Carfilzomib-based antibody mediated rejection therapy in pediatric kidney transplant recipients.

BACKGROUND: To date, the evidence for proteasome-inhibitor (PI) based antibody mediated rejection (AMR) therapy has been with the first-generation PI bortezomib. Results have demonstrated encouraging efficacy for early AMR with lesser efficacy for late AMR. Unfortunately, bortezomib is associated with dose-limiting adverse effects in some patients. We report use of the second generation proteosome inhibitor carfilzomib for AMR treatment in two pediatric patients with a kidney transplant. METHODS: The clinical data on two patients who experienced dose limiting toxicities from bortezomib were collected along with their short- and long-term outcomes. RESULTS: A two-year-old female with simultaneous AMR, multiple de novo DSAs (DR53 MFI 3900, DQ9 MFI 6600, DR15 2200, DR51 MFI 1900) and T-cell mediated rejection (TCMR) completed three carfilzomib cycles and experienced stage 1 acute kidney injury after the first two cycles. At 1 year follow up, all DSAs resolved, and her kidney function returned to baseline without recurrence. A 17-year-old female also developed AMR with multiple de novo DSAs (DQ5 MFI 9900, DQ6 MFI 9800, DQA*01 MFI 9900). She completed two carfilzomib cycles, which were associated with acute kidney injury. She had resolution of rejection on biopsy and decreased but persistent DSAs on follow-up. CONCLUSIONS: Carfilzomib treatment for bortezomib-refractory rejection and/or bortezomib toxicity may provide DSA elimination or reduction, but also appears to be associated with nephrotoxicity. Clinical development of carfilzomib for AMR will require a better understanding of efficacy and development of approaches to mitigate nephrotoxicity.

Urine biomarker score captures response to induction therapy with lupus nephritis.

BACKGROUND: The Renal Activity Index for Lupus (RAIL) consists of urine protein assessment of neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, monocyte chemotactic protein 1, adiponectin, hemopexin, and ceruloplasmin, which non-invasively identifies lupus nephritis (LN). We aimed to delineate RAIL scores with inactive versus active LN and changes over time with response to LN induction therapy. METHODS: There were 128 pediatric patients with systemic lupus erythematosus (SLE) and age-matched healthy controls recruited in a prospective case control study, with kidney biopsy confirmation of LN. Laboratory and clinical information was recorded and urine collected at diagnosis and end of induction and during maintenance therapy. Response to therapy was assessed by repeat kidney biopsy or laboratory parameters. Urine was assayed for RAIL biomarkers and the RAIL score calculated. RESULTS: Pediatric RAIL (pRAIL) scores from 128 children and young adults with SLE (with/without LN: 70/38) including 25 during LN induction therapy, differentiated clinically active LN from inactive LN or without LN, and controls (all p < 0.0017). pRAIL scores significantly decreased with complete LN remission by 1.07 ± 1.7 (p = 0.03). CONCLUSIONS: The RAIL biomarkers differentiate LN patients based on activity of kidney disease, with decreases of ≥ 1 in pRAIL scores indicating complete response to induction therapy. Significantly lower RAIL scores in healthy controls and in SLE patients without known LN raise the possibility of subclinical kidney disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Usefulness of the lupus low disease activity state as a treatment target in childhood-onset SLE.

OBJECTIVE: Treat-to-target (T2T) strategies are advocated to improve prognosis in childhood-onset SLE (cSLE). Proposed T2T states include SLEDAI score of <4 (SLEDAI-LD), limited corticosteroid use (low-CS), and lupus low disease activity state (LLDAS). We sought to compare T2T states for their association with cSLE prognosis under consideration of relevant disease characteristics such as pre-existing damage, race and lupus nephritis (LN). METHODS: Longitudinal data from 165 patients enrolled in the Cincinnati Lupus Registry were included. LN presence was based on renal biopsy, and patients were followed up until 18 years of age. RESULTS: The 165 patients (LN: 45, white: 95) entered the registry within a median of 0 (IQR: 0-1) year post diagnosis and were followed up for a median of 4 (IQR: 2-5) years during which 80%, 92% and 94% achieved LLDAS, low-CS and SLEDAI-LD. Patients with LN were significantly less likely to achieve any T2T state (all p<0.03) and required a significantly longer time to reach them (all p<0.0001). Over the study period, patients maintained low-CS, SLEDAI-LD or LLDAS for a median of 76% (IQR: 48%-100%), 86% (IQR: 55%-100%) or 39% (IQR: 13%-64%) of their follow-up. Significant predictors of failure to maintain LLDAS included LN (p≤0.0062), pre-existing damage (p≤0.0271) and non-white race (p≤0.0013). There were 22%, 20% and 13% of patients who reached SLEDAI-LD, CS-low and LLDAS and nonetheless acquired new damage. Patients with LN had a higher risk of new damage than patients without LN even if achieving low-CS (p=0.009) or LLDAS (p=0.04). CONCLUSIONS: Patients with LN and pre-existing damage are at higher risk of increased future damage acquisition, even if achieving a T2T state such as LLDAS. Among proposed common T2T states, the LLDAS is the hardest to achieve and maintain. The LLDAS may be considered the preferred T2T measure as it conveys the highest protection from acquiring additional disease damage.

Biomarkers in Childhood-Onset Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex, multisystem chronic autoimmune disease. Because of its diverse phenotypes, diagnosis of SLE can be challenging, and current biomarkers are insufficient. Childhood-onset SLE (cSLE), although less prevalent, has higher morbidity and mortality, and early diagnosis is critical for improving outcomes. Many studies have focused on discovering new biomarkers to better diagnose and monitor SLE and cSLE. Herein, the authors aim to review the most investigated biomarkers in development for cSLE, focusing on those that can be measured in the blood or urine.

Stability of novel urinary biomarkers used for lupus nephritis.

Background: The Renal Activity Index for Lupus (RAIL) is a composite score of six urinary biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), kidney injury molecule-1 (KIM-1), ceruloplasmin, adiponectin, and hemopexin) used to monitor lupus nephritis activity in children. We tested stability of RAIL biomarkers prior to meaningful clinical use. Methods: Urine samples were tested by ELISA under shipping conditions, freeze/thaw, ambient and longer-term storage. Statistical analysis was performed via Deming Regression, Bland-Altman and Spearman Correlation Coefficient. Results: Biomarker concentration were comparable to freshly collected urine following storage at -80 °C for up to 3 months, and at 4 or 25 °C up to 48 h followed by -80 °C. Neither shipping on dry or wet ice exposure nor addition of two freeze-thaw cycles led to loss of signal, with excellent Spearman Correlation coefficients under all conditions. Conclusions: RAIL biomarkers are stable following short-term storage at clinically relevant conditions.

Corrigendum to "Successful Urine Multiplex Bead Assay to Measure Lupus Nephritis Activity" Kidney Int. Rep. 2021;6:1949-1960.

[This corrects the article DOI: 10.1016/j.ekir.2021.04.016.].

Successful Urine Multiplex Bead Assay to Measure Lupus Nephritis Activity.

INTRODUCTION: Lupus nephritis (LN) confers a poor prognosis, mainly from lack of effective laboratory tests to diagnose and to evaluate therapies. We have previously shown that a set of 6 urinary biomarkers (NGAL, KIM-1, MCP-1, adiponectin, hemopexin, and ceruloplasmin) are highly sensitive and specific to identify adult and pediatric patients with active LN using renal biopsy as reference standard. Using these combinatorial urinary biomarkers, the Renal Activity Score for Lupus (RAIL) score was established, with biomarkers measured by enzyme-linked immunosorbent assay (ELISA). To enhance clinical utility of the biomarkers and RAIL, we tested the performance of RAIL with biomarkers measured by ELISA to that of biomarkers measured by the bead multiplex method, hypothesizing that the multiplex bead method would be comparable. METHODS: Spot urine samples (n = 341) of 46 patients aged 20 to 73 years with or without LN were used. Samples were assayed both by ELISA and multiplex using LUMINEX. RAIL scores and biomarker quantities were assessed for agreement with intraassay correlation coefficients and compared using Bland-Altman and regression. RESULTS: Biomarker measurement by LUMINEX was successful for NGAL, KIM-1, MCP-1, and adiponectin, but not for ceruloplasmin and hemopexin. There was good agreement of the RAIL obtained from these 4 biomarkers, irrespective of assay method (intraclass correlation coefficient [ICC] = 0.78, 95% confidence interval [CI] = 0.78-0.82). The RAIL scores from 4 biomarkers further correlated with those when considering all 6 biomarkers (ICC = 0.97, 95% CI = 0.96-0.98). CONCLUSION: The LUMINEX platform allows for the convenient and simultaneous measurement of 4 RAIL biomarkers. RAIL scores considering only these 4 biomarkers may be sufficient to accurately capture LN activity.

Hemolytic Uremic Syndrome.

Hemolytic uremic syndrome (HUS) is the clinical triad of thrombocytopenia, anemia, and acute kidney injury. Classically associated with enterocolitis from Shiga toxin-producing Escherichia coli, HUS is also associated with Streptococcus pneumoniae infections; genetic dysregulation of the alternative complement pathway or coagulation cascade; and, rarely, a hereditary disorder of cobalamin C metabolism. These share a common final pathway of a prothrombotic and proinflammatory state on the endothelial cell surface, with fibrin and platelet deposition. Much work has been done to distinguish between the different mechanisms of disease, thereby informing the optimal therapeutic interventions for each entity.