Borislav D. Dimitrov

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial

BACKGROUND Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts.

Insulin Resistance and Microalbuminuria: A Cross-Sectional, Case-Control Study of 158 Patients With Type 2 Diabetes and Different Degrees of Urinary Albumin Excretion

Microalbuminuria is a risk factor for renal and cardiovascular disease. A role for insulin resistance in the pathogenesis of microalbuminuria has been suggested but is still unproven. In this case-control, cross-sectional study, we compared glucose disposal rate (GDR), measured by hyperinsulinemic-euglycemic clamp, in 50 pairs of matched type 2 diabetic patients with micro- or normoalbuminuria (main study) and in 29 matched pairs of diabetic patients with macro- or microalbuminuria (substudy). In the main study, GDR was ∼25% lower in micro- than in normoalbuminuric patients (5.20 ± 1.91 vs. 6.86 ± 2.88 mg · kg−1 · min−1, P < 0.05) and was independently associated with microalbuminuria (P = 0.002), with each 1 mg · kg−1 · min−1 decrease predicting ∼40% increased prevalence (odds ratio 1.37 [95% CI 1.14–1.70]). Microalbuminuria was threefold more frequent in patients with GDR ≤7.50 ± 2.56 mg · kg−1 · min−1 than in those with higher GDR (60% vs. 20%, P < 0.005). In the substudy, GDR in macro- and microalbuminuric patients was comparable (5.52 ± 2.56 vs. 5.16 ± 1.61 mg · kg−1 · min−1) and independent of macroalbuminuria. GDR was significantly correlated with urinary albumin excretion rate in the main study (P = 0.004) but not in the substudy (P = 0.60). In type 2 diabetes, more severe insulin resistance is independently associated with microalbuminuria. Longitudinal studies are needed to clarify the role of insulin resistance in the pathogenesis of microalbuminuria and related complications.

Treatment of unruptured cerebral aneurysms by embolization with guglielmi detachable coils: case-fatality, morbidity, and effectiveness in preventing bleeding--a systematic review of the literature.

OBJECTIVE:Guglielmi detachable coils (GDCs) increasingly are being used to treat unruptured cerebral aneurysms (UCAs). We systematically reviewed the literature to assess the case-fatality and permanent morbidity rates of GDC embolization of UCAs and the postembolization bleeding rate. METHODS:Through a MEDLINE search of the English, Italian, and French literature from January 1990 through December 2002, we retrieved studies on GDC embolization of aneurysms and extracted data on UCAs. Inclusion criteria were: 1) attempted GDC embolization of at least five consecutive patients with UCAs, 2) reported percentage of at least either case-fatality or permanent morbidity rate or crude data allowing an independent calculation. When data on UCAs could not be characterized with certainty among data on other, different lesions, the study was rejected. RESULTS:We included 30 studies. One thousand three hundred seventy-nine patients were available for the calculation of the case-fatality rate, 794 for the permanent morbidity rate, and 703 for the bleeding rate. The case-fatality rate was 0.6% (95% confidence interval, 0.2–1%), the permanent morbidity rate was 7% (95% confidence interval, 5.3–8.7%), and the bleeding rate was 0.9% per year (95% confidence interval, 0.41–1.4%). Only incompletely coiled UCAs of 10 mm or more accounted for the bleeding events. Morbidity decreased from 8.6% to 4.5% (P < 0.05) when the midyear of study (average calendar year of treatment) was 1995 or later. CONCLUSION:GDC embolization of UCAs is relatively safe, and the outcome is progressively improving. Partial embolization of UCAs of 10 mm or more is unlikely to provide an acceptable protection. Most of the source publications suffer from methodological weaknesses. Prospective studies with longer follow-up periods are needed to definitively assess the effectiveness of GDCs on UCAs.

Validation of the CHADS2 clinical prediction rule to predict ischaemic stroke. A systematic review and meta-analysis.

The CHADS2 predicts annual risk of ischaemic stroke in non-valvular atrial fibrillation. This systematic review and meta-analysis aims to determine the predictive value of CHADS2. The literature was systematically searched from 2001 to October 2010. Data was pooled and analysed using discrimination and calibration statistical measures, using a random effects model. Eight data sets (n = 2815) were included. The diagnostic accuracy suggested a cut-point of ≥ 1 has higher sensitivity (92%) than specificity (12%) and a cut-point of ≥ 4 has higher specificity (96%) than sensitivity (33%). Lower summary estimates were observed for cut-points ≥ 2 (sensitivity 79%, specificity 42%) and ≥ 3 (specificity 77%, sensitivity 50%). There was insufficient data to analyse cut-points ≥ 5 or ≥ 6. Moderate pooled c statistic values were identified for the classic (0.63, 95% CI 0.52-0.75) and revised (0.60, 95% CI 0.43-0.72) view of stratification of the CHADS2. Calibration analysis indicated no significant difference between the predicted and observed strokes across the three risk strata for the classic or revised view. All results were associated with high heterogeneity, and conclusions should be made cautiously. In conclusion, the pooled c statistic and calibration analysis suggests minimal clinical utility of both the classic and revised view of the CHADS2 in predicting ischaemic stroke across all risk strata. Due to high heterogeneity across studies and low event rates across all risk strata, the results should be interpreted cautiously. Further validation of CHADS2 should perhaps be undertaken, given the methodological differences between many of the available validation studies and the original CHADS2 derivation study.

Continuum of Renoprotection with Losartan at All Stages of Type 2 Diabetic Nephropathy: A Post Hoc Analysis of the RENAAL Trial Results

Renin angiotensin system inhibitor therapy is seldom offered to individuals who have diabetes and advanced chronic kidney disease because of safety concerns. In this post hoc, secondary analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, angiotensin antagonism risk/benefit profile was assessed in 1513 individuals with type 2 diabetes and overt nephropathy. Incidence of ESRD, hospitalizations for heart failure, withdrawals for adverse events, and proteinuria during losartan or conventional treatment were compared within three tertiles of baseline serum creatinine concentration (highest, 2.1 to 3.6 mg/dl; middle, 1.6 to 2.0 mg/dl; lowest, 0.9 to 1.6 mg/dl). Losartan decreased the risk of ESRD by 24.6, 26.3, and 35.3% in highest, middle, and lowest tertiles, respectively. For every 100 patients with serum creatinine >2.0, 1.6 to 2.0, or <1.6 mg/dl, respectively, 4 yr of losartan therapy was estimated to save 18.9, 8.4, and 2.9 ESRD events and US

Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial

1,502,855, US

Effect of Estrogen on Pseudomonas Mucoidy and Exacerbations in Cystic Fibrosis

1,021,770, and US

Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms

528,591 costs for renal replacement therapy. Losartan also decreased the hospitalizations for heart failure by 50.2 and 45.1, in the highest and middle tertile, respectively. Withdrawals for adverse events other than heart failure were comparable between tertiles and treatment groups. Proteinuria decreased more on losartan than on placebo in all tertiles (highest, 24 versus -8%; middle, 16 versus -8%; lowest, 15 versus -10%). In proteinuric individuals with type 2 diabetes, losartan therapy reduced ESRD and hospitalizations for heart failure and was well tolerated at all levels of renal function. Angiotensin II antagonism is a suitable and well-tolerated treatment for individuals with type 2 diabetes even with GFR levels approaching renal replacement therapy.

Predicting acute uncomplicated urinary tract infection in women: a systematic review of the diagnostic accuracy of symptoms and signs

BACKGROUND Angiotensin-converting-enzyme (ACE) inhibitors reduce packed cell volume and haemoglobin concentration in polycythaemia that follows renal transplantation, which, like altitude polycythaemia, is an erythropoietin-dependent form of polycythaemia. We aimed to establish the effect of ACE-inhibitor treatment in people with altitude polycythaemia. METHODS We did a prospective randomised study in 26 people with altitude polycythaemia (packed cell volume > or = 55%) and 24-h rate of urinary protein excretion greater than 150 mg, who had been referred to the Renal Disease Project in La Paz, Bolivia. 13 participants were assigned 5 mg/day enalapril for 2 years (study group), and 13 no treatment (controls). Blood pressure, packed cell volume and haemoglobin concentration, proteinuria, and renal function were compared by intention-to-treat analyses. FINDINGS Baseline packed cell volume and haemoglobin concentration were positively correlated with bodyweight (p=0.02), systolic (p=0.01) and diastolic (p=0.04) blood pressure, serum creatinine (p=0.009), blood urea (p=0.008), and proteinuria (p=0.003). Systolic and diastolic blood pressure remained stable in the study group, but increased in controls. In study patients, mean (SD) packed cell volume, haemoglobin concentration, and proteinuria fell from 63.5% (4.9) to 56.8% (4.1), p<0.0001; 207 (18) to 164 g/L (13), p<0,0001; and from 358.6 (260.3) to 247.7 mg/24-h (208.2), p<0.002, respectively, but did not change significantly in controls. At 12 and 24 months of follow-up, packed cell volume, haemoglobin concentration, and proteinuria differed significantly between the groups (p<0.0001 for each comparison). In study patients, follow-up changes in packed cell volume (r=0.88, p<0.0001) or haemoglobin concentration (r=0.83, p<0.0001) and proteinuria were strongly correlated. Enalapril was well tolerated by all patients. INTERPRETATION ACE-inhibition therapy effectively and safely ameliorates altitude polycythaemia and reduces proteinuria.

The prevalence of alpha-1 antitrypsin deficiency in Ireland

BACKGROUND Women with cystic fibrosis are at increased risk for mucoid conversion of Pseudomonas aeruginosa, which contributes to a sexual dichotomy in disease severity. METHODS We evaluated the effects of estradiol and its metabolite estriol on P. aeruginosa in vitro and in vivo and determined the effect of estradiol on disease exacerbations in women with cystic fibrosis. RESULTS Estradiol and estriol induced alginate production in P. aeruginosa strain 01 and in clinical isolates obtained from patients with and those without cystic fibrosis. After prolonged exposure to estradiol, P. aeruginosa adopted early mucoid morphology, whereas short-term exposure inhibited bacterial catalase activity and increased levels of hydrogen peroxide, which is potentially damaging to DNA. Consequently, a frameshift mutation was identified in mucA, a key regulator of alginate biosynthesis in P. aeruginosa. In vivo levels of estradiol correlated with infective exacerbations in women with cystic fibrosis, with the majority occurring during the follicular phase (P<0.05). A review of the Cystic Fibrosis Registry of Ireland revealed that the use of oral contraceptives was associated with a decreased need for antibiotics. Predominantly nonmucoid P. aeruginosa was isolated from sputum during exacerbations in the luteal phase (low estradiol). Increased proportions of mucoid bacteria were isolated during exacerbations occurring in the follicular phase (high estradiol), with a variable P. aeruginosa phenotype evident in vivo during the course of the menstrual cycle corresponding to fluctuating estradiol levels. CONCLUSIONS Estradiol and estriol induced mucoid conversion of P. aeruginosa in women with cystic fibrosis through a mutation of mucA in vitro and were associated with selectivity for mucoid isolation, increased exacerbations, and mucoid conversion in vivo. (Funded by the Molecular Medicine Ireland Clinician-Scientist Fellowship Programme.).