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The bone-renal axis in early chronic kidney disease: an emerging paradigm.

The prevailing paradigm of mineral metabolism in chronic kidney disease (CKD) is based on two principles. First, as the tradeoff hypothesis suggests, phosphate retention leads to hyperparathyroidism, a response that maintains normal levels of serum phosphorus until relatively late in the CKD process [1–3]. In addition, it is believed that dietary deficiency of 25 hydroxylated vitamin D (25OHD) is important in early CKD, with the deficiency of the activated version, 1,25-hydroxylated vitamin D (1,25OHD), developing only in the later stages. Since the hydroxylation to 1,25OHD is considered to be a renal-dependent mechanism, the deficiency of this activated form is thought to reflect renal dysfunction. Various mechanisms have been impugned, including loss of renal mass, hyperparathyroidism, hyperphosphatemia and uremic toxins. These two principles have shaped the current KDOQI guidelines for the treatment of mineral metabolism in CKD. However, more recent data suggest that this approach to mineral metabolism in CKD may not be wholly accurate. A recent large trial has illustrated that 1,25OHD levels begin to fall at the earliest stage of renal decline, before the development of hyperparathyroidism, hyperphosphatemia or any changes in renal mass [4]. Furthermore, although loss of 1-alpha hydroxylase has been impugned as the cause of 1,25OHD deficiency, animal data suggest that this enzyme is not decreased in CKD [5]. In addition, 1-alpha hydroxylase is expressed in diverse tissues beyond the kidney, potentially providing an extra-renal source of 1,25OHD [6]. It seems that the 1,25OHD decline in CKD is actually a much more complicated process than originally proposed.