Evaluation of filtration biomarkers in obese patients, with and without Chronic Kidney Disease (CKD), undergoing bariatric surgery, and tubular biomarkers in the diagnosis and progression of Obesity related CKD, and in Membranous and Lupus Nephropathy

• Grant number: 23/08810-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: January 01, 2025
• End date: December 31, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Luis Yu
• Grantee: Luis Yu
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Dirce Maria Trevisan Zanetta ; Leila Antonangelo ; Marco Aurélio Santo
• Associated researchers: Caroline Silvério Faria ; Denise Maria Avancini Costa Malheiros ; Emmanuel de Almeida Burdmann ; Marcelo Tatit Sapienza ; Roberto de Cleva

Abstract

This project includes three sub-projects aimed at evaluating diagnostic and progression biomarkers on three prevalent glomerulopathies: obesity related glomerulopathy (ORG), membranous nephropathy and lupus membranous nephritis. The incidence of overweight and obesity is increasing worldwide, and its occurrence raises the risk of developing other chronic diseases such as diabetes, hypertension, cardiovascular diseases, and dyslipidemia and CKD. The effects of obesity on the kidneys include albuminuria, reduced glomerular filtration rate (GFR), obesity-related glomerulopathy (ORG), and progression to CKD. Glomerular filtration is estimated through calculations based on creatinine levels, but its accuracy is limited, particularly in conditions where the concentration is altered. In extreme situations of increased muscle mass or body size, such as obesity, creatinine synthesis can be affected, potentially impacting GFR estimation. The best markers of GFR and their respective formulas for accurate evaluation in obese patients, with or without CKD, and the variation of these formulas over time are not yet well established. Previous studies have demonstrated the benefits of bariatric surgery combined with anti-proteinuric treatment in obese diabetic patients with CKD. Reduction of albuminuria and improvement in GFR were some of the favorable renal outcomes, findings that will be tested in the population of obese individuals with CKD undergoing metabolic surgery and optimization of anti-proteinuric measures with the addition of SGLT2 inhibitors (iSGLT2). It is expected that the introduction of iSGLT2 agents in conjunction with conventional treatment will lead to better renal outcomes in obese patients with CKD undergoing metabolic surgery. The role of renal tubular biomarkers remains unknown in obese individuals with CKD. Therefore, it is aimed at evaluating tubular biomarkers such as NGAL, KIM-1, and CCL-14 in the CKD progression in obese patients with CKD undergoing bariatric surgery.Additionally, new tissue renal biomarkers will also be evaluated for the diagnosis of MN and LN, correlating with the progression of CKD in lupus patients. MN is the leading cause of nephrotic syndrome in adults. This glomerulopathy has a significant impact as it leads to terminal CKD in 30% of cases. It can be primary or secondary, including autoimmunity, nephrotoxicity, neoplasms, and infections. In recent years, antibodies against podocyte antigens have been discovered in MN: phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), neuroepidermal growth factor-like 1 (NELL1), and exostosin 1 (EXT1) and exostosin 2 (EXT2). PLA2R is strongly associated with primary MN, while THSD7A seems to be related to neoplasms. There is evidence that NELL1 is associated with secondary MN and EXT1/EXT2 with autoimmune diseases. Investigating these antibodies in renal biopsies and the clinicopathological characterization of these MN subgroups will allow for a more precise diagnosis, enhancing the possibility of therapeutic intervention. LN is a serious complication associated with increased morbidity and mortality, affecting about 40% of lupus patients. Recently, in patients with MN negative for PLA2R and THSD7A, two new proteins, EXT1 and EXT2, were identified. Patients expressing EXT1/EXT2 had clinical findings suggestive of autoimmune diseases, including systemic lupus erythematosus. Subsequently, studies demonstrated tissue positivity of 32.6% to 46% for EXT1/EXT2 in patients with membranous LN. These patients had lower indices of chronicity, lower creatinine levels, higher proteinuria at diagnosis, and slower progression of CKD. However, these new renal biomarkers have not been evaluated in other populations, such as the Brazilian population. (AU)