Hirotake Kasuga

Prognostic Value of Reduced Left Ventricular Ejection Fraction at Start of Hemodialysis Therapy on Cardiovascular and All-Cause Mortality in End-Stage Renal Disease Patients

BACKGROUND AND OBJECTIVES Cardiac failure is directly affected by left ventricular (LV) dysfunction, and particularly LV systolic dysfunction is strongly associated with survival in ESRD patients. The aim of this study was to determine the prognostic value of reduced LV ejection fraction (LVEF) measured at the time of initiation of hemodialysis (HD) in incident HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 1254 consecutive ESRD patients who electively started HD therapy were screened by echocardiography within 1 month after its inception. They were divided into five groups according to LVEF levels with a decrease of 0.1 each and were followed up for up to 7 years. Survival was examined with the Kaplan-Meier method and compared using the log-rank test. RESULTS Among the 1254 patients, LVEF levels ≥0.6, 0.5 to 0.6, 0.4 to 0.5, 0.3 to 0.4, and <0.3 were seen in 842 (67.1%), 247 (19.7%), 107 (8.5%), 41 (3.3%), and 17 (1.4%) patients, respectively. On Kaplan-Meier analysis, 7-year event-free rates from cardiovascular death were 84.2, 83.7, 73.6, 59.4, and 30.9% in order of groups with decreasing LVEF of 0.1 each, respectively. Seven-year event-free rates from all-cause death were 69.2, 61.7, 57.1, 45.9, and 23.1% in the respective groups. Even after adjustment for other risk factors, decreasing LVEF was a strong independent predictor for cardiovascular death. CONCLUSIONS Reduced LVEF on starting HD therapy could stratify risk of cardiovascular and all-cause mortality in ESRD patients. Screening by echocardiography at start of HD therapy might be recommended to predict prognosis in patients with ESRD.

Comparison of Percutaneous Coronary Intervention with Medication in the Treatment of Coronary Artery Disease in Hemodialysis Patients

It has been reported that percutaneous coronary intervention (PCI) is beneficial for coronary artery disease (CAD) among the general population. However, its effects in patients who are on hemodialysis (HD) remain unclear. A prospective cohort study was performed to clarify whether PCI has a therapeutic advantage over medical therapy among HD patients with CAD. A follow-up study to 5 yr was conducted among 259 HD patients with ischemic heart disease. Mean follow-up was 39 mo. Patients were divided into three groups: 122 patients without significant stenosis, 88 patients who had significant stenosis and were treated with PCI, and 49 patients who had significant stenosis and were treated with medication only. The primary end point was cardiac death, and the secondary end point was all-cause death. The results showed that the 5-yr cardiac survival rate was 41.6% in the medication group, 77.1% in the PCI group (P = 0.0006), and 84.5% in the nonstenosis group (P < 0.0001). The 5-yr all-cause survival rate was 19.3% in the medication group, 48.4% in the PCI group (P = 0.004), and 64.3% in the nonstenosis group (P < 0.0001). Even after adjustment for other risk factors, effects of PCI on the risk for cardiac and all-cause death remained significant and independent (odds ratio 0.14; 95% confidence interval 0.08 to 0.25, P = 0.0006; and odds ratio 0.37; 95% confidence interval 0.26 to 0.54, P = 0.0062, respectively). Results were consistent when the therapeutic effect of PCI or medication was analyzed using propensity-matched patients. These data suggested that PCI could improve the prognosis of HD patients with CAD. PCI would be recommended for HD patients with CAD.

Effects of Combination Treatment with Losartan and Trandolapril on Office and Ambulatory Blood Pressures in Non-Diabetic Renal Disease: A COOPERATE-ABP Substudy

Background: In the COOPERATE trial, the combination treatment of the angiotensin-II receptor blocker losartan and the angiotensin-converting-enzyme inhibitor trandolapril significantly retarded progression of non-diabetic kidney disease compared with each monotherapy. The benefit could be greatly attributable to the potent reduction of proteinuria, because the three treatment groups showed the same reductions of office blood pressure (OBP). Ambulatory blood pressure (ABP) is reported to be better than OBP in predicting progression of kidney disease. Methods: Ninety-two patients enrolled in the COOPERATE trial underwent 24-hour ABP monitoring at randomization and at month 6, year 1, year 2 and year 3 on randomized treatment. Results: Both OBP and ABP were similarly reduced among the three groups at all measurement points (p = NS) and throughout the whole study period (p = NS). No significant correlation between the change in 24-hour ABP and the change in proteinuria was seen (p = NS). A Cox-multivariable analysis showed that covariates affecting the renal outcomes (a doubling serum-Cr level and/or end-stage renal failure) were the change in proteinuria (hazard ratio 0.49, 95% CI 0.34–0.78, p = 0.01) and treatments (0.58, 0.45–0.99, 0.03), but not 24-hour ABP (0.98, 0.89–2.01, 0.17). Conclusion: The better renoprotective effect of the combination treatment is attributed to BP-independent mechanisms by more complete renin-angiotensin system blockade.

Peritonitis is still an important factor for withdrawal from peritoneal dialysis therapy in the Tokai area of Japan

BackgroundIn Japan, the population of patients on peritoneal dialysis (PD) is <4% of the total number of patients with end-stage renal disease. Few systemic analyses have examined why the number of PD patients has not increased in Japan. We organized a registry to analyze PD patients and retrospectively investigated 561 PD patients (about 5% of all Japanese PD patients) from 13 hospitals in the Tokai area for 3 years from 2005.MethodsWe investigated background, physical status, laboratory data, status of PD therapy, and the occurrence of PD-related complications, and analyzed reasons for withdrawal from PD.ResultsNutrition did not change significantly during our observation. Urinary volume showed continued decreases after the introduction period. In contrast, PD fluid demand and ultrafiltration volume were significantly increased. For calcium metabolism, multiple phosphate binders were required after the second year of PD therapy. Early drop-out within 3 years after starting PD therapy comprised 50.9% of total withdrawals, with PD-related peritonitis as the most common reason, mainly caused by Gram-positive organisms. Incidence of peritonitis was 42.8 months/patient. Culture-negative results were obtained for 32% of peritonitis cultures. Diabetes affects the prognosis of PD therapy, but not the incidence of peritonitis.ConclusionWe examined clinical status over 3 years in the Tokai area. The results suggest that the incidence of peritonitis needs to be decreased to prevent early withdrawal of PD patients. Education systems to decrease the incidence of peritonitis and techniques to decrease culture-negative results might be important for improving the prognosis of peritonitis.

Low circulating CD34+ cell count is associated with poor prognosis in chronic hemodialysis patients

Circulating CD34-positive (CD34(+)) cells, a population that includes endothelial progenitor cells, are believed to contribute to vascular homeostasis. Here we determine the prognostic value of CD34(+) cell measurements in 216 chronic hemodialysis patients. A total of 43 cardiovascular events and 13 deaths occurred over an average 23 months follow-up in this cohort. A cutoff number for circulating CD34(+) cells was determined by receiver operating characteristic curve analysis to maximize the power of the CD34(+) cell count in predicting future cardiovascular events. Based on this, 93 patients were categorized as having low and 123 patients as having high numbers of CD34(+) cells, determined by flow cytometry at the time of enrollment. Both cumulative cardiovascular event-free survival and all-cause survival were significantly less in the group of patients with low numbers of CD34(+) cells. By multivariate analyses, a low level of circulating CD34(+) cells was an independent and significant predictor for both cardiovascular events and all-cause mortality. Our study shows that a reduced number of circulating CD34(+) cells is significantly associated with vascular risks and all-cause mortality in patients on chronic hemodialysis. These cells may be a useful biomarker.

Long-Term Effects of Spironolactone in Peritoneal Dialysis Patients

ESRD treated with dialysis is associated with increased left ventricular hypertrophy, which, in turn, is related to high mortality. Mineralocorticoid receptor antagonists improve survival in patients with chronic heart failure; however, the effects in patients undergoing dialysis remain uncertain. We conducted a multicenter, open-label, prospective, randomized trial with 158 patients receiving angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist and undergoing peritoneal dialysis with and without (control group) spironolactone for 2 years. As a primary endpoint, rate of change in left ventricular mass index assessed by echocardiography improved significantly at 6 (P=0.03), 18 (P=0.004), and 24 (P=0.01) months in patients taking spironolactone compared with the control group. Rate of change in left ventricular ejection fraction improved significantly at 24 weeks with spironolactone compared with nontreatment (P=0.02). The benefits of spironolactone were clear in patients with reduced residual renal function. As secondary endpoints, renal Kt/V and dialysate-to-plasma creatinine ratio did not differ significantly between groups during the observation period. No serious adverse effects, such as hyperkalemia, occurred. In this trial, spironolactone prevented cardiac hypertrophy and decreases in left ventricular ejection fraction in patients undergoing peritoneal dialysis, without significant adverse effects. Further studies, including those to determine relative effectiveness in women and men and to evaluate additional secondary endpoints, should confirm these data in a larger cohort.

Ankle brachial pressure index but not brachial-ankle pulse wave velocity is a strong predictor of systemic atherosclerotic morbidity and mortality in patients on maintenance hemodialysis

BACKGROUND Ankle brachial pressure index (ABPI) and pulse wave velocity (PWV) have been widely recognized as a marker of systemic atherosclerosis. We examined whether ABPI and brachial-ankle PWV (baPWV) predict individual cardiovascular events in patients on maintenance hemodialysis (HD). METHODS We prospectively followed-up 445 HD patients undergoing both ABPI and baPWV measurements for up to 5 years. They were divided into 2 groups [group with ABPI > 0.9 to ≤ 1.3 (n = 328) and group with ABPI ≤ 0.9 or >1.3 (n = 117)] and were also divided into tertiles according to the baPWV level (T1: <1850 cm/s; T2: 1850-2310 cm/s and T3: ≥ 2310 cm/s). RESULTS During the follow-up period (mean 43 ± 17 months), 206 cardiovascular events [cardiac event: 125 (28.1%), cerebrovascular events: 39 (8.8%), and peripheral arterial events: 42 (9.4%)] occurred, and 36 (8.1%) and 42 (9.4%) patients experienced cardiovascular and non-cardiovascular deaths, respectively. Cox multivariable analysis showed that presence of ABPI ≤ 0.9 or >1.3 was a significant predictor of cardiac events [hazard ratio (HR) 1.78, 95% confidential interval (CI) 1.27-2.49, p = 0.0008], cerebrovascular event (HR 1.95, 95%CI 1.13-3.36, p = 0.017), peripheral arterial event (HR 3.64, 95%CI 2.10-6.29, p < 0.0001), composite endpoint of cardiovascular events (HR 2.22, 95%CI 1.64-2.99, p < 0.0001), cardiovascular mortality (HR 2.42, 95%CI 1.44-4.06, p = 0.0008) and all-cause mortality (HR 1.52, 95%CI 1.03-2.25, p = 0.037). However, baPWV did not predict cardiovascular events on multivariate analysis. CONCLUSION ABPI but not baPWV is useful for risk stratification of systemic atherosclerotic morbidity and mortality in HD patients. Furthermore, ABPI could predict not only individual peripheral arterial events but also cardiac and cerebrovascular events.

Combined Values of Serum Albumin, C-Reactive Protein and Body Mass Index at Dialysis Initiation Accurately Predicts Long-Term Mortality

Background: Protein-energy wasting and chronic inflammation are prevalent in patients with end-stage renal disease (ESRD). We investigated the combination of serum albumin, C-reactive protein (CRP) and body mass index (BMI) at initiation of hemodialysis therapy as a predictor of all-cause and cardiovascular disease (CVD) mortality in Japanese ESRD patients. Methods: A total of 1,228 consecutive Japanese ESRD patients on hemodialysis therapy were enrolled and followed for up to 10 years. Patients were divided into quartiles according to levels of albumin, CRP and BMI. Furthermore, to clarify the joint role of these factors, albumin <3.5 g/dl, CRP >4.0 mg/l and BMI <19.6 were defined as risk factors using receiver operating characteristic analysis; thereafter, patients were divided into groups according to the positive number of these factors. Results: Adjusted hazard ratios (HRs) for lower serum albumin, elevated CRP and lower BMI for 10-year all-cause mortality were 1.97, 3.13 and 2.61, respectively. Regarding the combination of these variables, adjusted HRs for mortality were 2.31, 4.28 and 8.07, respectively, in patients having any one factor, any two factors and all three factors. The C-index for an established risk model with these three positive markers was the most accurate for predicting mortality (0.768), as compared to other models with one or two markers. Similar results were seen for CVD mortality. Conclusions: Serum albumin, CRP and BMI at the start of hemodialysis therapy were able to individually stratify the risk of long-term mortality in ESRD patients. Furthermore, a combination of these variables could more accurately predict mortality.

Expression patterns of connective tissue growth factor and of TGF-β isoforms during glomerular injury recapitulate glomerulogenesis

Transforming growth factor (TGF)-beta(1), -beta(2), and -beta(3) are involved in control of wound repair and development of fibrosis. Connective tissue growth factor (CTGF) expression is stimulated by all TGF-beta isoforms and is abundant in glomerulosclerosis and other fibrotic disorders. CTGF is hypothesized to mediate profibrotic effects of TGF-beta(1) or to facilitate interaction of TGF-beta(1) with its receptor, but its interactions with TGF-beta isoforms in nonpathological conditions are unexplored so far. Tissue repair and remodeling may recapitulate gene transcription at play in organogenesis. To further delineate the relationship between CTGF and TGF-beta, we compared expression patterns of CTGF and TGF-beta isoforms in rat and human glomerulogenesis and in various human glomerulopathies. CTGF mRNA was present in the immediate precursors of glomerular visceral and parietal epithelial cells in the comma- and S-shaped stages, but not in earlier stages of nephron development. During the capillary loop and maturing glomerular stages and simultaneous with the presence of TGF-beta(1), -beta(2), and -beta(3) protein, CTGF mRNA expression was maximal and present only in differentiating glomerular epithelial cells. CTGF protein was also present on precursors of mesangium and glomerular endothelium, suggesting possible paracrine interaction. Concomitant with the presence of TGF-beta(2) and -beta(3) protein, and in the absence of TGF-beta(1), CTGF mRNA and protein expression was restricted to podocytes in normal adult glomeruli. However, TGF-beta(1) and CTGF were again coexpressed, often with TGF-beta(2) and -beta(3), in particular in podocytes in proliferative glomerulonephritis and also in mesangial cells in diabetic nephropathy and IgA nephropathy (IgA NP). Coordinated expression of TGF-beta isoforms and of CTGF may be involved in normal glomerulogenesis and possibly in maintenance of glomerular structure and function at adult age. Prolonged overexpression of TGF-beta(1) and CTGF is associated with development of severe glomerulonephritis and glomerulosclerosis.

Geriatric nutritional risk index accurately predicts cardiovascular mortality in incident hemodialysis patients

BACKGROUND Cardiovascular disease (CVD) is a leading cause of death in end-stage renal disease (ESRD) patients. Protein-energy wasting (PEW) or malnutrition is common in this population, and is associated with increasing risk of mortality. The geriatric nutritional risk index (GNRI) has been developed as a tool to assess the nutritional risk, and is associated with mortality not only in elderly patients but also in ESRD patients. However, whether the GNRI could predict the mortality due to CVD remains unclear in this population. We investigated the prognostic value of GNRI at initiation of hemodialysis (HD) therapy for CVD mortality in a large cohort of ESRD patients. METHODS Serum albumin, body weight, and height for calculating GNRI were measured in 1568 ESRD patients. Thereafter, the patients were divided into quartiles according to GNRI levels [quartile 1 (Q1): < 84.9; Q2: 85.0-91.1; Q3: 91.2-97.2; and Q4: >97.3], and were followed up for up to 10 years. RESULTS GNRI levels independently correlated with serum C-reactive-protein levels (β = -0.126, p < 0.0001). Rates of freedom from CVD mortality for 10 years were 57.9%, 73.3%, 80.8%, and 89.2% in Q1, Q2, Q3, and Q4, respectively (p < 0.0001). The GNRI was an independent predictor of CVD mortality (hazard ratio 3.42, 95% confidence interval 2.05-5.70, p < 0.0001 for Q1 vs. Q4). C-index was also greater in an established CVD risk model with GNRI (0.749) compared to that with albumin (0.730), body mass index (0.732), and alone (0.710). Similar results were observed for all-cause mortality. CONCLUSION GNRI at initiation of HD therapy could predict CVD mortality with incremental value of the predictability compared to serum albumin and body mass index in ESRD patients.