Julius J. Schmidt

Circulating microRNAs are not eliminated by hemodialysis.

Background Circulating microRNAs are stably detectable in serum/plasma and other body fluids. In patients with acute kidney injury on dialysis therapy changes of miRNA patterns had been detected. It remains unclear if and how the dialysis procedure itself affects circulating microRNA level. Methods We quantified miR-21 and miR-210 by quantitative RT-PCR in plasma of patients with acute kidney injury requiring dialysis and measured pre- and post-dialyser miRNA levels as well as their amount in the collected spent dialysate. Single treatments using the following filters were studied: F60 S (1.3 m2, Molecular Weight Cut Off (MWCO): 30 kDa, n = 8), AV 1000 S (1.8 m2, MWCO: 30 kDa, n = 6) and EMiC 2 (1.8 m2, MWCO: 40 kDa, n = 6). Results Circulating levels of miR-21 or -210 do not differ between pre- and post-dialyzer blood samples independently of the used filter surface and pore size: miR-21: F60S: p = 0.35, AV 1000 S p = 1.0, EMiC2 p = 1.0; miR-210: F60S: p = 0.91, AV 1000 S p = 0.09, EMiC2 p = 0.31. Correspondingly, only traces of both miRNAs could be found in the collected spent dialysate and ultrafiltrate. Conclusions In patients with acute kidney injury circulating microRNAs are not removed by dialysis. As only traces of miR-21 and -210 are detected in dialysate and ultrafiltrate, microRNAs in the circulation are likely to be transported by larger structures such as proteins and/or microvesicles. As miRNAs are not affected by dialysis they might be more robust biomarkers of acute kidney injury.

New High-Cutoff Dialyzer Allows Improved Middle Molecule Clearance without an Increase in Albumin Loss: A Clinical Crossover Comparison in Extended Dialysis

Background: Accumulation of middle molecules is thought to have adverse effects in patients with acute kidney injury (AKI). Elimination of middle molecules by non-convective means, i.e. hemodialysis, remains difficult. The aim of the study was to investigate the removal characteristics of a new high permeability membrane in AKI patients undergoing extended dialysis (ED). Patients and Methods: We performed a prospective, crossover study comparing the EMiC2 dialyzer (1.8 m2, FMC, Germany) and AV 1000S (1.8 m2, FMC) in 11 critically ill patients with AKI. β2-Microglobulin, cystatin c, creatinine, and urea were measured before and after 0.5, 5.0 and 10 h of ED. Serum reduction ratios, dialyzer clearances, and mass in the total collected dialysate were determined. Results: Dialyzer clearance of β2-microglobulin (EMiC2: 52 ± 1.7 ml/min, AV 1000S: 41.7 ± 1.5 ml/min, p = 0.0002) and cystatin c (EMiC2: 47.2 ± 1.2 ml/min, AV 1000S: 34.2 ± 2.3 ml/min, p < 0.0001) was markedly different, as was the reduction of serum levels of β2-microglobulin (EMiC2: 54.3 ± 3.6%, AV 1000S: 39.1 ± 4.5%, p = 0.025) and cystatin c (EMiC2: 38.9 ± 2.6%, AV 1000S: 28.0 ± 3.9%, p = 0.043). Additionally, we observed a higher total amount of these substances in the collected dialysate. There was no significant difference in the total amount of albumin eliminated per treatment. Conclusion: The new EMiC2 dialyzer enhances removal of middle molecules without an increase in albumin loss. The clinical relevance of this finding needs to be determined.

Single- and multiple-dose pharmacokinetics and total removal of colistin in a patient with acute kidney injury undergoing extended daily dialysis

Sir, The emergence of multidrug-resistant bacteria has recently renewed interest in colistin, which was first introduced in 1959. For intravenous administration, not colistin itself, but its inactive prodrug colistin methanesulfonate (CMS) is administered. As 70% of CMS is excreted unchanged in the urine, its t1 2 increases with a decline in glomerular filtration rate (GFR) to up to 14 h in patients with a GFR ,15 mL/min. Additionally, a larger fraction of the CMS dose is converted into colistin with decreasing renal function. Thus, dose reduction is recommended with decreasing GFR. Data from 1968 on four patients treated with twice-weekly dialysis for 11–16 h using a cuprophane membrane are the foundation for current dosing regimens in chronic haemodialysis. In these patients a dose of 1 million units every 48 h is recommended. Data on dosing in critically ill patients undergoing extended dialysis are missing. We here report for the first time, singleand multiple-dose pharmacokinetics of colistin in a critically ill patient undergoing extended dialysis. Written informed consent was obtained from the patient’s mother for publication of this study. Ethical approval for reporting this case was obtained from the Medical School Hannover. A patient aged between 30 and 40 years (height 163 cm, weight 53 kg) was admitted to our intensive care unit (ICU) for rapidly progressive respiratory failure. The patient had undergone lung transplantation for pulmonary hypertension 10 months earlier. The patient’s post-transplant course had been complicated by acute rejection and an Aspergillus fumigatus infection. On admission, the patient required non-invasive ventilation. Bronchoalveolar lavage revealed a multiresistant Klebsiella pneumoniae in addition to the previously known Aspergillus. Endotracheal intubation was required owing to worsening respiratory failure. Extended dialysis for acute kidney injury was started. As the K. pneumoniae was only susceptible to colistin, we initiated treatment with 3 million units every 8 h after an initial dose of 6 million units. Blood samples were taken at regular intervals on day 1 and day 9 of treatment. Colistin and CMS concentrations were determined separately by HPLC combined with tandem mass spectrometry, as recently used in its modified form. The average dialysis time between day 1 and day 9 was 552 min; mean blood and dialysate flow were 191 mL/min and 121 mL/ min, respectively. After a loading dose of 6 million units, peak levels of colistin and CMS were 10.01 mg/mL and 24.76 mg/mL, respectively. The lowest plasma concentrations on day 1 were 3.83 mg/mL for colistin and ,0.1 mg/mL for CMS. Extended dialysis with the above-mentioned specifications led to a reduction of peak colistin levels (Figure 1). After 9 days of treatment with 3 million units every 8 h there was neither an accumulation of colistin (peak level day 9: 8.96 mg/mL, trough level 2.13 mg/mL) nor an accumulation of CMS (peak level day 9: 11.83 mg/mL, trough level ,0.1 mg/mL). Depending on the blood and dialysate flow, the dialyser clearance of colistin ranged between 54 and 71 mL/min and the CMS clearance between 25 and 62 mL/min. The amount of colistin in the total collected dialysate was 245 mg on day 1 and 191 mg on day 9. Although the patient responded well to this antibiotic therapy, subsequent cerebral aspergillosis could not be treated, leading to the death of the patient after 5 weeks of treatment in the ICU. There are scarce data on the dosing of antibiotics in patients undergoing renal replacement therapy. Our data suggest that extended dialysis eliminates colistin effectively and to a larger extent than regular intermittent outpatient haemodialysis. This is in line with recent data on two critically ill patients undergoing a modern type of intermittent dialysis (1.6 m polymethylacrylate membrane, blood/dialysate flow 300/500 mL/min, duration 4 h), in whom a CMS dialyser clearance of 90 mL/min was reported. Li et al. described a dialyser clearance of 11.9 mL/min for colistin and 11.2 mL/min for CMS in one critically ill patient undergoing continuous venovenous haemodiafiltration, which due to its continuous mode would remove approximately the same amount of the drug. Lastly, dialyser clearance in five patients receiving continuous venovenous haemodiafiltration was recently reported to be 72 mL/min for colistin and 32 mL/min for CMS. Thus, dosing colistin as recommended during regular haemodialysis is inadequate and would result in a significant under-dosing, which could be associated with a substantial risk, especially in critically ill patients in the ICU. A dose of 3 million units every 8 h seems to be adequate for patients undergoing daily extended dialysis for 9 h a day with a high flux 1.3 m dialyser. This dose of 9 million units per day did not lead to accumulation of the drug.

Cotrimoxazole plasma levels, dialyzer clearance and total removal by extended dialysis in a patient with acute kidney injury: risk of under-dosing using current dosing recommendations

BackgroundDosing of antibiotics in critically ill patients is challenging. It becomes even more difficult if renal or hepatic impairment ensue. Modern means of renal replacement therapy are capable of removing antibiotics to a higher rate than decades ago, leaving clinicians with a high degree of uncertainty concerning the dose of antibiotics in this patient population. Cotrimoxazole, a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) is frequently used in the treatment of several infections including Pneumocystis jirovecii pneumonia (PCP).Case presentationHere we describe a patient with acute kidney injury in which we investigated the TMP and SMX levels during the course of an ICU stay. Cotrimoxazole was administered every six hours i.v. in a dose of TMP/SMX 15/75 mg/kg/day. Extended dialysis was performed with a high-flux dialyzer. Blood samples, as well as pre- and postdialyzer samples and aliquots of the collected spent dialysate were collected.Observed peak concentrations (Cmax) were 7.51 mg/l for TMP and 80.80 mg/l for SMX. Decline of blood levels during extended dialysis (TMP 64%; SMX 84%) was mainly due to removal by the dialysis procedure, illustrated by the high dialyzer clearances (median of 4 extended dialysis sessions: TMP 94.0 / SMX 51.0 ml/min), as well as by the absolute amount of both substances in the collected spent dialysate (median of 6 extended dialysis sessions: TMP 556 mg / SMX 130 mg). Within the limitation of a case report our data from 4 consecutive extended dialysis sessions suggest that this procedure substantially removes both TMP and SMX.ConclusionsDose reduction, which is usually advocated in patients with acute kidney injury under renal replacement therapy, might lead to significant under-dosing. Pharmacokinetic studies for TMP/SMX dosing in this patient population are necessary to allow adequate dosing.

Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment

The dosing of drugs in critically ill patients undergoing renal replacement therapy is based on limited data. We report for the first time single- and multiple-dose pharmacokinetics of ethambutol (EMB), which is cleared renally to 80%, and rifampicin (RIF), which is cleared renally to <30%, in a patient requiring both extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. Extended dialysis removed a considerable amount of both EMB and RIF, with a dialyser plasma clearance ranging between 37 and 95 ml/min for EMB and between 39 and 53 ml/min for RIF. The EMB peak level (3h after a 2-h infusion) using a dose of 1000 mg/day on the first day of treatment was 2.3mg/l, which is in the low therapeutic range (2-5mg/l). Doubling the dose to 2000 mg/day resulted in peak levels slightly to markedly above the recommended range. There was no detectable effect of the ECMO membrane on the removal of both drugs. After an initial dose as for patients without renal impairment (15 mg/kg/day), therapeutic drug monitoring should be used to guide EMB dosing in patients undergoing extended daily dialysis.

Removal characteristics and total dialysate content of glutamine and other amino acids in critically ill patients with acute kidney injury undergoing extended dialysis.

Background: Acute kidney injury in critically ill patients is associated with the activation of protein catabolism and a negative nitrogen balance. Renal replacement therapy (RRT) aggravates this problem by eliminating a substantial amount of amino acids. However, there is scarce data on the removal characteristics of modern dialysis membranes in extended dialysis. Methods: This is a prospective study in 10 extended dialysis sessions using a 1.8-m2 polysulfone membrane (EMiC2 dialyzer or AV 1000S; FMC, Germany). Blood samples for 19 amino acids were drawn before, during, and after 10 h of extended dialysis (blood/dialysate flow 150 ml/min). In addition, samples for the calculation of dialyzer clearance and samples from the total spent dialysate were measured using a Biochrom 30 amino acid analyzer. Results: Despite no significant difference in pre- and postdialysis plasma amino acid levels, we found an impressive amount of amino acids in collected spent dialysate, i.e. 10.5 g/10 h of treatment. The dialyzer clearance ranged from 67.6 ml/min for phenylalanine to 140.0 ml/min for valine. The total eliminated masses of the measured amino acids had equal values for both membranes. There was a significant difference between the dialyzer clearance of the investigated membranes for glutamine (AV 1000S: 83.3 ml/min vs. EMiC2: 92.0 ml/min, p = 0.02) and serine (88.8 ml/min vs. 91.8 ml/min, p = 0.005). Discussion: Our data indicate that the modern forms of RRT eliminate amino acids to an extent that has not been met by our nutritional support standards. Especially the removal of glutamine, important for immune function and cell regeneration, might have detrimental effects on the recovery of critically ill patients.

Saving two lives with one dialysis treatment Successful treatment of life threatening diphenhydramine intoxication by intermittent hemodialysis using a high cut-off membrane

Hemodialysis is the extracorporeal treatment of choice for various life-threatening intoxications, with the exception of highly protein-bound substances, which are preferably removed by charcoal hemoperfusion. This technique, however, is limited by its availability and its significant side effects. We present a potentially lifethreatening diphenhydramine (DPH) overdose in a stuporous female patient in which high cut-off hemodialysis was used. Timely detoxification resulted in rapid gain of consciousness, allowing the patient to state the existence and location of another poison victim.

Treatment of amitriptyline intoxications by extended high cut-off dialysis.

Antidepressants, especially amitriptyline, are among the most frequent drug classes involved in intoxications. Despite its small molecular weight, amitriptyline is not considered to be eliminated by extracorporeal treatment methods due to its high protein binding and large volume of distribution. New high cut-off dialysers have so far not been used for removal of amitriptyline. We report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using extended high cut-off (HCO) dialysis. Despite dialyser clearances of 33 and 58 mL/min, resulting in the reduction of initial serum concentrations by ∼30%, only 211 and 920 µg of amitryptilin, respectively, (<3% of the ingested amount) could be recovered in the total collected dialysate. Hence, due to the high volume of distribution of amitriptyline, even HCO dialysis does not contribute substantially to the extracorporeal removal of amitryptilin.

Effect of Isovolemic, Isothermic Hemodialysis on Cerebral Perfusion and Vascular Stiffness Using Contrast Computed Tomography and Pulse Wave Velocity

Background Patients undergoing hemodialysis treatment have a six-fold increased risk for stroke relative to the general population. However, the effect of hemodialysis on cerebral blood flow is poorly studied and confounding factors like blood pressure and ultrafiltration as well as temperature changes have rarely been accounted for. The aim of our study was to use state-of-the-art technology to evaluate the effect of a single dialysis session on cerebral perfusion as well as on vascular stiffness. Methods Chronic hemodialysis patients (7 male/3 female, mean age 58 years) were recruited. Cerebral blood flow and arterial pulse wave velocity were measured before and immediately after a hemodialysis session. To exclude effects of volume changes we kept ultrafiltration to a minimum, allowing no change in body weight. Isothermic conditions were maintained by using the GENIUS single-pass batch-dialysis system with a high-flux polysulfone dialyser. Cerebral blood flow was measured by contrast-enhanced computed tomography. Pulse wave velocity was measured using the SphygmoCor (AtCor Medical, USA) device by a single operator. Results This study shows for the first time that isovolemic, isothermic hemodialysis neither affected blood pressure or heart rate, nor total or regional cerebral perfusion. There was also no change in pulse wave velocity. Conclusions Mechanisms other than the dialysis procedure itself might be causative for the high incidence of ischemic strokes in this patient population. Moreover, the sole removal of uremic toxins does not lead to short-term effects on vascular stiffness, underlying the importance of volume control in this patient population.

Pharmacokinetics and total removal of fosfomycin in two patients undergoing intermittent haemodialysis and extended dialysis: prescription needs to avoid under-dosing

Sir, Fosfomycin, first isolated in 1969 from cultures of Streptomyces fradiae, is the single representative of the epoxide family of antimicrobial drugs and shows bactericidal activity against various Gram-positive, Gram-negative and anaerobic pathogens through inhibition of peptidoglycan synthesis destroying the inner bacterial cell wall. The unique properties (molecular weight1⁄4138 Da; protein binding1⁄4 10%; volume of distribution1⁄40.2–0.4 L/kg) allow easy penetration into soft tissue, bone, muscle, heart, eye, lung, wound fluids and liquor. As fosfomycin is not significantly metabolized but mainly excreted unchanged via the kidneys its half-life is highly dependent on kidney function. Usually, fosfomycin susceptibility is defined by a breakpoint of the MIC of 32 mg/L. Fosfomycin is indicated and most commonly used in urinary tract infections and offers a treatment alternative in soft tissue infections, spondylodiscitis, osteomyelitis and infections of the CNS when systemically administered. Owing to the emerging increase in infections with antimicrobial drug resistance, old antibiotics such as fosfomycin are increasingly used. The elimination of fosfomycin during haemodialysis was described about 30 years ago using dialysis techniques that have long been considered outdated. Owing to the scarce use of fosfomycin over the last decade, pharmacokinetic data for modern dialysis techniques are almost completely missing. In this report we describe two cases of single-dose pharmacokinetics of fosfomycin during intermittent haemodialysis, as well as during extended dialysis, a prolonged haemodialysis modality commonly used in critically ill patients. To our knowledge, this is the first report that provides data on the total eliminated amount of fosfomycin during an intermittent and an extended dialysis therapy session in the spent collected dialysate. Written informed consent was obtained from the patients for publication of this article. See Table S1 (available as Supplementary data at JAC Online) for the main dialysis and patient characteristics. Both patients were treated at a tertiary care hospital (Hannover Medical School). Case 1: A female patient in her seventies (158 cm, 49 kg body weight, BMI 19.6 kg/m) was admitted to the emergency ward due to distinct dorsalgia denying any trauma. She had been undergoing chronic haemodialysis for 11 years. Owing to former morbid obesity, the patient had undergone bariatric surgery 5 years earlier, which decreased her BMI to 19.6 kg/m. A punch biopsy of the lumbar spine was performed, which showed focal osteomyelitis. As the patient was allergic to penicillin, antibiotic therapy with 300 mg of clindamycin thrice daily and 8 g of intravenous fosfomycin sodium on dialysis days was empirically started; while 3 g of the total fosfomycin dosage was administered 4 h prior to the intermittent haemodialysis session the other 5 g was given directly at the end of the intermittent haemodialysis. A 3 h intermittent haemodialysis session was performed with a blood and dialysate flow of 220 mL/ min using a polysulfone high-flux dialyser (1.3 m surface) during therapy with the GENIUS dialysis batch system. Details are described elsewhere. Heparin was used for anticoagulation. The maximum plasma concentration (Cmax) after the 3 g infusion was 496 mg/L. As shown in Figure 1(a) the 3 h dialysis session led to a distinct reduction of fosfomycin plasma levels of 61%, with a dialyser clearance of 75 mL/min. The total amount of fosfomycin in the total collected dialysate was 2430 mg. Cmax after the additional administration of 5 g of fosfomycin after dialysis treatment was 467 mg/L. Fosfomycin concentrations were measured by LC-MS/ MS according to a previously described procedure. Case 2: A female patient in her twenties (167 cm, 40 kg body weight, BMI 14.3 kg/m) with sepsis due to severe osteomyelitis was admitted to the medical ICU. Owing to the severe clinical state of the patient a femur resection was performed and intraoperative swabs showed an infection with multiresistant Escherichia coli bacteria susceptible to fosfomycin and therapy with meropenem and fosfomycin was started. Owing to acute kidney injury extended dialysis was performed every other day. A daily dosage of 3 g of fosfomycin was administered intravenously. On the day after initial fosfomycin administration a 6 h extended dialysis treatment with a polysulfone high-flux dialyser (1.3 m) was performed. Blood and dialysis flow were set at 240 mL/min. Total ultrafiltration volume during therapy was 3440 mL. Citrate was used for anticoagulation. The fosfomycin peak concentration after administration of 3 g of fosfomycin was 207.4 mg/L after a trough concentration of 106.5 mg/L. The serum concentration declined to 49.5 mg/L after the end of the procedure, resulting in a reduction ratio of 68% (Figure 1b). After the 6 h dialysis treatment a total of 3591 mg of fosfomycin was found in the total spent dialysate. Dialyser plasma clearance was 116 mL/min. Three weeks after the ICU admission the patient died due to multiple septic complications and multi-organ failure. Fosfomycin dosing guidelines in patients undergoing haemodialysis are based on publications from the 1970s and 1980s, when cuprophan membranes were used. These earlier publications indicate a high elimination of fosfomycin during haemodialysis