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R J Unwin

Publications and source records attributed to R J Unwin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Tubular proteinuria defined by a study of Dent's (CLCN5 mutation) and other tubular diseases.

UNLABELLED: Tubular proteinuria defined by a study of Dent's ( CLCN5 mutation) and other tubular diseases. BACKGROUND: The term "tubular proteinuria" is often used interchangeably with "low molecular weight proteinuria" (LMWP), although the former implies a definite etiology. A specific quantitative definition of tubular proteinuria is needed, and we address this by studying five different renal disorders. METHODS: Tubular proteinuria was assessed by measuring urinary retinol-binding protein (RBP), beta2-microglobulin (beta2M), alpha1-microglobulin (alpha1M), and albumin in 138 patients: 26 affected males and 24 female carriers of the X-linked syndrome "Dent's disease," 6 patients with other Fanconi syndromes, 17 with distal renal tubular acidosis (dRTA), 39 with glomerulonephritis (GN), and 26 with Chinese herbs nephropathy (CHN). RESULTS: RBP was better than beta2M or alpha1M in identifying the tubular proteinuria of Dent's disease. Median urinary RBP levels in mg/mmol creatinine were: affected male Dent's, 18.2, N = 26; carrier female Dent's, 0. 30, N = 24; dRTA, 0.027, N = 17; GN, 0.077, N = 39; and normal adults, 0.0079, N = 61. Elevated urinary RBP (>0.017) and albumin < (10 x RBP) + 2 identified all patients with the LMWP of Dent's disease and clearly distinguished their LMWP from that of dRTA and GN. This is a quantitative definition of tubular proteinuria. Consistent with this definition, 80% of those patients with CHN who had an elevated RBP had tubular proteinuria. Urinary RBP and albumin in carriers of Dent's disease were strikingly correlated over a 100-fold range (R = 0.933). CONCLUSION: The combination of elevated urinary RBP (>0.017) and albumin < (10 x RBP) + 2 (mg protein/mmol creatinine) is a quantitative definition of tubular proteinuria. Furthermore, our findings suggest that a shared defect in tubular RBP and albumin reuptake causes this form of proteinuria.

Adolescent↗
PubMed2000

Presentation, diagnosis, and management of renal failure in patients with HIV infection.

HIV infected patients are at increased risk of developing renal failure when compared to the general population. Renal disease occurs both as a primary manifestation of HIV infection and secondary to complications such as intercurrent illness or drug therapy. Examples of primary HIV renal disease, including HIV associated nephropathy (HIV AN) and immune complex glomerulonephronephritis, and secondary causes of renal failure are reviewed with full discussion about investigation and treatment methods.

AIDS-Associated Nephropathy↗
PubMed2000

Are calcium antagonists effective in preventing complications of hypertension and progression of renal disease?

Long-acting calcium antagonists have been shown to be safe and effective in lowering blood pressure, both as first-line agents and in combination with other classes of antihypertensive drug. They have also been shown to reduce the incidence of cerebrovascular and cardiovascular events in elderly patients with predominantly systolic hypertension. It is clear that reduced morbidity and mortality in hypertension is related to the degree to which blood pressure is reduced, regardless of the therapy used. This is the single most important conclusion of all recent trials, especially in the sub-group of hypertensive patients with diabetes. The World Health Organization-International Society of Hypertension guidelines acknowledge this and do not make specific recommendations as to initial therapy in the absence of other medical factors. However the use of thiazide diuretics and beta-blockers has strong support from large placebo-controlled trials in patients with mild-moderate essential hypertension. The British Hypertension Society and JNC VI guidelines restrict their recommendations for the use of calcium antagonists to isolated systolic hypertension and angina, or when other agents have failed, are contraindicated or are not tolerated. However, their efficacy in lowering blood pressure, their tolerability and potentially beneficial secondary effect on proteinuria, especially in combination with an angiotensin-converting enzyme inhibitor, still make them attractive antihypertensive agents. The results of further long-term outcome trials that make direct comparisons between calcium antagonists and other classes of antihypertensive drug are still awaited. Unlike angiotensin-converting enzyme inhibitors, the antiproteinuric effect of calcium antagonists, even that of the non-dihydropyridine type, seems to depend on an adequate and stable reduction in blood pressure.

Calcium Channel Blockers↗
PubMed2000

Axial distribution and characterization of basolateral P2Y receptors along the rat renal tubule.

BACKGROUND: Several groups have identified P2Y receptors in the basolateral membrane of the rat nephron. These studies have not covered all segments of the nephron and have relied solely on the relative potency of receptor agonists for classification. METHODS: We measured purine and pyrimidine-induced changes in intracellular free calcium concentration ([Ca(2+)](i)) in anatomically defined segments of the rat nephron. To complement these functional studies, we have used reverse transcription-polymerase chain reaction methodology to identify specific P2Y receptor transcripts in these segments. RESULTS: Adenosine 5'-triphosphate (ATP) mobilized [Ca(2+)](i) in all nephron segments, except for the thick ascending limb of Henle, which was poorly responsive. Adenosine (100 micromol/L) was without effect, confirming that the effect of ATP was mediated by P2 receptors. In the proximal convoluted tubule (PCT) and outer medullary collecting duct (OMCD), there was evidence for two receptor subtypes with characteristics of P2Y(1)- and either P2Y(2)- or P2Y(4)-like receptors. A novel finding in the thin limbs was the presence of a receptor with properties of both P2Y(2) and P2Y(4) receptor subtypes. To aid classification, we identified P2Y receptor mRNA in rat nephron segments. In the PCT and OMCD and thin ascending limb of Henle, we found expression of P2Y(1), P2Y(2), and P2Y(4) receptors. In the descending limb of Henle, P2Y(1) and P2Y(2) mRNA was found, but P2Y(4) was not expressed. CONCLUSION: These data suggest that extracellular ATP can influence tubular cell function in all segments of the rat nephron, through P2Y receptors via multiple (and coexpressed) P2Y receptor subtypes.

Adenosine Triphosphate↗
PubMed2000

Localization of diuretic effects along the loop of Henle: an in vivo microperfusion study in rats.

In order to clarify the effects on sodium reabsorption in the loop of Henle of methazolamide (a carbonic anhydrase inhibitor), chlorothiazide and the loop diuretics frusemide and bumetanide, superficial loops were perfused in vivo in anaesthetized rats and the individual diuretics were included in the perfusate. Differentiation between effects in the pars recta and in the thick ascending limb of Henle (TALH) was achieved by comparing responses to the diuretics when using a standard perfusate, designed to mimic native late proximal tubular fluid, and a low-sodium perfusate, designed to block net sodium reabsorption in the pars recta. With the standard perfusate, methazolamide caused decreases in sodium reabsorption (J(Na)) and water reabsorption (J(V)); with the low-sodium perfusate, a modest effect on J(Na) persisted, suggesting that carbonic anhydrase inhibition reduces sodium reabsorption in both the pars recta and the TALH. The effects of chlorothiazide were very similar to those of methazolamide with both the standard and low-sodium perfusates, suggesting that chlorothiazide also inhibits sodium reabsorption in the pars recta and TALH, perhaps through inhibition of carbonic anhydrase. With the standard perfusate, both frusemide and bumetanide produced the expected large decreases in J(Na), but J(V) was also lowered. With the low-sodium perfusate, the inhibitory effects of the loop diuretics, particularly those of frusemide, were substantially reduced, while net potassium secretion was found. These observations indicate that a significant component of the effect of frusemide (and possibly of bumetanide) on overall sodium reabsorption is located in the pars recta, and that loop diuretics induce potassium secretion in the TALH.

Absorption↗
PubMed1999

Community nephrology: audit of screening for renal insufficiency in a high risk population.

BACKGROUND: The rate of acceptance onto dialysis programmes has doubled in the past 10 years and is steadily increasing. Early detection and treatment of renal failure slows the rate of progression. Is it feasible to screen for patients who are at increased risk of developing renal failure? We have audited primary care records of patients aged 50-75 years who have either hypertension or diabetes, and are therefore considered to be at high risk of developing renal insufficiency. Our aim was to see whether patients had had their blood pressure measured and urine tested for protein within 12 months, and plasma creatinine measured within 24 months. METHODS: This was a retrospective study of case notes and computer records in 12 general practices from inner and greater London. A total of 16,855 patients were aged 50-75 years. From this age group, 2693 (15.5%) patients were identified as being either hypertensive or diabetic, or both. RESULTS: Of the 2561 records audited, 1359 (53.1%) contained a plasma creatinine measured within 24 months, and 11% of these (150) had a value > 125 micromol/l. This equates to a prevalence of renal insufficiency of > 110,000 patients per million in this group. Forty two patients (28%) had been referred to a nephrologist. Of records audited, 73% contained a blood pressure measurement and 29% contained a test for proteinuria within 12 months. CONCLUSIONS: There is a high prevalence of chronic renal insufficiency in hypertensive and diabetic patients. It is feasible to detect renal insufficiency at a primary care level, but an effective system will require computerized databases that code for age, ethnicity, measurement of blood pressure and renal function, as well as diagnoses.

Aged↗
PubMed1998

Transepithelial electrochemical gradients in the proximal convoluted tubule during potassium depletion in the rat.

1. In order to examine the electrochemical gradient for potassium reabsorption across the S2 segment of the proximal convoluted tubule, transepithelial potential differences and transepithelial potassium concentrations were measured in anaesthetized potassium-replete and potassium-depleted rats. 2. Potassium-depleted rats were markedly hypokalaemic (plasma potassium, 1.4 +/- 0.1 vs. 4.1 +/- 0.1 mmol l-1 in potassium-replete rats) and had a significantly reduced muscle potassium content. In confirmation of previous reports, glomerular filtration rate was slightly reduced, while fractional reabsorption in the proximal convoluted tubule was enhanced. 3. In potassium-replete animals, the transepithelial potential difference (PD) at the late proximal convoluted tubule was +2.1 +/- 0.3 mV (lumen positive) and the tubular fluid to plasma ultrafiltrate concentration ratio for potassium (TFK/UFK) at the same site was 1. 03 +/- 0.01. In potassium-depleted rats, there was a striking reversal of the transepithelial PD (to -4.0 +/- 0.4 mV), while the TFK/UFK was increased to 1.19 +/- 0.03. 4. The data from both potassium-replete and potassium-depleted animals are consistent with accumulating evidence that potassium reabsorption in the proximal convoluted tubule is passive in nature and depends partly on diffusion down an electrochemical gradient.

Absorption↗
PubMed1998

Contribution of Na+-H+ exchange to sodium reabsorption in the loop of henle: a microperfusion study in rats.

1. The contribution of apical Na+-H+ exchange to sodium reabsorption in the thick ascending limb of the loop of Henle (TALH) in vivo was examined in anaesthetized rats by perfusing loops of Henle of superficial nephrons with solutions containing the Na+-H+ exchange inhibitor, ethyl isopropyl amiloride (EIPA). 2. Using a standard perfusate, no statistically significant effect of EIPA on net sodium reabsorption (JNa) was detected. However, when sodium reabsorption in the pars recta of the proximal tubule was minimized by using a low-sodium perfusate, EIPA reduced JNa from 828 +/- 41 to 726 +/- 37 pmol min-1 (P < 0.05), indicating that apical Na+-H+ exchange can make a small contribution to net sodium reabsorption in the TALH in vivo. This contribution appears to be dependent on the bicarbonate load, since an increase in the latter led to an enhancement of EIPA-sensitive sodium transport. 3. Addition of the Na+-K+-2Cl- cotransport inhibitor, bumetanide, to the low-sodium perfusate reduced baseline JNa to 86 +/- 27 pmol min-1. In this setting, EIPA reduced JNa further, to -24 +/- 18 pmol min-1 (P < 0.05), an effect similar to that seen in the absence of bumetanide. This finding argues against previous suggestions (based on in vitro evidence) that inhibition of the Na+-K+-2Cl- cotransporter leads to an increase in apical Na+-H+ exchange in the TALH.

Amiloride↗
PubMed1998

Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis.

Primary distal renal tubular acidosis (dRTA) is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. Kindreds showing either autosomal dominant or recessive transmission are described. Mutations in the chloride-bicarbonate exchanger AE1 have recently been reported in four autosomal dominant dRTA kindreds, three of these altering codon Arg589. We have screened 26 kindreds with primary dRTA for mutations in AE1. Inheritance was autosomal recessive in seventeen kindreds, autosomal dominant in one, and uncertain due to unknown parental phenotype or sporadic disease in eight kindreds. No mutations in AE1 were detected in any of the autosomal recessive kindreds, and analysis of linkage showed no evidence of linkage of recessive dRTA to AE1. In contrast, heterozygous mutations in AE1 were identified in the one known dominant dRTA kindred, in one sporadic case, and one kindred with two affected brothers. In the dominant kindred, the mutation Arg-589/Ser cosegregated with dRTA in the extended pedigree. An Arg-589/His mutation in the sporadic case proved to be a de novo mutation. In the third kindred, affected brothers both have an intragenic 13-bp duplication resulting in deletion of the last 11 amino acids of AE1. These mutations were not detected in 80 alleles from unrelated normal individuals. These findings underscore the key role of Arg-589 and the C terminus in normal AE1 function, and indicate that while mutations in AE1 cause autosomal dominant dRTA, defects in this gene are not responsible for recessive disease.

Acidosis, Renal Tubular↗
PubMed1998

Presentation, pathology, and outcome of HIV associated renal disease in a specialist centre for HIV/AIDS.

OBJECTIVES: To describe the presentation, pathology, and outcome of biopsy proved renal disease in HIV infected patients at a central London HIV unit from 1992 to 1996. METHODS: Retrospective review of a computerised database and case notes to identify patients with renal disease confirmed by antemortem percutaneous renal biopsy or necropsy. RESULTS: 17 patients were identified, 13 had biopsy and four necropsy confirmed renal disease. Abnormalities included HIV associated nephropathy (HIVAN) in seven (41%) patients, membranous glomerulonephritis (GN) in four (23%), haemolytic uraemic syndrome (HUS) in two (12%), and interstitial nephritis, rhabdomyolysis, IgA nephropathy, and membranoproliferative GN in one patient each. Although renal disease was the first presentation of HIV disease in six (35%) patients the majority had advanced HIV disease (median CD4 count 40 x 10(6)/l). The commonest presentation was acute renal failure (ARF) in 10 (59%) patients, chronic renal failure (CRF) in five (29%), and proteinuria alone in two (12%). Although the majority of patients died during the study period (9/13) only three deaths were attributable to their renal disease. Survival ranged in those with HIVAN from 0 to 31 (median 10) months and, in those with membraneous GN from 1 to 46 (median 29) months. CONCLUSIONS: HIVAN was the commonest renal disease found in this group of patients; however, a variety of other pathologies were seen with variable outcomes. All cases of HIVAN were in patients of African or Afro-Caribbean origin and for the majority this was their first presentation of HIV disease. Nephrologists need to be aware of the possibility of HIV infection in patients presenting with renal disease.

AIDS-Associated Nephropathy↗
PubMed1998

The association between familial distal renal tubular acidosis and mutations in the red cell anion exchanger (band 3, AE1) gene.

In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone disease. The condition can be familial, when it is usually inherited as an autosomal dominant, though there is a rarer autosomal recessive form associated with nerve deafness. It has been shown that the autosomal dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heterozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of proposed helices 6 and 7 of the membrane domain of band 3 and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies of red cell band 3 from these families have provided information on the effect these mutations have on the structure and function of erythrocyte band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chloride transport activity, suggesting that the disease in the dRTA families is not related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 from the basolateral to the apical membrane of the alpha-intercalated cell.

Acidosis, Renal Tubular↗
PubMed1998

Localization of P2X1 purinoceptors by autoradiography and immunohistochemistry in rat kidneys.

P2 receptors have been identified in rat kidney by autoradiography, using the radioligand [3H] alpha, beta-methylene ATP, and by immunohistochemistry, using a polyclonal antibody to the P2X1 purinoceptor. They have been localized to the vascular smooth muscle of intrarenal arteries, including arcuate and interlobular arteries, and afferent arterioles, but not glomeruli, postglomerular efferent arterioles, or renal tubules. We conclude that at least some of the P2 receptors present on vascular smooth muscle are of the P2X1 subtype. The functional significance of these findings in the vascular control of the kidney is discussed.

Animals↗
PubMed1998

Upregulation of H+-ATPase in the distal nephron during potassium depletion: structural and functional evidence.

In the present study, we have investigated the effects of dietary potassium depletion on the activity and distribution of the H+-ATPase in the distal nephron of the Sprague-Dawley rat. H+-ATPase activity was assessed from the change in transepithelial potential difference (Vte) in response to bafilomycin A1 during perfusion of the late distal tubule in vivo, with solutions containing inhibitors of known ion channels. Bafilomycin A1 caused a negative deflection in Vte in control animals, an effect that was significantly enhanced during potassium depletion (P < 0.01). The distribution of H+-ATPase within the population of intercalated cells was assessed using a specific monoclonal antibody (E11). Hypokalemia was associated with a highly significant redistribution of the staining pattern (P < 0. 001), with an increase in the percentage of cells displaying immunoreactivity in the apical membrane. These results indicate that dietary potassium depletion increases electrogenic H+-ATPase activity in the rat distal tubule; this may be associated with increased insertion of pumps into the apical membrane.

Animals↗
PubMed1998

Inhibition of renal 11beta-hydroxysteroid dehydrogenase in vivo by carbenoxolone in the rat and its relationship to sodium excretion.

1. The type 2 isoform of 11beta-hydroxysteroid dehydrogenase, an enzyme which converts cortisol or corticosterone to inactive 11-ketosteroid metabolites, is thought to be responsible for preventing access of endogenous glucocorticoids to mineralocorticoid receptors in the distal nephron; although direct in vivo evidence for this is still lacking. We have examined whether graded inhibition of renal 11beta-hydroxysteroid dehydrogenase activities in vivo results in corresponding changes in urinary electrolyte excretion due to exposure of mineralocorticoid receptors to circulating endogenous glucocorticoids.2. Anaesthetized rats were infused intravenously with vehicle alone or with one of three doses of carbenoxolone: 0.06, 0.6 or 6 mg/h. After measurement of renal electrolyte excretion, the kidneys were snap-frozen in liquid nitrogen and 11beta-hydroxysteroid dehydrogenase activities were measured directly by enzyme assay in the presence of NAD+ or NADP+.3. A dose-dependent inhibition of renal 11beta-hydroxysteroid dehydrogenase activities was observed: the low, intermediate and high doses of carbenoxolone causing approximately 50%, 80% and >90% inhibition respectively. Only with the high dose was an effect on renal function observed (decreased fractional Na+ excretion and urinary Na+/K+ ratio).4. The poor correlation between the extent of inhibition of renal 11beta-hydroxysteroid dehydrogenase and altered urinary Na+ excretion, apparent at the lower doses of carbenoxolone, suggests either that 11beta-hydroxysteroid dehydrogenase has considerable functional reserve, or that it may not be the only mechanism determining mineralocorticoid receptor specificity in the distal nephron.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene.

All affected patients in four families with autosomal dominant familial renal tubular acidosis (dRTA) were heterozygous for mutations in their red cell HCO3-/Cl- exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the nine normal family members studied. The mutation Arg589--> His was present in two families, while Arg589--> Cys and Ser613--> Phe changes were found in the other families. Linkage studies confirmed the co-segregation of the disease with a genetic marker close to AE1. The affected individuals with the Arg589 mutations had reduced red cell sulfate transport and altered glycosylation of the red cell band 3 N-glycan chain. The red cells of individuals with the Ser613--> Phe mutation had markedly increased red cell sulfate transport but almost normal red cell iodide transport. The erythroid and kidney isoforms of the mutant band 3 proteins were expressed in Xenopus oocytes and all showed significant chloride transport activity. We conclude that dominantly inherited dRTA is associated with mutations in band 3; but both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗