Broad organ acceptance and equitable access to early kidney transplantation.

BACKGROUND: Broad organ acceptance can increase early kidney transplantation (KTX) within <1-year of dialysis initiation while improving access inequity. METHODS: Single-center data of adult isolated deceased-donor KTX recipients between 2013 and 2020 were stratified into three 2.5-year periods before-, early after-, and late after our center's deceased-donor organ acceptance practice change, excluding a 6-month implementation period. Outcomes were assessed within five recipient subgroups based on demographic and clinical characteristics. RESULTS: Of 704 recipients, the frequency of early KTX was 22% pre-change, 36% early post-change, and 34% late post-change. Given similar post-change frequencies of early KTX, post-change eras were combined to improve analytic power of subgroup analyses. After the organ acceptance practice change (vs. pre-change), the likelihood of early KTX increased variably within historically underserved groups, including recipients who were older (37%-39%, p = .859), Black (10%-21%, p = .136), female (21%-37%, p = .034), diabetic (13%-32%, p = .010), and BMI≥35 kg/m2 (20%-34%, p = .007). Despite the practice change, Black recipients continued to experience less early KTX compared to non-Black recipients. The likelihood of delayed graft function was significantly increased (p < .001), and 1-year creatinine was significantly higher (p < .001) post-practice change, but between-era risk-adjusted death-censored graft survival was similar. CONCLUSIONS: Transition to broader donor acceptance was associated with more early KTXs among historically underserved patient subgroups. However, the effect was non-significant among Black recipients, suggesting the need for additional strategies to impact early transplant access for this population. Studies of broad organ acceptance are needed to examine both access and outcomes.

Outcomes of DCD kidneys with CIT-induced delayed graft function.

Donation after circulatory death (DCD) kidneys are exposed to warm ischemia, which, coupled with cold ischemia time (CIT) exacerbates delayed graft function (DGF) and is possibly associated with worse graft survival. To analyze the risk of CIT-induced DGF on DCD kidney outcomes, we evaluated national data between 2008 and 2018 of adult kidney-only recipients of paired DCD kidneys where one kidney recipient experienced DGF and the other did not. Of 5602 paired DCD kidney recipients, multivariate analysis between recipients with higher CIT relative to lower CIT showed that increasing CIT differences had a significant dose-dependent effect on overall graft survival. The graft survival risk was minimal with CIT differences of ≥1-h (adjusted hazard ratio [aHR] 1.07, 95% CI .95- 1.20, n = 5602) and ≥5-h (aHR 1.09, 95% CI .93-1.29, n = 2710) and became significant at CIT differences of ≥10-h (aHR 1.37, 95% CI 1.05-1.78, n = 1086) and ≥15-h (aHR 1.78, 95% CI 1.15-2.77, n = 1086). Between each of the four delta-CIT levels of shorter and longer CIT, there were no statistically significant differences in the proportion of acute rejection. These results suggest that in the setting of DCD kidney transplantation (KTX), DGF, specifically mediated by prolonged CIT, impacts long-term graft outcomes.

Donor rhabdomyolysis, acute kidney injury, and kidney transplant outcomes.

BACKGROUND: Donor rhabdomyolysis may constrain kidney utilization due to anticipated unfavorable graft outcomes-especially in combination with acute kidney injury (AKI). There is a paucity of empiric data to inform organ acceptance decision-making. METHODS: A single-center retrospective cohort study of adult transplant recipients of deceased-donor kidneys with reported donor creatine phosphokinase (CPK) levels was conducted between 2014 and 2020. Recipients of CPK ≥ 1000 U/L kidneys were propensity matched to CPK < 1000 recipients according to outcome-predictive baseline covariates, except AKI. RESULTS: A total of 254 kidney transplants were propensity matched into CPK ≥ 1000 (n = 90) versus CPK < 1000 (n = 90) groups. Transplant outcomes with high versus low CPK kidneys were similar in terms of delayed graft function (P = 0.64), 1-year estimated glomerular filtration rate < 25th percentile (P = 0.69) and mean (P = 0.58), and time to all-cause graft failure (P = 0.58). There was no interaction between AKI and high CPK for these outcomes. Extreme CPK thresholds as high as > 8672 U/L were not associated with overall graft survival in the unmatched sample (P = 0.81). CONCLUSIONS: In a single center study, donor rhabdomyolysis was not associated with short-term kidney transplant graft outcomes, nor was there an additive effect of AKI. However, studies with greater CPK and AKI severity and longer follow-up are warranted.

Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma.

Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.

Can Aortic Balloon Occlusion Reduce Blood Loss During Resection of Sacral Tumors That Extend Into the Lower Lumber Spine?

BACKGROUND: Although aortic balloon occlusion has been shown to reduce blood loss during sacral tumor resections, it has not been validated in larger sacral tumors involving the lower lumbar spine. If such an approach were shown to be associated with less blood loss, it might aid the tumor surgeon in resecting these difficult tumors. QUESTIONS/PURPOSES: (1) Is the use of aortic balloon occlusion associated with reduced blood loss in sacral tumor resections when the lower lumbar spine is also involved? (2) Does the use of the aortic balloon prolong total operating time? (3) What complications are associated with the use of a balloon? METHODS: We retrospectively studied all 56 patients diagnosed with sacral tumors involving the lower lumbar spine (L4, L5) who were treated surgically between 2004 and 2015 at our institute. During that time, 30 of the patients received aortic balloon occlusion therapy, whereas 26 of the patients did not. We generally used aortic balloon occlusion during procedures for hypervascular lesions (for example, giant cell tumors or metastatic renal cancers), primary malignant lesions, and recurrent lesions. We generally avoided use of aortic balloon occlusion in patients with anatomic defects of the aorta (aortic dissection or aneurysm was strictly contraindicated), renal artery bifurcation caudal to the L2 to L3 disc, age older than 70 years or younger than 12 years, history of Stage 2 hypertension [], history of balloon use in previous surgeries, and presence of unstable plaque on abdominal CT. The demographic data, intraoperative blood loss, transfusion volume, operating time, and postoperative wound drainage between the two groups were collected and analyzed. Balloon-related complications were identified. Followup in terms of balloon-related complications was conducted in all 56 patients for at least 6 months after surgery. RESULTS: Intraoperative blood loss was determined to be less in patients treated with the balloon compared with those treated without the balloon (median volume, 2000 mL, range, 400-6000 mL versus 2650 mL, range, 550-6800 mL, respectively; median difference, 605 mL; 95% confidence interval [CI], 100-1500 mL; p = 0.035). Total operative time was not prolonged in the balloon group (including balloon insertion time) compared with those treated without it (median time, 215 minutes, range, 110-430 minutes versus 225 minutes, range, 115-340 minutes, respectively; median difference, 10 minutes; 95% CI, -40 to 30 minutes; p = 0.902). Balloon-related vascular complications included local hematoma at the puncture site in five patients, femoral artery spasm in three patients, lower limb ischemia in one patient, and femoral artery pseudoaneurysm in one patient. Acute kidney injury was found in two patients in the balloon group. CONCLUSIONS: This study demonstrated that placement of the aortic balloon at a level just caudal to the renal artery bifurcation was associated with lower intraoperative blood loss and transfusion in lumbosacral tumor resections. However, procedure-specific complications were common and there was no benefit to total operative time. We suggest that the surgical procedures still need to be further refined to minimize complications. We also recommend that prospective studies be undertaken to confirm the efficacy of aortic balloon occlusion in surgery for lumbosacral tumors. LEVEL OF EVIDENCE: Level III, therapeutic study.

U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo.

U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2) and metabotropic glutamate receptor 1 (GRM1), in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv) administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6) indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups) validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases.Molecular Therapy - Nucleic Acids (2013) 2, e92; doi:10.1038/mtna.2013.24; published online 14 May 2013.