Biomedical subjects
Publications and source records attributed to Robert Unwin.
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BACKGROUND/AIMS: Alpha-galactosidase A (alpha-GLA) deficiency (Fabry disease) is an X-linked lysosomal storage disorder. The associated visceral complications are progressive and multiorgan; renal involvement is common, usually leading to end-stage renal failure (ESRF). The reported benefits of specific enzyme replacement therapy (ERT) indicate the importance of screening for Fabry disease in high-risk populations, as this approach should make it possible to identify other family members with little or no clinical features of the disease, and for them to be considered for early preventive treatment. METHODS: We screened for Fabry disease in 106 patients on hemodialysis in our hospital-based hemodialysis unit. We did this by measuring alpha-GLA enzyme activity in blood leukocytes taken from each patient and we then carried out gene analysis when indicated. RESULTS: We were able to discover 1 patient with low residual alpha-GLA activity (a prevalence of 0.94%). Alpha-GLA gene analysis identified a point mutation within the coding region producing a N215S amino acid substitution in the protein. Among the relatives of this index case, molecular testing found 7 family members with the same N215S alpha-GLA mutation. Of these, 3 had reduced alpha-GLA activity and clinical features of Fabry disease, and for which ERT was subsequently given. CONCLUSION: Screening for Fabry disease is simple and although the yield is small, it is potentially significant and of possible benefit to the relatives of affected cases in this 'at-risk' ESRF population, many of who do not have a clear renal diagnosis.
Proteomics is a promising new tool for functional genomics. In addition to two-dimensional gel electrophoresis, other methods that are based on liquid chromatography and mass spectrometry are now available to study proteins. In this brief article, we review the strengths and limitations of the proteomic approaches currently available to the researcher, and we provide examples of how proteomics has been, and can in the future be, used to study the kidney.
OBJECTIVE: We investigated the effect of cardiac surgery on a marker of tubular damage, an enzyme called neutral endopeptidase (NEP), and on a marker of tubular function, retinol binding protein (RBP). Markers of tubular damage or function are useful in the early detection of acute renal failure and help identify the risk factors for this disease. We also examined if colloid interfered with NEP measurement. DESIGN: A controlled prospective cohort study. SETTING: A teaching cardio-thoracic unit in London, England. PATIENTS AND PARTICIPANTS: Thirty-four patients underwent cardiac surgery. Eight patients waiting for cardiac surgery acted as controls. INTERVENTIONS: Twenty-five patients had coronary artery bypass graft, four patients had valve replacements, one patient had a coronary artery bypass graft with a valve replacement and one patient had a left ventricular aneurysm repair. MEASUREMENTS AND RESULTS: Neutral endopeptidase was measured in all the patients and controls. In separate subgroups RBP ( n=5) and Gelofusine use ( n=12) were recorded. Urine samples were collected pre-operatively, 3 h, 1 and 4 days post-operatively. NEP rose significantly ( p<0.05) after cardiac surgery compared with the control population. RBP also rose significantly ( p<0.05) after cardiac surgery. NEP correlated with RBP 3 h post-operatively ( p<0.05, r(2)=0.97). There was no correlation between the amount of Gelofusine given and NEP excretion. CONCLUSION: Excretion of NEP and RBP were both increased after cardiac surgery. Colloid did not affect the excretion of NEP, although in other studies it has affected the excretion of RBP. This may make NEP excretion a better index of acute and impending renal damage following cardiac surgery.
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The loop of Henle (LOH) is an important site of renal tubule acidification. A combination of several techniques, including in vivo microperfusion, perfusion in vitro of the S3 segment of the proximal tubule and of the thick ascending limb (TAL) of Henle's loop, as well as quantitative PCR performed on isolated TAL, has permitted the definition of key transporters and their role in modulating bicarbonate reabsorption in physiological and pathophysiological conditions. Na(+)-H+ exchange is the most important transport mechanism responsible for bicarbonate reabsorption, although a small but significant contribution of H(+)-ATPase-mediated bicarbonate reabsorption can also be identified. NHE3 is the main of several NHE isoforms expressed in the TAL and in the S3 segment of the proximal tubule. Special properties of the Na(+)-H+ exchanger in the TAL are its relative insensitivity to changes in cell pH (pHi) and the tight coupling between apical and basolateral Na(+)-H+ exchange. Several hormones, including anti-diuretic hormone (ADH), angiotensin II (AII), and gluco- and mineralocorticoids regulate Na(+)-H+ exchange. Loop diuretics such as furosemide stimulate bicarbonate transport along the LOH. Systemic acid-base disturbances also modulate bicarbonate transport: acidosis increases bicarbonate reabsorption, while metabolic alkalosis has the opposite effect. Neither hypokalemic alkalosis nor respiratory alkalosis or respiratory acidosis alter bicarbonate transport along the LOH. A significant role of HCO3 backflux, most likely through the paracellular pathway of the TAL, can also be observed. Changes in extracellular osmolality also affect bicarbonate reabsorption: hypertonicity inhibits, whereas hypotonicity stimulates transport. Transport activation is also observed as an adaptive response to glomerular hyperfiltration.