Urinary Liver-Type Fatty Acid Binding Protein, a Biomarker for Disease Progression, Dialysis and Overall Mortality in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major public health concern with an increasing proportion of sufferers progressing to renal replacement therapy (RRT). Early identification of those at risk of disease progression could be key in improving outcomes. We hypothesise that urinary liver-type fatty acid binding protein (uL-FABP) may be a suitable biomarker for CKD progression and can add value to currently established biomarkers such as the urinary protein-to-creatinine ratio (uPCR). A total of 583 participants with CKD 1-5 (not receiving renal replacement therapy) entered a 2 yr prospective longitudinal study. UPCR and uL-FABP were measured at baseline and CKD progression was defined as either (i) a decline in eGFR of >5 mL/min/1.73 m2 or an increase in serum creatinine by 10% at 1 yr; (ii) a decline in eGFR of >6 mL/min/1.73 m2 or an increase in serum creatinine by 20% at 2 yrs; or (iii) the initiation of RRT. A combined outcome of initiating RRT or death was also included. Approximately 40% of participants showed CKD progression. uL-FABP predicted CKD progression at both years 1 and 2 (OR 1.01, p < 0.01). Sensitivity and specificity were comparable to those of uPCR (AUC 0.623 v 0.706) and heat map analysis suggested that uL-FABP in the absence of significant proteinuria can predict an increase in serum creatinine of 10% at 1 yr and 20% at 2 yrs. The risk of the combined outcome of initiating RRT or death was 23% higher in those with high uL-FABP (p < 0.01) independent of uPCR. uL-FABP appears to be a highly sensitive and specific biomarker of CKD progression. The use of this biomarker could enhance the risk stratification of CKD and its progression and should be assessed further.

Extracellular resistance is sensitive to tissue sodium status; implications for bioimpedance-derived fluid volume parameters in chronic kidney disease.

Multifrequency bioimpedance spectroscopy (BIS) is an established method for assessing fluid status in chronic kidney disease (CKD). However, the technique is lacking in predictive value and accuracy. BIS algorithms assume constant tissue resistivity, which may vary with changing tissue ionic sodium concentration (Na+). This may introduce significant inaccuracies to BIS outputs. To investigate this, we used 23Na magnetic resonance imaging (MRI) to measure Na+ in muscle and subcutaneous tissues of 10 healthy controls (HC) and 20 patients with CKD 5 (not on dialysis). The extracellular (Re) and intracellular (Ri) resistance, tissue capacitance, extracellular (ECW) and total body water (TBW) were measured using BIS. Tissue water content was assessed using proton density-weighted MRI with fat suppression. BIS-derived volume indices were comparable in the two groups (OH: HC - 0.4 ± 0.9 L vs. CKD 0.5 ± 1.9 L, p = 0.13). However, CKD patients had higher Na+ (HC 21.2 ± 3.0, CKD 25.3 ± 7.4 mmol/L; p = 0.04) and significantly lower Re (HC 693 ± 93.6, CKD 609 ± 74.3 Ohms; p = 0.01); Ri and capacitance did not vary. Na+ showed a significant inverse linear relationship to Re (rs = - 0.598, p < 0.01) but not Ri. This relationship of Re (y) and Na+ (x) is described through equation y = - 7.39x + 814. A 20% increase in tissue ionic Na+ is likely to overestimate ECW by 1.2-2.4L. Tissue Na+ concentration has a significant inverse linear relationship to Re. BIS algorithms to account for this effect could improve prediction accuracy of bioimpedance derived fluid status in CKD.

Salt and Water Retention Is Associated with Microinflammation and Endothelial Injury in Chronic Kidney Disease.

BACKGROUND: Progressive chronic kidney disease (CKD) inevitably leads to salt and water retention and disturbances in the macro-and microcirculation. OBJECTIVES: We hypothesize that salt and water dysregulation in advanced CKD may be linked to inflammation and microvascular injury pathways. METHODS: We studied 23 CKD stage 5 patients and 11 healthy controls (HC). Tissue sodium concentration was assessed using 23Sodium magnetic resonance (MR) imaging. Hydration status was evaluated using bioimpedance spectroscopy. A panel of inflammatory and endothelial biomarkers was also measured. RESULTS: CKD patients had fluid overload (FO) when compared to HC (overhydration index: CKD = 0.5 ± 1.9 L vs. HC = -0.5 ± 1.0 L; p = 0.03). MR-derived tissue sodium concentrations were predominantly higher in the subcutaneous (SC) compartment (median [interquartile range] CKD = 22.4 mmol/L [19.4-31.3] vs. HC = 18.4 mmol/L [16.6-21.3]; p = 0.03), but not the muscle (CKD = 24.9 ± 5.5 mmol/L vs. HC = 22.8 ± 2.5 mmol/L; p = 0.26). Tissue sodium in both compartments correlated to FO (muscle: r = 0.63, p < 0.01; SC: rs = 0.63, p < 0.01). CKD subjects had elevated levels of vascular cell adhesion molecule (p < 0.05), tumor necrosis factor-alpha (p < 0.01), and interleukin (IL)-6 (p = 0.01) and lower levels of vascular endothelial growth factor-C (p = 0.04). FO in CKD was linked to higher IL-8 (r = 0.51, p < 0.05) and inversely associated to E-selectin (r = -0.52, p = 0.01). Higher SC sodium was linked to higher intracellular adhesion molecule (ICAM; rs = 0.54, p = 0.02). CONCLUSION: Salt and water accumulation in CKD appears to be linked with inflammation and endothelial activation pathways. Specifically IL-8, E-Selectin (in FO), and ICAM (in salt accumulation) may be implicated in the pathophysiology of FO and merit further investigation.

Transcapillary Refilling Rate and Its Determinants during Haemodialysis with Standard and High Ultrafiltration Rates.

BACKGROUND: Achieving euvolaemia using ultrafiltration (UF) during haemodialysis (HD) without inducing haemodynamic instability presents a major clinical challenge. Transcapillary refill is a key factor in sustaining the circulating blood volume (BV) during UF, which is in turn predicted by the rate of refilling. However, absolute plasma refilling rate (PRR), its determinants and variability with UF rate (UFR), have not been reported in the literature. METHOD: We studied paired HD sessions (n = 48) in 24 patients over 2 consecutive mid-week HD treatments. Plasma refilling was measured using real-time, minute-by-minute relative BV changes obtained from the integrated BV monitoring device during UF. A fixed bolus dilution approach at the start of HD was used to calculate absolute BV. The first control HD session was undertaken with a standard UFR required to achieve the prescribed target weight, while during the second study session, a fixed (high) UFR (1 L/h) was applied, either in the first (n = 12 patients) or in the final hour (n = 12 patients) of the HD session. Participants' had their hydration status measured pre- and post-HD using multifrequency bioimpedance (BIS). Blood pressure was measured at 15-min intervals and blood samples were collected at 7 intervals during HD sessions. RESULTS: The mean PRR during a standard 4-hr HD session was 4.3 ± 2.0 mL/kg/h and varied between 2 and 6 mL/kg/h. There was a mean time delay of 22 min (range 13.3-35.0 min) for onset of plasma refilling after the application of UF irrespective of standard or high UFRs. The maximum refilling occurred during the second hour of HD (mean max PRR 6.8 mL/kg/h). UFR (beta = 0.60, p < 0.01) and BIS derived pre-HD overhydration index (beta = 0.44, p = 0.01) were consistent, independent predictors of the mean PRR (R2 = 0.49) in all HD sessions. At high UFRs, PRR exceeded 10 mL/kg/h. The total overall plasma refill contribution to UF volume was not significantly different between standard and high UF. During interventions no significant haemodynamic instability was observed in the study. CONCLUSION: We describe absolute transcapillary refilling rate and its profile during HD with UF. The findings provide the basis for the development of UF strategies to match varying PRRs during HD. An approach to fluid removal, which is tailored to patients' refilling rates and capacity, provides an opportunity for more precision in the practice of UF.

Cardiovascular and Patient Phenotype of Extended Haemodialysis: A Critical Analysis of Studying a Unique Patient Population.

BACKGROUND: Extended haemodialysis (EHD) has been associated with better outcomes compared to conventional (CHD) regimes. The cardiovascular (CV) profile of these patients has not been assessed in detail. METHODS: We report baseline demographic and CV phenotype of 36 CHD and 36 EHD participants to a longitudinal multicentre study. We measured pulse wave velocity (PWV), 24-h ambulatory blood pressure, sublingual dark-field capillaroscopy and vascular biomarkers. RESULTS: EHD patients were younger (p < 0.01), with less CV comorbidity (p = 0.04) and higher dialysis vintage (p < 0.01). Higher PWV in CHD (p = 0.02) was not independent of demographic differences in the 2 groups. Biomarker profiles were similar in EHD and CHD but abnormal compared to healthy controls. CONCLUSION: Although CV profiles in these 2 cohorts were similar, EHD patients were distinct from the CHD population in terms of age and dialysis vintage and appear to comprise a unique group. Direct comparison of outcomes in these groups is challenging due to clinical bias.

Inflammatory and Angiogenic Factors Linked to Longitudinal Microvascular Changes in Hemodialysis Patients Irrespective of Treatment Dose Intensity.

BACKGROUND: Cardiovascular disease is a major contributor to the poor outcomes observed in hemodialysis. We investigated the relationship between hemodialysis intensity and vascular parameters in high-dose (HDHD; >12hrs/week) and Conventional (CHD; ≤12hrs/week) hemodialysis intensity over a 6-month period. METHODS: We present the 6-month longitudinal analysis of a 2-year multicenter study investigating the effects of HDHD on cardiovascular parameters. We used pulse wave velocity, 24hr ambulatory blood pressure and sublingual dark field capillaroscopy measurements to assess macro- and microcirculation on 6-monthly basis. Pro-inflammatory and endothelial biomarkers were also measured at 6-monthly intervals. RESULTS: 47 participants (21 HDHD, 26 CHD) were studied. CHD were older (63.5±14.2 vs 53.7±12.6 yr; p=0.018), with shorter dialysis vintage (median 23 vs 61 months; p=0.001). There was considerable variability in the degree and direction of change of circulatory measurements over a 6-month period. Hemodialysis intensity (hrs/week) did not correlate to these changes, when adjusted for age, dialysis vintage and comorbidity. Higher levels of Interleukin (IL)-8 measured at baseline independently predicted an increase in the Perfused Boundary Region (5-25µm) of the endothelial glycocalyx (p=0.010) whilst higher levels of soluble Flt-1 had a significant inverse effect (p=0.002) in an adjusted linear model. CONCLUSION: Hemodialysis intensity did not predict changes in either macro- or microvascular parameters. Inflammation mediated through the IL-8 pathway predicted microvascular injury while Flt-1, a potential marker of angiogenesis and endothelial repair, might have a significant protective role. Further understanding of these pathways will be necessary to improve dialysis outcomes.

Extracellular overhydration linked with endothelial dysfunction in the context of inflammation in haemodialysis dependent chronic kidney disease.

BACKGROUND: Haemodialysis (HD) patients are predisposed to dysregulated fluid balance leading to extracellular water (ECW) expansion. Fluid overload has been closely linked with outcome in these patients. This has mainly been attributed to cardiac volume overload, but the relation between abnormalities in fluid status with micro- and macrovascular dysfunction has not been studied in detail. We studied the interaction of macro- and microvascular factors in states of normal and over- hydration in HD-dependent CKD. METHODS: Fluid compartments [total body water (TBW) and ECW] and overhydration index (OH) were measured with Multifrequency bio-impedance (BCM). Overhydration was defined as OH/ECW>7%. Overhydration was also assessed using the ECW/TBW ratio. Macrocirculation was assessed by pulse-wave velocity (PWV) and mean arterial pressure (MAP) measurements while microcirculation through sublingual capillaroscopy assessment of the Perfused Boundary Region of the endothelial glycocalyx (PBR 5-25mcg). A panel of pro-inflammatory and vascular serum biomarkers and growth factors was analysed. RESULTS: Of 72 HD participants, 30 were in normohydration (N) range and 42 overhydrated according to the OH/ECW ratio. Average ECW/TBW was 0.48±0.03. Overhydrated patients had higher MAP (122.9±22.5 v 111.7±22.2mmHg, p = 0.04) and comorbidities (median Davies score 1.5 v 1.0, p = 0.03). PWV (p = 0.25) and PBR 5-25mcg (p = 0.97) did not differ between the 2 groups. However, Vascular Adhesion Molecule (VCAM)-1, Interleukin-6 and Thrombomodulin, and reduced Leptin were observed in the overhydrated group. Elevation in VCAM-1 levels (OR 1.03; 95% CI 1.01-1.06; p = 0.02) showed a strong independent association with OH/ECW>7% in an adjusted logistic regression analysis and exhibited a strong linear relationship with ECW/TBW (Bata = 0.210, p = 0.03) in an also adjusted model. CONCLUSION: Extracellular fluid overload is significantly linked to microinflammation and markers of endothelial dysfunction. The study provides novel insight in the cardiovascular risk profile associated with overhydration in uraemia.

Clinical, patient-related, and economic outcomes of home-based high-dose hemodialysis versus conventional in-center hemodialysis.

Despite technological advances in renal replacement therapy, the preservation of health and quality of life for individuals on dialysis still remains a challenge. The high morbidity and mortality in dialysis warrant further research and insight into the clinical domains of the technique and practice of this therapy. In the last 20 years, the focus of development in the field of hemodialysis (HD) has centered around adequate removal of urea and other associated toxins. High-dose HD offers an opportunity to improve mortality, morbidity, and quality of life of patients with end-stage kidney disease. However, the uptake of this modality is low, and the risk associated with the therapy is not fully understood. Recent studies have highlighted the evidence base and improved our understanding of this technique of dialysis. This article provides a review of high-dose and home HD, its clinical impact on patient outcome, and the controversies that exist.

Complications and outcomes of trimethoprim-sulphamethoxazole as chemoprophylaxis for pneumocystis pneumonia in renal transplant recipients.

BACKGROUND: Following a pneumocystis pneumonia (PCP) outbreak in our nephrology unit, all transplant patients were offered chemoprophylaxis with trimethoprim-sulphamethoxazole (TMP-SMX) as the first line agent. A high rate of complications was noted. We aimed to quantify TMP-SMX associated adverse events and evaluate its prophylactic benefit in their light. Potential risk factors for complications' development were also investigated. METHOD: This was an observational study of outcomes in transplant recipients commenced on TMP-SMX prophylaxis for 1year period. End-points were adverse events due to TMP-SMX, the additional medical burden resulting from these events, and PCP diagnosis. RESULTS: 290 patients commenced on TMP-SMX. 110 (38%) developed complications with most common being rise in serum creatinine (Cr) (n = 63, 22%) followed by gastrointestinal symptoms (n = 15, 5%), and leucopenia (n = 5, 2%). PCP incidence fell from 19 cases in 19 months to 2 cases in 12 months. Baseline renal function (P = 0.019) was an independent predictors for developing rise in Cr with TMP-SMX. CONCLUSION: Use of chemoprophylaxis is an effective strategy in dealing with a PCP outbreak but can lead to a high number of complications. Rises in serum Cr can cause significant concern and increase in the number of investigations.

Technology innovation for patients with kidney disease.

The loss of kidney function is a life-changing event leading to life-long dependence on healthcare. Around 5000 people are diagnosed with kidney failure every year. Historically, technology in renal medicine has been employed for replacement therapies. Recently, a lot of emphasis has been placed on technologies that aid early identification and prevent progression of kidney disease, while at the same time empowering affected individuals to gain control over their chronic illness. There is a shift in diversity of technology development, driven by collaborative innovation initiatives such the National Institute's for Health Research Healthcare Technology Co-operative for Devices for Dignity. This has seen the emergence of the patient as a key figure in designing technologies that are fit for purpose, while business involvement has ensured uptake and sustainability of these developments. An embodiment of this approach is the first successful Small Business Research Initiative in the field of renal medicine in the UK.

Observational study of need for thrombolytic therapy and incidence of bacteremia using taurolidine-citrate-heparin, taurolidine-citrate and heparin catheter locks in patients treated with hemodialysis.

Catheter-related blood stream infections may be reduced by interdialytic locking with Taurolidine, a nontoxic antimicrobial agent. A formulation of 1.35% Taurolidine in 4% citrate (TC) is associated with a greater need for thrombolysis to maintain catheter patency than 5000 U/ml heparin. Our aim was to determine whether addition of 500 Units/ml of heparin to TC reduces the need for thrombolysis. TCH (1.35% taurolidine, 4% citrate and 500 U/ml heparin) was compared to TC and Heparin 5000 U/ml using retrospective data. Hundred and six adult hemodialysis patients with internal jugular tunnelled intravascular catheters using TCH were compared with 34 patients using TC and 34 patients using heparin 5000 U/ml respectively. Outcomes were time to first use of thrombolysis and bacteremia rates.TCH reduced the need for thrombolysis compared to TC (hazard ratio, 0.2; 95%CI: 0.06, 0.5; p < 0.001) and was not significantly different from heparin 5000 U/ml (hazard ratio, 1.4; 95%CI: 0.5, 3.9; p = 0.5). The bacteremia rates from all causes were 1.33, 1.22 and 3.25 per 1000 catheter- days (p < 0.001) in the TCH, TC and heparin groups respectively. Addition of 500 U/ml heparin to TC reduces the need for thrombolysis without increasing bacteremia and may achieve patency comparable to heparin 5000 U/ml.