From Medicineworld.org: Links Between Kidney Function And Bone
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Links Between Kidney Function And Bone
Keith A. Hruska, MDMultitasking might seem like a modern invention, but in biology it's been an established technique for millennia.
The organs of the human body, for example, all have their well-known primary specialties, but a number of of them also play secondary roles in support of each other.
One such moonlighter is the human kidney, which purifies waste from the blood, but also has a more recently identified role as a contributor to the structural integrity of the human skeleton.
Keith A. Hruska, MD, professor of pediatrics, medicine and of cell biology and physiology at the School of Medicine and head of pediatric nephrology at St. Louis Children's Hospital, has developed several new insights into the connections between the kidney and the skeleton and hopes to put them to use soon in new therapys for kidney patients that will ease the harmful effects their condition inflicts on both the skeleton and the heart.
To recognize the connections between the kidney and the skeleton, doctors first had to understand that the skeleton isn't the dry and unchanging place it .
was once thought to be.
"In the past, the skeleton has been viewed as mostly a dead structure, but that's not the case at all," Hruska explains. "The adult skeleton is very active tissue that is continually remodeling, dismantling damaged bone and replacing it with new bone".
Cells inside the bone marrow accomplish this task, regularly destroying and rebuilding bone structure to adjust for wear, injury and changes in the mechanical loads and pressures placed on the bones.
Kidney disease's direct connection to bone health was initially masked by a complication of chronic kidney disease (CKD) known as secondary hyperparathyroidism. This complication, which afflicts about 100,000 new patients with kidney disease each year, raises bloodstream levels of the parathyroid hormone.
Parathyroid hormone's functions include control of calcium, phosphorus and vitamin D levels in the bloodstream. When disease or injury reduces the kidneys' mass, their ability to filter phosphorus out of the blood and to produce vitamin D for circulation in the blood declines. Researchers believed that the parathyroid glands in the neck ramp up their production of hormone in response, elevating the level of the hormone in the blood.
Researchers theorized that one way parathyroid hormone could regulate blood calcium was by controlling the activity of bone-dismantling cells known as osteoclasts. As they work, osteoclasts release calcium, phosphorus and other minerals from the bone structure into the bloodstream.
Scientists reasoned that increasing parathyroid levels increased the activity of the bone-dismantling cells, but if that increased activity wasn't matched by an equal increase in the activity of bone-building cells, it might weaken bone structure seen in kidney patients, who develop fractures and deformities as a result.
However, as physicians developed ways to suppress parathyroid hormone, they found that kidney patients still had weak bones, a condition called adynamic bone disorder.
This led Hruska and others to suspect that secondary hyperparathyroidism had been masking a more direct affect of CKD on bone health. He theorized that CKD might be causing the kidneys to produce factors that decrease the activity .
of cells on the building side of the skeletal construction and destruction dynamic.
In early 2004, his lab published a study that supported the hypothesis in a mouse model of chronic kidney disease. To create the mouse model, scientists removed a kidney and damaged the remaining kidney.
In some of the mice, they pre-vented secondary hyperparathyroidism with dietary changes and anutritional supplement. Those mice maintained normal calcium, phosphorus, vitamin D, and parathyroid hormone levels but developed an adynamic bone disorder.
"The conclusion was that CKD produces hormonal factors that shut down the production of new skeleton," Hruska explains. "That's not tolerated, and secondary hyperparathyroidism turns out to be a form of compensation by the body - an attempt to prevent that shutdown".
Hruska suspected that a recently discovered class of bone growth stimulators known as bone morphogenic proteins (BMPs) might be able to help patients with CKD. Hruska's lab showed that one of these proteins, BMP-7, could cause stem cells in bone marrow to develop into osteoblasts, the cells that rebuild bone.
"Mice lacking the gene for this protein have defects both in their skeletons and in their kidneys and related renal structures, proving that BMP-7 is linked not just to bone creation but also to development of the kidney," Hruska notes. "And BMP-7 is fairly unique in that it continues to be made at relatively high levels in the kidneys even after development is complete".
Spurred by BMP-7's continued high production levels in adults, Hruska and his associates gave the mouse model of CKD injections of the protein. He found it made the cells of the bones function normally.
"If we can use BMP-7 to eliminate this skeletal complication, it will produce a major increase in the well-being of the patients with CKD," Hruska notes.
Stopping bone loss may do more than help kidney patients - it may save lives. As per a research findings published early this year, Hruska found evidence that stopping bone loss in a mouse model eliminates the most deadly complication of CKD: vascular calcification, or stiffening of the blood vessels.
The circulatory system normally deposits minerals like calcium and phosphorus in the bones during bone reconstruction. With that process suppressed by the effects of CKD, pressure mounts for the body to deposit those minerals elsewhere.
"Serum phosphorus is a direct stimulus to the smooth muscle cells that line blood vessels, causing them to take on characteristics very similar to osteoblasts, the cells that form bone," Hruska explains.
The changed smooth muscle cells can deposit minerals outside their membranes, dramatically decreasing the flexibility of blood vessels and increasing the work the heart has to do to create a pulse. Consequences may include enlargement of one of the heart's chambers, increased risk of congestive heart failure, heart attack and other cardiac problems.
To assess the links between loss of mineral deposition in the bones and vascular calcification, Hruska and his colleagues studied mice that develop a condition known as metabolic syndrome as a result of both a genetic modification and a high-fat, high-cholesterol diet. To simulate chronic kidney disease, researchers again damaged or removed parts of the kidneys.
Hruska and colleagues first showed that injection of BMP-7 not only stopped bone weakening but also ended vascular calcification. In another group of experimental mice, injections of a substance that binds to compounds with phosphorus but has no effect on the skeleton stopped vascular calcification, proving that phosphorus was a key link between the skeleton and the vasculature.
"We already have drugs available that can control phosphorus levels in the blood," says Hruska. "I think we're going to get support soon for a single-center trial using one of these drugs on vascular calcification, and that would be the prelude to a much larger multicenter trial".
A trial of BMP-7 injections for CKD patients may also be just a little bit farther away. "If we're able to apply BMP-7 in humans, we could be on our way to producing a major improvement in the well-being of patients with chronic kidney disease," he says.
Source: Washington University in St.Louis - School of Medicine
Did you know?
Multitasking might seem like a modern invention, but in biology it's been an established technique for millennia. The organs of the human body, for example, all have their well-known primary specialties, but a number of of them also play secondary roles in support of each other.
Medicineworld.org: Links Between Kidney Function And Bone
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