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Biomedical subjects

C G Winearls

Publications and source records attributed to C G Winearls.

At least 19 recordsLinked to original sources
PubMed2004

Proliferative glomerulonephritis associated with mantle cell lymphoma--natural history and effect of treatment in 2 cases.

We describe 2 patients with mantle cell lymphoma who presented with dialysis-dependent acute renal failure and in whom the renal biopsies showed proliferative glomerulonephritis. The first patient had lymphadenopathy and the second splenomegaly, but no cause was initially identified in either case. The first patient was treated with immunosuppressive drugs, the second was given no specific therapy; renal function recovered in both. However, more than 1 year later, both again became dialysis-dependent but had also developed generalized lymphadenopathy. A diagnosis of mantle cell non-Hodgkin's lymphoma was made in both cases. The association of active lymphoma and renal disease supports a paraneoplastic mechanism for the occurrence of the glomerulonephritis in these patients. The literature describing the association between non-Hodgkin's lymphoma and glomerulonephritis is reviewed.

Aged↗
PubMed2002

Comparison of multilocus sequence typing and pulsed-field gel electrophoresis as tools for typing Staphylococcus aureus isolates in a microepidemiological setting.

Multilocus sequence typing (MLST) of Staphylococcus aureus is well suited to the study of global or long-term epidemiology, but its role in local epidemiology has not been defined. The present study has compared MLST with pulsed-field gel electrophoresis (PFGE) by using S. aureus isolates associated with carriage and disease in a busy regional renal unit. One hundred forty-four patients were prospectively recruited, of whom 103 were receiving hemodialysis and 41 were on continuous ambulatory peritoneal dialysis. Three nasal swab specimens were obtained 1 month apart on entering the study. A nasal swab was positive for S. aureus on at least one occasion in 50 patients (35%). Typing of the 104 carriage isolates demonstrated 21 PFGE types and 21 sequence types (STs). Thirty-one carriers had two or more positive nasal swabs; of these, the isolates in all swabs from a given carrier had identical PFGE types for 29 carriers; the isolates in all of the same 29 swabs had identical STs. The carriage strain in two patients changed both PFGE type and STs during the period of swabbing. Eight patients (6%) had an episode of S. aureus bacteremia during the 12-month study period, and two of these were nasal carriers. One of these invasive isolates had the same PFGE type and ST as the carriage isolate. There were no differences between Simpson's index of diversity for PFGE and Simpson's index of diversity for MLST for both invasive and carriage isolates, suggesting that the two methods have very similar discriminatory abilities. We conclude that PFGE and MLST performed equally in this study.

Adolescent↗
PubMed2001

Renal complications of jejuno-ileal bypass for obesity.

Jejuno-ileal bypass has until recently been an accepted treatment for refractory morbid obesity. Although hyperoxaluria causing renal tract calculi is a well-recognized complication, we describe eight patients who developed significant renal failure attributable to hyperoxaluria resulting from this procedure, three requiring renal replacement therapy. We review the literature, describing 18 other cases with renal failure, the mechanisms of hyperoxaluria and its treatment. Because reversal of the bypass may result in stabilization or partial improvement of renal function, these patients require long-term follow-up of renal function.

Adult↗
PubMed2000

Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications.

Mutation screening of the major autosomal dominant polycystic kidney disease (ADPKD) locus, PKD1, has proved difficult because of the large transcript and complex reiterated gene region. We have developed methods, employing long polymerase chain reaction (PCR) and specific reverse transcription-PCR, to amplify all of the PKD1 coding area. The gene was screened for mutations in 131 unrelated patients with ADPKD, using the protein-truncation test and direct sequencing. Mutations were identified in 57 families, and, including 24 previously characterized changes from this cohort, a detection rate of 52.3% was achieved in 155 families. Mutations were found in all areas of the gene, from exons 1 to 46, with no clear hotspot identified. There was no significant difference in mutation frequency between the single-copy and duplicated areas, but mutations were more than twice as frequent in the 3' half of the gene, compared with the 5' half. The majority of changes were predicted to truncate the protein through nonsense mutations (32%), insertions or deletions (29.6%), or splicing changes (6.2%), although the figures were biased by the methods employed, and, in sequenced areas, approximately 50% of all mutations were missense or in-frame. Studies elsewhere have suggested that gene conversion may be a significant cause of mutation at PKD1, but only 3 of 69 different mutations matched PKD1-like HG sequence. A relatively high rate of new PKD1 mutation was calculated, 1.8x10-5 mutations per generation, consistent with the many different mutations identified (69 in 81 pedigrees) and suggesting significant selection against mutant alleles. The mutation detection rate, in this study, of >50% is comparable to that achieved for other large multiexon genes and shows the feasibility of genetic diagnosis in this disorder.

Alleles↗
PubMed1999

Outcome following haemodialysis catheter-related Staphylococcus aureus bacteraemia.

Staphylococcus aureus is a frequent cause of haemodialysis access-related bacteraemia. The propensity for this organism to seed from the bloodstream to distant sites is well recognized, but the rate at which this occurs is poorly defined in patients with removable haemodialysis catheters. This retrospective study identified 47 patients with 50 episodes of S. aureus haemodialysis catheter-related bacteraemia between August 1993 and December 1995. Adverse events were recorded until February 1996. Thirty of 50 episodes (60%) were apparently uncomplicated. Bacterial seeding to heart valves or distant sites was documented in eight episodes (16%), of which six occurred during antibiotic therapy. A further 12 patients had persistent bacteraemia in the absence of a defined focus of infection, the last positive blood culture ranging from 2-19 days (mean 6.6, median 5) after removal of the haemodialysis catheter and commencing appropriate antibiotic treatment. The serious nature of this infection confirms the need for prevention, together with effective strategies for investigation and treatment in this patient population.

Adult↗
PubMed1998

Recombinant human erythropoietin: 10 years of clinical experience.

The need for a renewable source of erythropoietin to treat the anaemia of chronic renal failure was first recognized in the 1960s, but cloning and expression of the human gene was not achieved until 1983. Clinical testing of recombinant human erythropoietin (r-HuEPO) began in 1985, leading to the first licence as a therapeutic agent in 1988. The first clinical trials showed that an intravenous dose requirement of about 200 IU/kg/week would increase haemoglobin concentrations to 10-12g/dl in >90% of haemodialysis patients. Subcutaneous administration has subsequently been found to be effective, and may allow lower maintenance doses. It is now the route of choice in Europe, but not the USA. The best marker of benefit of the introduction of r-HuEPO is the reduction in need for regular blood transfusions. A marked improvement in anaemia-related symptoms has been clearly demonstrated. The most important factor in optimizing the response to r-HuEPO is iron supply. The marrow should be stimulated slowly, to allow mobilization of iron stores. Functional or absolute iron deficiency should be pre-empted by regular iron supplementation. It is also important to recognize resistant states induced by inflammation and bleeding, and to exclude severe hyperparathyroidism, aluminium overload and other haematological diseases. The most important adverse events associated with r-HuEPO are increased blood pressure and a possible increased risk of access failure. These are, however, challenges to improve practice, not reasons to avoid the use of r-HuEPO.

Clinical Trials as Topic↗
PubMed1997

Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.

Mutation screening of the major autosomal dominant polycystic kidney disease gene (PKD1) has been complicated by the large transcript size (> 14 kb) and by reiteration of the genomic area encoding 75% of the protein on the same chromosome (the HG loci). The sequence similarity between the PKD1 and HG regions has precluded specific analysis of the duplicated region of PKD1, and consequently all previously described mutations map to the unique 3' region of PKD1. We have now developed a novel anchored reverse-transcription-PCR (RT-PCR) approach to specifically amplify duplicated regions of PKD1, employing one primer situated within the single-copy region and one within the reiterated area. This strategy has been incorporated in a mutation screen of 100 patients for more than half of the PKD1 exons (exons 22-46; 37% of the coding region), including 11 (exons 22-32) within the duplicated gene region, by use of the protein-truncation test (PTT). Sixty of these patients also were screened for missense changes, by use of the nonisotopic RNase cleavage assay (NIRCA), in exons 23-36. Eleven mutations have been identified, six within the duplicated region, and these consist of three stop mutations, three frameshifting deletions of a single nucleotide, two splicing defects, and three possible missense changes. Each mutation was detected in just one family (although one has been described elsewhere); no mutation hot spot was identified. The nature and distribution of mutations, plus the lack of a clear phenotype/genotype correlation, suggest that they may inactivate the molecule. RT-PCR/PTT proved to be a rapid and efficient method to detect PKD1 mutations (differentiating pathogenic changes from polymorphisms), and we recommend this procedure as a firstpass mutation screen in this disorder.

Adult↗
PubMed1997

High serum D-lactate in patients on continuous ambulatory peritoneal dialysis.

BACKGROUND: As abnormally high serum D-lactate levels may cause neurological impairment, we determined whether patients undergoing continuous ambulatory peritoneal dialysis (CAPD) with lactate-containing fluids have increased serum D-lactate concentrations. METHODS: D- and L-lactate concentrations were determined in peritoneal dialysis fluids and in serum from control subjects (n = 10), haemodialysis patients (n = 10), and CAPD patients (n = 30) before and after 1 h of dialysis. RESULTS: We found the median D-lactate concentration in Dianeal CAPD fluid to be 26 mM (range 19-27), whereas it was less than 0.5 mM in DPCA2 fluid. Control, haemodialysis, and CAPD (DPCA2) patient median serum D-lactate concentrations were below 0.07 mM. However, CAPD (Dianeal) patient serum D-lactate concentrations were 4-fold higher than controls (P < 0.0001), at 0.28 mM, an hour after instillation of D-lactate-containing fluid. Three patients, whose serum D-lactate averaged 0.59 mM, were found to have D-lactate concentrations at 0.22 mM after overnight cessation of dialysis. CONCLUSION: We conclude that CAPD with D-lactate-containing fluids raises serum D-lactate to abnormal levels.

Adult↗
PubMed1997

Presentation and survival of patients with severe renal failure and myeloma.

We reviewed the clinical features and outcome of 56 patients with myeloma and severe renal failure managed in a single institution over a 15-year period. Renal failure was recognized within 2 months of the diagnosis of myeloma in 75% of patients, and was the initial presentation of myeloma in 50%. Patients were staged by the Durie and Salmon classification. Light-chain and IgD myeloma accounted for 46% of cases, and Bence-Jones proteinuria was identified in > 90%. In 43%, a potential precipitant of renal failure was identified, usually hypercalcaemia or a non-steroidal anti-inflammatory agent. A preserved corrected calcium at presentation was characteristic (2.40 +/- 0.15 mmol/l, n = 42), even after excluding those with hypercalcaemia requiring specific intervention (n = 14, 2.76 +/- 0.51; p < 0.01): this finding in patients with unexplained acute renal failure should alert clinicians to the possibility of myeloma. Forty-seven patients (84%) required dialysis. Only seven (15%) ever regained renal function. Median survival (all patients) was 8 months. One-third died within 3 months of referral and one-third survived > 1 year. Hypoalbuminaemia and reduced platelet count at presentation were associated with reduced survival, but hypercalcaemia, infection, dialysis, (urgent or long-term), and dialysis modality were not. Chemotherapy was associated with increased survival, but progression of myeloma and infection were the two most frequent causes of death. Severe renal failure was associated with advanced myeloma stage and light-chain/IgD paraproteinaemia. Survival was related to severity of myeloma and not requirement for dialysis per se.

Adult↗
PubMed1996

Long term effect of renal transplantation on dialysis-related amyloid deposits and symptomatology.

We report the five year outcome of nine patients with dialysis-related amyloid (DRA) who underwent successful renal transplantation (RT) and six patients who remained on hemodialysis (HD). Amyloid bone cysts, a radiologic feature of DRA, and scintigraphy with 123I-labeled serum amyloid P component (SAP), a specific technique for evaluating amyloid deposits in vivo, were monitored and compared with clinical features. In all HD patients there was clinical, scintigraphic and/or radiologic evidence that DRA progressed. In contrast, eight of the RT patients experienced profound early relief of DRA symptoms following transplantation that persisted throughout follow-up, despite the reduction or withdrawal of corticosteroids. Amyloid bone cysts improved in four patients and SAP scans demonstrated regression of articular amyloid in eight out of nine cases. The modest radiographic improvement suggests that amyloid is mobilized more slowly in bone cysts than elsewhere or that cystic bone is remodeled poorly. This is the first objective evidence that DRA regresses following renal transplantation, and suggests that this may contribute to the long-term relief of DRA symptoms in transplant recipients who discontinue corticosteroids.

Adult↗
PubMed1996

Human erythrocyte choline uptake in uraemia: the role of intracellular substrate and an investigation into the effects of haemodialysis.

1. Erythrocyte choline transport was studied in 10 haemodialysis patients immediately before and after a haemodialysis session and in 10 control subjects. Choline uptake was measured in erythrocytes from normal and uraemic patients after washing in vitro and subsequent incubation in autologous plasma. Amines present in uraemic plasma were examined for their effect on choline transport in normal erythrocytes. 2. NMR spectroscopy was used to measure choline, trimethylamine and dimethylamine in erythrocyte extracts from nine control subjects, 32 subjects with renal impairment and nine samples from haemodialysis patients. 3. The increased choline influx in uraemic erythrocytes is significantly decreased by prior haemodialysis (mean Vmax pre-dialysis 146 +/- 20 mumol h-1 l-1, post-dialysis 113 +/- 13 mumol h-1 l-1 (P < 0.005). After in vitro washing there is a fall in Vmax, and no longer any significant difference between pre- and post-dialysis samples. There remains a significant difference in the erythrocyte choline Vmax between samples from patients with chronic renal failure and from normal subjects (P < 0.005). 4. Human plasma was found to contain factors capable of increasing choline uptake. Trimethylamine and dimethylamine were found to inhibit choline uptake. Trimethylamine and trimethylamine-N-oxide trans-stimulated choline efflux, but the major transport substrate present in erythrocyte extracts from all groups was choline, which was higher in those with renal impairment (71 +/- 10 mumol/l) than in haemodialysis patients (47 +/- 10 mumol/l) and control subjects with normal renal function (40 +/- 9 mumol/l). 5. Our data suggest that erythrocyte choline transport is increased in uraemia as a consequence of increased transporter number or activity, rather than the presence of intracellular substrate.

Choline↗