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Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/β-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-β1, and Wnt/β-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats.

The groups involved in the study received research support from Fondo Europeo de Desarrollo Regional (FEDER), Plan de Ciencia, Tecnología e Innovación 2013–2017 y 2018–2022 del Principado de Asturias (GRUPIN 14‑028, IDI‑2018‑000‑152, IDI/2021/000080). Red Cooperativa en Salud REDinREN y RICORS2040 del Instituto de Salud Carlos III (RD12/0021/1023; RD16/0009/0017;RD21/0005/0019). Instituto de Salud Carlos III (ISCIII)‑Fondo de Investigación Sanitaria: PI17/00715, PI17/00384, PI17/02181, PI19/00532, PI20/00633, PI20/00753. Ayuda para la formación de Profesorado Universitario (FPU). Programa de Ayudas “Severo Ochoa” para la Formación en investigación y Docencia del Principado de Asturias, convocatoria 2019., Cannata-Andía JB, Díaz-Sottolano A, Fernández P, Palomo-Antequera C, Herrero-Puente P, Mouzo R, Carrillo-López N, Panizo S, Ibañez GH, Cusumano CA, Ballarino C, Sánchez-Polo V, Pefaur-Penna J, Maderuelo-Riesco I, Calviño-Varela J, Gómez MD, Gómez-Alonso C, Cunningham J, Naves-Díaz M, Douthat W, Fernández-Martín JL; COVID-VIT-D trial collaborators

Mineral and bone metabolism disorders are common complications in haemodialysis patients that present significant geographical variability.The objective of this study was to assess these disorders for the first time in haemodialysis patients from Peru.The study included 1551 haemodialysis patients from 55 centres affiliated with the Social Health System of Peru in the city of Lima. Demographic data, comorbidities, treatments and biochemical parameters were collected from each patient. Serum calcium, phosphorus and PTH levels were categorised according to the recommended ranges in the KDOQI and KDIGO guidelines.The mean age of the patients was 59.5±15.6 years, with a mean time on haemodialysis of 58.0±54.2 months. All patients were dialysed with a calcium concentration in the dialysis fluid of 3.5 mEq/l and 68.9% of patients were prescribed phosphate-binding agents (98.4% of them calcium carbonate). A high percentage of patients showed serum calcium above, and serum phosphorus below, the recommended ranges in the KDOQI guidelines (32.8% and 37.3%, respectively). More than half of the patients had serum PTH values below the recommended ranges of both the KDOQI and KDIGO guidelines (56.4% and 51.6%, respectively).Patients included in this study were younger than those from other studies and showed both hypophosphataemia and suppressed PTH, probably due to an excessive calcium overload through dialysis fluid and the use of calcium-containing phosphate binding agents.