Hiroki Hase

Expression of ACE and ACE2 in Individuals With Diabetic Kidney Disease and Healthy Controls

BACKGROUND Angiotensin-converting enzyme (ACE) 2 (ACE2) is expressed mainly in the heart and kidney and forms angiotensin-1-7 from angiotensin II. ACE2 might act in a counterregulatory manner to ACE. There is little information about renal ACE and ACE2 expression in human diabetic nephropathy. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS Kidney tissue from 20 patients with type 2 diabetes and overt nephropathy and 20 healthy kidney donors. PREDICTOR Diabetes status. OUTCOMES & MEASUREMENTS Renal expression of ACE and ACE2 assessed by means of immunohistochemistry and in situ hybridization. Correlation between ACE and ACE2 expression and levels of various biochemical parameters. RESULTS Decreased ACE2 and increased ACE expression in both the tubulointerstitium and glomeruli resulted in a significant (P < 0.001) increase in ACE/ACE2 ratio in patients with diabetes with overt nephropathy compared with controls, although ACE messenger RNA in the tubulointerstitium did not significantly increase. ACE/ACE2 ratio correlated positively with values for mean blood pressure, fasting blood glucose, serum creatinine, proteinuria, and hemoglobin A(1c) and inversely with estimated glomerular filtration rate (P < 0.001). LIMITATIONS Inclusion of small number of human renal biopsy specimens with structural distortion of cortical tissue. CONCLUSIONS The high ACE/ACE2 ratio in kidneys of patients with type 2 diabetes with overt nephropathy may contribute to renal injury.

Association between hemoglobin variability, serum ferritin levels, and adverse events/mortality in maintenance hemodialysis patients

In recent times, therapy for renal anemia has changed dramatically in that iron administration has increased and doses of erythropoiesis-stimulating agents (ESAs) have decreased. Here we used a prospective, observational, multicenter design and measured the serum ferritin and hemoglobin levels every 3 months for 2 years in 1086 patients on maintenance hemodialysis therapy. The associations of adverse events with fluctuations in ferritin and hemoglobin levels and ESA and iron doses were measured using a Cox proportional hazards model for time-dependent variables. The risks of cerebrovascular and cardiovascular disease (CCVD), infection, and hospitalization were higher among patients who failed to maintain a target-range hemoglobin level and who exhibited high-amplitude fluctuations in hemoglobin compared with patients who maintained a target-range hemoglobin level. Patients with a higher compared with a lower ferritin level had an elevated risk of CCVD and infectious disease. Moreover, the risk of death was significantly higher among patients with high-amplitude ferritin fluctuations compared with those with a low ferritin level. The risks of CCVD, infection, and hospitalization were significantly higher among patients who were treated with high weekly doses of intravenous iron compared with no intravenous iron. Thus, there is a high risk of death and/or adverse events in patients with hemoglobin levels outside the target range, in those with high-amplitude hemoglobin fluctuations, in those with consistently high serum ferritin levels, and in those with high-amplitude ferritin fluctuations.

Japanese Society for Dialysis Therapy Guidelines for Management of Cardiovascular Diseases in Patients on Chronic Hemodialysis

Hideki Hirakata, Kosaku Nitta, Masaaki Inaba, Tetsuo Shoji, Hideki Fujii, Shuzo Kobayashi, Kaoru Tabei, Nobuhiko Joki, Hiroki Hase, Masato Nishimura, Shigeyuki Ozaki, Yuji Ikari, Yoshitaka Kumada, Kazuhiko Tsuruya, Shouichi Fujimoto, Tohru Inoue, Hiroyoshi Yokoi, Sumio Hirata, Kazuaki Shimamoto, Kiyotaka Kugiyama, Takashi Akiba, Kunitoshi Iseki, Yoshiharu Tsubakihara, Tadashi Tomo, and Tadao Akizawa

Association Between Abnormal Myocardial Fatty Acid Metabolism and Cardiac-Derived Death Among Patients Undergoing Hemodialysis: Results From a Cohort Study in Japan

BACKGROUND Detecting myocardial ischemia in hemodialysis patients is crucial given the high incidence of silent ischemia and the high cardiovascular mortality rates. Abnormal myocardial fatty acid metabolism as determined by imaging with (123)I-labeled BMIPP (β-methyl iodophenyl-pentadecanoic acid) might be associated with cardiac-derived death in hemodialysis patients. STUDY DESIGN Prospective observational study. SETTING & PARTICIPANTS Asymptomatic hemodialysis patients with one or more cardiovascular risk factors, but without known coronary artery disease, were followed up for 3 years at 48 Japanese hospitals (406 men, 271 women; mean age, 64 years). PREDICTOR Baseline BMIPP summed scores semiquantified using a 17-segment 5-point system (normal, 0; absent, 4). OUTCOMES Cardiac-derived death, including cardiac and sudden death. MEASUREMENTS HRs were estimated using a Cox model for associations between BMIPP summed scores and cardiac-derived death, adjusting for potential confounders of age, sex, body mass index, dialysis duration, and cardiovascular risk factors. RESULTS Rates of all-cause mortality and cardiac-derived death were 18.5% and 6.8%, respectively. Cardiac-derived death (acute myocardial infarction [n = 10], congestive heart failure [n = 13], arrhythmia [n = 2], valvular heart disease [n = 1], and sudden death [n = 20]) accounted for 36.8% of all-cause deaths. Cardiac-derived death (n = 46) was associated with age, history of heart failure, and BMIPP summed scores of 4 or higher (HR, 2.9; P < 0.001). Three-year cardiac-derived death-free survival rates were 95.7%, 90.6%, and 78.8% when BMIPP summed scores were 3 or lower, 4-8, and 9 or higher, respectively. BMIPP summed score also was a predictor of all-cause death (HR, 1.6; P = 0.009). LIMITATIONS Sudden death of unknown cause was considered to have been cardiac derived, although a coronary origin was not confirmed. CONCLUSIONS Abnormal myocardial fatty acid metabolism is associated with cardiac-derived death in hemodialysis patients. BMIPP single-proton emission computed tomography appears clinically useful for predicting cardiac-derived death in this population.

Oxygen Uptake Efficiency Slope as Monitoring Tool for Physical Training in Chronic Hemodialysis Patients

Abstract:  The purpose of this study was to clarify the utility of oxygen uptake efficiency slope (OUES) as a monitoring tool, and to investigate the effects of physical training in chronic hemodialysis (HD) patients. Seventeen patients (Trained Group) received physical training 2–3 times per week for 20 weeks at the intervals between exercise tests. Patients underwent a combination training of bicycle ergometry, walking and jogging for 30 min duration. The intensity of physical training was adjusted to maintain the exercising heart rate at between 50 and 60% of the peak heart rate. Twelve patients (Control Group) lived without physical training throughout the 20 weeks. Both the Groups received the symptom limited exercise tests before and after the 20 week physical training. Minute ventilation (V̇E), carbon dioxide output (V̇CO2) and oxygen uptake (V̇O2) were continuously measured during the exercise tests. Oxygen uptake efficiency slope was derived from the logarithmic relation between V̇O2 and V̇E during an incremental exercise test. In the Trained Group, OUES after physical training (30.1 ± 5.8) was significantly (P < 0.01) higher than that before physical training (25.2 ± 2.6), while in the Control Group, OUES did not change in this study period of 20 weeks. In the Trained Group, changes in OUES correlated with those in the maximum oxygen uptake (r = 0.78, P < 0.001) and the anaerobic threshold (r = 0.61, P < 0.01). It was suggested that OUES was applicable as a monitoring tool for cardiorespiratory functional reserve during physical training in HD patients.

Calcaneal Osteopenia Is a New Marker for Arterial Stiffness in Chronic Hemodialysis Patients

Background: A high frequency of simultaneous low estimated bone mineral density (BMD) and atherosclerotic vascular disease is found in chronic dialysis patients. The degree of BMD may be closely related to the severity of atherosclerosis in dialysis patients. The purpose of this study was to determine the association of estimated BMD with severity of atherosclerosis using popular economical non-invasive strategies in chronic dialysis patients. Methods: This cross-sectional design study included 58 subjects receiving maintenance hemodialysis (HD) therapy. The mean age was 68 ± 12 years (range 39–93), 22 subjects were female, and 26 subjects (45%) had diabetic nephropathy. The brachial-ankle pulse wave velocity (baPWV) and estimated BMD, using calcaneal quantitative ultrasound measurements of the osteo-sono index (OSI) were measured in all of the subjects. Results: The mean levels of OSI and baPWV were 2.3 ± 0.3 and 21 ± 5 m/s, respectively. Based on single variable regression analysis, the C-reactive protein concentration correlated with baPWV (r = 0.272, p = 0.039), and the serum albumin concentration was inversely correlated with baPWV (r = –0.318, p = 0.015). In addition, OSI had a strong negative correlation with baPWV (r = –0.470, p = 0.0002). To identify the independent factors correlating with baPWV, multivariate regression analysis was performed using confounding variables which had significant association in univariate analysis. OSI and diabetic nephropathy were found to be significant independent parameters. Conclusion: Calcaneal OSI, a surrogate marker for estimated BMD, has a strong ability to predict the severity of arterial stiffness independent of classical risk factors and markers of inflammation and malnutrition.

Angiographical severity of coronary atherosclerosis predicts death in the first year of hemodialysis

Background: Cardiac deaths andevents tend to cluster within the early-phaseafter starting dialysis. Our goal is toclarify the influence of severity of coronaryatherosclerosis on early-phase death afterstarting hemodialysis (HD) therapy. Patients and Methods: Eighty-threeconsecutive patients [mean age 62 years;male/female 64/19; diabetic nephropathy in 50(54%)] with end-stage renal disease whoadmitted to our hospital to initiate regular HDtreatment, and then received coronaryangiography within 3 months after firstdialysis therapy, were eligible for this study. Angiographical severity of coronaryatherosclerosis was scored by numerically usingGensini scoring system. The patients who diedwithin one year from starting HD were comparedwith those who survived as control by means oflogistic regression analysis.Results: Of 83 patients, 12 (14%) died lessthan one year after starting dialysis therapy. Of these 12 patients, nine died for cardiaccauses. Confirmed predictors of death fromcardiac cause were older age (>70 years),lower mean blood pressure (<100 mmHg),presence of ischemic heart disease (IHD),myocardial infarction (MI), angina pectoris(AP), chronic heart failure (CHF), poor cardiacfunction, abnormal wall motion of leftventricule (LV) and angiographical severity ofcoronary atherosclerosis by univariate model. Adjusting for confounding variables bymultivariate model, only severity of coronaryatherosclerosis (Gensini score >40 points)had a powerful influence, increasing risk forcardiac cause of early-phase death by about 17times. Conclusions: Severity ofcoronary atherosclerosis predicts death in thefirst year of HD. These findings suggest thatthe strategy for prevention of coronaryatherosclerosis should be instituted during theearly phase of chronic renal failure.

Increased ACE and decreased ACE2 expression in kidneys from patients with IgA nephropathy.

Background: Angiotensin-converting enzyme (ACE)2 forms angiotensin-1–7 which may protect kidney in a counterregulatory manner to angiotensin II. Recent studies revealed increased ACE and decreased ACE2 expression in kidneys of patients with diabetic nephropathy. However, these changes may not be specific for diabetic nephropathy. We studied ACE and ACE2 expression in patients with IgA nephropathy. Methods: Renal ACE and ACE2 expression was assessed by immunohistochemistry and in situ hybridization in 30 patients with IgA nephropathy and 21 healthy controls. Correlation between ACE and ACE2 expression and levels of various biochemical parameters was also assessed. Gene expression was also assessed in minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN) as disease controls. Results: Reduced ACE2 expression (p < 0.01) and increased ACE expression in glomeruli (p < 0.001), and reduced ACE2 expression in tubulointerstitium (p < 0.001) were observed in patients with IgA nephropathy compared to healthy controls, although the changes in ACE2 mRNA were not statistically significant. Reduced renal ACE2 expression was also found in MN but not in MCNS. Correlation between renal ACE and ACE2 expression and proteinuria was not observed in IgA nephropathy. Conclusion: IgA nephropathy is associated with increased ACE and decreased ACE2 expression in kidneys, as in diabetic nephropathy.

The impact of chronic kidney disease as a predictor of major cardiac events in patients with no evidence of coronary artery disease

BACKGROUND Normal stress myocardial perfusion images (MPI) generally show good prognosis for cardiovascular events. However, chronic kidney disease (CKD) is one of the important risk factors for coronary artery disease (CAD), and the interpretation of normal stress MPI has not been well established in CKD patients with no evidence of CAD. The purpose of this study was to evaluate the long-term prognostic value of stress MPI in CKD patients with no evidence of myocardial ischemia or infarction. METHODS Patients who had no history but were suspected of CAD and had normal stress MPI (n=307, male=208, age=67 years, CKD/non-CKD=46/261) were followed-up for 4.5 years. CKD was defined as a glomerular filtration ratio of <60 ml/min/1.73 m(2) and/or persistent proteinuria. Cardiac death, non-fatal myocardial infarction, and unstable angina requiring hospitalization were defined as major cardiac events. RESULTS Major cardiac events were observed in 3 of 261 (1.1%) non-CKD patients and 6 of 46 (13%) CKD patients (p<0.001, with log-rank test). CKD was an independent risk factor for major cardiac events (hazard ratio=13.1, p<0.001, multivariate Cox regression analysis). CONCLUSIONS Normal stress MPI does not always promise a good prognosis for major cardiac events. Even in patients with no evidence of CAD from stress MPI, CKD can be an independent and significant risk factor for major cardiac events.

A suspected case of paradoxical renal embolism through the patent foramen ovale.

We experienced a case of cryptogenic renal infarction in a previously healthy 60-year-old man. He had no systemic atherosclerotic changes. Holter monitoring revealed no atrial fibrillation. Transthoracic echocardiography showed no thrombus. Because the onset occurred while he was swinging a golf club (a similar maneuver to holding the breath), further examination was performed with a view to detecting paradoxical embolism through the foramen ovale. A positive bubble test with the Valsalva maneuver during transesophageal echocardiography led to the diagnosis of patent foramen ovale (PFO). This was a suspected case of paradoxical embolism through a PFO leading to renal infarction.