Risk stratification based on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome

The incidence of myelodysplastic syndromes increases with age and a high prevalence of co-morbid conditions has been reported in these patients. So far, risk assessment in myelodysplastic syndromes has been mainly based on disease status. We studied the prognostic impact of comorbidity on the natural history of myelodysplastic syndrome with the aim of developing novel tools for risk assessment. The study population included a learning cohort of 840 patients diagnosed with myelodysplastic syndrome in Pavia, Italy, and a validation cohort of 504 patients followed in Duesseldorf, Germany. Information on comorbidity was extracted from detailed review of the patients' medical charts and laboratory values at diagnosis and during the course of the disease. Univariable and multivariable survival analyses with both fixed and time-dependent covariates were performed using Cox's proportional hazards regression models. Comorbidity was present in 54% of patients in the learning cohort. Cardiac disease was the most frequent comorbidity and the main cause of non-leukemic death. In multivariable analysis, comorbidity had a significant impact on both non-leukemic death (P=0.01) and overall survival (P=0.02). Cardiac, liver, renal, pulmonary disease and solid tumors were found to independently affect the risk of non-leukemic death. A time-dependent myelodysplastic syndrome-specific comorbidity index (MDS-CI) was developed for predicting the effect of comorbidity on outcome. This identified three groups of patients which showed significantly different probabilities of non-leukemic death (P<0.001) and survival (P=0.005) also in the validation cohort. Landmark survival analyses at fixed time points from diagnosis showed that the MDS-CI can better define the life expectancy of patients with myelodysplastic syndrome stratified according to the WHO-classification based Prognostic Scoring System (WPSS).Comorbidities have a significant impact on the outcome of patients with myelodysplastic syndrome. Accounting for both disease status by means of the WPSS and comorbidity through the MDS-CI considerably improves risk stratification in myelodysplastic syndromes.     

Vesicoureteral reflux in adults

Vesicoureteral reflux (VUR) may be congenital or acquired. The most frequent form of congenital VUR is primary VUR. Its prevalence in adults is not exactly known, but it is higher in women, whose greater propensity for urinary tract infections increases the likelihood of an instrumental examination leading to the diagnosis of less severe cases. In men, even severe VUR may go undiagnosed for a long time. Primary VUR is due to a defect in the valve mechanism of the ureterovesical junction. In physiological conditions, the terminal ureter enters the bladder wall obliquely and bladder contraction leads to compression of this intravesical portion. Abnormal length of the intravesical portion of the ureter due to a genetic mutation (whose location is yet to be established) leads to VUR. In its less severe forms VUR may be asymptomatic, but in 50-70% of cases it manifests with recurrent cystitis or pyelonephritis. The manifestations leading to a diagnosis of VUR in adults, besides urinary tract infections, are proteinuria, renal failure and hypertension. The gold-standard diagnostic examination is a micturating cystourethrogram. Reflux nephropathy develops as a result of a pathogenetic mechanism unrelated to high cavity pressure or urinary tract infections but due to reduced formation of the normal renal parenchyma (hypoplasia or dysplasia). Abnormal renal parenchyma development is attributable to the same genes that control the development of the ureters and ureterovesical junction. VUR is considered only a marker of this abnormal development, playing no role in scar formation. There is no conclusive evidence regarding the indications for VUR correction. However, the risk that VUR leads to recurrent pyelonephritis and reflux nephropathy must be kept in mind. VUR certainly has to be corrected in women who contemplate pregnancy.     

Microcrystalline cellulose membrane for re‐epithelisation of chronic leg wounds: a prospective open study

Treatment of chronic leg ulcers remains a major health care issue. Although many reports have examined different topical dressings, none have specifically looked at microcrystalline cellulose (MCC). We aimed to evaluate in a prospective, open study the safety and performance of a MCC membrane (Veloderm) in a series of chronic leg wounds of different aetiology. Fifty‐five patients participated in this study. The membrane was applied every 5–10 days for 1 month, immediately after surgical debridement. The wound bed was assessed on days 7, 15 and 30 for erythema, pain, exudate level and infection. The wound size change at 30 days was the primary efficacy parameter and any adverse events were collected and analysed. A wound size change of 55% was achieved at the end of follow‐up, with an improvement in all the collected parameters, but the erythema, which showed a mild increase. To date, this is the largest experience with a MCC product in chronic wounds. Our study suggests that this treatment may be safe and useful and deserves further investigation.     

Angiotensin II receptor antagonism with telmisartan increases number of endothelial progenitor cells in normotensive patients with coronary artery disease: A randomized,double-blind,placebo-controlled study

IntroductionCirculating endothelial progenitor cells (EPCs) provide an endogenous repair mechanism of the dysfunctional endothelium and therefore can play a crucial role in the pathophysiology of coronary artery disease (CAD). Angiotensin II receptor antagonism has been shown to be able to increase EPCs in hypertension but its effect in patients with CAD is unknown. Aim of this study was to evaluate whether telmisartan, an angiotensin II receptor antagonist, can modify the number of subpopulations of EPCs and may in turn affect the endothelial function of normotensive patients with CAD.MethodsIn a prospective double-blind parallel group study, 40 normotensive patients with CAD were randomly treated with telmisartan (80 mg) or placebo for 4 weeks at time of coronary angiography. Measurements of EPCs and assessment of flow-mediated dilatation (FMD) of the brachial artery was performed before and after therapy.ResultsAbsolute number of EPCs was similar at baseline in the telmisartan and placebo groups. After 4 weeks treatment, CD34+/KDR+/CD45? cells increased significantly in the telmisartan group (from 0.010 ± 0.003 to 0.014 ± 0.004%, P = 0.0001) but not in the placebo group (from 0.009 ± 0.004 to 0.009 ± 0.005%, NS). Similarly, CD133+/KDR+/CD45? cells raised significantly with telmisartan (from 0.003 ± 0.002 to 0.006 ± 0.002%, P = 0.0001) but not with placebo (from 0.004 ± 0.003 to 0.003 ± 0.002%, NS). Also, CD14+/CD45+ cells increased significantly with telmisartan (from 0.005 ± 0.002 to 0.008 ± 0.002%, P = 0.0001) and were unchanged with placebo (0.006 ± 0.002 vs. 0.005 ± 0.003%, NS). FMD improved significantly in patients who received telmisartan (10.4 ± 3.9%, P = 0.0015 vs. baseline) but did not change in the placebo group (5.9 ± 2.8%; P = 0.32 vs. baseline; telmisartan vs. placebo, P = 0.002). A significant positive correlation was found in the telmisartan group between the improvement in FMD and the increase in CD34+/KDR+/CD45? cells and CD133+/KDR+/CD45? cells (r = 0.55, P < 0.01, and r = 0.49, P < 0.05, respectively).ConclusionAngiotensin II receptor antagonism with telmisartan increases the number of regenerative EPCs and improves endothelial function in normotensive patients with CAD. These novel effects are interrelated and can explain, at least in part, why telmisartan has beneficial cardiovascular effects independent of its blood pressure lowering action.     

Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study

Background

Transfusion-dependency affects the natural history of myelodysplastic syndromes. Secondary iron overload may concur to this effect. The relative impact of these factors on the outcome of patients with myelodysplastic syndrome receiving allogeneic stem-cell transplantation remains to be clarified.

Design and Methods

We retrospectively evaluated the prognostic effect of transfusion history and iron overload on the post-transplantation outcome of 357 patients with myelodysplastic syndrome reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry between 1997 and 2007.

Results

Transfusion-dependency was independently associated with reduced overall survival (hazard ratio=1.48, P=0.017) and increased non-relapse mortality (hazard ratio=1.68, P=0.024). The impact of transfusion-dependency was noted only in patients receiving myeloablative conditioning (overall survival: hazard ratio=1.76, P=0.003; non-relapse mortality: hazard ratio=1.70, P=0.02). There was an inverse relationship between transfusion burden and overall survival after transplantation (P=0.022); the outcome was significantly worse in subjects receiving more than 20 red cell units. In multivariate analysis, transfusion-dependency was found to be a risk factor for acute graft-versus-host disease (P=0.04). Among transfusion-dependent patients undergoing myeloablative allogeneic stem cell transplantation, pre-transplantation serum ferritin level had a significant effect on overall survival (P=0.01) and non-relapse mortality (P=0.03). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload.

Conclusions

Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome.     

Lack of Association between Dialysis Modality and Outcomes in Atheroembolic Renal Disease

Background and objectives: Atheroembolic renal disease (AERD) can require dialytic support. Because anticoagulation may trigger atheroembolization, peritoneal dialysis may be preferred to hemodialysis. However, the effect of dialysis modality on renal and patient outcomes in AERD is unknown.Design, settings, participants, & measurements: A subcohort of 111 subjects who developed acute/subacute renal failure requiring dialysis was identified from a larger longitudinal study of AERD. The main exposure of interest was dialysis modality (peritoneal versus extracorporeal therapies). Logistic regression was used to study the probability of renal function recovery. Times from dialysis initiation to death were studied using Cox''s regression.Results: Eighty-six patients received hemodialysis and 25 received peritoneal dialysis. The probability of renal function recovery was similar by dialysis modality (25% among hemodialysis patients and 24% among peritoneal dialysis patients; P = 0.873). During follow-up, 58 patients died, 14 among peritoneal patients and 44 among hemodialysis patients (P = 0.705). In multivariable analysis, gastrointestinal tract involvement and use of statins maintained an independent effect on the risk of patient death.Conclusions: This study does not support the notion that one dialysis modality is superior to the other. However, the observational nature of the data precludes any firm conclusions.Atheroembolic renal disease (AERD) is due to the occlusion of small renal arteries and glomerular capillaries by cholesterol crystals derived from atherosclerotic aortic plaques (1). The severity of renal dysfunction depends on the amount and frequency of embolic showers and inflammatory reactions. Although chronic “spontaneous” AERD may represent an underdiagnosed, slowly progressive cause of ESRD mimicking nephrosclerosis, in patients developing acute or subacute renal failure AERD is usually “iatrogenic” and dialysis may be required in 25% to 60% of the patients. In one third of these patients renal function may recover. Recovery may be related to reversal of inflammation, resolution of acute tubular necrosis in ischemic areas, hypertrophy in surviving nephrons, and reduction in intensity of embolic showers (2–6).Invasive aortic manipulation, including angiography and vascular surgery, is the leading cause of AERD. However, the disease may be rarely precipitated by anticoagulation; by preventing the formation of a protective thrombus overlying the ulcerated plaques; or even disrupting the fibrin cap of atherosclerotic plaques and exposing their soft, cholesterol-laden core to the arterial circulation (1–3,7–12). The requirement for systemic anticoagulation makes extracorporeal dialysis treatments less attractive for patients with AERD who need dialysis. Although systemic anticoagulation can be avoided or at least minimized initially, this can be more difficult in the long run. On the other hand, peritoneal dialysis may not be available in all facilities to treat acute kidney injury and can be contraindicated in patients with AERD for gut ischemia or protein losses.Current data on benefits and harms of extracorporeal and peritoneal dialysis therapies are scant and come from small cohorts or case series (2,3,13–16). Although evidence from clinical trials of interventions is ideally necessary to inform practice, for rare disorders cohort studies may provide relevant information. In this study, we sought to determine whether peritoneal dialysis is superior to extracorporeal therapies in terms of renal and patient outcomes of acute/subacute AERD using data from a large longitudinal study (12).