Fredrik Uhlin

Noninvasive investigation of blood pressure changes using the pulse wave transit time : A novel approach in the monitoring of hemodialysis patients

Severe blood pressure changes are well known in hemodialysis. Detection and prediction of these are important for the well-being of the patient and for optimizing treatment. New noninvasive methods for this purpose are required. The pulse wave transit time technique is an indirect estimation of blood pressure, and our intention is to investigate whether this technique is applicable for hemodialysis treatment. A measurement setup utilizing lower body negative pressure and isometric contraction was used to simulate dialysis-related blood pressure changes in normal test subjects. Systolic blood pressure levels were compared to different pulse wave transit times, including and excluding the cardiac preejection period. Based on the results of these investigations, a pulse wave transit time technique adapted for dialysis treatment was developed and tried out on patients. To determine systolic blood pressure in the normal group, the total pulse wave transit time was found most suitable (including the cardiac preejection period). Correlation coefficients were r = 0.80 ± 0.06 (mean ± SD) overall and r = 0.81 ± 0.16 and r = 0.09 ± 0.62 for the hypotension and hypertension phases, respectively. When applying the adapted technique in dialysis patients, large blood pressure variations could easily be detected when present. Pulse wave transit time is correlated to systolic blood pressure within the acceptable range for a trend-indicating system. The methods applicability for dialysis treatment requires further studies. The results indicate that large sudden pressure drops, like those seen in sudden hypovolemia, can be detected.

Estimation of delivered dialysis dose by on-line monitoring of the ultraviolet absorbance in the spent dialysate

BACKGROUND Several methods are available to determine Kt/V, from predialysis and postdialysis blood samples to using on-line dialysate urea monitors or to ionic dialysance using a conductivity method. The aim of this study is to compare Kt/V calculated from the slope of the logarithmic on-line ultraviolet (UV) absorbance measurements, blood urea Kt/V, dialysate urea Kt/V, and Kt/V from the Urea Monitor 1000 (UM; Baxter Healthcare Corp, Deerfield, IL). METHODS Thirteen uremic patients on chronic thrice-weekly hemodialysis therapy were included in the study. The method uses absorption of UV radiation by means of a spectrophotometric set-up. Measurements were performed on-line with the spectrophotometer connected to the fluid outlet of the dialysis machine; all spent dialysate passed through a specially designed cuvette for optical single-wavelength measurements. UV absorbance measurements were compared with those calculated using blood urea and dialysate urea, and, in a subset of treatments, the UM. RESULTS Equilibrated Kt/V (eKt/V) obtained with UV absorbance (eKt/Va) was 1.19 +/- 0.23; blood urea (eKt/Vb), 1.30 +/- 0.20, and dialysate urea (eKt/Vd), 1.26 +/- 0.21, and Kt/V in a subset measured by the UM (UM Kt/V) was 1.24 +/- 0.18. The difference between eKt/Vb and eKt/Va was 0.10 +/- 0.11, showing a variation similar to the difference between eKt/Vb and eKt/Vd (0.03 +/- 0.10) and in a subset between eKt/Vb and UM Kt/V (-0.02 +/- 0.11). CONCLUSION The study suggests that urea Kt/V can be estimated by on-line measurement of UV absorption in the spent dialysate.

Optical Online Monitoring of Uric Acid Removal during Dialysis

This study estimates the total removal of uric acid (TRUA) by online UV absorbance measurements in the spent dialysate in two different dialysis centers in Estonia and Sweden. Sixteen dialysis patients were included. All dialysate was collected that gave the reference for TRUA. Two regression models were investigated: one for each patient (UV1) and one for the entire material (UV2). TRUA from the three methods was in the same order but showed a statistically significant difference when the UV2 model was built on data from both centers together. TRUA, (n = 56) was (mean ± SD, µmol): 5,854 ± 1,377 for reference, 6,117 ± 1,795 for UV1 and 5,762 ± 1,591 for UV2. Six patients were monitored 1 year after the first study session, using the same models as the previous year, still having a nonsignificant difference. The results show the possibility of estimating TRUA by using UV absorbance. The method appeared to be reliable also in long-term patient monitoring.

Do Only Small Uremic Toxins, Chromophores, Contribute to the Online Dialysis Dose Monitoring by UV Absorbance?

The aim of this work was to evaluate the contributions of the main chromophores to the total UV absorbance of the spent dialysate and to assess removal dynamics of these solutes during optical on-line dialysis dose monitoring. High performance chromatography was used to separate and quantify UV-absorbing solutes in the spent dialysate sampled at the start and at the end of dialysis sessions. Chromatograms were monitored at 210, 254 and 280 nm routinely and full absorption spectra were registered between 200 and 400 nm. Nearly 95% of UV absorbance originates from solutes with high removal ratio, such as uric acid. The contributions of different solute groups vary at different wavelengths and there are dynamical changes in contributions during the single dialysis session. However, large standard deviation of the average contribution values within a series of sessions indicates remarkable differences between individual treatments. A noteworthy contribution of Paracetamol and its metabolites to the total UV absorbance was determined at all three wavelengths. Contribution of slowly dialyzed uremic solutes, such as indoxyl sulfate, was negligible.

Optical Method for Cardiovascular Risk Marker Uric Acid Removal Assessment during Dialysis

The aim of this study was to estimate the concentration of uric acid (UA) optically by using the original and processed ultraviolet (UV) absorbance spectra of spent dialysate. Also, the effect of using several wavelengths (multi-wavelength algorithms) for estimation was examined. This paper gives an overview of seven studies carried out in Linköping, Sweden, and Tallinn, Estonia. A total of 60 patients were monitored over their 188 dialysis treatment procedures. Dialysate samples were taken and analysed by means of UA concentration in a chemical laboratory and with a double-beam spectrophotometer. The measured UV absorbance spectra were processed. Three models for the original and three for the first derivate of UV absorbance were created; concentrations of UA from the different methods were finally compared in terms of mean values and SD. The mean concentration (micromol/L) of UA was 49.7 ± 23.0 measured in the chemical laboratory, and 48.9 ± 22.4 calculated with the best estimate among all models. The concentrations were not significantly different (P ≥ 0.17). It was found that using a multi-wavelength and processed signal approach leads to more accurate results, and therefore these approaches should be used in future.

Fibroblast Growth Factor 23, Hepatocyte Growth Factor, Interleukin‐6, High‐Sensitivity C‐Reactive Protein and Soluble Urokinase Plasminogen Activator Receptor. Inflammation Markers in Chronic Haemodialysis Patients?

Sera from 84 haemodialysis (HD) patients and 68 healthy blood donors were analysed with commercially available ELISA techniques for fibroblast growth factor 23 (FGF‐23), hepatocyte growth factor (HGF), interleukin‐6 (Il‐6), high‐sensitivity C‐reactive protein (hs‐CRP) and soluble urokinase plasminogen activator receptor (suPAR), to find a possible correlation of FGF‐23 and HGF with the earlier recognized inflammatory markers Il‐6 and hs‐CRP or suPAR. All patients studied had significantly elevated levels of FGF‐23, HGF, hs‐CRP and suPAR as compared to the controls. Il‐6 and hs‐CRP correlated for patients (R = 0.6) as well as for patients and controls altogether. Ln (natural logarithm) of HGF correlated weakly with Ln Il‐6 and Ln CRP (R 0.28–0.37). Ln FGF‐23 correlated only with Ln HGF (r = −0.25) in controls. Ln HGF correlated with ln suPAR (r = 0.6) in both patients and controls. Although elevated as compared to controls, we found no correlation of FGF‐23 with the recognized inflammatory markers Il‐6, hs‐CRP, nor HGF or the new marker suPAR in HD patients. Ln HGF correlated with Ln Il‐6, Ln CRP and Ln suPAR. Although probably involved in vessel disease, FGF‐23 and HGF may play other roles than acting in inflammatory vessel disease in HD patients. Further studies are necessary to evaluate the role of these immunological markers in chronic haemodialysis patients with atherosclerosis.

Optical measurement of creatinine in spent dialysate

AIM The aim of the study was to develop an optical method for the estimation of creatinine (Cr) removal during dialysis using UV-absorbance. MATERIAL AND METHODS 29 hemodialysis patients on chronic 3-times-a-week hemodialysis were studied in 6 separate studies. Double-beam pectrophotometer was used for the determination of UV-absorbance in the collected spent dialysate samples. A single wavelength (SW) and a multi-wavelength (MW) model were developed using stepwise regression utilizing Cr values from the laboratory as the dependent parameter. The reduction ratio (RR) and total removed Cr (TRCr) were estimated. RESULTS For blood-Cr RRb (mean ± SD) was 60.9 ± 5.0% (calibration set) and 58.1 ± 6.0% (validation set), for SW UVabsorbance RR_SW was 61.5 ± 5.9% and 57.3 ± 6.0%, and for MW UV-absorbance RR_MW was 65.8 ± 5.8% and 61.7 ± 6.4% respectively. RR_SW and RRb were not statistically different. RR_MW was higher compared to RRb (p < 0.05). TRCr_lab was 13.8 ± 3.8 mmol, TRCr_SW 14.5 ± 2.5 mmol and TRCr_MW 13.8 ± 2.6 mmol, being not statistically different. CONCLUSION In summary, creatinine removal during dialysis can be estimated as reduction ratio and total removed creatinine with the UV-absorbance technique.

Determinants of Fibroblast Growth Factor-23 and Parathyroid Hormone Variability in Dialysis Patients

Background/Aims: Treatment strategies for abnormal mineral metabolism in chronic kidney disease are largely based on achieving target ranges of biomarkers that vary considerably over time, yet determinants of their variability are poorly defined. Methods: Observational study including 162 patients of three dialysis cohorts (peritoneal dialysis, n = 78; hemodialysis, n = 49; hemodiafiltration, n = 35). Clinical and biochemical determinants of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) variability were analyzed in the peritoneal dialysis cohort. All cohorts were used for comparison of PTH and FGF23 intra-subject variability (intra-class correlation), and their intra-subject variability in different modes of dialysis was explored. Results: High PTH variability was independently associated with lower 25-hydroxyvitamin D concentration and factors of lipid and glucose metabolism, whereas high FGF23 variability was mainly associated with lower baseline serum phosphorous. These results were consistent in multivariate and sensitivity analyses. The intra-subject variability of FGF23 was lower than for PTH irrespective of dialysis mode. Conclusions: Baseline vitamin D status and serum phosphorous are independent determinants of the longitudinal variation in PTH and FGF23, respectively. The clinical utility of FGF23 measurement remains unknown, yet it appears favorable based on its greater temporal stability than PTH in dialysis patients.

Utilization of UV Absorbance for Estimation of Phosphate Elimination during Hemodiafiltration

Background: Phosphate is an important factor in explaining the high progress of vascular calcification among dialysis patients. Today, phosphate concentration is measured in plasma on a regular basis. The aim of this study was to find out if it is possible to estimate total removed phosphate (TRp) in spent dialysate utilizing UV absorbance during hemodiafiltration. Methods: Eleven patients were monitored online with UV absorbance at 297 nm, three times during one week each (n = 33). Dialysate samples were taken at different times during treatment and from a collection tank to chemically determine phosphate concentrations. Two mathematical models (UVIND and UVGROUP) were tested to estimate TRp with supervision by UV absorbance and compared with TRp measured in the tank (reference). Results: High correlation between UV absorbance and phosphate concentration for each single patient and lower for the whole group together was found. TRp was (mean ± SD) 30.7 ± 7.3 mmol for the reference and 30.8 ± 8.2 and 29.1 ± 5.2 mmol for UVIND and UVGROUP, respectively (p > 0.05). Conclusion: This study demonstrates a novel possibility to estimate TRp based on linear relationship between online monitoring of UV absorbance and concentration of phosphate in spent dialysate.

Sclerostin, TNF-alpha and Interleukin-18 Correlate and are Together with Klotho Related to Other Growth Factors and Cytokines in Haemodialysis Patients

Patients with chronic renal failure are known to have renal osteodystrophy (bone disease) and increased calcification of vessels. A new marker of bone disease, sclerostin, the two pro‐inflammatory cytokines tumour necrosis factor‐alpha (TNF‐alpha) and interleukin‐18 (IL‐18), and the fibroblast growth factor‐23 (FGF‐23) receptor‐associated marker Klotho were tested in 84 haemodialysis (HD) patients and in healthy controls. The patients had significantly higher levels of the three former markers than of the controls while Klotho was significantly higher in the controls. Low level, but significant, correlations were observed in the patient group when the levels of these four markers were compared to each other and to those of 5 cytokines and growth factors tested earlier; high‐sensitive CRP (hsCRP), interleukin‐6 (IL‐6), hepatocyte growth factor (HGF), fibroblast growth factor‐23 (FGF‐23) and soluble urokinase plasminogen activator (suPAR). Ln sclerostin correlated positively to Ln hsTNF‐alpha, Ln HGF and Ln suPAR. Ln hsTNF‐alpha correlated positively to Ln sclerostin, Ln hsCRP, Ln IL‐6, Ln FGF‐23, Ln suPAR and Ln IL‐18. Ln IL‐18 correlated positively to Ln suPAR and Ln TNF‐alpha. Ln Klotho correlated negatively to Ln hsCRP but did not correlate to Ln FGF‐23. The markers studied here may be involved in the calcification of vessels seen in HD patients due to a combination of inflammation and bone disease. The mechanisms are still not fully known but may be of importance for future therapeutic possibilities in this group of patients.