CYP3A5 as a candidate gene for hypertension: no support from an unselected indigenous West African population.

CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) expression stimulates the sodium retentive actions of the mineralocorticoid receptor causative of hypertension, probably by means of its ability to substantially increase the level of 6ß-hydroxylase activity. Most Black individuals are functional CYP3A5 expressers, and this is a candidate gene for the high incidence of hypertension in Black populations. The study investigates whether CYP3A5 expression results in higher blood pressure in a Ghanaian population. Real-time PCR was used to genotype 898 DNA samples for the CYP3A5*3 and CYP3A5*6 single-nucleotide polymorphisms with technically adequate genotyping for 881 samples. Of these, 803 were genetic CYP3A5 expressers, 44 nonexpressers and 34 uncertain (CYP3A5*3/*6). Although there was a trend in the proportion of hypertensive individuals as CYP3A5 expression decreased, using a two-sided t-test, no statistically significant relationship was established between systolic or diastolic pressure and CYP3A5*3 or CYP3A5*6 genotypes, or their haplotypes (Systolic confidence interval: -8.44 to -7.70, P=0.93, Diastolic confidence interval: -4.89 to 4.85, P=0.99). We conclude, therefore, that there is either no association between CYP3A5 expression and blood pressure or, if there is a relationship, the strength of the association is very small.

Shortage of healthcare workers in sub-Saharan Africa: a nephrological perspective.

AIMS: The paper assesses the lack of healthcare workers, the consequences, and possible solutions. MATERIALS AND METHODS: Review of existing literature and global health reports. RESULTS: The 47 countries of sub-Saharan Africa have a critical shortage of healthcare workers, the deficit amounting to 2.4 million doctors and nurses. There are 2 doctors and 11 nursing/midwifery personnel per 10,000 population, compared with 19 doctors and 49 nursing/midwifery personnel per 10,000 for the Americas, and 32 doctors and 78 nursing/midwifery personnel per 10,000 for Europe. And, whereas there are 28 doctors and 87 nurses/midwifery personnel per 10,000 in high income regions of the world, there are only 5 doctors and 11 nurses/ midwifery personnel per 10,000 in low income regions. The shortage of nephrologists in Africa, and especially sub-Saharan Africa, remains a critical issue, with many countries having < 1 nephrologist per million population; some have no nephrologists at all. The USA, UK, Canada and Australia have benefitted considerably from the migration of nurses and doctors over the past half century. Opportunities for training as well as employment have attracted doctors from many countries to these developed countries. Since 2006, new legislation in the UK has limited the inflow of health workers. Developing countries are also beginning to take steps to mitigate the problem of health worker loss and are developing strategies to both train increasing numbers of different cadres of healthcare worker and also to retain those already working in these countries. CONCLUSIONS: The forces of globalization are tending to increase the worldwide movement of all types of professionals, including those working in health care. It is this lack of health workers in developing countries that has been such a major constraint in limiting progress on initiatives such as the HIV "3 by 5" and Millennium Development Goals. More specifically, lack of resources, both human and financial, in developing countries has hampered nephrology programs both in the detection and prevention of chronic kidney disease and in the ability of doctors, nurses and other nephrological personnel to provide acute/chronic dialysis and transplantation.

Prevalence of chronic kidney disease stages 3-5 among acute medical admissions: another opportunity for screening.

BACKGROUND: Early identification of chronic kidney disease (CKD) can help delay or prevent its progression, but the opportunities for systematic screening of patients are not well defined. AIM: To define the prevalence of CKD Stages 3-5 and related anaemia among acute medical admissions. DESIGN: Retrospective analysis. METHODS: We studied all acute medical admissions to a major London teaching hospital during one year. The lowest creatinine, highest haemoglobin (Hb) and average mean corpuscular volume (MCV) were determined for 3 months before and after admission. Patients were categorized as CKD Stages 3-5 if the highest estimated GFR (eGFR) was <60 ml/min/1.73 m2. CKD-related anaemia was diagnosed if these patients had Hb <11 g/dl with normal MCV. RESULTS: A total of 6073 patients were studied: male 49.0%, age 65.4 +/- 19.6 years (mean +/- SD), creatinine 82.7 +/- 46.7 micromol/l, eGFR 89.1 +/- 32.5 ml/min/1.73 m2, Hb 13.6 +/- 1.73 g/dl, MCV 87.7 +/- 7.2 fl. There was an inverse correlation between eGFR and age (r2 = 0.5; P < 0.001). Males were younger than females (63.5 +/- 18.4 years vs. 67.3 +/- 20.5) and had higher eGFR (93.6 +/- 34.1 vs. 84.7 +/- 30.2 ml/min/1.73 m2; P < 0.001). A total of 743 patients (12.2%) had raised creatinine >110 micromol/l, however using eGFR <60 ml/min/1.73 m2, 1075 patients (17.7%) were identified. The patients were categorized as follows: Stage 3: 950 (15.6%), Stage 4: 100 (1.7%), Stage 5: 25 (0.4%). Ninety-nine (9.2%) of the 1075 patients had normocytic anaemia. CONCLUSION: We have found a high prevalence of CKD Stages 3-5 (17.7%) among acute medical admissions, of whom 9.2% had a related anaemia. Our findings highlight an important opportunity (amongst the 1.9 million acute medical admissions annually in England) for detecting patients with CKD.

Loss of health professionals from sub-Saharan Africa: the pivotal role of the UK.

The already inadequate health systems of sub-Saharan Africa have been badly damaged by the emigration of their health professionals, a process in which the UK has played a prominent part. In 2005, there are special opportunities for the UK to take the lead in addressing that damage, and in focusing the attention of the G8 on the wider problems of health-professional migration from poor to rich countries. We suggest some practical measures to these ends. These include action the UK could take on its own, with the African countries most affected, and with other developed countries and WHO.

T594M mutation of the beta-subunit of the epithelial sodium channel in Ghanaian populations from Kumasi and London and a possible association with hypertension.

We have tested 186 individuals from Ghana, 95 indigenous and 91 who have settled in the United Kingdom, for the presence of the T594M mutation in the beta-subunit of the epithelial sodium channel, which is associated with hypertension in black populations. The group living in Ghana had a mean age of 27 years and were normotensive, but had an increased frequency of the T allele compared to the London-based population. If this is reflected in larger studies, and the link with hypertension is maintained in the Ghanaian population, this mutation could be a significant cause of hypertension in Ghana.

A community study of health promotion in rural West Africa: details of a household survey and population census.

BACKGROUND: Hypertension is an important problem in sub-Saharan Africa. The low use of processed food in this area makes a population approach to reducing salt intake feasible. AIM: To create an age-sex register for 12 villages in Ghana as the first stage of a community study of the effect of dietary salt reduction on blood pressure and urinary sodium excretion in West African villagers. DESIGN: Household survey and population census. METHODS: Over three months, village maps were sketched and a complete list of total number of households, adults (with age and gender) and children in each village was obtained. RESULTS: The six semi-urban villages were larger than the six rural villages (10368 vs. 6597 inhabitants) and almost half the total population was under 16. CONCLUSIONS: Accurate census data are important in the design, implementation and interpretation of community studies and intervention trials. We outline the methods by which census data can be collected in rural and semi-urban sub-Saharan African villages, and emphasize the importance of painstaking, thorough work in the collection of such data.

Unravelling the links between calcium excretion, salt intake, hypertension, kidney stones and bone metabolism.

Evidence from animal, clinical and epidemiological studies suggests that high blood pressure is associated with abnormalities of calcium metabolism, leading to increased calcium loss, secondary activation of the parathyroid gland, increased movement of calcium from bone and increased risk of urinary tract stones. Some of these abnormalities are detectable in children and young people and continue throughout adult life. The cluster of abnormalities may be due either to a primary renal tubular defect ('renal calcium leak' hypothesis) or to the effect of central volume expansion seen in hypertension ('central blood volume' hypothesis). A high salt intake is known to aggravate these abnormalities and their consequences. If substantial calcium loss related to high blood pressure is sustained over many decades, increased excretion of calcium in the urine may result in an increased risk of urinary tract stones, and the increased movement of calcium from bone may result in higher rates of bone mineral loss, thereby increasing the risk of osteoporosis. The present review summarises the evidence, suggests a unifying hypothesis and discusses clinical and public health implications.

Pharmacokinetics of mycophenolate mofetil in patients with end-stage renal failure.

BACKGROUND: Mycophenolate mofetil (MMF) acts as a prodrug for the immunosuppressive drug mycophenolic acid (MPA). It is rapidly converted to MPA following oral ingestion. MPA is metabolized to MPA glucuronide (MPAG), which is renally excreted. This study examines the pharmacokinetics of MPA and MPAG in patients with end-stage renal failure who were on hemodialysis (N = 10) or peritoneal dialysis (N = 10) treatment. METHODS: After an overnight fast, a single oral dose of 1 g MMF was given. Plasma concentrations of MPA and MPAG were measured from 0 (predose) to 36 hours after administration, using high-performance liquid chromatography (HPLC). The area under the concentration time curve (AUC) from 0 to 36 hours was calculated using the trapezoidal rule. RESULTS: Mean (+/- SD) AUC for MPA was 55.7 +/- 32.6 mg/L.h for hemodialysis patients and 44.7 +/- 14.7 mg/L.h for peritoneal dialysis patients, which is similar to expected values for subjects with normal renal function. The mean (+/- SD) maximum plasma concentration (Cmax) for MPA was lower than would be expected for subjects with normal renal function (16.01 +/- 10.61 mg/L for hemodialysis, 11.48 +/- 4.98 mg/L for peritoneal dialysis). MPAG clearance was prolonged with AUC approximately five times what would be expected in subjects with normal renal function (1565 +/- 596 mg/L.h for hemodialysis, 1386 +/- 410 mg/L.h for peritoneal dialysis). There was no significant difference for any of the pharmacokinetic parameters between subjects on hemodialysis and those on peritoneal dialysis. Plasma concentrations of MPA and MPAG did not fall significantly during hemodialysis. No MPA was detectable in hemodialysis or peritoneal dialysis fluid, but small amounts of MPAG were detected in hemodialysis fluid in 1 out of 10 subjects and in peritoneal dialysis fluid in 3 out of 10 subjects. CONCLUSIONS: The accumulation of MPAG may be responsible for the poor gastrointestinal tolerance of this drug in dialysis patients and probably limits the maximum dose of MMF that can be tolerated.

Lack of association of ACE/angiotensinogen genotype with renal function in autosomal dominant polycystic kidney disease.

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.

A training course for the UEB examination. The case for retaining an examination for overseas doctors excluded from practising in the UK.

BACKGROUND: Some overseas medical graduates choose to take the United Examining Board (UEB) examination to achieve UK registration; others have no other option. We have devised a course for overseas doctors who wish to re-qualify via this route. THE COURSE: Eighteen doctors enrolled during 1995-1997; all passed the UEB examination. Regular formative assessment allowed us to identify students adequately prepared to pass the examination. The main predictor of examination outcome was performance in a mock examination. Gender, residential status and interval since original qualification were not predictive. The eight doctors whose primary medical course was conducted in a language other than English did not seem to be disadvantaged. OUTCOME: Successful examinees obtained pre-registration house officer posts without delay; one has since passed the full MRCP (UK) and another MRCP Part I. All but one of the intend to pursue their medical careers in the UK. SUMMARY: After a structured course (average 9.5 months) at this medical school, selected overseas doctors can reach a standard appropriate to a UK primary qualifying examination. These findings have implications for overseas doctors living here and not practising, as well as for those concerned with expanding the UK medical workforce.

Hypertension and renal failure in Kumasi, Ghana.

Hypertension is common in West Africa and likely to become more common as urbanisation increases. There are at present few facilities for the detection and management of hypertension so the influence it has on overall morbidity and mortality in the population is not clear. The objectives of the study were to assess: (a) renal disease and blood pressure related admissions and deaths among acute medical admissions to Komfo Anokye Teaching Hospital, Kumasi, during an 8-month period; and (b) the burden of renal disease among out-patient hypertensives at the same hospital. Ward admission books were examined in the four acute medical wards to ascertain admission diagnosis and cause of death (two 4-month periods in 1995 and 1996). Clinical assessment (blood pressure, plasma creatinine, proteinuria) was also made of 448 consecutive out-patient hypertensives seen between March 1995 and April 1996. Five hundred and ninety-three (17.9%) of 3317 acute medical admissions were ascribable to a cardiovascular cause (hypertension, heart failure, stroke); 171 (28.8%) of these died. One hundred and sixty-six (5.0%) had renal disease of whom 45 (27.1%) died, usually of end-stage renal disease. Among the 448 hypertensive out-patients, 30.2% (110 out of 365) had a plasma creatinine >140 micromol/l (48 > or = 400 micromol/l) and 25.5% (96 out of 376) had proteinuria. Eighty-nine of the 448 had a diastolic blood pressure > or =115 mm Hg; in this group 38 (42.7%) had a plasma creatinine of >140 micromol/l (and 18 or 20.2% > or =400 micromol/l). In conclusion, cardiovascular and renal disease are important contributors to morbidity and mortality among acute medical admissions to a large city hospital in Ghana. Among out-patient hypertensives renal disease is an important complication, especially in those with the more severe hypertension.

Monocyte expression of tissue factor and adhesion molecules: the link with accelerated coronary artery disease in patients with chronic renal failure.

OBJECTIVE: To investigate the expression of monocyte tissue factor (MTF) and adhesion molecules in patients with chronic renal failure (CRF) and to look for any correlation with thrombin generation and Lp(a) lipoprotein. DESIGN: A study of MTF expression and adhesion molecules, prothrombin fragments 1+2 (PTf1+2), an index of thrombin generation, and lipoproteins in patients with CRF and in normal control subjects. BACKGROUND: Patients with end stage renal failure have an increased risk of coronary artery disease despite advances in therapy. Stimulated monocytes are potent activators of blood coagulation through the generation of MTF, which was recently implicated in the aetiology of acute coronary ischaemic syndromes. METHODS: MTF expression and adhesion molecules were measured in whole blood using immunofluorescence of monocytes labelled with anti-tissue factor antibody and CD11b and c by flow cytometry. PTf1+2 and Lp(a) lipoprotein in plasma were measured by enzyme linked immunosorbent assay (ELISA). PATIENTS: 70 patients with CRF without documented coronary artery disease (30 patients with CRF undialysed, 20 patients undergoing chronic ambulatory peritoneal dialysis (CAPD), and 20 undergoing haemodialysis (HD)), together with 20 normal controls, were studied. RESULTS: The (mean (SD)) increased MTF of CRF (48.0 (29) v 33.3 (7.2) mesf unit/100 monocytes in controls, p = 0.04) was more pronounced in patients undergoing dialysis (HD 73.1 (32.8) (p < 0.003) and CAPD 62.8 (28.9) mesf unit/100 monocytes, p < 0.04). MTF activity showed a positive correlation with both PTf1+2 and serum creatinine (p < 0.003) but not with Lp(a) lipoprotein. Lp(a) lipoprotein was significantly increased in both dialysis groups compared with controls (p < 0.005) and non-dialysis CRF groups (p < 0.02). Monocyte adhesion molecule (CD11b) was significantly higher in all three CRF groups than in the controls (p = 0.006). CONCLUSION: This study has demonstrated a hypercoagulable state in patients with CRF. This was especially pronounced in the dialysis patients. These findings provide a possible explanation for the increased cardiovascular and cerebrovascular morbidity and mortality in these patients.

Evidence from a Ghanaian population of known African descent to support the proposition that hemochromatosis is a Caucasian disorder.

Mutations in the HFE gene on chromosome 6 are believed to cause the iron overload disorder hemochromatosis, the most common single gene disorder in northern Europeans. Two mutations have been described previously: C282Y, with an allele frequency of between 3% and 10% in the caucasian population, and H63D, which has an allele frequency of 16%. Published data shows that C282Y appears to be causative in the homozygous state, while the frequency of H63D/C282Y compound heterozygotes is much greater than expected in patient groups. There also appears to be a slightly elevated risk for H63D homozygotes. Hemochromatosis has been thought to be primarily a caucasian disorder. We have studied 97 healthy, black Ghanaian subjects, whose parents and grandparents were also African, to find the frequency of the two mutations. C282Y was absent, while H63D occurred in 2 individuals. These differences are significant at the 0.05 and 0.001 levels, respectively. The prevalence of H63D homozygotes in this population at 1 in 10,000 is clearly of no use in studying the effect of this genotype on phenotype. However, this study suggests an absence of the C282Y mutation in African populations, and the possibility that other populations might provide different genotypes and hence an analysis of H63D risk. A possible heterozygote advantage for the mutation is discussed.