Thursday, December 12, 2013

Article Review (2006) - Amyloidosis-associated kidney disease

In the previous post I discussed a couple of papers that give us an indication of how rare fibrinogen amyloidosis actually is, at least in the US. Oddly enough, the day after I published that post I found some additional data that would have been nice to add to that discussion. I have updated the previous post with the new info, but for the benefit of you email subscribers I will go ahead and include the update in this post, and then we'll move on.

[Start of update to previous post.]

As luck would have it, I found some more data the day after I published this blog post. This additional info is from an abstract presented December 7, 2013, at the 2013 Meeting of the American Society of Hematology. Here is the title and a link to the abstract:

Title: Proteome of Amyloidosis: Mayo Clinic Experience In 4139 Cases


First of all, what is a proteome? The dictionary definition is that a proteome is the entire complement of proteins found within a cell, tissue or organism. In this context, the proteome of amyloidosis is the complete list of proteins that are known to cause amyloidosis. (These are often referred to as precursor proteins.) This paper gives the breakdown of amyloid subtypes found in 4139 cases where a tissue biopsy was evaluated at Mayo Clinic since 2008, when they started using a newly developed method for subtyping amyloid deposits. (It's called liquid chromatography electrospray tandem mass spectrometry, or LC-MS/MS. This is probably the technique people refer to as mass spec.) I assume there will be some overlap with the previous article that covered the years 2007 to 2011 in the Renal Pathology Lab at Mayo Rochester.

Here is the table showing the distribution of amyloid subtypes in these 4139 cases.

Frequency of amyloid subtypes observed in the Mayo Clinic Amyloid Cohort (n=4139).
Asterisk denotes non-canonical subtypes.

As shown in the table, there were 26 fibrinogen amyloidosis (AFib) diagnoses among these 4139 cases (0.63%), over a period of five to six years (2008 to 2013 inclusive). So that is still only 4 or 5 cases per year diagnosed at Mayo Clinic. But what if we compare the data in this article to the previous one, which had data from the Mayo Clinic Renal Pathology Laboratory from 2007 to 2011? The earlier article reported six cases of Afib, whereas this more recent article reported 26 cases. Does that mean there have been at least 20 cases diagnosed at Mayo Clinic since the data was gathered for the earlier paper? It looks that way based solely on the data we have, but we cannot say for certain without more information, such as the date of each fibrinogen amyloidosis diagnosis at Mayo Clinic since 2007.

Whatever the true numbers may be, the data clearly shows that fibrinogen amyloidosis is among the rare types of familial amyloidosis, and familial amyloidosis only accounts for about 20% of the total amyloidosis cases, and amyloidosis itself is a rare disease.

[End of update to previous post.]

Today's article under review is the last of the articles from 2006. Although this is a rather long article (ten pages plus four more to list the 107 references), there is only a small amount of information specifically related to fibrinogen amyloidosis. My review here will not go into detail on most of this article, so you do not have to worry about this review being longer than the article. I also detour a bit and go over Mom's biopsy report again due to some information in this article.

Title: Amyloidosis-associated Kidney Disease (1)

Author: Laura M. Dember (Boston University, Boston, MA)

Journal: Journal of the American Society of Nephrology

The amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing progressive organ dysfunction. The kidney is one of the most frequent sites of amyloid deposition in AL, AA, and several of the hereditary amyloidoses. Amyloid fibril formation begins with the misfolding of an amyloidogenic precursor protein. The misfolded variants self-aggregate in a highly ordered manner, generating protofilaments that interact to form fibrils. The fibrils have a characteristic appearance by electron microscopy and generate birefringence under polarized light when stained with Congo red dye. Advances in elucidating the mechanisms of amyloid fibril formation, tissue deposition, and tissue injury have led to new and more aggressive treatment approaches for these disorders. This article reviews the pathogenesis, diagnosis, clinical manifestations, and treatment of the amyloidoses, focusing heavily on the renal aspects of each of these areas.

Here is a link to the article if you would like to follow along:

This article is a very thorough discussion of how all types of amyloidosis affect the kidneys. It was written by Dr. Laura Dember, who was a nephrologist at Boston University at the time and is now with The University of Pennsylvania. The article starts with a general overview of amyloidosis, including the various types and subtypes. It then discusses detection of amyloid deposits in tissue biopsies using Congo red dye. It also mentions something I was unaware of, which is amyloid fibrils have a characteristic look when viewed with an electron microscope. Whereas Congo red staining is not always a routine part of a biopsy evaluation, electron microscopy is. If amyloid fibrils are detected with an electron microscope, then the tissue should be stained with Congo red to confirm the presence of amyloid.

The next section of the article is "Determination of the Type of Amyloidosis." We know how tricky that can be, so I will skip right to the end of that section and just copy the last sentence here: "Isolated glomerular involvement on kidney biopsy with no amyloid in the tubules, interstitium, or vessels has been found to be characteristic of fibrinogen A alpha amyloidosis, and this histologic pattern should raise suspicion for fibrinogen A alpha disease." No real surprise there, as we know from previous articles that kidney biopsies of fibrinogen amyloidosis patients show amyloid deposits predominantly in the glomeruli.

The next section of the article is "Renal Pathology." This section seems to be written for pathologists, as it goes into detail on what amyloid looks like in a kidney biopsy and exactly where in the kidney the deposits typically form. There are the usual pictures of biopsy slides, with the Congo red stained amyloid deposits under nonpolarized and polarized light, plus some other stains for AL amyloidosis. There is also a picture of what amyloid fibrils look like under an electron microscope, which I don't think I have seen before. The pictures (with captions) are available at this link: If you click on the pictures you get an even larger view. (In my opinion, the one with Congo red stain under polarized light (photo C), is not very impressive. There are much better examples out there.)

Sometimes when I read about techniques for analyzing kidney biopsies I go back and read over Mom's biopsy report to see if I understand it any better. I did that again after reading over this article, and a few things stood out this time. (Feel free to skip the rest of this paragraph if biopsy findings do not excite you.) If you look at Mom's biopsy report from the October 1, 2012 blog post, you will see three sections under Microscopic Description. They are Light Microscopy, Immunofluorescence, and Electron Microscopy. The Light Microscopy section details the findings from just looking at the tissue under a microscope with very high magnification. I believe that section says 12 of 28 glomeruli did have amyloid deposits. The Immunofluorescence section has the results of applying the various stains in an attempt to determine the type of amyloid deposits. One of the stains used is intended to detect fibrinogen, but it came up negative as did most of the others. That is not unusual, as these immunofluorescence techniques are far from 100 percent accurate. The Electron Microscopy section has the results of examining material under an electron microscope. I believe the part about the glomerular sections having "crosshatched fibrilla material having size characteristics of amyloid" is exactly what this article is talking about.

Ok, back to the article. It gets even more technical in the next few sections, and I did not highlight much of anything worth discussing here. The section headings are Clinicopathologic Correlates, Determinants of Renal Deposition of Amyloid, and How Does Amyloidosis Cause Renal Disease? The next section, Treatment Approaches and Impact on the Kidney, primarily deals with the treatment of AL and AA amyloidosis, but there is a subsection on hereditary amyloidosis. It begins by discussing the use of liver transplantation to treat TTR amyloidosis. Then it states that there is considerably less experience in using liver transplantation to treat fibrinogen amyloidosis, and it refers to three of the articles we have previously reviewed which contain case reports of combined liver and kidney transplantation, with satisfactory outcomes. It then gives some reasons why liver transplantation is not as successful, or not appropriate at all, for some of the other types of hereditary amyloidosis.

The remainder of the article discusses in more general terms end stage renal disease, regression of amyloid deposits and improvement of kidney function after treatment to eliminate the precursor protein, and then it closes with a short section on emerging treatment strategies. (It does mention diflunisal, a drug which is now very far along in clinical trials and is showing good outcomes in the treatment of TTR amyloidosis.)


So overall, we do not learn much new information about fibrinogen amyloidosis from this article, but we do see how it compares with other types of amyloidosis. And if you want some very detailed information about what is happening to kidneys that are affected by amyloidosis and how amyloidosis appears to a pathologist (with the tools available in 2006), this article is a very good reference.

Next up: Is fibrinogen only produced in the liver? How do we know?



(1) Dember, L. M. Amyloidosis-associated kidney disease. J. Am Soc Nephrol 2006; 17: 3458-3471.

No comments: