEP inhibitor candoxatrilat or placebo in random order in a double-blind crossover study. GFR (51CR-EDTA), ERPF (125I-hippuran). ANF (IRMA), urinary cGMP (RIA) and albumin (RIA) and sodium excretion and flow rate were measured hourly for two hours before and for seven hours after candoxatrilat administration. After candoxatrilat plasma ANF rose two- to threefold from baseline, and remained elevated for 5(N) and 7(M,S) hours (P < 0.01(N,S), P < 0.03(M)) associated with an immediate rise in urine cGMP excretion from 23.5(N), 25.4(M) and 10.4(S) nmol/hr (base) to 51.7(N), 73.8(M) and 27.5(S)(peak) lasting 7(N,M,S) hours (P < 0.01(N,M,S)). There was a marked natriuresis in all three groups, the cumulative sodium excretion at seven hours post-candoxatrilat being 104(N), 140(M), 102(S) mmol (P < 0.05(N,M,S)). This was greatest in those with moderate CRF (moderate CRF vs. normal, P = 0.036, moderate vs. severe CRF, P = 0.01, normal vs. severe CRF, P = 0.74). Following candoxatrilat there was a near doubling of the urine flow rate (P < 0.01(N,S), P < 0.02(M)). Urine albumin excretion increased in patients with renal failure (P < 0.01), but there was no change in GFR, ERPF or systemic blood pressure. We conclude that the marked natriuretic effects of acute NEP inhibition seen in normal subjects are enhanced in the presence of moderate CRF and sustained even in severe renal impairment.

Adult↗
PubMed1996

Effects of parathyroid hormone and 1,25(OH2)D3 on protein glycation in moderate uraemia.

Glucose intolerance in uraemia may be a consequence of secondary hyperparathyroidism. In this study fructosamine and glycated albumin have been used as markers of long-term glycaemic control in a group of pre-end-stage, non-diabetic uraemic patients with secondary hyperparathyroidism. The serum fructosamine level (mumol/100 g total protein) was significantly higher (p = 0.005) in uraemic patients (364 +/- 42) than in a group of 25 non-uraemic controls (332 +/- 27), but the content of glycated albumin did not differ (p > 0.05; 1.6 +/- 0.5 vs. 1.5 +/- 0.3%). In the uraemic patients, there was a significant relationship between serum 1,25-dihydroxycholecalciferol [1,25(OH2)D] (median 4.2, range 1.0-38 ng/l) and fructosamine (r = -0.66, p < 0.01; fructosamine = -2.76 1,25(OH2)D + 389), but not glycated albumin (r = -0.22, p > 0.1). No relationship existed between serum parathyroid hormone (median 15.4, range 7.0-55 pmol/l) and either glycated albumin or fructosamine (p > 0.1). In patients treated with oral calcitriol (0.25 microgram/day), significant reductions in serum parathyroid hormone after both 4 (p = 0.03) and 8 weeks (p = 0.02) and concomitant increases in serum 1,25(OH2)D (p < 0.02) after 8 weeks of treatment were not accompanied by any change in fructosamine, glycated albumin, total calcium, or ionized calcium (p > 0.05). Elevation of serum fructosamine in these patients is consistent with the impaired glucose tolerance of uraemia. The evidence presented supports a relationship between long-term glycaemic control and 1,25(OH2)D3, but not parathyroid hormone, in moderately uraemic patients with secondary hyperparathyroidism; however, serum fructosamine was not altered by treatment with calcitriol over an 8-week period.

Calcitriol↗
PubMed1995

Effect of diabetes and peritonitis on the peritoneal equilibration test.

Peritoneal equilibration tests (PET) were performed on 47 patients (15 diabetics) who had been on CAPD for 1 to 112 months. Among new patients on CAPD (1 to 3 months) with no history of peritonitis, diabetics had higher D/PCr than non-diabetics (P < 0.02). However, after > or = 7 months of CAPD, in patients with < or = 2 episodes of peritonitis, glucose and creatinine transport rates were lower (P < 0.05) in diabetic than non-diabetic patients. Among patients on CAPD for > or = 7 months, creatinine (P < 0.05) and glucose transport (P < 0.01) were higher in patients with a history of > or = 3 episodes of peritonitis than in those with < or = 2 episodes. Drain volumes did not differ between any of the subgroups (all P > 0.05). The observations in patients newly established on CAPD were substantiated in a larger study of 55 non-diabetic and 35 non-insulin dependent diabetic patients. D/D0 glucose correlated with plasma glucose (r = 0.40, P < 0.02) in the diabetic group. Net ultrafiltration was reduced in hyperglycemic (P = 0.022) but not normoglycemic diabetics (non-diabetics 231 +/- 167 ml, hyperglycemic diabetics 127 +/- 177 ml, normoglycemic diabetics 238 +/- 159 ml). Creatinine clearance was higher in normoglycemic (P = 0.02) but not hyperglycemic diabetics (non-diabetics 6.8 +/- 0.9 ml/min, hyperglycemic diabetics 6.9 +/- 0.8 ml/min, normoglycemic diabetics 7.4 +/- 0.7 ml/min). These data show that diabetes and peritonitis incidence should be borne in mind when interpreting results of the PET.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

In vitro formation of advanced glycation end products in peritoneal dialysis fluid.

Glycation of proteins in the peritoneum might occur due to the extremely high glucose concentrations (75 to 214 mmol/liter) in the dialysate of patients on continuous ambulatory peritoneal dialysis (CAPD) and may be involved in the etiology of ultrafiltration failure. Formation of both early (glycated albumin) and late (advanced glycation end products; AGE, measured as protein-derived fluorescence intensity, FI) Maillard reaction products was studied in vitro in dialysis fluids obtained from seven patients on CAPD and in phosphate buffered saline (PBS) controls paired for glucose and albumin concentrations. Percentage glycated albumin (median, range) increased (P < 0.02) from baseline after 10 and 21 days in both dialysate and PBS but did not differ (P > 0.05) between the two media at any time point (day 0, 3.6, 3.1-4.5 vs. 4.1, 3.0-4.6; day 10, 19.4, 7.9-54.8 vs. 19.1, 8.7-50.1; day 21, 29.0, 12.0-75.6 vs. 30.0, 11.7-69.8). Glycated albumin formation was linearly related to the glucose concentration (r > 0.98, P < 0.001) in both dialysate and PBS at 10 and 21 days. FI (U/g/liter albumin, median, range) increased (P < 0.02) from baseline after 10 and 21 days in dialysate but only after 21 days in PBS; this increase was significantly greater (P < 0.02) in dialysate than in PBS after 10 and 21 days (day 0, 41, 36-46 vs. 42, 37-46; day 10, 99, 88-161 vs. 51, 34-68; day 21, 113, 102-239 vs. 68, 54-91). After 21 days, FI was significantly related to glucose concentration (r = 0.90, P < 0.01) and to % glycated albumin (r = 0.92, P < 0.01) in PBS but not in dialysate (P > 0.05). AGE formation, but not glycation, decreased as a function of the dialysate dwell time and was inhibited by aminoguanidine. Our results demonstrate that formation of AGE products occurs in dialysis fluid and that factors in dialysate can modulate this process.

Buffers↗
PubMed1992

Renal haemodynamic, hormonal and excretory effects of low-dose atrial natriuretic factor infusion in renal transplant recipients.

1. In experimental studies, activation of renal sympathetic nerves attenuates the natriuretic response to atrial natriuretic factor. We therefore investigated the response to low-dose infusion of atrial natriuretic factor in renal transplant recipients. 2. Eight male cyclosporin-treated renal transplant recipients received human-alpha atrial natriuretic factor (1-28) at a dose of 1.2 pmol min-1 kg-1 or placebo for 2 h in a placebo-controlled, randomized, cross-over study. The plasma atrial natriuretic factor concentration rose from 18.5 to 49.2 pmol/l in association with an immediate natriuresis (a rise of 49.1 mumol/min in the first 30 min, P less than 0.05; peaking at a 61% increase from baseline, P less than 0.01), diuresis (from 3.37 to 7.46 ml/min) and a threefold rise in urinary cyclic GMP excretion. 3. In response to infusion of atrial natriuretic factor, the packed cell volume rose by 4.2% (P less than 0.001) and the filtration fraction by 5% (from 22 to 27%, P less than 0.05), but there was no significant change in renal plasma flow, glomerular filtration rate or mean arterial blood pressure. Likewise, the plasma catecholamine concentrations, plasma renin activity and serum erythropoietin concentration remained unchanged. 4. The sensitivity of the renal allograft to plasma atrial natriuretic factor concentrations in the high physiological range suggests a role for endogenous atrial natriuretic factor in the modulation of graft function. Furthermore, the immediate natriuretic response to atrial natriuretic factor in the effectively denervated transplant kidney, in contrast to the delayed response seen in normal subjects, may imply that sympathetic nerves have an inhibitory effect on the renal response to atrial natriuretic factor in normal man.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗
PubMed1992

Platelet cytosolic free calcium concentration and parathyroid hormone: changing relationships with haemodialysis in end-stage renal disease.

1. Twelve patients receiving haemodialysis for end-stage renal failure were studied at a single dialysis session. Platelet cytosolic calcium concentration, plasma ionized calcium concentration and serum parathyroid hormone concentration were measured before dialysis, mid-dialysis and 30 min after dialysis. 2. Plasma ionized calcium concentration increased towards dialysate calcium concentrations, falling insignificantly after cessation of dialysis. Serum parathyroid hormone concentration fell by 39% during dialysis, with incomplete recovery afterwards. There was no overall change in platelet cytosolic calcium concentration. 3. Patients were divided into two subgroups: low parathyroid hormone (serum parathyroid hormone concentration less than 10 pmol/l) and high parathyroid hormone (serum parathyroid hormone concentration greater than 10 pmol/l). Before dialysis, values of platelet cytosolic calcium concentration or plasma ionized calcium concentration were not statistically different between the subgroups, but the platelet cytosolic calcium concentration was higher in the high-parathyroid hormone subgroup during and after dialysis. 4. Before haemodialysis there was a linear correlation between plasma ionized calcium concentration and platelet cytosolic calcium concentration, which disappeared during dialysis. In contrast, there was no relationship between serum parathyroid hormone concentration and platelet cytosolic calcium concentration before dialysis, but after dialysis a hyperbolic relationship was evident. 5. These results suggest that uraemic toxins may interfere with cytosolic calcium homoeostasis, allowing passive diffusion of extracellular calcium to influence the resting concentration, and that this effect is reversible by haemodialysis.

Adult↗
PubMed1991

Investigation and validation of the affinity chromatography method for measuring glycated albumin in serum and urine.

Affinity chromatography on m-aminophenyl boronate columns together with albumin measurement by radioimmunoassay has been validated as a method for determining glycated albumin in serum and urine. Optimisation of sample volume and of elution buffer composition and volume ensured reproducibility of results. Fructosamine assay confirmed the absence of glycated albumin species from the non-glycated fraction. It was possible to elute the glycated fraction from the affinity columns with Tris or glycine which do not contain 1,2 diols but have similar functional groups. Column affinity was, therefore, not specific for glycated protein moieties. Inhibition of binding by glucose, and other small molecules in urine, necessitated ultrafiltration or dialysis of samples before analysis. Reference ranges for glycated albumin in non-diabetic subjects were 0.6-1.8% in serum and 0.9-2.6% in urine. In patients with diabetes mellitus, glycated albumin ranged from 1.4-10.9% in serum and from 1.5-12.5% in urine.

Adult↗
PubMed1990

The effect of renal ischemia on cyclosporine clearance in rabbits.

The renal handling of cyclosporine was studied in ischemically damaged kidneys in New Zealand White rabbits and nonischemic control animals. CsA, 25 mg/kg/day, was administered intravenously for 10 days starting with the day of operation. Blood CsA (B CsA) was higher in the ischemic group compared with the controls (median: 285 micrograms/L, range 95-785 micrograms/L vs. 170 micrograms/L, range 110-185 micrograms/L, P = 0.05) on day 1 after operation. B CsA dropped rapidly to a level equivalent to the controls by day 4 (median: 105 micrograms/L, range 60-280 micrograms/L vs. 195 micrograms/L, range 70-215 micrograms/L, P = NS). Median CsA clearance (C CsA) as a percentage of creatinine clearance (C Cr) was some ten-fold greater in the ischemic animals (6.32%, range 2.93-18.41% vs. 0.55%, range 0.13-0.78%, P less than 0.001) on day 1. The ratio gradually declined, approaching the value in controls by day 10 (0.86%, range 0.24-7.21% vs. 0.23%, range 0.16-0.73%, P = 0.05). The data suggest that renal impairment has an important effect on CsA blood levels. In the clinical situation this may be of particular importance during both oliguria and the recovery from acute tubular necrosis.

Animals↗
PubMed1982

An improved radioimmunoassay for urinary Tamm-Horsfall glycoprotein. Investigation and resolution of factors affecting its quantification.

A rapid, specific radioimmunoassay has been used to measure Tamm-Horsfall glycoprotein (TH glycoprotein) in urine. The apparent concentration increased with increasing dilution of urine in water, reaching a plateau at 1 in 20. This increase was greater the higher the osmolality and TH glycoprotein concentration and the lower the pH of the original sample. A dilution of 1 in 100 was chosen for routine assay. Whole urine was centrifuged and the dissolved precipitate and supernatant assayed to quantify the proportion of TH glycoprotein of TH glycoprotein initially present in highly aggregated form. This correlated positively and significantly with increasing osmolality, decreasing pH and increasing TH glycoprotein concentration. When the urine was diluted 1 in 100 in water, no TH glycoprotein was precipitated by centrifugation and the measured concentrations were unaffected by alterations of urine pH or calcium concentration or by addition of sodium dodecyl sulphate. Parallelism was demonstrated between the diluted samples and the disaggregated standard preparation. Recovery of added standard to diluted urine varied between 96 and 114%. The apparent concentration of TH glycoprotein in neat or diluted urine was not affected by freezing or by storage at 4 degrees C or room temperature for at least 2 days. A physiological range for the urinary excretion rate was established as 22--56 mg/24 h, based on samples from 29 individuals with normal renal function, as defined by their creatinine clearance. There was no significant correlation between serum concentrations of TH glycoprotein and its urinary excretion rate, nor between urinary excretion rate and creatinine clearance.

Calcium↗
PubMed1981

Serum Tamm-Horsfall glycoprotein levels in health and in renal disease.

Serum Tamm-Horsfall glycoprotein (THG) concentrations were measured by radioimmunoassay in a group of 95 people with normal renal function and lay in the range of 70 to 540 ng/ml. None was detectable in 6 anephric patients. Patients on hemodialysis but with both kidneys in situ had concentrations below the lower limit of normal, and in some cases THG was undetectable. Healthy kidney donors generally showed a decrease in serum levels following uninephrectomy although these remained within the normal range. In contrast, all transplant recipients showed a marked increase in serum THG concentration, the rates of rise being apparently dependent upon initial graft function. These findings support the view that THG is a normal constituent of human serum whose levels are related to the amount of renal functioning mass.

Adult↗
PubMedDate not supplied

Tamm-Horsfall glycoprotein excretion and aggregation during intravenous urography. Relevance to acute renal failure.

The effect of intravenous urography (IVU) on the excretion rate and precipitation of Tamm-Horsfall glycoprotein (THG) has been evaluated in 19 patients. Urine samples were collected immediately before the administration of contrast medium (U1) and then during the period of the excretion urogram (U2). The urinary THG: creatinine clearance ratio decreased in 15 patients by a mean of 28.2% (range 2.9-70.8) and increased in four by a mean of 22.8% (range 13.5-36.4). In 18 of 19 patients the amount of THG precipitated following the IVU decreased from an average of 75.6% of the total in U1 (range 2.2-100) to 19.5% (range 2.0-59) in U2. In the one exception the fraction precipitated was only 2.2% in U1 and 2.5% in U2. It is concluded that during routine IVU there is no marked increase in the excretion rate of THG. More importantly, the percentage of THG precipitated actually decreases.

Acute Kidney Injury↗
PubMedDate not supplied

Tamm-Horsfall protein excretion during chronic alterations in urinary concentration and protein intake in the rat.

Tamm-Horsfall protein (THP), a normal constituent of mammalian urine, has been determined in rat urine under various conditions in an attempt to elucidate the physiological role of this glycoprotein. Experiments were designed to assess whether THP production is related to the process of urine concentration or to the transport activity of the thick ascending limb of the loop of Henle (TAL), the nephron segment where it is produced. For this purpose, THP excretion was measured, by radioimmunoassay, in adult male rats under 4 different conditions induced by the following chronic treatments: (1) furosemide (12 mg/day in osmotic minipumps); (2) increased water intake; (3) antidiuretic hormone (ADH) infusion (50 ng DDAVP/day in osmotic minipumps) in rats of the Brattleboro strain with hereditary hypothalamic diabetes insipidus; (4) high-protein (32% casein) versus low-protein diet (10% casein). Each experiment included 6 experimental and 6 control rats. After treatment for 1-3 weeks, 24-h urines were collected for determination of urine flow rate, osmolality, and creatinine and THP concentrations. No significant changes in THP excretion were observed in experiments (1) and (2) despite 5- to 7-fold-differences in urine flow rate. Antidiuretic hormone treatment in (3) slightly lowered THP excretion (287 +/- 53 vs. 367 +/- 41 micrograms/day per 100 g body weight; p less than 0.005), whereas high-protein diet, in experiment (4), led to a 50% increase in THP excretion (446 +/- 57 vs. 304 +/- 79 micrograms/day per 100 g body weight; p less than 0.001). Expressing THP excretion relative to that of creatine did not change these findings. These results show (1) that chronically established changes in the level of diuresis, chronic furosemide-induced blockade of the Na,K,Cl-cotransporter or the absence of ADH in Brattleboro rats have little or no impact on the level of THP production, and (2) that THP production is independent of the intensity of transport in the TAL, since two conditions which both are known to increase the transport rate of solutes in the TAL (ADH infusion and high-protein diet), resulted in opposite changes in THP excretion. It is concluded that the rate of THP synthesis is neither linked to the process of urine concentration nor to the ion transport activity of the TAL.

Animals↗
PubMedDate not supplied

Release of ouabain-like compound (OLC) from the intact perfused rat adrenal gland.

The present study was designed to investigate the effect of ACTH on release of OLC from the intact isolated rat adrenal, perfused in situ. OLC was measured by EIA. The limit of detection of the assay was 23 pmol/10 minutes. Basal levels of OLC varied from 240 to <23 pmol/10 min. Basal corticosterone levels were generally higher than OLC while aldosterone were generally lower. In 3 of the 5 perfusions the addition of ACTH was followed by rapid increases in both OLC and corticosterone secretion rates within 10 minutes of stimulation. Stimulated levels of OLC were 2 to 4-fold and of corticosterone were 3 to 7-fold those found in basal samples. OLC was found to co-elute with authentic ouabain under isocratic HPLC analysis whilst perfusion medium itself contained no detectable OLC immunoreactivity. These preliminary data suggest that the intact perfused rat adrenal preparation is a useful model for investigating the acute regulation of OLC secretion.

Adrenal Glands↗
PubMedDate not supplied

Glycation and advanced glycation end-product formation with icodextrin and dextrose.

OBJECTIVE: To review protein glycation and advanced glycation end-product formation with particular reference to its occurrence in the peritoneum following exposure to peritoneal dialysis fluid. DATA SOURCES: Articles identified through searches on MEDLINE and BIDS and references cited therein. STUDY SELECTION: Studies on the interaction of amino groups with glucose, maltose and glucose polymers. Studies containing evidence of peritoneal advanced glycation end-product formation. DATA EXTRACTION: Studies evaluated as to whether they are in vivo, ex vivo or in vitro under non-physiological or physiological conditions. RESULTS: Protein glycation is slower with maltose and glucose polymers than with equimolar glucose. Advanced glycation end-product formation occurs with all three sugars, but to a greater extent after standard heat sterilization of dialysis fluid and to a lesser extent in heat sterilized fluids containing icodextrin rather than glucose. Glucose degradation products significantly contribute to protein-linked advanced glycation end-product-like fluorescence. Histology and immunohistochemistry demonstrate diabetiform changes and advanced glycation end-products in the peritoneal membrane following exposure to glucose-containing peritoneal dialysis fluids. Their presence is likely to be detrimental to peritoneal function and may contribute to loss of ultrafiltration. CONCLUSIONS: Advanced glycation end-product formation is lower but still significant with heat sterilized peritoneal dialysis fluid containing icodextrin than with glucose. More research is needed to investigate the interaction of glucose degradation products and glucose polymers with proteins and the possible consequences of advanced glycation end-product formation on peritoneal function.

Dialysis Solutions↗