ABSTRACT
Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Renal Insufficiency , Humans , Animals , Mice , Diabetic Nephropathies/etiology , Lactic Acid , Albuminuria/etiology , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Diabetes Mellitus, Type 2/complications , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Kidney , Protein IsoformsSubject(s)
Cysts/pathology , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/surgery , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Biopsy, Needle , Cysts/diagnostic imaging , Diagnosis, Differential , Follow-Up Studies , Gastrointestinal Neoplasms , Hepatectomy/methods , Hepatomegaly/etiology , Hepatomegaly/pathology , Humans , Immunohistochemistry , Liver Neoplasms/diagnostic imaging , Male , Middle Aged , Monitoring, Physiologic/methods , Neoplasm Metastasis/diagnostic imaging , Neoplasm Metastasis/pathology , Positron Emission Tomography Computed Tomography/methods , Time Factors , Treatment OutcomeABSTRACT
AIMS: To validate the Singapore nomogram for outcome prediction in breast phyllodes tumours in a large cohort of Singaporean patients, as previous validation studies were conducted on small numbers of patients. We also investigate the association of fibroadenomas and phyllodes tumours within a subset of our cohort. METHODS: Histological parameters, surgical margin status and clinical follow-up data of 259 women diagnosed with phyllodes tumours were analysed. Patients with concurrent malignant or premalignant disease were excluded from the validation to minimise confounding influences. Biostatistics modelling was performed, and the concordance between predicted and observed survivals was calculated. The association between fibroadenomas and phyllodes tumours was quantified in a subset of the women. RESULTS: Phyllodes tumours with higher number of mitoses, stromal overgrowth and positive surgical margins were found to be associated with greater risk of clinical recurrence. Patients with a higher nomogram score had a significantly higher risk of developing relapse. Forty out of 78 (51.3%) of the subset of phyllodes cases reviewed showed either fibroadenoma-like areas within the phyllodes tumours or concurrent fibroadenomas in the ipsilateral or contralateral breast. CONCLUSIONS: The Singapore nomogram is useful in predicting outcome in breast phyllodes tumours when applied to a large cohort of Singaporean women.
Subject(s)
Breast Neoplasms/diagnosis , Decision Support Techniques , Nomograms , Phyllodes Tumor/diagnosis , Adolescent , Adult , Aged , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Female , Fibroadenoma/diagnosis , Fibroadenoma/mortality , Fibroadenoma/pathology , Fibroadenoma/surgery , Follow-Up Studies , Humans , Margins of Excision , Middle Aged , Models, Statistical , Phyllodes Tumor/mortality , Phyllodes Tumor/pathology , Phyllodes Tumor/surgery , Prognosis , Singapore , Survival Analysis , Young AdultABSTRACT
AIM: To validate the utility of the Singapore nomogram for outcome prediction in breast phyllodes tumours. METHODS: Histological parameters, surgical margin status and clinical follow-up data of 34 women diagnosed with phyllodes tumours were analysed. Biostatistics modelling was performed, and the concordance between predicted and observed survivals was calculated. RESULTS: Women with a high nomogram score had an increased risk of developing relapse, which was predicted using the parameters defined by the Singapore nomogram. CONCLUSIONS: The Singapore nomogram is useful in predicting outcome in breast phyllodes tumours when applied to an Australian cohort of 34 women.
