C4d staining of renal allografts is regarded as an in situ marker of active humoral rejection. Few data are available about the incidence of C4d deposition in protocol biopsies compared to indication biopsies. To evaluate whether center-specific factors influence the incidence of C4d detection, we performed a multicenter study. From three European centers, 551 protocol and 377 indication biopsies were reclassified according to the updated Banff criteria and stained for C4d. C4d results were recorded as diffuse or focal positive and statistically correlated to clinical parameters, morphology and graft survival. In the protocol biopsies, a diffuse C4d stain was found in 2.0%, and a focal stain in 2.4%. In indication biopsies, 12.2% were diffusely and 8.5% focally C4d positive (protocol:indication p < 0.0001). The incidence of C4d deposition varied significantly between centers, attributable to variable numbers of presensitized patients with more C4d positive indication and protocol biopsies. Diffuse and focal C4d stain correlated with morphology of humoral rejection in protocol as well as in indication biopsies. Protocol biopsies show a significantly lower incidence of C4d deposition than indication biopsies. Subclinical C4d detection in protocol biopsies had no significant impact on allograft survival in our series.

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In general, proposals for continuing or stopping metformin therapy in CKD involve a threshold (whether based on serum creatinine or estimated glomerular filtration rate) rather than the dose adjustment as a function of renal status (in stable patients) performed for other drugs excreted by the kidney.

Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in secondary hyperparathyroidism (sHPT). These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and myocardium, ultimately associated with increased risk of mortality in patients with chronic kidney disease (CKD). sHPT may lead to cardiovascular calcifications by other mechanisms including an impaired effect of parathyroid hormone (PTH), and a decreased calcium-sensing receptor (CaR) expression on cardiovascular structures. PTH may play a direct role on vascular calcifications through activation of a receptor, the type-1 PTH/PTHrP receptor, normally attributed to PTH-related peptide (PTHrP). The CaR in vascular cells may also play a role on vascular mineralization as suggested by its extremely reduced expression in atherosclerotic calcified human arteries. Calcimimetic compounds increasing the CaR sensitivity to extracellular calcium efficiently reduce serum PTH, calcium, and phosphate in dialysis patients with sHPT. They upregulate the CaR in vascular cells and attenuate vascular mineralization in uremic states. In this article, the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT, the biology of the CaR in vascular structures and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications are reviewed.

Bisphosphonates are inhibitors of bone resorption that are widely used to treat osteoporosis. Price and colleagues demonstrate that ibandronate suppressed the development of uremia-related vascular calcification in rats. These findings extend the link between bone remodeling and vascular calcification to the context of chronic renal failure, opening perspectives toward novel therapeutic strategies.