ADDITIONAL FUNCTIONS: ERYTHROPOIESIS AND VITAMIN D
Red blood cells must be plentiful enough to ensure adequate oxygenation of peripheral tissues, yet not so numerous as to compromise the free ﬂow of blood. Therefore, erythropoiesis must be under tight control. The kidneys play an essential role in this process because they sense hypoxia, the major sign of inadequate erythrocyte mass, and respond by secreting erythropoietin, the major promoter of erythrocyte production.
The oxygen-sensitive production of erythropoietin occurs in peritubular ﬁbroblasts. These cells are responsible for constitutive production of hypoxia-inducible factor 1 (HIF-1), a heterodimeric protein with α and β subunits.
In the setting of high oxygen tension, the α subunit undergoes rapid hydroxylation by proline hydroxylases (PHDs). The hydroxylated α subunit then combines with the von Hippel-Lindau tumor suppressor, under-goes ubiquitination, and is degraded in proteasomes.
In contrast, in the setting of hypoxia, the HIF-1 heterodimer persists and combines with various proteins, such as p300 and CBP, to form a transcription factor. This factor binds to the hypoxia-responsive element located near the EPO gene and upregulates the synthesis of many proteins, including erythropoietin. In the bone marrow, erythropoietin enhances the survival and maturation of colony forming units-erythroid (CFU- E), which then give rise to erythrocytes.
Erythropoietin deﬁciency occurs in advanced renal failure, resulting in the emergence of a signiﬁcant normocytic anemia. The increasing availability of recombinant erythropoietin agents, however, has all but eliminated the need for transfusion in dialysis patients. Nonetheless, there is a small but signiﬁcant increased risk of cardiovascular events and death associated with this class of drugs.
Vitamin D is a fat-soluble vitamin that can be acquired either from diet or from sunlight-induced conversion of epidermal fats. In either case, vitamin D undergoes numerous modiﬁcations in various organs, including the kidneys, to become a bioactive hormone. (For an illustration, see Plate 4-67).
Vitamin D synthesis begins when ultraviolet waves in sunlight cause photoisomerization of 7- dehydrocholesterol to vitamin D3 (cholecalciferol), or when vitamin D2 (ergocalciferol) or D3 is ingested and absorbed. Major dietary sources of vitamin D include fatty ﬁsh and fortiﬁed milk. Because vitamin D is fat soluble, inadequate absorption occurs in fat malabsorption states, such as pancreatic insufﬁciency or cystic ﬁbrosis.
Vitamins D2 and D3 are carried on plasma vitamin D–binding proteins to the liver, where 25-hydroxylase converts them to 25-hydroxyvitamin D [calcidiol, abbreviated as 25(OH)D]. From there, 25(OH)D eventually reaches the kidneys, again on vitamin D–binding proteins. 25(OH)D enters proximal tubular epithelial cells via receptor-mediated endocytosis, where it is converted by 1-α-hydroxylase to 1,25-dihydroxyvitamin D [calcitriol, the bioactive vitamin, abbreviated as 1,25(OH)2D]. 1-α-hydroxylase is upregulated in the presence of PTH, hypocalcemia, and hypophospha-temia. Another proximal tubular enzyme, known as 24-α-hydroxylase, can synthesize an inactive form of vitamin D known as 24,25-dihydroxyvitamin D. This enzyme is upregulated in the presence of 1,25(OH)2D, which therefore regulates its own synthesis.
Vitamin D’s major functions are to increase the intestinal reabsorption of calcium and phosphate, to stimulate bone metabolism, and to suppress the release of PTH. As a result, profound bone mineralization defects occur in states of deﬁciency. Such defects are a major component of the phenomenon known as renal osteodystrophy, which occurs in end-stage renal disease (see Plate 4-70).