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M R Weir

Publications and source records attributed to M R Weir.

At least 19 recordsLinked to original sources
PubMed2005

Angiotensin-receptor blockers and diuretics--advantages of combination.

Surveys have shown that in as many as half of patients treated for hypertension, blood pressure (BP) is not controlled to target levels; many more persons have undertreated hypertension. Uncontrolled hypertension is a serious risk factor for cardiovascular events such as stroke, heart failure, myocardial infarction and target-organ diseases. Studies have shown that strict BP control significantly reduces the occurrence of these cardiovascular outcomes, in the majority of patients, effective BP control requires two or more antihypertensive agents. The combination of an angiotensin-receptor blocker (ARB) and a thiazide diuretic is appealing, since these agents have complimentary effects on BP reduction, left ventricular hypertrophy and progression of renal diseases. In addition, this combination provide excellent tolerability. The combination of an ARB and a thiazide diuretic may be of particular value in patient populations who tend to have poor BP control on monotherapy, or have additional cardiovascular or renal risk factors.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

An alarmingly high prevalence of diabetic nephropathy in Asian type 2 diabetic patients: the MicroAlbuminuria Prevalence (MAP) Study.

AIM/HYPOTHESIS: Microalbuminuria represents the earliest clinical evidence of diabetic nephropathy and is a marker of increased cardiovascular morbidity and mortality. Its early detection allows the implementation of individualised and aggressive intervention programmes to reduce cardiovascular risk factors. There is limited information on the prevalence of microalbuminuria among hypertensive type 2 diabetic patients in Asia. METHODS: This cross-sectional epidemiological study aimed to assess the prevalence of microalbuminuria and macroalbuminuria among consecutively screened hypertensive type 2 diabetic adult patients in 103 centres in 10 Asian countries or regions. Predictive factors for microalbuminuria and macroalbuminuria were characterised using a stepwise logistic regression model. RESULTS: A total of 6,801 patients were enrolled and 5,549 patients constituted the per-protocol population (patients with bacteriuria and haematuria were excluded). The prevalence of microalbuminuria was 39.8% (39.2-40.5; 95% CI) and the prevalence of macroalbuminuria was 18.8% (18.2-19.3; 95% CI). Only 11.6% of the patients had systolic and diastolic blood pressure below the 130/80 mm Hg target. In the multivariate analyses, the predictive factors for the presence of microalbuminuria were age, BMI, systolic blood pressure and ethnic origin. The highlighted predictive factors for the presence of macroalbuminuria were age, sex, ethnic origin, BMI, duration of diabetes, presence of diabetic complications, intake of diuretics, intake of calcium channel blockers, diastolic and systolic blood pressure. CONCLUSIONS/INTERPRETATION: The high prevalence (58.6%) of micro or macroalbuminuria observed in these patients is alarming and indicates an impending pandemic of diabetic cardiovascular and renal diseases in Asia with its potential economic consequences.

Albuminuria↗
PubMed2004

Improved outcome of polyoma virus allograft nephropathy with early biopsy.

Polyoma virus allograft nephropathy often results in accelerated graft loss despite reduction of immunosuppression and/or treatment with antiviral agents. Irreversible renal fibrosis due to late diagnosis is likely to be one of the important causes of treatment failure. Early biopsy in 14 patients resulted in stable graft function after a mean follow-up of 22 months.

Biopsy↗
PubMed2001

CD103+ CTL accumulate within the graft epithelium during clinical renal allograft rejection.

BACKGROUND: We have previously reported that activated CD8+TCRalphabeta+ cells that express high levels of the beta7 integrin CD103 (formerly alphaE, MLA) are present at the graft site during clinical renal allograft rejection. This observation potentially provides new insight into the mechanisms underlying renal allograft destruction because the ligand of CD103 is the epithelial cell-specific molecule E-cadherin, which is known to be expressed by critical graft functional elements such as the renal tubular epithelium. We herein used combined fluorescence-activated cell sorter (FACS) and immunohistochemical (IHC) analyses of transplant nephrectomy (TN) specimens to demonstrate that CD103+ cytolytic T lymphocytes (CTLs) specifically home to the graft epithelium during rejection episodes. METHODS: Serial sections of TN specimens undergoing histologically confirmed cellular rejection (n=7) were stained with anti-CD8 or anti-CD103 and were scored for the presence of positively stained cells within the tubular basement membrane. Freshly isolated graft-infiltrating lymphocytes were subjected to three-color FACS analyses to define the extended phenotypic characteristics of CD103+ cells detected by IHC. RESULTS: CD103+ cells in all specimens were biased towards an intratubular localization. On average, the percentage of CD103+ cells with an intraepithelial localization was 52.2+/-13.1 compared to 12.0+/-3.5 for pan CD8+ cells (mean+/-SE, n=5). FACS analyses confirmed that CD103+ cells detected by IHC exhibited the salient characteristics of CD8+ CTLs (large CD8+TCRalphabeta+CD62L-CD11a(hi)perforin+). The CD103- subset of graft-infiltrating CD8 cells also exhibited a CTL phenotype, but these were predominantly restricted to the graft interstitium. CONCLUSIONS: These data implicate CD103 as a homing receptor that targets graft-infiltrating CD8+ CTLs to the graft epithelium. Given the strong association of tubulitis with clinical rejection, these data are consistent with a role for the CD103+ CTL subset as an effector mechanism in renal allograft destruction.

Antigens, CD↗
PubMed2001

Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.

BACKGROUND: In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs. METHODS AND RESULTS: CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists' Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing >14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen. CONCLUSIONS: This analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.

Aged↗
PubMed2001

Appropriate use of calcium antagonists in hypertension.

The paradigm for treating hypertension has shifted: Tighter control is the goal and a multidrug regimen is often the means, especially in high-risk patients. Although renin-angiotensin blockers are now the key components of such regimens, calcium antagonists can play an important role as well, given their demonstrated efficacy in controlling blood pressure.

Angiotensin Receptor Antagonists↗
PubMed2001

Efficacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy: a clinical experience trial. ACTION Study Investigators.

A large-scale, 8-week, open-label, clinical experience trial evaluated the efficacy of the angiotensin II receptor (AT1 subtype) blocker candesartan cilexetil (16 to 32 mg once daily) either alone or as add-on therapy in 6465 hypertensive patients. The study population was 52% female and 16% African American with a mean age of 58 years. It included 5,446 patients who had essential hypertension (HBP) and 1,014 patients who had isolated systolic hypertension (ISH). These patients had either untreated or uncontrolled hypertension (systolic blood pressure [SBP] 140 to 179 mm Hg or diastolic blood pressure [DBP] 90 to 109 mm Hg inclusive at baseline) despite a variety of antihypertensive medications including diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and alpha- or beta-blockers, either singly or in combination. The mean baseline blood pressure for the HBP group was 156/97 mm Hg. Candesartan cilexetil as monotherapy (in 51% of HBP patients) reduced mean SBP/DBP by 18.7/ 13.1 mm Hg. As add-on therapy (in 49% of HBP patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.8/11.3 mm Hg), calcium antagonists (16.6/11.2 mm Hg), beta-blockers (16.5/ 10.4 mm Hg), ACE inhibitors (15.3/10.0 mm Hg), alpha-blockers (16.4/10.4 mm Hg). The mean baseline blood pressure for the ISH group was 158/81 mm Hg. Candesartan cilexetil, as monotherapy (in 34% of ISH patients), reduced SBP/DBP by 17.0/4.4 mm Hg. As add-on therapy (in 66% of ISH patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.4/5.1 mm Hg), calcium antagonists (15.6/3.6 mm Hg), beta-blockers (14.0/4.8 mm Hg), ACE inhibitors (13.4/4.3 mm Hg), and alpha-blockers (11.6/4.5 mm Hg). The further blood pressure lowering effects of candesartan cilexetil as add-on therapy were seen regardless of age, sex, and race. Overall, 6.8% of the 6465 patients withdrew because of adverse events, most commonly headache (6.3%) and dizziness (5.0%). Orthostatic hypotension was infrequent; 0.2% with candesartan cilexetil alone, and 0.8% with candesartan cilexetil as add-on therapy. Thus, candesartan cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice settings.

Adult↗
PubMed2001

Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake.

Previous clinical trials have demonstrated the important influence of ethnicity and dietary salt on the antihypertensive efficacy of drugs that block the renin angiotensin system. Angiotensin II receptor blockers are a new therapeutic entity that have not been widely studied in African American hypertensives, either alone, or in combination with other therapies such as diuretics or angiotensin converting enzyme inhibitors. We performed a pilot, prospective, open label, randomized design clinical trial to evaluate the effects of the angiotensin II receptor blocker valsartan (160 mg once a day) on systolic and diastolic blood pressure in hypertensive African Americans (n = 88) on a low salt (100 mEq Na+/day) for 2 weeks and the same diet supplemented by 100 mEq Na+ for 4 weeks. After this evaluation, while continuing the Na+ supplementation, patients were randomized to valsartan 320 mg/day (n = 28), or the addition of hydrochlorothiazide (HCTZ) 12.5 mg/day (n = 30), or benazepril 20 mg/day to the valsartan 160 mg/day for an additional 6 weeks. Valsartan (160 mg/day) lowered blood pressure significantly in African American patients on both low salt (-6.4/-4.8 mm Hg: P < .001) and a high salt diet (-4.9/-3.8 mm Hg: P = .01). The high salt diet attenuated the antihypertensive effect slightly (1.6/1.3 mm Hg, P = not significant). When comparing the efficacy of the three randomized therapeutic regimens while on the Na+ supplement, the valsartan 160 mg/HCTZ 12.5 mg was the most effective therapy with an incremental reduction in blood pressure of -10.5/-6.9 mm Hg (P < .01), compared to valsartan 160 mg/day alone. Doubling the dose of valsartan to 320 mg incrementally lowered blood pressure by -3.8/-3.3 mm Hg (P = not significant). The least effective approach was adding benazepril 20 mg/day to valsartan 160 mg/day with no incremental reduction in systolic blood pressure and diastolic blood pressure reduction of only 1.7 mm Hg (P = not significant). We conclude that in our open label pilot study, the antihypertensive activity of valsartan is not significantly attenuated by supplemented salt diet in hypertensive African Americans. Moreover, adding a low dose of HCTZ appears to be the most effective strategy in enhancing the antihypertensive activity of this angiotensin II receptor blocker in contrast to either doubling the dose or adding an angiotensin converting enzyme inhibitor.

Adult↗
PubMed2001

Diabetes and hypertension: how low should you go and with which drugs?

Diabetes and hypertension are the most common causes of end-stage renal disease in the United States. Both experimental and clinical studies have demonstrated the importance of more intensive control of systolic blood pressure (SBP) in delaying progression of renal disease, particularly in diabetic patients with macroproteinuria. Although traditional recommendations have suggested that reducing systolic to < 140 mm Hg is appropriate, there is consistent evidence in clinical trials demonstrating that, in the presence of diabetes, macroproteinuria, and impaired renal function, reducing systolic to < 125 mm Hg will result in a more successful attenuation of the rate of progression of renal disease. In addition, there is convincing evidence demonstrating that blockade of the renin angiotensin system, particularly with angiotensin converting enzyme inhibitors, results in an improved opportunity to delay progression of renal disease. Despite the advantages of angiotensin converting enzyme inhibitors, most patients will require three to five medications to achieve optimal levels of goal SBP to attenuate the rate of progression of renal disease.

Albuminuria↗
PubMed2001

Pilot study to evaluate a water displacement technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity edema due to dihydropyridine calcium antagonists.

Combination therapy is required in many patients to achieve goal blood pressure (BP). Calcium antagonists are highly effective antihypertensive drugs in a broad range of demographic groups. Yet, higher doses are associated with an increased frequency of lower extremity edema. The purpose of our open label, single-center clinical trial was to evaluate the use of concomitant pharmacologic therapies to attenuate the lower extremity edema associated with dihydropyridine calcium antagonists therapy using a water displacement technique. Forty-seven patients received 5 mg/day of oral amlodipine for a period of 6 weeks after a 4-week wash-out off of all antihypertensive medications to establish baseline BP. They were then randomized to receive either an additional 5 mg of amlodipine, 25 mg of hydrochlorothiazide (HCTZ), or 20 mg of benazepril for an additional 6 weeks. Blood pressure determinations and water displacement measurements were obtained at the end of the 4-week placebo wash-out period, after 6 weeks of 5 mg/day of oral amlodipine therapy, and after an additional 6 weeks of 5 mg of amlodipine and randomized drug therapy. Adjusted BP reductions (based on pretreatment BP) were -6.8/-3.8 mm Hg for the 10-mg amlodipine group, -9.9/-8.2 mm Hg for the amlodipine (5 mg)/HCTZ (25 mg) group, and -26.2/-16.4 mm Hg for the amlodipine (5 mg)/benazepril (20 mg) group (P < .0167, group 3 v group 1 diastolic BP, which was statistically significant by the improved Bonferroni method). Seventeen of the 47 patients developed at least a 10% increase in lower extremity edema water displacement in response to 5 mg/day of oral amlodipine therapy (36.2%). Adding 5 mg of amlodipine to a baseline of 5 mg of amlodipine resulted in no net change in lower extremity edema (+58.0 mL,+ 0.6% change, n=5). Adding 25 mg of HCTZ reduced lower extremity edema by a mean of 136.3 mL (-11.1% change, n=4). Benazepril reduced water displacement by 204.4 mL (-14.3% change, n=8). Our pilot study indicates that adding an angiotensin converting enzyme inhibitor to a dihydropyridine calcium channel blocker is the most effective way to not only reduce systolic and diastolic BP but also attenuate lower extremity edema. Due to the inherent daily variability of lower extremity edema, power calculations indicate many patients (n=702, 356 in each group) would be needed to compare the antiedema efficacy of the angiotensin converting enzyme inhibitor and the thiazide diuretic.

Adult↗
PubMed2001

Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy is the major cause of progressive renal failure in renal transplant recipients. It has no definitive treatment. METHODS: One hundred eighteen renal transplant recipients with declining kidney function and biopsy-proven chronic allograft nephropathy had their cyclosporine or tacrolimus dose reduced or discontinued with either the addition or continuation of mycophenolate mofetil and low-dose steroids at a mean of 853.3 days post-transplantation. Their renal function was modeled before and after this intervention by two methods: A least-square regression was used to assess the decay of renal function after the intervention and to compare that with the slope pre-intervention, whereas a hinge regression line method was used to assess the correlation of the intervention with the inflection point and the impact of the intervention on the decay of renal function. Mean follow-up was 651.0 days after the intervention. Serum creatinine at the time of intervention was 2.8 +/- 0.9 mg/dL in the reduced dose cyclosporine (N = 67) and reduced dose tacrolimus (N = 33) groups, and was 2.7 +/- 0.7 mg/dL in the group with discontinued calcineurin inhibitor (N = 18). RESULTS: Using the least-square method, 91.7% of the no calcineurin inhibitor group, 51.6% of the reduced dose cyclosporine group, and 59.3% of the reduced dose tacrolimus group had improved or lack of deterioration in slope after the intervention. Using the hinge regression line method, there was a statistically significant correlation of the inflection point with the intervention (P = 0.001). Moreover, there was a similar relationship with stabilized or improved graft function observed with the hinge regression line method and the least-square method, as 72.2% of the calcineurin inhibitor withdrawal group, 54.4% of reduced-dose cyclosporine group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration after the inflection point. The difference between the calcineurin inhibitor withdrawal group and the reduced-dose cyclosporine/tacrolimus groups on the decay in renal function was significant (P = 0.038) with the least-square method and nearly significant (P = 0.056) using the hinge regression line method. CONCLUSION: This intervention was safe, well tolerated, and associated with a minimal risk of acute rejection. We conclude that the reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of loss of renal function in patients with chronic allograft nephropathy and deteriorating renal function.

Adrenal Cortex Hormones↗
PubMed2001

Morphological spectrum of polyoma virus disease in renal allografts: diagnostic accuracy of urine cytology.

The morphological features of polyoma virus disease (PVDz) in 571 concurrent urine and biopsy samples from 413 patients are described. In 54 patients PV was found in both biopsy and urine samples. Histologically, PV presented as: (a) mild, viral cytopathic/cytolytic changes, with absent or minimal inflammation involving isolated tubules; (b) moderate and severe, cytopathic/cytolytic changes associated with patchy or diffuse tubulo-interstitial inflammation and atrophy; (c) advanced, graft sclerosis with rare or absent viral cytopathic changes, indistinguishable from chronic allograft nephropathy. Histological progression from mild to moderate or severe disease was seen in 28 patients. The mean post-transplantation time at diagnosis was similar in patients with mild or moderate-severe renal involvement (1.05 and 1.3 years, respectively). All patients presented with similarly increased values of serum creatinine (mean 1.35 mg/dL). There was strong correlation between the number of PV infected cells in urine and the concurrent biopsies (p = 0.0001). In 13 patients PV was found only in urine; of these, two developed PVDz later. The positive predictive value of a positive urine was 90%, the negative predictive value of a negative urine was 99% and the accuracy of the test was 97%. We conclude that urine cytology is useful to evaluate renal transplant patients with PV reactivation because sloughed tubular cells are found in urine and positive urine samples are a consistent manifestation of PV renal involvement.

Atrophy↗
PubMed2000

CMV allograft pancreatitis: diagnosis, treatment, and histological features.

BACKGROUND: Cytomegalovirus (CMV) infection is a common problem in solid organ transplant recipients. CMV infection of pancreas allografts is not, however, well described. METHODS: We report the clinical presentation, histologic findings, treatment, and outcome in four patients with CMV allograft pancreatitis. These patients presented 18 weeks to 44 months after transplantation with elevated serum amylase and lipase and were suspected to have acute rejection. Percutaneous pancreas allograft biopsy specimens showed evidence of tissue invasive CMV infection. One patient had simultaneous CMV infection and acute rejection. RESULTS: Prolonged treatment with ganciclovir resulted in clinical and histologic resolution of the CMV disease. Rejection was successfully treated. Primary CMV infection in seronegative recipients seemed to be a risk factor. Three patients maintain normal allograft function; one patient lost function due to chronic rejection. The histology of tissue-invasive CMV pancreas allograft infection and its differentiation from acute rejection is described. CONCLUSION: Prompt diagnosis and prolonged therapy with antiviral agents can result in maintenance of allograft function.

Adult↗