Predictors of successful discontinuation of continuous kidney replacement therapy in a pediatric cohort.

BACKGROUND: Recognizing the optimal time to discontinue continuous kidney replacement therapy (CKRT) is necessary to advance patient recovery and mitigate complications. The aim of this study was to identify predictors of successful CKRT cessation in pediatric patients. METHODS: All patients requiring CKRT between January 2010 and March 2021 were evaluated. Patients on peritoneal or hemodialysis, who transferred between institutions, or who did not trial off CKRT were excluded. Successful discontinuation was defined as remaining off CKRT for at least 7 days. Demographics, admission diagnoses, PRISM III scores, and reasons for CKRT initiation were obtained. Clinical and biochemical variables were evaluated at CKRT initiation and discontinuation and in the 12-h period following discontinuation. Comparisons were conducted using Wilcoxon rank sum and Fisher's exact tests for continuous and categorical variables, respectively. A logistic regression model was fitted to identify significant factors. RESULTS: Ninety-nine patients underwent a trial off CKRT. Admission and initiation characteristics of the success and failure groups were similar. Patients who required re-initiation (n = 26) had longer ICU lengths of stay (27.2 vs. 44.5 days, p = 0.046) and higher in-hospital mortality (15.1% vs. 46.2%, p = 0.002). Urine output greater than 0.5 mL/kg/h irrespective of diuretic administration in the 6-h period before CKRT discontinuation was a significant predictor (AUC 0.72, 95% CI 0.60-0.84, p = 0.0009). CONCLUSIONS: Determining the predictors of sustained CKRT discontinuation is critical. Urine output greater than 0.5 mL/kg/h in this pediatric cohort predicted successful discontinuation. Future studies are needed to validate this threshold in disease- and age-specific cohorts and evaluate additional biomarkers of kidney injury. A higher resolution version of the Graphical abstract is available as Supplementary information.

Persistent Severe Hyperlactatemia and Metabolic Derangement in Lethal SDHB-Mutated Metastatic Kidney Cancer: Clinical Challenges and Examples of Extreme Warburg Effect.

To describe the unique clinical features, determine the genomics, and investigate the metabolic derangement of an extremely rare form of a hereditary lethal kidney cancer syndrome. Patients and Methods: Three patients with lethal kidney cancer (age 19, 20, and 37 years) exhibiting persistent (1 to 3 months) extremely high levels of blood lactate (> 5 mM) despite normal oxygen perfusion, highly avid tumors on [18F]fluorodeoxyglucose positron emission tomography (PET), and pleomorphic histopathologic features were identified and treated in a single institute. Integrated studies including whole-genome sequencing (WGS), targeted sequencing, immunohistochemistry, cell-based assays, and 18F-glutamine PET imaging were performed to investigate this rare kidney cancer syndrome. Results: All three patients with kidney cancer were initially given various diagnoses as a result of diverse tumor histopathology and atypical clinical presentations. The correct diagnoses of these SDHB-mutated renal cell carcinomas were first made based on cancer genomics. Genomic studies of the blood and tumors of these patients identified three different kinds of germline loss-of-function mutations in the SDHB gene and the common loss of heterozygosity in the remaining SDHB allele thorough somatic chromosome 1p deletion. In one patient, WGS revealed that a germline mutation of SDHB coupled with loss of heterozygosity was the sole genetic event. Cancer evolution analysis of SDHB tumors based on WGS demonstrated that SDHB in kidney epithelium fulfills the Knudson two-hit criteria as a major tumor suppressor gene. SDHB -/- tumor cells displayed increase in glucose uptake and lactate production, alteration in mitochondrial architecture, and defect in oxidative respiration. 18F-Glutamine PET imaging studies demonstrated increased glutamine metabolism. Conclusion: SDHB-deficient metastatic renal cell carcinoma is a rare, aggressive form of kidney cancer that manifests with clinical evidence of a severe Warburg effect, and genomic studies demonstrated two genetic hits at SDHB genes during kidney tumorigenesis.

A river model to map convergent cancer evolution and guide therapy in RCC.

Intratumoural heterogeneity in clear cell renal cell carcinoma (ccRCC) complicates identification and validation of biomarkers and thwarts attempts to improve precision medicine. Efforts to depict intratumoural heterogeneity and to pinpoint strategies for disease control resulted in the creation of the trunk-branch model of mutational cancer evolution, which emphasizes targeting trunk mutations. However, most patients with ccRCC receiving current therapeutics that target these mutations, such as inhibitors of vascular endothelial growth factors, eventually develop resistance. A novel paradigm might improve depiction of cancer evolution and advise therapeutic selection: the river model is based on findings from multiregion sequencing in samples from exceptional responders to mTOR inhibitors. The accumulating data on genotypic and phenotypic convergence in renal cell carcinoma and other malignancies can be used to examine how a mutable river model might best describe clinically significant phenotype-convergent events that could guide effective cancer control. This model originates from studying exceptional responders and its generalizability awaits validation.

Genomic characterisation of two cancers of unknown primary cases supports a kidney cancer origin.

Cancer of unknown primary (CUP) comprises of 3-5% of new cancer diagnoses in the USA. Diagnostic work up typically includes CT of the chest, abdomen and pelvis, and histopathological review of tissue specimens. These measures are neither sensitive nor specific in determining tissue of origin (ToO) of primary tumours and, therefore, are unable to guide therapy. We present two cases of CUP for which we utilised ultra-deep genomic sequencing to identify the candidate ToO and to propose treatment. Patient 1 presented with metastases involving the lung, lymph nodes and bone. Patient 2 presented with an acute pathological fracture of the T7 vertebral body and metastases involving the bone, lymph nodes and soft tissue. No primary renal mass was found. Sequencing revealed SETD2 and NF2 mutations, and heterozygous loss of the short arm of chromosome 3 (3p). Mutations in conjunction with clinicopathological features strongly support a diagnosis of renal cell carcinoma. Both patients initially responded to mTORC1 inhibition therapy.