[A delicate balance: Gitelman syndrome and gestational diabetes. A case report].

Gitelman's syndrome (GS) is a rare autosomal recessive disorder characterized by hypokalemia, hypomagnesaemia, metabolic alkalosis, hypocalciuria and secondary hyperaldosteronism. The impact of GS on pregnant patients is still not clear, despite the many clinical cases described in literature. In particular, there is no data on the development of gestational diabetes. Altered glucose metabolism and insulin sensitivity have recently been described in patients with GS. We describe here the clinical case of a young woman suffering from GS who started pregnancy and developed gestational diabetes. Our experience, while confirming the need of assiduous ionic monitoring especially in the first trimester of pregnancy, seems to help scaling down the maternal-fetal risk in patients suffering from GS. We also suggest the introduction of a low-glucose diet to prevent the onset of gestational diabetes, a condition burdened with severe complications. Finally, a reminder that drugs active on ionic balance must be of proven maternal and fetal safety.

Mixed hemodiafiltration reduces erythropoiesis stimulating agents requirement in dialysis patients: a prospective randomized study.

BACKGROUND: Improved responsiveness to erythropoiesis stimulating agents (ESAs) in patients on on-line post-dilution hemodiafiltration (Post-HDF) compared with conventional hemodialysis (HD) was reported by some authors but challenged by others. This prospective, cross-over randomized study tested the hypothesis that an alternative infusion modality of HDF, mixed-dilution HDF (Mixed HDF), could further reduce ESAs requirement in dialysis patients compared to the traditional Post-HDF. METHODS: One-hundred-twenty prevalent patients from 6 Dialysis Centers were randomly assigned to two six-months treatment sequences: A-B and B-A (A, Mixed HDF; B, Post-HDF). Primary outcome was comparative evaluation of ESA (darbepoetin alfa) requirement and ESA resistance. Treatments efficiency, iron and vitamins status, inflammation and nutrition parameters were monitored. RESULTS: In sequence A, darbepoetin requirement decreased during Mixed HDF from 29.5 to 23.7 µg/month and increased significantly during Post-HDF (32.3 µg/month at 6th month) while, in sequence B, it increased during Post-HDF from 38.2 to 43.7 µg/month and decreased during Mixed HDF (23.9 µg/month at 6th month). Overall, EPO doses at 6 months on Mixed and Post-HDF were 23.8 and 38.4 µg/month, respectively, P < 0.01. A multiple linear model confirmed that Mixed HDF vs Post-HDF reduced significantly ESA requirement and ESA resistance (P < 0.0001), by a mean of 29% (CI 23-35%) in the last three months of the observation periods. CONCLUSIONS: Mixed HDF decreased darbepoetin-alfa requirement in dialysis patients. This might help preventing the untoward side effects of high ESA doses, besides having a remarkable economic impact. Additional evidence is needed to confirm this potential benefit of Mixed-HDF.

Effects of high-volume online mixed-hemodiafiltration on anemia management in dialysis patients.

BACKGROUND: Anemia is a major comorbidity of patients with end-stage renal disease and poses an enormous economic burden to health-care systems. High dose erythropoiesis-stimulating agents (ESAs) have been associated with unfavorable clinical outcomes. We explored whether mixed-dilution hemodiafiltration (Mixed-HDF), based on its innovative substitution modality, may improve anemia outcomes compared to the traditional post-dilution hemodiafiltration (Post-HDF). METHODS: We included 174 adult prevalent dialysis patients (87 on Mixed-HDF, 87 on Post-HDF) treated in 24 NephroCare dialysis centers between January 2010 and August 2016 into this retrospective cohort study. All patients were dialyzed three times per week and had fistula/graft as vascular access. Patients were matched at baseline and followed over a one-year period. The courses of hemoglobin levels (Hb) and monthly ESA consumption were compared between the two groups with linear mixed models. RESULTS: Mean baseline Hb was 11.9±1.3 and 11.8±1.1g/dl in patients on Mixed- and Post-HDF, respectively. While Hb remained stable in patients on Mixed-HDF, it decreased slightly in patients on Post-HDF (at month 12: 11.8±1.2 vs 11.1±1.2g/dl). This tendency was confirmed by our linear mixed model (p = 0.0514 for treatment x time interaction). Baseline median ESA consumption was 6000 [Q1:0;Q3:16000] IU/4 weeks in both groups. Throughout the observation period ESA doses tended to be lower in the Mixed-HDF group (4000 [Q1:0;Q3:16000] vs 8000 [Q1:0;Q3:20000] IU/4 weeks at month 12; p = 0.0791 for treatment x time interaction). Sensitivity analyses, adjusting for differences not covered by matching at baseline, strengthened our results (Hb: p = 0.0124; ESA: p = 0.0687). CONCLUSIONS: Results of our explorative study suggest that patients on Mixed-HDF may have clinical benefits in terms of anemia management. This may also have a beneficial economic impact. Future studies are needed to confirm our hypothesis-generating results and to provide additional evidence on the potential beneficial effects of Mixed-HDF.

Patterns of Proteins Removed with High-Flux Membranes on High-Volume Hemodiafiltration Detected with a MultiDimensional LC-MS/MS Strategy.

Background: Aim of this prospective crossover study was to identify the nature of the middle-molecular weight solutes removed during high-volume post-dilution HDF. Methods: The efficiency in removing small molecules, protein-bound and middle-molecular proteins was evaluated in 16 chronic dialysis patients on post-dilution HDF with two high-flux dialyzer membranes (Amembris and Polyamix). Multidimensional Protein Identification Technology (MudPIT) was employed to identify middle-molecular weight solutes in spent dialysate. Results: Efficiency of post-dilution HDF in removing solutes of different MW was high with both membranes, but higher with Amembris than with Polyamix. With MudPIT analysis, 277 proteins were identified in the dialysate fluids. Although the protein-removal pattern was similar among patients and tested membranes, the total and protein-specific peptide spectral count (mass spectrometric quantitation criteria) of most proteins were higher using the Amembris membrane. Conclusions: The MudPIT approach showed to be a powerful tool to identify a broad molecular weight spectrum of proteins removed with post-dilution HDF. Short Summary: Aim of this prospective crossover study was to analyze the hydraulic properties of two high-flux dialyzer membranes (Amembris and Polyamix) during high-volume, post-dilution HDF and to evaluate the influence of these properties on the removal of proteins and peptides using an in-depth analysis of the spent dialysate. For this analysis, a liquid chromatography tandem mass spectrometry approach called MudPIT (Multidimensional Protein Identification Technology) was used to identify the middle molecular weight solutes present in the spent dialysate of patients. The capability of post-dilution HDF in removing solutes of different MW was very high with both dialyzers, but higher with the Amembris membrane. The proteomic MudPIT approach showed to be a powerful tool to identify a wide molecular spectrum of proteins removed from blood during post-dilution HDF. These results may contribute to address research toward a better knowledge of uremic toxins and the balance between the intended and unintended removal of undesired and beneficial proteins next to identification of new target proteins as potential candidates for uremic toxicity. © 2014 S. Karger AG, Basel.

Phosphate levels in patients treated with low-flux haemodialysis, pre-dilution haemofiltration and haemodiafiltration: post hoc analysis of a multicentre, randomized and controlled trial.

BACKGROUND: Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial. METHODS: This analysis was performed in the database of a multicentre, open label and randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: on-line pre-dilution HF (36 patients) or on-line pre-dilution haemodiafiltration (40 patients). RESULTS: CTs did not affect P (P = 0.526), calcium (Ca) (P = 0.849) and parathyroid hormone levels (P = 0.622). P levels were associated with the use of phosphate binders including aluminium-based phosphate binders (P < 0.001) and sevelamer (P < 0.001), pre-dialysis bicarbonate levels (P < 0.001) and pre-dialysis blood K levels (P < 0.001). On multivariate analysis (generalized linear model), serum P was again largely unassociated with CTs (P = 0.631). Notably, participating centres were by far the strongest independent correlate of serum P, explaining 45.3% of the variance of serum P over the trial and this association was confirmed at multivariate analysis. Bicarbonate (P < 0.001) and, to a weaker extent, serum K (P = 0.032) were independently related to serum P. CONCLUSIONS: In comparison with low-flux HD, CTs did not significantly affect serum P levels. Participating centres were the main source of P variability during the trial followed by treatment with phosphate binders, serum bicarbonate and, to a weak extent, serum potassium levels (ClinicalTrials.gov Identifier: NCT011583309).

[Mixed hemodiafiltration]. / Emodiafiltrazione mista.

Mixed hemodiafiltration is a novel technique in which the traditional infusion modes of predilution and postdilution are carried out simultaneously in the same dialyzer to overcome the limits and risks of each and join their advantages. It is performed under the control of transmembrane pressure feedback, which constantly monitors blood and dialysate compartments and adjusts both the total infusion amount and its ratio in predilution and postdilution mode, in order to achieve the safest rheological and hydraulic conditions. The ensuing maximization of the convective fraction optimizes middle-molecule removal. The technical characteristics, method of application, and clinical results of mixed hemodiafiltration are described in this article.

Predictors of haemoglobin levels and resistance to erythropoiesis-stimulating agents in patients treated with low-flux haemodialysis, haemofiltration and haemodiafiltration: results of a multicentre randomized and controlled trial.

BACKGROUND: Predictors of haemoglobin (Hb) levels and resistance to erythropoiesis-stimulating agents (ESAs) in dialysis patients have not yet been clearly defined. Some mainly uncontrolled studies suggest that online haemodiafiltration (HDF) may have a beneficial effect on Hb, whereas no data are available concerning online haemofiltration (HF). The objectives of this study were to evaluate the effects of convective treatments (CTs) on Hb levels and ESA resistance in comparison with low-flux haemodialysis (HD) and to evaluate the predictors of these outcomes. METHODS: Primary multivariate analysis was made of a pre-specified secondary outcome of a multicentre, open-label, randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: online pre-dilution HF (36 patients) or online pre-dilution HDF (40 patients). RESULTS: CTs did not affect Hb levels (P = 0.596) or ESA resistance (P = 0.984). Hb correlated with polycystic kidney disease (P = 0.001), C-reactive protein (P = 0.025), ferritin (P = 0.018), ESA dose (P < 0.001) and total cholesterol (P = 0.021). The participating centres were the main source of Hb variability (partial eta(2) 0.313, P < 0.001). ESA resistance directly correlated with serum ferritin (P = 0.030) and beta2 microglobulin (P = 0.065); participating centres were again a major source of variance (partial eta(2) 0.367, P < 0.001). Transferrin saturation did not predict either outcome variables (P = 0.277 and P = 0.170). CONCLUSIONS: In comparison with low-flux HD, CTs did not significantly improve Hb levels or ESA resistance. The main sources of variability were participating centres, ESA dose and the underlying disease.

Overcoming the limitations of post-dilution on-line hemodiafiltration: mixed dilution hemodiafiltration.

The impact of hemodiafiltration (HDF) on survival is still a topic of under investigation. Most recently, the results of two large prospective trials (the CONTRAST Study and the Turkish HDF Study) did not find any difference in survival between on-line HDF versus low- and high-flux hemodialysis (HD) in the overall dialysis population. However, secondary subgroup analyses of both studies showed a significant reduction in death risk among patients on HDF with high volume exchange, confirming the preliminary observation of the European DOPPS Study. Higher middle molecule removal is definitely attained in high-efficiency HDF compared to high-flux HD, and lower basal ß(2)-microglobulin levels may result in reduced death risk, as suggested by an analysis of the HEMO Study.

Efficiency of post-dilution hemodiafiltration with a high-flux α-polysulfone dialyzer.

PURPOSE: Intra-individual comparison of technical and clinical characteristics of two hemodiafiltration (HDF) strategies, namely, post-dilution HDF (post-HDF) with a high-flux α-polysulfone hemodiafilter and reverse mid-dilution HDF (MD-HDF). METHODS: Fifteen patients who were stable on RRT were randomly submitted to both HDF techniques under matched operational conditions. Removal of small and middle molecular compounds was compared. The pressure regimen within the dialyzers and the hydraulic and solute permeability indexes of the membrane were monitored on-line during the sessions. RESULTS: Urea removed was not statistically different between post-HDF and MD-HDF (41.7±10.2 vs. 39.9±8.2 g/session). High and comparable removal of phosphate (KDQ,132±30 vs. 138±21 ml/min) and middle molecules (ß2-m KDQ, 79.1±6.1 vs. 74.1±13.5 ml/min) was shown in post-HDF and MD-HDF. Albumin leakage tended to be lower after post-HDF (914±370 vs. 1313±603 mg/session, p=0.075). There were no cases of blood circuit clotting, hypotensive episodes, or other clinical or technical problems. In post-HDF, a very high ultrafiltration rate (QUF, 7.4 l/h) and filtration fraction of 59% were maintained through the sessions with safe trans-membrane pressure (TMP) values strictly retained within the planned range (280-350 mmHg). Larger volume exchange (10 l/h) was obtained in MD-HDF, but the very high QUF established high and risky TMP in the post-dilution section of the MD 220 dialyzer. CONCLUSIONS: The hemodiafilter tested in this study proved its high efficiency when used in post-dilution HDF with the application of an automatic ultrafiltration/pressure feedback, which guaranteed maximal convection within controlled hydraulic conditions.

Long-term effects of high-efficiency on-line haemodiafiltration on uraemic toxicity. A multicentre prospective randomized study.

BACKGROUND: Haemodiafiltration (HDF) may improve survival of chronic dialysis patients. This prospective, multicentre randomized cross-over study evaluated the effects of long-term on-line HDF on the levels of solutes of different molecular weight markers or causative agents of the most common metabolic derangements in uraemia. METHODS: Sixty-nine patients from eight Italian centres were randomly assigned to two 6-month treatment sequences: A-B and B-A [A, low-flux haemodialysis (HD) and B, on-line HDF]. Comparative evaluation of basal levels of small, medium-sized and protein-bound solutes at the end of the two treatment periods and analysis of parameters dependence during the interventions were performed. RESULTS: On-line HDF showed greater efficiency than low-flux HD in removing small solutes (eKt/Vurea 1.60 ± 0.31 versus 1.44 ± 0.26, P < 0.0001) and in reducing basal levels of beta2-microglobulin (22.2 ± 7.8 versus 33.5 ± 11.8 mg/L, P < 0.0001), total homocysteine (15.4 ± 5.0 versus 18.7 ± 8.2 µmol/L, P = 0 .003), phosphate (4.6 ± 1.3 versus 5.0 ± 1.4 mg/dL, P = 0.008) and, remarkably, of intact parathyroid hormone (202 ± 154 versus 228 ± 176 pg/mL, P = 0.03). Moreover, in on-line HDF, lower levels of C-reactive protein (5.5 ± 5.5 versus 6.7 ± 6.1 mg/L, P = 0.03) and triglycerides (148 ± 77 versus 167 ± 87 mg/dL, P = 0.008) and increased HDL cholesterol (49.2 ± 12.7 versus 44.7 ± 12.4 mg/dL, P = <0.0001) were observed. The asymmetric dimethylarginine level was not significantly affected (0.97 ± 0.4 versus 0.84 ± 0.37 µmol/L). Erythropoietin and phosphate binders' doses could be reduced. CONCLUSIONS: On-line high-efficiency HDF resulted in enhanced removal and lower basal levels of small, medium-sized and protein-bound solutes, which are markers or causative agents of uraemic pathologies, mainly inflammation, secondary hyperparathyroidism and dyslipidaemia. This may contribute to reducing uraemic complications and possibly to improving patient survival.

Hemofiltration and hemodiafiltration reduce intradialytic hypotension in ESRD.

Symptomatic intradialytic hypotension is a common complication of hemodialysis (HD). The application of convective therapies to the outpatient setting may improve outcomes, including intradialytic hypotension. In this multicenter, open-label, randomized controlled study, we randomly assigned 146 long-term dialysis patients to HD (n = 70), online predilution hemofiltration (HF; n = 36), or online predilution hemodiafiltration (HDF; n = 40). The primary end point was the frequency of intradialytic symptomatic hypotension (ISH). Compared with the run-in period, the frequency of sessions with ISH during the evaluation period increased for HD (7.1 to 7.9%) and decreased for both HF (9.8 to 8.0%) and HDF (10.6 to 5.2%) (P < 0.001). Mean predialysis systolic BP increased by 4.2 mmHg among those who were assigned to HDF compared with decreases of 0.6 and 1.8 mmHg among those who were assigned to HD and HF, respectively (P = 0.038). Multivariate logistic regression demonstrated significant risk reductions in ISH for both HF (odds ratio 0.69; 95% confidence interval 0.51 to 0.92) and HDF (odds ratio 0.46, 95% confidence interval 0.33 to 0.63). There was a trend toward higher dropout for those who were assigned to HF (P = 0.107). In conclusion, compared with conventional HD, convective therapies (HDF and HF) reduce ISH in long-term dialysis patients.

A simple approach for assessing equilibrated Kt/V beta 2-M on a routine basis.

BACKGROUND: Large observational studies have shown a reduction in morbidity and mortality in patients on high-flux haemodialysis (HD) or convective techniques, compared with low-flux HD. An index to evaluate treatment efficiency in middle molecule (MM) removal would be recommended. Since beta-2-microglobulin (beta2-M) is a recognized MM marker, we evaluated an easy approach for Kt/V(beta2-M) assessment on a routine basis, avoiding other complex methods. METHODS: An equation that estimates single-pool (sp) Kt/V(beta2-M) was derived from Leypoldt's formula, which calculates beta2-M dialyser clearance (K(beta2-M)) from the post/pre-dialysis beta2-M concentration (C(t)/C(0)) ratio and the weight loss/end-dialysis weight (Delta W/W) ratio. Our equation, spKt/V(beta2-M) = 6.12 Delta W/W [1 - ln(C(t)/C(0))/ln(1 + 6.12 Delta W/W)], was derived by assuming urea distribution volume (V(u)) as 49% of W and beta2-M volume (V(beta2-M)) as V(u)/3, in agreement with the average patient values in the HEMO Study. The spKt/V(beta2-M) values calculated with our equation (F) in 129 patients on 407 sessions of different high-flux treatments were compared with those calculated with the method applied in the HEMO Study (HM). Equilibrated beta2-M concentration (C(eq)) of the same sessions was also estimated with the equation for C(eq) by Tattersall, and equilibrated Kt/V (eKt/V(beta2-M)) was calculated by introducing Tattersall's equation into our simplified spKt/V(beta2-M) formula. RESULTS: Mean results of our spKt/V(beta2-M) equation (F) were very close to those of the HM method (1.48 +/- 0.38 vs 1.47 +/- 0.37). The difference was less than +/-0.1 in 95% of cases. A mean end-session beta2-M rebound of 44 +/- 14% was predicted, which caused a mean reduction in actual Kt/V(beta2-M) of ~27% (eKt/V(beta2-M) = 1.08 +/- 0.26). CONCLUSIONS: The method proposed to estimate spKt/V(beta2-M) and eKt/V(beta2-M) could become a simple tool to monitor the efficiency of high-flux HD and convective techniques and to evaluate the adequacy of treatments in terms of MM removal. Moreover, it might help to better understand the effects of different dialysis schedules. Validation on a larger dialysis population is required.

Optimization of mid-dilution haemodiafiltration: technique and performance.

BACKGROUND: Mid-dilution haemodiafiltration (MD-HDF), reported as a highly efficient convective-mixed technique, has demonstrated serious drawbacks in relation to the high pressure originating inside the blood compartment of the filter during clinical application. This randomized crossover design study was planned to optimize the efficiency of the MD-HDF technique while reducing its inherent risks. METHODS: Fifteen patients on RRT were submitted in random sequence to standard and reverse MD-HDF under similar operating conditions. Efficiency in solute removal was evaluated by measuring urea (U), phosphate (P) and beta2-microglobulin (beta2-m), mean dialysate clearances (K(DQ)) and eKt/V. Blood and dialysate compartment pressures were monitored on-line during the sessions, and instantaneous hydraulic and membrane permeability indexes were calculated. RESULTS: During standard MD-HDF sessions, unlike with reverse MD-HDF, excessive blood inlet and transmembrane pressure prevented the planned infusion from being maintained. Resistance index and membrane permeability to water and middle molecules substantially improved with reverse MD-HDF. This resulted in higher beta2-m removal (221.3 +/- 81.3 versus 185.1 +/- 65.5 mg/session, P = 0.007). Phosphate removal was comparable, while U removal was greater with standard MD-HDF (K(DQ) 272 +/- 35 versus 252 +/- 29 ml/min, P = 0.002; eKt/V 1.63 +/- 0.23 versus 1.49 +/- 0.17, P = 0.005). CONCLUSIONS: This study demonstrated the ability of MD-HDF to remove significant amounts of medium-sized uraemic compounds and phosphate, but safe rheologic and hydraulic conditions were only maintained by carrying out treatments with the dialyser used in reverse configuration. For this purpose, the larger MD-220 dialyser ensured better tolerance together with higher middle molecules clearance, even though small molecule removal was slightly worsened. The results of this study may provide some insight into the complex interactions between pressures and flux within the original structure of MD-dialysers and help optimize the clinical application of the technique and reduce its risks.

Mixed-dilution hemodiafiltration.

Mixed-dilution hemodiafiltration (mixed HDF) controlled by the transmembrane pressure (TMP) feedback, improves the depurative capacity of the more traditional HDF techniques by fully exploiting the convective mechanism of small- and middle-molecular-weight solute removal. The feedback allows the TMP to be set and profiled from patient and operational parameters recorded online by the machine. It automatically adjusts the infusion ratio between predilution and postdilution at the maximum filtration fraction without reducing the total infusion/ultrafiltration rate and taking into account fl ow conditions, internal pressures and hydraulic permeability of the dialyzer, and their complex interactions and changes during the session. The application of the TMP profile, while avoiding dangerous hydrostatic pressures within the dialyzer and their negative effects, helps better preserve the permeability of the membrane with the effect of a significantly increased solute removal in a wide molecular range and with minimal protein leakage. In the light of the more recent observations in the literature, the high biocompatibility resulting from the use of synthetic membranes and ultrapure dialysate, combined with the enhanced removal of small- and middle-molecular-weight uremic toxins obtained with high-efficiency HDF, seems to be the best available strategy to prevent or delay the occurrence of long-term dialysis complications and to promote improved survival of dialysis patients. Preliminary results of its application indicate that TMP-modulated mixed-dilution HDF could be one of the most powerful strategies to achieve this goal.

New strategies in haemodiafiltration (HDF): prospective comparative analysis between on-line mixed HDF and mid-dilution HDF.

BACKGROUND: Improvement in the uraemic toxicity profile obtained with the application of convective and mixed dialysis techniques has stimulated the development of more efficient strategies. Our study was a prospective randomized evaluation of the clinical and technical characteristics of two new haemodiafiltration (HDF) strategies, mixed HDF and mid-dilution HDF, which have recently been proposed with the aim of increasing efficiency and safety with respect to the standard traditional HDF infusion modes. METHODS: Ten stable patients on renal replacement therapy (mean age 64.7 +/- 8.2 years) were submitted in randomized sequence to one mid-week session of mid-dilution HDF and one of mixed HDF with trans-membrane pressure feedback control. All sessions were carried out under similar operating conditions and involved monitoring pressure within the internal dialyser compartments and calculating the rheological and hydraulic indexes. Efficiency in removing urea, phosphate and beta2-microglobulin (beta2-m) was tested. RESULTS: In mixed HDF, safer and more effective flux/pressure conditions resulted in better preservation of the hydraulic and solute membrane permeability (mean in vivo ultrafiltration coefficient 36.9 +/- 3.9 vs 20.1 +/- 3.3 ml/h/mmHg) and ensured higher volume exchange (38.7 +/- 4.2 vs 35.3 +/- 6.5 l/session, P = 0.02) and greater efficiency in removing small and middle molecules (mean urea clearance: 274 +/- 42 vs 264 +/- 47 ml/min, P = 0.028; eKt/V: 1.78 +/- 0.22 vs 1.71 +/- 0.26, P = 0.036; mean phosphate clearance: 138 +/- 16 vs 116 +/- 45 ml/min, P = 0.2; mean beta2-m clearance: 81 +/- 13 vs 59 +/- 13 ml/min, P = 0.001). CONCLUSIONS: Mixed HDF was the most efficient technique in the highest range of safe operating conditions. In mid-dilution HDF, high pressures generated inside the dialyser compromised membrane permeability and limited the total infusion rate, resulting in an overall reduction in solute removal.