Cystatin C Outperforms Creatinine in Predicting Cefepime Clearance in Pediatric Stem Cell Transplant Recipients.

Pediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Since cefepime's antimicrobial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. Objectives of this study were to describe how eGFR impacts cefepime pharmacokinetic/pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients, to investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, and to explore additional predictors of cefepime clearance. Patients admitted to the pediatric HSCT unit who received ≥2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the second and fourth cefepime doses and measured SCr and CysC if not already obtained clinically within 24h of cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA-normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (%fT>1x MIC) and 4x MIC (%fT>4x MIC) using a susceptibility breakpoint of 8 mg/L for Pseudomonas aeruginosa. We enrolled 53 patients (ages 1 to 30 years, median 8.9 years). SCr- and CysC-eGFRs were lower in patients who attained 100% fT>1xMIC compared to those who did not attain this target: 115 versus 156 mL/min/1.73m2 (p = .01) for SCr-eGFR and 73.5 versus 107 mL/min/1.73m2 (p < .001) for CysC-eGFR. SCr-eGFR was weakly positively correlated with cefepime clearance (adjusted [a]r2= 0.14), while CysC-eGFR and SCr-/CysC-eGFR had stronger positive correlations (ar2 = 0.30 CysC, ar2 = 0.28 combo. There was a weak, significant linear association between increasing CysC-eGFR and decreased %fT>1xMIC (ar2 = 0.32) and %fT>4xMIC (ar2 = 0.14). No patients with a CysC-eGFR >120 mL/min/1.73 m2 achieved 100% fT>1xMIC or 50% fT>4x MIC. In multiple regression models, underlying diagnosis of hemoglobinopathy (in all models) and being pretransplant (in SCr and combined models) were associated with increased cefepime clearance, while concomitant use of calcineurin inhibitors was associated with decreased cefepime clearance in all models. Overall, the combo-eGFR model with timing pretransplant, hemoglobinopathy, and use of calcineurin inhibitors had the best performance (ar2 = 0.63). CysC-based eGFRs (CysC alone and combined) predicted cefepime clearance better than SCr-eGFR, even after considering steroid use. Increasing CysC eGFR correlated with decreased probability of PD target attainment, raising concerns for underdosing at high eGFRs. CysC should be included when estimating kidney function to provide adequate dosing of cefepime in pediatric HSCT patients.

Pre-transplant glomerular hyperfiltration is not a risk factor for increased renal morbidity and mortality in pediatric stem cell transplant patients.

Low glomerular filtration rate (GFR) prior to stem cell transplant (SCT) is associated with increased morbidity and mortality. The implications of abnormally high GFRs, or glomerular hyperfiltration, prior to SCT are unknown. Twenty-two of 74 consecutive pediatric SCT patients over 2 years old at a single center were hyperfiltrating prior to SCT, median nuclear medicine GFR 154 mL/min/1.73 m2 [interquartile range: 146-170]. There was no association between hyperfiltration and any transplant demographics, nor between hyperfiltration and acute kidney injury (p = .8), renal replacement therapy (p = .63), 1-year event-free survival (p = 1), or abnormal creatinine-based estimated GFR at a median follow-up of 4.7 years (p = .73).

Humoral Response in Hemodialysis Patients Post-SARS-CoV-2 mRNA Vaccination: A Systematic Review of Literature.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has infected over 600 million individuals and caused nearly 7 million deaths worldwide (10 January 2023). Patients with renal disease undergoing hemodialysis are among those most adversely affected, with an increased predisposition to SARS-CoV-2 infection and death. This systematic review aimed to pool evidence assessing the humoral response of hemodialysis patients (HDP) post-mRNA SARS-CoV-2 vaccination. A systematic search of the literature was performed through MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers up to 10 January 2023. Cohort and case-control studies were included if they reported an immune response in one group of patients undergoing hemodialysis who received mRNA SARS-CoV-2 vaccination compared with another group of patients receiving the same vaccine but not on hemodialysis. The methodological quality was assessed using the Newcastle-Ottawa Scale. Meta-analysis was not deemed appropriate due to the high heterogeneity between studies. From the 120 studies identified, nine (n = 1969 participants) met the inclusion criteria. Most studies (n = 8/9, 88%) were of high or medium methodological quality (≥6/9 stars). The results revealed that HDP developed lower antibody levels across all timepoints post-vaccination when compared with controls. Patients with chronic kidney disease elicited the highest antibody immune response, followed by HDP and, lastly, kidney transplant recipients. Overall, post-vaccination antibody titers were comparatively lower than in the healthy population. Current results imply that robust vaccination strategies are needed to address waning immune responses in vulnerable populations.

Urinary Biomarkers for the Assessment of Acute Kidney Injury of Pediatric Sickle Cell Anemia Patients Admitted for Severe Vaso-occlusive Crises.

Sickle cell nephropathy is a progressive morbidity, beginning in childhood, which is incompletely understood partially due to insensitive measures. We performed a prospective pilot study of pediatric and young adult patients with sickle cell anemia (SCA) to assess urinary biomarkers during acute pain crises. Four biomarkers were analyzed with elevations potentially suggesting acute kidney injury: (1) neutrophil gelatinase-associated lipocalin (NGAL), (2) kidney injury molecule-1, (3) albumin, and (4) nephrin. Fourteen unique patients were admitted for severe pain crises and were found to be representative of a larger SCA population. Urine samples were collected at the time of admission, during admission, and at follow-up after discharge. Exploratory analyses compared cohort values to the best available population values; individuals were also compared against themselves at various time points. Albumin was found to be moderately elevated for an individual during admission compared with follow-up ( P = 0.006, Hedge g : 0.67). Albumin was not found to be elevated compared with population values. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephrin were not found to be significantly elevated compared with population values or comparing admission to follow-up. Though albumin was found to be minimally elevated, further research should focus on alternative markers in efforts to further understand kidney disease in patients with SCA.

Dual phenotype: co-occurring Leber congenital amaurosis and familial exudative vitreoretinopathy: a case report.

PURPOSE: To report the concurrent presentation and management of IQCB1-associated Leber Congenital Amaurosis and NDP-associated Familial Exudative Vitreoretinopathy (FEVR). MATERIALS AND METHODS: A 6-month-old Caucasian infant presented with poor visual response, high hypermetropia, and infantile-nystagmus with a provisional diagnosis of Leber Congenital Amaurosis based on clinical findings. Genetic counseling and testing were performed with a 285 gene retinal dystrophy panel (Blueprint Genetics). Clinical characteristics, presentation, ancillary testing results, and management are described. RESULTS: Two previously reported heterozygous pathogenic variants in ICQB1 were identified (c.1518_1519del (p.His506Glnfs*13) and c.1381C>T, p.Arg461*) segregating in trans. In addition, a variation of uncertain significance (VUS) was found in NDP (c.280C>T; p.His94Tyr). Fluorescein angiography was performed demonstrating peripheral avascularity and retinal telangiectasia without frank neovascularization. Peripheral ablative laser was applied to the avascular zone. CONCLUSIONS: The NDP VUS likely represents a pathogenic variant given the FEVR phenotype in addition to retinal degeneration, creating a rare dual phenotype. The combination of low oxygen demand from the IQCB1-associated retinal degeneration and NDP variant may have led to a more attenuated FEVR presentation with uncertain prognosis. A molecular diagnosis informed ocular and renal surveillance, as well as the recurrence risk for future offspring.

Use of extracorporeal immunomodulation in a toddler with hemophagocytic lymphohistiocytosis and multisystem organ failure.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a dysregulated immune disorder in children, associated with Epstein-Barr virus (EBV) infection or malignancies. In severe forms, HLH presents with signs and symptoms of hyperinflammation that progress to life-threatening multiorgan failure. Intervention with an extracorporeal immunomodulatory treatment utilizing a selective cytopheretic device (SCD) could be beneficial. The SCD with regional citrate anticoagulation selectively binds the most highly activated circulating neutrophils and monocytes and deactivates them before release to the systemic circulation. Multiple clinical studies, including a multicenter study in children, demonstrate SCD therapy attenuates hyperinflammation, resolves ongoing tissue injury and allows progression to functional organ recovery. We report the first case of SCD therapy in a patient with HLH and multi-organ failure. CASE DIAGNOSIS/TREATMENT: A previously healthy 22-month-old toddler presented with fever, abdominal distension, organomegaly, pancytopenia, and signs of hyperinflammation. EBV PCR returned at > 25 million copies. The clinical and laboratory pictures were consistent with systemic EBV-positive T-cell lymphoma with symptoms secondary to HLH. The patient met inclusion criteria for an ongoing study of integration of the SCD with a continuous kidney replacement therapy (CKRT) as part of standard of care. The patient received CKRT-SCD for 4 days with normalization of serum markers of sepsis and inflammation. The patient underwent hematopoietic stem cell transplantation 52 days after presentation and has engrafted with normal kidney function 8 months later. CONCLUSIONS: SCD treatment resulted in improvement of poor tissue perfusion reflected by rapid decline in serum lactate levels, lessened systemic capillary leak with discontinuation of vasoactive agents, and repair and recovery of lung and kidney function with extubation and removal of hemodialysis support.

Cefepime-Associated Neurotoxicity in a Pediatric Patient With Stage V Chronic Kidney Disease.

BACKGROUND: Studies in adult patients suggest cefepime can cause neurotoxicity, including disorientation, seizures, and coma, particularly when present at high concentrations. Patients with underlying kidney dysfunction or central nervous system anomalies are at particularly high risk. There is a relative paucity of pediatric literature on the neurotoxic effects of cefepime. CASE REPORT: Herein is reported the case of a 2-year-old patient with chronic kidney disease receiving cefepime for Serratia marcescens bacteremia who experienced agitation, tremor, and inconsolability in the setting of an elevated cefepime trough that improved with cefepime discontinuation alone. CONCLUSIONS: Pediatric patients with acute and chronic kidney disease are at risk of cefepime-related neurologic changes. Therapeutic drug monitoring for cefepime in patients with kidney dysfunction or baseline neurologic abnormalities may help inform appropriate antimicrobial dosing and avoidance of toxicity.

Complement Levels at Admission Reflecting Progression to Severe Acute Kidney Injury (AKI) in Coronavirus Disease 2019 (COVID-19): A Multicenter Prospective Cohort Study.

Background: Dysregulation of complement system is thought to be a major player in development of multi-organ damage and adverse outcomes in patients with coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement system activity and development of severe acute kidney injury (AKI) among hospitalized COVID-19 patients. Materials and Methods: In this multicenter, international study, complement as well as inflammatory and thrombotic parameters were analyzed in COVID-19 patients requiring hospitalization at one US and two Hungarian centers. The primary endpoint was development of severe AKI defined by KDIGO stage 2+3 criteria, while the secondary endpoint was need for renal replacement therapy (RRT). Complement markers with significant associations with endpoints were then correlated with a panel of inflammatory and thrombotic biomarkers and assessed for independent association with outcome measures using logistic regression. Results: A total of 131 hospitalized COVID-19 patients (median age 66 [IQR, 54-75] years; 54.2% males) were enrolled, 33 from the US, and 98 from Hungary. There was a greater prevalence of complement over-activation and consumption in those who developed severe AKI and need for RRT during hospitalization. C3a/C3 ratio was increased in groups developing severe AKI (3.29 vs. 1.71; p < 0.001) and requiring RRT (3.42 vs. 1.79; p < 0.001) in each cohort. Decrease in alternative and classical pathway activity, and consumption of C4 below reference range, as well as elevation of complement activation marker C3a above the normal was more common in patients progressing to severe AKI. In the Hungarian cohort, each standard deviation increase in C3a (SD = 210.1) was independently associated with 89.7% increased odds of developing severe AKI (95% CI, 7.6-234.5%). Complement was extensively correlated with an array of inflammatory biomarkers and a prothrombotic state. Conclusion: Consumption and dysregulation of complement system is associated with development of severe AKI in COVID-19 patients and could represent a promising therapeutic target for reducing thrombotic microangiopathy in SARS-CoV-2 infection.

Anti-Endothelial Cell Antibodies are not frequently elevated in hospitalized patients with COVID-19.

n/a.

Transplantation-Associated Thrombotic Microangiopathy Risk Stratification: Is There a Window of Opportunity to Improve Outcomes?

Transplantation-associated thrombotic microangiopathy (TA-TMA) can range from a self-limiting condition to a lethal transplantation complication. It is important to identify TA-TMA patients at risk for severe multiorgan endothelial injury to implement targeted therapies in a timely manner. Current therapeutic approaches with complement blockade have improved survival markedly in high-risk TA-TMA patients, yet one-third of these patients respond inadequately to eculizumab therapy. Poor response may indicate that substantial endothelial injury has already occurred and raises the possibility that earlier intervention may improve outcomes. The goal of this study was to identify additional TA-TMA patients who would benefit from early targeted intervention and update TA-TMA risk stratification methods to reflect these findings. We studied 130 HSCT recipients with a diagnosis of TA-TMA who were screened prospectively and stratified into 3 TA-TMA risk groups (high-risk, n = 64; moderate-risk, n = 48; 18 low-risk, n = 18). We specifically examined TA-TMA biomarkers and clinical outcomes in subjects who were not offered complement blocking therapy (moderate-risk and low-risk TA-TMA subjects) and compared them with those who received TA-TMA-targeted therapy (high-risk TA-TMA subjects). One-year post-HSCT survival for subjects with untreated moderate-risk TA-TMA was similar to those with high-risk TA-TMA receiving eculizumab therapy (71% versus 66%; P = .40), indicating that a subset of moderate-risk patients may benefit from therapy. A detailed analysis of moderate-risk subjects highlighted the importance of relative as well as absolute complement pathway activation in determining organ injury. We demonstrated that activated terminal complement (measured by elevated blood sC5b-9) alone is a valuable indicator of reduced survival. Moderate-risk TA-TMA subjects with elevated sC5b-9 levels had a nearly 3-fold higher risk of mortality that was statistically significant in multivariant analyses (P = .01). A "dose effect" also was observed, and higher sC5b-9 levels were associated with worse outcomes. Furthermore, all moderate-risk patients with sustained sC5b-9 elevation for >2 weeks ultimately developed multiorgan dysfunction syndrome (MODS). This indicates that scheduled sC5b-9 measurements could promptly identify patients at risk for poor outcomes and would facilitate early TA-TMA-directed therapy to prevent organ injury. Untreated low-risk TA-TMA patients had a 1-year post-HSCT survival of 94% and should be observed without targeted interventions. Routine TA-TMA screening and complement-blocking therapies have markedly improved the outcomes for high-risk TA-TMA patients, and our study suggests that additional patients may benefit from TA-TMA treatment. This study provides further support for prospective TA-TMA screening as an integral tool for identifying patients at greatest risk for organ injury and death from TA-TMA. An updated TA-TMA risk algorithm that incorporates relevant laboratory biomarkers, clinical findings, and comorbid conditions was generated using this study's findings, and we propose clinical implementation of this algorithm for the management of TA-TMA.

Cell-Free DNA, Neutrophil extracellular traps (NETs), and Endothelial Injury in Coronavirus Disease 2019- (COVID-19-) Associated 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.

The Predictive Value of Serum ACE2 and TMPRSS2 Concentrations in Patients with COVID-19-A Prospective Pilot Study.

One of the major challenges for healthcare systems during the Coronavirus-2019 (COVID-19) pandemic was the inability to successfully predict which patients would require mechanical ventilation (MV). Angiotensin-Converting Enzyme 2 (ACE2) and TransMembrane Protease Serine S1 member 2 (TMPRSS2) are enzymes that play crucial roles in SARS-CoV-2 entry into human host cells. However, their predictive value as biomarkers for risk stratification for respiratory deterioration requiring MV has not yet been evaluated. We aimed to evaluate whether serum ACE2 and TMPRSS2 levels are associated with adverse outcomes in COVID-19, and specifically the need for MV. COVID-19 patients admitted to an Israeli tertiary medical center between March--November 2020, were included. Serum samples were obtained shortly after admission (day 0) and again following one week of admission (day 7). ACE2 and TMPRSS2 concentrations were measured with ELISA. Of 72 patients included, 30 (41.6%) ultimately required MV. Serum ACE2 concentrations >7.8 ng/mL at admission were significantly associated with the need for MV (p = 0.036), inotropic support, and renal replacement therapy. In multivariate logistic regression analysis, elevated ACE2 at admission was associated with the need for MV (OR = 7.49; p = 0.014). To conclude, elevated serum ACE2 concentration early in COVID-19 illness correlates with respiratory failure necessitating mechanical ventilation. We suggest that measuring serum ACE2 at admission may be useful for predicting the risk of severe disease.

Multiparametric quantitative renal MRI in children and young adults: comparison between healthy individuals and patients with chronic kidney disease.

PURPOSE: Multiparametric quantitative renal MRI may provide noninvasive radiologic biomarkers of chronic kidney disease (CKD) based on investigations in animal models and adults. We aimed to (1) obtain normative multiparametric quantitative MRI data from the kidneys of healthy children and young adults, (2) compare MRI measurements between healthy control participants and patients with CKD, and (3) determine if MRI measurements correlate with clinical and laboratory data as well as histology. METHODS: This was a prospective, case-control study of 20 healthy controls and 12 CKD patients who underwent percutaneous renal biopsy ranging from 12 to 23 years of age between October 2018 and March 2020. Kidney function was documented and pathology assessed for fibrosis/inflammation. Utilizing a field strength of 1.5T, we examined renal T1, T2, and T2* relaxation mapping, MR elastography (MRE), and diffusion-weighted imaging (DWI). A single analyst made all manual measurements for quantitative MRI pulse sequences. Independent measurements from cortex, medulla, and whole kidney were obtained by drawing regions of interest on single slices from the upper, mid, and lower kidney. A weighted average was calculated for each kidney; if two kidneys, the right and left were averaged. Continuous variables were compared with Mann-Whitney U test; bivariate relationships were assessed using Spearman rank-order correlation. RESULTS: Median estimated glomerular filtration rate (eGFR) was 112.3 ml/min/1.73 m2 in controls (n = 20, 10 females) and 55.0 ml/min/m2 in CKD patients (n = 12, 2 females) (p < 0.0001). Whole kidney (1333 vs. 1291 ms; p = 0.018) and cortical (1212 vs 1137 ms; p < 0.0001) T1 values were higher in CKD patients. Cortical T1 values correlated with eGFR (rho = - 0.62; p = 0.0003) and cystatin C (rho = 0.58; p = 0.0007). Whole kidney (1.87 vs. 2.02 10-3 mm2/s; p = 0.007), cortical (1.89 vs. 2.04 10-3 mm2/s; p = 0.008), and medullary (1.87 vs. 1.98 10-3 mm2/s; p = 0.0095) DWI apparent diffusion coefficients (ADC) were lower in CKD patients. Whole kidney ADC correlated with eGFR (rho = 0.45; p = 0.012) and cystatin C (rho = - 0.46; p = 0.009). Cortical histologic inflammation correlated with DWI ADC (rho = - 0.71; p = 0.011). CONCLUSION: Renal T1 relaxation and DWI ADC measurements differ between pediatric healthy controls and CKD patients, correlate with laboratory markers of CKD, and may have histologic correlates.

Anti-Endothelial Cell Antibodies are not frequently elevated in hospitalized patients with COVID-19.

COVID-19 is now established to be associated with a thrombotic phenomenon, now called COVID-19 associated coagulopathy (CAC). Anti-Endothelial Cell Antibodies (AECA) are a heterogenous group of autoantibodies targeting various endothelial cell antigens or antigens adhering to endothelial cells, They are commonly observed in a variety of auto-immune and rheumatologic conditions, and were observed in patients with the severe acute respiratory syndrome (SARS) in 2005. We aimed to assess AECA status in patients with COVID-19 and their potential contributing role to endothelial injury and CAC. AECA identification was a relatively infrequent finding in COVID-19 patients on admission, and their presence, albeit in only 2/33 patients, was not associated with disease severity. However, as the autoantibodies were only measured at admission, we cannot exclude the possibility of pathogenic AECA developing later in the course of diseaseFurther studies using additional methods are needed to evaluate the presence and potential pathogenic role of AECA in later stages of COVID-19.

A case of treatment-resistant membranous nephropathy associated with graft versus host disease successfully treated with daratumumab.

BACKGROUND: Membranous nephropathy (MN) is the most common cause of glomerulopathy after hematopoietic cell transplantation (HCT), most often occurring in the setting of graft versus host disease (GVHD). Twenty percent of patients will fail to respond to standard therapy and may progress to end stage renal disease. Here we present the case of a pediatric patient who developed chronic oral GVHD more than one-year post-HCT, who subsequently developed nephrotic syndrome (anasarca, nephrotic range proteinuria, hypoalbuminemia) and had a renal biopsy consistent with MN. Treated with ibrutinib for her GVHD, and steroids, tacrolimus, and rituximab for her MN, she failed to achieve even partial remission of her kidney disease after 8 months. Due to steroid toxicity and 0% CD19 cells on lymphocyte subpopulation flow cytometry, the decision was made to trial plasma cell depletion therapy with daratumumab. METHOD: She received three doses of daratumumab at weeks 1, 4, and 17. RESULTS: Her nephrotic syndrome resolved and her serum albumin was greater than 3.0 gm/dl by week 10. She was weaned off of both steroids and tacrolimus by week 16, at which time she had near-complete remission of her renal disease. CONCLUSION: Daratumumab may be an important, novel therapeutic option for post-HCT MN patients who are not responsive to standard therapies.

Case Report: Atypical HUS Presenting With Acute Rhabdomyolysis Highlights the Need for Individualized Eculizumab Dosing.

Background: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare orphan disease caused by dysregulated complement activation resulting in thrombotic microangiopathy. Although complement-mediated endothelial injury predominantly affects the renal microvasculature, extra-renal manifestations are present in a significant proportion of patients. While eculizumab has significantly improved the morbidity and mortality of this rare disease, optimizing therapeutic regimens of this highly expensive drug remains an active area of research in the treatment of aHUS. Case Presentation: This report describes the case of a previously healthy 4 year-old male who presented with rhabdomyolysis preceding the development of aHUS with anuric kidney injury requiring dialysis. Clinical stabilization required increased and more frequent eculizumab doses compared with the standardized weight-based guidelines. In the maintenance phase of his disease, pharmacokinetic analysis indicated adequate eculizumab levels could be maintained with an individualized dosing regimen every 3 weeks, as opposed to standard 2 week dosing, confirmed in this patient over a 4 year follow up period. Cost analyses show that weight-based maintenance dosing costs $312,000 per year, while extending the dosing interval to every 3 weeks would cost $208,000, a savings of $104,000 per year, relative to the cost of $72,000 from more frequent eculizumab dosing during his initial hospitalization to suppress his acute disease. Conclusion: This case exemplifies the potential of severe, multisystem involvement of aHUS presenting with extra-renal manifestations, including rhabdomyolysis as in this case, and highlights the possibility for improved clinical outcomes and higher value care with individualized eculizumab dosing in patients over the course of their disease.

Early prediction of COVID-19-associated acute kidney injury: Are serum NGAL and serum Cystatin C levels better than serum creatinine?

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with a high risk of acute kidney injury (AKI), often requiring renal replacement therapy (RRT). Serum Cystatin C (sCysC) and serum Neutrophil Gelatinase-Associated Lipocalin (sNGAL) are emerging biomarkers for kidney injury, and were suggested to be superior to serum creatinine (sCr) in several clinical settings. Moreover, elevated sCysC is associated with disease severity and mortality in COVID-19. We aimed to assess the utility of sCysC and sNGAL for predicting COVID-19-associated AKI, need for RRT, and need for intensive care unit (ICU) admission, when measured at presentation to the emergency department (ED). METHODS: Patients presenting to the ED with laboratory-confirmed COVID-19 were included. The primary outcome was development of COVID-19-associated AKI, while the secondary outcomes were need for RRT and ICU admission. RESULTS: Among 52 COVID-19 patients, 22 (42.3%) developed AKI with 8/22 (36.4%) requiring RRT. Both sCr and sCysC demonstrated excellent performance for predicting AKI (AUC, 0.86 and 0.87, respectively) and need for RRT (AUC, 0.94 and 0.95, respectively). sNGAL displayed acceptable performance for predicting AKI (AUC, 0.81) and need for RRT (AUC, 0.87). CONCLUSIONS: SCr and sCysC measured at ED presentation are both highly accurate predictors of AKI and need for RRT, whereas sNGAL demonstrated adequate diagnostic performance. While sCyC was previously shown to be superior to sCr as a diagnostic biomarker of kidney injury in certain etiologies, our findings demonstrate that sCr is comparable to sCyC in the context of predicting COVID-19-associated AKI. Given the high sensitivity of these biomarkers for predicting the need for RRT, and as sCysC is associated with mortality in COVID-19 patients, we recommend their measurement for enabling risk stratification and early intervention.

Cytokeratin 18 cell death assays as biomarkers for quantification of apoptosis and necrosis in COVID-19: a prospective, observational study.

BACKGROUND: The mechanism by which SARS-CoV-2 triggers cell damage and necrosis are yet to be fully elucidated. We sought to quantify epithelial cell death in patients with COVID-19, with an estimation of relative contributions of apoptosis and necrosis. METHODS: Blood samples were collected prospectively from adult patients presenting to the emergency department. Circulating levels of caspase-cleaved (apoptosis) and total cytokeratin 18 (CK-18) (total cell death) were determined using M30 and M65 enzyme assays, respectively. Intact CK-18 (necrosis) was estimated by subtracting M30 levels from M65. RESULTS: A total of 52 COVID-19 patients and 27 matched sick controls (with respiratory symptoms not due to COVID-19) were enrolled. Compared with sick controls, COVID-19 patients had higher levels of M65 (p = 0.046, total cell death) and M30 (p = 0.0079, apoptosis). Hospitalised COVID-19 patients had higher levels of M65 (p= 0.014) and intact CK-18 (p= 0.004, necrosis) than discharged patients. Intensive care unit (ICU)-admitted COVID-19 patients had higher levels of M65 (p= 0.004), M30 (p= 0.004) and intact CK-18 (p= 0.033) than hospitalised non-ICU admitted patients. In multivariable logistic regression, elevated levels of M65, M30 and intact CK-18 were associated with increased odds of ICU admission (OR=22.05, p=0.014, OR=19.71, p=0.012 and OR=14.12, p=0.016, respectively). CONCLUSION: Necrosis appears to be the main driver of hospitalisation, whereas apoptosis and necrosis appear to drive ICU admission. Elevated levels CK-18 levels are independent predictors of severe disease, and could be useful for risk stratification of COVID-19 patients and in assessment of therapeutic efficacy in early-phase COVID-19 clinical trials.