The role of apheresis and insulin therapy in hypertriglyceridemic acute pancreatitis-a concise review.

Severe hypertriglyceridemia (HTG) is the third most common cause of acute pancreatitis (AP) and is involved in its pathogenesis. Chylomicrons increase blood viscosity and induce ischemia, while free fatty acids induce inflammation and distant organ damage. Conservative treatment options include fasting and insulin; limited evidence shows their comparable efficacy. Plasma exchange might provide more rapid lowering of triglycerides and amelioration of systemic effects of severe AP. Available data from controlled studies show only moderately faster lowering of triglycerides with apheresis (about 70% vs. 50% with conservative treatment within 24 h) and limited data from non-randomized studies show no improvement in clinical outcomes. New evidence is expected soon from ongoing large randomized trials. Until then, insulin may be used in mild HTG-AP and plasma exchange should be considered only in severe HTG-AP, especially if the decline of triglycerides with conservative treatment is slow, and in HTG-AP during pregnancy.

Extracorporeal Removal of Myoglobin in Patients with Rhabdomyolysis and Acute Kidney Injury: Comparison of High and Medium Cut-Off Membrane and an Adsorber Cartridge.

INTRODUCTION: The role of extracorporeal myoglobin removal in the treatment of rhabdomyolysis-associated severe acute kidney injury (AKI) is not yet fully established. High cut-off (HCO) and medium cut-off (MCO) dialysis membrane and cytokine adsorber (CytoSorb®) have been used to this purpose in clinical practice. The data on comparative effectiveness of those methods are scarce. METHODS: In this single-center retrospective study, we included patients with AKI and concomitant rhabdomyolysis (myoglobin >20,000 µg/L), who underwent at least one extracorporeal myoglobin removal procedure. The main outcome parameter was myoglobin reduction ratio, whereas albumin was assessed as a safety parameter. RESULTS: We analyzed data for 15 patients, who underwent 28 procedures (13 HCO, 9 MCO, and 6 adsorber). Pre-treatment serum myoglobin levels were similar between the groups and myoglobin reduction was significant in HCO (p = 0.03) and MCO groups (p < 0.01) and borderline significant in adsorber group (p = 0.06). Reduction ratios were comparable between the groups (median 0.64 (inter-quartile range IQR 0.13-0.72), 0.54 (IQR 0.51-0.61) and 0.50 (IQR 0.37-0.62), respectively, p = 0.83). Both pre- and post-procedure serum albumin levels were significantly lower in the MCO group. However, with routine albumin substitution in the HCO group only, serum albumin remained stable during the procedures in all subgroups. CONCLUSIONS: Novel MCO membrane might represent the optimal mode of treatment of severe rhabdomyolysis-associated AKI, as it allows for efficient removal of myoglobin, avoids albumin supplementation and is associated with lower costs. For patients requiring cytokine removal, the adsorption capsule can simultaneously reduce cytokine and myoglobin levels.

Treatment of preeclampsia at extremely preterm gestation with therapeutic plasma exchange.

AIMS: Different forms of apheresis have been proposed as potential therapeutic approaches to remove soluble Fms-like tyrosine kinase-1 (sFlt-1) and allow safe pregnancy prolongation in cases of extremely preterm preeclampsia. This is a follow-up study presenting our experiences with therapeutic plasma exchange (TPE) in 5 women with preeclampsia at < 28 weeks of gestational age. MATERIALS AND METHODS: All women received standard treatment for preeclampsia and 2 - 3 TPE treatments per week. Blood samples for sFlt-1 and placental growth factor (PlGF) measurements were collected before and after each TPE. RESULTS: Seventeen TPE procedures were performed, 2 - 5 per patient. TPE significantly reduced sFlt-1 (by 35 ± 6%), sFlt-1/PlGF ratio (by 24 ± 13%), and to a lesser degree also PlGF (by 12 ± 16%), with a rebound observed on day 1 post procedure. TPE procedures were well tolerated by pregnant women and fetuses. Stabilization of sFlt-1 allowed pregnancy prolongation for a median of 8 (range 2 - 14) days from first TPE and for a median of 10 (range 4 - 17) days from hospital admission. There were no signs of increased risks of adverse neonatal outcome associated with TPE. One neonate died due to extreme prematurity 3 days after delivery, 2 had bronchopulmonary dysplasia, and 1 had retinopathy of prematurity. CONCLUSION: This study provides new evidence of effective reduction in sFlt-1 and sFlt-1/PlGF ratio with TPE treatment, which seems to allow a clinically meaningful prolongation of pregnancy. Controlled studies are necessary to convincingly show the potential benefit of apheresis treatment in preeclampsia at extremely preterm gestation.

A national cohort study on hemodialysis arteriovenous fistulas after kidney transplantation - long-term patency, use and complications.

OBJECTIVE: To describe the long-term hemodialysis arteriovenous fistula (AVF) patency, incidence of AVF use, incidence and nature of AVF complications and surgery in patients after kidney transplantation. PATIENTS AND METHODS: We retrospectively analysed the AVF outcome and complications in all adult kidney allograft recipients transplanted between January 1st, 2000 and December 31, 2015 with a functional AVF at the time of transplantation. Follow-up was until December 31, 2019. RESULTS: We included 626 patients. Median AVF follow-up was 4.9 years. One month after kidney transplantation estimated AVF patency rate was 90%, at 1 year it was 82%, at 3 years it was 70% and at 5 years it was 61%; median estimated AVF patency was 7.9 years. The main cause of AVF failure was spontaneous thrombosis occurring in 76% of AVF failure cases, whereas 24% of AVFs were ligated or extirpated. In a Cox multivariate model female sex and grafts were independently associated with more frequent AVF thrombosis. AVF was used in about one third of our patients. AVF-related complications occurred in 29% of patients and included: growing aneurysms, complicated thrombosis, high-flow AVF, signs of distal hypoperfusion, venous hypertension, trauma of the AVF arm, or pain in the AVF/arm. CONCLUSIONS: AVFs remain functional after kidney transplantation in the majority of patients and are often re-used after graft failure. AVF-related complications are common and require proper care.

Therapeutic plasma exchange and dextran-sulfate plasma adsorption as extracorporeal treatments of extremely preterm preeclampsia with fetal growth restriction.

AIM: To evaluate effectiveness and safety of therapeutic plasma exchange (TPE) and dextran-sulfate plasma adsorption (DSA) for extracorporeal removal of soluble Fms-like tyrosine kinase-1 (sFlt-1) as part of expectant management of preeclampsia at extremely preterm gestational age. METHODS: Retrospective case series of six patients with preeclampsia at <28 weeks of gestation, treated with DSA or TPE. Laboratory results, clinical characteristics and neonatal outcomes were collected from charts and National Perinatal Information System. RESULTS: Fetal growth restriction (FGR) was diagnosed in all cases. Pregnancy was prolonged for a median of 14 (range 5-74) days from admission and 10 (3-73) days from first apheresis. A mixed effects model showed a decrease in sFlt-1 and sFlt-1/PlGF ratio during DSA/TPE (significant effect of time [before/after]), which was comparable between DSA and TPE (no effect of procedure type). Median absolute reduction in sFlt-1 was 42% (inter-quartile range [IQR] 13%-57%) during DSA and 34% (16%-40%) during TPE; for sFlt-1/PlGF ratio it was 29% (22%-36%) and 38% (29%-42%), respectively. All procedures were well tolerated by fetuses. Anaphylactoid reaction, often with angioedema, occurred in 4/6 patients undergoing DSA and was attributed to bradykinin activation. One patient developed wound hematoma after cesarean section, possibly attributed to depletion coagulopathy. CONCLUSIONS: As potential novel treatment of early preeclampsia, a non-selective and widely available TPE was comparable to DSA regarding sFlt-1 reduction but was associated with fewer side-effects. Both seem to allow maternal stabilization and pregnancy prolongation even when early preeclampsia is complicated by FGR.

Regional citrate anticoagulation for continuous renal replacement therapy in newborns and infants: Focus on citrate accumulation.

Continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA) in newborns and infants is challenging and accumulation of citrate can occur. There are only a few studies reporting the detailed data on RCA. We aimed to analyze RCA-CRRT at our institution with focus on citrate accumulation. Critically ill newborns and infants up to 11 kg of body weight (BW), treated with RCA-CRRT in the 2011-2016 period were included in this retrospective observational study. Prismaflex(R) and Multifiltrate-CiCa(R) dialysis monitors were used with either automated or manual RCA. Data was collected regarding the circuit lifetime, parameters of RCA, markers of citrate accumulation (total/ionized calcium ratio > 2.5), and metabolic complications. We included 10 children with mean age of 2.6 ± 3.8 months and BW of 4.6 ± 2.7 kg. In-hospital mortality was 60%. RCA-CRRT parameters were: blood flow 46 ± 9 mL/min (12 ± 5 mL/min/kg BW), citrate dose 2.8 ± 0.6 mmol/L of blood resulting in estimated citrate load to the patient of 1.7 ± 0.8 mmol/h/kg BW. In total, 57 dialysis circuits were used with mean filter lifetime of 39 ± 29 h. Citrate accumulation (total/ionized calcium ratio > 2.5) was observed in 7/10 patients and in 14/57 (25%) of circuits; those circuits were performed in children with lower age and BW, had higher relative blood flow and citrate load, while citrate dose was similar. When citrate load to the patient was used to predict citrate accumulation, AUC under the ROC curve was 0.78 and 1.7 mmol/h/kg BW was considered the optimal cutoff value (sensitivity 71% and specificity 72%). CRRT with RCA using equipment, developed for adult population, is feasible in newborns and infants. Signs of citrate accumulation developed relatively often. To prevent it, we suggest avoiding citrate loads above 1.7 mmol/h/kg BW, which can best be achieved by keeping the blood flow below 9 mL/min/kg BW.

Distal Arterial Embolization from an Abandoned Native Brachio-Cephalic Fistula: A Case Report.

Abandoned thrombosed arterivenous fistulas are usually left in place with very rare complications. We describe a case of distal embolization from a thrombosed aneurismatic arteriovenous brachiocephalic fistula in a patient who vigorously used the affected arm for pushing his wheelchair. Vigorous physical activity with the hand bearing arteriovenous fistula (AVF) should probably be discouraged even after AVF thrombosis and especially, if the initial part of fistula vein is aneurysmatic. Antiagregation therapy should be considered in such cases.

Anticoagulation assessment methods in plasma exchange with regional citrate anticoagulation: evaluation of post-filter and filtered plasma ionized calcium.

AIM: To assess the possibility of using filtered plasma instead of postfilter ionized calcium (iCa) for the assessment of anticoagulation in plasma exchange (PE) with citrate anticoagulation. METHODS: 140 PE treatments were performed using either 4% or 15% citrate at a comparable dose. Paired samples of postfilter blood and filtered plasma were taken for iCa measurements with a point-of-care analyzer. Anticoagulation was also assessed with a bedside clotting time and visual assessment of the circuit after procedures. RESULTS: In 490 paired samples, mean postfilter iCa was 0.39 ± 0.14 mmol/L, and filtered plasma iCa was 0.33 ± 0.11 mmol/L. Mean bedside clotting time was 18 ± 7 minutes. Neither the postfilter (r = 0.03, p = 0.73) nor the filtered plasma iCa (r = 0.09, p = 0.25) correlated significantly with bedside clotting time. Bland-Altman analysis showed a modest agreement between filtered plasma and postfilter iCa values (mean difference -0.07 mmol/L, upper and lower 95% limits of agreement 0.10 and -0.23 mmol/L). Median visual assessment score was excellent at all three checkpoints. CONCLUSIONS: A modest agreement between filtered plasma and postfilter iCa values could be acceptable if only a confirmation of anticoagulant effect is required. Measuring filtered plasma instead of postfilter iCa would reduce blood loss with sampling, which could be important in some settings.
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Treatment of antibody-mediated rejection of kidney grafts with bortezomib and/or rituximab compared to standard regimen: experience of Slovene National Center.

BACKGROUND: The aim of our study was to determine outcomes of standard treatment of antibody-mediated rejection (ABMR) of kidney grafts as compared to the addition of bortezomib or rituximab. METHODS: The cohort of this retrospective study included patients treated for ABMR of kidney grafts at our national center in the period of 2005 - 2017, divided into two groups: standard (ST) group treated standardly with plasmapheresis or immunoadsorption, intravenous immunoglobulins, and corticosteroids, and BR group treated with the addition of bortezomib and/or rituximab. Patient and graft survival at 2 years was analyzed by Kaplan-Meier method, and predictors of graft survival were analyzed by Cox regression. RESULTS: There were 78 patients with ABMR (48 in the ST group, 30 in the BR group), 41 (53%) were men, mean age 49.5 ± 13.8 years. In ST and BR, respectively, mean serum creatinine was 267 ± 164 and 208 ± 112 µmol/L (p = 0.088), donor-specific antibodies (DSA) were positive in 75% and 97% (p = 0.022), and ABMR was acute in 50% and 33% (p = 0.149). Patient survival at 2 years was 89% in the ST and 100% in the BR group (p = 0.125). Cumulative proportion of kidney graft survival at 1 and 2 years was 67% and 53% in the ST group and 73% and 48% in the BR group, respectively, (p = 0.641). Chronic ABMR (HR 5.22, p = 0.004) was significant, while dialysis dependency at biopsy (HR 3.28, p = 0.072), serum creatinine at kidney biopsy (HR 1.003, p = 0.082), and presence of DQ-DSA (HR 3.37, p = 0.062) were borderline significant predictors of worse graft outcome. Infections were relatively common in both groups, with a trend towards more rehospitalizations due to infections in the first 6 months after treatment in the BR group (p = 0.066). In 5 patients (17%), treatment with bortezomib was discontinued prematurely due to cytopenia. CONCLUSIONS: Bortezomib or rituximab, added to standard treatment, did not significantly improve kidney graft survival and was also not associated with significant side effects, except cytopenia in some cases. Treatment of acute ABMR resulted in better graft survival than chronic ABMR.
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Treatment Efficacy and Safety During Plasma Exchange With Citrate Anticoagulation: A Randomized Study of 4 Versus 15% Citrate.

In plasma exchange (PE), contrary to dialysis, there is no ultrafiltration, and the volume of anticoagulant contributes to volume overload of the patient and might also reduce PE efficiency through dilution. To reduce the volume of citrate, we compared 4 and 15% citrate anticoagulation protocols in PE in a randomized study, aiming to evaluate PE efficacy, anticoagulation efficiency, and overall safety. In addition to standard biochemical analyses during PE treatments, the elimination rate (ER) of immunoglobulins was calculated to evaluate PE efficacy. Anticoagulation was evaluated by postfilter ionized calcium, visual evaluation of the extracorporeal system, and change in the sieving coefficient (SC) during PE. Accumulation of citrate was determined by calculating the total-to-ionized calcium ratio and measuring the citrate concentration after PE. One hundred forty procedures (70 in each group) were performed in 37 patients. The mean citrate infusion rate was 197 ± 10 mL/h in the 4% and 59 ± 5.5 mL/h in the 15% groups, respectively; the total volume of infused citrate was 502 ± 77 mL versus 164 ± 52 mL (P < 0.001). ER for immunoglobulin G (0.57 ± 0.06 vs. 0.55 ± 0.1, P = 0.18), M, and A were comparable. Ionized calcium was stable during the procedures, and there were no significant side effects. Although postfilter ionized calcium was on the upper limit of the target range (0.41 ± 0.16 vs. 0.37 ± 0.14 mmol/L, P = 0.38), the visual assessment score was excellent, and even a rise in SC was observed during the procedures in both groups. The total-to-ionized calcium ratio was increased in 20 versus 22% of procedures, and citrate concentrations after PE were also similar (1306 ± 441 vs. 1263 ± 405 µmol/L). To conclude, we were unable to show superior PE efficacy in the 15% citrate group, but we significantly reduced the infused volume, which is important in patients with fluid overload. Both citrate protocols were found to provide excellent anticoagulation without significant metabolic disturbances or other side effects, confirming the safety of 15% citrate as anticoagulant during PE.

Very old patients on hemodialysis: how they start and can we predict survival?

BACKGROUND: We describe circumstances of dialysis initiation, dialysis prescription and factors affecting survival in elderly patients. METHODS: We included all incident patients ≥ 80 years old from a National Registry for which clinical and laboratory data at dialysis initiation could retrospectively be obtained. RESULTS: Of 170 patients included, 24% had diabetes, 30% ischemic heart disease, 13% peripheral arterial disease, 15% active malignancy and 60% prior nephrology care. Mean creatinine was 672 ± 225 µmol/l, eGFR 7.3 ± 3.7 ml/min/1.73 m2, 81% started dialysis in hospital and 78% with a catheter. 32% had < 2 sessions/week and 29% had single-needle dialysis. One-year survival was 74% (median 26 months). In multivariate analysis only age (HR 1.10) and prior nephrology care (HR 0.48) were significant predictors of survival. CONCLUSIONS: The majority of elderly patients started dialysis with a catheter and in hospital setting. We estimate observed survival as good. Only age and prior nephrology care were independent predictors of survival.

Tick-borne encephalitis associated with consumption of raw goat milk, Slovenia, 2012.

Tick-borne encephalitis (TBE) developed in 3 persons in Slovenia who drank raw milk; a fourth person, who had been vaccinated against TBE, remained healthy. TBE virus RNA was detected in serum and milk of the source goat. Persons in TBE-endemic areas should be encouraged to drink only boiled/pasteurized milk and to be vaccinated.

The Role of Ultrasound Examination in the Assessment of Suitability of Calcified Arteries for Vascular Access Creation-Mini Review.

Arterial calcifications are present in 20-40% of patients with end-stage kidney disease and are more frequent among the elderly and diabetics. They reduce the possibility of arterio-venous fistula (AVF) formation and maturation and increase the likelihood of complications, especially distal ischemia. This review focuses on methods for detecting arterial calcifications and assessing the suitability of calcified arteries for providing inflow before the construction of an AVF. The importance of a clinical examination is stressed. A grading system is proposed for quantifying the severity of calcifications in the arteries of the arm with B-mode and Doppler ultrasound exams. Functional tests to assess the suitability of the artery to provide adequate inflow to the AVF are discussed, including Doppler indices (peak systolic velocity and resistive index during reactive hyperemia). Possible predictors of the development of distal ischemia are discussed (finger pressure, digital brachial index, acceleration and acceleration time), as well as the outcomes of AVFs placed on calcified arteries. It is concluded that a noninvasive ultrasound examination is probably the best tool for a morphologic and functional assessment of the arteries. An arterial assessment is of utmost importance if we are to create distal radiocephalic AVFs in our elderly patients whenever possible without burdening them with futile surgical attempts.

A matched case-control study on the effectiveness of extracorporeal cytokine adsorption in critically ill patients.

Extracorporeal cytokine adsorption aims to reduce cytokine levels in critically ill patients. However, little convincing data exist to support its widespread use. This retrospective study compared interleukin-6 (IL-6) levels in patients treated with or without cytokine adsorber (CytoSorb®). Intensive care patients between Jan 2017 and Dec 2021 who had at least two IL-6 measurements were included. They were divided into an adsorber group and a standard of care group. We screened 3865 patients and included 52 patients in the adsorber group and 94 patients in the standard of care group. Matching was performed and the groups were compared regarding IL-6, lactate, CRP, procalcitonin, vasopressor requirement, and mortality rate. After matching, there were 21 patients in each group. Patients had similar age, ECMO and renal replacement therapy use, baseline noradrenaline requirement, serum lactate, pH, CRP, and IL-6 levels. There were no significant differences in the time course of IL-6, lactate, CRP, procalcitonin and noradrenaline requirement between groups. Two-day and ICU mortality and Kaplan-Meier estimated survival were also comparable. In this matched case-control study no difference in IL-6, inflammatory parameters, noradrenaline requirement or mortality was observed between patients treated with adsorber or standard of care.

Doppler ultrasound assessment of calcified radial arteries prior to radio-cephalic arterio-venous fistula placement: an observational study.

BACKGROUND: In elderly and diabetic patients, arterial calcifications are prevalent and result in worse outcomes of arterio-venous fistulas (AVFs). Optimal ultrasound criteria for assessment of calcified arteries are unknown. We report our experience with ultrasound assessment of calcified arteries prior to placement of radio-cephalic (RC) AVFs. MATERIAL AND METHODS: We included 85 patients in whom a RC-AVF placement was planned. Patients were divided according to the presence of radial artery calcifications into a calcified group (moderate/severe calcifications, N = 18) and control group (no changes/mild atherosclerosis, N = 67). Doppler ultrasound parameters were analyzed in the calcified group with focus on assessment of the artery, including grading of calcifications and Doppler measurements at rest and during reactive hyperemia (RH). RESULTS: In the calcified group mean patients' age was 72 ± 11 years, 72% were diabetics, mean resistance index (RI) during RH was 0.78 ± 0.09 (range 0.63-0.90). In 14 (78%) patients an AVF was successfully placed and in 12 it matured (67% maturation rate). A lower RI at rest was observed in the primary failure sub-group with high area under the ROC curve (0.89) and a cut-off value of 0.90 for RI. There was no difference in RI at RH between failed and matured AVFs. 1-year secondary patency was 66% and in eight patients with follow-up ultrasound available, blood flow was 350-1300 ml/min. For comparison, in the control group a radio-cephalic AVF was placed in all patients, primary failure rate was 6%, maturation rate 85% and 1-year secondary patency was 77%. CONCLUSIONS: Our very limited experience suggests that successful RC-AVF placement and maturation with good 1-year patency rates is possible in patients with moderately/severely calcified arteries and RI during RH of up to 0.90.

Effect of CytoSorb Coupled with Hemodialysis on Interleukin-6 and Hemodynamic Parameters in Patients with Systemic Inflammatory Response Syndrome: A Retrospective Cohort Study.

Excessive release of cytokines during systemic inflammatory response syndrome (SIRS) often leads to refractory hypotension and multiple organ failure with high mortality. Cytokine removal with hemoadsorption has emerged as a possible adjuvant therapy, but data on interleukin-6 (IL-6) reduction and outcomes in clinical practice are scarce. We aimed to evaluate the effect of CytoSorb hemoadsorption on laboratory and clinical outcomes in shocked patients with SIRS. We designed a retrospective analysis of all patients with SIRS treated with CytoSorb in intensive care units (ICU). IL-6, laboratory and hemodynamic parameters were analyzed at approximate time intervals during CytoSorb treatment in the whole cohort and in a subgroup with septic shock. Observed and predicted mortality rates were compared. We included 118 patients with various etiologies of SIRS (septic shock 69%, post-resuscitation shock 16%, SIRS with acute pancreatitis 6%, other 9%); in all but one patient, CytoSorb was coupled with renal replacement therapy. A statistically significant decrease in IL-6 and vasopressor index with an increase in pH and mean arterial pressure was observed from 6 h onward. The reduction of lactate became significant at 48 h. Results were similar in a subgroup of patients with septic shock. Observed ICU and in-hospital mortalities were lower than predicted by Sequential Organ Failure Assessment (SOFA) (61% vs. 79%, p = 0.005) and Acute Physiology and Chronic Health Evaluation (APACHE) II (64% vs. 78%, p = 0.031) scores. To conclude, hemoadsorption in shocked patients with SIRS was associated with a rapid decrease in IL-6 and hemodynamic improvement, with improved observed vs. predicted survival. These results need to be confirmed in a randomized study.