Corrigendum to PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF PEGCETACOPLAN IN THE TREATMENT OF PATIENTS WITH POSTTRANSPLANT RECURRENCE OF C3G OR IC MPGN (Kidney International Reports (2022) 7(6S) (S458"“S459), (S2468024922013468), (10.1016/j.ekir.2022.04.069))
The authors regret that N. Palakow was incorrectly listed as an author for this abstract. She should be removed from the author slate. The authors would like to apologise for any inconvenience caused. DOI of original article: 10.1016/j.ekir.2022.04.069
A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation
OBJECTIVES/OBJECTIVE:We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN/METHODS:Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING/METHODS:Five U.S. medical centers. PATIENTS/METHODS:Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS/METHODS:Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5â€‰mg) or high-dose (25â€‰mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS/RESULTS:The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival ,frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS:Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.
Interleukin-2 Receptor Antagonists Induction Therapy in Simultaneous Heart - Kidney Transplantation [Meeting Abstract]
Pancreas Transplantation from Hepatitis C Viremic Donors to Uninfected Recipients
Despite utilization of hepatitis C viremic organs for hepatitis C naÃ¯ve recipients (HCV D+/R-) in other solid organ transplants, HCV viremic pancreata remain an unexplored source of donor organs. This study reports the first series of HCV D+/R- pancreas transplants. HCV D+/R- had shorter wait list times compared to HCV D-/R-, waiting a mean of 16 days from listing for HCV positive organs. HCV D+/R- had a lower match allocation sequence than HCV D-/R-, and this correlated to receipt of organs with a lower Pancreas Donor Risk Index (PDRI) score. All HCV D+R- had excellent graft function with a mean follow up of 438 days and had undetectable HCV RNA levels by a mean of 23 days after initiation of HCV-directed therapy. The rates of infectious complications, re-operation, readmission, rejection, and length of stay were not impacted by donor HCV status. A national review of potential ideal pancreas donors found that 37% of ideal HCV negative pancreas allografts were transplanted, compared to only 5% of ideal HCV positive pancreas allografts. The results of the current study demonstrate the safety of accepting HCV positive pancreata for HCV naÃ¯ve recipients and advocates for increased utilization of ideal HCV positive pancreas allografts.
Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease
Outpatient management of kidney transplant recipients with suspected COVID-19-Single-center experience during the New York City surge
Data describing the clinical progression of coronavirus disease 2019 (COVID-19) in transplant recipients are limited. In New York City during the surge in COVID-19 cases, a systematic approach to monitoring and triaging immunocompromised transplant patients was required in the context of strained healthcare resources, limited outpatient testing, and heightened hospital exposure risks. Public health guidance at the onset of the COVID-19 outbreak recommended outpatient monitoring of mildly symptomatic patients without specific recommendations for special populations such as transplant recipients. We developed and implemented a systematic monitoring algorithm for kidney transplant recipients at our transplant center who reported mild symptoms suggestive of COVID-19. We describe the outcomes of the first 44 patients monitored through this algorithm. A total of 44 kidney transplant recipients thought to be symptomatic for COVID-19 disease were followed for a minimum of 14Â days. The majority of mildly symptomatic patients (34/44) had clinical progression of disease and were referred to the emergency department where they all tested PCR positive and required hospitalization. More than half of these patients presented with hypoxia requiring supplemental oxygen, 39% were intubated within 48Â hours, and 53% developed acute kidney injury but did not require dialysis. There were 6 deaths. During surge outbreaks, kidney transplant patients with even mild symptoms have a high likelihood of COVID-19 disease and most will worsen requiring hospitalization for supportive measures. Earlier outpatient testing and hospitalization may improve COVID-19 outcomes among transplant recipients.
Discoidin Domain Receptor 1 (DDR1) tyrosine kinase is upregulated in PKD kidneys but does not play a role in the pathogenesis of polycystic kidney disease
Tolvaptan is the only drug approved to slow cyst growth and preserve kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD). However, its limited efficacy combined with significant side effects underscores the need to identify new and safe therapeutic drug targets to slow progression to end stage kidney disease. We identified Discoidin Domain Receptor 1 (DDR1) as receptor tyrosine kinase upregulated in vivo in 3 mouse models of ADPKD using a novel mass spectrometry approach to identify kinases upregulated in ADPKD. Previous studies demonstrating critical roles for DDR1 to cancer progression, its potential role in the pathogenesis of a variety of other kidney disease, along with the possibility that DDR1 could provide new insight into how extracellular matrix impacts cyst growth led us to study the role of DDR1 in ADPKD pathogenesis. However, genetic deletion of DDR1 using CRISPR/Cas9 failed to slow cyst growth or preserve kidney function in both a rapid and slow mouse model of ADPKD demonstrating that DDR1 does not play a role in PKD pathogenesis and is thus a not viable drug target. In spite of the negative results, our studies will be of interest to the nephrology community as it will prevent others from potentially conducting similar experiments on DDR1 and reinforces the potential of performing unbiased screens coupled with in vivo gene editing using CRISPR/Cas9 to rapidly identify and confirm new potential drug targets for ADPKD.
Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease
Background/UNASSIGNED:Metabolism of glutamine by glutaminase 1 (GLS1) plays a key role in tumor cell proliferation via the generation of ATP and intermediates required for macromolecular synthesis. We hypothesized that glutamine metabolism also plays a role in proliferation of autosomal-dominant polycystic kidney disease (ADPKD) cells and that inhibiting GLS1 could slow cyst growth in animal models of ADPKD. Methods/UNASSIGNED:Primary normal human kidney and ADPKD human cyst-lining epithelial cells were cultured in the presence or absence of two pharmacologic inhibitors of GLS1, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) and CB-839, and the effect on proliferation, cyst growth in collagen and activation of downstream signaling pathways were assessed. We then determined if inhibiting GLS1 in vivo with CB-839 in the Aqp2-Cre; Pkd1fl/fl and Pkhd1-Cre; Pkd1fl/fl mouse models of ADPKD slowed cyst growth. Results/UNASSIGNED:We found that an isoform of GLS1 (GLS1-GAC) is upregulated in cyst-lining epithelia in human ADPKD kidneys and in mouse models of ADPKD. Both BPTES and CB-839 blocked forskolin-induced cyst formation in vitro. Inhibiting GLS1 in vivo with CB-839 led to variable outcomes in two mouse models of ADPKD. CB-839 slowed cyst growth in Aqp2-Cre; Pkd1fl/fl mice, but not in Pkhd1-Cre; Pkd1fl/fl mice. While CB-839 inhibited mammalian target of rapamycin (mTOR) and MEK activation in Aqp2-Cre; Pkd1fl/fl, it did not in Pkhd1-Cre; Pkd1fl/fl mice. Conclusion/UNASSIGNED:These findings provide support that alteration in glutamine metabolism may play a role in cyst growth. However, testing in other models of PKD and identification of the compensatory metabolic changes that bypass GLS1 inhibition will be critical to validate GLS1 as a drug target either alone or when combined with inhibitors of other metabolic pathways.
Regulation of KATPChannel Trafficking in Pancreatic Î² Cells by Protein Histidine Phosphorylation
Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14 kDa protein that dephosphorylates phosphohistidine.PHPT-1
Novel screen to identify kinase drug targets for autosomal dominant polycystic kidney disease [Meeting Abstract]
Background: Activation of kinases and the downstream signaling pathways they activate is central to the pathogenesis of cyst growth in ADPKD. However, while the human kinome consists of more than 500 kinases, only a fraction of these kinases have been tested to determine if they play a role in ADPKD pathogenesis. As a result, there are likely many kinases that are more active in ADPKD kidneys that play prominent roles in disease that are yet-to-be discovered and may be good therapeutic targets. We have now adapted a novel approach to broadly screen PKD kidneys in an unbiased manner for kinases that are more active in PKD kidneys compared with wild type kidneys.
Method(s): Active kinases were affinity captured by passing wild type and PKD kidney lysates through columns containing multiplexed kinase inhibitor beads. Bound kinases were then identified by LC separation followed by tandem mass spectrometry. Increase in kinase expression and/or activity was validated by Western Blot and the specific kidney cells expressing the kinase was determined by Immunohistochemistry. The relevance of a kinase to cyst growth in vivo was assessed by treating PKD mutant mice with specific kinase inhibitors and/or genetically by generating kinase knockouts using CRISPR/Cas9.
Result(s): We identified a number of both known and unknown kinases specifically upregulated or downregulated in mouse PKD kidneys. Focal adhesion Kinase (FAK) is one of the promising kinase identified in the screen. We found that FAK and phospho-FAK expression was upregulated in cyst lining epithelium in PKD kidneys. Consistent with FAK playing an important role in cyst growth, treatment of Pkhd1-Cre;Pkd1fl/fl mice with the FAK inhibitor VS-4718 slowed cyst growth, preserved renal function, and prolonged survival. VS-4718 treatment led to the inhibition of multiple signaling pathways that could account for the therapeutic benefit including paxillin, p130cas, AKT and Stat3.
Conclusion(s): This is the first time PKD kidneys have been probed proteomically in an unbiased manner to identify the full range of kinases that are more active in PKD kidneys with the goal of identifying new therapeutic targets. So far we have identified FAK as a potential drug target that can slow cyst growth and preserve renal function and are currently in the process of working up several other promising kinases