Nobuhiko Joki

Effect of simvastatin in apolipoprotein E deficient mice with surgically induced chronic renal failure.

PURPOSE Patients with a surgically reduced renal mass are at increased risk for progressive renal failure, which often requires renal replacement therapy or kidney transplantation. We investigated the effects of simvastatin supplementation on uremia enhanced atherosclerosis and vascular calcification in apoE(-/-) (apolipoprotein E deficient) mice (Charles Rivers Laboratories, Wilmington, Massachusetts) with or without superimposed chronic kidney disease. MATERIALS AND METHODS The mice were randomly assigned to 4 groups, including 2 groups with normal renal function (simvastatin vs control in 13 mice) and the other 2 with surgically created chronic kidney disease (simvastatin vs control in 18). Simvastatin (100 mg/kg) was administered by daily oral gavage for 4 weeks. RESULTS Simvastatin treatment did not prevent uremia accelerated atherosclerosis in chronic kidney disease apoE(-/-) mice, nor did it retard atherosclerosis progression in control nonchronic kidney disease mice. However, aortic plaques in simvastatin treated chronic kidney disease mice showed significantly less calcification than those in controls with chronic kidney disease (p <0.03). In addition, the increase of aortic nitrotyrosine staining in mice with chronic kidney disease was prevented by simvastatin treatment (p <0.02). Serum total cholesterol was increased to a similar extent in the 2 chronic kidney disease groups compared with that in the nonchronic kidney disease groups. The beneficial effect of simvastatin on uremia enhanced vascular calcification in apoE(-/-) mice with chronic kidney disease was observed despite the absence of changes in uremia accelerated atherosclerosis progression, serum total cholesterol levels or osteopontin and alkaline phosphatase expression. CONCLUSIONS Our observation opens the possibility of a cholesterol independent action of statins on vascular calcification via a decrease in oxidative stress.

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.

Tissue Accumulation of Lanthanum as Compared to Aluminum in Rats with Chronic Renal Failure – Possible Harmful Effects after Long-Term Exposure

Background: Lanthanum (La) carbonate is a new treatment for hyperphosphatemia. We tested the effects of oral La carbonate and aluminum hydroxide, respectively, on tissue accumulation and liver function in rats with chronic renal failure (CRF). Methods: Adult male non-CRF and CRF rats were randomly assigned to 3 groups receiving either standard diet (St.D), or the same diet supplemented with 3% La carbonate (non-CRF La vs. CRF La) or 3% aluminum hydroxide (non-CRF Al vs. CRF Al). Results: After 12 weeks, serum phosphorus was decreased in both CRF La and Al groups. Urinary La and Al excretion was increased in these two groups, and so was liver and bone La content, and liver Al content. Both total body and liver weight were decreased in CRF La and CRF Al rats. Liver cell proliferation was decreased in these groups, while plasma total alkaline phosphatases and alanine aminotransferase were increased. Hepatic total cytochrome p450 content was reduced in CRF La, but not in CRF Al rats. Conclusion: Long-term oral La overload in rats with CRF was associated with a decrease in liver (and total body) weight and mild alterations of liver function, as was Al overload, possibly as a consequence of trace element accumulation.

Significance of Serum Magnesium as an Independent Correlative Factor on the Parathyroid Hormone Level in Uremic Patients

CONTEXT PTH is a critical factor in mineral homeostasis, and chronic kidney disease mineral and bone metabolism disorder is a very important problem in patients with renal failure. Abnormal levels of PTH, serum phosphate, and calcium influence chronic kidney disease mineral and bone metabolism disorder, but there is little information about the influence of magnesium (Mg) on PTH. OBJECTIVE The aim of this study was to elucidate the correlation between magnesium and PTH levels in uremic patients just prior to beginning hemodialysis (HD) for the first time. PATIENTS We enrolled 1231 patients in nine Japanese facilities who had begun HD for end-stage renal disease. We investigated their serum Mg levels and the correlation between intact PTH (iPTH) and the serum Mg levels and other clinical parameters and medications. RESULTS The mean serum Mg was 2.2 ± 0.5 mg/dL, and hypermagnesemia was found in 663 patients (53.9%). Divided into two groups according to median iPTH level, the serum Mg levels were significantly higher in patients with low iPTH (2.3 ± 0.5 vs 2.1 ± 0.5, P < .01). Furthermore, divided into two groups according to the Mg level, iPTH levels were lower in patients with high Mg than in patients with normal serum Mg levels (277.9 ± 195.9 pg/mL vs 321.9 ± 203.7 pg/mL, P < .01). In the multiple regression analysis according to the effect of iPTH level, the serum Mg level was an independent variable after adjustment for other factors. CONCLUSIONS A high serum level of Mg is frequent in uremic patients with end-stage renal disease just prior to beginning HD. In the present set of patients, there was a significant correlation between the serum Mg and iPTH levels. Furthermore, the serum Mg level was an independent factor apart from the other factors regulating iPTH. These results suggest that serum Mg may be one of the factors regulating the serum PTH level in uremic patients.

Association between the Hemoglobin Level and Cardiothoracic Ratio in Patients on Incident Dialysis

Background/Aim: The present study explores associations between hemoglobin (Hb) levels and patients with cardiac enlargement in end-stage kidney disease (ESKD) to help prevent cardiac remodeling during the predialysis phase of chronic kidney disease (CKD). Methods: This cross-sectional study included 2,249 patients with ESKD (age, 67 w 13 years; male, 67%; diabetic kidney disease, 41%) who started hemodialysis (HD) between January 2006 and October 2013 at eight participating hospitals. We examined associations between Hb levels immediately before the first HD session and cardiothoracic ratios (CTRs). Clinical factors associated with the CTR were also assessed. Results: The mean Hb level was 8.7 w 1.6 g/dl, and the mean and median CTRs were 55.0 and 54.7%, respectively. The correlation between the Hb level and the CTR was linear and negative (r = -0.129, p < 0.001). The mean CTR and the prevalence of patients with a CTR >50% obviously decreased with increasing Hb levels (both p < 0.001 for trend). Univariate logistic regression analysis revealed an approximately 20% reduction in the odds ratio for complicating CTRs >50% per 1 g/dl increase in Hb. Hb levels of <9 g/dl were significantly associated with CTRs >50%. Numerical and categorical Hb remained significantly associated with CTRs >50% after adjusting for confounding variables. Conclusions: Lower Hb levels participate in progressive CTR enlargement in patients with ESKD, and maintaining Hb levels of >9 g/dl might help prevent cardiac remodeling during the predialysis phase of CKD. i 2014 S. Karger AG, Basel

Combined Assessment of Cardiac Systolic Dysfunction and Coronary Atherosclerosis Used to Predict Future Cardiac Deaths after Starting Hemodialysis

Background/Aims: Identification of end-stage renal disease (ESRD) patients at high risk for cardiac events is important for clinical dialysis management. The present study determined whether the combination of cardiac function and coronary atherosclerosis could predict future cardiac events after starting renal replacement therapy (RRT). Methods: We prospectively assessed left ventricle ejection fraction (EF) and Gensini score (GS) using angiographic severity of coronary atherosclerosis in 88 consecutive ESRD patients [mean age 62 years; 69 males (78%); 55 patients (64%) with diabetic nephropathy] at the initiation of RRT. EF was analyzed by echocardiogram, and GS was scored by coronary angiography within 3 months after starting RRT. The study end point was cardiac death. For analysis of the association between cardiac death and EF and GS measures, the univariate and multivariate Cox proportional hazards model was used. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value, and accuracy of event-free prediction were evaluated. Results: Twenty-four patients (27%) had low cardiac function (EF <50%; low EF) and 44 patients (50%) had severe coronary atherosclerosis (GS >15; high GS). During a follow-up period of 3 years, cardiac death occurred in 21 patients (24%). The PPV of low EF and high GS was 42 and 39%, respectively; the highest PPV (53%) was obtained when low EF and high GS were combined. The cumulative survival rate at 5 years in patients with both low EF and high GS was significantly lower than those with high EF and low GS (91 vs. 22%, p < 0.0005). Conclusion: The combined assessment of cardiac function and coronary atherosclerosis at the initiation of RRT strongly predicts future cardiac events.

Usefulness of an Upright T-Wave in Lead aVR for Predicting the Short-Term Prognosis of Incident Hemodialysis Patients: A Potential Tool for Screening High-Risk Hemodialysis Patients

Background/Aims: An upright T-wave in lead aVR (aVRT) has recently been reported to be associated with cardiovascular death and mortality among the general population and patients with prior cardiovascular disease (CVD). However, evidence for the predictive ability of aVRT in patients with chronic kidney disease is lacking. Therefore, a hospital-based, prospective, cohort study was conducted to evaluate the predictive ability of an upright aVRT for the short-term prognosis in incident hemodialysis patients. Methods: Among 208 patients who started maintenance hemodialysis, 79 with preexisting CVD (CVD cohort) and 129 with no history of CVD (non-CVD cohort), were studied. An upright and non-upright aVRT were defined as a wave with a positive deflection in amplitude of ≥0 mV and a negative deflection in amplitude of <0 mV, respectively. The endpoint was all-cause death. Results: Overall, the prevalence of an upright aVRT was 22.6% at baseline. During the mean follow-up period of 2.1 ± 1.0 years, 33 deaths occurred. Cumulative survival rates at 3 years after starting dialysis in patients with an upright and non-upright aVRT were 50.0 and 80.7%, respectively, in the CVD cohort and 92.0 and 91.3%, respectively, in the non-CVD cohort. In the CVD cohort, multivariate Cox regression analysis showed that an upright aVRT was an independent predictor of death after adjusting for confounding variables. Conclusion: Among Japanese hemodialysis patients at high risk for CVD, an upright aVRT seems to be useful for predicting death.

Increment of monthly mean predialysis heart rate reflects early cardiac overload in hemodialysis patients with normal cardiac function.

BACKGROUND The aim of our study was to examine the association of heart rate (HR) with the onset of congestive heart failure (CHF), and to compare the predictive value of HR with that of the serum level of human atrial natriuretic peptide (hANP) and the cardiothoracic ratio (CTR). METHODS Thirty-eight patients on chronic hemodialysis (HD) aged 68 ± 11 years (61% men, 41% with diabetes) who had normal cardiac function were enrolled in this study. Among them, 6 patients had suffered CHF. Baseline characteristics and HR, hANP and CTR were compared between the 2 groups. RESULTS At baseline, the monthly mean pre-HR (before HD), CTR and hANP values were higher in CHF patients compared with non-CHF patients. In the CHF group, the monthly mean pre-HR increased progressively beginning 10 months before the onset of CHF, which was earlier than the increments of hANP and CTR. A significant difference between the CHF and non-CHF groups was observed earlier for monthly mean pre-HR (4 months before CHF) and ANP (4 months before CHF) than for CTR (2 months before CHF). CONCLUSIONS The increment of monthly mean pre-HR may reflect the early phase of cardiac overload, and is of equal significance to hANP. Further large-scale prospective studies are required to confirm these results.

Association of Lead aVR T-wave Amplitude With Cardiovascular Events or Mortality Among Prevalent Dialysis Patients: ECGs and Mortality During Dialysis

In dialysis patients, electrocardiogram (ECG) abnormalities are common. However, the associations between the T‐wave of the lead aVR (aVRT) amplitude and cardiovascular (CV) events or total mortality are unknown. We performed a prospective, observational cohort study of prevalent hemodialysis patients (N = 474), followed for 4 years. Outcomes were composite CV events and all‐cause mortality. Predictors were baseline aVRT and other ECG findings. ECG parameters were analyzed in three models: model 1, univariate; model 2, basic adjustments; and model 3, model 2 plus serum albumin, C‐reactive protein level, and NT‐proBNP. By Cox analysis, aVRT was best associated with both endpoints through model 1 to 3 compared to other ECG findings. Patients categorized according to aVRT amplitude showed a step‐by‐step increase in hazard ratios for both endpoints. The aVRT amplitude level was significantly associated with not only composite CV events but also with all‐cause mortality in prevalent dialysis patients.

Ischemic Heart Disease in Patients with End-Stage Kidney Disease

Background: It was recently reported that the severity of coronary and carotid atherosclerosis in patients with end-stage kidney disease (ESKD) has improved over the last two decades. However, the frequency of coronary artery events observed at the initiation of dialysis remains high. Summary: Recently, 5 different clinical types of acute myocardial infarction (MI) were introduced in the third universal definition of MI. Type 2 MI, known as secondary MI, is a more heterogeneous entity, where a condition other than coronary artery narrowing contributes to an acute imbalance in oxygen supply and demand. In patients with chronic kidney disease, it has been demonstrated that type 2 MI is more common than type 1 MI, which is associated with coronary occlusive disease. It is suspected that patients with ESKD also often have type 2 MI. Factors associated with incremental increases in oxygen demand may cause myocardial ischemia in ESKD. Key Messages: Significant epicardial coronary narrowing might not be a necessary precursor of myocardial ischemia in ESKD. To prevent ischemic heart disease and improve prognosis in patients with ESKD, we need to pay attention not only to coronary stenotic lesions, but also to the factors associated with the induction of an imbalance in myocardial oxygen supply and demand.