“Amyloidosis” refers to any one of several diseases in which abnormal protein fibrils accumulate in a person’s organs. The most common type is called AL amyloidosis, and the protein fibrils are made up of fragments of antibody proteins called light chains. I posted a slide which illustrates what a light chain is in a previous post (“Why is AL amyloid bad for hearts?“). In AL amyloidosis, the levels of light chains (usually lambda type, but sometimes kappa type) in the blood and urine are elevated. Light chains are made by plasma cells in the bone marrow, and current AL amyloid therapy targets these plasma cells.
Any organ’s function can be compromised by amyloid deposits. The kidney is one of the most commonly affected organs, and patients with injured kidneys may have symptoms, including swelling (edema) of the legs, decreased urine output, and lightheadedness due to sudden drops in blood pressure.
In order to understand how amyloid injures the kidneys, it is helpful to understand how the kidney works.
A summary of kidney anatomy and function relevant to amyloidosis:
- The kidney is made up of a million microscopic filtration units called nephrons.
- Each nephron has a filter called the glomerulus, which filters the blood.
- Some parts of the blood, namely water and electrolytes (sodium, potassium, etc), flow through this filter into a tube system where it is processed further. The material that eventually comes out of the end of all this tubing is urine.
- Other components of the blood, like red blood cells, do not pass through the filter.
- Although under normal circumstances there is essentially no protein in our urine, it is not because proteins do not pass through the filter. Filtered protein may be reabsorbed (taken back up into the body) in the first part of the tubing system. The part of the tubing where this takes place is called the proximal tubule.
- The part of the tubing further down the line is called the distal tubule.
- All of these structures, as well as blood vessels within the kidney, are surrounded by tissue which serves as scaffolding to hold it all together. This is the interstitial space, or matrix. (Its the Jell-O holding all the little pieces of fruit in place in that dessert your mother used to make on Thanksgiving)
- Amyloid light chains, in addition to being filtered, form deposits in the glomerulus itself. This is because these abnormal light chains are taken up by cells within the filter called mesangial cells. Mesangial cells do not take up normal light chains. After the abnormal amyloid light chains are snagged by these cells, they get processed and deposited within the matrix of the filter in strands called fibrils. When a pathologist is looking for amyloid in a kidney biopsy, s/he applies Congo Red stain, which makes these deposits look red under normal light and green under polarized light. As amyloid accumulates in the tissue around the mesangial cells in the glomerulus, the filter is damaged. It becomes “leaky” and the amount of protein lost through the filter increases.
|Kidney biopsy stained with Congo Red stain. Top image is the view under normal light, and the bottom one is the same slide viewed under polarized light. Everything that turned fluorescent green in the second image is amyloid!
Images snagged from http://www.pathguy.com/lectures/imm-iii.htm
- Increased protein delivery to the proximal tubule is bad for one’s kidneys. The receptors to reabsorb albumin and light chains can become overwhelmed. Excess albumin is lost in the urine, and it can make the urine appear “foamy.” Very low blood albumin levels are what cause the swelling (edema) and low blood pressure (hypotension) amyloidosis patients experience. Even though I.V. albumin solutions exist, it is not feasible to replace it because infused albumin suffers the same fate as the patient’s “home-grown” albumin: flushed. Excess light chains can also cause problems, as they can bind to other proteins in the urine and form casts (clumps that clog up the distal tubule, which in turn causes problems upstream). Cast formation is the leading cause of kidney injury in multiple myeloma, but less of an issue in amyloidosis. I posted about cast nephropathy previously (check that out).
- Inflammation plays a role in amyloid kidney injury. Abnormal light chains, when taken up by the cells in the proximal tubule actually injure the cells in that part of the kidney. Excess albumin in the tubular system and abnormal amyloid light chains in the cells lining the tubular system trigger inflammation and eventually scarring of the interstitial area. This is why AL amyloidosis patient with persisting heavy albuminuria (albumin in the urine) due to filter damage may have continued worsening of their renal function even after the amyloidosis has been treated and the light chain levels are no longer elevated: albumin-mediated kidney injury. In my own practice, this is a common and frustrating problem. One glimmer of hope: it is possible that one of the treatments commonly used in the treatment of AL amyloidosis – the proteasome inhibitor bortezomib (Velcade) – targets this inflammatory pathway. Other drugs in this same family (carfilzomib (Kyprolis) and ixazomib (MLN-9708)) are currently undergoing testing as therapy for AL amyloidosis. These drugs may not only kill bad-acting plasma cells, but also help the kidney dodge some albumin-mediated damage. Friend and colleague Meletios Dimopoulos has published extensively on this topic; check out this article describing the improvement in kidney function seen in myeloma patients who received bortezomib therapy.