Iara daSilva

Lanthanum carbonate for the control of hyperphosphatemia in chronic renal failure patients: a new oral powder formulation – safety, efficacy, and patient adherence

Chronic kidney disease (CKD) is associated with very high mortality rates, mainly of cardiovascular origin. The retention of phosphate (P) and increased fibroblast growth factor-23 levels are common, even at early stages of CKD, due to disturbances in normal P homeostasis. Later, hyperphosphatemia appears, which has also been strongly associated with high mortality rates linked to P-mediated cardiovascular and procalcifying effects. Treatment guidelines for these patients continue to be poorly implemented, at least partially due to the lack of adherence to a P-restricted diet and P-binder therapy. Calcium-free P binders, such as lanthanum carbonate, have been associated with a decreased progression of vascular calcification, rendering them an important therapeutic alternative for these high cardiovascular risk CKD patients. Lanthanum carbonate has typically been available as chewable tablets, and the new presentation as an oral powder may provide a useful alternative in the therapeutic armamentarium. This powder is a tasteless, odorless, and colorless semisolid compound miscible with food. In a recent study in healthy individuals, the safety and efficacy of this novel form were evaluated, and it was concluded that it is well tolerated and pharmacodynamically equivalent to the chewable form. In the long run, individualization of preferences and treatments seems an achievable goal prior to final demonstration of improvements in hard outcomes in wide clinical trials in CKD patients.

Alkaline Phosphatases in the Complex Chronic Kidney Disease-Mineral and Bone Disorders

Alkaline phosphatases (APs) remove the phosphate (dephosphorylation) needed in multiple metabolic processes (from many molecules such as proteins, nucleotides, or pyrophosphate). Therefore, APs are important for bone mineralization but paradoxically they can also be deleterious for other processes, such as vascular calcification and the increasingly known cross-talk between bone and vessels. A proper balance between beneficial and harmful activities is further complicated in the context of chronic kidney disease (CKD). In this narrative review, we will briefly update the complexity of the enzyme, including its different isoforms such as the bone-specific alkaline phosphatase or the most recently discovered B1x. We will also analyze the correlations and potential discrepancies with parathyroid hormone and bone turnover and, most importantly, the valuable recent associations of AP’s with cardiovascular disease and/or vascular calcification, and survival. Finally, a basic knowledge of the synthetic and degradation pathways of APs promises to open new therapeutic strategies for the treatment of the CKD-Mineral and Bone Disorder (CKD-MBD) in the near future, as well as for other processes such as sepsis, acute kidney injury, inflammation, endothelial dysfunction, metabolic syndrome or, in diabetes, cardiovascular complications. However, no studies have been done using APs as a primary therapeutic target for clinical outcomes, and therefore, AP’s levels cannot yet be used alone as an isolated primary target in the treatment of CKD-MBD. Nonetheless, its diagnostic and prognostic potential should be underlined.

Early Macrophage Infiltration and Sustained Inflammation in Kidneys From Deceased Donors Are Associated With Long-Term Renal Function.

Kidney transplants from living donors (LDs) have a better outcome than those from deceased donors (DDs). Different factors have been suggested to justify the different outcome. In this study, we analyzed the infiltration and phenotype of monocytes/macrophages and the expression of inflammatory and fibrotic markers in renal biopsy specimens from 94 kidney recipients (60 DDs and 34 LDs) at baseline and 4 months after transplantation. We evaluated their association with medium‐ and long‐term renal function. At baseline, inflammatory gene expression was higher in DDs than in LDs. These results were confirmed by the high number of CD68‐positive cells in DD kidneys, which correlated negatively with long‐term renal function. Expression of the fibrotic markers vimentin, fibronectin, and α–smooth muscle actin was more elevated in biopsy specimens from DDs at 4 months than in those from LDs. Gene expression of inflammatory and fibrotic markers at 4 months and difference between 4 months and baseline correlated negatively with medium‐ and long‐term renal function in DDs. Multivariate analysis point to transforming growth factor‐β1 as the best predictor of long‐term renal function in DDs. We conclude that early macrophage infiltration, sustained inflammation, and transforming growth factor‐β1 expression, at least for the first 4 months, contribute significantly to the difference in DD and LD transplant outcome.

Vitamin D Receptor and Interaction with DNA: From Physiology to Chronic Kidney Disease

The biologically most active vitamin D metabolite, 1,25-dihydroxyvitamin D3 [calcitriol or 1,25(OH)2D3] exerts the vast majority of its classical actions and attributed “non-traditional” effects by means of interaction with the vitamin D receptor (VDR). Here, we review the VDR structure and function, as well as the molecular actions of vitamin D mediated via this classical endocrine receptor. We also describe the interactions of the 1,25(OH)2D3/VDR complex with the retinoid X receptor, VDR coregulators (coactivators and corepressors) and the vitamin D-response element, whereby the expression of many 1,25(OH)2D3–responsive genes is positively or negatively controlled in many different tissues through complex conformational changes. On the other hand, chronic kidney disease (CKD) may be considered “a disease of dysfunctional receptors” since CKD has been associated with resistance to the action of many hormones including 1,25(OH)2D3. CKD and uremic toxins interfere not only with 1,25(OH)2D3 metabolism but also with various VDR processes such as basal VDR synthesis, binding and function. In view of the ubiquitous nature of VDR, several VDR activators are being developed with the aim of achieving an improved biological profile for a therapeutic application in one of the pleiotropic functions of the natural hormone, while avoiding untoward effects including excessive calcium and phosphate loading. However, randomized clinical trials are required to confirm all the proposed cardiovascular and survival benefits of the old and new VDR activators.