145 results on '"Coles GA"'
Search Results
2. A randomized controlled trial of a bicarbonate - and a bicarbonate/lactate - containing dialysis solution in CAPD
- Author
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Coles, Ga, Gokal, R, Ogg, C, Jani, F, O’Donoghue, Dt, Cancarini, Giovanni, Maiorca, Rosario, Tranaeus, A, Faict, D, and DE VOS, C.
- Subjects
peritoneal dialysis ,randomized controlled trial ,bicarbonate ,bicarbonate/lactate - Published
- 1997
3. A controlled trial of two bicarbonate-containing dialysis fluids for CAPD - Final report.
- Author
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Coles, GA, O'Donoghue, DJ, Pritchard, N, Ogg, CS, Jani, FM, Gokal, R, Cancarini, GC, Maiorca, R, Tranaeus, A, De Vos, C, Hopwood, A, and Faict, D
- Abstract
Background.The combination of a low pH and a high concentration of lactate which is present in most dialysis fluids is found to be cytotoxic in vitro. For these reasons it would seem logical to use a bicarbonate-containing solution and thus automatically provide a solution with a neutral pH. [ABSTRACT FROM PUBLISHER]
- Published
- 1998
- Full Text
- View/download PDF
4. Phenotype PKD2 vs. PKD1; results from the European concerted action
- Author
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Hateboer, N., Dijk, M., Torra, R., Bogdanova, N., Davies, F., Lazarou, L., Breuning, M., Saggarmalik, Ak, Jeffery, S., Millan, Jls, Martinez, I., Walker, R., Peter Holmans, Ravine, D., and Coles, Ga
5. Polycystic Kidney Disease Re-evaluated: A Population-based Study
- Author
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DAVIES, F, COLES, GA, HARPER, PS, WILLIAMS, AJ, EVANS, C, and COCHLIN, D
- Abstract
A genetic register of all known cases of autosomal dominant polycystic kidney disease occurring in South and Mid-Wales has been established. In a population of 2.1 million, 209 families with affected members were identified, 303 of whom are currently alive, 70 on renal replacement therapy. An additional 551 cases would be predicted amongst family members at 50 per cent and 25 per cent risk, giving an apparent prevalence of 1:2459 in the general population. Five possible new mutations were seen where adults with phenotypic autosomal dominant polycystic kidney disease had both parents alive, age > 55 years with no cysts visible on ultrasound. The take-on rate for renal replacement therapy increased during 1970–79 but has apparently reached a plateau of 4.8 cases per million population per year over the last 8 years, despite a rapidly increasing acceptance of uraemic patients as a whole (72/106/year in 1988–89). Considerably more patients with autosomal dominant polycystic kidney disease aged over 50 years were started on treatment in 1980–89 than in 1970–79, but the survival overall improved with time. All cases of autosomal dominant polycystic kidney disease reaching end-stage renal disease are now being treated, but the apparent clinical prevalence of this condition in our region is less than half the supposed gene frequency, suggesting that undiagnosed cases have a benign prognosis.
- Published
- 1991
6. Continuous dialysis with bicarbonate/lactate-buffered peritoneal dialysis fluids results in a long-term improvement in ex vivo peritoneal macrophage function.
- Author
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Jones S, Holmes CJ, Mackenzie RK, Stead R, Coles GA, Williams JD, Faict D, and Topley N
- Subjects
- Aged, Buffers, Cell Count, Dose-Response Relationship, Drug, Drug Combinations, Female, Humans, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal pathology, Male, Middle Aged, Recovery of Function, Time Factors, Tumor Necrosis Factor-alpha biosynthesis, Zymosan administration & dosage, Zymosan therapeutic use, Bicarbonates administration & dosage, Dialysis Solutions, Lactic Acid administration & dosage, Macrophages, Peritoneal physiology, Peritoneal Dialysis, Continuous Ambulatory
- Abstract
To circumvent the potentially negative consequences of long-term exposure to unphysiologic acidic lactate-buffered peritoneal dialysis fluids (PDF), neutral pH solutions buffered with bicarbonate/lactate have recently been introduced in phase 2 and 3 clinical trials. This study examines the longitudinal changes in peritoneal macrophage (PMØ) function in patients dialyzed continuously with either lactate (LPD; 40 mM lactate, pH 5.2)-buffered or bicarbonate/lactate (TBL; 25 mM/15 mM bicarbonate/lactate, pH 7.3)-buffered PDF. Before the study, during the run in period of a phase 3 clinical trial, all patients had been taking LPD for at least the previous 18 wk. At the beginning of the study (day 0), both constitutive and serum-treated zymosan (STZ) stimulated tumor necrosis factor alpha (TNF-alpha) synthesis were assessed in PMØ isolated from 12-h dwell effluent (with 1.36% glucose) in all patients. The patients were subsequently randomized to either continuous TBL or LPD therapy and PMØ function was assessed after further 3- and 6-mo periods in all patients. At all time points measured STZ induced a dose-dependent increase in PMØ TNF-alpha secretion (P = 0.043 versus control for doses greater than 100 microg/ml). In patients continuously dialyzed with LPD, constitutive PMØ TNF-alpha synthesis levels (mean +/- SEM, pg/10(6) PMØ per18 h, n = 5 patients) were 154 +/- 65, 261 +/- 60, and 101 +/- 99 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1340 +/- 519, 1046 +/- 586, and 758 +/- 250 at 0, 3, and 6 mo, respectively. In patients dialyzed with TBL, constitutive PMØ TNF-alpha synthesis levels (pg/10(6) PMØ per 18 h, n = 5 patients) were 300 +/- 136, 106 +/- 35, and 213 +/- 62 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1969 +/- 751, 1541 +/- 330, and 2670 +/- 671 at 0, 3, and 6 mo, respectively. At 6 mo, STZ-stimulated PMØ TNF-alpha synthesis was significantly higher in patients treated with TBL compared with those treated with LPD (P = 0.0035). These data suggest that in patients continuously dialyzed with a neutral pH solution, there is a long-term improvement in PMØ function compared with patients on conventional therapy. Better PMØ function suggests improved host defense status and may affect the peritoneum's susceptibility to infection and potentially reduce the negative consequences of repeated intraperitoneal inflammation on long-term membrane function.
- Published
- 2002
7. Confirmation of a gene locus for medullary cystic kidney disease (MCKD2) on chromosome 16p12.
- Author
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Hateboer N, Gumbs C, Teare MD, Coles GA, Griffiths D, Ravine D, Futreal PA, and Rahman N
- Subjects
- Adult, Female, Genetic Linkage, Genetic Predisposition to Disease, Humans, Kidney Medulla, Lod Score, Male, Middle Aged, Pedigree, Chromosome Mapping, Chromosomes, Human, Pair 16 genetics, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Background: Autosomal-dominant medullary cystic kidney disease (MCKD) is an interstitial nephropathy characterized by structural renal tubular defects that result in salt wasting and a reduction in urinary concentration. The condition has clinical and morphological similarities to autosomal-recessive juvenile nephronophthisis. Two genes predisposing to MCKD have been localized. MCKD1 on chromosome 1q21 was localized in two Cypriot families, and MCKD2 on chromosome 16p12 was localized in a single Italian family. We have evaluated a large Welsh MCKD family for linkage at these two loci., Methods: Clinical data and DNA samples were collected from affected family members. Polymorphic microsatellite markers spanning the critical regions on chromosome 1 and chromosome 16 that encompass MCKD1 and MCKD2 were analyzed. Two-point and multipoint LOD scores were calculated., Results: The family fulfilled previously published criteria for the diagnosis of MCKD, but hyperuricemia and gout were not prominent features. Twenty-one affected individuals were identified. Mean age at death or end-stage renal disease was 47 years (37 to 60). Linkage and haplotype analysis generated strongly negative results at MCKD1 on chromosome 1q21 (two-point LOD score = -5.32). Strong evidence of linkage to MCKD2 was generated with a maximum multi-point LOD score of 3.75., Conclusion: These results provide the first independent confirmation of a gene predisposing to MCKD on chromosome 16p12 and indicate that mutation of this gene is not restricted to a single family or population. The absence of hyperuricemia and gout in our family indicates that these are not obligatory features of MCKD2 mutations.
- Published
- 2001
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8. Bicarbonate/lactate-based peritoneal dialysis solution increases cancer antigen 125 and decreases hyaluronic acid levels.
- Author
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Jones S, Holmes CJ, Krediet RT, Mackenzie R, Faict D, Tranaeus A, Williams JD, Coles GA, and Topley N
- Subjects
- Adult, Aged, Bicarbonates therapeutic use, CA-125 Antigen metabolism, Dialysis Solutions chemistry, Female, Humans, Hyaluronic Acid metabolism, Lactates therapeutic use, Male, Middle Aged, Peptide Fragments metabolism, Procollagen metabolism, Time Factors, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta1, Bicarbonates administration & dosage, Dialysis Solutions therapeutic use, Lactates administration & dosage, Peritoneal Dialysis
- Abstract
Background: In a randomized, controlled trial comparing a pH neutral, bicarbonate/lactate (B/L)-buffered PD solution to conventional acidic, lactate-buffered solution (C), the overnight dialysate levels of markers of inflammation/wound healing [hyaluronic acid (HA)], mesothelial cell mass/membrane integrity [cancer antigen 125 (CA125)], and fibrosis [transforming growth factor-beta1 (TGF-beta1) and procollagen I peptides (PICP)] were assessed over a six-month treatment period., Methods: One hundred six patients were randomized (2:1) to either the B/L group or C group. Overnight effluents were collected at entry into the study (time = 0 all patients on control solution) and then at three and six months after randomization. Aliquots were filtered, stored frozen, and assayed for HA, CA125, TGF-beta1, and PICP. Differences between groups were assessed by repeated-measures analysis of variance for unbalanced data using the SAS procedure MIXED., Results: In patients treated with B/L, there was a significant (P = 0.03) increase in CA125 after six months compared with time = 0 (19.76 +/- 11.8 vs. 24.4 +/- 13.8 U/mL; mean +/- SD; N = 51). In the same group of patients, HA levels were significantly decreased at both three and six months in the B/L-treated group (time = 0, 336.0 +/- 195.2; time = 3 months, 250.6 +/- 167.6; and time = 6 months, 290.5 +/- 224.6 ng/mL; mean +/- SD; P = 0.006, N = 47 and P = 0.003, N = 48, respectively). No significant changes in CA125 or HA levels were observed in the control group. There were no significant changes observed in the levels of PICP or TGF-beta1 in the B/L or C group over the six-month treatment period., Conclusions: These results suggest that continuous therapy with the B/L solutions modulates the levels of putative markers of peritoneal membrane integrity and inflammation. In the long term, this may positively impact the peritoneal membrane, increasing its life as a dialyzing organ.
- Published
- 2001
- Full Text
- View/download PDF
9. Clinical research in peritoneal dialysis.
- Author
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Coles GA
- Subjects
- Biological Transport, Biomarkers, Case-Control Studies, Clinical Trials as Topic methods, Collagen chemistry, Collagen drug effects, Creatinine blood, Dialysis Solutions adverse effects, Epithelium drug effects, Epithelium pathology, Fibrosis, Glucose adverse effects, Glucose pharmacology, Humans, Metabolic Clearance Rate, Molecular Weight, Peritoneal Dialysis, Continuous Ambulatory adverse effects, Peritoneal Dialysis, Continuous Ambulatory methods, Peritoneum blood supply, Peritoneum drug effects, Peritoneum metabolism, Research Design, Uremia metabolism, Uremia mortality, Uremia pathology, Uremia therapy, Peritoneal Dialysis adverse effects, Peritoneal Dialysis methods, Peritoneum pathology
- Published
- 2001
- Full Text
- View/download PDF
10. Long-term peritoneal membrane changes.
- Author
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Coles GA and Topley N
- Subjects
- Humans, Kidney Failure, Chronic metabolism, Peritoneum metabolism, Sclerosis, Time Factors, Ultrafiltration, Kidney Failure, Chronic pathology, Kidney Failure, Chronic therapy, Peritoneal Dialysis, Peritoneum pathology
- Abstract
There is increasing evidence that long-term peritoneal dialysis (PD) is associated with structural changes in the peritoneal membrane. These consist of thickening of the sub-mesothelial space owing to collagen deposition and alterations in small blood vessel morphology. These alterations become more pronounced with duration of PD therapy. These changes are associated with a tendency to increasing small solute transport rate with reduced ultrafiltration. The relationship between these structural and functional changes remains unknown, but the evidence suggests that both peritonitis and exposure to dialysate contribute. The most likely components of the fluid responsible for this effect are glucose and/or its degradation products generated during heat sterilisation. Serial monitoring of peritoneal function is well established, but repeat biopsies are not practical. Effluent markers are not yet of proven value but do alter in response to a change in dialysate composition. Hopefully, a combination of reduced inflammation and more biocompatible fluids will reduce long-term changes in peritoneal membrane structure and function with a consequent improvement in patient and technique survival., (Copyright 2000 by the National Kidney Foundation, Inc.)
- Published
- 2000
- Full Text
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11. In vivo exposure to bicarbonate/lactate- and bicarbonate-buffered peritoneal dialysis fluids improves ex vivo peritoneal macrophage function.
- Author
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Mackenzie RK, Jones S, Moseley A, Holmes CJ, Argyle R, Williams JD, Coles GA, Pu K, Faict D, and Topley N
- Subjects
- Adult, Aged, Bicarbonates adverse effects, Female, Humans, Hydrogen-Ion Concentration, Lactic Acid adverse effects, Macrophage Activation drug effects, Macrophage Activation immunology, Macrophages, Peritoneal immunology, Male, Middle Aged, Peritonitis immunology, Tumor Necrosis Factor-alpha metabolism, Bicarbonates administration & dosage, Dialysis Solutions, Lactic Acid administration & dosage, Macrophages, Peritoneal drug effects, Peritoneal Dialysis, Continuous Ambulatory
- Abstract
The impact on peritoneal macrophage (PMO) function of acidic lactate-buffered (Lac-PDF [PD4]; 40 mmol/L of lactate; pH 5.2) and neutral-pH, bicarbonate-buffered (TB; 38 mmol/L of bicarbonate; pH 7. 3) and bicarbonate/lactate-buffered (TBL; 25 mmol/L of bicarbonate/15 mmol/L of lactate; pH 7.3) peritoneal dialysis fluids (PDFs) was compared during a study of continuous therapy with PD4, TB, or TBL. During a run-in phase of 6 weeks when all patients (n = 15) were treated with their regular dialysis regimen with Lac-PDF, median PMO tumor necrosis factor alpha (TNFalpha) release values were 203.6, 89.9, and 115.5 pg TNFalpha/10(6) PMO in the patients subsequently randomized to the PD4, TB, and TBL treatment groups, respectively. Median stimulated TNFalpha values (serum-treated zymosan [STZ], 10 microgram/mL) were 1,894.6, 567.3, and 554.5 pg TNFalpha/10(6) PMO in the same groups, respectively. During the trial phase of 12 weeks, when the three groups of patients (n = 5 per group) were randomized to continuous treatment with PD4, TB, or TBL, median constitutive TNFalpha release values were 204.7, 131.4, and 155.4 pg TNFalpha/10(6) PMO, respectively. Stimulated TNFalpha values (STZ, 10 microgram/mL) were 1,911, 1,832, and 1,378 pg TNFalpha/10(6) PMO in the same groups, respectively. Repeated-measures analysis of variance comparing the run-in phase with the trial phase showed that PMO TNFalpha release was significantly elevated in patients treated with both TB (P = 0.040) and TBL (P = 0.014) but not in patients treated with Lac-PDF (P = 0. 795). These data suggest that patients continuously exposed to bicarbonate- and bicarbonate/lactate-buffered PDFs might have better preserved PMO function and thus improved host defense status.
- Published
- 2000
- Full Text
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12. Biocompatibility and new fluids.
- Author
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Coles GA
- Subjects
- Animals, Humans, Biocompatible Materials, Dialysis Solutions toxicity, Peritoneal Dialysis instrumentation
- Published
- 1999
13. What is the place of peritoneal dialysis in the integrated treatment of renal failure?
- Author
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Coles GA and Williams JD
- Subjects
- Evaluation Studies as Topic, Humans, Quality of Life, Renal Dialysis, Renal Replacement Therapy, Treatment Outcome, Kidney Failure, Chronic therapy, Peritoneal Dialysis
- Abstract
The role of peritoneal dialysis (PD) in renal replacement therapy (RRT) remains unclear. There are no controlled trials to provide hard evidence of its efficacy. Comparative studies with haemodialysis from different centres and countries have given conflicting results even when allowing for case mix. Data from the United States on patients starting or receiving treatment in the late 1980s suggested a worse prognosis for older patients, particularly diabetics receiving PD as compared to HD. Analysis of the USRDS data base for patients starting in the early 1990s shows an improvement in outcome but with no difference in overall mortality. The Canadian registry has recently published data showing a better survival with PD than with HD in the first two years of RRT. Morbidity is similar with both therapies, although hospitalization is increased with PD. Unfortunately long-term technique survival is not as good with PD. However, PD has certain medical advantages, particularly the maintenance of residual renal function that contributes to solute and fluid removal. It may also postpone the onset of amyloidosis. Patients transplanted after previous PD have a decreased risk of early acute renal failure and equally good long-term results when compared to those patients who were on HD before transplantation. The quality of life is as good with PD as with center HD, and there are social advantages to PD including an increased chance of employment, more flexible holidays and avoidance of thrice weekly travel to a dialysis center. PD also has logistical advantages and can be utilized by the majority of new patients. We therefore conclude that PD has potential advantages early in the course of RRT, and should therefore be offered as a first option to all suitable new patients. Whether PD has a major or minor role in later years (> 5) remains unclear.
- Published
- 1998
- Full Text
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14. Bicarbonate/lactate- and bicarbonate-buffered peritoneal dialysis fluids improve ex vivo peritoneal macrophage TNFalpha secretion.
- Author
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MacKenzie RK, Holmes CJ, Moseley A, Jenkins JP, Williams JD, Coles GA, Faict D, and Topley N
- Subjects
- Aged, Bicarbonates, Buffers, Female, Glucose, Humans, In Vitro Techniques, Lactates, Lipopolysaccharides pharmacology, Male, Middle Aged, Peritonitis etiology, Peritonitis prevention & control, Dialysis Solutions pharmacology, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal metabolism, Peritoneal Dialysis adverse effects, Peritoneal Dialysis methods, Tumor Necrosis Factor-alpha metabolism
- Abstract
Peritoneal macrophage (PMO) function was examined ex vivo after their in vivo exposure to either acidic, lactate-buffered solutions (PD4; 40 mM lactate, pH 5.2), bicarbonate/lactate-buffered solution (TBL; 25 mM/15 mM bicarbonate/lactate, pH 7.3), or bicarbonate-buffered solution (TB; 38 mM bicarbonate, pH 7.3), containing either 1.36 or 3.86% glucose. Initial experiments demonstrated that tumor necrosis factor-alpha (TNFalpha) release (assessed by TNF-direct immunoassay [DIA]) from PMO isolated from the peritoneal cavities of patients exposed to conventional fluid (PD4 1.36% glucose) was lowest after 30 min of intraperitoneal dwell (3591+/-1200 versus 28,946+/-9359 for 240-min dwell [pg/ml], n=5, P < 0.05). Five patients were exposed on 3 successive days to PD4, TBL, and TB for 30-min acute dwells containing 1.36% glucose in the first week and 3.86% glucose during the second. PMO TNFalpha release was assessed after ex vitro exposure to lipopolysaccharide (LPS). Exposure of PMO to TBL or TB (1.36% glucose) resulted in a significant increase in the generation of TNFalpha (pg/2 X 10(6) PMO) compared with PD4. TBL: 68,659+/-35,633, TB: 53,682+/-26,536 versus PD4 17,107+/-8996 (LPS 1.0 ng/ml, n=5 patients, P=0.043 versus PD4 for both). PMO that were recovered from PD4 and TB dwells (3.86% glucose) showed no significant difference in TNFalpha secretion (21,661+/-6934 and 23,923+/-9147, respectively). In contrast, exposure to TBL resulted in a significant increase (41,846+/-11,471) compared with PD4 (LPS 1.0 ng/ml, n=5 patients, P=0.043). These data demonstrate enhanced PMO function after in vivo exposure to bicarbonate- and bicarbonate/lactate-buffered solutions. This response was sustained in TBL alone at the highest glucose concentrations. These results suggest that the newer solutions, and particularly bicarbonate/lactate, might improve host defense status in peritoneal dialysis patients.
- Published
- 1998
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15. Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease.
- Author
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Baboolal K, Ravine D, Daniels J, Williams N, Holmans P, Coles GA, and Williams JD
- Subjects
- Adult, Age of Onset, Female, Humans, Kidney Failure, Chronic epidemiology, Male, Gene Deletion, Kidney Failure, Chronic genetics, Peptidyl-Dipeptidase A genetics, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant genetics, Polymorphism, Genetic genetics
- Abstract
To determine the effect of the ACE gene insertion/deletion (I/D) polymorphism, angiotensinogen gene M235T polymorphism and the angiotensin 1 receptor gene A1166C polymorphism on the age of onset of end-stage renal failure (ESRF) in PKD1 adult autosomal-dominant polycystic kidney disease (ADPKD), 189 individuals from 46 families with PKD1 were genotyped for each polymorphism. Of the 189 patients 52 (28%) reached ESRF at an average age of 48 +/- 1 year. In patients genotyped for the ACE gene insertion/deletion polymorphism the frequencies of the DD, ID and II genotypes were similar to those expected from Hardy Weinberg equilibrium. In patients with ESRF there was an excess of patients homozygous for the deletion allele (DD: 48% chi2 = 9.97 (1df) P = 0.002). Cumulative renal survival was significantly reduced among those with DD genotype compared to ID and II genotypes. The estimated mean renal survival (95% confidence intervals) were: DD, 52 years [48, 57]; II, 59 years [54, 63]; ID, 64 years [56, 72]; chi2 = 6.13 (1df) P = 0.013, DD versus ID/II. The mean age of renal failure was significantly younger in the DD genotype compared to ID and II genotypes (DD, ID, and II: 44 +/- 2, 49 +/- 2 and 54 +/- 3 years, respectively; P < 0.05 DD vs. ID, P < 0.05 DD vs. II). Ten of the eleven patients who reached ESRF before the age of 40 were homozygous for the deletion allele. The relative risk for ESRF below the age 40 for DD genotype was 17. For all ages there was an overall increased risk of 1.4 for ESRF with the DD genotype. There was no interaction between age of onset of ESRF and either the angiotensinogen M235T allele or angiotensin 1 receptor A1166C polymorphism. This study strongly suggests that PKD 1 patients homozygous for the deletion allele of the ACE gene are at increased risk of developing ESRF at a early age.
- Published
- 1997
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16. Have we underestimated the importance of fluid balance for the survival of PD patients?
- Author
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Coles GA
- Subjects
- Humans, Peritoneal Dialysis adverse effects, Peritoneal Dialysis mortality, Peritoneal Dialysis, Continuous Ambulatory, Water-Electrolyte Imbalance diagnosis, Water-Electrolyte Imbalance etiology, Peritoneal Dialysis methods, Water-Electrolyte Balance
- Published
- 1997
17. Staphylococcal exoproducts down-regulate cyclooxygenase 1 and 2 in peritoneal macrophages.
- Author
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Mackenzie RK, Topley N, Neubauer A, Coles GA, and Williams JD
- Subjects
- Adolescent, Adult, Aged, Antibodies analysis, Cell Culture Techniques, Cyclooxygenase 1, Cyclooxygenase 2, Down-Regulation physiology, Eicosanoids biosynthesis, Female, Humans, Isoenzymes immunology, Isoenzymes metabolism, Male, Membrane Proteins, Middle Aged, Polymerase Chain Reaction methods, Prostaglandin-Endoperoxide Synthases immunology, Prostaglandin-Endoperoxide Synthases metabolism, RNA, Messenger biosynthesis, RNA, Messenger drug effects, Staphylococcus aureus isolation & purification, Exotoxins pharmacology, Isoenzymes drug effects, Macrophages, Peritoneal enzymology, Peritoneal Dialysis, Continuous Ambulatory, Prostaglandin-Endoperoxide Synthases drug effects, Staphylococcus aureus metabolism
- Abstract
Peritoneal macrophages (PMOs) are important components of the host defense against microbial infection in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Incubation of human PMOs with cell-free supernatant (BFS), prepared from Staphylococcus aureus, inhibited prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) production. Slot-blot analysis of cyclooxygenase-1 (Cox-1) and Cox-2 demonstrated a decrease in both Cox-1 (29%) and, to a greater extent, Cox-2 (65%) protein expression after BFS stimulation. When competitive polymerase chain reaction (PCR) was used, the peak levels of Cox-1 and Cox-2 messenger ribonucleic acid (mRNA) in unstimulated PMOs were 0.304+/-0.13 pmol/L and 9.61+/-2.84 pmol/L (mean+/-SEM, n = 3), respectively. After exposure of samples to BFS for 30 minutes, the level of Cox-2 mRNA was reduced to 0.59+/-0.449 pmol/L (16-fold reduction, p < 0.05), and the level of Cox-1 mRNA was reduced to 0.02+/-0.002 pmol/L (15-fold reduction, p < 0.05). In contrast, these same PMOs showed an increased expression of IL-6 mRNA and increased secretion of IL-6 protein. These results indicate that prostaglandin production in PMOs is regulated by alterations in both immunoreactive Cox-1 and Cox-2. The down-regulation of Cox metabolism in these cells is primarily related to the delayed and depressed increase in the Cox-2 gene product.
- Published
- 1997
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18. Progressive renal failure.
- Author
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el Nahas AM and Coles GA
- Subjects
- Aged, Dietary Proteins administration & dosage, Humans, Kidney Failure, Chronic therapy
- Abstract
Blood pressure control is important and lower target values are required in those with proteinuria. ACEI are suitable agents provided the doctor is aware of the risks of renovascular disease in the elderly. Renal function should be checked after two weeks treatment; deterioration calls for cessation of ACEI treatment and investigation for renal arterial disease. Low protein diet should not be used routinely but high protein diet should be avoided. If a highly motivated patient wishes to try protein reduction in case it is beneficial, no less than 0.6 g protein/day should be prescribed. The patient must be reviewed regularly by a specialist dietitian who can check nutritional state. Regular medical follow-up is essential; it has been shown to slow progression of renal failure probably because patients become more compliant with therapy, particularly antihypertensives. When should this follow-up be transferred to the renal unit? Studies from many countries have shown that late referral and/or emergency first dialysis are associated with substantially increased mortality and morbidity. Patients in whom the primary diagnosis is in doubt should be seen early; those in whom the cause is known, conservative treatment in place and without uraemic symptom should be transferred by the time the serum creatinine reaches 300 mumol/l.
- Published
- 1997
19. A randomized controlled trial of a bicarbonate- and a bicarbonate/lactate-containing dialysis solution in CAPD.
- Author
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Coles GA, Gokal R, Ogg C, Jani F, O'Donoghue DT, Cancarini GC, Maiorca R, Tranaeus A, Faict D, and de Vos C
- Subjects
- Adult, Aged, Humans, Middle Aged, Prospective Studies, Bicarbonates blood, Dialysis Solutions adverse effects, Lactic Acid blood, Peritoneal Dialysis, Continuous Ambulatory
- Abstract
Objective: To evaluate the safety and efficacy of bicarbonate- and bicarbonate/lactate-based PD fluids., Design: A randomly allocated prospective controlled trial lasting eight weeks., Setting: Five renal units in Europe., Patients: Individuals who have been treated by CAPD for at least three months and who have had at least one month's therapy with 40 mmol/L lactate PD fluid. Those with recent infection, diabetes or other serious illness are excluded. Forty-seven individuals have entered the study so far., Interventions: Patients are randomly allocated to three groups. Group 1 receive 40 mmol/L lactate dialysate, Group 2 are given 38 mmol/L bicarbonate fluid and Group 3 are tested with a 25 mmol/L bicarbonate and 15 mmol/L lactate dialysate., Outcome Measures: The primary outcome measure is the plasma bicarbonate level. Adverse events and ease of use of the two-chambered bags used by Groups 2 and 3 are also being assessed., Results: To date, plasma bicarbonate levels have been the same in all treatment groups up to the end of the trial period. There are no differences in serum lactate levels. No side effects are attributable to the test fluids. The patients have managed the two-chambered bags successfully., Conclusion: This trial is still ongoing, but to date, neutral bicarbonate based fluids have been as effective as lactate dialysate in treating uremic acidosis.
- Published
- 1997
20. IL-1 beta, a major stimulator of hyaluronan synthesis in vitro of human peritoneal mesothelial cells: relevance to peritonitis in CAPD.
- Author
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Yung S, Coles GA, and Davies M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cells, Cultured, Cytokines pharmacology, Dialysis Solutions pharmacology, Epithelial Cells, Epithelium drug effects, Hemoglobins, Humans, Hyaluronic Acid chemistry, Middle Aged, Hyaluronic Acid biosynthesis, Interleukin-1 pharmacology, Peritoneal Cavity cytology, Peritoneal Dialysis, Continuous Ambulatory, Peritonitis metabolism
- Abstract
The effect of several different growth factors and cytokines on the synthesis of hyaluronan (HA) by human peritoneal mesothelial cells (HPMC) was investigated. Growth arrested HPMC synthesized low levels of HA, but co-culture with PDGF-bb, TGF-beta 1, TNF-alpha, and IL-6 at a concentration of 10 ng/ml all increased HA synthesis between two- to three-fold. At the same concentration IL-1 beta significantly increased the synthesis eight-fold (N = 3; P < 0.05). The effect of IL-1 beta was also dose- and time-dependent and could be totally negated with interleukin-1 receptor antagonist (IL-1 beta RcA). Non-infected and infected dialysate from patients receiving CAPD was also found to stimulate HA synthesis by HPMC. The levels found with non-infected fluid were 4 x 10(4) dpm/ml (N = 6) and 12.9 x 10(4) dpm/ml (N = 6; P < 0.002) and 8.7 x 10(4) dpm/ml (N = 6; P < 0.003) for infected fluid collected one and two days after the commencement of peritonitis. IL-1 beta RcA dramatically reduced the effect of infected but not non-infected dialysate. These results provide new insights into the manner in which HA synthesis is controlled in the mesothelium and suggest that IL-1 beta is a key cytokine in the inflammatory response in CAPD patients.
- Published
- 1996
- Full Text
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21. Superinduction of IL-6 synthesis in human peritoneal mesothelial cells is related to the induction and stabilization of IL-6 mRNA.
- Author
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Witowski J, Jörres A, Coles GA, Williams JD, and Topley N
- Subjects
- Cell Division drug effects, Cells, Cultured, Culture Media, Conditioned pharmacology, Cycloheximide pharmacology, Dactinomycin pharmacology, Dialysis Solutions pharmacology, Dose-Response Relationship, Drug, Electrophoresis, Agar Gel, Epithelial Cells, Epithelium drug effects, Humans, Interleukin-1 pharmacology, Macrophages, Peritoneal metabolism, Models, Biological, Peritoneal Cavity cytology, Peritonitis etiology, Polymerase Chain Reaction, RNA, Messenger analysis, Receptors, Interleukin-1 antagonists & inhibitors, Time Factors, Epithelium metabolism, Gene Expression Regulation, Interleukin-6 biosynthesis, Interleukin-6 genetics
- Abstract
The initiation of peritonitis is accompanied by a massive increase in intraperitoneal levels of IL-6. The source of this cytokine and the mechanism by which its levels are increased so dramatically are unknown. We examined the mechanism of IL-6 secretion by HPMC exposed to the milicu present in the peritoneal cavity during the initiation of inflammation. Exposure of HPMC to spent peritoneal dialysis effluent (PDE) or IL-1 beta resulted in a time- and dose-dependent increase in IL-6 secretion. After 24 hours the IL-6 release (pg/microgram cell protein) was increased from 5.0 +/- 0.8 in control cells to 16.0 +/- 2.4 and to 83.8 +/- 17.4 in HPMC treated with PDE and IL-1 beta (1000 pg/ml), respectively (N = 5, P < 0.05). If, however, PDE and IL-1 beta were combined, then the secretion of IL-6 was synergistically increased to 747.7 +/- 349.9 (P < 0.05 vs. expected additive value). The same effect was evident when PDE was combined with TNF alpha or mixed with peritoneal macrophage conditioned medium. These changes were not a reflection of HPMC proliferation as estimated by 3H-thymidine incorporation. The "superinduction" of IL-6 release was associated both with the induction and stabilization of IL-6 mRNA. Competitive PCR demonstrated that the amount of IL-6 mRNA (fM/microgram total RNA) was increased from 0.35 +/- 0.13 in control cells to 11.66 +/- 3.89 and to 10.83 +/- 5.17 in HPMC treated with PDE and IL-1 beta (100 pg/ml), respectively (N = 5, P < 0.05). The combination of PDE + IL-1 beta synergistically increased IL-6 mRNA levels to 56.33 +/- 8.79 (P < 0.05 vs. additive value). RNA stability experiments using actinomycin D revealed that the half life of IL-6 mRNA (hours) was increased from 2.8 hours in control cells to 6.7 and 9.4 in HPMC exposed to PDE and IL-1 beta, respectively. The combination of PDE together with IL-1 beta resulted in a prolonged stabilization of IL-6 mRNA with levels remaining constant over the 12 hours of the experiment. These data demonstrate that HPMC IL-6 synthesis can be synergistically amplified in the presence of peritoneal dialysis effluent and PMO-derived cytokines. The results suggest that the peritoneal mesothelium may be responsible for the dramatic rise in IL-6 levels seen during the initial stages of CAPD peritonitis.
- Published
- 1996
- Full Text
- View/download PDF
22. Effects of intravenous adenosine on renal function in healthy human subjects.
- Author
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Balakrishnan VS, Coles GA, and Williams JD
- Subjects
- Adult, Hemodynamics drug effects, Humans, Injections, Intravenous, Kidney Tubules drug effects, Kidney Tubules physiology, Male, Osmolar Concentration, Reference Values, Renal Circulation drug effects, Renin blood, Adenosine pharmacology, Kidney drug effects, Kidney physiology
- Abstract
The vasoactive nucleoside adenosine has an important regulatory influence on most aspects of renal function in experimental animals. In this study, we evaluated the effects of intravenous adenosine on systemic and renal hemodynamics, tubular function, and plasma renin concentration in 10 healthy male subjects. Each of the subjects received two intravenous infusions of adenosine (70 micrograms.kg-1.min-1) and saline on three separate study days. There was no significant change in systemic blood pressure in response to adenosine, although there was a significant rise in heart rate postcommencement of adenosine (61.5 +/- 2.9 to 78.0 +/- 7.9 beats/min, 1 h postcommencement of adenosine on day 1, P < 0.01 vs. saline). There was a significant decline in 51Cr-EDTA clearance (glomerular filtration rate) (118.5 +/- 13.2 to 88.0 +/- 8.3 ml/min, P < 0.05 vs. saline) and filtration fraction (19.4 +/- 1.01 to 16.0 +/- 1.03%, P < 0.01 vs. saline) 1 h postcommencement of adenosine, although there was no significant change in 125I-hippuran clearance (effective renal plasma flow). Urine flow rate and osmolar and free water clearance decreased significantly in response to adenosine (particularly on study day 1). There was, in addition, a significant reduction in absolute and fractional excretion rates of sodium, lithium, phosphate, uric acid, chloride, and urea in response to adenosine. There was a rise in plasma renin concentration in response to adenosine, reaching levels of statistical significance on study day 1 (15.0 +/- 2.02 to 22.2 +/- 2.00 microU/ml, 1 h postcommencement of adenosine; P < 0.05 vs. saline). These data are consistent with observations in experimental animals and complement the results of previous studies in man using a selective adenosine A1-receptor antagonist, thereby confirming that adenosine has a significant regulatory influence on human renal function.
- Published
- 1996
- Full Text
- View/download PDF
23. Biocompatibility of bicarbonate buffered peritoneal dialysis fluids: influence on mesothelial cell and neutrophil function.
- Author
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Topley N, Kaur D, Petersen MM, Jörres A, Passlick-Deetjen J, Coles GA, and Williams JD
- Subjects
- Adenosine Triphosphate metabolism, Base Sequence, Bicarbonates, Biocompatible Materials, Buffers, DNA Primers genetics, Epithelium pathology, Epithelium physiopathology, Humans, Hydrogen-Ion Concentration, In Vitro Techniques, Interleukin-6 genetics, Kidney Failure, Chronic pathology, Kidney Failure, Chronic physiopathology, Kidney Failure, Chronic therapy, Luminescent Measurements, Molecular Sequence Data, Neutrophils physiology, Phagocytosis, RNA, Messenger genetics, RNA, Messenger metabolism, Staphylococcus aureus immunology, Staphylococcus epidermidis immunology, Dialysis Solutions chemistry, Peritoneal Dialysis, Continuous Ambulatory methods
- Abstract
The present study compares the effects of lactate and bicarbonate buffered PDF on human neutrophil (PMN) and human peritoneal mesothelial cell (HPMC) viability and function. Acute exposure of PMN to lactate buffered PDF at pH 5.5 (CAPD 2, 1.5% and CAPD 3, 4.25% glucose) resulted in significant reductions in cellular ATP levels, the phagocytosis of serum treated zymosan (STZ) and respiratory burst activation (CL). Exposure of PMN to bicarbonate buffered PDF (BIC 20, 1.5% glucose and BIC 30, 4.25% glucose both at pH 7.2) had no significant effect on cell viability or the CL response. Phagocytosis was, however, depressed significantly more following exposure to BIC 30 than BIC 20. PMN cellular ATP levels and phagocytosis were significantly better in cells exposed to BIC 30 than to CAPD 3 at pH 7.4 (P = 0.043 for both). Pre-exposure of HPMC to CAPD 2, CAPD 3 or BIC 30 for 30 minutes resulted in a significant reduction in cellular ATP content compared to control medium. Pre-exposure to BIC 20 did not result in a reduction in HPMC ATP levels. HPMC synthesis of IL-6 was unaffected by 15 or 30 minutes pre-exposure to BIC 20 or BIC 30, in contrast pre-exposure to CAPD 2 or CAPD 3 for 15 or 30 minutes resulted in a significant reduction in stimulated IL-6 synthesis (24.5 +/- 3.01 and 32.3 +/- 5.0 vs. 43.9 +/- 10 pg/microgram cell protein in M199, N = 6; P = 0.02). Neutralization of the pH of CAPD 2 and CAPD 3 resulted in normalization of HPMC IL-6 secretion. Analysis of IL-6 mRNA expression in control, BIC 20 and 30 pre-treated HPMC subsequently stimulated with IL-1 beta revealed no differences in the expression of the IL-6 specific 465 base pair transcripts. The improved cellular function in bicarbonate buffered PDF indicates potentially improved host defence status and preservation of the peritoneal membrane in CAPD patients.
- Published
- 1996
- Full Text
- View/download PDF
24. Effects of a selective adenosine A1 receptor antagonist on the development of cyclosporin nephrotoxicity.
- Author
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Balakrishnan VS, von Ruhland CJ, Griffiths DF, Coles GA, and Williams JD
- Subjects
- Animals, Blood Pressure drug effects, Drug Interactions, Glomerular Filtration Rate drug effects, Kidney Diseases chemically induced, Male, Nifedipine pharmacology, Rats, Rats, Sprague-Dawley, Renal Plasma Flow, Effective drug effects, Vasodilator Agents pharmacology, Cyclosporine toxicity, Immunosuppressive Agents toxicity, Kidney Diseases prevention & control, Purinergic Antagonists, Pyrazoles pharmacology, Pyridines pharmacology
- Abstract
1. The clinical application of cyclosporin as an immunosuppressive agent is limited by its nephrotoxicity. 2. The effect of FK453, a selective A1-receptor antagonist, administered twice daily to rats at a dose of 100 mg kg-1 was assessed on the development of nephrotoxicity induced by cyclosporin (10 mg kg-1 i.p. daily) administered for 14 days. The effects of nifedipine administered twice daily (0.3 mg kg-1 s.c.) for 14 days, on cyclosporin nephrotoxicity were also studied. 3. Cyclosporin induced a 46.58% and 35.78% decline in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) respectively and a reduction of 16.69% in filtration fraction (FF). Co-administration of FK453 resulted in falls of 30.5%, 18.59% and 14.7% in GFR, ERPF and FF respectively, the former two significantly less than the falls seen with cyclosporin (CyA) alone (P < 0.05 vs CyA, ANOVA). 4. Nifedipine appeared to have a more pronounced protective effect resulting in a decline of only 20.91% in GFR, with no significant change in ERPF (increase of 0.93%) when co-administered with CyA. 5. These observations indicate adenosine plays a minor role in the pathophysiology of CyA nephrotoxicity.
- Published
- 1996
- Full Text
- View/download PDF
25. Functional role of endogenous adenosine in human chronic renal disease.
- Author
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Balakrishnan VS, Coles GA, and Williams JD
- Subjects
- Adult, Chronic Disease, Diuresis drug effects, Double-Blind Method, Electrolytes urine, Female, Glomerular Filtration Rate drug effects, Humans, Kidney Tubules physiopathology, Male, Middle Aged, Natriuresis drug effects, Osmolar Concentration, Purinergic P1 Receptor Antagonists, Pyrazoles pharmacology, Pyridines pharmacology, Renal Circulation, Renal Plasma Flow, Effective drug effects, Renin blood, Adenosine physiology, Kidney Diseases physiopathology
- Abstract
Endogenous adenosine has been postulated to have a pathophysiological role both in the initiation and persistence of acute renal failure. The recent advent of selective adenosine receptor antagonists suitable for clinical studies now makes it possible to assess the influence of this vasoactive compound in chronic renal disease. In this study we evaluated the effects of FK453, a non-xanthine selective adenosine A1 receptor antagonist on renal haemodynamics, tubular function and plasma renin release in two groups of patients with stable chronic renal disease. Group I (n = 6) consisted of patients with creatinine clearance > or = 71 ml/min and group II (n = 7) patients with moderate renal impairment (creatinine clearance 31-70 ml/min). Each patient received two single oral doses of FK453 (50 and 200 mg) and one matched placebo dose in a random order, each on separate study days. Renal haemodynamics, tubular function and plasma renin concentrations were assessed at baseline and after the dose on each study day. There were no significant changes in mean arterial blood pressure, effective renal plasma flow (clearance of 125I-hippuran) or glomerular filtration rate (clearance of 51Cr-EDTA) in response to FK453 in either group. In contrast, there were statistically significant increases in urine flow rate and osmolar clearance, as well as absolute and fractional sodium, phosphate, bicarbonate, lithium, uric acid, magnesium and chloride excretion in response to FK453 in both groups of patients. There was, in addition, a significant increase in the plasma renin concentration in response to FK453 in both groups. These data would be consistent with a regulatory role for adenosine in chronic renal disease in the control of tubular function, especially proximal, as well as plasma renin release by activation of the A1 receptor.
- Published
- 1996
26. Tumor necrosis factor-alpha augments the pro-inflammatory interaction between PMN and GBM via a CD18 dependent mechanism.
- Author
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Donovan KL, Coles GA, and Williams JD
- Subjects
- Basement Membrane immunology, Basement Membrane metabolism, Cell Adhesion, Collagen metabolism, Humans, Kidney Glomerulus immunology, Neutrophils drug effects, Receptors, Fc physiology, CD18 Antigens physiology, Glomerulonephritis etiology, Kidney Glomerulus metabolism, Neutrophils physiology, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Acute glomerulonephritis is frequently associated with intraglomerular neutrophil (PMN) accumulation and the intensity of the inflammatory reaction is correlated with elevated concentrations of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha). PMN are thought to damage glomeruli due to a combination of reactive oxygen species and proteolytic enzymes. Using an in vitro model of anti-GBM nephritis the effects of TNF alpha on GBM damage by PMN were evaluated. The interaction of GBM and PMN resulted in a low grade respiratory burst that was significantly augmented by the addition of TNF alpha. Luminol dependent chemiluminescence (LCL) was increased from 2.4 x 10(6) to 48.1 x 10(6) (P < 0.05). The GBM induced LCL could be > 85% inhibited by blocking with monoclonal antibodies (mAbs) to the common beta chain of the PMN beta 2 integrin family (CD18), but was unaffected by mAbs to CD11a or CD11b subunits. Degradation of GBM, however, was not influenced by either TNF alpha priming of PMN or anti-beta 2 integrin mAbs. When PMN were incubated with GBM-anti-GBM IgG complex they underwent an increase in LCL from 2.4 x 10(6) to 31.1 x 10(6). They also degraded more GBM than controls (10.1% vs. 1.8%). These aspects of PMN activation were Fc receptor mediated, dependent upon anti-GBM IgG being bound to GBM and inhibited by mAb to the PMN Fc receptor. These studies show that TNF alpha can modulate the inflammatory response of PMN in contact with GBM in a CD18 dependent manner. In contrast, Fc receptor mediated events are uninfluenced by TNF alpha.
- Published
- 1995
- Full Text
- View/download PDF
27. Staphylococcus aureus infections during peritoneal dialysis.
- Author
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Coles GA
- Subjects
- Humans, Nose microbiology, Staphylococcal Infections drug therapy, Staphylococcal Infections prevention & control, Staphylococcus aureus isolation & purification, Peritoneal Dialysis adverse effects, Staphylococcal Infections etiology
- Abstract
Peritoneal dialysis is in widespread use for the treatment of chronic renal failure. Infection is still one of the major complications and can include peritonitis and pericannular problems. The rate of peritonitis is currently 0.5 episodes per patient year with disconnect systems, and there are about 0.4 exit-site infections (ESIs) per patient year. ESI is associated with a high rate of catheter removal and replacement. Staphylococcus aureus is a common cause of peritonitis and accounts for more than half of all ESIs. Nasal carriage of S. aureus is associated with a much higher rate of ESI. Treatment of ESIs is unsatisfactory. The type of exit-site care, however, does influence the rate of infection and prophylaxis with oral rifampicin and local or nasal mupirocin has been claimed to reduce ESIs. A large multicentre double-blind trial of nasal mupirocin has just been completed and preliminary results show a reduction in the incidence of S. aureus-induced ESI. The cost benefits of such a regimen are being evaluated.
- Published
- 1995
28. Results of surgical treatment of renal hyperparathyroidism.
- Author
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Neonakis E, Wheeler MH, Krishnan H, Coles GA, Davies F, and Woodhead JS
- Subjects
- Follow-Up Studies, Humans, Parathyroid Hormone blood, Recurrence, Renal Dialysis, Retrospective Studies, Treatment Outcome, Chronic Kidney Disease-Mineral and Bone Disorder surgery, Kidney Transplantation adverse effects, Parathyroidectomy adverse effects
- Abstract
Objective: To assess the outcome of parathyroidectomy for renal failure-related hyperparathyroidism., Design: A retrospective analysis with a mean follow-up of 4.34 years of a case series of 67 consecutive patients with renal failure-associated hyperarathyroidism., Setting: All patients were operated on at the University Hospital of Wales and Cardiff Royal Infirmary between October 1981 and December 1991., Patients: Of the 67 consecutive patients, 35 were receiving hemodialysis and 32 had received a renal transplant., Intervention: Total parathyroidectomy with autotransplantation was performed in 52 patients and subtotal parathyroidectomy was performed in 15., Main Outcome Measures: Symptomatic improvement after parathyroidectomy, the normalization of biochemical parameters, and the rate of recurrent hyperparathyroidism after parathyroidectomy., Results: Symptomatic improvement after parathyroidectomy occurred in 81% of hemodialysis patients and in 72% of transplant patients. The best predictor for successful relief of skeletal pain after parathyroidectomy was an elevated preoperative alkaline phosphatase level. Recurrent hyperparathyroidism developed in four of 38 patients after total parathyroidectomy with autotransplantation and in one of 14 surviving patients after subtotal parathyroidectomy. All five patients with recurrent disease were hemodialysis patients (22%)., Conclusions: Transplant patients usually present with less severe disease, have better normalization of biochemical parameters after parathyroidectomy, and rarely develop recurrent hyperparathyroidism compared with hemodialysis patients. Both total parathyroidectomy with autotransplantation and subtotal parathyroidectomy result in good control of renal hyperparathyroidism with excellent improvement of symptoms.
- Published
- 1995
- Full Text
- View/download PDF
29. An alternative view of 5-ASA formulations.
- Author
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Rhodes J and Coles GA
- Subjects
- Aminosalicylic Acids chemistry, Chemistry, Pharmaceutical, Humans, Inflammatory Bowel Diseases drug therapy, Kidney Diseases chemically induced, Mesalamine, Aminosalicylic Acids adverse effects
- Published
- 1995
- Full Text
- View/download PDF
30. Source of peritoneal proteoglycans. Human peritoneal mesothelial cells synthesize and secrete mainly small dermatan sulfate proteoglycans.
- Author
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Yung S, Thomas GJ, Stylianou E, Williams JD, Coles GA, and Davies M
- Subjects
- Biglycan, Chondroitin Sulfates chemistry, Chondroitin Sulfates isolation & purification, Chondroitin Sulfates metabolism, Decorin, Dermatan Sulfate isolation & purification, Dermatan Sulfate metabolism, Epithelium metabolism, Extracellular Matrix Proteins, Humans, Proteoglycans chemistry, Ascitic Fluid chemistry, Kidney Failure, Chronic therapy, Peritoneal Dialysis, Continuous Ambulatory, Peritoneum metabolism, Proteoglycans isolation & purification, Proteoglycans metabolism
- Abstract
This study describes experiments that compare the proteoglycans (PGs) extracted from the dialysate from patients receiving continuous peritoneal ambulatory dialysis (CAPD) with those secreted by metabolically labeled human peritoneal mesothelial cells in vitro. The PGs isolated from both sources were predominantly small chondroitin sulfate/dermatan sulfate PGs. Western blot of the core proteins obtained after chondroitin ABC lyase treatment with specific antibodies identified decorin and biglycan. With [35S]sulfate and [35S]methionine as labeling precursors it was shown that dermatan sulfate rather than chondroitin sulfate were the major glycosaminoglycan chains and that decorin was the predominant species. These data provide the first evidence that human peritoneal mesothelial cells may be the principal source of PGs in the peritoneum. Given the proposed functions of decorin and biglycan, the results suggest that these PGs may be involved in the control of transforming growth factor-beta activity and collagen fibril formation in the peritoneum.
- Published
- 1995
31. Effect of lactate-buffered peritoneal dialysis fluids on human peritoneal mesothelial cell interleukin-6 and prostaglandin synthesis.
- Author
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Witowski J, Topley N, Jörres A, Liberek T, Coles GA, and Williams JD
- Subjects
- Base Sequence, Buffers, Cell Survival, Cells, Cultured, DNA Primers chemistry, Epithelium drug effects, Epithelium metabolism, Humans, Hydrogen-Ion Concentration, Molecular Sequence Data, Peritoneum cytology, Peritoneum drug effects, Polymerase Chain Reaction, RNA, Messenger biosynthesis, 6-Ketoprostaglandin F1 alpha biosynthesis, Dialysis Solutions pharmacology, Interleukin-6 biosynthesis, Lactates pharmacology, Peritoneal Dialysis, Peritoneum metabolism
- Abstract
The present study focused on the evaluation of constitutive and cytokine-stimulated human peritoneal mesothelial cell (HPMC) IL-6 and 6-keto-PGF1 alpha release following pre-exposure to peritoneal dialysis fluid (PDF). Exposure of HPMC to PDF pH 5.2 resulted in a time-dependent increase in cell cytotoxicity [as assessed by lactate dehydrogenase (LDH) release] and concomitant inhibition of constitutive and IL-1 beta stimulated IL-6 and 6-keto-PGF1 alpha synthesis. After 15 minutes of exposure to PDF constitutive and IL-1 beta stimulated IL-6 release were reduced by 32.0 +/- 9.7% and 76.0 +/- 7.4% (N = 6, P < 0.046 and P < 0.027, respectively). PCR amplification of reverse transcribed mRNA from HPMC pre-exposed to PDF pH 5.2 demonstrated suppression of IL-1 beta stimulated IL-6 and cyclooxygenase (Cox-1 and Cox-2) transcripts. In order to mimic the dialysis cycle in vivo, an in vitro dialysis system was established. HPMC were exposed first to control medium, PDF pH 5.2 or PDF 7.3 for 15 minutes and then sequentially to pooled spent peritoneal dialysis effluent for up to four hours. The cells were subsequently allowed to recover in control medium for 12 hours in the presence or absence of IL-1 beta or TNF-alpha (both at 1000 pg/ml). There was no evidence of significant cell toxicity as assessed by LDH release during either the 'in vitro dialysis' or 'recovery' phases. Under these conditions short term exposure to PDF pH 5.2 followed by 'in vitro dialysis' resulted in significant inhibition of cytokine stimulated IL-6 (69.6 +/- 18.2 vs. 96.7 +/- 27.9 pg/microgram, N = 13; P < 0.020 for IL-1 beta) and 6-keto-PGF1 alpha (197.5 +/- 89.2 vs. 289.6 +/- 114.5 pg/microgram, N = 13; P < 0.020 for IL-1 beta) and 6-keto-PGF1 alpha (197.5 +/- 89.2 vs. 289.6 +/- 114.5 pg/microgram, N = 13; P < 0.003) release when compared to cells incubated in control medium. Adjustment of the pH of PDF to 7.3 reversed its inhibitory effects. We conclude that short-term exposure to PDF pH 5.2 significantly inhibits HPMC cytokine and prostaglandin release, an effect which appears to be related to its initial pH. Repeated exposure to nonphysiological PDF might impair mesothelial cell function and thus modulate intraperitoneal inflammatory processes.
- Published
- 1995
- Full Text
- View/download PDF
32. Biocompatibility of various osmotic solutes.
- Author
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Coles GA
- Subjects
- Amino Acids pharmacology, Biocompatible Materials, Cells, Cultured, Glucose pharmacology, Humans, Osmolar Concentration, Peritoneum cytology, Dialysis Solutions pharmacology, Peritoneal Dialysis, Peritoneum drug effects
- Published
- 1995
33. Are solutions presently used bioincompatible?
- Author
-
Coles GA
- Subjects
- Biocompatible Materials, Cells, Cultured, Humans, Osmolar Concentration, Peritoneum cytology, Dialysis Solutions pharmacology, Peritoneal Dialysis, Peritoneum drug effects
- Published
- 1995
34. The management of ultrafiltration failure in peritoneal dialysis.
- Author
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Coles GA and Williams JD
- Subjects
- Dialysis Solutions therapeutic use, Humans, Peritoneal Dialysis standards, Peritoneum physiopathology, Peritonitis physiopathology, Peritonitis therapy, Treatment Failure, Ultrafiltration, Peritoneal Dialysis adverse effects
- Published
- 1994
35. An ELISA for the detection of type IV collagen in human urine--application to patients with glomerulonephritis.
- Author
-
Donovan KL, Coles GA, and Williams JD
- Subjects
- Cross Reactions, Cyclophosphamide therapeutic use, Glomerulonephritis therapy, Humans, Kidney Failure, Chronic therapy, Kidney Failure, Chronic urine, Plasma Exchange, Prednisolone therapeutic use, Renal Dialysis, Reproducibility of Results, Sensitivity and Specificity, Collagen urine, Enzyme-Linked Immunosorbent Assay methods, Glomerulonephritis urine
- Published
- 1994
- Full Text
- View/download PDF
36. Human peritoneal mesothelial cell prostaglandin synthesis: induction of cyclooxygenase mRNA by peritoneal macrophage-derived cytokines.
- Author
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Topley N, Petersen MM, Mackenzie R, Neubauer A, Stylianou E, Kaever V, Davies M, Coles GA, Jörres A, and Williams JD
- Subjects
- Base Sequence, Cells, Cultured, Chromatography, High Pressure Liquid, Culture Media, Conditioned, DNA Primers, Enzyme Induction drug effects, Epithelium drug effects, Epithelium metabolism, Gene Expression Regulation, Enzymologic, Humans, Macrophages immunology, Molecular Sequence Data, Peritoneal Cavity cytology, Peritoneum cytology, Peritoneum drug effects, Polymerase Chain Reaction, Prostaglandin-Endoperoxide Synthases genetics, Radioimmunoassay, Cytokines immunology, Macrophages metabolism, Peritoneum metabolism, Prostaglandin-Endoperoxide Synthases biosynthesis, Prostaglandins biosynthesis, RNA, Messenger biosynthesis
- Abstract
Increasing evidence suggests that the mesothelial cell contributes to the control of inflammation in both the normal and inflamed peritoneal cavity. The present study examines the regulation of prostaglandin production by human peritoneal mesothelial cells (HPMC) following stimulation with peritoneal macrophage-conditioned medium and the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha). IL-1 beta and TNF-alpha stimulated significant release of prostaglandin above background levels in a time and dose dependent manner. Stimulation of HPMC with IL-1 beta (500 pg/ml) or TNF-alpha (100 pg/ml) for 24 hours resulted in the release of 24.5 +/- 4.3 (N = 11) (z = 3.40, P < 0.001 vs. control) and 19.4 +/- 4.5 (N = 10; z = 3.29, P < 0.001 vs. control) pg 6-keto-PGF1 a/micrograms cellular protein, respectively. Pretreatment of HPMC with dexamethasone (10(-6) to 10(-9) M) inhibited both constitutive and cytokine stimulated prostaglandin synthesis in a dose dependent manner. Both PMø-CM and PMø-S.epiCM stimulated 6-keto-PGF1 alpha and PGE2 synthesis by HPMC in a time and dose dependent manner (PMø-S.epiCM >> PMø-CM). Co-incubation of HPMC with PMø-S.epiCM in the presence of anti-IL-1 beta and/or anti-TNF-alpha antibody, interleukin-1 receptor antagonist or soluble TNF receptor (TNF p75) significantly reduced the capacity of these supernatants to stimulate prostaglandin synthesis. Exposure of HPMC to cytokines or PMø-S.epiCM resulted in the time dependent increase in the levels of both Cox-1 and Cox-2 mRNA as assessed by RT/PCR analysis with the greatest increase being seen for Cox-2. These data demonstrate specific stimulation of eicosanoid metabolism in HPMC by peritoneal macrophage derived cytokines, indicating the possible importance of these mediators in the activation of intraperitoneal prostaglandin synthesis. HPMC prostaglandins might act as important pro/anti-inflammatory mediators contributing to a cytokine network in the peritoneal cavity during CAPD peritonitis.
- Published
- 1994
- Full Text
- View/download PDF
37. Dopamine does not mediate protein-induced hyperfiltration.
- Author
-
Thomas DM, Coles GA, and Williams JD
- Subjects
- Carbidopa pharmacology, Dopamine metabolism, Dopamine urine, Glomerular Filtration Rate drug effects, Hemodynamics physiology, Humans, Kidney metabolism, Kidney physiology, Dopamine physiology, Eating physiology, Glomerular Filtration Rate physiology, Proteins pharmacology
- Abstract
Dopamine and a meat meal have both been used to stimulated hyperfiltration. Urinary dopamine has been said to rise after a meal. It has been suggested that the responses are the same. In order to clarify this relationship, the DOPA decarboxylase inhibitor carbidopa was used to abolish dopamine synthesis during a meat meal. Eight normal individuals were studied twice. On each occasion they ate a meat meal and resting and post-prandial haemodynamics were measured. On 1 of the 2 study days they received carbidopa which abolished renal dopamine synthesis. Despite this there was no change in resting haemodynamics and the meat meal response was preserved. We conclude that urinary dopamine does not rise after a meal and that dopamine does not mediate the meat meal response.
- Published
- 1994
38. The source and possible significance of hyaluronan in the peritoneal cavity.
- Author
-
Yung S, Coles GA, Williams JD, and Davies M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cells, Cultured, Chromatography, Gel, Humans, Hyaluronic Acid isolation & purification, Kidney Failure, Chronic therapy, Middle Aged, Peritoneal Cavity cytology, Peritonitis physiopathology, Ascitic Fluid metabolism, Dialysis Solutions metabolism, Hyaluronic Acid metabolism, Peritoneal Dialysis, Continuous Ambulatory
- Abstract
The levels of hyaluronan (HA) were determined in dialysate from patients receiving CAPD. The levels found after the four hour dwell were 0.162 +/- 0.08 micrograms/ml (N = 16) in non-infected fluid and 1.69 +/- 1.12 (N = 5) during peritonitis, P < 0.0025. Similarly concentrations in overnight (8 to 10 hours) dwell dialysate were 0.384 +/- 0.22 micrograms/ml (N = 13) when uninfected and 3.17 +/- 2.28 (N = 8) during peritonitis, P < 0.0002. Following de novo catheter insertion the initial peritoneal washout yielded HA levels of 0.0032 +/- 0.0018 micrograms/ml (N = 7). In vitro human peritoneal cells synthesized HA, 90% of which was secreted into the culture medium (CM). By dissociative gel permeation chromatography on Sephacryl 1000 there were no significant differences in the molecular size of HA extracted from (a) non-infected fluid, (b) infected fluid and (c), mesothelial cell culture medium. These results indicate that the process of CAPD results in an increase in HA levels in the peritoneal cavity. During episodes of peritonitis these functions are further augmented. The likely source of HA in the dialysate is the peritoneal mesothelial cells. This response may be an initial event in wound repair.
- Published
- 1994
- Full Text
- View/download PDF
39. Relative roles of elastase and reactive oxygen species in the degradation of human glomerular basement membrane by intact human neutrophils.
- Author
-
Donovan KL, Davies M, Coles GA, and Williams JD
- Subjects
- Catecholamines pharmacology, Collagen metabolism, Glomerulonephritis etiology, Humans, Immunoglobulin G metabolism, Neutrophils drug effects, Pancreatic Elastase antagonists & inhibitors, Pyrrolidines pharmacology, Respiratory Burst, alpha 1-Antitrypsin pharmacology, Basement Membrane metabolism, Cephalosporins, Imidazolines, Kidney Glomerulus metabolism, Neutrophils physiology, Pancreatic Elastase physiology, Reactive Oxygen Species metabolism
- Abstract
Glomerular basement membrane (GBM) damage and proteinuria occurring during the early phase of acute glomerulonephritis are often neutrophil (PMN) dependent. The present study sought to identify the potential roles of PMN derived elastase and reactive oxygen species (ROS) in the pathogenesis of glomerular basement damage in an homologous in vitro model of anti-GBM nephritis using intact PMN. Human PMN (5 x 10(6)), incubated with human GBM (0.5 mg) pretreated with human anti-GBM IgG, degraded 10.3 +/- 1.1% of the GBM type IV collagen in six hours (8 micrograms/hr), and underwent a two-hour respiratory burst. The same number of sonically disrupted PMN solubulized 22.4 +/- 5.1% of GBM under the same incubation conditions. The inclusion of the elastase inhibitors alpha 1 proteinase inhibitor (alpha 1Pi), and a smaller highly-specific synthetic compound (L658,758), reduced degradation by PMN homogenates by 84.8% and 85.7%, respectively, whereas they were only able to inhibit intact PMN mediated degradation by a maximum of 49.2% and 50.9%, respectively. The inclusion of EDTA (10 mM), an inhibitor of metalloproteinases, reduced GBM degradation by APMA activated and disrupted PMN by only 7.5%. Incubation of PMN with diphenylene iodonium (DPI) abolished PMN reactive oxygen species generation by > 95% but preserved elastase release. This compound did not directly affect GBM degradation. It did, however, abolish the inhibitory effect of ROS on alpha 1Pi activity and thus indirectly reduced GBM damage by up to 20%.
- Published
- 1994
- Full Text
- View/download PDF
40. Permselectivity in thin membrane nephropathy.
- Author
-
Thomas DM, Coles GA, Griffiths DF, and Williams JD
- Subjects
- Adult, Female, Humans, Male, Metabolic Clearance Rate, Particle Size, Permeability, Dextrans pharmacokinetics, Glomerulonephritis, Membranous physiopathology, Hemodynamics, Kidney Glomerulus physiopathology
- Abstract
The glomerular permselectivity to polydisperse neutral dextrans was compared in 6 patients with thin membrane nephropathy (TMN) and 10 healthy controls. Despite having normal renal hemodynamics and minimal proteinuria, the patients with TMN had significantly increased fractional clearance of neutral molecules with Stokes radius > 42 A. Conventional theories of glomerular barrier size selectivity cannot fully explain these data since they would predict that our patients would have had nephrotic range proteinuria.
- Published
- 1994
- Full Text
- View/download PDF
41. Proteinuria--a direct cause of renal morbidity?
- Author
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Williams JD and Coles GA
- Subjects
- Aging physiology, Animals, Blood Proteins metabolism, Dietary Proteins administration & dosage, Doxorubicin, Forecasting, Humans, Kidney Diseases chemically induced, Kidney Failure, Chronic etiology, Kidney Failure, Chronic physiopathology, Kidney Glomerulus metabolism, Kidney Tubules metabolism, Nephrectomy, Puromycin Aminonucleoside, Kidney Diseases etiology, Proteinuria complications
- Published
- 1994
- Full Text
- View/download PDF
42. What does the renal reserve mean?
- Author
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Thomas DM, Coles GA, and Williams JD
- Subjects
- Animals, Dietary Proteins pharmacology, Hemodynamics, Humans, Kidney Diseases physiopathology, Renal Circulation, Glomerular Filtration Rate drug effects, Kidney physiology
- Published
- 1994
- Full Text
- View/download PDF
43. Biocompatibility studies on peritoneal cells.
- Author
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Topley N, Coles GA, and Williams JD
- Subjects
- Humans, Peritoneal Cavity cytology, Toxicity Tests, Biocompatible Materials, Dialysis Solutions toxicity, Peritoneal Dialysis, Continuous Ambulatory, Peritoneum drug effects
- Abstract
This review outlines the problems involved in assessing the biocompatibility of PD fluids. It has summarized the data available from conventional in vitro studies and highlights many of the inadequacies of this approach. In vivo data are lacking both on host defense and on the clinical effect of changing conventional PD fluids for a more "ideal" formulation. The best parameters for assessing biocompatibility need to be defined. Alternative formulation of fluids must be aimed towards (1) a system that interferes minimally with host defense, and (2) a system that maintains the integrity of the peritoneal membrane for ultrafiltration and clearance. Cell culture studies should be designed to model the in vivo situation. Ex vivo studies (cells exposed within the peritoneal cavity) should be used to support in vivo findings. Finally, in vitro results must be related to clinical significance, and changes in fluid composition should be followed by improvements in clinical outcome.
- Published
- 1994
44. Synthesis of phospholipids by human peritoneal mesothelial cells.
- Author
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Beavis J, Harwood JL, Coles GA, and Williams JD
- Subjects
- Cells, Cultured, Epithelium metabolism, Fatty Acids analysis, Humans, Phosphatidylcholines biosynthesis, Phosphatidylcholines chemistry, Phospholipids chemistry, Peritoneal Dialysis, Continuous Ambulatory, Peritoneum metabolism, Phospholipids biosynthesis
- Abstract
Objective: To assess the capacity of cultured human peritoneal mesothelial cells to synthesize choline-containing phospholipids. The study compares the phospholipids secreted from cultured cells with those which we, and others, have identified in the dialysate of patients treated by continuous ambulatory peritoneal dialysis (CAPD)., Patients: CAPD effluent was collected from 8 patients who had been receiving CAPD treatment for at least 11 months and who had normal ultrafiltration. CELL CULTURES: Using human omental tissue, homogeneous cultures of mesothelial cells were established., Methods: Synthesis of phospholipids by mesothelial cells was assessed following incubation with [methyl-14C] choline chloride--a precursor capable of being incorporated into phosphatidylcholine (PtdCho) and sphingomyelin. Lipids from CAPD effluent, cultured cells, and cell medium were extracted in chloroform/methanol. Phospholipids were separated and identified by thin layer chromatography. Synthesis and secretion of PtdCho and other choline-containing lipids by the mesothelial cells were determined by beta scintillation counting of the appropriate bands, while the fatty acid composition of the phospholipids was ascertained by gas liquid chromatography., Results: Synthesis and secretion of PtdCho by mesothelial cells were observed during a 96-hour period. When maintained in medium replete with essential fatty acids, the fatty acid composition of the PtdCho synthesized by cultured mesothelial cells closely resembled that isolated from the peritoneal cavity., Conclusion: The demonstration of phospholipid secretion from mesothelial cells, with a fatty acid composition similar to the phospholipids isolated from peritoneal dialysate, lends added support to the hypothesis that the mesothelial cells are the source of the peritoneal phospholipids. As such they offer a useful experimental system in which to study peritoneal phospholipid synthesis.
- Published
- 1994
45. Training in peritoneal dialysis.
- Author
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Coles GA and Uttley L
- Subjects
- Humans, Education, Medical, Continuing, Education, Nursing, Continuing, Nephrology education, Peritoneal Dialysis nursing, Peritoneal Dialysis, Continuous Ambulatory nursing, Practice Guidelines as Topic
- Published
- 1994
46. Reduced renal hemodynamic response to atrial natriuretic peptide in elderly volunteers.
- Author
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Mulkerrin EC, Brain A, Hampton D, Penney MD, Sykes DA, Williams JD, Coles GA, and Woodhouse KW
- Subjects
- Adult, Aged, Atrial Natriuretic Factor blood, Hemodynamics drug effects, Humans, Male, Aging physiology, Atrial Natriuretic Factor physiology, Kidney blood supply
- Abstract
Aging is associated with decreased ability to excrete salt and water, thus increasing the susceptibility to volume overload in older individuals. Meanwhile, plasma levels of atrial natriuretic peptide (ANP) increase progressively with age for unknown reasons. We compared the natriuretic and renal hemodynamic responses to low-dose ANP infusion in an elderly group of volunteers (mean age, 74 years) with those of a group of younger subjects (mean age, 29 years). A significant reduction below baseline values in effective renal plasma flow occurred in the young group after the 2-hour peptide infusion (657 +/- 125 v 476 +/- 92 mL/min [mean +/- 1 SD]) when compared with the elderly group (two-way analysis of variance; P < 0.02). A concomitant increase in renal vascular resistance was noted in the young group only during the same period (6,631 +/- 1,384 v 9,136 +/- 2,126 dyn s cm2 x 10(6)). This increase was also significantly higher than that in the elderly group (analysis of variance; P < 0.02). Both groups demonstrated similar natriuretic responses. Absolute sodium excretion had increased significantly above baseline values in both young and elderly subjects at the end of the 2-hour peptide infusion (111 +/- 25 mumol/min to 183 +/- 33 mumol/min v 107 +/- 23 mumol/min to 198 +/- 56 mumol/min) and remained elevated until 1 hour postinfusion. We conclude that the elderly subjects in our study demonstrated a diminished renal hemodynamic response to infusion of ANP while preserving a natriuretic response similar to that found in the younger subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
- Full Text
- View/download PDF
47. Preservation of renal haemodynamic response to an oral protein load in non-insulin-dependent diabetes mellitus.
- Author
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Vora JP, Thomas D, Peters JR, Coles GA, and Williams JD
- Subjects
- Adult, Albuminuria, Blood Glucose metabolism, Diabetes Mellitus, Type 2 blood, Humans, Middle Aged, Reference Values, Regional Blood Flow, Diabetes Mellitus, Type 2 physiopathology, Dietary Proteins, Glomerular Filtration Rate, Kidney blood supply
- Abstract
Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) were determined, for 2 h prior to and 3 h following the ingestion of a 1.2 g kg-1 meat meal, in seven normotensive normoalbuminuric Type 2 diabetic patients exhibiting good glycaemic control (fasting plasma glucose (mean +/- SD): 7.2 +/- 2.0 mmol l-1; glycosylated haemoglobin: 8.1 +/- 1.7%) and in nine normal subjects selected for similar basal GFR values. Baseline GFR and ERPF (corrected to 1.73 m2 surface area) were 83 +/- 10 and 410 +/- 76 ml min-1 for the Type 2 diabetic patients and 86 +/- 11 and 405 +/- 113 ml min-1 for the normals. GFR increased by 38 +/- 8 and 32 +/- 15% in the diabetic patients and normals, to 108 +/- 25 and 105 +/- 26 ml min-1 (p < 0.01 vs baseline). Peak ERPF was 501 +/- 127 and 476 +/- 119 ml min-1 for the two respective groups (p < 0.01 vs baseline). Filtration fractions at peak GFR and EPRF values were unchanged from baseline for either groups. Fractional clearance of albumin for the Type 2 diabetic patients was unaltered by protein ingestion. Therefore, protein ingestion in Type 2 diabetes, as in normals, results in an acute elevation of GFR. Absolute and incremental changes in GFR were identical for the two groups. These data demonstrate a preserved capacity for renal vasodilatation in Type 2 diabetic patients despite their greater chronological age.
- Published
- 1993
- Full Text
- View/download PDF
48. A potential role for endogenous adenosine in control of human glomerular and tubular function.
- Author
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Balakrishnan VS, Coles GA, and Williams JD
- Subjects
- Adult, Hemodynamics drug effects, Humans, Kidney Tubules drug effects, Male, Osmolar Concentration, Purinergic P1 Receptor Antagonists, Pyrazoles pharmacology, Pyridines pharmacology, Renal Circulation drug effects, Renin blood, Adenosine physiology, Kidney Glomerulus physiology, Kidney Tubules physiology
- Abstract
Adenosine has profound effects on renal function in experimental animals, but little is known about its role in human subjects. The recent advent of specific adenosine agonists and antagonists suitable for human use, however, now makes it possible to evaluate the influence of this potent vasoactive compound in both normal and pathological states. In this study we assessed the effects of FK-453, a nonxanthine, selective adenosine A1-receptor antagonist, on normal renal hemodynamics, tubular function, and plasma renin release. Eight healthy, male subjects each received three single oral doses of FK-453 (50, 100, and 200 mg) in ascending dose order with random allocation of one matched placebo dose, each on a separate study day. Renal hemodynamics, tubular function, and plasma renin concentrations (PRC) were assessed at baseline and postdose on each study day. Glomerular filtration rate (clearance of 51Cr-labeled EDTA) rose by 18.0%, 3 h after the administration of 100 mg of FK-453 and by 18.3% and 23.5%, 2 and 3 h, respectively, after the 200-mg dose, which was significantly different from the changes following placebo. There were no significant changes in mean arterial blood pressure or effective renal plasma flow (clearance of 125I-Hippuran). In contrast there were statistically significant increases in urine flow rate and osmolar clearance, as well as absolute and fractional excretions of sodium, phosphate, bicarbonate, chloride, magnesium, and uric acid in response to FK-453. No glycosuria or aminoaciduria was detected on urinalysis. There was, in addition, a marked increase in PRC in response to FK-453.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
- Full Text
- View/download PDF
49. Intra-peritoneal free elastase in CAPD peritonitis.
- Author
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Donovan KL, Pacholok S, Humes JL, Coles GA, and Williams JD
- Subjects
- Acute Disease, Ascitic Fluid enzymology, Humans, Neutrophils enzymology, Pancreatic Elastase antagonists & inhibitors, alpha 1-Antitrypsin metabolism, Bacterial Infections enzymology, Bacterial Infections etiology, Leukocyte Elastase, Pancreatic Elastase metabolism, Peritoneal Dialysis, Continuous Ambulatory adverse effects, Peritonitis enzymology, Peritonitis etiology
- Abstract
Neutrophil (PMN) recruitment into the peritoneum during acute bacterial peritonitis is an important part of the host defense barrier in CAPD patients. However, the subsequent phagocytosis of bacteria may also lead to PMN degranulation and the release of lysosomal enzymes. We determined the concentration of neutrophil elastase, both in complex with its natural inhibitor alpha 1Pi (E alpha 1Pi), and in uncomplexed, free form, in infected and normal CAPD peritoneal fluid by ELISA. In addition elastase activity was estimated in a casein degradation assay. Infected fluid contained a median (range) of 1.4 nM (0 to 9.2) free elastase by ELISA and 1.2 nM (0 to 11.9) activity. There were strong correlations between the peritoneal leukocyte count and both immunoreactive elastase and activity (r = 0.816, P < 0.001, 0.687, P < 0.01, respectively). In contrast, normal fluid contained 0.0 nM (0 to 0.32) immunoreactive elastase (P < 0.01) and 0.0 nM (0 to 0.6) elastase activity (P < 0.001). E alpha 1Pi complexes were raised significantly during peritonitis at 6.2 nM (0 to 34.3) and were barely detectable in normal fluid 0.0 nM (0 to 0.17; P < 0.005). The study shows that small but significant quantities of uninhibited elastase can be detected in the peritoneal fluid of CAPD patients with acute bacterial peritonitis. This observation may have important implications for the pathogenesis of peritoneal membrane damage and the phlogistic response to infection.
- Published
- 1993
- Full Text
- View/download PDF
50. Effects of the correction of renal anaemia by erythropoietin on physiological changes during exercise.
- Author
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Lewis NP, Macdougall IC, Willis N, Coles GA, Williams JD, and Henderson AH
- Subjects
- Adolescent, Adult, Aged, Anemia blood, Anemia etiology, Bicarbonates blood, Female, Humans, Kidney Diseases blood, Kidney Diseases etiology, Lactates blood, Lactic Acid, Male, Middle Aged, Oxygen Consumption physiology, Renal Insufficiency therapy, Anemia therapy, Erythropoietin therapeutic use, Exercise Tolerance physiology, Kidney Diseases therapy, Renal Dialysis adverse effects
- Abstract
The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 +/- 1.2 to 11.1 +/- 1.1 g dl-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant PaO2 and PaCO2. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial PCO2 before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.
- Published
- 1993
- Full Text
- View/download PDF
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