Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans.

Altered cellular metabolism in kidney proximal tubule (PT) cells plays a critical role in acute kidney injury (AKI). The transcription factor Krüppel-like factor 6 (KLF6) is rapidly and robustly induced early in the PT after AKI. We found that PT-specific Klf6 knockdown (Klf6PTKD) is protective against AKI and kidney fibrosis in mice. Combined RNA and chromatin immunoprecipitation sequencing analysis demonstrated that expression of genes encoding branched-chain amino acid (BCAA) catabolic enzymes was preserved in Klf6PTKD mice, with KLF6 occupying the promoter region of these genes. Conversely, inducible KLF6 overexpression suppressed expression of BCAA genes and exacerbated kidney injury and fibrosis in mice. In vitro, injured cells overexpressing KLF6 had similar decreases in BCAA catabolic gene expression and were less able to utilize BCAA. Furthermore, knockdown of BCKDHB, which encodes one subunit of the rate-limiting enzyme in BCAA catabolism, resulted in reduced ATP production, while treatment with BCAA catabolism enhancer BT2 increased metabolism. Analysis of kidney function, KLF6, and BCAA gene expression in human chronic kidney disease patients showed significant inverse correlations between KLF6 and both kidney function and BCAA expression. Thus, targeting KLF6-mediated suppression of BCAA catabolism may serve as a key therapeutic target in AKI and kidney fibrosis.

Contemporary Treatment of Microtia-Atresia.

Microtia-atresia is a congenital deformity affecting the external ear and ear canal that can present with varying degrees of severity and morbidity. Treatment occurs along a spectrum and primarily centers on improving aesthetic appearance. Many cases of microtia will not be effectively treated with conservative measures and will require some form of reconstruction. There are several options available, including porous polyethylene implants, autologous rib grafting, and autologous chondrocyte frameworks. Equally significant is the treatment of hearing loss, as many patients with microtia-atresia will have a component of conductive hearing loss. This article aims to comprehensively review contemporary treatment modalities for microtia-atresia and discuss the advantages, disadvantages, and practicality of each. Treatment and reconstruction often take a multidisciplinary and multistaged approach to achieve optimal results, with ideal management determined by each patient's individualized needs.

Diabetic nephropathy in a nonobese mouse model of type 2 diabetes mellitus.

A large body of research has contributed to our understanding of the pathophysiology of diabetic nephropathy. Yet, many questions remain regarding the progression of a disease that accounts for nearly half the patients entering dialysis yearly. Several murine models of diabetic nephropathy secondary to Type 2 diabetes mellitus (T2DM) do exist, and some are more representative than others, but all have limitations. In this study, we aimed to identify a new mouse model of diabetic nephropathy secondary to T2DM in a previously described T2DM model, the MKR (MCK-KR-hIGF-IR) mouse. In this mouse model, T2DM develops as a result of functional inactivation of insulin-like growth factor-1 receptor (IGF-1R) in the skeletal muscle. These mice are lean, with marked insulin resistance, hyperinsulinemia, hyperglycemia, and dyslipidemia and thus are representative of nonobese human T2DM. We show that the MKR mice, when under stress (high-fat diet or unilateral nephrectomy), develop progressive diabetic nephropathy with marked albuminuria and meet the histopathological criteria as defined by the Animal Models of Diabetic Complications Consortium. Finally, these MKR mice are fertile and are on a common background strain, making it a novel model to study the progression of diabetic nephropathy.

Impact of Adenotonsillectomy on Homework Performance in Children With Obstructive Sleep-Disordered Breathing.

OBJECTIVE: As a first line treatment for pediatric obstructive sleep-disordered breathing (SDB), adenotonsillectomy (AT) has been shown to confer physiologic and neurocognitive benefits to a child. However, there is a scarcity of data on how homework performance is affected postoperatively. Our objective was to evaluate the impact of AT on homework performance in children with SDB. METHODS: Children in grades 1 to 8 undergoing AT for SDB based on clinical criteria with or without preoperative polysomnography along with a control group of children undergoing surgery unrelated to the treatment of SDB were recruited. The primary outcome of interest was the differential change in homework performance between the study group and control at follow-up as measured by the validated Homework Performance Questionnaire (HPQ-P). Adjustments were made for demographics and Pediatric Sleep Questionnaire (PSQ) scores. RESULTS: 116 AT and 47 control subjects were recruited, and follow-up data was obtained in 99 AT and 35 control subjects. There were no significant differences between the general (total) HPQ-P scores and subscale scores between the AT and control subjects at entry and there were no significant differences in the change scores (follow-up minus initial scores) between the groups. Regression modeling also demonstrated that there were no group (AT vs control) by time interactions that predicted differential improvements in the HPQ-P (P > .10 for each model) although initial PSQ score was a significant predictor of lower HPQ-P scores for all models. CONCLUSIONS: Children with SDB experienced improvement in HPQ-P scores postoperatively, but the degree of change was not significant when compared to controls. Further studies incorporating additional educational metrics are encouraged to assess the true scholastic impact of AT in children with SDB.

Accuracy and outcomes of virtual surgical planning and 3D-printed guides for osseous free flap reconstruction of mandibular osteoradionecrosis.

OBJECTIVES: Virtual surgical planning, 3D-printed osteotomy guides and preoperatively-bent or custom-milled mandibular reconstruction plate (VSP/3Dprinted-guide/plate) have been shown to ease intraoperative decision making and reduce operative time. Few studies have examined outcomes of VSP/3Dprinted-guide/plate specifically for mandibular osteoradionecrosis (mORN) cases, which pose unique challenges. We aimed to examine reconstruction accuracy, functional outcomes, and postoperative complications following osseous-free-flap reconstruction with VSP/3Dprinted-guide/plate for mORN. MATERIALS AND METHODS: Single academic medical center retrospective case series of ORN-related osseous-free-flap mandibular reconstructions with VSP/3Dprinted-guide/plate between January 2015 and March 2021. Most cases were performed by the same two-surgeon team. Outcomes include reconstruction accuracy (assessed by 3D-overlay computer models with cephalometric and donor-bone segment length measurements), complications and function. RESULTS: Twenty-six cases were identified with a mean follow-up of 85 weeks. Most patients were male (69 %); mean age was 64 years. 3D-model-overlay demonstrated minimal deviation between planned and actual reconstruction among 18 evaluable cases: intercondylar distance = 1.46 mm (SD 2.4); intergonial distance = 1.82 mm (SD 2.0); anterior-posterior distance = 2.14 mm (SD 1.9); gonial angle = 3.33 degrees (SD 2.4). Mean change donor-bone segment length inferiorly 4.39 mm (SD 4.3) and superiorly 3.43 mm (SD 4.0). COMPLICATIONS: returned to operating room (N = 2), minor primary/neck site infection/dehiscence (N = 11). Function improved postoperatively: 20/21 (95 %) cases with preoperative pain, resolved; 13/20 (65 %) with preoperative trismus, improved; 21/24 (87 %) with preoperative malocclusion/jaw malignment, improved. CONCLUSIONS: This is the largest series of VSP/3Dprinted-guide/plate surgery for mORN to date. Mandibular reconstruction for ORN is aided by VSP/3Dprinted-guide/plate with accurate results, acceptable complications, and improved function.

Virtual planning and 3D-printed guides for mandibular reconstruction: Factors impacting accuracy.

Objectives: Examine accuracy and factors impacting accuracy for mandibular reconstruction with virtual surgical planning, 3D printed osteotomy guides and preoperatively bent mandibular reconstruction plate (VSP/3Dprinted-guide/plate). Method: Retrospective review of osseous-free-flap mandibular reconstructions with VSP/3Dprinted-guide/plate between January 2015 and July 2020 at a single academic medical center.Patient demographics, disease, and treatment variables were extracted. Accuracy was assessed by 3D-model-overlay with cephalometric and donor-bone segment length measurements. Multivariate analyses were performed to determine factors impacting cephalometric accuracy. Results: 60 cases met criteria: 41 (68%) cancer, 14 (23%) osteoradionecrosis (ORN), 5 (8%) secondary mandibular reconstruction. Thirteen cases (22%) were Brown class III or IV. Thirty-nine cases (65%) had ≥2 flap bone segments. Average donor-bone length was 82 mm (SD: 28). 3D-model-overlay accuracy demonstrated minimal deviation between planned and actual reconstruction: intercondylar distance = 2.10 mm (SD: 2.2); intergonial distance = 2.23 mm (SD: 1.9); anterior-posterior distance (APD) = 1.76 mm (SD: 1.5); gonial angle (GA) = 3.11 degrees (SD: 2.4). Mean change in donor-bone segment length inferiorly was 2.67 mm (SD: 2.6) and superiorly 3.27 mm (SD: 3.2). Higher number of donor-bone segments was associated with decreased accuracy in GA (p = .023) and longer donor-bone length was associated with decreased accuracy in APD (p = .031). Conclusion: To our knowledge this is the largest series assessing surgical accuracy of VSP/3Dprinted-guide/plate for osseous-free-flap mandibular reconstruction. We demonstrate highly accurate results, with increased number of donor-bone segments and donor-bone length associated with decreased accuracy. Our findings further support VSP/3Dprinted-guide/plate as a reliable and accurate tool for mandibular reconstruction. Level of Evidence: Level 4.

Surgical Management of Sialorrhea: A Systematic Review and Meta-analysis.

OBJECTIVE: Chronic sialorrhea commonly occurs in patients with neurodevelopmental disorders. While conservative management can provide sufficient symptom control, surgical intervention is often required. One of the most common procedures utilized is submandibular gland excision (SMGE), with or without parotid duct ligation or rerouting (PDL or PDR). This study aims to compare these surgical approaches and their outcomes. DATA SOURCES: PubMed, Web of Science, and Embase. REVIEW METHODS: This systematic review includes studies of patients with chronic sialorrhea treated with SMGE alone or SMGE plus PDR or PDL and reports on postintervention outcomes and complications. Two independent investigators assessed study eligibility, rated quality, and extracted data for analysis. A random effects model was used for meta-analysis of pooled data. RESULTS: Of 3186 studies identified, 21 met inclusion criteria, with 708 patients: 103 underwent SMGE alone (15%); 299 (42%), SMGE and PDL; and 306 (43%), SMGE plus PDR. Overall, a majority of patients had significant improvement, with very good to excellent control of symptoms after surgery: SMGE, 82% (95% CI, 73%-89%); SMGE and PDL, 79% (95% CI, 73%-85%); and SMGE and PDR, 85% (95% CI, 75%-92%). Importantly, there was no significant difference in outcomes with the addition of PDL or PDR. Reported complications included sialocele, parotitis, dental caries, and dry mouth. CONCLUSION: Our systematic review identified consistent positive outcomes with SMGE for patients with chronic sialorrhea but no additional benefit when PDR or PDL was performed as a concurrent procedure.

Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease.

Mitochondrial injury is uniformly observed in several murine models as well as in individuals with diabetic kidney disease (DKD). Although emerging evidence has highlighted the role of key transcriptional regulators in mitochondrial biogenesis, little is known about the regulation of mitochondrial cytochrome c oxidase assembly in the podocyte under diabetic conditions. We recently reported a critical role of the zinc finger Krüppel-like factor 6 (KLF6) in maintaining mitochondrial function and preventing apoptosis in a proteinuric murine model. In this study, we report that podocyte-specific knockdown of Klf6 increased the susceptibility to streptozotocin-induced DKD in the resistant C57BL/6 mouse strain. We observed that the loss of KLF6 in podocytes reduced the expression of synthesis of cytochrome c oxidase 2 with resultant increased mitochondrial injury, leading to activation of the intrinsic apoptotic pathway under diabetic conditions. Conversely, mitochondrial injury and apoptosis were significantly attenuated with overexpression of KLF6 in cultured human podocytes under hyperglycemic conditions. Finally, we observed a significant reduction in glomerular and podocyte-specific expression of KLF6 in human kidney biopsies with progression of DKD. Collectively, these data suggest that podocyte-specific KLF6 is critical to preventing mitochondrial injury and apoptosis under diabetic conditions.

Krüppel-like factor 6 regulates mitochondrial function in the kidney.

Maintenance of mitochondrial structure and function is critical for preventing podocyte apoptosis and eventual glomerulosclerosis in the kidney; however, the transcription factors that regulate mitochondrial function in podocyte injury remain to be identified. Here, we identified Krüppel-like factor 6 (KLF6), a zinc finger domain transcription factor, as an essential regulator of mitochondrial function in podocyte apoptosis. We observed that podocyte-specific deletion of Klf6 increased the susceptibility of a resistant mouse strain to adriamycin-induced (ADR-induced) focal segmental glomerulosclerosis (FSGS). KLF6 expression was induced early in response to ADR in mice and cultured human podocytes, and prevented mitochondrial dysfunction and activation of intrinsic apoptotic pathways in these podocytes. Promoter analysis and chromatin immunoprecipitation studies revealed that putative KLF6 transcriptional binding sites are present in the promoter of the mitochondrial cytochrome c oxidase assembly gene (SCO2), which is critical for preventing cytochrome c release and activation of the intrinsic apoptotic pathway. Additionally, KLF6 expression was reduced in podocytes from HIV-1 transgenic mice as well as in renal biopsies from patients with HIV-associated nephropathy (HIVAN) and FSGS. Together, these findings indicate that KLF6-dependent regulation of the cytochrome c oxidase assembly gene is critical for maintaining mitochondrial function and preventing podocyte apoptosis.