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.

Clinical and dialysis-related characteristics of extremely long-term hemodialysis survivors: Three case reports.

More than 40-year hemodialysis survivors are living evidence of the achievements of hemodialysis therapy. We present the case reports of three patients treated by chronic hemodialysis for 47 (Patient 1), 43 (Patient 2), and 42 years (Patient 3) from a single center. These patients possess characteristics that were already shown to be associated with improved long-term survival: initiation of hemodialysis at a young age, absence of diabetes, and a relatively low and stable body weight with good nutritional status. Although all of them underwent complications of long-term hemodialysis treatment, they lived (Patient 3), or are still living (Patients 1 and 2), an independent and full life. Their hemodialysis prescriptions included long sessions with a moderate blood flow rate, state-of-the-art hemodialysis technology, vascular access surgeries and care provided by nephrologists, good overall management of chronic kidney disease, and preventive measures and/or immediate action in case of cardiovascular disease.

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.

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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Acute kidney injury in critically-ill adult patients with seasonal influenza infection.

BACKGROUND: Acute kidney injury (AKI) occurs in 22.4 - 100% of critically-ill hospitalized patients with influenza infection. In up to 2/3, it is severe enough to necessitate renal replacement therapy. We aimed to document the incidence of AKI among patients with influenza-related critical illness and its relation to clinical outcomes. METHODS: We conducted a retrospective observational study of all adult patients with acute respiratory illness and laboratory-confirmed influenza infection admitted to non-surgical intensive care units at the University Medical Centre Ljubljana between January 1, 2016, and March 31, 2016. RESULT: Our sample consisted of 28 adult patients with mean age in years of 57.5 ± 20.2. Incidence of AKI was 71.4%. Mortality was 28.6% (35% in patients with AKI and 41.6% in patients who required renal replacement therapy). CONCLUSIONS: Influenza-related critical illness is rare but can cause AKI in a large proportion of affected patients. In this setting, requirement for renal replacement therapy could be associated with increased mortality risk.
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Does Guidewire Exchange Influence Infection Rate Related to Catheters Used for Vascular Access in Children on Chronic Hemodialysis?

A central venous catheter (CVC) can either be inserted "de novo" or placed by guidewire exchange (GWE). From September 1998 to September 2015, 32 children (19 boys, 13 girls) were hemodialyzed in our unit by using a CVC. The mean age at CVC insertion was 12.6 ± 0.5 years. A total of 121 uncuffed catheters were placed, either "de novo" or by GWE in 64 (52.9%) and 57 (47.1%) cases, respectively. The most frequent cause for line revision was catheter dysfunction in 40/121 (33.1%) patients. The overall incidence of bacteremia was 1.5/1000 catheter-days. The incidence in newly inserted and GWE catheters was 1.4 and 1.7/1000 catheter-days, respectively. The difference did not reach statistical significance (P = 0.939). The infection rate correlated with patient age, and was higher in younger children (P = 0.006). GWE is an effective option of line revision, and did not influence the infection rate in our study.

Calcium Mass Balance during Citrate Hemodialysis: A Randomized Controlled Trial Comparing Normal and Low Ionized Calcium Target Ranges.

BACKGROUND: Regional citrate anticoagulation (RCA) during hemodialysis interferes with calcium homeostasis. Optimal ionized calcium (iCa) target range during RCA and consequent calcium balance are unknown. METHODS: In a randomized controlled trial (ACTRN12613001029785) 30 chronic hemodialysis patients were assigned to normal (1.1-1.2 mmol/) or low (0.95-1.05 mmol/l) iCa target range during a single hemodialysis with RCA. The primary outcome was calcium mass balance during the procedure, using a partial spent dialysate collection method; magnesium mass balance was also measured. Intact parathormone (iPTH), total calcium (tCa) and magnesium were measured before and after procedures. RESULTS: Mean iCa during procedures was significantly different in the two groups (1.12±0.06 in normal and 1.06±0.07 mmol/l in low iCa group, p <0.001), resulting in different tCa (2.18±0.22 vs. 1.95±0.17, p = 0.003) after the procedure. Mean delivered calcium during the procedure was 58.3±4.8 mmol in the normal and 51.5±8.2 mmol in the low iCa group (p = 0.010), which resulted in a significantly higher mean positive calcium mass balance of 14.6±8.3 mmol (584±333 mg) per procedure in normal as compared to 7.2±8.5 mmol (290±341 mg) in low iCa group (p = 0.024). Linear mixed effects model showed a significant interaction effect of time and iCa target range group on iPTH, i.e. a significant increase in iPTH in the low as compared to normal iCa target group (p = 0.008). Magnesium mass balance was mildly negative and comparable in both groups. CONCLUSIONS: Low iCa target range resulted in a significantly less positive calcium mass balance, but in a significant increase in iPTH. To achieve a more neutral calcium balance, we recommend allowing a mild hypocalcemia during hemodialysis with RCA, especially when it is used for prolonged periods.

Renal Replacement Therapy in Slovenia: Excerpts From 2013 Data.

This report provides a summary of the 2013 Slovenian renal replacement therapy (RRT) data, obtained from 24 renal centers: 23 dialysis and one transplant center, referring from 31 December 2013, with 100% response rate to individual patient questionnaires. Slovenia had a population of 2 061 085 on 1 January 2014. The total number of patients treated by RRT was 2077, i.e. 1008.3 per million of population (pmp); 1349 (65%) were treated by hemodialysis, 52 (2.5%) by peritoneal dialysis, and 676 (32.5%) had a functioning kidney graft. A total of 260 incident patients, 126.2 pmp (at day one), started RRT, their median age was 69 years, 59.8% were men,. 58.5% of hemodialysis patients were treated with on-line hemodiafiltration. Vascular access was arteriovenous fistula in 79%, polytetrafluoroethylene graft in 8%, and catheter in 13% of patients, mean blood flow 276 ± 41 mL/min, 5.5% dialyzed in a single-needle mode. The crude death rate was 11.4% in all RRT patients (incident patients day 1 included, 15.9% in hemodialysis, 12.3% in peritoneal dialysis, 2.1% in transplant recipients). 60 kidney transplantations were performed in 2013, from deceased donors.

Citrate Anticoagulation in Tandem Membrane Plasma-Exchange or Immunoadsorption and Hemodialysis in Patients With Immunological Diseases and Dialysis-Dependence.

In 1996 we performed tandem membrane plasma exchange-hemodialysis in a 3-year-old girl and tandem immunoadsorption-hemodialysis with citrate as the only anticoagulant in a patient with Goodpasture's syndrome. In the present study, we evaluated the feasibility, efficacy and safety of 24 tandem plasma exchange/immunoadsorption hemodialysis procedures in four different circuit setups with citrate as the only anticoagulant. In two setups, the tandem procedures were connected in series (plasma exchange hemodialysis and immunoadsorption hemodialysis), while in the other two setups they were in parallel (plasma exchange hemodialysis with independent blood circuits and plasma exchange hemodialysis with independent arterial blood lines, but with a common return line). All tandem procedures were feasible, efficient and safe. No serious side-effects were recorded. The most elegant setup was the procedure with independent, parallel blood circuits. However, serial tandem procedures provided for the elimination of citrate and normalization of electrolytes before blood was returned to the patient.

Treatment of Antibody-Mediated Rejection After Kidney Transplantation - 10 Years' Experience With Apheresis at a Single Center.

Antibody-mediated rejection (AMR) is a major cause of kidney graft failure. We aimed to analyze treatment and outcome of AMR in a national cohort of 75 biopsy-proven acute (43 patients, 57%) or chronic active (32 patients, 43%) AMR episodes between 2000 and 2015. The mean patients' age was 46 ± 16 years, the majority was treated with plasma exchange, 4% received immunoadsorption and 7% received both. The majority received pulse methylprednisolone and low-dose CMV hyperimmune globulin, 20% received bortezomib and 13% rituximab. Concomitant infection was treated in 40% of patients. The immediate treatment outcome was successful in 91%, the 1- and 3-year graft survival rates were 71% and 57%, while 3-year patient survival was 97%. Chronic active AMR was associated with worse graft survival than acute AMR (log rank P = 0.06). To conclude, intensive treatment with apheresis and additional immunosuppression was effective in reversing AMR, but long-term graft survival remains markedly decreased, especially in chronic active AMR.

Citrate Extended High Cut-Off Hemodiafiltration for Renal Recovery in Patients With Multiple Myeloma.

We proposed a combination of convective and diffusive transport mechanisms as high cut-off (HCO) post-dilution hemodiafiltration dialysis technique to optimize serum immunoglobulin free light chains (FLCs) removal which may improve dialysis dependent renal failure in patients with multiple myeloma. To reduce bleeding risk regional citrate anticoagulation was successfully used for the first 7 h followed by 1 h anticoagulant-free hemodiafiltration to avoid citrate accumulation. We retrospectively assessed the effect of FLCs reduction on the renal outcome of 28 patients treated with 133 citrate extended post-dilution HCO (Theralite 2100; Gambro, Lund, Sweden) hemodiafiltration sessions between 2010 and 2016. Renal recovery was demonstrated in 61% of all patients. Twenty-three patients achieved more than 50% reduction of FLCs concentrations and 88% of those became dialysis independent. Our experience supports the extended citrate HCO hemodiafiltration as a good treatment strategy that enable a sustained reduction in serum FLCs concentration and recovery of renal function.

Temporary Catheters as a Permanent Vascular Access in Very Elderly Hemodialysis Patients: Frequency of Complications and Interventions.

The choice of vascular access in very elderly hemodialysis patients can be complex. Data on the frequency of interventions and complications when temporary catheters are used for long periods in this population are lacking. All incident patients ≥80 years old, dialyzed over non-tunneled catheters, were included and the frequency of interventions (re-insertions and wire-exchanges) and complications (catheter-related blood stream infections) were recorded. In 31 patients aged 84 ± 4 years, dialyzed for 1.4 ± 1.1 years, 87 interventions were needed (2.02/patient-year). The median time to first intervention was 5.5 months and the 1-year intervention-free rate was 32%. There were three catheter-related blood stream infections (0.2/1000 access-days), comparing favorably to tunneled catheters. To conclude, temporary catheters are associated with a low rate of complications and an acceptable rate of interventions. Therefore, they could be the optimal vascular access in very elderly patients when the placement of an arterio-venous fistula is not feasible.

Comparison of the Pharmacological Effects of Paricalcitol Versus Calcitriol on Secondary Hyperparathyroidism in the Dialysis Population.

Management of secondary hyperparathyroidism (SHPT) in dialysis population includes the use of active vitamin D forms, among which paricalcitol was shown to be more effective at reducing parathyroid hormone (PTH) concentrations. A prospective randomized study comparing the effectiveness and safety of peroral paricalcitol and calcitriol in suppressing PTH concentrations in 20 hemodialysis patients was performed comparing the influence of agents on PTH suppression, calcium (Ca) and phosphate (P) level and calcium-phosphorus product (C×P). The study was performed in an "intent to treat" manner with primary end point in reduction of PTH level in the target area of 150 > PTH < 300 ng/L after 3 months. At the time point 3 months after therapy induction paricalcitol and calcitriol were equally efficient at correcting PTH levels, with paricalcitol showing significantly less calcemic effect than calcitriol.

Phosphate Removal During Long Nocturnal Hemodialysis/Hemodiafiltration: A Study With Total Dialysate Collection.

The aim of our prospective study was to quantify phosphate removal during long nocturnal high-flux hemodialysis or hemodiafiltration (HD) with total dialysate collection. Eight patients (two women) were studied for the first-in-the-week HD session that lasted 7-8 h. Total dialysate was collected. Serum and collected dialysate phosphate concentrations were measured every hour. Phosphate removal as assessed from the serum concentration was most important during the first 2 h of HD, and then a plateau was reached. The highest average phosphate concentration in the total dialysate was in the 1(st) hour, thereafter the concentration decreased but remained stable. The average total removed mass of phosphate quantified from hourly collected dialysate was 5195.7 ± 1898 mg. Phosphate had been removed in a consistent manner during the whole duration of nocturnal HD as assessed through dialysate (despite stable serum phosphate concentration). This could indicate phosphate transfer from intracellular space. The total removed phosphate quantified from the total dialysate collection was higher than previously reported and exceeded the normal phosphate food intake.

Malnutrition in Renal Failure: Pleiotropic Diagnostic Approaches, Inefficient Therapy and Bad Prognosis.

Malnutrition is very common and connected with high morbidity and mortality of patients on chronic hemodialysis. A cross-sectional, longitudinal study was performed in maintenance dialysis patients intending to determine association between modified Subjective Global Assessment (SGA), serum albumin and mortality. Cross-sectional study of phase angle (PhA) values and other indices of bioelectrical impedance body analysis (BIA) were correlated to biochemical data and malnutrition-inflammation score (MIS). In the group of 184 hemodialysis patients, we found 39 malnourished patients. In overall 50 months of observation, 25 out of 39 malnourished patients died. All patients with albumin values less than 30 g/L died. The group with albumin values greater than 30 g/L (N = 26) showed higher survival rate, 12 patients died in the observed period. SGA values higher than 21 and albumin values lower than 30 g/L are useful predictors of death in malnourished dialysis patients. PhA is an independent predictor of malnutrition with promising potential to replace other diagnostic tools.

Chronic Hemodialysis in Small Children.

When peritoneal dialysis is inapplicable, chronic hemodialysis (HD) becomes the only available treatment option in small children. Due to small patient size, central venous catheters (CVC) are mainly used for vascular access. Over the past 4 years, four children weighing less than 15 kg received chronic HD in our unit. A total of 848 dialysis sessions were performed. Altogether, 21 catheters were inserted. In all but one occasion, uncuffed catheters were used. Catheter revision was performed 15 times during the study period, either due to infection or catheter malfunction. The median number of catheter revisions and the median line survival was 3.0/patient-year and 53 days (range; 6-373 days), respectively. There were 14 episodes of catheter related infections requiring 11 CVC revisions (78.6%). The median rate of line infections was 2.8/patient-year. Chronic HD in small children is demanding and labor intensive. Issues pertain mainly to CVCs and limit its long-term use.