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Biomedical subjects

C R Dudley

Publications and source records attributed to C R Dudley.

16 recordsLinked to original sources
PubMed1999

The spouse as a kidney donor: ethically sound?

A shortage of cadaver donor organs requires transplant units to examine all possible alternatives. Transplantation from living donors accounts for only approximately 10% of kidney transplants in the UK. Recent studies have shown that the results of kidney transplantation between spouses are at least as good as those of well-matched cadaver organs, but very few transplants of this type have been performed in this country so far. As part of the assessment process, the proposed donor and recipient are required to provide written statements about the issues. We reproduce here the personal statements made by one of our patients and his wife: we believe that the statements support our contention that spousal transplantation is ethically justifiable and should be more widely available. We report our early experience in Bristol with seven kidney transplants from spousal donors and we encourage other renal units in this country and elsewhere to consider this method of improving the prospects of kidney transplantation for their patients.

Adult↗
PubMed1996

Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression.

BACKGROUND: The combination of cyclosporin, azathioprine, and prednisolone (triple immunosuppression) is the most commonly used immunosuppressive regimen early after renal transplantation, but the risks and benefits of maintaining the steroid component of this regimen in the long term are uncertain. METHODS: A randomised controlled trial of steroid withdrawal was conducted among renal transplant patients receiving triple immunosuppression. Between one and six years after transplantation, 100 such patients were randomised either to reduce prednisolone treatment to zero over about four months or to maintain their triple immunosuppression unchanged. Outcome was analysed according to "Intention-to-treat". FINDINGS: In 42 (86%) of 49 patients allocated to steroid withdrawal, complete steroid withdrawal was achieved. Although these patients did not experience defined acute rejection episodes, insidious increases in plasma creatinine were observed more frequently in this group than in the controls. In 97 patients surviving one year after trial entry, plasma creatinine exceeded the baseline by more than 25% at some time in the first year in 25 (53%) of 47 in the steroid withdrawal group compared with 9 (18%) of 50 in the control group (p < 0.001, chi-square test). In some cases these increases were transient. However, when corrected for the baseline (entry) value significant differences between groups were apparent in both mean plasma creatinine and mean creatinine clearance; mean (SD) plasma creatinine values at entry, immediately after withdrawal, and at one year were 138 (27), 151 (36), and 150 (36) mumol/L in the steroid withdrawal group versus 138 (34), 140 (51), and 139 (47) mumol/L in the control group (p = 0.017, analysis of covariance). Steroid withdrawal patients showed a further rise in mean plasma creatinine to 160 (44) and 161 (65) mumol/L at two and three years from trial entry. Changes in several clinical and metabolic indices were also observed in association with steroid withdrawal. Blood pressure declined but the reduction was incompletely sustained, being more evident immediately after steroid withdrawal than at one year. Total cholesterol declined about 1 mmol/L in the steroid withdrawal group. Other changes associated with steroid withdrawal were reductions in white cell count and haemoglobin and increases in plasma phosphate and alkaline phosphatase. INTERPRETATION: Late steroid withdrawal is feasible in most patients with stable graft function on triple immunosuppression and has potentially beneficial metabolic effects. However, a substantial proportion of patients show a reduction in graft function, indicating a need for caution in considering the long term outcome.

Adult↗
PubMed1995

UK prospective diabetes study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM.

The deletion allele of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene has been suggested to be an independent risk factor for myocardial infarction, particularly in subjects judged to be "low-risk" by the criteria of lipid status and body mass index. In a prospective, matched case-control study, we have investigated the role of this polymorphism as a risk factor for myocardial infarction in 173 newly-diagnosed British Caucasian non-insulin-dependent diabetic subjects taken from the United Kingdom Prospective Diabetes Study who subsequently developed myocardial infarction and 297 control subjects from the same study population matched for known cardiovascular risk factors including age at diagnosis of diabetes, gender, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and smoking habit. A trend towards increased risk conferred by homozygosity for the deletion allele was observed in cases (odds ratio 1.63, p = 0.09). When the population was stratified according to the matched risk factors, the deletion allele was associated with myocardial infarction in those with low plasma low-density lipoprotein cholesterol (odds ratio 3.67, p = 0.002), or low triglyceride (odds ratio 3.14, p = 0.005). The strongest association of the deletion allele with myocardial infarction was observed in subjects with both low low-density lipoprotein cholesterol and low triglyceride levels (odds ratio 9.0, p < 0.001). These results show that the deletion allele is a risk factor for myocardial infarction in non-insulin-dependent diabetic patients who have a favourable lipid profile.

Case-Control Studies↗
PubMed1995

U.K. Prospective Diabetes Study. XV: Relationship of renin-angiotensin system gene polymorphisms with microalbuminuria in NIDDM.

We performed a case-control study to determine whether molecular variants of genes of the renin-angiotensin system were associated with the presence of albuminuria in non-insulin dependent diabetes mellitus (NIDDM). A total of 180 diabetic patients with persistent microalbuminuria [median urinary albumin (interquartile range) of 74 (54 to 126 mg/liter)] were matched with two control groups of diabetic patients without microalbuminuria [median urinary albumin 7 (5 to 10) mg/liter] for variables known to be associated with raised urinary albumin concentration including hemoglobin A1c and triglyceride. One control group was also matched for blood pressure and the other group was not, to allow assessment of interactions with hypertension. Association with the I/D polymorphism of the ACE gene and M235T variant of the angiotensinogen gene (AGT) with microalbuminuria and retinopathy was examined. There were no significant differences in genotype frequency between cases and controls for ACE or AGT irrespective of blood pressure matching. However, among subjects with microalbuminuria, those with the ACE DD genotype had a significantly greater urinary albumin excretion than individuals with a non-DD genotype [median 88 (68 to 170) mg/liter vs. 67 (53 to 113) mg/liter, P < 0.001]. More subjects with the DD than non-DD genotype had persistent albuminuria > 100 mg/liter, twice the upper normal range (60% vs. 38%, P = 0.006). When increased albumin excretion occurs, the presence of the ACE DD genotype appears to be associated with higher urinary albumin levels. No association with retinopathy was observed.

Albuminuria↗
PubMed1992

Identifying genetic determinants in human essential hypertension.

Genetic factors play an important role in the pathophysiology of human essential hypertension. The remarkable success of molecular genetic techniques in identifying the basis for single gene disorders at the DNA level has encouraged investigators to apply similar techniques in an attempt to identify blood pressure genes. In contrast to single gene disorders, however, the study of blood pressure is complicated by its quantitative, complex, heterogeneous, and polygenic nature. This article examines current methods and strategies for identifying genetic determinants in human hypertension. The availability of highly polymorphic markers, the advances in quantitative trait analysis, and the mapping of blood pressure-determining genes in a polygenic rat model of hypertension suggest that molecular genetic research in human hypertension has come of age.

Animals↗
PubMed1991

Assessing the role of APNH, a gene encoding for a human amiloride-sensitive Na+/H+ antiporter, on the interindividual variation in red cell Na+/Li+ countertransport.

The "reverse genetic" approach to essential hypertension is complicated by the fact that blood pressure is a heterogeneous, quantitative, complex trait. One strategy is to use "intermediate phenotypes" that are not only associated with hypertension but that also have a simple mode of inheritance, compatible with the action of a single gene. Red cell sodium-lithium countertransport (SLC) is one of the best characterized intermediate phenotypes for hypertension. The similarity in stoichiometry and kinetics between SLC and Na+/H+ exchange has led to the proposal that the gene encoding the Na+/H+ antiporter (APNH) may be responsible for the individual variance in SLC. We have tested this hypothesis by both an association study and Haseman and Elston's sib pair method of linkage analysis, by using a polymorphism at the APNH locus detected by denaturing gradient gel electrophoresis. Both analytical techniques were performed before and after correction of SLC values for known covariates. There was no significant association between mean SLC values and any of the three possible genotypes of the APNH locus either before or after regressing out covariates (F = 0.64 and P greater than 0.52; F = 0.63 and P greater than 0.53, respectively). Linkage analysis similarly failed to demonstrate a relationship between the squared difference in SLC values and the identity by descent status for APNH as well as other loci that map close to APNH (D1S57, RH, and ALPL). Taking these results together, we conclude that mutations at the APNH locus are not responsible for the observed variation in SLC values.

Amiloride↗
PubMed1990

The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1.

The Na+/H+ antiporter is a ubiquitous membrane-associated protein that plays an important role in the regulation of intracellular pH. APNH, a gene encoding the antiporter, has been cloned and mapped to the short arm of chromosome 1 by in situ hybridization. Using the polymerase chain reaction, we have amplified a 376 base pair fragment corresponding to the 5' end of APNH. We have detected a polymorphism within this fragment by denaturing gradient gel electrophoresis. Using polymorphisms at other 1p loci (ALPL, the gene for alkaline phosphatase, RH and D1S57), we have been able to map APNH telomeric to D1S57 and close to RH and ALPL by genetic linkage. APNH is a plausible candidate gene for human essential hypertension; the APNH polymorphism combined with a knowledge of its genetic map location allow this candidate to be tested in hypertensive kindreds and sib-pairs.

Alleles↗
PubMed1990

Evidence for abnormal Na+/H+ antiport activity detected by phosphorus nuclear magnetic resonance spectroscopy in exercising skeletal muscle of patients with essential hypertension.

1. Exercise-induced pH changes in skeletal muscle were studied in a group of eight subjects with essential hypertension by using 31P n.m.r. spectroscopy. 2. Leucocyte Na+/H+ antiport activity was measured in vitro in the same subjects using a pH-sensitive fluorescent dye. 3. Resting skeletal muscle pH and unstimulated leucocyte pH values were similar to those in control subjects, but increased Na+/H+ antiport activity was demonstrated in the leucocytes from hypertensive subjects by acid loading in vitro. Decreased skeletal muscle acidification and an increased rate of pH recovery was also demonstrated in vivo in these same patients during an acid load induced by isotonic exercise. 4. These findings suggest that the increased cellular Na+/H+ antiport activity, which has been demonstrated in vitro in essential hypertension, also affects the biochemical response of skeletal muscle to physiological levels of exercise. This strengthens the argument that increased Na+/H+ antiport activity in hypertension is a generalized and physiologically relevant cellular abnormality.

Biological Transport, Active↗
PubMed1989

Food intolerance and the irritable bowel syndrome.

Two hundred patients (156 women) with the irritable bowel syndrome were treated with dietary exclusion for three weeks. Of the 189 who completed this study, 91 (48.2%) showed symptomatic improvement. Subsequent challenge with individual foods showed that 73 of these 91 responders were able to identify one or more food intolerances and 72 remained well on a modified diet during the follow up period (mean (SD), 14.7 (7.98) months). Of the 98 patients who showed no symptomatic improvement after three weeks of strict exclusion only three were symptomatically well at follow up (mean (SD), 12.48 (8.09 months). There was no close correlation between response and symptom complex. There was a wide range of food intolerance. The majority (50%) identified two to five foods which upset them (range 1-14). The foods most commonly incriminated were dairy products (40.7%) and grains (39.4%).

Adolescent↗