Inadvertent Intoxication with Salbutamol, Treated with Hemodialysis: A Case Report and Brief Review of the Literature.

Introduction: Salbutamol is a moderately selective beta-2-adrenergic agonist. Various side effects can occur because of beta-1 and beta-2 receptor activation. Due to the large volume of distribution, it is not considered dialyzable. Case Presentation: A patient with salbutamol intoxication, which developed as a result of a medical error in a patient with sepsis, Down syndrome, and liver cirrhosis, is presented. Initial treatment was partially successful and antibiotic adjustments were made. After his respiratory failure worsened, the patient needed non-invasive ventilation, and previously undiagnosed chronic obstructive pulmonary disease was suspected. He was prescribed intravenous methylprednisolone but accidently received 5 mg of salbutamol (albuterol), which led to immediate severe arrhythmic tachycardia with hemodynamic collapse. After unsuccessful cardioversion and treatment with landiolol infusion, salvage hemodialysis was commenced to decrease suspectedly highly elevated serum salbutamol levels. After 30 min, sinus rhythm with normocardia was observed. After the hemodialysis termination, no rebound tachycardia was noted, but due to severe septic shock, the hypotension was ongoing and vasoactive medications were adjusted. However, the measured levels of plasma salbutamol and data from literature do not support the view that hemodialysis was the cause of the described improvement: the total amount of the drug cleared was very small (2.8% of total dose). Conclusion: Our results confirm a large volume of salbutamol distribution; the measured levels are within observed therapeutic levels; and the measured half-life time during hemodialysis (3.1 h) is comparable to observed half-life times in therapeutic settings. The observed favorable clinical benefit associated with dialysis may be fortuitous, highlighting potential bias toward positive clinical outcomes and unproven ("salvage") therapies.

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.

Predictive value of inflammatory and coagulation biomarkers for venous thromboembolism in COVID-19 patients.

BACKGROUND: The predictive value of coagulation markers for venous thromboembolism (VTE) in COVID-19 patients has been investigated with conflicting results. OBJECTIVE: Our aim was to investigate the correlation between biomarkers and VTE and the predictive value of D-dimer for VTE in hospitalized COVID-19 patients. METHODS: Complete blood count, inflammatory and coagulation biomarkers at admission were collected. VTE was defined as diagnosed pulmonary embolism or deep vein thrombosis. Events were defined as in-hospital death or ICU admission. Predictors of VTE were identified with Pearson prediction models. A ROC curve was constructed to assess the predictive value of D-dimer. RESULTS: 1651 participants were included, 111 VTE were identified. Events incidence was higher in the VTE group (49.5% vs 28.2%, p < 0.001). Neutrophil-lymphocyte ratio (NLR, 0.001; 95% CI 0.000-0.002; p 0.019) and D-dimer (0.00005; 95% CI 0.00002-0.00008; p < 0.001), Geneva score (0.026; 95% CI 0.012-0.040; p < 0.001) and Wells score (0.047; 95% CI 0.033-0.061; p < 0.001) were associated with VTE. D-dimer had a goor predictive value for VTE (ROC area 0.85, 95% CI 0.816-0.893), with an optimal cut-off value of 2677µg/L (Youden index of 0,602). CONCLUSIONS: Among coagulation biomarkers D-dimer had the best predictive value for VTE, but higher cut-off values should be used in COVID-19.

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.

Comparable Triglyceride Reduction With Plasma Exchange and Insulin in Acute Pancreatitis - A Randomized Trial.

Background and Aims: Both insulin and plasma exchange (PE) are used in hypertriglyceridemic acute pancreatitis (HTG-AP). Our aim was to compare the efficacy of both treatments. Methods: A randomized, parallel group study performed in a tertiary hospital in 22 HTG-AP patients with non-severe prognosis and triglycerides between 15 and 40 mmol/L. Patients were randomized to daily PE or insulin infusion until triglycerides were <10 mmol/L. Primary outcome was % reduction in triglycerides within 24 h. Secondary outcomes were days needed to lower triglycerides <10 mmol/L, highest CRP and percentage of patients with a severe course of pancreatitis. Results: There was a trend toward a greater decrease in triglycerides within the first 24 h in the PE group (67 ± 17% vs. 53 ± 17%, p = 0.07), but the absolute difference was modest [mean difference of 6 mmol/L (14% of initial value)]. Triglycerides fell below 10 mmol/L in a median (IQR) of 1 (1-2) and 2 (1-2) days, respectively (p = 0.25). Secondary outcomes related to disease severity were also comparable: highest CRP 229 vs. 211 mg/L (p = 0.69) and severe course of pancreatitis in 2/11 cases in both groups (p = 1.0). Regarding treatment complications, there was one mild hypoglycemia and one allergic reaction during PE. Survival was 100% in both groups. Conclusion: There was no significant difference, but only a trend toward a greater decrease in triglycerides with PE, and the clinical course was also comparable. These results do not support universal use of PE in patients with HTG-AP. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT02622854].

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.

The predictive value of urinary erythrocyte morphology for proliferative glomerular kidney disease.

BACKGROUND AND AIM: Glomerular erythrocyturia (GlomEry) is usually associated with proliferative kidney diseases. In our retrospective cohort, we aimed to validate the predictive value of GlomEry criteria ≥ 40% dysmorphic erythrocytes (DysEry) or ≥ 5% acanthocytes (AcaEry) or at least 1 erythrocytic cast (CastEry) and of two new indices - the count of DysEry per high power field (HPF) and per microliter of urine (Stansfeld-Webb (SW)) method, for proliferative disease. MATERIALS AND METHODS: We included patients with erythrocyturia from 2015 to 2016. Based on renal histology, we divided them into a proliferative and a non-proliferative disease group. Urine erythrocyte count was done using SW and urinary sediment examination was carried out by skilled nephrologists. Sensitivity, specificity, and cutoff values were determined using ROC curves. RESULTS: We included 90 patients (33% women), median age of 63 (IQR 51, 71) years. In the proliferative group, proteinuria was lower (2.4 vs. 6.6 g/day), and SW erythrocyturia was higher (174 (IQR 60, 353) vs. 44 (IQR 20, 67) × 106/L) than in the non-proliferative group. The threshold to differentiate between the proliferative and non-proliferative group was determined at ˃ 43% of DysEry (sensitivity 73%, specificity 79%, AUC 0.808) and at ˃ 2% AcaEry (sensitivity 71%, specificity 56%, AUC 0.647). No significant difference in CastEry was found between groups. Among tested parameters, the calculated number of DysEry/HPF > 6.7 (sensitivity 77%, specificity 92%, AUC 0.878), followed by DysEry/SW > 28 × 106/L (sensitivity 76%, specificity 86%, AUC 0.879), discriminated those two groups best. CONCLUSION: In concordance with known GlomEry criteria, > 43% of DysEry predicted proliferative kidney disease, whereas CastEry did not, and AcaEry predicted poorly. The best predictor of proliferative glomerular disease was DysEry/HPF, closely followed by DysEry/SW.

Current state of the morphological assessment of urinary erythrocytes in The Netherlands: a nation-wide questionnaire.

Background The morphological assessment of urinary erythrocytes (uRBC) is a convenient screening tool for the differentiation of nephrological (dysmorphic) and urological (isomorphic) causes of hematuria. Considering the morphological heterogeneity, this analysis is often perceived as difficult. There is no clear (inter)national consensus and there is a lack of external quality assessment programs. To gain insight into the heterogeneity within and between laboratories, we scrutinized the current state of this analysis in Dutch medical laboratories. Methods The laboratories, affiliated with the Dutch Foundation for Quality Assessment in Medical Laboratories, were invited to participate in a web-based survey, consisting of two questionnaires. The first one provided information about the institution and laboratory organization, and the second explored the variability in the morphological analysis of uRBC on the basis of categorization of 160 uRBC images. Statistical analysis was premised on binomial significance testing and principal component analysis. Results Nearly one third of the Dutch medical laboratories (65/191) with 167 staff members participated in the survey. Most of these laboratories (83%) were an integral part of secondary care. The statistical analysis of the evaluations of the participants in comparison to the consensus (three experts from two different medical laboratories) suggested a great degree of heterogeneity in the agreement. Nearly half of the participants consciously disagreed with the consensus, whereas one fifth demonstrated a random relationship with it. Conclusions In Dutch medical laboratories, results from morphological analysis of uRBC are heterogeneous, which point out the necessity for standardization and harmonization.

Association of Uremic Toxins and Inflammatory Markers with Physical Performance in Dialysis Patients.

Association of higher serum levels of uremic toxins and inflammatory markers with poorer physical performance is understudied. We measured the six-minute walk test (6MWT), 10 repetition sit-to-stand test (STS-10), handgrip strength (HGS), and Human Activity Profile (HAP) questionnaire score in 90 prevalent hemodialysis patents, with low comorbidity to reduce the potential confounding of concomitant disease. Midweek pre-dialysis serum levels of asymmetric dimethyl-arginine (ADMA), ß2-microglobulin (B2M), high-sensitivity C-reactive protein (hs-CRP), indoxyl sulfate (IS), insulin-like growth factor 1 (IGF-1), interleukin 6 (IL-6), myostatin, and urea were analyzed as predictor parameters of physical performance measures in adjusted models. Serum levels of most measured toxins were not significantly related to performance, except for ADMA, which was significantly related to poorer performance in the STS-10 test (B = 0.11 ± 0.03 s, p < 0.01). Higher hs-CRP was associated with poorer results in the 6MWT (B = -2.6 ± 0.97 m, p < 0.01) and a lower HAP score (B = -0.36 ± 0.14, p = 0.01). There were no other significant associations found. We conclude that inflammation may be a more important pathway to physical impediment than uremic toxemia. This suggests that there is a large physical rehabilitation potential in non-inflamed uremic patients.

Rituximab for the treatment of membranous nephropathy: a single-center experience.

BACKGROUND: Treatment of idiopathic membranous nephropathy with rituximab was introduced more than a decade ago following experimental data that suggested involvement of B-cell-mediated reactions in its pathogenesis. It was a logical step towards a more selective therapy with less severe side effects as compared to the recommended first-line immunosuppressive therapy with corticosteroids and different immunosuppressant drugs. METHODS: We retrospectively analyzed the anonymous data of patients who were treated with rituximab for idiopathic membranous nephropathy at our institution from January 2006 to July 2016. Daily proteinuria and serum creatinine were analyzed 3, 6, 9, and 12 months after rituximab application. The patients were divided into 4 groups according to proteinuria. We separately analyzed remission rates in the whole group and in groups with different quantity of daily proteinuria. Other history data and laboratory parameters were also compared within different groups of patients. RESULTS: The study involved 29 rituximab treatments in 26 patients: 7 (26.9%) female and 19 (73.1%) male patients. In 16 out of 29 treatment cases (55.1%), patients had been previously treated with cyclophosphamide and steroids, or cyclosporine with low dose of steroids, or both. In 72.4% of patients, antiphospholipase A2 receptor antibodies were present. In 2 cases of treatment (6.9%), patients received rituximab 375 mg/m2 of body surface area in 3 and 4 weekly doses, respectively. In all other cases, repeated rituximab applications were given as needed according to the levels of circulating CD-20 B-cells. The total remission rate in our cohort of patients was 37.9% (11 out of 29 cases). The average serum creatinine in the group of patients who achieved remission was significantly lower than in the group without remission (86.5 vs. 155.5 µmol/L, p = 0.003). There was no difference in the duration of the disease prior to treatment with rituximab between the groups (53.6 and 56.4 months, respectively). The remission rate was highest in the group with daily proteinuria less than 4 g per day (83.3%). There were no remissions in the group of patients with daily proteinuria more than 12 g per day. CONCLUSION: The remission rate after rituximab treatment in our cohort of patients with idiopathic membranous nephropathy was lower than in other studies. The reason for this is possibly the application of a single dose of rituximab in the majority of patients, which might have been insufficient in patients with higher proteinuria.
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Determination of red blood cells in urinary sediment: Do pH and specific gravity of urine matter?

INTRODUCTION: It has been postulated that erythrocyte cell lysis in urine is common in the case of low urine specific gravity and high urine pH. We aimed to verify the influence of urine dipstick pH and specific gravity on erythrocyturia in the urine sediment in the case of positive dipstick hemoglobinuria. METHODS: We retrospectively collected data on dipstick specific gravity, pH, and urine sediment analysis done by nephrologists in the clinical and research urine laboratory at the Department of Nephrology, University Medical Center Ljubljana. RESULTS: During the 6-year observation period, we analyzed 843 second morning midstream urine samples with positive dipstick hemoglobinuria. Erythrocyturia in urinary sediment was detected significantly less often in urine samples with concomitant hemoglobinuria 1+ and pH < 6.0, (odds ratio (OR) 0.40; 95% confidence interval (CI) 0.21 - 0.76, p = 0.005). The difference was maintained in multivariate analysis including patient age, gender, and specific gravity (OR 0.32; 95% CI 0.15 - 0.65, p = 0.002). In samples with higher grade of hemoglobinuria (≥ 2+), the impact of cell lysis in the case of low pH was negligible. Specific gravity did not have any influence on erythrocyte detection in urinary sediment. CONCLUSIONS: Urinary pH < 6.0 impaired the detection of erythrocytes in urinary sediment, while the dipstick measured urine specific gravity did not have any impact on it. Urine samples with low-grade hemoglobinuria and low pH without erythrocyte detection in urinary sediment should be evaluated again to avoid false-negative results.
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Rhabdomyolysis and interferon-ß: case report and short review.

BACKGROUND: We present a case of acute rhabdomyolysis in the setting of interferon-ß treatment and concomitant pomelo juice ingestion, with concern of possible pharmacological interaction, which has not yet been described in the literature. CASE PRESENTATION: A young Caucasian female with multiple sclerosis on chronic therapy with interferon-ß presented with acute rhabdomyolysis after mild exercise and concomitant ingestion of pomelo extract. After stopping the suspected drugs, the signs of rhabdomyolysis diminished, the subsequent course was favorable. CONCLUSIONS: The most probable cause of rhabdomyolysis in our patient could have been the combination of interferon effect, which down-regulates P450 expression, with inhibition of the P450 activity by furanocoumarin derivatives from pomelo juice. Therefore, patients treated with drugs that have a possible interaction with inhibitors of cytochrome P450 should be warned against pomelo ingestion.
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Prevalence and risk factors for nonvertebral bone fractures in kidney transplant recipients - a single-center retrospective analysis.

BACKGROUND: Complex and longstanding bone disease superimposed by harmful influences of immunosuppression is the reason for increased risk of bone fracture in kidney transplant recipients. The aim of our study was to analyze the incidence and prevalence of nonvertebral bone fractures and early (in the first post-transplant year) clinical and laboratory risk factors for suffering bone fracture in the long-term post-transplant period. METHODS: Clinical and laboratory data as well as bone mineral density (BMD) measurements of 507 first kidney transplant recipients who were transplanted in the period from 1976 to 2011 were analyzed. RESULTS: The mean age of included patients was 54.3 ± 12.0 years, there were 45% females, and mean time on renal replacement treatment prior to transplantation was 63.4 ± 43.6 months. The average observation time post-transplant was 9.7 years (1.4 - 36.3 years). Post-transplant, 64 (12.6%) patients suffered 89 nonvertebral fractures (44 patients suffered 1 fracture, 15 patients 2 fractures, and 5 patients 3 fractures). Patients with fractures had significantly lower late BMD of femoral neck in the period of 1 - 10 years post-transplant, had osteopenia and osteoporosis more frequently in the same time period, and higher serum alkaline phosphatase in the first year post-transplant. 13 patients (13/64, 20.3%) had major fractures. Patients with major fractures were significantly older than patients with no major fractures and had lower serum albumin. Frequency of treatment with bisphosphonate, calcium, or phosphate did not differ between the groups. Vitamin D supplement (active form in 98% of cases) was prescribed more frequently in the group without fractures, but this was not statistically significant. CONCLUSION: Fracture rate in our transplant patient population was comparable to that reported in the literature. Except for a higher level of serum total alkaline phosphatase in the fracture group, we found no other early laboratory risk factors for bone fractures. BMD at the femoral region 1 - 10 years after kidney transplantation but not BMD at the time of transplantation was a risk factor for nonvertebral fractures. Osteopenia and osteoporosis in the post-transplant period were found to be a fracture risk factor.
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