Metformin-Associated Lactic Acidosis Undergoing Renal Replacement Therapy in Intensive Care Units: A Five-Million Population-Based Study in the North-West of Italy.

BACKGROUND: Metformin-associated lactic acidosis (MALA) is a severe complication of drug administration with significant morbidity and mortality. So far no study in large population areas have examined the incidence, clinical profile and outcome of acute kidney injury (AKI)-MALA patients admitted in intensive care units (ICUs) and treated by renal replacement therapy (MALA-RRT). METHODS: Retrospective analysis over a 6-year period (2010-2015) in Piedmont and Aosta Valley regions (5,305,940 inhabitants, 141,174 diabetics treated with metformin) of all MALA-RRT cases. RESULTS: One hundred and seventeen cases of AKI-MALA-RRT were observed (12.04/100,000 metformin treated diabetics, 1.45% of all RRT-ICU patients). Survival rate was 78.3%. The average duration of RRT was 4.0 days at mean dialysis effluent of 977 mL/kg/day. At admission most patients were dehydrated, and experienced shock and oliguria. CONCLUSION: Our data showed that MALA-RRT is a common complication, needing more prevention. Adopted policy of early, extended, continuous and high efficiency dialysis could contribute to an observed high survival rate. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=471917.

Increase of continuous treatments and regional citrate anticoagulation during renal replacement therapy in the ICUs of the North-West of Italy from 2007 to 2015.

BACKGROUND: Few reports have addressed the change in renal replacement therapy (RRT) management in the Intensive care Units (ICUs) over the years in western countries. This study aims to assess the trend of dialytic practice in a 4.5-million population-based study of the northwest of Italy. METHODS: A nine-year survey covering all the RRT provided in the ICUs. Consultant nephrologists of the 26 Nephrology and Dialysis centers reported their activities in the years 2007, 2009, 2012, and 2015. RESULTS: From 2007 to 2015 the patients treated increased from 1042 to 1139, and the incidence of RRT from 254 to 263 cases/10^6 inhabitants. The workload for dialysis center was higher in the larger hub hospitals. RRT for acute kidney injury (AKI), continuation of treatment in chronically dialyzed patients, or extrarenal indications accounted for about the stable rate of 70, 25 and 5% of all RRT sessions, respectively. Continuous modality days increased from 2731 days (39.5%) in 2007 to 5076 (70.6%) in 2015, when the continuous+prolonged treatment days were 6880/7196 (95.6% of total days). As to RRT timing, in 2015 only the classical clinical criteria, and no K-DIGO stage were adopted by most Centers. As to RRT interruption, in 2015 urine volume was the first criterion. Implementation of citrate anticoagulation (RCA) for RRT patients significantly increased from 2.8% in 2007 to 30.9% in 2015, when it was applied in all 26 Centers. CONCLUSIONS: From 2007 to 2015, current practice has changed towards shared protocols, with increasing continuous modality and RCA implementation.

Optimizing the dialysate calcium concentration in bicarbonate haemodialysis.

BACKGROUND: There is no consensus regarding the optimal dialysate calcium concentration (DCa) during haemodialysis (HD). Low DCa may predispose to acute arrhythmias, whereas high DCa increases the long-term risk of soft tissue calcifications. METHODS: Twenty-two HD patients treated in four dialysis centres underwent two HD sessions, respectively, with 1.5 and 1.25 mmol/L total DCa. Calcium mass balance (CMB) was calculated from ionized calcium (iCa) in the dialysate and blood at the start and end of each run, using a kinetic formula to define the mean concentrations in the blood and dialysate and then estimating CMBs over the entire treatments. RESULTS: Mean blood iCa levels increased using 1.5 DCa, whereas they remained unchanged using 1.25 DCa. Diffusive CMB positively correlated with the dialysate/blood iCa gradient. With 1.5 DCa, diffusive CMBs were strongly positive at the blood side and negative at the dialysate side, indicating transfer from dialysate to blood. With 1.25 DCa, despite a negative dialysate/blood iCa gradient, diffusive CMB was slightly positive in blood and negative in dialysate. The global balances based on both the convective and diffusive components showed a positive net transfer of Ca from dialysate to blood with 1.5 DCa and an approximately neutral Ca flux with 1.25 DCa. CONCLUSIONS: While CMB is nearly neutral when using 1.25 DCa, the use of 1.5 DCa results in a gain of Ca during HD. The risks associated with Ca load should be considered in the choice of DCa prescription for HD but need also be weighed against the risk of worse haemodynamic dialysis tolerance.

Citrate high volume on-line hemodiafiltration modulates serum Interleukin-6 and Klotho levels: the multicenter randomized controlled study "Hephaestus".

BACKGROUND: Studies addressing the anti-inflammatory properties of citrate dialysate enrolled patients in both hemodialysis (HD) and hemodiafiltration (HDF), the latter not adjusted for adequate convective exchange. This is a potential source of confounding in that HDF itself has anti-inflammatory effects regardless of the buffer, and optimal clinical outcomes are related to the amount of convection. METHODS: To distinguish the merits of the buffer from those of convection, we performed a 6-month, prospective, randomized, crossover AB-BA study. Comparisons were made during the 3-month study period of on-line HDF with standard dialysate containing three mmol of acetic acid (OL-HDFst) and the 3-month of OL-HDF with dialysate containing one mmol of citric acid (OL-HDFcit). Primary outcome measure of the study was interleukin-6 (IL-6). Klotho, high sensitivity C-reactive protein (hsCRP), fetuin and routine biochemical parameters were also analyzed. RESULTS: We analyzed 47 patients (mean age 64 years, range 27-84 years) enrolled in 10 participating Nephrology Units. Convective volumes were around 25 L/session with 90 percent of sessions > 20 L and ß2-microglobulin reduction rate 76% in both HDFs. Baseline median IL-6 values in OL-HDFst were 5.6 pg/ml (25:75 interquartile range IQR 2.9:10.6) and in OL-HDFcit 6.6 pg/ml (IQR 3.4:11.4 pg/ml). The difference was not statistically significant (p 0.88). IL-6 values were lower during OL-HDFcit than during OL-HDFst, both when analyzed as the median difference of overall IL-6 values (p 0.02) and as the median of pairwise differences between the baseline and the 3-month time points (p 0.03). The overall hsCRP values too, were lower during OL-HDFcit than during OL-HDFst (p 0.01). Klotho levels showed a time effect (p 0.02) and the increase was significant only during OL-HDFcit (p 0.01). CONCLUSIONS: Citrate buffer modulated IL-6, hsCRP and Klotho levels during high volume OL-HDF. These results are not attributable to differences in the dialysis technology that was applied and may suggest a potential biological effect of citrate on CKD-associated inflammatory state. ClinicalTrials.gov identifier NCT02863016.

Two-operator glucose infusion test (GIT2) for vascular access recirculation measurement during hemodialysis.

Vascular access recirculation rate (AR) monitoring is fundamental to guarantee treatment adequacy and to detect access failure early. We have evaluated the GIT2 test to measure AR unaffected by cardio-pulmonary recirculation (CPR), based on a short glucose infusion in place of the bolus and on a two-operator sampling, differently from the classical glucose infusion test (GIT). The GIT2 test is based on four steps: 1) basal (B) glucose arterial sample; 2) 10% glucose infusion for 1 min, by infusion pump at 600 ml/hr; (or 20% at 300 ml/hr); 3) simultaneous sampling at arterial (A) and venous (V) ports, after 35-40 sec from starting the infusion, taking care to avoid blood pump stop during the test; 4) AR=100*((A-B)/(V-B)). In vitro tests by dialysis on a 40 L tank containing a urea solution, with AR volumetrically simulated at 0, 5, 10, 20%, and in vivo comparison of GIT, GIT2 with stop-flow (SF) urea method. Our results have shown in vitro an almost perfect correspondence of SF urea method and a better reliability of GIT2 than GIT. The methylene-blue test has shown that a single color bolus in V reaches the A port after variable time, depending on blood flow and AR, while the continuous infusion determines a steady gradient after about 30". In vivo tests (n=24) show good correspondence between GIT2 (4.37 +/- 3.36) and SF (4.51 +/- 3.62), while GIT data (1.01 +/- 0.51) are significantly underestimated. In conclusion, our preliminary results have evidenced a good reliability of the new test, the continuous infusion causing a steady gradient in V and A that more precisely reflects the AR rate.

Effectiveness of Switch to Erythropoiesis-Stimulating Agent (ESA) Biosimilars versus Maintenance of ESA Originators in the Real-Life Setting: Matched-Control Study in Hemodialysis Patients.

BACKGROUND: In hemodialysis (HD), switching from erythropoiesis-stimulating agent (ESA) originators to biosimilars is associated with the need for doses approximately 10% higher, according to industry-driven studies. OBJECTIVE: The aim of this study was to evaluate the efficacy on anemia control of switching from ESA originators to biosimilars in daily clinical practice. METHODS: We retrospectively selected consecutive HD patients receiving stable intravenous ESA doses, and who had not been transfused in the previous 6 months, from 12 non-profit Italian centers. Patients switched from originators to biosimilars (n = 163) were matched with those maintained on ESA originators (n = 163) using a propensity score approach. The study duration was 24 weeks, and the primary endpoint was the mean dose difference (MDD), defined as the difference between the switch and control groups of ESA dose changes during the study (time-weighted average ESA dose minus baseline ESA dose). RESULTS: Age (70 ± 13 years), male sex (63%), diabetes (29%), history of cardiovascular disease (40%), body weight (68 ± 14 kg), vascular access (86% arteriovenous fistula), hemoglobin [Hb] (11.2 ± 0.9 g/dL) and ESA dose (8504 ± 6370 IU/week) were similar in the two groups. Hb remained unchanged during the study in both groups. Conversely, ESA dose remained unchanged in the control group and progressively increased in the switch group from week 8 to 24. The time-weighted average of the ESA dose was higher in the switch group than in the control group (10,503 ± 7389 vs. 7981 ± 5858 IU/week; p = 0.001), leading to a significant MDD of 2423 IU/week (95% confidence interval [CI] 1615-3321), corresponding to a 39.6% (95% CI 24.7-54.6) higher dose of biosimilars compared with originators. The time-weighted average of Hb was 0.2 g/dL lower in the switch group, with a more frequent ESA hyporesponsiveness (14.7 vs. 2.5%). Iron parameters and other resistance factors remained unchanged. CONCLUSIONS: In stable dialysis patients, switching from ESA originators to biosimilars requires 40% higher doses to maintain anemia control.

Internal hemodiafiltration versus low-flux bicarbonate dialysis: Results from a long-term prospective study.

INTRODUCTION: About ten years ago it was discovered that changes in filter design which increase passive filtration improved dialysis efficiency. Later, these modified membranes showed similar intra-dialytic efficiency when used in on-line hemodiafiltration or in bicarbonate dialysis, called internal hemodiafiltration. AIM AND METHODS: On the basis of these previous results, we studied the long-term effects of internal hemodiafiltration, in comparison with low-flux bicarbonate dialysis. The pre-dialysis beta2-microglobulin level was chosen as the primary outcome variable. A prospective multicenter study with a cross-over scheme, 2 treatments and 3 periods, was designed. Twenty-four patients, followed in two dialysis centers, were enrolled. Many other parameters were measured every month at the first dialysis session of the week. The intra-dialytic removal of urea, beta2-microglobulin and homocysteine was also calculated. RESULTS: The removal of uremic toxins was significantly higher in internal hemodiafiltration than in low-flux bicarbonate dialysis. The pre-dialysis value of urea, phosphorus, beta2-microglobulin and homocysteine was lower during internal hemodiafiltration as compared with low-flux bicarbonate dialysis. The mean pre-dialysis value of hemoglobin was significantly higher during internal hemodiafiltration than low-flux bicarbonate dialysis, with a trend towards a significantly lower consumption of erythropoiesis stimulating agents during internal hemodiafiltration as compared with low-flux bicarbonate dialysis. CONCLUSIONS: Long-term treatment with internal hemodiafiltration improves the removal of small molecules and stops the continuous increase of middle molecules as seen in low-flux bicarbonate dialysis. Internal hemodiafiltration may substitute low-flux bicarbonate dialysis, but we need new prospective studies about long-term hard end-points.