Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Left ventricular hypertrophy (LVH) is common in end-stage renal disease (ESRD) and has been advocated as a therapeutic target. We review the considerations for targeting LVH as a modifiable risk factor in ESRD. RECENT FINDINGS/RESULTS:Pathologic myocardial changes underlying LVH provide an ideal substrate for the spread of arrhythmia and may be key contributors to the occurrence of sudden death in ESRD. LVH is present in 68-89% of incident hemodialysis patients and is frequently progressive, although regression is observed in a minority of patients. Higher degrees of baseline LVH, as well as greater increases in left ventricular mass index over time, are associated with decreased survival, but whether these associations are causal remains uncertain. Several interventions, including angiotensin blockade and frequent dialysis, can reduce the left ventricular mass index, but whether this is associated with improved survival has not been definitively demonstrated. SUMMARY/CONCLUSIONS:LVH is a highly prevalent and reversible risk factor, which holds promise as a novel therapeutic target in ESRD. Interventional trials are needed to provide additional evidence that LVH regression improves survival before prevention and reversal of LVH can be definitively adopted as a therapeutic paradigm in ESRD.

BACKGROUND:Sudden cardiovascular death is increased in chronic kidney disease (CKD). Experimental CKD models suggest that angiogenesis and nitric oxide (NO) inhibitors induce myocardial fibrosis and microvascular dropout thereby facilitating arrhythmogenesis. We undertook this study to characterize associations of CKD with human myocardial pathology, NO-related circulating angiogenesis inhibitors, and endothelial cell behavior. METHODS:We compared heart (n=54) and serum (n=162) samples from individuals with and without CKD, and assessed effects of serum on human coronary artery endothelial cells (HCAECs) in vitro. Left ventricular fibrosis and capillary density were quantified in post-mortem samples. Endothelial to mesenchymal transition (EndMT) was assessed by immunostaining of post-mortem samples and RNA expression in heart tissue obtained during cardiac surgery. Circulating asymmetric dimethylarginine (ADMA), endostatin (END), angiopoietin-2 (ANG), and thrombospondin-2 (TSP) were measured, and the effect of these factors and of subject serum on proliferation, apoptosis, and EndMT of HCAEC was analyzed. RESULTS:Cardiac fibrosis increased 12% and 77% in stage 3-4 CKD and ESRD and microvascular density decreased 12% and 16% vs. preserved renal function. EndMT-derived fibroblast proportion was 17% higher in stage 3-4 CKD and ESRD (P trend = 0.02). ADMA, ANG, TSP, and END concentrations increased in CKD. Both individual factors and CKD serum increased HCAEC apoptosis (P=0.02), decreased proliferation (P=0.03), and induced EndMT. CONCLUSIONS:CKD is associated with an increase in circulating angiogenesis and NO inhibitors, which impact proliferation and apoptosis of cardiac endothelial cells and promote EndMT, leading to cardiac fibrosis and capillary rarefaction. These processes may play key roles in CKD-associated CV disease.

The lack of evidence on the effectiveness and safety of interventions in chronic dialysis patients has been a subject of continuing criticism. New technologies are often introduced into the market without having specifically studied or even included patients with advanced kidney disease. Therefore, the need to generate valid effectiveness and safety data in this vulnerable subpopulation is of utmost importance. The US Food and Drug Administration has recently placed an increased focus on safety surveillance, and sponsors must now meet this additional postmarketing commitment. In patients with ESRD, the unique data collection environment in the United States allows for creative and efficient study designs to meet the needs of patients, providers, and sponsors. The purpose of this manuscript is to review the methodological and practical aspects of the different options for postmarketing study design in this field, with critical appraisal of their advantages and disadvantages.

BACKGROUND: Individuals with chronic kidney disease (CKD) have high rates of myocardial infarction (MI), but whether the nature of coronary lesions susceptible to plaque rupture is altered and whether the high rate of MI is related to a greater burden of atherosclerotic lesions in individuals with CKD is uncertain. METHODS: We used quantitative coronary angiography to assess atherosclerotic plaque location and characteristics at baseline and at the time of MI in 62 patients with and without CKD. Univariate and multivariable conditional logistic regression models were used to assess whether the association between pre-MI angiographic findings and MI differs in individuals with and without CKD. RESULTS: The risk of MI rose as the distance from the coronary ostium decreased both in patients with CKD (odds ratio per 10 mm 0.92 [95 % CI 0.87-0.99]) and in those without CKD (odds ratio 0.83 [95 % CI 0.75-0.93]). Although tighter degrees of coronary stenosis were associated with increased risks of MI in patients with and without CKD, the majority of MIs (70.9 % in patients with CKD and 89.5 % in those without CKD) occurred in segments with <50 % diameter stenosis at baseline. CONCLUSIONS: The characteristics of lesions progressing to MI are similar in individuals with and without CKD and the majority of events occur in areas with <50 % stenosis at baseline. Given the high burden of non-stenotic lesions in patients with CKD, an interventional strategy aimed solely at sites with high-grade stenosis is unlikely to markedly reduce the risk of MI in patients with CKD.

BACKGROUND:Reliable data regarding absolute and relative risks of death and graft failure after coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) in renal transplant patients are unavailable. METHODS AND RESULTS/RESULTS:Renal transplant patients undergoing inpatient CABG (n=1400) or PCI (n=4097) were identified from United States Renal Data System data. Cumulative incidence of nonfatal graft failure and death was reported for observed events. A Cox model with the Fine-Gray method was used to account for competing risks in assessing relative hazards. Age and race were similarly distributed; patients who underwent CABG were more likely to have acute arrhythmia and congestive heart failure but less likely to have acute myocardial infarction on index admission. In-hospital death was more frequent after CABG (5.6% versus 3.0%, P<0.001). Cumulative incidence of death, graft failure, and the combined outcome at 3 years were 23.1%, 15.4%, and 38.5% after CABG and 22.9%, 13.3%, and 36.1% after PCI, respectively. In adjusted analyses, CABG was not associated with increased risk of graft failure versus PCI during the first 6 months (hazard ratio 1.06, 95% CI 0.79 to 1.43) or from 6 to 36 months (0.98, 0.78 to 1.22). Risk of death increased after CABG during the first 3 months (1.37, 1.08 to 1.73), but decreased from 6 months on (0.76, 0.63 to 0.93). CONCLUSIONS:CABG does not appear to be associated with a difference in risk of graft failure compared with PCI in renal transplant patients. Compared with PCI, adjusted risk of early death is higher after CABG; however, mortality from 6 months on is lower.

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.

OBJECTIVES/OBJECTIVE: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.

BACKGROUND AND PURPOSE/OBJECTIVE: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/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.