Branched-chain ketoacid co-ingestion with protein lowers amino acid oxidation during hemodialysis: A randomized controlled cross-over trial.

BACKGROUND & AIMS: Hemodialysis removes amino acids from the circulation, thereby stimulating muscle proteolysis. Protein ingestion during hemodialysis can compensate for amino acid removal but may also increase uremic toxin production. Branched-chain ketoacid (BCKA) co-ingestion may provide an additional anabolic stimulus without adding to uremic toxin accumulation. In the present study we assessed the impact of BCKA co-ingestion with protein on forearm amino acid balance and amino acid oxidation during hemodialysis. METHODS: Nine patients (age: 73 ± 10 y) on chronic hemodialysis participated in this crossover trial. During two 4-h hemodialysis sessions, patients ingested 18 g protein with (PRO + BCKA) or without (PRO) 9 g BCKAs in a randomized order. Test beverages were labeled with L-[ring-13C6]-phenylalanine and provided throughout the last 3 h of hemodialysis as 18 equal sips consumed with 10-min intervals. Arterial and venous plasma as well as breath samples were collected frequently throughout hemodialysis. RESULTS: Arterial plasma total amino acid (TAA) concentrations during PRO and PRO + BCKA treatments were significantly lower after 1 h of hemodialysis (2.6 ± 0.3 and 2.6 ± 0.3 mmol/L, respectively) when compared to pre-hemodialysis concentrations (4.2 ± 1.0 and 4.0 ± 0.5 mmol/L, respectively; time effect: P < 0.001). Arterial plasma TAA concentrations increased throughout test beverage ingestion (time effect: P = 0.027) without differences between treatments (time∗treatment: P = 0.62). Forearm arteriovenous TAA balance during test beverage ingestion did not differ between timepoints (time effect: P = 0.31) or treatments (time∗treatment: P = 0.34). Whole-body phenylalanine oxidation was 33 ± 16% lower during PRO + BCKA when compared to PRO treatments (P < 0.001). CONCLUSIONS: BCKA co-ingestion with protein during hemodialysis does not improve forearm net protein balance but lowers amino acid oxidation.

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.

Biphasic Dynamics of Inflammatory Markers Following Hemodialysis Initiation: Results From the International MONitoring Dialysis Outcome Initiative.

Introduction: Inflammation is highly prevalent among patients with end-stage kidney disease and is associated with adverse outcomes. We aimed to investigate longitudinal changes in inflammatory markers in a diverse international incident hemodialysis patient population. Methods: The MONitoring Dialysis Outcomes (MONDO) Consortium encompasses hemodialysis databases from 31 countries in Europe, North America, South America, and Asia. The MONDO database was queried for inflammatory markers (total white blood cell count [WBC], neutrophil count, lymphocyte count, serum albumin, and C-reactive protein [CRP]) and hemoglobin levels in incident hemodialysis patients. Laboratory parameters were measured every month. Patients were stratified by survival time (≤6 months, >6 to 12 months, >12 to 18 months, >18 to 24 months, >24 to 30 months, >30 to 36 months, and >36 months) following dialysis initiation. We used cubic B-spline basis function to evaluate temporal changes in inflammatory parameters in relationship with patient survival. Results: We studied 18,726 incident hemodialysis patients. Their age at dialysis initiation was 71.3 ± 11.9 years; 10,802 (58%) were males. Within the first 6 months, 2068 (11%) patients died, and 12,295 patients (67%) survived >36 months (survivor cohort). Hemodialysis patients who died showed a distinct biphasic pattern of change in inflammatory markers where an initial decline of inflammation was followed by a rapid rise that was consistently evident approximately 6 months before death. This pattern was similar in all patients who died and was consistent across the survival time intervals. In contrast, in the survivor cohort, we observed initial decline of inflammation followed by sustained low levels of inflammatory biomarkers. Conclusion: Our international study of incident hemodialysis patients highlights a temporal relationship between serial measurements of inflammatory markers and patient survival. This finding may inform the development of prognostic models, such as the integration of dynamic changes in inflammatory markers for individual risk profiling and guiding preventive and therapeutic interventions.

Intradialytic Protein Ingestion and Exercise do Not Compromise Uremic Toxin Removal Throughout Hemodialysis.

OBJECTIVE: Dietary protein and physical activity interventions are increasingly implemented during hemodialysis to support muscle maintenance in patients with end-stage renal disease (ESRD). Although muscle maintenance is important, adequate removal of uremic toxins throughout hemodialysis is the primary concern for patients. It remains to be established whether intradialytic protein ingestion and/or exercise modulate uremic toxin removal during hemodialysis. METHODS: We recruited 10 patients with ESRD (age: 65 ± 16 y, BMI: 24.2 ± 4.8 kg/m2) on chronic hemodialysis treatment to participate in this randomized cross-over trial. During hemodialysis, patients were assigned to ingest 40 g protein or a nonprotein placebo both at rest (protein [PRO] and placebo [PLA], respectively) and following 30 min of exercise (PRO + exercise [EX] and PLA + EX, respectively). Blood and spent dialysate samples were collected throughout hemodialysis to assess reduction ratios and removal of urea, creatinine, phosphate, cystatin C, and indoxyl sulfate. RESULTS: The reduction ratios of urea and indoxyl sulfate were higher during PLA (76 ± 6% and 46 ± 9%, respectively) and PLA + EX interventions (77 ± 5% and 45 ± 10%, respectively) when compared to PRO (72 ± 4% and 40 ± 8%, respectively) and PRO + EX interventions (73 ± 4% and 43 ± 7%, respectively; protein effect: P = .001 and P = .023, respectively; exercise effect: P = .25 and P = .52, respectively). Nonetheless, protein ingestion resulted in greater urea removal (P = .046) during hemodialysis. Reduction ratios and removal of creatinine, phosphate, and cystatin C during hemodialysis did not differ following intradialytic protein ingestion or exercise (protein effect: P > .05; exercise effect: P>.05). Urea, creatinine, and phosphate removal were greater throughout the period with intradialytic exercise during PLA + EX and PRO + EX interventions when compared to the same period during PLA and PRO interventions (exercise effect: P = .034, P = .039, and P = .022, respectively). CONCLUSION: The removal of uremic toxins is not compromised by protein feeding and/or exercise implementation during hemodialysis in patients with ESRD.

On the potential of wearable bioimpedance for longitudinal fluid monitoring in end-stage kidney disease.

Bioimpedance spectroscopy (BIS) has proven to be a promising non-invasive technique for fluid monitoring in haemodialysis (HD) patients. While current BIS-based monitoring of pre- and post-dialysis fluid status utilizes benchtop devices, designed for intramural use, advancements in micro-electronics have enabled the development of wearable bioimpedance systems. Wearable systems meanwhile can offer a similar frequency range for current injection as commercially available benchtop devices. This opens opportunities for unobtrusive longitudinal fluid status monitoring, including transcellular fluid shifts, with the ultimate goal of improving fluid management, thereby lowering mortality and improving quality of life for HD patients. Ultra-miniaturized wearable devices can also offer simultaneous acquisition of multiple other parameters, including haemodynamic parameters. Combination of wearable BIS and additional longitudinal multiparametric data may aid in the prevention of both haemodynamic instability as well as fluid overload. The opportunity to also acquire data during interdialytic periods using wearable devices likely will give novel pathophysiological insights and the development of smart (predicting) algorithms could contribute to personalizing dialysis schemes and ultimately to autonomous (nocturnal) home dialysis. This review provides an overview of current research regarding wearable bioimpedance, with special attention to applications in end-stage kidney disease patients. Furthermore, we present an outlook on the future use of wearable bioimpedance within dialysis practice.

Estimation of Muscle Mass in the Integrated Assessment of Patients on Hemodialysis.

Assessment of muscle mass (MM) or its proxies, lean tissue mass (LTM) or fat-free mass (FFM), is an integral part of the diagnosis of protein-energy wasting (PEW) and sarcopenia in patients on hemodialysis (HD). Both sarcopenia and PEW are related to a loss of functionality and also increased morbidity and mortality in this patient population. However, loss of MM is a part of a wider spectrum, including inflammation and fluid overload. As both sarcopenia and PEW are amendable to treatment, estimation of MM regularly is therefore of major clinical relevance. Whereas, computer-assisted tomography (CT) or dual-energy X-ray absorptiometry (DXA) is considered a reference method, it is unsuitable as a method for routine clinical monitoring. In this review, different bedside methods to estimate MM or its proxies in patients on HD will be discussed, with emphasis on biochemical methods, simplified creatinine index (SCI), bioimpedance spectroscopy (BIS), and muscle ultrasound (US). Body composition parameters of all methods are related to the outcome and appear relevant in clinical practice. The US is the only parameter by which muscle dimensions are measured. BIS and SCI are also dependent on either theoretical assumptions or the use of population-specific regression equations. Potential caveats of the methods are that SCI can be influenced by residual renal function, BIS can be influenced by fluid overload, although the latter may be circumvented by the use of a three-compartment model, and that muscle US reflects regional and not whole body MM. In conclusion, both SCI and BIS as well as muscle US are all valuable methods that can be applied for bedside nutritional assessment in patients on HD and appear suitable for routine follow-up. The choice for either method depends on local preferences. However, estimation of MM or its proxies should always be part of a multidimensional assessment of the patient followed by a personalized treatment strategy.

Amino acid removal during hemodialysis can be compensated for by protein ingestion and is not compromised by intradialytic exercise: a randomized controlled crossover trial.

BACKGROUND: Patients with end-stage renal disease (ESRD) undergoing hemodialysis experience a rapid decline in skeletal muscle mass and strength. Hemodialysis removes amino acids (AAs) from the circulation, thereby lowering plasma AA concentrations and stimulating proteolysis. OBJECTIVES: In the present study, we evaluate the impact of intradialytic protein ingestion at rest and following exercise on AA removal and plasma AA availability in patients with ESRD. METHODS: Ten patients (age: 65 ± 16 y, male/female: 8/2, BMI: 24.2 ± 4.8 kg/m2, serum albumin: 3.4 ± 0.3 g/dL) with ESRD undergoing hemodialysis participated in this randomized controlled crossover trial. During 4 hemodialysis sessions, patients were assigned to ingest 40 g protein or a placebo 60 min after initiation, both at rest (PRO and PLA, respectively) and following exercise (PRO + EX and PLA + EX, respectively). Spent dialysate and blood samples were collected every 30 min throughout hemodialysis to assess AA removal and plasma AA availability. RESULTS: Plasma AA concentrations declined by 26.1 ± 4.5% within 30 min after hemodialysis initiation during all interventions (P < 0.001, η2p > 0.79). Protein ingestion, but not intradialytic exercise, increased AA removal throughout hemodialysis (9.8 ± 2.0, 10.2 ± 1.6, 16.7 ± 2.2, and 17.3 ± 2.3 g during PLA, PLA + EX, PRO, and PRO + EX interventions, respectively; protein effect P < 0.001, η2p = 0.97; exercise effect P = 0.32, η2p = 0.11). Protein ingestion increased plasma AA concentrations until the end of hemodialysis, whereas placebo ingestion resulted in decreased plasma AA concentrations (time effect P < 0.001, η2p > 0.84). Plasma AA availability (incremental AUC) was greater during PRO and PRO + EX interventions (49 ± 87 and 70 ± 34 mmol/L/240 min, respectively) compared with PLA and PLA + EX interventions (-227 ± 54 and -208 ± 68 mmol/L/240 min, respectively; protein effect P < 0.001, η2p = 0.98; exercise effect P = 0.21, η2p = 0.16). CONCLUSIONS: Protein ingestion during hemodialysis compensates for AA removal and increases plasma AA availability both at rest and during recovery from intradialytic exercise. Intradialytic exercise does not compromise AA removal or reduce plasma AA availability during hemodialysis in a postabsorptive or postprandial state.

Effect of citric-acid dialysate on the QTC-interval.

Lower dialysate calcium (dCa) concentration and dialysate citric-acidification may positively affect calcification propensity in serum of haemodialysis (HD) patients. However, the accompanying lower ionized blood calcium concentration may lead to a prolonged cardiac action potential, which is possibly pro-arrhythmic. The aim of this study is to investigate the influence of citric-acid dialysate on the QT-interval corrected for heart rate (QTc) compared to conventional dialysate with different dCa concentrations. We conducted a four-week multicentre, randomized cross-over trial. In week one and three patients received acetic-acid dialysate with a dCa of 1.50 mmol/l (A1.5), in week two and four acetic-acid dialysate with a dCa of 1.25 mmol/l (A1.25) or citric-acid dialysate (1.0 mmol/l) with a dCa of 1.50 mmol/l (C1.5) depending on randomization. Patients had continuous ECG monitoring during one session in week one, two and four. The data of 13 patients were available for analysis. Results showed a significant though limited increase of QTc with C1.5 (from 427 to 444 ms (start to end); p = 0.007) and with A1.25 (from 431 to 449 ms; p < 0.001), but not with A1.5 (from 439 to 443 ms; p = 0.13). In conclusion, we found that the use of C1.5 or A1.25 is associated with a significant prolongation of QTc which was however relatively limited.

The impact of volume overload on technique failure in incident peritoneal dialysis patients.

BACKGROUND: Technique failure in peritoneal dialysis (PD) can be due to patient- and procedure-related factors. With this analysis, we investigated the association of volume overload at the start and during the early phase of PD and technique failure. METHODS: In this observational, international cohort study with longitudinal follow-up of incident PD patients, technique failure was defined as either transfer to haemodialysis or death, and transplantation was considered as a competing risk. We explored parameters at baseline or within the first 6 months and the association with technique failure between 6 and 18 months, using a competing risk model. RESULTS: Out of 1092 patients of the complete cohort, 719 met specific inclusion and exclusion criteria for this analysis. Being volume overloaded, either at baseline or Month 6, or at both time points, was associated with an increased risk of technique failure compared with the patient group that was euvolaemic at both time points. Undergoing treatment at a centre with a high proportion of PD patients was associated with a lower risk of technique failure. CONCLUSIONS: Volume overload at start of PD and/or at 6 months was associated with a higher risk of technique failure in the subsequent year. The risk was modified by centre characteristics, which varied among regions.

Relationship between serum phosphate levels and survival in chronic hemodialysis patients: interactions with age, malnutrition and inflammation.

BACKGROUND: Evidence indicates that the inverse relationships between phosphate levels and mortality maybe modified by age. Furthermore, malnutrition and inflammation could strengthen the risk associated with phosphate abnormalities. This study aimed to assess the associations between phosphate levels and mortality while accounting for the interactions with age and parameters associated with malnutrition and inflammation in hemodialysis (HD) patients. METHODS: Adult HD patients (n = 245 853) treated in Fresenius Medical Care North America clinics from January 2010 to October 2018 were enrolled. Baseline was defined as Months 4-6 on dialysis, with the subsequent 12 months as the follow-up period. Univariate and multivariate Cox proportional hazard models with spline terms were applied to study the nonlinear relationships between serum phosphate levels and mortality. The interactions of phosphate levels with albumin, creatinine, normalized protein catabolic rate (nPCR) and neutrophil-lymphocyte ratio (NLR) were assessed with smoothing spline analysis of variance Cox proportional hazard models. RESULTS: Older patients tended to have lower levels of serum phosphate, albumin, creatinine and nPCR. Additionally, both low (<4.0 mg/dL) and high (>5.5 mg/dL) phosphate levels were associated with higher risk of mortality across all age strata. The U-shaped relationships between phosphate levels and outcome persisted even for patients with low or high levels of serum albumin, creatinine, nPCR and NLR, respectively. CONCLUSION: The consistent U-shaped relationships between serum phosphate and mortality across age strata and levels of inflammatory and nutritional status should prompt the search for underlying causes and potentially nutritional intervention in clinical practice.

Sudden cardiac death in dialysis patients: different causes and management strategies.

Sudden cardiac death (SCD) represents a major cause of death in end-stage kidney disease (ESKD). The precise estimate of its incidence is difficult to establish because studies on the incidence of SCD in ESKD are often combined with those related to sudden cardiac arrest (SCA) occurring during a haemodialysis (HD) session. The aim of the European Dialysis Working Group of ERA-EDTA was to critically review the current literature examining the causes of extradialysis SCD and intradialysis SCA in ESKD patients and potential management strategies to reduce the incidence of such events. Extradialysis SCD and intradialysis SCA represent different clinical situations and should be kept distinct. Regarding the problem, numerically less relevant, of patients affected by intradialysis SCA, some modifiable risk factors have been identified, such as a low concentration of potassium and calcium in the dialysate, and some advantages linked to the presence of automated external defibrillators in dialysis units have been documented. The problem of extra-dialysis SCD is more complex. A reduced left ventricular ejection fraction associated with SCD is present only in a minority of cases occurring in HD patients. This is the proof that SCD occurring in ESKD has different characteristics compared with SCD occurring in patients with ischaemic heart disease and/or heart failure and not affected by ESKD. Recent evidence suggests that the fatal arrhythmia in this population may be due more frequently to bradyarrhythmias than to tachyarrhythmias. This fact may partly explain why several studies could not demonstrate an advantage of implantable cardioverter defibrillators in preventing SCD in ESKD patients. Electrolyte imbalances, frequently present in HD patients, could explain part of the arrhythmic phenomena, as suggested by the relationship between SCD and timing of the HD session. However, the high incidence of SCD in patients on peritoneal dialysis suggests that other risk factors due to cardiac comorbidities and uraemia per se may contribute to sudden mortality in ESKD patients.

Artificial intelligence enabled applications in kidney disease.

Artificial intelligence (AI) is considered as the next natural progression of traditional statistical techniques. Advances in analytical methods and infrastructure enable AI to be applied in health care. While AI applications are relatively common in fields like ophthalmology and cardiology, its use is scarcely reported in nephrology. We present the current status of AI in research toward kidney disease and discuss future pathways for AI. The clinical applications of AI in progression to end-stage kidney disease and dialysis can be broadly subdivided into three main topics: (a) predicting events in the future such as mortality and hospitalization; (b) providing treatment and decision aids such as automating drug prescription; and (c) identifying patterns such as phenotypical clusters and arteriovenous fistula aneurysm. At present, the use of prediction models in treating patients with kidney disease is still in its infancy and further evidence is needed to identify its relative value. Policies and regulations need to be addressed before implementing AI solutions at the point of care in clinics. AI is not anticipated to replace the nephrologists' medical decision-making, but instead assist them in providing optimal personalized care for their patients.

Changes in pre-dialysis blood pressure variability in the first year of dialysis associate with mortality in European hemodialysis patients: a retrospective cohort study on behalf of the MONDO Initiative.

Pre-hemodialysis systolic blood pressure variability (pre-HD SBPV) has been associated with outcomes. The association of a change in pre-HD SBPV over time with outcomes, and predictors of this change, has not yet been studied. Therefore, we studied this in a cohort of 8825 incident hemodialysis (HD) patients from the European Monitoring Dialysis Outcomes Initiative database. Patient level pre-HD SBPV was calculated as the standard deviation of the residuals of a linear regression model of systolic blood pressure (SBP) over time divided by individual mean SBP in the respective time periods. The pre-HD SBPV difference between months 1-6 and 7-12 was used as an indicator of pre-HD SBPV change. The association between pre-HD SBPV change and all-cause mortality in year 2 was analyzed by multivariate Cox models. Predictors of pre-HD SBPV change was determined by logistic regression models. We found the highest pre-HD SBPV tertile, in the first 6 months after initiation of HD, had the highest mortality rates (adjusted HR 1.44 (95% confidence intervals (95% CI): 1.15-1.79)). An increase in pre-HD SBPV between months 1-6 and 7-12 was associated with an increased risk of mortality in year 2 (adjusted HR 1.29 (95% CI: 1.05-1.58)) compared with stable pre-HD SPBV. A pre-HD SBPV increase was associated with female gender, higher mean pre-HD SBP and pulse pressure, and lower HD frequency.

Coronary artery disease in dialysis patients: evidence synthesis, controversies and proposed management strategies.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among patients with end-stage renal disease (ESRD). Clustering of traditional atherosclerotic and non-traditional risk factors drive the excess rates of coronary and non-coronary CVD in this population. The incidence, severity and mortality of coronary artery disease (CAD) as well as the number of complications of its therapy is higher in dialysis patients than in non-chronic kidney disease patients. Given the lack of randomized clinical trial evidence in this population, current practice is informed by observational data with a significant potential for bias. Furthermore, guidelines lack any recommendation for these patients or extrapolate them from trials performed in non-dialysis patients. Patients with ESRD are more likely to be asymptomatic, posing a challenge to the correct identification of CAD, which is essential for appropriate risk stratification and management. This may lead to "therapeutic nihilism", which has been associated with worse outcomes. Here, the ERA-EDTA EUDIAL Working Group reviews the diagnostic work-up and therapy of chronic coronary syndromes, unstable angina/non-ST elevation and ST-elevation myocardial infarction in dialysis patients, outlining unclear issues and controversies, discussing recent evidence, and proposing management strategies. Indications of antiplatelet and anticoagulant therapies, percutaneous coronary intervention and coronary artery bypass grafting are discussed. The issue of the interaction between dialysis session and myocardial damage is also addressed.