Introduction: Acute kidney injury (AKI) is common in critically ill neonates, including very and extremely low birth weight (VLBW, ELBW) neonates. In severe cases, kidney replacement therapy (KRT) may be warranted. Currently, available KRT devices are only indicated for those weighing >= 2.5 kg and require a double lumen or 2 separate single lumen catheters. We miniaturized the Kirpa Kit manual dialysis device, naming it the Brophy Kit, and we assessed its in vitro clearance and ultrafiltration (UF) performance. Methods: We diluted packed red blood cells to a normal hematocrit (Hct: 31.1%-36.8%) and conducted 12 clearance and 3 UF experiments. A cycle consisted of aspirating 10 ml of blood from the blood bag, passing it through a hemofilter, and returning it in a circular path. For clearance experiments, we tested 4 configurations, with varied timing and volume of saline flushes to refresh the dialysis compartment, then measured blood urea nitrogen (BUN) and potassium concentrations every 5 cycles. For each UF cycle, 1 ml of ultrafiltrate was removed, and Hct was measured every 10 cycles. Results: Median BUN and potassium reduction were 31.0% (interquartile range [IQR]: 17.6-37.9) and 35.0% (IQR: 26.9-41.7), respectively, after 30 clearance cycles. Median Hct increased to 52.6% (IQR: 52.5- 53.8) after 60 UF cycles, more than the expected Hct (47.7%). Conclusion: The Brophy Kit performs in vitro clearance efficiently and UF consistently. The Brophy Kit may address a technological KRT gap for small neonates because of its minimal extracorporeal volume and ability to function with single lumen access.

Acute kidney injury (AKI) remains a common cause of preventable death in low-resource settings because of cost and lack of dialysis access. AKI occurs in 24-59% of children with severe malaria, and when severe malaria-associated acute kidney injury (SM-AKI) is complicated by hyperkalemia, mortality approaches 40%. Treatment of these children with severe anemia becomes challenging as packed red blood cells (pRBCs) have high potassium (K+) loads. We describe a protocol using the novel manual single-lumen alternating microbatch (mSLAMB) dialysis system to deplete pRBCs of K+, hypothesizing that this system can decrease K+ >80% in 20 minutes. Herein, we ran pRBC aliquots through the mSLAMB system using diffusive clearance. Three cycles were completed in each of four experiments. K+ was measured at baseline and after every cycle to calculate K+ reduction. Active ultrafiltration was performed to control net volumes, assessed as percentage of blood volume reduction and hematocrit rise. We reduced K+ in pRBC aliquots by a median of 93.2% (interquartile range [IQR], 89.9-95.1) in a median of 20.5 minutes (IQR, 17.8-23.1) per experiment. Greatest median K+ reduction occurred in cycle 1 (80.9%; IQR, 80.8-80.9), with minimal additional clearance achieved by cycle 3. Median hematocrit rise at experiment conclusion was 2.5% (IQR, 1.8-3.3). We conclude that mSLAMB dialysis consistently and effectively removed >80% of K+ from pRBCs in just over 20 minutes and facilitated volume control. Further studies are assessing transfusion risks in children with SM-AKI and hyperkalemia as this technique may allow for safer resuscitation.

Acute kidney injury (AKI) remains a common cause of preventable death in low-middle income countries due to cost and lack of dialysis access. AKI occurs in 24-59% of children with severe malaria (SM-AKI) and worsens mortality. Hyperkalemia, an understudied risk factor, occurs in 6% of Ugandan children with SM; coupled with AKI, mortality approaches 40%. Treatment of these children, especially those with severe anemia, becomes challenging, as packed red blood cells (pRBCs) may have high potassium (K+) loads.

Background Access to pediatric dialysis is challenged in low-resource settings by high costs, scarcity of equipment, and lack of qualified personnel availability. We demonstrated the manual Single Lumen Alternating Micro-Batch (mSLAMB) device can remove small solutes in vitro without the need for electricity, batteries or pumps. We developed a new version (Kirpa Kit™) to address some of the technical limitations of mSLAMB. Here we compare the in vitro clearance performance and ease of use of Kirpa Kit™ with that of prior mSLAMB configurations. Methods A mixture of expired packed red blood cells, 0.9% NaCl, urea and heparin was used to test the efficiency of two mSLAMB configurations and Kirpa Kit™ in removing potassium and urea. Clearance was evaluated by measuring percent reduction after 25-minute sessions with each device. A survey was used to evaluate the ease of use of each configuration. Results The Kirpa Kit™ achieved a median urea reduction of 82.4% and potassium reduction of 82.1%, which were higher than those achieved with the best-performing mSLAMB configuration (urea 71.9%, potassium 75.4%). The Kirpa Kit™ was easier to use with a shorter perceived time of use than the mSLAMB. Conclusions The Kirpa Kit™, evolution of mSLAMB, is easy to use and may have improved efficacy, making it an optimal candidate for in vivo testing.

We evaluate the association of early postoperative urinary c-c motif chemokine ligand 14 (CCL14) and persistent severe acute kidney injury (AKI) in pediatric post-cardiac surgery patients. This is a retrospective single-center cohort study of patients < 18 years of age undergoing cardiac surgery who provided a biorepository urine sample within the first 24 postoperative hours. Persistent severe AKI was defined as any AKI stage lasting for ≥ 72 h with at least one time point of AKI stage 2 or 3 during that time frame. Patients with persistent severe AKI were matched 2:1 with non-AKI patients on age and sex. Urine samples were measured for CCL14 concentration. Logistic regression was used to evaluate associations between CCL14 and persistent severe AKI. Persistent severe AKI occurred in 14 (5.4

Access to pediatric dialysis is challenged in low-resource settings due to high costs, scarcity of equipment, and the lack of qualified personnel availability. We demonstrated the manual single lumen alternating micro-batch (mSLAMB) device can remove small solutes in vitro without the need for electricity, batteries, or pumps. We developed a new version (Kirpa Kit™) to address some of the technical limitations of mSLAMB. Here, we compare the in vitro clearance performance and ease of use of the Kirpa Kit™ with that of prior mSLAMB configurations. A mixture of expired packed red blood cells, 0.9

Introduction: Electrolyte derangements, acidosis, and volume overload remain life-threatening emergencies in people with acute kidney injury in austere environments. A single-lumen alternating micro-batch (SLAMB) dialysis technique was designed to perform renal replacement therapy using a single-lumen access, low-cost disposable bags and tubing, widely available premade fluids, and a dialysis filter. A manual variation (mSLAMB) works without electricity, battery, or a pump. We modeled mSLAMB dialysis and predicted it could achieve adequate small solute clearance, blood flow rates, and ultrafiltration accuracy. Methods: A 25- to 30-kg pediatric patient’s blood volume was simulated by a 2-L bag of expired blood and spiked with 5 g of urea initially, then with 1–2 g between experiments. Experiments had 8 cycles totaling prescription volumes of 800–2,400 mL and were conducted with different ratios of hemofiltration fluid to blood volume. Concentrations of urea and potassium, final effluent volumes, and cycle duration were measured at the end of each cycle to determine clearance, ultrafiltration accuracy, and blood flow rates. Results: Each cycle lasted 70–145 s. Experiments achieved a mean urea reduction ratio of 27.4 ± 7.1% and a mean potassium reduction of 23.4 ± 9.3%. The largest urea and potassium reduction percentage occurred with the first cycle. Increased hemofiltration fluid to blood volume ratio did not increase clearance. Mean (+/− standard deviation) blood flow ranged from 79.7 +/− 4.4 mL/min to 90.8 +/− 6.5 mL/min and increased with larger batch volume and height difference between reservoirs. Ultrafiltration accuracy ranged from 0 to 2.4% per cycle. Discussion: mSLAMB dialysis is a simple, manual, cost-effective mode of dialysis capable of providing clearance and accurate ultrafiltration. With further refinement of technique, we believe this can be a potentially lifesaving treatment in austere conditions and low-resource settings.

Background: Abnormal serum magnesium (Mg) concentrations are common and associated with worse mortality in kidney-transplant recipients. Many kidney and transplant -related factors affect Mg homeostasis. The concentration of the active form, ionized Mg (iMg), is not measured clinically, and total Mg (tMg) and iMg correlations have conflicted. We hypothesized that iMg and tMg concentrations show poor categorical agreement (i.e., low, normal, and high) in kidney-transplant recipients but that ionized calcium (iCa) correlates with iMg.Methods: We retrospectively evaluated hypomagnesemia in kidney-transplant recipients over a 2-yr period. We prospectively collected blood at 0-28 days post-transplant to measure correlations between iMg and iCa/tMg. iMg and iCa concentrations in the reference ranges of 0.44-0.65 and 1.0-1.3 mmol/L, respectively, were considered normal. Fisher's exact test and unweighted kappa statistics revealed category agreements. Pearson's correlation coefficients and linear regression measured correlations.Results: Among 58 retrospective kidney-transplant recipients, 54 (93%) had tMg < 0.66 mmol/L, 28/58 (48%) received Mg supplementation, and 20/28 (71%) had tacrolimus dose adjustments during supplementation. In 13 prospective transplant recipients (N =43 samples), iMg and tMg showed strong category agreement (P = 0.0003) and correlation (r= 0.71, P < 0.001), whereas iMg and iCa did not (P = 0.7; r=-0.25, P = 0.103, respectively).Conclusions: tMg and iMg exhibited strong correlation following kidney transplantation. However, iCa may not be an accurate surrogate for iMg. Determining the effect of Mg supplementation and the Mg concentration where supplementation is clinically necessary are important next steps.

Acute kidney injury (AKI) is associated with increased morbidity and mortality in critically ill patients. Olfactomedin 4 (OLFM4), a secreted glycoprotein expressed in neutrophils and stressed epithelial cells, is upregulated in loop of Henle (LOH) cells following AKI. We hypothesized that urine OLFM4 (uOLFM4) will increase in patients with AKI and may predict furosemide responsiveness. Urine from critically ill children was collected prospectively and tested for uOLFM4 concentrations with a Luminex immunoassay. Severe AKI was defined by KDIGO (stage 2/3) serum creatinine criteria. Furosemide responsiveness was defined as > 3 mL/kg/h of urine output in the 4 h after a 1 mg/kg IV furosemide dose administered as part of standard of care. Fifty-seven patients contributed 178 urine samples. Irrespective of sepsis status or AKI cause, uOLFM4 concentrations were higher in patients with AKI (221 ng/mL [IQR 93–425] vs. 36 ng/mL [IQR 15–115], p = 0.007). uOLFM4 concentrations were higher in patients unresponsive to furosemide (230 ng/mL [IQR 102–534] vs. 42 ng/mL [IQR 21–161], p = 0.04). Area under the receiver operating curve for association with furosemide responsiveness was 0.75 (95

Abstract Background Sepsis-induced endothelial dysfunction is proposed to cause angiotensin-converting enzyme (ACE) dysfunction and renin–angiotensin–aldosterone system (RAAS) derangement, exacerbating vasodilatory shock and acute kidney injury (AKI). Few studies test this hypothesis directly, including none in children. We measured serum ACE concentrations and activity, and assessed their association with adverse kidney outcomes in pediatric septic shock. Methods A pilot study of 72 subjects aged 1 week–18 years from an existing multicenter, observational study. Serum ACE concentrations and activity were measured on Day 1; renin + prorenin concentrations were available from a previous study. The associations between individual RAAS components and a composite outcome (Day 1–7 severe persistent AKI, kidney replacement therapy use, or mortality) were assessed. Results 50/72 subjects (69%) had undetectable ACE activity (< 2.41 U/L) on Day 1 and 27/72 (38%) developed the composite outcome. Subjects with undetectable ACE activity had higher Day 1 renin + prorenin compared to those with activity (4533 vs. 2227 pg/ml, p = 0.017); ACE concentrations were no different between groups. Children with the composite outcome more commonly had undetectable ACE activity (85% vs. 65%, p = 0.025), and had higher Day 1 renin + prorenin (16,774 pg/ml vs. 3037 pg/ml, p < 0.001) and ACE concentrations (149 vs. 96 pg/ml, p = 0.019). On multivariable regression, increasing ACE concentrations (aOR 1.01, 95%CI 1.002–1.03, p = 0.015) and undetectable ACE activity (aOR 6.6, 95%CI 1.2–36.1, p = 0.031) retained associations with the composite outcome. Conclusions ACE activity is diminished in pediatric septic shock, appears uncoupled from ACE concentrations, and is associated with adverse kidney outcomes. Further study is needed to validate these findings in larger cohorts.

BACKGROUND:Acute kidney injury is a cause of preventable deaths in low resource settings due to lack of dialysis access and cost. A manual single lumen alternating micro-batch (mSLAMB) dialysis technique performs kidney replacement therapy using single lumen access, low-cost bags/tubing, intravenous fluids, and a filter without electricity, a battery, or a pump. We propose a protocol whereby mSLAMB can perform diffusive clearance simply and efficiently to bring dialysis to underserved populations. METHODS:Expired packed red blood cells mixed with crystalloid solution were spiked with urea and anticoagulated with heparin. A Static diffusion Technique (with short flushes of fluid before each filter pass) was compared to a Dynamic diffusion Technique (with fluid running through the filter during the forward pass) to assess urea and potassium clearance. Passive ultrafiltration was the difference between the 200 mL batch volume and volume returned to the blood bag per cycle. RESULTS:Five cycles achieved urea reduction ratios (URR) between 17-67% and potassium clearance of 18-60%, with higher percentages achieved from higher proportions of batch volume dialyzed to patient volume. Dynamic Technique increased clearance over the Static Technique. Passive ultrafiltration volumes were 2.5-10% of batch volume. CONCLUSION:mSLAMB dialysis performs diffusive clearance and passive ultrafiltration efficiently, while preserving resources and available manpower. IMPACT:mSLAMB is a dialysis technique that can perform efficient diffusive clearance and passive ultrafiltration without electricity, batteries, or a pump. With basic medical supplies and limited manpower, mSLAMB is a cost-effective means of providing emergency dialysis in low resource areas. We propose a basic algorithm for safe and cost-effective dialysis for people of different ages and sizes.

OBJECTIVE:Several human studies have associated nitric oxide administration via the cardiopulmonary bypass circuit with decreased incidence of cardiopulmonary bypass-associated acute kidney injury, but histopathologic and serologic evidence of nitric oxide efficacy for acute kidney injury attenuation are lacking. METHODS:By using a survival ovine model (72 hours), acute kidney injury was induced by implementing low-flow cardiopulmonary bypass for 2 hours, followed by full-flow cardiopulmonary bypass for 2 hours. The nitric oxide cohort (n = 6) received exogenous nitric oxide through the cardiopulmonary bypass circuit via the oxygenator, and the control group (n = 5) received no nitric oxide. Serial serologic biomarkers and renal histopathology were obtained. RESULTS:Baseline characteristics (age, weight) and intraoperative parameters (cardiopulmonary bypass time, urine output, heart rate, arterial pH, and lactate) were equivalent (P > .10) between groups. Postoperatively, urine output, heart rate, respiratory rate, and peripheral arterial saturation were equivalent (P > .10) between groups. Post-cardiopulmonary bypass creatinine elevations from baseline were significantly greater in the control group versus the nitric oxide group at 16, 24, and 48 hours (all P < .05). Histopathologic evidence of moderate/severe acute kidney injury (epithelial necrosis, tubular slough, cast formation, glomerular edema) occurred in 60% (3/5) of the control group versus 0% (0/6) of the nitric oxide group. Cortical tubular epithelial cilia lengthening (a sensitive sign of cellular injury) was significantly greater in the control group than in the nitric oxide group (P = .012). CONCLUSIONS:In a survival ovine cardiopulmonary bypass model, nitric oxide administered with cardiopulmonary bypass demonstrated serologic and histologic evidence of renal protection from acute kidney injury. These results provide insight into 1 potential mechanism for cardiopulmonary bypass-associated acute kidney injury and supports continued study of nitric oxide via cardiopulmonary bypass circuit for prevention of acute kidney injury.

Introduction: Neutrophil extracellular traps (NETs) release (i.e., NETosis) has been recently implicated in the pathomechanism underlying severe end-organ damage in Coronavirus Disease 2019 (COVID-19) and could present a novel therapeutic target. We aimed to determine whether circulating levels of cell-free DNA (cfDNA), a surrogate for NETosis, may be associated with the development of acute kidney injury (AKI), a major contributor to poor outcomes and mortality in COVID-19. Methods: Blood samples were collected prospectively from adult patients infected with SARS-CoV-2 presenting to the emergency department (ED). Circulating levels of cfDNA were quantified from patients' serum. Further assessment of correlations between cfDNA levels and markers of AKI (i.e., serum creatinine (SCr), cystatin C, neutrophil gelatinase–associated lipocalin (NGAL)), biomarkers of thrombotic microangiopathy and of inflammation in patients' serum was performed. Results: Fifty-one COVID-19 patients were enrolled. cfDNA levels were found to be significantly higher in those who developed severe AKI (p < 0.001) and those needing renal replacement therapy (p = 0.020). cfDNA positively correlated with ED SCr, NGAL, cystatin C, neutrophil count, neutrophil-to-lymphocyte ratio, C3a, C5a, Scb5-9, IL-6, IL-8, IL-10, TNF-α, LDH, CRP, ferritin, and fibrinogen and negatively correlated with ADAMTS13/von-Willebrand factor ratio and lymphocyte count. In a multivariate logistic regression, a one-unit increase in cfDNA value was associated with 4.6% increased odds of severe AKI (OR = 1.046; p = 0.040). Finally, cfDNA significantly correlated with established NETs components, myeloperoxidase, and neutrophil elastase. Conclusion: Intravascular NETosis could be an important contributing factor in the development of microthrombosis and COVID-19-associated AKI. Further research is urgently needed to understand the role of NETosis in COVID-19 and evaluate therapeutic avenues for targeting this process.

Hasson, Denise C.; Rose, James; Merrill, Kyle; Varnell, Charles D.; Goldstein, Stuart; Benoit, Stefanie W. Author Information

Significant controversy has arisen over the role of the renin-angiotensin-aldosterone system (RAAS) in COVID-19 pathophysiology. In this prospective, observational study, we evaluated plasma angiotensin converting enzyme (ACE) concentration and serum ACE activity in 52 adults with laboratory-confirmed SARS-CoV-2 infection and 27 non-COVID-19 sick controls. No significant differences were observed in ACE activity in COVID-19 patients versus non-COVID-19 sick controls (41.1 [interquartile range (IQR): 23.0-55.2] vs. 42.9 [IQR 13.6-74.2] U/L, p = .649, respectively). Similarly, no differences were observed in ACE concentration in COVID-19 patients versus non-COVID-19 sick controls (108.4 [IQR: 95.8-142.2] vs. 133.8 [IQR: 100.2-173.7] μg/L, p = .059, respectively). Neither ACE activity (p = .751), nor ACE concentration (p = .283) was associated with COVID-19 severity. Moreover, neither ACE activity, nor ACE concentration was correlated with any inflammatory biomarkers.