A Role for SGLT-2 Inhibitors in Treating Non-diabetic Chronic Kidney Disease.

In recent years, inhibitors of the sodium-glucose co-transporter 2 (SGLT2 inhibitors) have been shown to have significant protective effects on the kidney and the cardiovascular system in patients with diabetes. This effect is also manifested in chronic kidney disease (CKD) patients and is minimally due to improved glycaemic control. Starting from these positive findings, SGLT2 inhibitors have also been tested in patients with non-diabetic CKD or heart failure with reduced ejection fraction. Recently, the DAPA-CKD trial showed a significantly lower risk of CKD progression or death from renal or cardiovascular causes in a mixed population of patients with diabetic and non-diabetic CKD receiving dapagliflozin in comparison with placebo. In patients with heart failure and reduced ejection fraction, two trials (EMPEROR-Reduced and DAPA-HF) also found a significantly lower risk of reaching the secondary renal endpoint in those treated with an SGLT2 inhibitor in comparison with placebo. This also applied to patients with CKD. Apart from their direct mechanism of action, SGLT2 inhibitors have additional effects that could be of particular interest for patients with non-diabetic CKD. Among these, SGLT2 inhibitors reduce blood pressure and serum acid uric levels and can increase hemoglobin levels. Some safety issues should be further explored in the CKD population. SGLT2 inhibitors can minimally increase potassium levels, but this has not been shown by the CREDENCE trial. They also increase magnesium and phosphate reabsorption. These effects could become more significant in patients with advanced CKD and will need monitoring when these agents are used more extensively in the CKD population. Conversely, they do not seem to increase the risk of acute kidney injury.

[A case of left ventricular thrombosis in a patient with beta-thalassemia major]. / Un caso di trombosi ventricolare sinistra in una paziente affetta da beta-talassemia maior.

In patients with beta-thalassemia major cardiac events due to iron overload are the main cause of death. Moreover, a chronic hypercoagulable state has been described in these patients, which sometimes complicates with thromboembolic events, mainly cerebral ischemic accidents and deep venous thrombosis. We describe a case of cardiac hemochromatosis complicated with fatal massive multiorgan embolism due to a large left ventricular thrombus in a patient with beta-thalassemia major.

Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: implications for pathogenesis.

OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis (LCH) of unknown etiology, characterized by diffuse histiocyte infiltration of bones and soft tissue. The purpose of this study was to assess cell proliferation and expression of cytokines, chemokines, and chemokine receptors that may potentially be important in histiocyte accumulation in ECD lesions. METHODS: Biopsies were performed on 3 patients with ECD. The diagnosis of the disease was based on clinical signs including typical radiologic osteosclerosis, and on the detection of foamy CD68+,CD1a- non-Langerhans' cell histiocytes on histologic examination. The expression of the proliferation marker Ki-67 as well as of selected chemokine/chemokine receptor pairs and cytokines was analyzed by immunohistochemistry. RESULTS: In all samples, Ki-67 was undetectable in CD68+ histiocytes. Conversely, these cells expressed the chemokines CCL2 (monocyte chemotactic protein 1), CCL4/macrophage inflammatory protein 1beta (MIP-1beta), CCL5/RANTES, CCL20/MIP-3alpha, and CCL19/MIP-3beta, and their counter-receptors CCR1, CCR2, CCR3, CCR5, CCR6, and CCR7. Moreover, ECD histiocytes expressed interferon-gamma-inducible 10-kd protein (CXCL10), which is specifically induced by interferon-gamma, and interleukin-6 and RANKL, which are both implicated in bone remodeling. Finally, all cases showed a Th1-type lymphocyte infiltrate. CONCLUSION: Our data indicate that, similar to LCH, ECD lesions are characterized by a complex cytokine and chemokine network, which may orchestrate histiocyte activation and accumulation through an autocrine loop and contribute to the pathogenesis of the disease.