Fibroblast growth factor 23 (FGF23) level is associated with ultrafiltration rate in patients on hemodialysis.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. High circulating FGF23 levels are associated with increased mortality in patients with chronic kidney disease and those on dialysis. Current data also suggest higher circulating levels of FGF23 are associated with cardiovascular mortality, vascular calcification, and left ventricular hypertrophy; however, evidence on the role of FGF23 in patients on dialysis is incomplete, and some of the data, especially those on cardiovascular disease (CVD), are controversial. This study aimed to evaluate factors associated with FGF23 in hemodialysis patients with or without CVD. Randomly selected 76 patients on maintenance hemodialysis at a single hemodialysis center were enrolled. After the exclusion of eight patients with extremely outlying FGF23 levels, 68 patients, including 48 males and 46 patients with a CVD history, were included in the study. The mean age was 64.4 ± 12.1 years, and the mean dialysis duration was 12.7 ± 7.1 years. Dialysis duration, time-averaged concentration of urea (TAC-urea), ultrafiltration rate (UFR), blood pressure during hemodialysis session, laboratory data, and echocardiographic parameters including interventricular septum thickness (IVST), left ventricular mass indices (LVMI), and ejection fraction were included in univariate and multivariate analyses. The median lgFGF23 levels in the overall cohort and in those with and without CVD were 2.14 (interquartile range, IQR - 0.43 to - 4.23), 2.01 (- 0.52 to 4.12), and 2.59 (0.07 to 4.32), respectively, and there was no difference between the patients with and without CVD (p = 0.14). The univariate analysis revealed that FGF23 was significantly associated with age (r = - 0.12, p < 0.01), duration of hemodialysis (r = - 0.11, p < 0.01), TAC-urea (r = 0.29, p = 0.01), UFR (r = 0.26, p = 0.04), alkaline phosphatase (ALP; r = - 0.27, p = 0.03), corrected serum calcium (cCa; r = 0.32, p < 0.01), serum phosphate (iP, r = 0.57, p < 0.01), intact parathyroid hormone (iPTH; r = 0.38, p < 0.01), IVST (r = 0.30, p = 0.01), and LVMI (r = 0.26, p = 0.04). In multivariate regression analysis, FGF23 was significantly associated with cCa (F = 25.6, p < 0.01), iP (F = 22.5, p < 0.01), iPTH (F = 19.2, p < 0.01), ALP (F = 5.34, p = 0.03), and UFR (F = 3.94, p = 0.05). In addition, the univariate analysis after the categorization of patients according to CVD indicated that FGF23 was significantly associated with cCa (r = 0.34, p = 0.02), iP (r = 0.41, p < 0.01), iPTH (r = 0.39, p = 0.01), and TAC-urea (r = 0.45, p < 0.01) in patients with CVD, whereas only IVST (r = 0.53, p = 0.04) was associated with FGF23 in those without CVD. FGF23 levels in hemodialysis patients were extremely high and associated not only with mineral bone disease-related factors but also with UFR. Additionally, dialysis efficacy might be associated with lower FGF23 levels in patients with CVD.

Efficacy of antihistamines on mortality in patients receiving maintenance hemodialysis: an observational study using propensity score matching.

Antihistamines are widely used to treat pruritus in patients receiving hemodialysis. In a previous cross-sectional study, we reported an association between antihistamine use and the absence of eccentric cardiac hypertrophy in patients receiving hemodialysis. Therefore, in this study, we sought to evaluate the efficacy of antihistamines on all-cause and cardiovascular mortality in patients receiving hemodialysis according to our outpatient dialysis database. We used a propensity score matching method. Among the 389 patients receiving hemodialysis according to our database, we extracted those taking antihistamines and matched them with patients not taking antihistamines using propensity scores based on 38 variables. All-cause mortality and cardiovascular mortality were estimated by the Kaplan-Meier method, and a log-rank test was used to examine the differences between the survival curves. We included 154 patients, or 77 matched pairs, from the entire cohort (c-statistic = 0.78, p < 0.0001). There were no differences in any background factor between the antihistamine and non-antihistamine group. During the mean observational period of 5.4 years, 50 patients died, and the all-cause mortality rate was 27.3% (21 patients) in the antihistamine group and 37.3% (29 patients) in the non-antihistamine group (p = 0.0314). The cardiovascular mortality rate was 16.9% (13 patients) in the antihistamine group and 25.9% (20 patients) in the non-antihistamine group (p = 0.0417). The results of this study suggest that all-cause and cardiovascular mortality improved with antihistamine use in patients receiving hemodialysis. However, the clinical efficacy of antihistamines needs to be confirmed in a prospective randomized study in the future.

Serum oxalate concentration is associated with coronary artery calcification and cardiovascular events in Japanese dialysis patients.

Coronary artery calcification (CAC) is associated with cardiovascular disease (CVD). CAC might contain calcium oxalate, and a high serum oxalate (SOx) concentration is associated with cardiovascular mortality in dialysis patients. We assessed the associations between SOx and CAC or CVD events in Japanese hemodialysis patients. This cross-sectional and retrospective cohort study was done in 2011. Seventy-seven hemodialysis patients' Agatston CAC score was measured, and serum samples were collected. SOx concentrations were measured in 2021 by using frozen samples. Also, new-onset CVD events in 2011-2021 were retrospectively recorded. The association between SOx concentration and CAC score ≥ 1000, and new-onset CVD events were examined. Median SOx concentration and CAC score were 266.9 (229.5-318.5) µmol/L and 912.5 (123.7-2944), respectively. CAC score ≥ 1000 was associated with SOx [adjusted odds ratio (OR) 1.01, 95% confidence interval (CI), 1.00-1.02]. The number of new-onset CVD events was significantly higher in patients with SOx ≥ median value [hazard ratio (HR) 2.71, 95% CI 1.26-6.16]. By Cox proportional hazard models, new-onset CVD events was associated with SOx ≥ median value (adjusted HR 2.10, 95% CI 0.90-4.91). SOx was associated with CAC score ≥ 1000 and new-onset CVD events in Japanese hemodialysis patients.

Left atrial dilatation and ST-T changes predict cardiovascular outcome in chronic hemodialysis patients.

The left atrium (LA) is afterload-sensitive, meaning that it responds to changes in left ventricular diastolic pressure, and left atrial volumetric remodeling has been reported. We prospectively examined the effects of LA enlargement and ST-T changes on cardiovascular outcome of chronic hemodialysis (HD) patients. Echocardiography was performed twice, a mean interval of 2.1 ± 0.4 years apart, and LA size, left ventricular mass index (LVMI), and other indices were evaluated. The prognostic value of ST-T changes and LA dilatation for cardiovascular events was investigated in a cohort of 112 HD patients. The LVDd, interventricular septum thickness, fractional shortening, and LVMI values were higher in the HD patients with ST-T changes and LA dilatation at the second echocardiography. Moreover, LV hypertrophy (LVH) and new cardiovascular events were more common in HD patients with both ST-T changes and LA dilatation (p = 0.0127). Interdialysis weight gain, presence of ST-T changes and LA dilatation, and use of calcium channel blockers were significantly associated with LVH, and the odds ratios were 1.740, 2.870, and 0.304, respectively. Over a mean follow-up period of 2.1 ± 0.4 years, 27 patients experienced new cardiovascular event. A Cox proportional hazard analysis revealed that complication of coronary artery diseases, the presence of ST-T changes and LA dilatation, and serum albumin levels were significantly associated with incident cardiovascular events, and the hazard ratios were 3.898, 5.182, and 0.185 (1 g/dl per year increase), respectively. In a Kaplan-Meier analysis, incident cardiovascular events were significantly less common in HD patients without ST-T changes and LA dilatation than those with (p < 0.0001), 50% event-free period was about 2 years in HD patients with ST-T changes and LA dilatation. In conclusion, ST-T changes and LA dilatation predict the cardiovascular outcome of chronic HD patients. Detecting ST-T changes on ECG and LA dilatation is useful for monitoring cardiovascular risk in chronic HD patients.

Therapeutic advantage of angiotensin-converting enzyme inhibitors in patients with proteinuric chronic kidney disease.

Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) is recommended for the treatment of hypertension in patients with chronic kidney disease (CKD). The relation of ACEI to renal prognosis was investigated in CKD patients in a retrospective cohort study. The objectives were patients with nondiabetic CKD of stage 4 or below receiving monotherapy with calcium channel blocker (CCB), ACEI, or ARB, and combination therapy. For the endpoint of progression to CKD stage 5, Cox's proportional hazards analysis was conducted with explanatory variables of age, sex, baseline estimated GFR (eGFR), and proteinuria (UP) at the start of the observation period, and final blood pressure (BP) and UP at completion of the observation period. Analyzed patients comprised 131 males and 117 females, with mean age of 47.8 years. Patients were observed for 44.2 months, and the parameters of final SBP, DBP, eGFR, and UP were 127.6 +/- 6.9 mmHg, 77.8 +/- 5.8 mmHg, 38.1 +/- 10.6 ml/min/1.73 m(2), and 1.08 +/- 0.57 g/gCr, respectively, where 42 patients progressed to CKD stage 5. Drugs of CCB, ACEI, and ARB types were administered to 93, 85, and 127 patients, respectively. In the multivariate analysis, extracted common prognostic factors included the baseline eGFR and final UP, the odds ratio of which was 0.876 (every increase by 1 ml/min of eGFR) and 2.229 (every increase by 1 g of UP), respectively. Among drugs in use, ACEI was an independent prognostic factor, whose odds ratio was 0.147. The present study suggests that ACEI is a prognostic factor independent of hypotensive action and UP in CKD patients.

The use of H1-receptor antagonists and left ventricular remodeling in patients on chronic hemodialysis.

Suppression of left ventricular (LV) remodeling secondary to heart failure seems critical to improve the prognosis of hemodialysis (HD) patients. This is a retrospective study on the relationship of an antiallergic drug and antihistamines with LV hypertrophy. A total of 149 patients (88 males and 61 females) were entered in the study. Mean age was 66.7 years and mean duration of dialysis 14.4 years. Twenty-three patients received oral treatment with an antiallergic drug or second-generation antihistamines, 3 with the antiallergic drug and 20 with antihistamines. The multivariate analysis using LV mass index (LVMI) as the objective variable extracted the following independent factors: male sex, erythropoietin (EPO)/w, uric acid (UA), total cholesterol, antihistamines, antiallergic drug, and calcium channel blocker (CCB), with a standard regression coefficient of 0.187, 0.196, 0.212, -0.262, -0.215, -0.149 and -0.173, respectively. This study suggests a suppressive role of second-generation antihistamines on LV remodeling. Male sex, high-dose EPO/w, and elevated UA were considered as aggravating factors, and CCB as a suppressive factor.

Low-density lipoprotein apheresis for PLA2R-related membranous glomerulonephritis accompanied by IgG4-related tubulointerstitial nephritis.

IgG4-related disease preferentially involves the kidney by tubulointerstitial nephritis with IgG4-positive plasma cell filtration and/or membranous glomerulonephritis. We reported the case of a 68-year-old man with IgG4-related tubulointerstitial nephritis combined with antiphospholipase A2 receptor (PLA2R)-related membranous glomerulonephritis, in which distinguishing between idiopathic PLA2R-related and IgG4-related secondary membranous glomerulonephritis was difficult. We diagnosed him as having IgG4-related disease, based on a serum IgG4 level of 170 mg/dL and the presence of IgG4-related parotiditis. On renal biopsy, there was tubulointerstitial nephritis with IgG4-positive plasma cell filtration, which was compatible with IgG4-related disease and membranous glomerulonephritis, with concomitant positive staining for PLA2R on immunofluorescence microscopy. The renal function immediately recovered after steroid treatment, probably because of the improvement in the tubulointerstitial lesions, but his nephrotic syndrome was steroid-resistant. Low-density lipoprotein (LDL) apheresis therapy was effective for membranous glomerulonephritis and increased his serum albumin from 1.4 to 2.8 g/dL. Although IgG4-related kidney disease usually accompanies secondary membranous glomerulonephritis, the positive PLA2R staining suggested a concomitant primary membranous glomerulonephritis. The recent treatment strategy, including LDL apheresis, for primary and secondary membranous glomerulonephritis was discussed briefly in this report.

Influence of T-calcium channel blocker treatment on deterioration of renal function in chronic kidney disease.

Some calcium channel blockers (CCBs) have renoprotective effects. Our aim was to compare the effects of different subclasses of CCBs on the deterioration of renal function in chronic kidney disease (CKD). This is a prospective, observational cohort study in a single center. The subjects were 107 nondiabetic CKD patients. The rate of deterioration of estimated glomerular filtration rate (DeltaeGFR) was calculated by [last visit eGFR - baseline eGFR/follow-up duration]. Multivariate analysis was performed using the change in urinary protein (DeltaUP) and DeltaeGFR during follow-up as response variables. CCB subclasses were L-type in 76 patients, T- and L-type in 28 patients, and nondihydropyridines in 6 patients. Multiregression analysis indicated that higher baseline proteinuria (UP) and the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers were associated with the decrease of UP, while the use of L-type CCBs, prednisolone, and probucol was associated with the increase of UP. The use of T- and L-type CCBs, ACEIs and diuretics was associated with a good outcome in terms of DeltaeGFR, whereas chronic glomerulonephritis, polycystic kidney disease, and higher baseline eGFR and UP were associated with a poor outcome. It is suggested that the use of T- and L-type CCB among other subclasses may improve the outcome of patients with nondiabetic CKD in terms of renal function.

Use of Beta-Blockers on Maintenance Dialysis Patients and Ischemic Cerebral and Cardiovascular Deaths: An Examination Using Propensity Score.

Beta-blockers are frequently used in dialysis patients because of their cardioprotective properties. However, the effect of beta-blockers on reducing dialysis mortality has not been sufficiently examined to date. Thus, we sought to examine the effects on cardiovascular prognosis of beta-blockers using our outpatient dialysis database. From 389 dialysis patients registered in our database, subjects taking beta-blockers were extracted and matched with patients not taking beta-blockers using propensity scores based on 39 variables. Cardiovascular mortality, mortality of heart failure/sudden cardiac death, and mortality of ischemic cerebral and cardiovascular death were estimated using Kaplan-Meier method, and a log-rank test was used to analyze the difference between these survival curves for significance. A total of 216 patients, 108 matched pairs, were extracted from the whole cohort. There was no difference in background factors between the two groups. During mean observation periods of 4.4 years, 76 patients died, including 51 cases of cardiovascular death. Cardiovascular deaths included 30 heart failure/sudden deaths and 13 ischemic cerebral and cardiovascular deaths. For both cardiovascular and heart failure/sudden death, the survival curves did not indicate a significant difference between the 2 groups. On the contrary, in case of ischemic cerebral and cardiovascular deaths, 11 patients died in the beta-blocker group, with a significantly poor prognosis observed in the survival curve (p = 0.0132). Through the use of beta-blockers, a significant increase in ischemic cerebral and cardiovascular deaths was observed. The administration of beta-blockers to dialysis patients was found to worsen the cardiovascular prognosis, so sufficient examination will be needed in the future.

Prediction of Development of Critical Limb Ischemia in Hemodialysis Patients.

Hemodialysis (HD) patients with critical limb ischemia (CLI) suffer chronic inflammation and repeated infection, require intervention, and may have a protracted hospital stay. Therefore, early prediction is particularly important for management of CLI in patients with suspected peripheral artery disease. The purpose of this study is to develop a simple score for predicting the incidence of CLI in HD patients with suspected peripheral artery disease. The subjects were 139 asymptomatic patients receiving maintenance HD and with ABI <1.0. Multivariate logistic regression analysis was used to identify factors associated with development of CLI. These factors were subsequently weighted and integrated into a scoring system for the prediction of onset of CLI. Twenty-five patients had onset of CLI. Five factors selected from the multivariate model were weighted proportionally using their respective odds ratio (OR) for incidence of CLI (history of cerebral vascular disease, OR 6.42 [3 points]; diabetes, OR 3.92 [2 points]; hypoesthesia, OR 4.21 [2 points]; left ventricular ejection fraction <50%, OR 3.89 [2 points]; serum albumin <3.5 g/dL, OR 4.39 [2 points]). Three strata of risk were defined (low risk, 0 to 3 points; intermediate risk, 4 to 6 points; and high risk 7 to 11 points) with excellent prognostic accuracy for progression to CLI using the Kaplan-Meier method. Five factors were identified that increased the risk of progression to CLI in HD patients with suspected peripheral artery disease. A combination of those factors permitted establishment of three risk strata for accurate prediction of onset of CLI.