Iron levels in the body are largely controlled by activity in two key organs: the gut, where we absorb iron from our diet, and the spleen, where we recycle red blood cells. The hormone hepcidin controls the availability of iron in the blood stream by inhibiting the iron exporter ferroportin in the gut and spleen. It has long been speculated that a third organ could be involved: an abundance of ferroportin has been observed in the kidney, implicating it in the reabsorption of iron from urine back into the circulation. However, the extent to which the kidney contributes to the regulation of iron in the body has so far been little understood. We do not know how important the kidney iron reabsorption is, nor how it is regulated.
A new study from the Lakhal-Littleton group has formally demonstrated that the kidney indeed reabsorbs iron back into the blood stream using ferroportin. Their findings show that if ferroportin in the kidney is blocked, there is a reduction in the body’s iron levels, which is quickly corrected by a compensatory increase in gut iron absorption. According to Associate Professor Samira Lakhal-Littleton: “This means that under normal physiological conditions, the kidney is a less important source of iron than the gut and spleen.”
The team were also able to show that hepcidin, the hormone that controls iron release from the gut and spleen, also controls iron reabsorption in the kidney. In a genetically modified animal model, researchers removed the kidney’s ability to respond to hepcidin. As a consequence, iron overload was observed due to more iron in the blood being deposited in critical tissues, such as the liver and heart. Crucially, the kidney itself did not become overloaded, as it was able to redirect iron back into the bloodstream and towards other tissues. The results mirrored a human iron overload disorder called hemochromatosis. In this disease, there is either a lack of hepcidin or patients cannot respond to hepcidin, leading to increased iron availability and consequently, excess iron deposited on tissues including the liver, heart and pancreas. Prof Lakhal-Littleton said: “People have been puzzled for some time as to why these patients do not develop iron deposition in the kidney. Our work shows that loss of hepcidin or hepcidin responsiveness causes an increase in kidney iron reabsorption, meaning that the kidney itself is protected from excess iron deposition while contributing to excess iron availability in the circulation and consequently iron deposition in other tissues. This shows that altered iron handling in the kidney is particularly important in determining the magnitude and pattern of iron deposition in the setting of hemochromatosis.”
“These results also reinforce a long-held belief that we do not have an active method of iron excretion into the urine. This is possibly because our bodies evolved to help us retain all the iron that it can. Historically we have had little iron in the diet, so we couldn’t afford to get rid of it in the urine. The kidney reabsorbs everything it can. When you have too much iron coming through the gut, this maximal iron reabsorption becomes a problem.”
Consequently, the kidney has been identified as a potential target in disease settings where there is too much iron in the body. There is now a potential new avenue of research to determine if blocking iron reabsorption in the kidney could reduce iron load and treat conditions such as hemochromatosis. There are also clinical implications for conditions leading to too little iron in the body. Prof Lakhal-Littleton said: "Now we know the kidney has this role in iron reabsorption, it would be important to see if this function is changed in patients with chronic kidney disease, and to what extent that change contributes to the development of iron deficiency anaemia in these patients. If the kidney can no longer reabsorb iron, is it possible that, over time it causes a decrease in iron availability of sufficient magnitude to cause anaemia.”
Prof Lakhal-Littleton said: "Understanding normal iron physiology helps us understand iron disorders better. In this case, better understanding of iron handling in the kidney has helped us understand the pathology of hemochromatosis.”
The full paper "The kidney hepcidin/ferroportin axis controls iron reabsorption and determines the magnitude of kidney and systemic iron overload" is available to read in Kidney International.