Keisuke Maruyama

Malnutrition, renal dysfunction and left ventricular hypertrophy synergistically increase the long-term incidence of cardiovascular events

Although malnutrition indicates an unfavorable prognosis in some clinical settings, the synergistic impact of nutritional state, renal dysfunction and left ventricular hypertrophy (LVH) on cardiovascular events is unknown. Among 338 patients aged 40–80 years who underwent echocardiographic evaluation between 2003 and 2005, 161 patients who were followed for >7 years were recruited. Malnutrition was defined as a geriatric nutritional risk index (GNRI) of ⩽96. The mean patient age was 63.5±9.2 years; the mean estimated glomerular filtration rate (eGFR) was 72.9±18.7 ml min−1 per 1.73 m2; the mean LV mass index was 114±33 g m−2; and the mean GNRI was 100.4±6.0. Among the patients, 25% (n=40) had an eGFR of <60 ml min−1 per 1.73 m2, 29% (n=46) exhibited chronic kidney disease (CKD) and 37% (n=59) had LVH. During the follow-up period (median: 96 months), cardiovascular events were observed in 15 patients (9%). Kaplan–Meier curves showed a significantly higher incidence of cardiovascular events in patients with an eGFR of <60 ml min−1 per 1.73 m2 (log-rank P=0.007), a GNRI of ⩽96 (P=0.003) or LVH (P=0.010). In a Cox regression analysis, eGFR, LVH and GNRI were independent determinants of cardiovascular event incidence after adjusting for age, gender and the presence of hypertension and diabetes. Furthermore, the combination of LVH and lower GNRI was significantly associated with a higher rate of cardiovascular events not only in all patients but also in patients with CKD. In conclusion, malnutrition, low eGFR and LVH were independent determinants of cardiovascular event incidence; they synergistically increased rates of these events in the long term. The evaluation and management of LVH progression and the improvement of nutritional status are critical for preventing cardiovascular complications even in non-dialysis patients.

Apoptosis‐Resistant Cardiac Progenitor Cells Modified With Apurinic/Apyrimidinic Endonuclease/Redox Factor 1 Gene Overexpression Regulate Cardiac Repair After Myocardial Infarction

Overcoming the insufficient survival of cell grafts is an essential objective in cell‐based therapy. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE1) promotes cell survival and may enhance the therapeutic effect of engrafted cells. The aim of this study is to determine whether APE1 overexpression in cardiac progenitor cells (CPCs) could ameliorate the efficiency of cell‐based therapy. CPCs isolated from 8‐ to 10‐week‐old C57BL/6 mouse hearts were infected with retrovirus harboring APE1‐DsRed (APE1‐CPC) or a DsRed control (control‐CPC). Oxidative stress‐induced apoptosis was then assessed in APE1‐CPCs, control‐CPCs, and neonatal rat ventricular myocytes (NRVMs) cocultured with these CPCs. This analysis revealed that APE1 overexpression inhibited CPC apoptosis with activation of transforming growth factor β‐activated kinase 1 (TAK1) and nuclear factor (NF)‐κB. In the coculture model, NRVM apoptosis was inhibited to a greater extent in the presence of APE1‐CPCs compared with control‐CPCs. Moreover, the number of surviving DsRed‐positive CPC grafts was significantly higher 7 days after the transplant of APE1‐CPCs into a mouse myocardial infarction model, and the left ventricular ejection fraction showed greater improvement with attenuation of fibrosis 28 days after the transplant of APE1‐CPCs compared with control‐CPCs. Additionally, fewer inflammatory macrophages and a higher percentage of cardiac α‐sarcomeric actinin‐positive CPC‐grafts were observed in mice injected with APE1‐CPCs compared with control‐CPCs after 7 days. In conclusion, antiapoptotic APE1‐CPC graft, which increased TAK1‐NF‐κB pathway activation, survived effectively in the ischemic heart, restored cardiac function, and reduced cardiac inflammation and fibrosis. APE1 overexpression in CPCs may serve as a novel strategy to improve cardiac cell therapy.

Minimal Change Nephrotic Syndrome Associated with Gefitinib and a Successful Switch to Erlotinib

Minimal change nephrotic syndrome (MCNS) is a common form of nephrotic syndrome (NS). We herein present the case of a 57-year-old woman with advanced lung adenocarcinoma treated with the tyrosine kinase inhibitor (TKI) gefitinib who developed NS. A renal biopsy revealed minor glomerular abnormalities, and the patients symptoms improved exclusively with the discontinuation of gefitinib. Therefore, we diagnosed her with MCNS associated with gefitinib treatment. A few months later, however, she developed recurrent lung tumors. Following the challenging initiation of the TKI erlotinib, she achieved remission without proteinuria. We thus conclude that erlotinib is a potential treatment option in patients with NS associated with gefitinib therapy.

Malnutrition Increases the Incidence of Death, Cardiovascular Events, and Infections in Patients with Stroke after Rehabilitation

BACKGROUND Although the impact of malnutrition in patients with acute stroke has been reported, its significance after rehabilitation is not well understood. The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional screening tool that predicts poor prognosis in elderly patients and in those with a high risk of cardiovascular events. We investigated the associations between GNRI and all-cause mortality, cardiovascular events, and infectious diseases in patients with stroke after rehabilitation. METHODS This study included 138 patients aged 80 years or below who were discharged between 2010 and 2013 in a single center, and followed up for more than 1 year. Malnutrition was defined as a GNRI of 96 or lower. RESULTS The mean age was 63.9 ± 11.0 years,  the mean GNRI at discharge was 98.8 ± 6.5, and the mean total functional independence measure (FIM) score at discharge was 91.8 ± 25.8. Among the patients, 37 (27%) had malnutrition. During the follow-up period, all-cause mortality, cardiovascular events, and infectious diseases were recorded in 11 (8%), 21 (15%), and 20 (15%) patients, respectively. Kaplan-Meier curves showed a significantly higher incidence of each outcome in patients with a GNRI of 96 or lower. In the Cox proportional analysis, GNRI was an independent determinant of all-cause mortality (hazard ratio [HR], .71; 95% confidence interval [CI], .61-.83), cardiovascular events (HR, .87; 95% CI, .80-.95), and infectious diseases (HR, .80; 95% CI, .74-.87) after adjusting for age, gender, and total FIM score. CONCLUSIONS Malnutrition has a negative impact on prognosis in patients with stroke even after rehabilitation.

Pazopanib-induced Endothelial Injury with Podocyte Changes

Pazopanib has been reported to induce proteinuria; however, no pathological findings have been reported. We herein report the case of a 31-year-old man with rhabdomyosarcoma treated with pazopanib who developed nephrotic syndrome. A renal biopsy revealed endothelial injury with podocyte changes. Based on the biopsy findings, we diagnosed the patient with nephrotic syndrome caused by pazopanib. Following the discontinuation of pazopanib, the patients proteinuria gradually decreased without any specific treatment. We should be careful when encountering drug-induced proteinuria in patients taking pazopanib.

Hemocholecyst complicated in a hemodialysis patient with microscopic polyangiitis.

Microscopic polyangiitis (MPA) is a systemic vasculitis associated with antineutrophil cytoplasmic antibodies, and it involves multiple organs, including the kidneys and lungs. We report on the case of a 72-year-old woman with MPA who developed hemocholecyst in addition to alveolar hemorrhage and rapidly progressive glomerulonephritis. Although her renal function was not salvaged, the alveolar hemorrhage and hemocholecyst were treated conservatively. Clinicians should consider the possibility of hemocholecyst in patients with MPA complaining of abdominal pain.

OS 19-05 COMBINATION OF ARB AND NIFEDIPINE CR REDUCES MICROALBUMINURIA IN ASSOCIATION WITH REDUCTION OF SERUM URIC ACID: SUB-ANALYSIS OF NICE-COMBI STUDY.

Objective: Uric acid is a risk factor for cardiovascular disease. We investigated the relationship between the change of urinary albumin excretion (UAE) and the changes of serum uric acid (SUA) during antihypertensive treatment in hypertensive patients with microalbuminuria as a subanalysis of the results of the NICE Combi (Nifedipine and Candesartan Combination) Study. Design and Method: A total of 86 subjects with essential hypertension with microalbuminuria (UAE < 300 mg•g-1 creatinine) were randomly assigned in a double-blind manner to a combination therapy group (standard-dose candesartan at 8 mg/day plus controlled-release (CR) nifedipine 20 mg/day) (n = 42) or an up-titrated monotherapy group (candesartan 12 mg/day) (n = 44) for 8 weeks of continuous treatment after initially receiving standard-dose candesartan (8 mg/day) monotherapy for 8 weeks (initial treatment). Results: After 8weeks, blood pressure was significantly reduced in both groups compared with at the end of initial treatment. The UAE was significantly reduced only in the N group (N group: 56.7 ⇒ 31.0 mg/gCr, P = 0.02, A group: 51.1 ⇒ 55.1 mg/gCr, NS). The SUA was not reduced in both groups, whereas reduction of SUA after 8 weeks of double-blind treatment was significantly and positively correlated with reduction of UAE and diastolic blood pressures after 8 weeks of double-blind treatment only in the N group. Conclusions: These findings show that combination therapy with standard-dose candesartan and nifedipine CR is more effective than up-titrated candesartan monotherapy for reducing blood pressure and improving UAE in accordance with SUA, and strongly suggest that the combination of an angiotensin II receptor blocker and long-acting calcium channel blocker is beneficial in hypertensive patients with microalbuminuria and hyperuricemia.

PS 05-37 MALNUTRITION, RENAL DYSFUNCTION, AND LEFT VENTRICULAR HYPERTROPHY SYNERGISTICALLY INCREASE THE LONG-TERM INCIDENCE OF CARDIOVASCULAR EVENTS

Objective: This study investigated the impact of malnutrition, low estimated glomerular filtration rate (eGFR) and left ventricular hypertrophy (LVH) on cardiovascular events in a long-term observational study. Design and Method: Among 338 patients aged 40–80 years who underwent echocardiographic evaluation between 2003 and 2005, 161 patients followed up for >7 years were recruited. Echocardiographic LVH was defined as left ventricular mass index (LVMI) ≥ 125 g/m2 for men and ≥ 110 g/m2 for women. The geriatric nutritional risk index (GNRI) was used to assess the nutritional status of the patients and was calculated using the following formula: GNRI = (14.89 × serum albumin) + [41.7 × (body weight / body weight at BMI of 22)]. Malnutrition was defined as GNRI ⩽ 96. Results: Mean age was 63.5 ± 9.2 years, mean eGFR: 72.9 ± 18.7 ml/min/1.73m2, mean GNRI: 100.4 ± 6.0 and mean LVMI: 114 ± 33 g/m2. The number of patients with eGFR <60 ml/min/1.73m2, GNRI ⩽ 96 and LVH was 40 (25%), 32 (20%) and 59 (37%), respectively. During the follow-up period (median: 95 months), cardiovascular events were recorded in 15 patients (9%), including 7 acute coronary syndromes, 4 heart failures, 2 strokes, 1 aortic dissection and 1 aortic rupture. Kaplan-Meier curves showed a significantly higher incidence in patients with eGFR < 60 mL/min/1.73m2 (log rank P = 0.007), GNRI ⩽ 96 (P = 0.003), or LVH (P = 0.010) (Figure 1). In Cox proportional hazards analysis, Age, eGFR, LVH, and GNRI were sifnificantly associated with cardiovascular events after adjusting for gender, hemoglobin level, and the prevalence of hypertension and diabetes (Table 1). Conclusions: Malnutrition, low eGFR, and LVH were independent determinants of cardiovascular events; they synergistically increased rates of these events in the long term. It is important to evaluate and manage the progression of LVH and improve nutritional status even in non-dialysis patients.

PS 11-19 IMPACT OF MALNUTRITION ON ALL-CAUSE MORTALITY AND CARDIOVASCULAR EVENTS IN PATIENTS WITH ACUTE STROKE

Objective: This study investigated the impact of malnutrition on all-cause mortality and cardiovascular events in patients with acute stroke in an observational study. Design and Method: Among 140 patients aged 40–80 years who had acute stroke and were admitted for rehabilitation in Asahikawa Rehabilitation Hospital between 2010 and 2011, 48 patients followed up for more than 1 year after discharge were recruited. The geriatric nutritional risk index (GNRI) was used to assess the nutritional status of the patients and was calculated using the following formula: GNRI = (14.89 × serum albumin) + [41.7 × (body weight / body weight at BMI of 22)]. Malnutrition was defined as GNRI ⩽96 at discharge. Results: Mean age was 66.0 ± 8.7 years; mean systolic blood pressure was 132.8 ± 13.7 mmHg; and mean GNRI was 97.8 ± 6.9. The number of patients with GNRI ⩽96 was 15 (31%). During the follow-up period (median: 60 months), 4 patients (8.3%) died. Three of them died of infection and 1 of them died of cardiopulmonary arrest. Eleven patients had cardiovascular events (22.9%) including 7 strokes, 3 heart failures and 1 acute coronary syndrome. Kaplan-Meier curves showed a significantly higher all-cause mortality in patients with GNRI ⩽96 (log rank P = 0.027), whereas it did not show a significant difference in cardiovascular events between patients with GNRI ⩽96 and > 96. In Cox regression analysis, GNRI is an independent determinant of all cause mortality after adjusting for age, gender, and systolic blood pressure. Conclusions: Malnutrition is an independent determinant of all-cause mortality in patients with stroke, suggesting that it is important to evaluate and manage the nutritional status in those patients.

PS 11-13 IMPACT OF MALNUTRITION AND MARKERS OF VASCULAR CALCIFICATION ON THE LEFT VENTRICULAR HYPERTROPHY IN HEMODIALYSIS PATIENTS

Objective: This study investigated the impact of malnutrition and various markers of vascular calcification on left ventricular hypertrophy (LVH) in hemodialysis patients. Design and Method: We recruited 60 hemodialysis patients (43 men and 17 women, mean age: 64.5 ± 12.6 years), and measured their serum fetuin-A, osteoprotegerin, osteopontin, arterial stiffness, and echocardiographic parameters, and then analyzed the relationships of these variables. The geriatric nutritional risk index (GNRI) was used to assess the nutritional status of the patients and was calculated using the following formula: GNRI = (14.89 × serum albumin) + [41.7 × (body weight/body weight at BMI of 22)]. Malnutrition was defined as GNRI ⩽96 based on our previous report (Nakagawa N, et al. Ther Apher Dial. 19:30–39, 2015). Results: Mean systolic blood pressure was 144.7 ± 23.2 mmHg, mean pulse pressure 69.1 ± 19.9 mmHg, mean GNRI 94.6 ± 8.0, mean brachial-ankle pulse wave velocity (baPWV) 2132 ± 607 cm/s, and mean LV mass index (LVMI) 126 ± 39 g/m2. GNRI was significantly and positively correlated with fetuin-A, and negatively with age, pulse pressure, osteopontin, baPWV, LVMI, and E/E’. When GNRI was divided at 96, the patients with lower GNRI had significantly lower fetuin-A, and higher osteoprotegerin, LVMI and baPWV compared with those with higher GNRI. In a stepwise multiple regression analysis, GNRI was an independent determinant of LVMI (&bgr; = −0.455, P = 0.002) after adjusting for age, pulse pressure and hemoglobin. Malnutirition positively reflected an increased vascular stiffness leading to an aggravation of LVH. Conclusions: Malnutrition was independent determinants of LVH in association with fetuin-A, osteopontin and vascular stiffness, suggesting that the assessment and improving the nutritional status are important for retarding the progression of LVH through mediating the balance of the tissue calcification regulators in hemodialysis patients.