Bone Metabolism and Cardiovascular Risk After Kidney Transplant in Adult Patients

BACKGROUND. Chronic kidney disease (CKD) affects millions of people worldwide. Cardiovascular (CV) events cause more than 50% of the mortality risk in CKD patients, and the relative excess mortality is observed in younger patients, below 45 years of age. Decreased renal function led to changes in biochemical parameters (calcium, phosphorus, PTH and vitamin D levels) and disturbed mineral metabolism, which translates into different bone disorders (related to bone turnover, mineralization, and volume) and all these are associated with extra-skeletal calcifications. Bone disease at any stage of CKD is associated with CV morbidity. This cross-talk between bone and vessels constitute a systemic syndrome known as CKD-mineral and bone disorder (CKD-MBD), that is thought to be one of the major non-traditional risk factors for the extremely high rate mortality observed in this disease.

CKD-MBD is classified into four major histological groups (in terms of turnover, mineralization and volume): hyperparathyroid bone disease (high turnover disease, with normal mineralization and variable volume); adynamic bone disease (low turnover disease, with normal mineralization and decreased bone volume); osteomalacia (low turnover disease, with reduced mineralization and with normal or high bone volume); and mixed renal osteodystrophy (reduced mineralization with or without increased bone formation).

Kidney transplantation is the treatment of choice for established stage 5 CKD. Even with correction of uremia, post-transplant MBD is frequent and reflects the pre-existing CKD-MBD, the effects of renal dysfunction after transplantation, and the effects and consequences of immunosuppression. Transplanted patients with CKD-MBD have reduced quality of life and require medical assistance for bone pain, fractures and CV events. Indeed, cardiovascular disease remains the leading cause of death after renal transplantation, still doubling risk of the general population.

The gold standard for the diagnosis of CKD-associated bone disease is bone biopsy, an expensive and invasive procedure. Non-invasive markers of bone disease presently lack sufficient specificity and sensitivity to allow the differential diagnosis of renal osteodystrophy. New biomarkers are needed and, osteocyte-derived factors, as FGF23 and sclerostin, are promising answers.

FGF23 acts as a phosphaturic hormone, a suppressor of vitamin D and has some non-consensual effect on parathyroid hormone (PTH). FGF23 has a specific receptor but needs a co-factor, klotho protein, to perform the majority of its functions. Serum klotho levels in CKD are low, influencing the resistance to FGF23 activity. What happens in transplanted patients is not yet totally understood; some studies pointed out for endothelial dysfunction and cardiovascular disease mediated by these factors in the transplant setting. Besides, graft loss and mortality were related with high serum levels of FGF23 and with bone mineral density loss but their relation with histological bone disease is unknown.