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
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).
