‘Form follows function’ and ‘time is precious’: these principles are conflated in the glomerular podocyte. They define its function but also the necessity to limit the exposure of podocytes to injurious agents. A number of glomerular disorders that may lead to chronic kidney disease are characterized by simplification and retraction of podocyte foot processes (FP) (effacement). These structural podocyte defects are highly reversible for a certain time and every effort should be undertaken to prevent disease progression and the need for renal replacement therapy, which harbors enormous financial and human costs. Podocytes elaborate a network of processes—major processes and FP, which surround glomerular capillaries. Together with the glomerular basement membrane (GBM) and the glomerular endothelial cells, podocytes provide the structural basis for glomerular filtration w1x. Although it is generally acknowledged that the GBM can restrict the passage of large plasma proteins, there is increasing evidence that the ultimate barrier for proteins larger than albumin is the slit diaphragm (SD). The past 4 years have been extremely fruitful in providing an extensive amount of information on the molecular composition of the SD, and opened up new avenues to understand podocyte function w2,3x. ACE inhibitors and angiotensin receptor blockers have proven effective in ameliorating glomerular proteinuria and slowing of disease progression in proteinuric renal diseases and in diabetic nephropathy in particular w4–8x. In addition, there are novel intriguing experimental data that link the salutary effects of these drugs to changes in the composition of the SD. This comment is focused on the recent progress in understanding the molecular mechanisms that underlie SD dysfunction and the development of proteinuria.

the Modification of Diet in Renal suggested a small of dietary protein restriction on the progression of chronic kidney disease one to of protein on CKD

the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease–related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease–related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n=118) compared with the atenolol or hydrochlorothiazide group (n=79) (HR, 1.54 [95% CI, 1.16-2.04]; P=.003). More cardiovascular disease–related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53). Conclusions The CONVINCE trial did not demonstrate equivalence of a COER verapamil–based antihypertensive regimen compared with a regimen beginning with a diuretic or -blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or -blocker treatment. JAMA. 2003;289:2073-2082 www.jama.com

doi:10.1016/j.jacc.2010.02.046 J. Am. Coll. Cardiol. 2010;56;77-85 Tsushung A. Hua, Allen Hester, Bertram Pitt, for the ACCOMPLISH Investigators Kjeldsen, Richard B. Devereux, Eric J. Velazquez, Bjorn Dahlof, Roxzana Y. Kelly,Michael A. Weber, George L. Bakris, Kenneth Jamerson, Matthew Weir, Sverre E.With Diabetes Cardiovascular Events During Differing Hypertension Therapies in PatientsThis information is current as of October 14, 2011 http://content.onlinejacc.org/cgi/content/full/56/1/77 located on the World Wide Web at: The online version of this article, along with updated information and services, isDownloaded from content.onlinejacc.org

by the trial physicians. Amazingly, the blood pressure decrease observed in the study was the same in both groups, 7 ± 11 and 5 ± 11 mm Hg, respectively. Either the trial physicians were incredibly adroit in lowering blood pressure in the placebo group or captopril 75 mg/day did not lower blood pressure. Thereafter, this experiment was repeated with a new class of RAAS inhibitors, the AT1 receptor blockers (ARB), with similarly favorable results for patients with type 2 diabetes [4, 5] . Suffice it to say that ‘something special’ has been associated with these agents that implying a magical action of RAAS above and beyond lowering blood pressure. Identifying such effects clinically, however, has been elusive [6] . Figure 1 summarizes a review of the putative advantages of ‘dual blockade’ as explained on a popular website. The dynamics of the RAAS are complex and the pharmacology of available agents does not guarantee uniform inhibition at all times. Furthermore, the discovery of various additional components, such as AT2 receptors, ACE2, further breakdown products of angiotensin (Ang 1–7, Ang 3–8, Ang 1–12), the renin receptor, and virtually a host of additional pathways (Mas) led to the attractive conclusion that blocking these systems at more than one point could be desirable. Several landmark studies were performed that did not have as their sole aim to test Type 2 diabetic patients not only have carbohydrate disturbances but also are commonly hypertensive, have lipid abnormalities, are often overweight, and not surprisingly have a high incidence of cardiovascular events. They are prone to chronic kidney disease, which amplifies their risk even further. Thus, diabetic patients are oftentimes selected targets for pharmacological intervention and appropriately so. They have an increased frequency of cardiovascular events in a day and age when regulatory agencies demand ‘hard’ endpoints for medication trials. Furthermore, they represent a genuine need and physicians desperately want to reach out and help them. The renin-angiotensin-aldosterone system (RAAS) has received intense attention in the last half century [1] and particularly its role in diabetes has been thoroughly scrutinized [2] . In terms of patient-oriented research, the development of angiotensin-converting enzyme (ACE) inhibitors opened a highly attractive therapeutic avenue for diabetic patients. The Collaborative Study Group published that captopril reduced a combined endpoint of death, dialysis, and transplantation in type 1 diabetic patients by 50% [3] . Both groups in that study received the best treatments of the day and captopril 25 mg three times daily was compared to placebo. Systolic and diastolic blood pressure was to be held below 140 and 90 mm Hg Published online: January 15, 2014 Nephrology American Journal of

Whereas much research has investigated equations for obtaining estimated GFR (eGFR) from serum creatinine in cross-sectional settings, little attention has been given to validating these equations as outcomes in longitudinal studies of chronic kidney disease. A common objective of chronic kidney disease studies is to identify risk factors for progression, characterized by slope (rate of change over time) or time to event (time until a designated decline in kidney function or ESRD). The relationships of 35 baseline factors with eGFR-based outcomes were compared with the relationships of the same factors with iothalamate GFR (iGFR)-based outcomes in the African American Study of Kidney Disease and Hypertension (AASK; n = 1094). With the use of the AASK equation to calculate eGFR, results were compared between time to halving of eGFR or ESRD and time to halving of iGFR or ESRD (with effect sizes expressed per 1 SD) and between eGFR and iGFR slopes starting 3 mo after randomization. The effects of the baseline factors were similar between the eGFR- and iGFR-based time-to-event outcomes (Pearson R = 0.99, concordance R = 0.98). Small but statistically significant differences (P < 0.05, without adjustment for multiple analyses) were observed for seven of the 35 factors. Agreement between eGFR and iGFR was somewhat weaker, although still relatively high for slope-based outcomes (Pearson R = 0.93, concordance R = 0.92). Effects of covariate adjustment for age, gender, baseline GFR, and urine proteinuria also were similar between the eGFR and iGFR outcomes. Sensitivity analyses including death in the composite time-to-event outcomes or using the Modification of Diet in Renal Disease equation instead of the AASK equation provided similar results. In conclusion, the data from the AASK provide tentative support for use of outcomes that are based on an established eGFR formula using serum creatinine as a surrogate for measured iGFR-based outcomes in analyses of risk factors for the progression of kidney disease.

What is the central question of this study? The mechanism by which PAI‐1R reduces proteinuria has not been previously explored. What is the main finding and its importance? Using cultured podocytes and diabetic db/db mice, we show that, similar to the effects of transforming growth factor‐β1, PAI‐1 directly injures podocytes. Reducing the increased PAI‐1 activity by PAI‐1R in diabetic db/db mice, in fact, reduces podocyte injury, thereby reducing albuminuria. Therefore, PAI‐1R may provide an additional therapeutic effect in slowing progression of diabetic nephropathy by maintaining podocyte integrity.

We will shortly celebrate the 25th anniversary of the publication of the Co‐operative North Scandinavian Enalapril Survival Study (CONSENSUS), a clinical trial which revolutionized the treatment of heart failure and highlighted the importance of the renin–angiotensin–aldosterone system (RAAS) in the pathophysiology of heart failure (Figure 1). In this article I will give a brief, historical overview of this exciting quarter‐century of discovery related to the RAAS. My focus is on the treatment of heart failure in patients with a low left ventricular ejection fraction.

We read with interest the comprehensive review of the management of glomerular proteinuria by Wilmer et al. ([1][1]). We found the commentary to be well organized and very informative, citing many relevant reports. We wish to take this opportunity to correct a statement regarding the RENAAL study

We investigated whether renal function and microalbuminuria are independent predictors and whether any interaction exists between them, regarding future cardiovascular disease in hypertensive patients (n=10 881) followed for 4.5 years. The primary end points (PEs) were fatal and nonfatal myocardial infarction and stroke and other cardiovascular deaths. Creatinine and glomerular filtration rate (GFR), estimated using the formulas of the Modification of Diet in Renal Disease study group and Cockroft and Gault and in a subsample (n=4929) of microalbuminuria and interaction terms of microalbuminuria and renal function, were related to the risk of the PE using Cox proportional hazards model after full adjustment. Increased creatinine (P<0.001), decreased GFR from Cockroft and Gault (P=0.001), and decreased GFR from the Modification of Diet in Renal Disease study group (P=0.001) were all independent risk factors for the PE. Stepwise exclusion of patients with the poorest renal function excluded the possibility that the relationship between decreasing renal function and the PE was driven only by patients with severely impaired renal function. Microalbuminuria and all 3 of the indices of renal function predicted the PE independent of each other. There was a significant interaction between microalbuminuria and GFR from Cockroft and Gault (P=0.040) in prediction of the PE. Both renal function and microalbuminuria add independent prognostic information regarding cardiovascular risk in hypertensive patients. The cardiovascular risk associated with microalbuminuria increases with a decline in GFR, as demonstrated by a significant interaction between microalbuminuria and GFR from Cockroft and Gault. Because estimation of the total cardiovascular risk is essential for the aggressiveness of risk factor interventions, simultaneous inclusion of GFR and microalbuminuria in global cardiovascular risk assessment is essential.

We investigated the association between worsening renal function (WRF) that occurs during renin–angiotensin–aldosterone system inhibition initation and outcome in heart failure (HF) patients with preserved ejection fraction (HFPEF) and compared this with HF patients with reduced ejection fraction (HFREF).

We apply a pattern-based classification method to identify clinical and genomic features associated with the progression of Chronic Kidney disease (CKD). We analyze the African-American Study of Chronic Kidney disease with Hypertension dataset and construct a decision-tree classification model, consisting 15 combinatorial patterns of clinical features and single nucleotide polymorphisms (SNPs), seven of which are associated with slow progression and eight with rapid progression of renal disease among African-American Study of Chronic Kidney patients. We identify four clinical features and two SNPs that can accurately predict CKD progression. Clinical and genomic features identified in our experiments may be used in a future study to develop new therapeutic interventions for CKD patients.

We analyzed data from 8,766 participants in the ADVANCE-ON study. Change in UACR was calculated from UACR measurements 2 years apart, classified into three groups: decrease in UACR of ‡30%,minor change, and increase in UACR of ‡30%. By analyzing changes from baseline UACR groups, categorized into thirds, we repeated these analyses accounting for regression to the mean (RtM). The primary outcome was the composite of major macrovascular events, renal events, and all-cause mortality; secondary outcomes were these components. Cox regression models were used to estimate hazard ratios (HRs).

WRITING COMMITTEE MEMBERS* Clyde W. Yancy, MD, MSc, FACC, FAHA, Chairyz; Mariell Jessup, MD, FACC, FAHA, Vice Chair*y; Biykem Bozkurt, MD, PhD, FACC, FAHAy; Javed Butler, MBBS, FACC, FAHA*y; Donald E. Casey, Jr, MD, MPH, MBA, FACP, FAHAx; Mark H. Drazner, MD, MSc, FACC, FAHA*y; Gregg C. Fonarow, MD, FACC, FAHA*y; Stephen A. Geraci, MD, FACC, FAHA, FCCPjj; Tamara Horwich, MD, FACCy; James L. Januzzi, MD, FACC*y; Maryl R. Johnson, MD, FACC, FAHA{; Edward K. Kasper, MD, FACC, FAHAy; Wayne C. Levy, MD, FACC*y; Frederick A. Masoudi, MD, MSPH, FACC, FAHAy#; Patrick E. McBride, MD, MPH, FACC**; John J. V. McMurray, MD, FACC*y; Judith E. Mitchell, MD, FACC, FAHAy; Pamela N. Peterson, MD, MSPH, FACC, FAHAy; Barbara Riegel, DNSc, RN, FAHAy; Flora Sam, MD, FACC, FAHAy; Lynne W. Stevenson, MD, FACC*y; W. H. Wilson Tang, MD, FACC*y; Emily J. Tsai, MD, FACCy; Bruce L. Wilkoff, MD, FACC, FHRS*yy

Vascular injury and remodeling are common pathological sequelae of hypertension. Previous studies have suggested that the renin-angiotensin system acting through the type 1 angiotensin II (AT1) receptor promotes vascular pathology in hypertension. To study the role of AT1 receptors in this process, we generated mice with cell-specific deletion of AT1 receptors in vascular smooth muscle cells using Cre/Loxp technology. We crossed the SM22&agr;-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Agtr1a gene (Agtr1aflox), encoding the major murine AT1 receptor isoform (AT1A). In SM22&agr;-Cre+Agtr1aflox/flox (SMKO) mice, AT1A receptors were efficiently deleted from vascular smooth muscle cells in larger vessels but not from resistance vessels such as preglomerular arterioles. Thus, vasoconstrictor responses to angiotensin II were preserved in SMKO mice. To induce hypertensive vascular remodeling, mice were continuously infused with angiotensin II for 4 weeks. During infusion of angiotensin II, blood pressures increased significantly and to a similar extent in SMKO and control mice. In control mice, there was evidence of vascular oxidative stress indicated by enhanced nitrated tyrosine residues in segments of aorta; this was significantly attenuated in SMKO mice. Despite these differences in oxidative stress, the extent of aortic medial expansion induced by angiotensin II infusion was virtually identical in both groups. Thus, vascular AT1A receptors promote oxidative stress in the aortic wall but are not required for remodeling in angiotensin II–dependent hypertension.

Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

Unlike the majority of patients with uncomplicated hypertension in whom minimal renal damage develops in the absence of severe blood pressure (BP) elevations, patients with diabetic and nondiabetic chronic kidney disease (CKD) exhibit an increased vulnerability to even moderate BP elevations. Investigations in experimental animal models have revealed that this enhanced susceptibility is a consequence of an impairment of the renal autoregulatory mechanisms that normally attenuate the transmission of elevated systemic pressures to the glomeruli in uncomplicated hypertension. The markedly lower BP threshold for renal damage and the steeper slope of relationship between BP and renal damage in such states necessitates that BP be lowered into the normotensive range to prevent progressive renal damage. When BP is accurately measured using radiotelemetry in animal models, the renal protection provided by renin-angiotensin system (RAS) blockade is proportional to the BP reduction with little evidence of BP-independent protection. A critical evaluation of the clinical data also suggests that the BP-independent renoprotection by RAS blockade has been overemphasized and that achieving lower BP targets is more important than the selection of antihypertensive regimens. However, achievement of such BP goals is difficult in CKD patients without aggressive diuresis, because of their proclivity for salt retention. The effectiveness of RAS blockers in lowering BP in patients who have been adequately treated with diuretics, along with their potassium-sparing and magnesium-sparing effects, provides a more compelling rationale for the use of RAS blockade in the treatment of CKD patients than any putative BP-independent renoprotective superiority.

Understanding the categorization of human diseases is critical for reliably identifying disease causal genes. Recently, genome-wide studies of abnormal chromosomal locations related to diseases have mapped >2000 phenotype–gene relations, which provide valuable information for classifying diseases and identifying candidate genes as drug targets. In this article, a regularized non-negative matrix tri-factorization (R-NMTF) algorithm is introduced to co-cluster phenotypes and genes, and simultaneously detect associations between the detected phenotype clusters and gene clusters. The R-NMTF algorithm factorizes the phenotype–gene association matrix under the prior knowledge from phenotype similarity network and protein–protein interaction network, supervised by the label information from known disease classes and biological pathways. In the experiments on disease phenotype–gene associations in OMIM and KEGG disease pathways, R-NMTF significantly improved the classification of disease phenotypes and disease pathway genes compared with support vector machines and Label Propagation in cross-validation on the annotated phenotypes and genes. The newly predicted phenotypes in each disease class are highly consistent with human phenotype ontology annotations. The roles of the new member genes in the disease pathways are examined and validated in the protein–protein interaction subnetworks. Extensive literature review also confirmed many new members of the disease classes and pathways as well as the predicted associations between disease phenotype classes and pathways.

Type 2 diabetes mellitus is a risk factor for incident heart failure and increases the risk of morbidity and mortality in patients with established disease. Secular trends in the prevalence of diabetes mellitus and heart failure forecast a growing burden of disease and underscore the need for effective therapeutic strategies. Recent clinical trials have demonstrated the shared pathophysiology between diabetes mellitus and heart failure, the synergistic effect of managing both conditions, and the potential for diabetes mellitus therapies to modulate the risk of heart failure outcomes. This scientific statement on diabetes mellitus and heart failure summarizes the epidemiology, pathophysiology, and impact of diabetes mellitus and its control on outcomes in heart failure; reviews the approach to pharmacological therapy and lifestyle modification in patients with diabetes mellitus and heart failure; highlights the value of multidisciplinary interventions to improve clinical outcomes in this population; and outlines priorities for future research.

Treatment of heart failure has undergone major changes in the last two decades. European and US guidelines have absorbed these major changes and set the new standards. It is therefore mandatory that treatment of heart failure is based on this knowledge. According to these guidelines, patients with chronic symptomatic heart failure should be treated with a diuretic and sometimes digoxin and vasodilators, to relieve symptoms, in addition to an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker (ARB) and a β-blocker to improve prognosis. An aldosterone antagonist should be added in patients with more advanced heart failure. Prevention of heart failure has also become a major goal. We summarise here the major issues regarding the pharmacological treatment of chronic heart failure as indicated by the European and US guidelines.