Predictors of Survival in Chronic Hemodialysis Patients: A 10-Year Longitudinal Follow-Up Analysis.

BACKGROUND: Risk factors of mortality in chronic hemodialysis patients have not yet been sufficiently evaluated. In particular, chronological transits and interactions of the impact of risk factors have rarely been described. METHODS: This study is a post hoc analysis of the participants in the Olme-sartan Clinical Trial in Okinawan Patients under OKIDS (OCTOPUS) study conducted between June 2006 and June 2011. We additionally followed up on the prognosis of the participants until July 31, 2018. Standardized univariable and multivariable Cox regression analyses were used to evaluate the influences of the participants' baseline characteristics on all-cause mortality. We also evaluated chronological changes in the impacts of risk factors, interactions among predictors, and the influence of missing values using sensitivity analyses. RESULTS: Of the 469 original trial participants, 461 participants were evaluated. The median time of follow-up was 10.2 years. A total of 211 (45.8%) participants were deceased. The leading causes of death were infection (n = 72, 34.1%) and cardiovascular disease (n = 66, 31.3%). Univariate and multivariate Cox regression analyses revealed that the impact of diabetes mellitus, history of coronary intervention, and hypoalbuminemia were significant risk factors for mortality during the whole follow-up period. During the early follow-up period (≤3 years), standardized univariate Cox regression analyses revealed that history of amputation (hazard ratio [HR] = 4.61, p < 0.001), lower dry weight, higher cardiothoracic ratio, and lower potassium levels were statistically significant risks. In those who survived for longer than 3 years, a history of stroke (HR = 1.73, p = 0.006), higher systolic blood pressure, lower serum sodium levels, and higher levels of hemoglobin, and serum phosphate were significant risks. We also observed a stable interaction between the impacts of serum phosphate and albumin on all-cause mortality. CONCLUSION: In chronic hemodialysis patients, targets to improve the short-term prognosis and long-term prognosis are not equivalent. Hyperphosphatemia was a significant risk factor for the all-cause mortality among patients with normal serum albumin levels but not among patients with compromised albumin levels.

Chronic kidney disease, inflammation, and cardiovascular disease risk in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA), a prototypic systemic autoimmune inflammatory condition, confers an increased risk of cardiovascular disease (CVD). Recently, chronic kidney disease (CKD) was suggested to increase the risk of CVD in RA patients, and inflammation was identified as a critical, nontraditional CKD-associated risk factor for CVD. This study aimed to examine the combined effects of CKD and CVD in RA patients. METHODS: In this retrospective evaluation of 428 RA patients, the outcome of interest was the incidence of CVD. CKD was defined as an estimated glomerular filtration rate of <60mL/min/1.73m2 and/or positive dipstick tests for proteinuria of ≥3 months duration. C-reactive protein (CRP) was used as an inflammation marker, and a high CRP level was defined as a mean CRP value of ≥0.57mg/dL during the first 6 months of follow-up. Patients were categorized as follows: non-CKD with low CRP, non-CKD with high CRP, CKD with low CRP, and CKD with high CRP. RESULTS: During a median follow-up of 89 months, 67 patients (16%) had CKD, and 38 (9%) developed CVD. Using patients with non-CKD and low CRP as a reference group, the adjusted hazard ratios (HR, 95% confidence interval) for CVD were 1.88 (0.25-9.44) for patients with CKD/low CRP and 9.71 (3.27-31.97) for those with CKD/high CRP. CONCLUSIONS: The coexistence of CKD and inflammation was associated with a higher risk of CVD than either condition alone in RA patients. Inflammation might increase the risk of CVD especially in patients with CKD.

Cystatin C-Based Equation Does Not Accurately Estimate the Glomerular Filtration in Japanese Living Kidney Donors.

BACKGROUND Precise evaluation of a living donor's renal function is necessary to ensure adequate residual kidney function after donor nephrectomy. Our aim was to evaluate the feasibility of estimating glomerular filtration rate (GFR) using serum cystatin-C prior to kidney transplantation. MATERIAL AND METHODS Using the equations of the Japanese Society of Nephrology, we calculated the GFR using serum creatinine (eGFRcre) and cystatin C levels (eGFRcys) for 83 living kidney donors evaluated between March 2010 and March 2016. We compared eGFRcys and eGFRcre values against the creatinine clearance rate (CCr). RESULTS The study population included 27 males and 56 females. The mean eGFRcys, eGFRcre, and CCr were, 91.4±16.3 mL/min/1.73 m² (range, 59.9-128.9 mL/min/1.73 m²), 81.5±14.2 mL/min/1.73 m² (range, 55.4-117.5 mL/min/1.73 m²) and 108.4±21.6 mL/min/1.73 m² (range, 63.7-168.7 mL/min/1.73 m²), respectively. eGFRcys was significantly lower than CCr (p<0.001). The correlation coefficient between eGFRcys and CCr values was 0.466, and the mean difference between the two values was -17.0 (15.7%), with a root mean square error of 19.2. Thus, eGFRcre was significantly lower than CCr (p<0.001). The correlation coefficient between eGFRcre and CCr values was 0.445, and the mean difference between the two values was -26.9 (24.8%), with a root mean square error of 19.5. CONCLUSIONS Although eGFRcys provided a better estimation of GFR than eGFRcre, eGFRcys still did not provide an accurate measure of kidney function in Japanese living kidney donors.

Supplementary Administration of Everolimus Reduces Cardiac Systolic Function in Kidney Transplant Recipients.

BACKGROUND The effect of everolimus, one of the mammalian targets of rapamycin inhibitors, on cardiac function was evaluated in kidney transplant recipients. MATERIAL AND METHODS Seventy-six participants who underwent kidney transplant between March 2009 and May 2016 were retrospectively reviewed. To standardize everolimus administration, the following criteria were used: (1) the recipient did not have a donor-specific antigen before kidney transplantation; (2) the recipient did not have proteinuria and uncontrollable hyperlipidemia after kidney transplantation; and (3) acute rejection was not observed on protocol biopsy 3 months after kidney transplantation. According to these criteria, everolimus administration for maintenance immunosuppression after kidney transplantation was included. Cardiac function was compared between the treatment group (n=30) and non-treatment group (n=46). RESULTS The mean observation periods of the treatment and non-treatment groups were 41.3±12.6 and 43.9±19.8 months, respectively (p=0.573). The mean ejection fraction and fractional shortening of the treatment and non-treatment groups after kidney transplant were 66.5±7.9% vs. 69.6±5.5% (p=0.024) and 37.1±6.2% vs. 39.3±4.7% (p=0.045), respectively. In the treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation did not differ significantly (p=0.604 and 0.606, respectively). In the non-treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation differed significantly (p=0.004 and 0.006, respectively). CONCLUSIONS Supplementary administration of everolimus after kidney transplantation can reduce cardiac systolic function.

Inflammation as a Risk of Developing Chronic Kidney Disease in Rheumatoid Arthritis.

OBJECTIVE: The relationship between chronic inflammation and the incidence of chronic kidney disease (CKD) remained not-clear in patients with rheumatoid arthritis (RA). This study aims to examine the relationship between persistently high C-reactive protein (CRP), a marker of inflammation, and the incidence of CKD in RA. METHODS: We retrospectively examined the relationship between the levels of CRP and incidence of CKD in 345 RA patients. The outcome of interest was incidence of CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and/or positive dipstick testing for proteinuria for ≥3 months. We defined high CRP, as >3.0 mg/L. On the basis of three measurements of CRP for 6-months period, patients were divided into three groups: group 1, including patients with no high CRP values; group 2, patients with transient high CRP values (once or twice) and group 3, patients with persistently high CRP values. RESULTS: During a median follow-up period of 89 months, 14% of all patients developed CKD. The cumulative incidence of CKD was 7% in group 1, 14% in group 2 and 22% in group 3 (P = 0.008, log-rank test). In a multivariate analysis, including classical risk factors for CKD, persistently high CRP was an independent predictor of the incidence of CKD (hazard ratio, 3.00; 95% confidence interval, 1.23-8.53; P = 0.01). CONCLUSIONS: Persistently high CRP was a significant risk factor for the incidence of CKD. Results suggest that persistent inflammation is a marker for the high risk of CKD in RA.

Effects of angiotensin receptor blockade (ARB) on mortality and cardiovascular outcomes in patients with long-term haemodialysis: a randomized controlled trial.

BACKGROUND: Hypertension is a major risk factor for death and cardiovascular disease (CVD) in patients undergoing chronic haemodialysis (HD), but there is uncertainty surrounding the effects of blood pressure (BP) lowering on this high-risk patient group. METHODS: In a multicenter, prospective, randomized, open-label, blinded-endpoint trial, 469 patients with chronic HD and elevated BP (140-199/90-99 mmHg) were assigned to receive the angiotensin receptor blockade (ARB) olmesartan (at a dose of 10-40 mg daily; n = 235) or another treatment that does not include angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors (n = 234). The primary outcomes were the following: (i) composite of death, nonfatal stroke, nonfatal myocardial infarction and coronary revascularization and (ii) all-cause death. RESULTS: During a mean follow-up of 3.5 years, the mean BP was 0.9/0.0 mmHg lower in the olmesartan group than in the control group (not significant). A total of 68 patients (28.9%) in the olmesartan group and 67 patients (28.6%) in the control group had subsequent primary composite endpoints [hazard ratio (HR) in the olmesartan group 1.00, 95% confidence interval (CI) 0.71-1.40, P = 0.99]. All-cause deaths occurred in 38 patients (16.2%) in the olmesartan group and 39 (16.7%) in the control group (HR, 0.97; 95% CI, 0.62-1.52, P = 0.91). Olmesartan did not alter the risks of serious adverse events. CONCLUSIONS: BP-lowering treatment with an ARB did not significantly lower the risks of major cardiovascular events or death among patients with hypertension on chronic HD. (Cochrane Renal Group Prospective Trial Register number CRG010600030).

Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy.

OBJECTIVES: We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). METHODS: A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4-6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a ≥10-fold or more increase in the OI. RESULTS: IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. CONCLUSIONS: TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX.

Olmesartan clinical trial in Okinawan patients under OKIDS (OCTOPUS) study: design and methods.

BACKGROUND: Guidelines for treatment of hypertension are not available for chronic hemodialysis (HD) population, despite the high mortality rate due to cardiovascular disease (CVD). Survival is much better among hypertensive patients than normal to hypotensive patients. Target levels of blood pressure and the class of antihypertensive drugs have not been examined in prospective studies. METHODS: We designed a prospective randomized controlled study among hypertensive HD patients in Okinawa (Okinawa Dialysis Study, OKIDS). The outcomes will be compared between two treatment regimens, such as (1) renin-angiotensin system (RAS) inhibitor Olmesartan and others, and (2) antihypertensive drugs without RAS inhibitors, in a parallel fashion. The title of the study is Olmesartan Clinical Trial in Okinawan Patients under OKIDS (OCTOPUS). Outcomes are any cause of death and CVD in 3 years in a total of 462 patients. Subjects are age 20-79 years and ambulatory on thrice weekly HD treatment. Eligible patients have resistant hypertension: pre-HD session blood pressure 140/90 mmHg and over for more than 1 month regardless with the use of antihypertensive drugs. Patients treated with RAS drugs are eligible if they continue to be hypertensive for more than 1 month after switching to non-RAS antihypertensive drugs. CONCLUSION: This study provides evidence for the target levels of blood pressure at a pre-HD session and the impact of RAS inhibitors. We also evaluate the usefulness of home blood pressure monitoring in HD patients.

Effect of high fiber density ratio polysulfone dialyzer on protein removal.

BACKGROUND/AIMS: A dialyzer (APS-EX) with a higher hollow fiber density ratio was manufactured using the highest performance polysulfone hollow fiber from Asahi-Kasei Medical. METHODS: We compared the performance of this device in comparison with hemodialysis (HD; APS-S) and hemodiafiltration (HDF) conditions (APS-S, 10 l post-HDF) to evaluate its merit as an internal filtration-enhanced dialyzer. RESULTS: With low molecular weight proteins, APS-EX had a reduction ratio of 74.3% for beta(2)-microglobulin (beta(2)-MG), and 31.0% for alpha(1)-MG. APS-EX had a significant higher removal amount of alpha(1)-MG compared to APS-S (HDF). Significant differences were seen in albumin loss, 4.0 g for APS-EX, 3.0 g for APS-S (HDF), and 0.9 g for APS-S (HD). Using HD mode, APS-EX demonstrated a performance which was more than equivalent to approximately 10 l post-HDF. CONCLUSIONS: The results suggested the possibility that HD equivalent to HDF can be performed safely with the ultrapure dialysate when using APS-EX with internal filtration.

Outcome study of renal biopsy patients in Okinawa, Japan.

Here we report a community-based epidemiologic study of patients who received renal biopsy in Okinawa, Japan between 1967 and 1994. The total number of cases was 2832 (1395 men and 1437 women), and the mean (SD) age at biopsy was 30.0 (10.0) years (range 1.0 to 88.0 years). The most common clinical indications for renal biopsy were proteinuria/hematuria (46.7%), nephrotic syndrome (21.2%), acute glomerulonephritis (10.1%), and systemic lupus erythematosus (7.5%). Patients who received renal biopsy between 1985 and 1994 (N= 1480) were much less likely to have acute glomerulonephritis than patients treated between 1967 and 1984 (N= 1352); the rates of proteinuria/hematuria, renal failure, and diabetes mellitus were slightly higher in the later period. Okinawa patients who began dialysis between 1971 and 2000 (N= 5246) were also studied. Among them, a total of 468 patients (260 men and 208 women) began dialysis after renal biopsy. The cumulative incidence of end-stage renal disease (ESRD) among these patients was 17% in 17 years. Half of these patients developed ESRD in the 5.8 years after renal biopsy. Among the dialysis patients, the biopsy rate was 12.6% in chronic glomerulonephritis, 1.7% in diabetes mellitus, 2.6% in nephrosclerosis, and 52.1% in systemic lupus erythematosus. The diagnoses of primary renal diseases were primarily made clinically. The survival rate after starting dialysis therapy was slightly better in those with than in those without renal biopsy but this finding was not statistically significant (adjusted hazards ratio 0.855, 95% CI 0.711-1.028, P= 0.095). The clinical significance of renal biopsy, other than its provision of histologic evidence, remains to be shown.

Effect of diabetes on peritoneal function assessed by personal dialysis capacity test in patients undergoing CAPD.

BACKGROUND: We evaluated differences in individual peritoneal membrane transport function and nutritional status in patients with diabetes mellitus (DM) and nondiabetic (non-DM) patients on continuous ambulatory peritoneal dialysis (CAPD). METHODS: We used a newly developed peritoneal function test, personal dialysis capacity, in 88 patients (44 DM and 44 non-DM) on CAPD for 1 to 210 months. Sex, age, past history of peritonitis, and duration of CAPD were matched in DM and non-DM patients. RESULTS: Serum albumin (mean +/- SEM) was lower in DM compared with non-DM patients: 3.0 +/- 0.1 g/dL (30 +/- 1 g/L) versus 3.5 +/- 0.1 g/dL (35 +/- 1 g/L), P < 0.001. Peritoneal area and dialysis protein loss were greater in DM versus non-DM patients. In multiple linear regression analysis, the only independent predictor of serum albumin in patients with DM was dialysis protein loss. In contrast, age, past history of peritonitis, duration of CAPD, caloric intake, protein nitrogen appearance and protein catabolic rate, and residual renal function did not correlate with serum albumin in DM patients. In non-DM patients, age, duration of CAPD, and past history of peritonitis, but not dialysis protein loss, were independent predictors of serum albumin. There was a significant correlation in DM patients, but not in non-DM CAPD patients, between dialysis protein loss and urinary excretion of protein (r = 0.866, P = 0.0005). CONCLUSION: In this multicenter study, peritoneal membrane transport and peritoneal protein permeability were significantly higher in DM than in non-DM patients. Hypoproteinemia in DM patients is attributable to the high permeability of the peritoneal membrane undergoing CAPD.