Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial.

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

Interactions between intradialytic central venous oxygen saturation, relative blood volume, and all-cause mortality in maintenance hemodialysis patients.

INTRODUCTION: In maintenance hemodialysis (HD) patients, low central venous oxygen saturation (ScvO2 ) and small decline in relative blood volume (RBV) have been associated with adverse outcomes. Here we explore the joint association between ScvO2 and RBV change in relation to all-cause mortality. METHODS: We conducted a retrospective study in maintenance HD patients with central venous catheters as vascular access. During a 6-month baseline period, Crit-Line (Fresenius Medical Care, Waltham, MA) was used to measure continuously intradialytic ScvO2 and hematocrit-based RBV. We defined four groups per median change of RBV and median ScvO2 . Patients with ScvO2 above median and RBV change below median were defined as reference. Follow-up period was 3 years. We constructed Cox proportional hazards model with adjustment for age, diabetes, and dialysis vintage to assess the association between ScvO2 and RBV and all-cause mortality during follow-up. FINDINGS: Baseline comprised 5231 dialysis sessions in 216 patients. The median RBV change was -5.5% and median ScvO2 was 58.8%. During follow-up, 44 patients (20.4%) died. In the adjusted model, all-cause mortality was highest in patients with ScvO2 below median and RBV change above median (HR 6.32; 95% confidence interval [CI] 1.37-29.06), followed by patients with ScvO2 below median and RBV change below median (HR 5.04; 95% CI 1.14-22.35), and ScvO2 above median and RBV change above median (HR 4.52; 95% CI 0.95-21.36). DISCUSSION: Concurrent combined monitoring of intradialytic ScvO2 and RBV change may provide additional insights into a patient's circulatory status. Patients with low ScvO2 and small changes in RBV may represent a specifically vulnerable group of patients at particularly high risk for adverse outcomes, possibly related to poor cardiac reserve and fluid overload.

Effect of Multiple Doses of Sparsentan on the Single-Dose Pharmacokinetics of Dapagliflozin: An Open-Label Drug-Drug Interaction Study in Healthy Adults.

Sparsentan is a single-molecule dual antagonist of the endothelin type A receptor and angiotensin II type 1 receptor under investigation for the treatment of focal segmental glomerulosclerosis and immunoglobulin A nephropathy. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has recently been indicated in chronic kidney disease. Sparsentan may be considered for concomitant use with dapagliflozin. The purpose of this open-label, 1-sequence crossover study was to determine whether drug-drug interactions between sparsentan and dapagliflozin affect dapagliflozin pharmacokinetics (PK). In addition, exposure to the inactive metabolite of dapagliflozin, dapagliflozin-3-O-glucuronide, was used to evaluate the effect of sparsentan on the primary metabolizing enzyme of dapagliflozin, uridine 5'-diphospho-glucuronosyltransferase 1A9. The study included 22 healthy adults treated with 10 mg of dapagliflozin on day 1, and 800 mg/day of sparsentan on days 5-14, with a 10-mg dose of dapagliflozin coadministered on day 11. PK samples were taken for dapagliflozin, dapagliflozin-3-O-glucuronide, and sparsentan before and after treatment throughout the study. Steady-state concentrations of sparsentan following daily dosing did not affect the PK of single-dose dapagliflozin in healthy adults. Dapagliflozin-3-O-glucuronide PK suggests a minimal effect of sparsentan on metabolism of dapagliflozin by uridine 5'-diphospho-glucuronosyltransferase 1A9. No deaths, serious adverse events, or unusual safety signals occurred. Results suggest dapagliflozin PK is not affected by sparsentan daily dosing.

Estimation of fluid status using three multifrequency bioimpedance methods in hemodialysis patients.

INTRODUCTION: Segmental eight-point bioimpedance has been increasingly used in practice. However, whether changes in bioimpedance analysis components before and after hemodialysis (HD) using this technique in a standing position is comparable to traditional whole-body wrist-to-ankle method is still unclear. We aimed to investigate the differences between two eight-point devices (InBody 770 and Seca mBCA 514) and one wrist-to-ankle (Hydra 4200) in HD patients and healthy subjects in a standing position. METHODS: Thirteen HD patients were studied pre- and post-HD, and 12 healthy subjects once. Four measurements were performed in the following order: InBody; Seca; Hydra; and InBody again. Electrical equivalent models by each bioimpedance method and the fluid volume estimates by each device were also compared. FINDINGS: Overall, total body water (TBW) was not different between the three devices, but InBody showed lower extracellular water (ECW) and higher intracellular water (ICW) compared to the other two devices. When intradialytic weight loss was used as a surrogate for changes in ECW (∆ECW) and changes in TBW (∆TBW), ∆ECW was underestimated by Hydra (-0.79 ± 0.89 L, p < 0.01), InBody (-1.44 ± 0.65 L, p < 0.0001), and Seca (-0.32 ± 1.34, n.s.). ∆TBW was underestimated by Hydra (-1.14 ± 2.81 L, n.s.) and InBody (-0.52 ± 0.85 L, p < 0.05) but overestimated by Seca (+0.93 ± 3.55 L, n.s.). DISCUSSION: Although segmental eight-point bioimpedance techniques provided comparable TBW measurements not affected by standing over a period of 10-15 min, the ECW/TBW ratio appeared to be significantly lower in InBody compared with Seca and Hydra. Results from our study showed lack of agreement between different bioimpedance devices; direct comparison of ECW, ICW, and ECW/TBW between different devices should be avoided and clinicians should use the same device to track the fluid status in their HD population in a longitudinal direction.

Arterial oxygen saturation and hypoxemia in hemodialysis patients with COVID-19.

BACKGROUND: Maintenance hemodialysis (MHD) patients are particularly vulnerable to coronavirus disease 2019 (COVID-19), a viral disease that may cause interstitial pneumonia, impaired alveolar gas exchange and hypoxemia. We ascertained the time course of intradialytic arterial oxygen saturation (SaO2) in MHD patients between 4 weeks pre-diagnosis and the week post-diagnosis of COVID-19. METHODS: We conducted a quality improvement project in confirmed COVID-19 in-center MHD patients from 11 dialysis facilities. In patients with an arterio-venous access, SaO2 was measured 1×/min during dialysis using the Crit-Line monitor (Fresenius Medical Care, Waltham, MA, USA). We extracted demographic, clinical, treatment and laboratory data, and COVID-19-related symptoms from the patients' electronic health records. RESULTS: Intradialytic SaO2 was available in 52 patients (29 males; mean ± standard deviation age 66.5 ± 15.7 years) contributing 338 HD treatments. Mean time between onset of symptoms indicative of COVID-19 and diagnosis was 1.1 days (median 0; range 0-9). Prior to COVID-19 diagnosis the rate of HD treatments with hypoxemia, defined as treatment-level average SaO2 <90%, increased from 2.8% (2-4 weeks pre-diagnosis) to 12.2% (1 week) and 20.7% (3 days pre-diagnosis). Intradialytic O2 supplementation increased sharply post-diagnosis. Eleven patients died from COVID-19 within 5 weeks. Compared with patients who recovered from COVID-19, demised patients showed a more pronounced decline in SaO2 prior to COVID-19 diagnosis. CONCLUSIONS: In HD patients, hypoxemia may precede the onset of clinical symptoms and the diagnosis of COVID-19. A steep decline of SaO2 is associated with poor patient outcomes. Measurements of SaO2 may aid the pre-symptomatic identification of patients with COVID-19.

Effect of Statewide Lockdown in Response to COVID-19 Pandemic on Physical Activity Levels of Hemodialysis Patients.

BACKGROUND/OBJECTIVES: On March 22, 2020, a statewide stay-at-home order for nonessential tasks was implemented in New York State. We aimed to determine the impact of the lockdown on physical activity levels (PAL) in hemodialysis patients. METHODS: Starting in May 2018, we are conducting an observational study with a 1-year follow-up on PAL in patients from 4 hemodialysis clinics in New York City. Patients active in the study as of March 22, 2020, were included. PAL was defined by steps taken per day measured by a wrist-based monitoring device (Fitbit Charge 2). Average steps/day were calculated for January 1 to February 13, 2020, and then weekly from February 14 to June 30. RESULTS: 42 patients were included. Their mean age was 55 years, 79% were males, and 69% were African Americans. Between January 1 and February 13, 2020, patients took on average 5,963 (95% CI 4,909-7,017) steps/day. In the week prior to the mandated lockdown, when a national emergency was declared, and in the week of the shutdown, the average number of daily steps had decreased by 868 steps/day (95% CI 213-1,722) and 1,222 steps/day (95% CI 668-2300), respectively. Six patients were diagnosed with COVID-19 during the study period. Five of them exhibited significantly higher PAL in the 2 weeks prior to showing COVID-19 symptoms compared to COVID-19 negative patients. CONCLUSION: Lockdown measures were associated with a significant decrease in PAL in hemodialysis patients. Patients who contracted COVID-19 had higher PAL during the incubation period. Methods to increase PAL while allowing for social distancing should be explored and implemented.

SARS-CoV-2 in Spent Dialysate from Chronic Peritoneal Dialysis Patients with COVID-19.

Background: To date, it is unclear whether SARS-CoV-2 is present in spent dialysate from patients with COVID-19 on peritoneal dialysis (PD). Our aim was to assess the presence or absence of SARS-CoV-2 in spent dialysate from patients on chronic PD who had a confirmed diagnosis of COVID-19. Methods: Spent PD dialysate samples from patients on PD who were positive for COVID-19 were collected between March and August 2020. The multiplexed, real-time RT-PCR assay contained primer/probe sets specific to different SARS-CoV-2 genomic regions and to bacteriophage MS2 as an internal process control for nucleic acid extraction. Demographic and clinical data were obtained from patients' electronic health records. Results: A total of 26 spent PD dialysate samples were collected from 11 patients from ten dialysis centers. Spent PD dialysate samples were collected, on average, 25±13 days (median, 20; range, 10-45) after the onset of symptoms. The temporal distance of PD effluent collection relative to the closest positive nasal-swab RT-PCR result was 15±11 days (median, 14; range, 1-41). All 26 PD effluent samples tested negative at three SARS-CoV-2 genomic regions. Conclusions: Our findings indicate the absence of SARS-CoV-2 in spent PD dialysate collected at ≥10 days after the onset of COVID-19 symptoms. We cannot rule out the presence of SARS-CoV-2 in spent PD dialysate in the early stage of COVID-19.

A mathematical model of the four cardinal acid-base disorders.

Precise maintenance of acid-base homeostasis is fundamental for optimal functioning of physiological and cellular processes. The presence of an acid-base disturbance can affect clinical outcomes and is usually caused by an underlying disease. It is, therefore, important to assess the acid-base status of patients, and the extent to which various therapeutic treatments are effective in controlling these acid-base alterations. In this paper, we develop a dynamic model of the physiological regulation of an HCO3-/CO2 buffering system, an abundant and powerful buffering system, using Henderson-Hasselbalch kinetics. We simulate the normal physiological state and four cardinal acidbase disorders: Metabolic acidosis and alkalosis and respiratory acidosis and alkalosis. We show that the model accurately predicts serum pH over a range of clinical conditions. In addition to qualitative validation, we compare the in silico results with clinical data on acid-base homeostasis and alterations, finding clear relationships between primary acid-base disturbances and the secondary adaptive compensatory responses. We also show that the predicted primary disturbances accurately resemble clinically observed compensatory responses. Furthermore, via sensitivity analysis, key parameters were identified which could be the most effective in regulating systemic pH in healthy individuals, and those with chronic kidney disease and distal and proximal renal tubular acidosis. The model presented here may provide pathophysiologic insights and can serve as a tool to assess the safety and efficacy of different therapeutic interventions to control or correct acid-base disorders.

Association of all-cause mortality with pre-dialysis systolic blood pressure and its peridialytic change in chronic hemodialysis patients.

BACKGROUND: Pre-dialysis systolic blood pressure (pre-HD SBP) and peridialytic SBP change have been associated with morbidity and mortality among hemodialysis (HD) patients in previous studies, but the nature of their interaction is not well understood. METHODS: We analyzed pre-HD SBP and peridialytic SBP change (calculated as post-HD SBP minus pre-HD SBP) between January 2001 and December 2012 in HD patients treated in US Fresenius Medical Care facilities. The baseline period was defined as Months 4-6 after HD initiation, and all-cause mortality was noted during follow-up. Only patients who survived baseline and had no missing covariates were included. Censoring events were renal transplantation, modality change or study end. We fitted a Cox proportional hazard model with a bivariate spline functions for the primary predictors (pre-HD SBP and peridialytic SBP change) with adjustment for age, gender, race, diabetes, access-type, relative interdialytic weight gain, body mass index, albumin, equilibrated normalized protein catabolic rate and ultrafiltration rate. RESULTS: A total of 172 199 patients were included. Mean age was 62.1 years, 61.6% were white and 55% were male. During a median follow-up of 25.0 months, 73 529 patients (42.7%) died. We found that a peridialytic SBP rise combined with high pre-HD SBP was associated with higher mortality. In contrast, when concurrent with low pre-HD SBP, a peridialytic SBP rise was associated with better survival. CONCLUSION: The association of pre-HD and peridialytic SBP change with mortality is complex. Our findings call for a joint, not isolated, interpretation of pre-HD SBP and peridialytic SBP change.

Association of Central Venous Oxygen Saturation Variability and Mortality in Hemodialysis Patients.

BACKGROUND: Central venous oxygen saturation (ScvO2) is correlated with cardiac output. In most patients, ScvO2 declines during hemodialysis (HD) due to factors such as reduced preload, myocardial stunning, and intermittent arrhythmias. Previous research has shown that low ScvO2 is associated with higher mortality in chronic HD patients. In this research, we tested the hypothesis that ScvO2 variability is associated with all-cause mortality. METHODS: We conducted a retrospective study in 232 chronic HD patients with central venous catheter as vascular access. ScvO2 was recorded 1× per minute during dialysis using the Crit-Line monitor. A 6-month baseline comprising at least 10 dialysis treatments with ScvO2 recordings preceded a follow-up period of up to 3 years. The coefficient of variation (CV) of ScvO2 (100 times the ratio of the standard deviation and mean of ScvO2) served as a measure of ScvO2 stability during baseline. Patients were stratified by median population CV of ScvO2 during baseline, and survival during follow-up was compared between the 2 groups by Kaplan Meier and multivariate Cox analysis. The association between CV of ScvO2 and all-cause mortality during follow-up was further assessed by Cox analysis with a spline term for CV of ScvO2. RESULTS: The mean CV ± standard deviation of ScvO2 in our population was 6.1 ± 2.7% and the median was 5.3%. Univariate Kaplan-Meier analysis (p = 0.043) and multivariate Cox analysis (hazard ratio [HR] 1.16; p = 0.0005) indicated that a CV of ScvO2 > 5.3% was significantly associated with increased mortality. In Cox analysis with spline term, a CV of ScvO2 >  11% was associated with a significantly increased HR for all-cause mortality. CONCLUSION: High ScvO2 variability during dialysis is associated with increased all-cause mortality.

All-cause mortality in relation to changes in relative blood volume during hemodialysis.

BACKGROUND: Relative blood volume (RBV) monitoring is widely used in hemodialysis (HD) patients, yet the association between intradialytic RBV and mortality is unknown. METHODS: Intradialytic RBV was recorded once/min during a 6-month baseline period; all-cause mortality was noted during follow-up. RBV at 1, 2 and 3 h into HD served as a predictor of all-cause mortality during follow-up. We employed Kaplan-Meier analysis, univariate and adjusted Cox proportional hazards models for survival analysis. RESULTS: We studied 842 patients. During follow-up (median 30.8 months), 249 patients (29.6%) died. The following hourly RBV ranges were associated with improved survival: first hour, 93-96% [hazard ratio (HR) 0.58 (95% confidence interval (CI) 0.42-0.79)]; second hour, 89-94% [HR 0.54 (95% CI 0.39-0.75)]; third hour, 86-92% [HR 0.46 (95% CI 0.33-0.65)]. In about one-third of patients the RBV was within these ranges and in two-thirds it was above. Subgroup analysis by median age (≤/> 61 years), sex, race (white/nonwhite), predialysis systolic blood pressure (SBP; ≤/> 130 mmHg) and median interdialytic weight gain (≤/> 2.3 kg) showed comparable favorable RBV ranges. Patients with a 3-h RBV between 86 and 92% were younger, had higher ultrafiltration volumes and rates, similar intradialytic average and nadir SBPs and hypotension rates, lower postdialysis SBP and a lower prevalence of congestive heart failure when compared with patients with an RBV >92%. In the multivariate Cox analysis, RBV ranges remained independent and significant outcome predictors. CONCLUSION: Specific hourly intradialytic RBV ranges are associated with lower all-cause mortality in chronic HD patients.

Relationships between Neighborhood Walkability and Objectively Measured Physical Activity Levels in Hemodialysis Patients.

BACKGROUND/AIMS: Neighborhood walkability is associated with indicators of health in the general population. We explored the association between neighborhood walkability and daily steps in hemodialysis (HD) patients. METHODS: We measured daily steps over 5 weeks using Fitbit Flex (Fitbit, San Francisco, CA, USA) and retrieved Walk Score® (WS) data by patient's home ZIP code (www.walkscore.com; 0 = poorest walkability; 100 = greatest walkability). RESULTS: HD patients took a mean of 6,393 ± 3,550 steps/day (n = 46). Median WS of the neighborhood where they resided was 28. Patients in an above-median WS (n = 27) neighborhood took significantly more daily steps compared to those (n = 19) in a below-median WS neighborhood (7,514 ± 3,900 vs. 4,800 ± 2,228 steps/day; p < 0.001, t test). Daily steps and WS were directly correlated (R = 0.425; p = 0.0032, parametric test; R = 0.359, p = 0.0143, non-parametric test). CONCLUSION: This is the first study conducted among HD patients to indicate a direct relationship between neighborhood walkability and the actual steps taken. These results should be considered when designing initiatives to increase and improvise exercise routines in HD populations.

Association between intradialytic central venous oxygen saturation and ultrafiltration volume in chronic hemodialysis patients.

Background: Cardiac disease is highly prevalent in hemodialysis (HD) patients. Decreased tissue perfusion, including cardiac, due to high ultrafiltration volumes (UFVs) is considered to be one of the drivers of cardiac dysfunction. While central venous oxygen saturation (ScvO2) is frequently used as an indicator of cardiac output in non-uremic populations, the relationship of ScvO2 and UFV in HD patients remains unclear. Our aim was to determine how intradialytic ScvO2 changes associate with UFV. Methods: We conducted a 6-month retrospective cohort study in maintenance HD patients with central venous catheters as vascular access. Intradialytic ScvO2 was measured with the Critline monitor. We computed treatment-level slopes of intradialytic ScvO2 over time (ScvO2 trend) and applied linear mixed effects models to assess the association between patient-level ScvO2 trends and UFV corrected for body weight (cUFV). Results: We studied 6042 dialysis sessions in 232 patients. In about 62.4% of treatments, ScvO2 decreased. We observed in nearly 80% of patients an inverse relationship between cUFV and ScvO2 trend, indicating that higher cUFV is associated with steeper decline in ScvO2 during dialysis. Conclusions: In most patients, higher cUFV volumes are associated with steeper intradialytic ScvO2 drops. We hypothesize that in a majority of patients the intradialytic cardiac function is fluid dependent, so that in the face of high ultrafiltration rates or volume, cardiac pre-load and consequently cardiac output decreases. Direct measurements of cardiac hemodynamics are warranted to further test this hypothesis.

Intradialytic hypertension is associated with low intradialytic arterial oxygen saturation.

Background: The pathophysiology of a paradoxical systolic blood pressure (SBP) rise during hemodialysis (HD) is not yet fully understood. Recent research indicated that 10% of chronic HD patients suffer from prolonged intradialytic hypoxemia. Since hypoxemia induces a sympathetic response we entertained the hypothesis that peridialytic SBP change is associated with arterial oxygen saturation (SaO2). Methods: We retrospectively analyzed intradialytic SaO2 and peridialytic SBP change in chronic HD patients with arteriovenous vascular access. Patients were followed for 6 months. We defined persistent intradialytic hypertension (piHTN) as average peridialytic SBP increase ≥10 mmHg over 6 months. Linear mixed effects (LME) models were used to explore associations between peridialytic SBP change and intradialytic SaO2 in univariate and adjusted analyses. Results: We assessed 982 patients (29 872 HD treatments; 59% males; 53% whites). Pre-dialysis SBP was 146.7 ± 26.5 mmHg and decreased on average by 10.1 ± 24.5 mmHg. Fifty-three (5.7%) patients had piHTN. piHTN patients had lower intradialytic SaO2, body weight and interdialytic weight gain. LME models revealed that with every percentage point lower mean SaO2, the peridialytic SBP change increased by 0.46 mmHg (P < 0.001). This finding was corroborated in multivariate analyses. Conclusion: We observed an inverse relationship between intradialytic SaO2 and the blood pressure response to HD. These findings support the notion that hypoxemia activates mechanisms that partially blunt the intradialytic blood pressure decline, possibly by sympathetic activation and endothelin-1 secretion. To further explore that hypothesis, specifically designed prospective studies are required.

An in silico method to predict net calcium transfer during hemodialysis.

International guidelines for chronic hemodialysis patients suggest a dialysate calcium concentration between 1.25 and 1.5 mmol/L. However, it is not certain if these dialysate calcium levels result in net calcium transfer into the patient. With ubiquitous prevalence of vascular calcification in hemodialysis patients, it is pertinent to model the mass balance of calcium during dialysis. To this end, we developed a two compartmental patient model and spatiotemporal representation of dialyzer model to investigate and quantify the calcium mass balance during dialysis. The model accounts for calcium-albumin binding and varying protein concentration; the latter accounts for the Gibbs-Donnan effect. The model simulations suggest that despite a lower dialysate calcium concentration of 1.25 mmol/L, some of our patients may be loaded with calcium during dialysis. This net calcium flux from dialysate to blood side may be a potential contributor to vascular calcification, a primary cause of cardiovascular mortality in hemodialysis patients.

Dialysis Access as an Area of Improvement in Elderly Incident Hemodialysis Patients: Results from a Cohort Study from the International Monitoring Dialysis Outcomes Initiative.

BACKGROUND: Commencing hemodialysis (HD) using a catheter is associated with a higher risk of adverse outcomes, and early conversion from central-venous catheter (CVC) to arteriovenous fistula/graft (non-CVC) improves outcomes. We investigated CVC prevalence and conversion, and their effects on outcomes during the first year of HD in a multinational cohort of elderly patients. METHODS: Patients ≥70 years from the MONDO Initiative who commenced HD between 2000 and 2010 in Asia-Pacific, Europe, North-, and South-America and survived at least 6 months were included in this investigation. We stratified by age (70-79 years [younger] vs. ≥80 years [older]) and compared access types (at first and last available date) and their changes. We studied the association between access at initiation and conversion, respectively, and all-cause mortality using Kaplan-Meier curve and Cox regression, and predicted the absence of conversion from catheter to non-CVC using adjusted logistic regression. RESULTS: In 14,966 elderly, incident HD patients, survival was significantly worse when using a CVC at all times. In Europe, the conversion frequency from CVC to non-CVC was higher in the younger fraction. Conversion from non-CVC to CVC was associated with worsened outcomes only in the older fraction. CONCLUSION: These results corroborate the need for early HD preparation in the elderly HD population. Treatment of elderly patients who commence HD with a CVC should be planned considering aspects of individual clinical risk assessment. Differences in treatment practices in predialysis care specific to the elderly as a population may influence access care and conversion rate.