Tom Cornelis

Intensive Hemodialysis Associates with Improved Pregnancy Outcomes: A Canadian and United States Cohort Comparison

Pregnancy is rare in women with ESRD and when it occurs, it is often accompanied by significant maternal and fetal morbidity and even mortality. Preliminary data from the Toronto Nocturnal Hemodialysis Program suggested that increased clearance of uremic toxins by intensified hemodialysis improves pregnancy outcomes, but small numbers and the absence of a comparator group limited widespread applicability of these findings. We compared pregnancy outcomes from 22 pregnancies in the Toronto Pregnancy and Kidney Disease Clinic and Registry (2000-2013) with outcomes from 70 pregnancies in the American Registry for Pregnancy in Dialysis Patients (1990-2011). The primary outcome was the live birth rate and secondary outcomes included gestational age and birth weight. The live birth rate in the Canadian cohort (86.4%) was significantly higher than the rate in the American cohort (61.4%; P=0.03). Among patients with established ESRD, the median duration of pregnancy in the more intensively dialyzed Toronto cohort was 36 weeks (interquartile range, 32-37) compared with 27 weeks (interquartile range, 21-35) in the American cohort (P=0.002). Furthermore, a dose response between dialysis intensity and pregnancy outcomes emerged, with live birth rates of 48% in women dialyzed ≤20 hours per week and 85% in women dialyzed >36 hours per week (P=0.02), with a longer gestational age and greater infant birth weight for women dialyzed more intensively. Pregnancy complications were few and manageable. We conclude that pregnancy may be safe and feasible in women with ESRD receiving intensive hemodialysis.

Acute Hemodynamic Response and Uremic Toxin Removal in Conventional and Extended Hemodialysis and Hemodiafiltration: A Randomized Crossover Study

BACKGROUND Intensive hemodialysis (HD) may have significant benefits. Recently, the role of extended hemodiafiltration (HDF) has gained interest. The aim of this study was to evaluate the acute effects of extended HD and HDF on hemodynamic response and solute removal. STUDY DESIGN Randomized crossover trial. SETTINGS & PARTICIPANTS Stable patients with end-stage renal disease undergoing conventional HD. INTERVENTION 13 patients randomly completed a single study of 4-hour HD (HD4), 4-hour HDF (HDF4), 8-hour HD (HD8), and 8-hour HDF (HDF8), with a 2-week interval between study sessions. Between study sessions, patients received routine conventional HD treatments. OUTCOMES Acute hemodynamic effects and uremic toxin clearance. MEASUREMENTS Blood pressure and heart rate, pulse wave analysis, cardiac output, and microvascular density by sublingual capillaroscopy, as well as relative blood volume and thermal variables, were measured. Clearance and removal of uremic toxins also were studied. RESULTS Long treatments showed more stability of peripheral systolic blood pressure (change during HD4, -21.7±15.6 mm Hg; during HDF4, -23.3±20.8 mm Hg; during HD8, -6.7±15.2 mm Hg [P=0.04 vs. HD4; P=0.08 vs. HDF4]; and during HDF8, -0.5±14.4 mm Hg [P=0.004 vs. HD4; P=0.008 vs. HDF4]). A similar observation was found for peripheral diastolic and central blood pressures. Cardiac output remained more stable in extended sessions (change during HD4, -1.4±1.5 L/min; during HDF4, -1.6±1.0 L/min; during HD8, -0.4±0.9 L/min [P=0.02 vs. HDF4]; and during HDF8, -0.5±0.8 L/min [P=0.06 vs. HD4; P=0.03 vs. HDF4), in line with the decreased relative blood volume slope in long dialysis. No differences in microvascular density were found. Energy transfer rates were comparable (HD4, 13.3±4.7 W; HDF4, 16.2±5.6 W; HD8, 14.2±6.0 W; and HDF8, 14.5±4.3 W). Small-molecule and phosphate removal were superior during long treatments. β2-Microglobulin and fibroblast growth factor 23 (FGF-23) reduction ratios were highest in HDF8. LIMITATIONS Small sample size, only acute effects were studied. CONCLUSIONS Treatment time, and not modality, was the determinant for the hemodynamic response. HDF significantly improved removal of middle molecules, with superior results in extended HDF.

Out of control: accelerated aging in uremia

Next to a high morbidity, patients with end-stage renal failure (ESRD) suffer from a complex spectrum of clinical manifestations. Both the phenotype of patients with ESRD as well as the pathophysiology of uremia show interesting parallels with the general aging process. Phenotypically, patients with ESRD have an increased susceptibility for both cardiovascular as well as infectious disease and show a reduction in functional capacity as well as muscular mass (sarcopenia), translating into a high prevalence of frailty also in younger patients. Pathophysiologically, the immune dysfunction, telomere attrition and the presence of low-grade inflammation in uremic patients also show parallels with the aging process. System models of aging, such as the homeodynamic model and reliability theory of Gavrilov may also have relevance for ESRD. The reduction in the redundancy of compensatory mechanisms and the multisystem impairment in ESRD explain the rapid loss of homeodynamic/homeostatic balance and the increased susceptibility to external stressors in these patients. System theories may also explain the relative lack of success of interventions focusing on single aspects of renal disease. The concept of accelerated aging, which also shares similarities with other organ diseases, may be of relevance both for a better understanding of the uremic process, as well as for the design of multidimensional interventions in ESRD patients, including an important role for early rehabilitation. Research into processes akin to both aging and uremia may result in novel therapeutic approaches.

Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol.

BACKGROUND Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients. METHODS VitaVasK is a prospective, randomized, parallel group, multicentre trial (EudraCT No.: 2010-021264-14) that will include 348 HD patients in an open-label, two-arm design. After baseline multi-slice computed tomography (MSCT) of the heart and thoracic aorta, patients with a coronary calcification volume score of at least 100 will be randomized to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly. Treatment duration will be 18 months, and MSCT scans will be repeated after 12 and 18 months. Primary end points are the progression of thoracic aortic and coronary artery calcification (calculated as absolute changes in the volume scores at the 18-month MSCT versus the baseline MSCT). Secondary end points comprise changes in Agatston score, mitral and aortic valve calcification as well as major adverse cardiovascular events (MACE) and all-cause mortality. VitaVask also aims to record MACE and all-cause mortality in the follow-up period at 3 and 5 years after treatment initiation. This trial may lead to the identification of an inexpensive and safe treatment or prophylaxis of VC in HD patients.

Renal Replacement Therapy in Geriatric End-Stage Renal Disease Patients: A Clinical Approach

The number of geriatric patients on dialysis is increasing. This is due to demographic factors, a wider acceptance of elderly patients on dialysis, and an earlier start of dialysis in this patient group. Recent studies have questioned the effect of dialysis on quality of life in elderly patients with severe comorbidity and showed limited survival in this specific patient group. Therefore, the decision whether or not to start dialysis may be a difficult one for both the clinician and patient. Risk scores can be of help in facilitating shared decision making, but not as a tool to withhold dialysis. However, in the elderly patient with severe comorbidity, conservative care can sometimes be a reasonable alternative to dialysis. In the process of shared decision making, a balance should be pursued between life expectancy and quality of life. If the decision to initiate dialysis is taken, choices have to be made regarding dialysis modality and treatment prescription. If adequate support is provided, assisted peritoneal dialysis can be an acceptable alternative to hemodialysis. Care for the elderly with end-stage renal disease should be undertaken by a multidisciplinary team with special dedication to a multidimensional approach in this population.

Update on potential medical treatments for encapsulating peritoneal sclerosis; human and experimental data

Encapsulating peritoneal sclerosis (EPS) is an infrequent but serious complication of peritoneal dialysis (PD). The pathogenesis is unknown but speculation is ongoing. The current management of EPS focuses on prevention and treatment of the inflammatory and fibrotic changes at the level of the peritoneal membrane with immunosuppressive and antifibrotic agents, respectively. This article reviews the currently available human and animal data on potential agents to prevent and/or treat EPS. We propose a strategy for early diagnose EPS in an attempt to avoid the development of the full-blown and potentially life-threatening clinical syndrome of EPS. Future research should focus on studying potential prophylactic and therapeutic agents in humans in large, multicenter, randomized trials but also on early detection of EPS in the inflammatory phase by means of biomarkers and the establishment of a composite EPS score.

Protein-Bound Uremic Toxin Profiling as a Tool to Optimize Hemodialysis.

Aim We studied various hemodialysis strategies for the removal of protein-bound solutes, which are associated with cardiovascular damage. Methods This study included 10 patients on standard (3x4h/week) high-flux hemodialysis. Blood was collected at the dialyzer inlet and outlet at several time points during a midweek session. Total and free concentration of several protein-bound solutes was determined as well as urea concentration. Per solute, a two-compartment kinetic model was fitted to the measured concentrations, estimating plasmatic volume (V1), total distribution volume (Vtot) and intercompartment clearance (K21). This calibrated model was then used to calculate which hemodialysis strategy offers optimal removal. Our own in vivo data, with the strategy variables entered into the mathematical simulations, was then validated against independent data from two other clinical studies. Results Dialyzer clearance K, V1 and Vtot correlated inversely with percentage of protein binding. All Ks were different from each other. Of all protein-bound solutes, K21was 2.7–5.3 times lower than that of urea. Longer and/or more frequent dialysis that processed the same amount of blood per week as standard 3x4h dialysis at 300mL/min blood flow showed no difference in removal of strongly bound solutes. However, longer and/or more frequent dialysis strategies that processed more blood per week than standard dialysis were markedly more adequate. These conclusions were successfully validated. Conclusion When blood and dialysate flow per unit of time and type of hemodialyzer are kept the same, increasing the amount of processed blood per week by increasing frequency and/or duration of the sessions distinctly increases removal.

Body Composition in Dialysis Patients: A Functional Assessment of Bioimpedance Using Different Prediction Models

OBJECTIVES The assessment of body composition (BC) in dialysis patients is of clinical importance given its role in the diagnosis of malnutrition and sarcopenia. Bioimpedance techniques routinely express BC as a 2-compartment (2-C) model distinguishing fat mass (FM) and fat-free mass (FFM), which may be influenced by the hydration of adipose tissue and fluid overload (OH). Recently, the BC monitor was introduced which applies a 3-compartment (3-C) model, distinguishing OH, adipose tissue mass, and lean tissue mass. The aim of this study was to compare BC between the 2-C and 3-C models and assess their relation with markers of functional performance (handgrip strength [HGS] and 4-m walking test), as well as with biochemical markers of nutrition. METHODS Forty-seven dialysis patients (30 males and 17 females) (35 hemodialysis, 12 peritoneal dialysis) with a mean age of 64.8 ± 16.5 years were studied. 3-C BC was assessed by BC monitor, whereas the obtained resistivity values were used to calculate FM and FFM according to the Xitron Hydra 4200 formulas, which are based on a 2-C model. RESULTS FFM (3-C) was 0.99 kg (95% confidence interval [CI], 0.27 to 1.71, P = .008) higher than FFM (2-C). FM (3-C) was 2.43 kg (95% CI, 1.70-3.15, P < .001) lower than FM (2-C). OH was 1.4 ± 1.8 L. OH correlated significantly with ΔFFM (FFM 3-C - FFM 2-C) (r = 0.361; P < .05) and ΔFM (FM 3-C - FM 2-C) (r = 0.387; P = .009). HGS correlated significantly with FFM (2-C) (r = 0.713; P < .001), FFM (3-C) (r = 0.711; P < .001), body cell mass (2-C) (r = 0.733; P < .001), and body cell mass (3-C) (r = 0.767; P < .001). Both physical activity (r = 0.456; P = .004) and HGS (r = 0.488; P = .002), but not BC, were significantly related to walking speed. CONCLUSIONS Significant differences between 2-C and 3-C models were observed, which are partly explained by the presence of OH. OH, which was related to ΔFFM and ΔFM of the 2-C and 3-C models, is therefore an important parameter for the differences in estimation of BC parameters of the 2-C and 3-C models. Both FFM (3-C) and FFM (2-C) were significantly related to HGS. Bioimpedance, HGS, and the 4-m walking test may all be valuable tools in the multidimensional nutritional assessment of both hemodialysis and peritoneal dialysis patients.

Antiangiogenic factors and maternal hemodynamics during intensive hemodialysis in pregnancy.

We report on a 21‐year‐old pregnant patient with IgA nephropathy who was initiated on intensive hemodialysis (8 hours of hemodialysis 3 times a week) at a gestational age of 26 weeks on the basis of worsening kidney function resulting in rapidly progressive fatigue and difficulties in metabolic control. Throughout the pregnancy, and while on intensive hemodialysis, 24‐hour ambulatory blood pressure control was within the target, and results of weekly 24‐hour measurement of central hemodynamics and pulse wave velocity, and of serial levels of circulating (anti‐)angiogenic factors were comparable to normal pregnancies. Estimated fetal growth evolved along the 50th percentile, and no polyhydramnios was detected. After induction for a sudden, unexplained increase in blood pressure, she delivered a healthy boy of 2480 g at a gestational age of 36 weeks. This case adds to the expanding literature that supports the use of intensive hemodialysis in pregnant patients with end‐stage renal disease and illustrates, for the first time, the potential use of serial (anti‐) angiogenic factors and 24‐hour measurements of blood pressure and hemodynamic indices in order to facilitate monitoring of these complicated patients.

Protein-bound uraemic toxins, dicarbonyl stress and advanced glycation end products in conventional and extended haemodialysis and haemodiafiltration

BACKGROUND Protein-bound uraemic toxins (PBUT), dicarbonyl stress and advanced glycation end products (AGEs) associate with cardiovascular disease in dialysis. Intensive haemodialysis (HD) may have significant clinical benefits. The aim of this study was to evaluate the acute effects of conventional and extended HD and haemodiafiltration (HDF) on reduction ratio (RR) and total solute removal (TSR) of PBUT, dicarbonyl stress compounds and AGEs. METHODS Thirteen stable conventional HD patients randomly completed a single study of 4-h HD (HD4), 4-h HDF (HDF4), 8-h HD (HD8) and 8-h HDF (HDF8) with a 2-week interval between the study sessions. RR and TSR of PBUT [indoxyl sulphate (IS), p-cresyl sulphate (PCS), p-cresyl glucuronide, 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid (CMPF), indole-3-acetic acid (IAA) and hippuric acid] of free and protein-bound AGEs [N(ε)-(carboxymethyl)lysine (CML), N(ε)-(carboxyethyl)lysine (CEL), Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine, pentosidine], as well as of dicarbonyl compounds [glyoxal, methylglyoxal, 3-deoxyglucosone], were determined. RESULTS Compared with HD4, HDF4 resulted in increased RR of total and/or free fractions of IAA and IS as well as increased RR of free CML and CEL. HD8 and HDF8 showed a further increase in TSR and RR of PBUT (except CMPF), as well as of dicarbonyl stress and free AGEs compared with HD4 and HDF4. Compared with HD8, HDF8 only significantly increased RR of total and free IAA and free PCS, as well as RR of free CEL. CONCLUSIONS Dialysis time extension (HD8 and HDF8) optimized TSR and RR of PBUT, dicarbonyl stress and AGEs, whereas HDF8 was superior to HD8 for only a few compounds.