Renal complications of sickle cell disease

Published on October 31, 2016   31 min

Other Talks in the Series: The Kidney in Health and Disease

0:00
Hello, my name is Claire Sharpe. I'm a consultant nephrologist at King's College Hospital and a senior lecturer at King's College, London. I have been interested in Sickle cell disease in the kidney since 2004, when I've started a joint sickle cell and kidney clinic along with the hematologists at King's College Hospital. I'm going to talk a little bit about pathophysiology of sickle cell and kidney complications, and talk about the clinical manifestations.
0:31
The first person to describe sickle cell disease in the western literature was James Herrick, who was working in Boston around 1910. He was looking after a young man from Grenada, who traveled to United States to do a dental degree. This young man had had a sickly childhood, and when he arrived in America, he was suffering with leg ulcers. This paper very clearly describes both the history and the clinical examination of this man. And of note, James Herrick brings out that he had increased urine volume of low specific gravity, which contained a distinct trace of serum albumin. And this very much sums up the sickle cell nephropathy, which we recognize in many of our patients today.
1:18
The underlying genetic mutation was first described in Cambridge by Vernon Ingram in 1957. A single point mutation results in a replacement to the glutamine with a valine at the six amino acid, and the beta-chain of adult hemoglobin. This results in the beta hemoglobin becoming less soluble, particularly under hypoxic and acidotic conditions. This results in polymerization of the beta hemoglobin which can form these rope like structures seen here in this middle picture. These structures make the red blood cell rigid and undeformable and it takes on this characteristic sickling shape. This polymerization sickling is initially reversible. However, after many cycles of sickling, the red blood cell becomes irreversibly sickled, and then can spill over into the peripheral circulation that's seen on the right. This is what James Herrick noted and more gave the disease its name.
2:18
The consequence of the sickling has profound effects on both red cell function and endothelial function. The changes in red cell membrane structure and function results in the red cells becoming dehydrated. This concentration of hemoglobin results in further polymerization and exacerbation of the disease. Alongside this, the endothelium becomes sticky and together this results in trapping of red blood cells and other fragments in the small capillary beds, which leads to ischaemia of the distal tissue and the familiar painful crises associated with sickle cell disease.
2:60
Focusing on the kidney, it is clear to see why the kidney is a target organ in sickle cell disease. These images demonstrate the complex vasculature within the kidney, which can be affected by acute sickling crises.
3:19
To understand why the kidney is such a target of damage, it's important to understand some renal physiology. The kidney receives 20% of the cardiac output, although, kidney volume only represents 3% of total volume. It's important that kidney receives this degree of blood flow in order to filter the blood and excrete the waste products. However, the cortex of the kidney actually gets a much better blood supply than it really requires. In order to ameliorate some of this oxygen delivery, there is shunting of oxygen from the arterial supplied to the venous drainage from the kidney. The oxygen tension in the cortex then is generally well maintained at 50 millimeter of mercury with the pH of 7.4. However, the blood supply to the medulla of the kidney comes off the afferent arteriole. It is sluggish in nature and has a lower oxygen tension, resulting in general hypoxia in medulla down to about 10 millimeters of mercury with an acidotic environment with pH of 6.4. This results in increased prostaglandin release, increase endothelin-1 and a decrease in nitric oxide bioavailability, all of which stimulate the sickling of red blood cells.
4:42
Nitric oxide is an important vasodilator, particularly in the kidney. It is generated from arginine through the function of nitric oxide synthase. Arginine however, can also be directed towards ornithine generation instead of nitric oxide. When red blood cell sickle, they are often destroyed releasing free haem into the circulation. Free haem soaks up nitric oxide and is very potent nitric oxide scavenger. Therefore, leading to vasoconstriction rather than vasodilation. In addition to this, when they hemolyze, red blood cells release arginines, which promotes ornithine generation from arginine, that's directing away from nitric oxide synthesis and again, producing vasodilation. This has vicious cycle effect of increasing vasoconstriction within the kidney, which worsens hypoxia, makes the environment more acidotic and again, stimulate sickling of red blood cells. This process leads the generation of reactive oxygen species, which further soak up nitric oxide.
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Renal complications of sickle cell disease

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