David M. Charytan

BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury

Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-β superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-β1–induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-β1–induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-β1–induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-β1 in the regulation of EMT in health and disease.

Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

Cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) is high, and the presence of CKD worsens outcomes of cardiovascular disease (CVD). CKD is associated with specific risk factors. Emerging evidence indicates that the pathology and manifestation of CVD differ in the presence of CKD. During a clinical update conference convened by the Kidney Disease: Improving Global Outcomes (KDIGO), an international group of experts defined the current state of knowledge and the implications for patient care in important topic areas, including coronary artery disease and myocardial infarction, congestive heart failure, cerebrovascular disease, atrial fibrillation, peripheral arterial disease, and sudden cardiac death. Although optimal strategies for prevention, diagnosis, and management of these complications likely should be modified in the presence of CKD, the evidence base for decision making is limited. Trials targeting CVD in patients with CKD have a large potential to improve outcomes.

Trends in the Use and Outcomes of Implantable Cardioverter-Defibrillators in Patients Undergoing Dialysis in the United States

BACKGROUND Sudden cardiac death constitutes the leading cause of death in patients receiving dialysis. Little is known about the trends in implantable cardioverter-defibrillator (ICD) use and the outcomes of such device placement. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS US long-term dialysis patients who received an ICD in 1994-2006. PREDICTORS, OUTCOMES, & MEASUREMENTS: ICD utilization rates and incident rates of all-cause mortality, device infections, and other device-related procedures were measured. We compared mortality between recipients and otherwise similar patients who did not receive such a device using high-dimensional propensity score matching. We also examined the associations of demographics, dialysis type, baseline comorbid conditions, cardiovascular events at the time of admission, and recent infection with the study outcomes. RESULTS 9,528 patients received an ICD in 1994-2006, with >88% placed after 2000. Almost all ICD use in the 1990s was for secondary prevention, however, half the patients received ICDs for apparent primary prevention in 2006. Mortality rates after implantation were high (448 deaths/1,000 patient-years) and most deaths were cardiovascular. Postimplantation infection rates were high, especially in the first year after implantation (988 events/1,000 patient-years) and were predicted by diabetes and recent infection. Patients receiving ICDs for secondary prevention had an overall 14% (95% CI, 9%-19%) lower mortality risk compared with propensity-matched controls, but these benefits seemed to be restricted to the early postimplantation time. LIMITATIONS Lack of clinical data, especially for laboratory and heart function studies. Residual confounding by indication. CONCLUSIONS ICD use in dialysis patients is increasing, but rates of all-cause and cardiovascular mortality remain high in dialysis patients receiving these devices. Device infections are common, particularly in patients with recent infections. Randomized trials of ICDs are needed to determine the efficacy, safety, and risk-benefit ratio of these devices in dialysis patients.

Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis

The functional contribution of myofibroblasts in fibrosis is not well understood. Using a new genetic mouse model to track and isolate myofibroblasts, we performed gene expression profiling followed by biological validation to identify HE4 (encoding human epididymis protein 4, also known as WAP 4-disulfide core domain-2 or Wfdc2) as the most upregulated gene in fibrosis-associated myofibroblasts. The HE4 gene encodes for a putative serine protease inhibitor that is upregulated in human and mouse fibrotic kidneys and is elevated in the serum of patients with kidney fibrosis. HE4 suppresses the activity of multiple proteases, including serine proteases and matrix metalloproteinases, and specifically inhibits their capacity to degrade type I collagen. In particular, we identified two serine proteases, Prss35 and Prss23, as HE4 targets with functional relevance in kidney fibrosis. Administration of HE4-neutralizing antibodies accelerated collagen I degradation and inhibited fibrosis in three different mouse models of renal disease. Collectively these studies suggest that HE4 is a potential biomarker of renal fibrosis and a new therapeutic target.

Loss of Hypoxia-Inducible Factor Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy

Background— Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment. Methods and Results— We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor &agr; variant in cardiomyocytes also led to dilated cardiomyopathy. Conclusion— Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.

Early Angiography in Patients with Chronic Kidney Disease: A Collaborative Systematic Review

BACKGROUND AND OBJECTIVES In the general population, an early invasive strategy of routine coronary angiography is superior to a conservative strategy of selective angiography in patients who are admitted with unstable angina or non-ST segment elevation myocardial infarction (MI), but the effectiveness of this strategy in individuals with chronic kidney disease (CKD) is uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a collaborative meta-analysis with data provided by the main authors of identified trials to estimate the effectiveness of early angiography in patients with CKD. The Cochrane, Medline, and EMBASE databases were searched to identify randomized trials that compared invasive and conservative strategies in patients with unstable angina or non-ST MI. Pooled risks ratios were estimated using data from enrolled patients with estimated GFR <60 ml/min per 1.73 m(2). RESULTS Five randomized trials that enrolled 1453 patients with CKD were included. An early invasive strategy was associated with nonsignificant reductions in all-cause mortality, nonfatal MI, and a composite of death or nonfatal MI. The invasive strategy significantly reduced rehospitalization. CONCLUSIONS This collaborative study suggests that the benefits of an early invasive strategy are preserved in patients with CKD and that an early invasive approach reduces the risk for rehospitalization and is associated with trends of reduction in the risk for death and nonfatal re-infarction in patients with CKD. Coronary angiography should be considered for patients who have CKD and are admitted with non-ST elevation acute coronary syndromes.

Coronary Vascular Dysfunction and Prognosis in Patients With Chronic Kidney Disease

OBJECTIVES This study sought to evaluate whether impaired vasodilator function, an early manifestation of coronary artery disease, which precedes angiographic stenosis, accounts for increased risk among patients with moderate to severe renal dysfunction. BACKGROUND Patients with renal dysfunction are at increased risk of adverse cardiac outcomes, even in the absence of overt myocardial ischemia or infarction. METHODS We included 866 consecutive patients with moderate to severe renal dysfunction referred for rest and stress myocardial perfusion positron emission tomography and followed them for a median of 1.28 years (interquartile range: 0.64 to 2.34). Regional myocardial perfusion abnormalities were assessed by semiquantitative visual analysis of positron emission tomography images. Rest and stress myocardial blood flow were calculated using factor analysis and a 2-compartment kinetic model; they were also used to compute coronary flow reserve (stress/rest myocardial blood flow). The primary endpoint was cardiac death. RESULTS Overall, 3-year cardiac mortality was 16.2%. After adjusting for clinical risk, left ventricular ejection fraction, as well as the magnitude of scar and/or ischemia, coronary flow reserve below the median (<1.5) was associated with a 2.1-fold increase in the risk of cardiac death (95% confidence interval [CI]: 1.3 to 3.5, p = 0.004). Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the C-index from 0.75 to 0.77 (p = 0.05) and in a net reclassification improvement of 0.142 (95% CI: 0.076 to 0.219). Among patients at intermediate risk based on all data other than coronary flow reserve, the net reclassification improvement was 0.489 (95% CI: 0.192 to 0.836). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated. CONCLUSIONS The presence of coronary vascular dysfunction in patients with moderate to severe renal dysfunction, as assessed by positron emission tomography, is a powerful, independent predictor of cardiac mortality and provides meaningful incremental risk stratification over conventional markers of clinical risk.

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.

Risks of Death and End-Stage Renal Disease After Surgical Compared With Percutaneous Coronary Revascularization in Elderly Patients With Chronic Kidney Disease

Background and Purpose— Revascularization by coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) is frequently deferred in patients with chronic kidney disease (CKD) to avoid precipitating end-stage renal disease (ESRD), but reliable estimates of absolute and relative risks of death and ESRD after CABG and PCI are unavailable. Methods and Results— CKD patients undergoing CABG (n=4547) or PCI (n=8620) were identified and tracked using the 5% Medicare sample. The cumulative incidence of ESRD and death were reported for observed events. A Cox model with the Fine-Gray method was used to account for competing risks in assessing relative hazards of death and ESRD. Three-year cumulative incidence of ESRD was lower (CABG, 6.8%; PCI, 5.4%) than death (CABG, 28.3%; PCI, 32.8%). The adjusted hazard ratio of death was higher during the first 3 months after CABG than after PCI (1.25; 95% confidence interval, 1.12–1.40; P<0.001), but lower from 6 months onward (0.61; 95% confidence interval, 0.55–0.69). Conversely, risk of ESRD after CABG was higher during the first 3 months (1.59; 95% confidence interval, 1.27–2.01; P<0.001), but was not statistically significant from 3 months onward. The adjusted hazard ratio of combined death or ESRD was similar to death. Conclusions— Among CKD patients undergoing coronary revascularization, death is more frequent than ESRD. The incidence of ESRD was lower throughout follow-up after PCI, but long-term risks of death or combined death and ESRD were lower after CABG. Our data suggest better overall clinical outcomes with CABG than with PCI in CKD patients.

Long and short-term outcomes following coronary artery bypass grafting in patients with and without chronic kidney disease

BACKGROUND Improved understanding of the incidence and risk factors for operative complications and long-term mortality following coronary artery bypass grafting (CABG) is needed to better define the optimal role for CABG in patients with chronic kidney disease (CKD). METHODS We analysed 2438 patients who underwent CABG at a single centre between 2005 and 2008. Multivariable regression was used to analyse associations and to generate a CKD-specific predictive tool. RESULTS Operative mortality was 4.8% in individuals with stage 3 CKD, 7.1% in individuals with stage 4-5 CKD and 2.2% in those without significant CKD (P < 0.001). CKD was associated with post-operative blood transfusion, acute kidney injury, myocardial injury and cardiac arrest, and use of exogenous blood and acute kidney injury were strongly associated with in-hospital death in CKD patients. Patients with stage 3 (HR 1.64, 95% CI 1.30-45.94) and stage 4-5 CKD (HR 2.77, 95% CI 1.00-2.68) were more likely to die during follow-up than those without CKD, but mortality rates were low among patients who survived to discharge-stage 3 (0.006 deaths/year) and stage 4-5 CKD (0.009/year). A scoring system including urgent or emergent surgery (OR 2.30), prior cardiac surgery (OR 3.06), concurrent valve surgery (OR 2.06), preoperative shock (OR 6.18), and prior stroke (OR 1.98) had 96.4% percent specificity for the detection of in-hospital death in patients with CKD. CONCLUSIONS Perioperative mortality and morbidity remain more frequent in patients with stage 3-5 CKD than patients with preserved renal function, but long-term outcomes in patients surviving hospitalization are favourable. We have developed a predictive tool that holds promise as a means of identifying CKD patients most likely to survive surgery and benefit from CABG.