Comparison of B-type natriuretic peptide and NT proBNP as predictors of survival in patients on high-flux hemodialysis and hemodiafiltration

End stage renal failure is associated with very high risk of cardiovascular disease. Serum levels of B-type natriuretic peptide (BNP) and NT proBNP reflect cardiovascular risk but it is unknown which of these peptides is a better predictor of survival in this population. BNP and NT proBNP levels and other relevant parameters were measured in 103 patients on high-flux hemodialysis (HD) and hemodiafiltration. Patients were followed for 4 years or until transplantation or death. Median BNP level was 262 pg/mL while the corresponding NT proBNP level was 362 pg/mL. Levels of these peptides were significantly lower in patients receiving hemodiafiltration than in those on high-flux HD. Only 1 of the 26 patients with normal NT proBNP died during follow-up while 3 of the 33 patients with normal BNP levels died in the same period. Both median BNP and NT proBNP levels were higher in those who died during follow-up than in those who survived 4 years. Cox Proportional Hazard models showed that both logBNP and log NT proBNP were independent predictors of survival. The area under the receiver operating characteristic curve was very similar for BNP and NT proBNP (0.779 vs. 0.781) for predicting 4-year survival. Net reclassification improvement analysis showed that adding NT proBNP to the baseline model lead to improved prediction of 4-year survival. BNP and NT proBNP levels were markedly elevated in HD patients and were highly predictive of survival. NT proBNP may have marginal advantage over BNP in predicting survival in this population.     

Which fluid space is affected by ultrafiltration during hemodiafiltration?

Ultrafiltration (UF) is a common procedure performed during almost all dialysis sessions. During UF, several liters of fluid are removed; however, what proportion of this fluid is removed from which fluid space could not be clinically measured easily until now; we designed this study to evaluate the fluid spaces most affected by UF. This is a prospective cohort study of 40 prevalent chronic hemodialysis patients receiving thrice weekly hemodiafiltration (HDF). We measured the patients' fluid spaces using a whole‐body bioimpedance apparatus to evaluate the changes of fluid spaces before and immediately after the HDF sessions. We recorded the data on fluid spaces, UF volume, and blood pressures. The cohort consisted of 40 prevalent HDF patients, aged 60.0 ± 5.2 years (37.5% men; 27.5% people with diabetes), and body weight 71.03 ± 15.48 kg. Achieved UF was 2.38 ± 0.98 L on HDF (measured fluid overload: 2.35 ± 1.44 L). The extracellular fluid (EC) volume decreased from 16.84 ± 3.52 to 14.89 ± 3.06 L (P < 0.0001) and intracellular fluid (IC) volume from 16.88 ± 4.40 to 16.55 ± 4.48 L (P = 0.45). Although urea volume of distribution remained effectively unchanged (31.38 ± 7.28 vs. 30.70 ± 7.32 L; P = 0.45), the degree of EC volume overload decreased from 13.60% ± 7.30% to 3.83% ± 8.32% (P < 0.0001). The mean arterial pressure also decreased from 122.95 ± 19.02 to 108.50 ± 13.91 mmHg (P < 0.0001). We conclude that source of net fluid loss by ultrafiltration is almost exclusively the EC fluid space. The intracellular fluid space is not significantly affected immediately after HDF.     

Volume estimation in dialysis patients: The concordance of brain‐type natriuretic peptide measurements and bioimpedance values

Correct estimation of the dialysis patients' hydration status remains an important clinical challenge. Bioimpedance measurements have been validated by various physiological tests, and the use of brain‐type natriuretic peptide (BNP) has been validated by inferior vena cava diameter measurements. This is an observational cohort study that evaluated the correspondence between bioimpedance‐measured overhydration percentage (OH%) and BNP. We measured predialysis OH% by bioimpedance apparatus (Body Composition Monitor) and BNP by microparticle enzyme‐linked immunoassay in 41 prevalent stable hemodialysis patients, 19 (46%) women, aged 58.9 ± 14.5 years. The cohort's average BNP was 2694 ± 3278 pg/mL and 10 (24.4%) of these 41 patients had BNP < 500 pg/mL (average 260.7 ± 108.5). The OH% was 8.5 ± 7.0% among those with a BNP < 500 pg/mL, while the rest of the population had an OH% of 21.4 ± 8.0%, corresponding to excess volumes of 1.6 ± 1.3 and 4.4 ± 3.8 L, respectively. The OH% vs. BNP relationship was best described by the exponential regression of y = 216.4e^0.097x, predicting a BNP of 216.4 pg/mL at 0% overhydration status (r 0.61). Receiver‐operating curves revealed an area under the curve of 0.885 for BNP when the OH% was set ≥15% of overhydration and an area under the curve of 0.918 for OH% when the BNP was set ≥500 pg/mL for being abnormal. We conclude that in our cohort there was a high degree of correspondence between these two tests with an exponential relationship between the measurements.     

Obstructive sleep apnea in incremental hemodialysis: Determinants,consequences, and impact on survival

Sleep disorders are common in hemodialysis patients, although causes and consequences remain unclear. We sought to establish prevalence, determinants, and outcomes of sleep disturbances in patients receiving incremental dialysis. One hundred two unselected patients undergoing incremental high‐flux hemodialysis or hemodiafiltration underwent limited overnight sleep study. Large subsets underwent echocardiography, interdialytic ambulatory blood pressure monitoring, and brain natriuretic peptide measurements. Patients were followed up to 44 months. Full sleep data were obtained in 91 patients. All had sleep disturbance as evidenced by an apnea–hypopnea index >5/min. We defined major obstructive sleep apnea (MOSA) as an apnea–hypopnea index ≥15, together with either significant oxygen desaturation or symptoms of daytime sleepiness. Forty patients met these criteria. Significant independent predictors of MOSA were age <65 years, male gender, has diabetes, and has a brain natriuretic peptide >2500 pg/mL. Mean ambulatory blood pressure and left ventricular mass index were significantly higher in these patients. In a model controlling for body mass index, high C‐reactive protein, and the presence of cancer, MOSA was associated with a twofold increased risk of mortality, although this did not reach statistical significance. MOSA was common, and was associated with hypertension and high left ventricular mass index. Whether obstructive sleep apnea contributes to the high mortality remains to be firmly established.     

Effect of ultrafiltration on placental‐fetal blood flow in pregnancy of woman undergoing chronic hemodialysis

Introduction: Patient who was undergoing hemodialysis (HD) thrice weekly usually gain 1 to 4 kg of weight in interdialytic period, mainly due to fluid accumulation by ingestion of water. Ultrafiltration (UF) during HD will be need to remove fluid excess to avoid severe medical complications secondary to fluid overload. However, in pregnant woman UF can increase the episodes of intradialytic hypotension which may lead to placental ischemic injury and predispose to fetal distress. There is little information about safe fluid amount withdrawn by UF during pregnancy. Methods: We prospectively study by obstetric Doppler ultrasonography the fluxometric parameters: pulsatility index (PI) and resistance index (RI) of fetal middle cerebral, uterine, and umbilical artery obtained at the beginning and the end of HD session, the acute and chronic effect of UF on placenta and fetus blood flow, as well as the fetal outcome in 1 pregnant woman on chronic HD. Findings: We did not observe any acute harmful effect on fetal middle cerebral, placental and umbilical artery blood flow when UF rate of 2.1 ± 0.04 L (6 < 8 mL/h/kg) during HD session, no significant statistical difference was observed when compared PI and RI before and after UF and also when we compared these data with reference value on normal pregnancy to the same gestational age. Discussion: UF rate of 6 < 8 mL/h/kg during HD did not bring any acute harmful effect on fetal middle cerebral, placental, and umbilical blood flow and the UF rate of 1.4 6 0.4 L (< 6 mL/h/kg) / HD session that was done in all others HD during pregnancy was safe, without any chronic fetal deleterious effect. Obstetric Doppler ultrasonography is a simple and noninvasive method to fetal follow‐up and can aid to determine safe UF rate in pregnant women during gestation.     

Gender,low Kt/V,and mortality in Japanese hemodialysis patients: Opportunities for improvement through modifiable practices

Guidelines have recommended single pool Kt/V > 1.2 as the minimum dose for chronic hemodialysis (HD) patients on thrice weekly HD. The Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown that “low Kt/V” (<1.2) is more prevalent in Japan than many other countries, though survival is longer in Japan. We examined trends in low Kt/V, dialysis practices associated with low Kt/V, and associations between Kt/V and mortality overall and by gender in Japanese dialysis patients. We analyzed 5784 HD patients from Japan DOPPS (1999–2011), restricted to patients dialyzing for >1 year and receiving thrice weekly dialysis. Logistic regression models estimated the relationships of patient characteristics with Kt/V. Logistic models also were used to estimate the proportion of low Kt/V cases attributable to various treatment practices. Multivariable Cox regression was used to estimate the associations of low Kt/V, blood flow rate (BFR), and treatment time (TT), with all‐cause mortality. From 1999 to 2009, the prevalence of low Kt/V declined in men (37–27%) and women (15–10%). BFR <200 mL/min, TT <240 minutes, and dialyzate flow rate (DFR) < 500 mL/min were common (35, 13, and 19% of patients, respectively) and strongly associated with low Kt/V. Fifteen percent of low Kt/V cases were attributable to BFR <200 and 13% to TT <240, compared to only 3% for DFR <500. Lower Kt/V was associated with elevated mortality, more so among women (hazard ratio [HR] = 1.13 per 0.1 lower Kt/V, 95% CI: 1.07–1.20) than among men (HR = 1.06 per 0.1 lower Kt/V, 95% CI: 1.00–1.12). The relatively large proportion of low Kt/V cases in Japanese facilities may potentially be reduced 30% by increasing BFR to 200 mL/min and TT to 4 hours thrice weekly in HD patients. Associations of low Kt/V with elevated mortality suggest that modification of these practices may further improve survival for Japanese HD patients.     

Plasma myeloperoxidase,NT‐proBNP,and troponin‐I in patients on CAPD compared with those on regular hemodialysis

Myeloperoxidase (MPO) is a hemoprotein that is released during inflammation and may lead to irreversible protein and lipid modification, increasing levels of oxidized low density lipoprotein, and promoting athrogenesis. Recently, it has been considered as a risk factor for cardiovascular diseases. Similarly, the measurement of carotid intima‐media thickness gives an indication about the degree of atherosclerosis and prediction of clinical cardiovascular events. Elevated white blood cells counts may indicate a state of acute inflammation and follow its progression. Dialysis patients are at a high risk of developing cardiovascular disease compared with healthy subjects. The role of N‐terminal pro‐brain natriuretic peptide and increased cardiac troponin in identification and prognostication of cardiovascular diseases in end‐stage renal disease patients has been investigated. The current study aimed to evaluate plasma MPO and its possible relationship with carotid intima‐media thickness, troponin I, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), and insulin resistance as measured by homeostatic model assessment (HOMA index) in a cohort of Saudi patients who are undergoing hemodialysis (HD) vs. continuous ambulatory peritoneal dialysis for end‐stage renal disease. Plasma MPO was significantly higher in patients on continuous ambulatory peritoneal dialysis (CAPD) than in those on HD and in normal subjects (P<0.001). Conversely, NT‐proBNP plasma levels were significantly higher in patients on HD (both predialysis and postdialysis) than in those on CAPD (P<0.01) and than normal subjects. Similarly, plasma troponin‐I levels were significantly higher in patients on HD compared with those of CAPD and than normal subjects (P<0.001). Plasma troponin‐I and NT‐proBNP levels were positively correlated in the 3 groups namely those on CAPD, Pre‐HD, and post‐HD (r: 0.464 and P=0.047; r: 0.330 and P=0.013; and r: 0.452 and P=0.024), respectively. There was no correlation between the MPO level and carotid intima‐media thickness (P>0.05). However, plasma MPO level correlated positively with the white blood cell count in patients on CAPD and in those on HD (P<0.05). Our findings suggest an increased oxidative stress in CAPD patients compared with HD patients, while the reported difference in plasma NT‐proBNP and troponin‐I may be related to the rapid decline of residual renal function in HD and type of membrane used in the HD dialysis procedure itself.     

Associations of microvascular dysfunction with cardiovascular outcomes: The cardiac,endothelial function and arterial stiffness in ESRD (CERES) cohort

Introduction: Patients with end‐stage renal disease (ESRD) have reduced endothelial function, but whether macro‐ and microvascular endothelial function correlate with baseline risk factors and cardiovascular outcomes in this population is not well understood. Methods: Among 146 participants of the Cardiac, Endothelial Function and Arterial Stiffness in ESRD (CERES) study, we evaluated macro‐ and microvascular endothelial dysfunction as flow‐mediated dilation (FMD) and velocity time integral (VTI), respectively. We examined cross‐sectional correlations of baseline characteristics, inflammatory and cardiac markers with FMD and VTI. We followed participants for the composite outcome of cardiovascular hospitalization or all‐cause death over fourteen months. Cox survival analyses were adjusted for demographics, comorbidities, medications, systolic blood pressure, inflammation, high‐sensitivity troponin T (hs‐TnT), and N‐terminal pro B‐type natriuretic peptide (NT‐proBNP). Findings: Impaired VTI was associated with older age and Black race (P < 0.05), as well as female gender, atherosclerosis, and hemodialysis (as opposed to peritoneal dialysis) (P < 0.2). Myocardial injury, measured as hs‐TnT, inflammatory markers and NT‐proBNP correlated with impaired VTI. In unadjusted analyses, VTI was significantly associated with the composite outcome (HR per SD VTI 0.65 [95%CI 0.45, 0.95]), but FMD was not (HR per SD FMD 0.97 [95%CI 0.69, 1.4]). When VTI was calculated as the ratio of (hyperemic VTI‐baseline VTI)/baseline VTI, its association with the outcome persisted after multivariable adjustment. Discussion: Microvascular function was associated with higher rates of cardiovascular hospitalizations and all‐cause mortality among individuals with ESRD on dialysis. Further research is needed to learn whether novel therapies that target microvascular endothelial function could improve outcomes in this high‐risk population.     

Hemodialysis‐induced regional left ventricular systolic dysfunction

Introduction Hemodialysis (HD) patients are under observably elevated cardiovascular mortality. Cardiac dysfunction is closely related to death caused by cardiovascular diseases (CVD). In the general population, repetitive myocardial ischemia induced left ventricular (LV) dysfunction may progress to irreversible loss of contraction step by step, and finally lead to cardiac death. In HD patients, to remove water and solute accumulated from 48 or 72 hours of interdialysis period in a 4‐hour HD session will induce myocardial ischemia. In this study, we evaluated the prevalence and potential risk factors associated with HD‐induced LV systolic dysfunction and provide some evidences for clinical strategies. Methods We recruited 31 standard HD patients for this study from Fudan University Zhongshan hospital. Echocardiography was performed predialysis, at peak stress during HD (15 minutes prior to the end of dialysis), and 30 minutes after HD. Auto functional imaging (AFI) was used to assess the incidence and persistence of HD‐induced regional wall motion abnormalities (RWMAs). Blood samples were drawn to measure biochemical variables. Findings Among totally 527 segments of 31 patients, 93.54% (29/31) patients and 51.40% (276/527) segments were diagnosed as RWMAs. Higher cTnT (0.060 ± 0.030 vs. 0.048 ± 0.015 ng/mL, P = 0.023), phosphate (2.07 ± 0.50 vs. 1.49 ± 0.96 mmol/L, P = 0.001), UFR (11.00 ± 3.89 vs. 8.30 ± 2.66 mL/Kg/h, P = 0.039) and lower albumin (37.83 ± 4.48 vs. 38.38 ± 2.53 g/L, P = 0.050) were found in patients with severe RWMAs (RWMAs in more than 50% segments). After univariate and multivariate analysis, interdialytic weight gain (IDWG) was found as independent risk factor of severe RWMAs (OR = 1.047, 95%CI 1.155–4.732, P = 0.038). Discussion LV systolic dysfunction induced by HD is prevalent in conventional HD patients and should be paid attention to. Patients would benefit from better weight control during interdialytic period to reduce ultrafiltration rate.     

Calcium‐phosphate and parathyroid intradialytic profiles: A potential aid for tailoring the dialysate calcium content of patients on different hemodialysis schedules

Severe hyperparathyroidism is a challenge on hemodialysis. The definition of dialysate calcium (Ca) is a pending issue with renewed importance in cases of individualized dialysis schedules and of portable home dialysis machines with low‐flow dialysate. Direct measurement of calcium mass transfer is complex and is imprecisely reflected by differences in start‐to‐end of dialysis Ca levels. The study was performed in a dialysis unit dedicated to home hemodialysis and to critical patients with wide use of daily and tailored schedules. The Ca‐phosphate (P)‐parathyroid hormone (PTH) profile includes creatinine, urea, total and ionized Ca, albumin, sodium, potassium, P, PTH levels at start, mid, and end of dialysis. “Severe” secondary hyperparathyroidism was defined as PTH > 300 pg/mL for ≥3 months. Four schedules were tested: conventional dialysis (polysulfone dialyzer 1.8–2.1 m²), with dialysate Ca 1.5 or 1.75 mmol/L, NxStage (Ca 1.5 mmol/L), and NxStage plus intradialytic Ca infusion. Dosages of vitamin D, calcium, phosphate binders, and Ca mimetic agents were adjusted monthly. Eighty Ca‐P‐PTH profiles were collected in 12 patients. Serum phosphate was efficiently reduced by all techniques. No differences in start‐to‐end PTH and Ca levels on dialysis were observed in patients with PTH levels < 300 pg/mL. Conversely, Ca levels in “severe” secondary hyperparathyroid patients significantly increased and PTH decreased during dialysis on all schedules except on Nxstage (P < 0.05). Our data support the need for tailored dialysate Ca content, even on “low‐flow” daily home dialysis, in “severe” secondary hyperparathyroid patients in order to increase the therapeutic potentials of the new dialysis techniques.     

Daily dialyses decrease plasma levels of brain natriuretic peptide (BNP), a biomarker of left ventricular dysfunction

Brain natriuretic peptide or B-type natriuretic peptide (BNP) is a sensitive marker of heart disease. Plasma levels of BNP increase in left ventricular failure and determination of plasma BNP has become a useful tool in the diagnosis of heart failure. Hemodialysis (HD) patients may have elevated plasma levels of BNP, particularly predialysis, that correlate with echocardiographic signs of left ventricular dysfunction. High BNP levels are also a strong predictor of mortality in both nonrenal and HD patients. We studied plasma BNP levels in patients who changed from conventional thrice-weekly dialysis to daily dialysis 6 times a week while maintaining a total weekly time on dialysis of 12 hr. Twelve HD patients, mean age 55 years, had 4 hr of conventional thrice-weekly treatment for 4 weeks. Predialysis and postdialysis blood samples were obtained at the last dialysis. Patients were then dialyzed for 2 hr, 6 times weekly, for 4 weeks (daily dialysis). Again, predialysis and postdialysis blood samples were collected at the last HD. Brain natriuretic peptide plasma concentrations were determined by immunoradiometric assay. Predialysis BNP levels decreased from 194+/-51 ng/L (68+/-19 pmol/L; mean+SE) during thrice-weekly HD to 113+/-45 ng/L (41+/-18 pmol/L; p = 0.001) after 4 weeks on daily dialysis. With thrice-weekly HD, predialysis BNP levels were higher than postdialysis levels: 120+/-26 ng/L (39+/-8 pmol/L; p = 0.059). With daily dialysis, predialysis BNP levels did not differ significantly from postdialysis levels. Elevated predialysis plasma levels of BNP, considered sensitive and early markers of left ventricular dysfunction, decreased when patients were changed from conventional thrice-weekly HD to daily dialysis maintaining total hours of dialysis per week constant. Given the accumulated evidence that BNP is a biomarker of left ventricular dysfunction and can be used for risk stratification and guidance in pharmacotherapy of heart failure, daily dialysis appears to lead to less cardiac distress.     

Endotoxins and inflammation in hemodialysis patients

Long‐term endotoxin challenge may promote frequent complications in dialysis patients, namely malnutrition, chronic inflammation, and atherosclerosis, which are recognized as the so‐called MIA syndrome. Circulating soluble vascular cell adhesion molecule‐1 (sVCAM‐1) levels may be used to determine the stage of atherosclerosis. This study aimed to assess endotoxin level in hemodialysis (HD) patients and its role in inducing inflammation. The study was conducted on 50 HD patients, chosen from four dialysis centers in Alexandria. Serum blood samples were collected for the determination of albumin and C‐reactive protein (CRP), and whole blood samples were used for the measurement of hemoglobin level. A heparinized whole blood sample was taken postdialysis for endotoxin assay by limulus amebocyte lysate test, and in addition to sVCAM‐1 was estimated using enzyme‐linked immunosorbent assay. The mean endotoxin level was 76.30 pg/mL;80% exhibited values higher than 60 pg/mL. Half the studied patients had CRP values that exceeded the upper limit of the laboratory reference range (<6.0 mg/L). A statistically significant correlation was found between endotoxin and CRP levels (r = 0.47, P = 0.001). The mean pre‐HD level of VCAM was 1851.00 ng/mL, while the mean post‐HD level was 2829.00 ng/mL with statistically significant correlation (r = 0.354, P = 0.012) and it also correlated significantly with endotoxin as well as CRP levels. Endotoxemia may play an important role in the aggravation of endothelial dysfunction in HD patients as indicated by the post‐HD rise in sVCAM‐1.     

SPECT MIBI imaging for cardiac output and index in end stage renal disease

To compare cardiac output (CO) and cardiac index (CI) and left ventricular ejection fraction (LVEF) in end-stage renal disease (ESRD) with a control group using gated single photon emission computed tomography (SPECT)/computed tomography (CT) imaging. Altered cardiovascular function with increased CO secondary to arterio-venous fistulas (AVF) for dialysis has been reported in patients with ESRD. Thirty-two patients (18 with AVF or graft) referred for pre-renal transplant cardiac assessment using SPECT/CT were studied with 2 comparison groups, 42 normal weight (body mass index<30) and 46 obese (body mass index>30) patients. End-stage renal disease patients had overall reduced mean hemoglobin 11.6 mg/dL and elevated mean parathyroid hormone of 396 pg/mL. Gated SPECT using MIBI was performed after Bruce protocol apart from 4 renal patients who underwent cardiac stressing with adenosine. Cardiac output was calculated by product of stroke volume and resting heart rate and CI determined. Mean CI was 2.6 L/min/m(2) for renal disease group compared with 2.2 and 2.3 L/min/m(2) for the normal weight and obese groups, P=0.005 and 0.005 respectively (Wilcoxon's rank test). Cardiac output was increased for the renal group; 4.9 L/min, equal to the obese group but greater than normal weight group at 4.3 L/min. No significant difference in LVEF was seen between the 3 patient groups. No significant difference in CI or output was seen between the renal disease patients with AVF and those without fistulas. Cardiac ouput and CI, assessed using SPECT/CT, are increased in patients with ESRD. This may be independent of the presence of AVF or grafts and other factors such as anemia and hyperparathyroidism may contribute to this high output cardiac function. As LVEF is not increased for these patients, increased heart rate, may also contribute to elevated CO.     

Survival with short‐daily hemodialysis: Association of time,site, and dose of dialysis

In thrice‐weekly hemodialysis, survival correlates with the length of time (t) of each dialysis and the dose (Kt/V), and deaths occur most frequently on Mondays and Tuesdays. We studied the influence of t and Kt/V on survival in 262 patients on short‐daily hemodialysis (SDHD) and also noted death rate by weekday. Contingency tables, Kaplan‐Meier analysis, regression analysis, and stepwise Cox proportional hazard analysis were used to study the associations of clinical variables with survival. Patients had been on SDHD for a mean of 2.1 (range 0.1–11) years. Mean dialysis time was 12.9 ± 2.3 h/wk and mean weekly stdKt/V was 2.7 ± 0.5. Fifty‐two of the patients died (20%) and 8‐year survival was 54 ± 5%. In an analysis of 4 groups by weekly dialysis time, 5‐year survival continuously increased from 45 ± 8% in those dialyzing <12 hours to 100% in those dialyzing >15 hours without any apparent threshold. There was no association between Kt/V and survival. In Cox proportional hazard analysis, 4 factors were independently associated with survival: age in years Hazard Ratio (HR)=1.05, weekly dialysis hours HR=0.84, home dialysis HR=0.50, and secondary renal disease HR=2.30. Unlike conventional HD, no pattern of excessive death occurred early in the week during SDHD. With SDHD, longer time and dialysis at home were independently associated with improved survival, while Kt/V was not. Homedialysis and dialysis 15+ h/wk appear to maximize survival in SDHD.     

Quantification of NTproBNP in rat serum using immunoprecipitation and LC/MS/MS: a biomarker of drug-induced cardiac hypertrophy

Brain natriuretic peptide (BNP) and N-terminal proBNP (NTproBNP) are well established in the clinic as biomarkers of heart failure. BNP hormone and the inactive NTproBNP are predominantly secreted in the ventricles of the heart in response to pressure overload and, consequently, are being investigated as markers of drug-induced cardiac hypertrophy in rat to support drug development. In the work presented here, an immunoaffinity-based LC/MS/MS assay was developed and validated to measure a selective tryptic fragment of NTproBNP in rat serum. The assay covers the range of 13-329 pg/mL of the tryptic fragment LLELIR, corresponding to 0.1-2.5 ng/mL intact NTproBNP. A stable isotope-labeled version of NTproBNP containing the tryptic fragment LLELI[13C615N1]R was prepared by solid-phase peptide synthesis and was used as an internal standard to minimize assay variability. Due to endogenous NTproBNP present in rat serum, human serum was used as the control matrix, and parallelism between rat and human serum was established by standard addition. Assay accuracy (% RE) and precision (% CV) were measured at three concentrations on each of 4 days and did not exceed 4.2 and 14.5%, respectively. Additionally, study data are presented from the application of this assay in which rats demonstrated a significant increase in NTproBNP serum concentration following administration of an agent known to induce cardiac hypertrophy. In this study, the relationship between serum NTproBNP and cardiac hypertrophy was corroborated by increases in heart weight and magnetic resonance imaging of the test subjects' left ventricle. To our knowledge, this represents the first reported assay for NTproBNP in preclinical species for the assessment of cardiac hypertrophy.     

Fallacies of High‐Speed Hemodialysis

Chronic hemodialysis sessions, as developed in Seattle in the 1960s, were long procedures with minimal intra‐ and interdialytic symptoms. Financial and logistical pressures related to the overwhelming number of patients requiring hemodialysis created an incentive to shorten dialysis time to four, three, and even two hours per session in a thrice weekly schedule. This method spread rapidly, particularly in the United States, after the National Cooperative Dialysis Study suggested that time of dialysis is of minor importance as long as urea clearance multiplied by dialysis time and scaled to total body water (Kt/V_urea) equals 0.95–1.0. This number was later increased to 1.3, but the assumption remained unchanged that hemodialysis time is of minimal importance as long as it is compensated by increased urea clearance. Patients accepted short dialysis as a godsend, believing that it would not be detrimental to their well‐being and longevity. However, Kt/V_urea measures only removal of low molecular weight substances and does not consider removal of larger molecules. Besides, it does not correlate with the other important function of hemodialysis, namely ultrafiltration. Whereas patients with substantial residual renal function may tolerate short dialysis sessions, the patients with little or no urine output tolerate short dialyses poorly because the ultrafiltration rate at the same interdialytic weight gain is inversely proportional to dialysis time. Rapid ultrafiltration is associated with cramps, nausea, vomiting, headache, fatigue, hypotensive episodes during dialysis, and hangover after dialysis; patients remain fluid overloaded with subsequent poor blood pressure control, left ventricular hypertrophy, diastolic dysfunction, and high cardiovascular mortality. Short, high‐efficiency dialysis requires high blood flow, which increases demands on blood access. The classic wrist arteriovenous fistula, the access with the best longevity and lowest complication rates, provides “insufficient” blood flow and is replaced with an arteriovenous graft fistula or an intravenous catheter. Moreover, to achieve high blood flows, large diameter intravenous catheters are used; these fit veins “too tightly,” so predispose the patient to central‐vein thrombosis. Longer hemodialysis sessions (5–8 hrs, thrice weekly), as practiced in some centers, are associated with lower complication rates and better outcomes. Frequent dialyses (four or more sessions per week) provide better clinical results, but are associated with increased cost. It is my strong belief that a wide acceptance of longer, gentler dialysis sessions, even in a thrice weekly schedule, would improve overall hemodialysis results and decrease access complications, hospitalizations, and mortality, particularly in anuric patients.     

Can twice weekly hemodialysis expand patient access under resource constraints?

The convention of prescribing hemodialysis on a thrice weekly schedule began empirically when it seemed that this frequency was convenient and likely to treat symptoms for a majority of patients. Later, when urea was identified as the main target and marker of clearance, studies supported the prevailing notion that thrice weekly dialysis provided appropriate clearance of urea. Today, national guidelines on hemodialysis from most countries recommend patients receive at least thrice weekly therapy. However, resource constraints in low‐ and middle‐income countries (LMIC) have resulted in a substantial proportion of patients using less frequent hemodialysis in these settings. Observational studies of patients on twice weekly dialysis show that twice weekly therapy has noninferior survival rates compared with thrice weekly therapy. In fact, models of urea clearance also show that twice weekly therapy can meet urea clearance “targets” if patients have significant residual function or if they follow a protein‐restricted diet, as may be common in LMIC. Greater reliance on twice weekly therapy, at least at the start of hemodialysis, therefore has potential to reduce health care costs and increase access to renal replacement therapy in low‐resource settings; however, randomized control trials are needed to better understand long‐term outcomes of twice versus thrice weekly therapy.