I'm baaaack . . .

Hello, loyal fibrinogen amyloidosis blog followers. Long time, no see. I'm still here, alive and kicking, and I don't have any good excuses for the extended absence. Yes, I've been busy with life, the universe, and everything, but that's not much of an excuse. I don't think I will get back to a one post per month pace any time soon but maybe I can aim for one post per quarter.

In blog news, the total pageviews for the blog is rapidly approaching a major milestone: 100,000. It should reach that in the next day or two if it has not already. (It was within 100 of reaching it as of the morning of September 30.) At the end of this post I have the monthly blog stats for the past six months, in a consolidated format to make it a little easier to read in case anyone cares.

There is not much happening with me health-wise, which is good. I had some lab work done this past week but I do not have the results yet. If there is anything interesting in those results I will do a post for that.

In other patient news there is a lot happening in terms of transplants, so much in fact that I may not remember them all. I know of one person who had a combined liver and kidney transplant late last year and another who had the same thing in July. Both are doing well as far as I know. There is another person currently on the waiting list for a liver transplant, and this will likely be the third case ever of a liver-only transplant for fibrinogen amyloidosis.

I also became aware of another person diagnosed with fibrinogen amyloidosis earlier this year, and this particular case is interesting for two reasons. The first reason is the age of this patient when diagnosed: 37. The youngest age of onset of any of the other patients I am aware of is approximately 46, and I think the journal articles mention some cases of patients developing symptoms in their mid-40s. But 37 is definitely the youngest I can recall (for the Glu526Val mutation). As if that was not special enough, the other interesting thing about this case is that there is a long history of kidney disease in the family and they have Portuguese ancestry. You may recall there is a concentration of fibrinogen amyloidosis patients in the Braga district of Portugal. (My most recent blog post about that was in April of 2014.) As of the date of this blog post no other family members of this patient have been tested for the mutation, but I do not think anyone will be surprised if genetic testing does show it was inherited from a Portuguese ancestor.

Getting back to some specifics regarding this case, she was found to have elevated creatinine in September of 2017, was referred to a nephrologist, and had a kidney biopsy in November of 2017. That biopsy was positive for amyloidosis but the type could not be determined. She started hemodialysis in February of 2018, and in May the original kidney biopsy was typed by Mayo Clinic as fibrinogen amyloidosis, Glu526Val mutation (or p.Glu545Val using the new nomenclature). She is about to begin evaluation for liver and kidney transplant.

Lastly, I am sure we would all prefer to have treatment options other than organ transplants. Unfortunately the number of fibrinogen amyloidosis patients is so small that our best hope is that a treatment developed for other types of amyloidosis will be effective for us, since pharmaceutical companies tend to focus on diseases with larger patient populations. However, there may be some progress in that area. Some of you may be aware of a web site called My Amyloidosis Pathfinder (https://www.myamyloidosispathfinder.org/), also known as MAP, that is for patients with any type of amyloidosis. Once a patient registers on that site, they are notified of treatment centers and clinical trials best suited for their situation.

The Amyloidosis Research Consortium monthly newsletter for July had this to say about MAP:

Do you have a rare type of amyloidosis? MAP needs you.

Just by knowing about you, we can accelerate research in your type of amyloidosis. A number of companies have expressed an interest in developing products for some of the rarer types of amyloidosis, including AA amyloidosis, beta-2 microglobulin (AB2M) amyloidosis, ALect2 amyloidosis and localized amyloidosis, among others.

The more patients there are with a disease, the more likely a company is to develop a product for it. So if you have not already registered at MAP and set up a profile, I hope you will consider it even if you are just a carrier of the mutation without any symptoms. We are like the Whos from "Horton Hears a Who!," and each and every one of us needs to shout, "We are here! We are here! We are here!"

That's it for this post. See you next . . . month? quarter? year? 


=====Monthly Blog Status Update for March through August, 2018=====

As of August 31, 2018:

Total posts: 183 (1 in March)

Total pageviews: 97,800 (Monthly views: 1200, 1100, 6100 (includes 4600 in one day from Israel), 1000, 1500, 1500)

Email subscribers: 16 (gained one in April, one in June)

Total number of countries that have viewed the blog: 148

Three new countries have viewed the blog since February:

Aruba
Guyana
Micronesia

FYI, there is not a country named Macronesia but there is a Macaronesia.
=====

Article Review (2013) - Delayed diagnosis of fibrinogen A alpha-chain amyloidosis after dual heart–kidney transplantation

Today's post will be our first article review since April of this year. So much for doing reviewing one article per month, right? As you can tell from the title of this post, the patient in this case underwent organ transplantation (heart and kidney) before being diagnosed with amyloidosis. Would a proper diagnosis before the transplant have made any difference? Let's see . . .

Title: Delayed diagnosis of fibrinogen A alpha-chain amyloidosis after dual heart–kidney transplantation (1)

Authors: Tristan Legris, Laurent Daniel, Valeris Moal (Marseille, France)

Journal: Transplant International (January 2013)

There is no abstract for this article since it is actually a letter to the editors of the journal. Here is the link to the article online: http://onlinelibrary.wiley.com/doi/10.1111/tri.12002/full

This article is about a male patient who had a heart attack in 2003 at the age of 55. His heart did not do well after the heart attack, despite angioplasty and implantation of a stent. He also had indications of moderate renal failure (elevated serum creatinine and and proteinuria), but that was not explored until 2004 when it worsened. His kidneys were too small for biopsy (8 cm), and no tests could explain the kidney problems. There was also no family history of renal failure. He started hemodialysis at the end of 2004 and was placed on the waiting list for combined heart-kidney transplantation, which he received in November of 2005.

The article discusses the issues with the heart over the next few years, including receiving a pacemaker in 2010. It also states there was septum wall thickening, an impaired relaxation pattern with restrictive profile, and normal ejection fraction (65%). The article also states that the septum had a "granular sparkling appearance." (Note: Those are common findings in a patient with cardiac amyloid involvement.)

In 2011 a renal biopsy showed the presence of amyloid with congo red staining. The amyloid deposits were primarily glomerular. Immunofluorescence was positive for fibrinogen, and genetic analysis found him to have the Glu526Val mutation. Then they examined some tissue from his explanted heart (the original heart that was removed for transplant) and found mild amyloid deposits. The biopsies from his transplanted heart, however, did not show amyloid deposits.

As of the writing of this article (presumably late in 2012), the patient was doing well, with mild proteinuria. The article states that recurrence of amyloid is proven in the transplanted kidney, but only suspected in the transplanted heart.

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As far as I know this article describes the only case of heart-kidney transplantation in a patient with fibrinogen amyloidosis. It is also an unusual case for the obvious reason that the diagnosis of fibrinogen amyloidosis was made after the transplant. As to whether that would have made a difference in this case, the conclusion of the article states the following: "The diagnosis of systemic AFib amyloidosis at the time of discovery of proteinuria would have led us to discuss combined heart-liver transplantation or heart-liver-kidney transplantation."

This patient is not the first patient described in the literature with fibrinogen amyloidosis and clinically significant heart involvement. Another patient was described in two articles reviewed in the blog on January 6, 2014. That patient presented with proteinuria at the age of 48, and then reported shortness of breath at age 51. Heart biopsies at age 53 showed amyloid involvement, and he eventually received a pacemaker and an implanted defibrillator.

The recurrence of amyloid in a transplanted kidney has been described in other articles. This one occurred about six years after transplant, which is within the normal range if I remember correctly. The fact that biopsies taken from the transplanted heart were negative for amyloid is not unusual, as that often happens in cases of AL amyloidosis with heart involvement.

It is still worth noting that significant heart involvement with AFib is rare, whereas mild involvement has been noted in some patients. My assessment of the published data indicates renal involvement can be expected to precede clinically significant heart involvement by several years. This patient's heart attack at a time when he had only mild renal involvement likely means the cause of the heart attack was something other than amyloid. My understanding is that amyloid deposits in the heart cause a gradually stiffening of the heart, reducing the ability of the heart to pump blood efficiently. So please do not worry about AFib causing a heart attack.

Next up will be an update on Mom.


=====Monthly Blog Status Update===== 

As of July 31, 2015:

Total posts: 154 (1 in July)

Total pageviews: 28,100 (~800 in July)

Email subscribers: 12 (unchanged)

Total number of countries that have viewed the blog: 105

One new country visited the blog in July.

Senegal

=====

Citation:

(1) Legris T, Daniel L, Moal V. Delayed diagnosis of fibrinogen Aα-chain amyloidosis after dual heart-kidney transplantation. Transpl Int. 2013;26(1):e1-3.

Article Review (2009) - A preemptive combined liver-kidney transplantation in A alpha fibrinogen chain renal amyloidosis

Note: Email subscribers are getting this blog post again because when it was first published, there was apparently some strange formatting embedded in it that made things appear wrong in some email readers and on blogspot. I suspect it was some text I copied over from the Google translation of the document. I have gone back and erased all formatting and reformatted it, and it looks much better on the web site now. Hopefully it looks better in email form this time. Here is the original post, again.


It is time for my second blog post of the month, and the first article review since October. Today's article is from 2009 and was published in a French medical journal. You might expect an article to be in French if it is from a French journal, and you would be correct. Although my knowledge of French does not go much beyond what I learned on a Steve Martin album from the 70s ("It's like those French have a different word for everything!"), a couple of things will help me do a half-decent review of this article. First, the abstract is in French and English. Second, Google Translate lets you upload a document for translation, and it did an OK job. So, here we go . . .

Title: A preemptive combined liver-kidney transplantation in A alpha fibrinogen chain renal amyloidosis (1)

Authors: Jean-Philippe Delabre, Georges-Philippe Pageaux, Alain Le Quellec, Pierre Raynaud, Gilles Grateau, Georges Mourad (various hospitals in France)

Journal: Nephrologie & Therapeutique (Nephrology and Therapeutics) (2009)

Abstract:

The predominant cause of hereditary renal amyloidosis is a mutation of the fibrinogen A alpha-chain (AFib), the most common being the E526V mutation. The evolution towards terminal renal insufficiency is constant and raises the question of renal transplantation and the risk of recurrence. We describe the case of a Portuguese woman with the E526V mutation without any renal or hepatic history in her family which developed a nephrotic syndrome at the age of 35, followed by stage 5 renal insufficiency. Because of the risk of recurrence of amyloidosis on its transplant, we carried out a combined transplantation liver-kidney despite the absence of clinical or biological hepatic abnormalities. Four years later, the result is excellent and there is no sign of the disease on the new organs. This successful experience as well as the five other published cases of combined liver-kidney transplantation in A alpha fibrinogen chain amyloidosis, demonstrates the faisability [sic] and efficacy of this treatment in AFib amyloidosis.

First, a note about the abstract: I have probably discussed this in previous posts, but the E526V mutation is the same thing as the Glu526Val mutation. In this context the letter "E" is the one-letter designation for glutamic acid, whereas "glu" is the three-letter abbreviation. Similarly, "V" is the one-letter designation for valine, whose three-letter abbreviation is "val."

The article starts with a brief discussion of hereditary amyloidosis, then states that fibrinogen amyloidosis accounts for the majority of cases of hereditary renal amyloidosis. Kidney transplantation has been performed in patients with fibrinogen amyloidosis, but there is frequently a recurrence of amyloid in the transplanted kidney. Recently there have been reported cases of patients receiving a combined liver-kidney transplant in fibrinogen amyloidosis patients who have either had some liver impairment or a history of amyloid recurrence in a transplanted kidney. The case described in this article is a patient who underwent a combined liver-kidney transplant although there was no liver impairment or family history of amyloid recurrence in a transplanted kidney.

A woman of Portuguese origin born in 1964 presented in January of 2000 with edema. She had proteinuria, high blood pressure, and elevated creatinine, and was determined to be in stage 3 renal failure. Ultrasounds of her kidneys and liver were normal. She had four sisters, two brothers, two uncles and five aunts, none of whom had any known kidney disease.

A kidney biopsy showed amyloid deposits exclusively in the glomeruli, but it could not be typed with immunofluorescence. AL and AA amyloidosis had been ruled out, so familial amyloidosis was suspected. She tested negative for an ATTR mutation. Her kidney disease progressed to the point where she started hemodialysis in November of 2001.

If I understand the translation correctly, the clinical practice where she was being seen in 2000 was only able to test for ATTR mutations. But in 2002 they were able to test for fibrinogen mutations, and she tested positive for the E526V mutation at that time. She was considered a transplant candidate by then, and they decided to do a combined liver-kidney transplant to avoid recurrence of amyloid in the transplanted kidney since such recurrence had already been reported in the medical literature.

She underwent a combined liver-kidney transplant in February of 2004, with her liver being part of a domino liver transplant. At the time this article was written the patient was doing well four years post-transplant, with normal liver function and no sign of amyloid recurrence.

The discussion section of the article discusses some the history and characteristics of fibrinogen amyloidosis, such as:

• First described in 1993 
• Likely to be underdiagnosed 
• Mode of inheritance is autosomal dominant. 
• Incomplete penetrance often leads to lack of a family history of kidney disease. 
• Discovery of the disease is always tied to renal issues. 
• All cases involve proteinuria, usually progressing to renal insufficiency in two to five years. 
• Hypertension is present in about half of the cases. 
• Symptoms other than renal issues are rare, with only a few reported cases of liver failure or splenic rupture. 

There is also a good comprehensive table listing all of the published cases of fibrinogen amyloidosis up to this time, giving the number of cases in each family, ethnicity, mutation, age of onset, extrarenal symptoms, and the type of transplant.

There were a few paragraphs discussing the difficulty of diagnosing fibrinogen amyloidosis, but that did not translate well enough for me to paraphrase it here. Then there was some discussion about the justification and considerations for kidney vs. combined liver-kidney transplantation, and the results of each that have been published to-date.

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I find the patient in this article noteworthy for two reasons. First, she is from Portugal, which has a very high concentration of fibrinogen amyloidosis patients as previously discussed in the blog posts from April 12, 2014 and April 19, 2014. Second, she first presented with symptoms at the age of 35, which is definitely toward the younger end of the range for age of onset.

As indicated in the title of this article, an important point discussed with regard to this case is the fact that the combined liver-kidney transplant was preemptive in the sense that there were no issues with her liver that would warrant a liver transplant. (The kidney transplant was not preemptive since she was on dialysis.) The first liver-kidney transplants reported were due to recurrence of amyloid in a previously transplanted kidney, so a preemptive liver-kidney transplant for fibrinogen amyloidosis was relatively new. It just so happens that in an article published two months before this one (the study of 71 patients published by Gillmore, et al, reviewed in the January 12, 2014 blog post), three of the seven patients receiving liver-kidney transplants received them preemptively.

The discussion of combined liver-kidney transplantation in this 2009 article, combined with the mention of three preemptive liver-kidney transplants in the study of 71 patients published in 2009, shows how the treatment for fibrinogen amyloidosis was evolving in the mid-2000s. Isolated kidney transplants were the first method of treatment, but then with recurrence of amyloid in the transplanted kidney, combined with the knowledge that the liver is the sole source of the mutant fibrinogen, it made sense to try combined liver-kidney transplants in certain patients. That is definitely a much riskier operation than a kidney transplant alone, so there is a lot to consider when deciding between those two options.

The third transplant option for fibrinogen amyloidosis is an isolated liver transplant, with the recipient from the only known case doing well over four years post-transplant. There is some debate in the medical community regarding that option, but there is certainly no data from that first case to eliminate it as a viable option for healthy patients who are early in the course of the disease. It will be interesting to see how these transplant options evolve over the next several years, and whether or not any drug treatments are successful enough to reduce the need for organ transplants.

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Citation

(1) J.-P. Delabre, G.-P. Pageaux, A. Le Quellec, P. Raynaud, G. Grateau, and G. Mourad, "Transplantation préemptive foie-rein pour une amylose rénale à fibrinogène Aα," Néphrologie & Thérapeutique, vol. 5, pp. 139-143, 4// 2009.

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Edit 4-17-15: Added citation.

Article Review (2012) - Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses

Today's article under review expands a bit on the topic of organ transplantation that was discussed in a previous article (reviewed in the May 4, 2014 blog post), and it has the first mention of milestone in the treatment of fibrinogen amyloidosis.

Title: Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses (1)

Authors: Arie J. Stangou, Luisa Lobato, Steven Zeldenrust, Mohamed Rela, Bernard Portmann, Reinhold P. Linke, Isabel Conceicao, Gerd Otto, Henryk Wilczek, Ole Suhr, Daniel Azoulay, Gilles Grateau, Maria Picken, John O’Grady, Nigel Heaton, Bo-Goran Ericzon, Merrill D. Benson (UK, Portugal, US, Germany, Sweden, France)

Journal: Amyloid (2012)

Abstract: 

Fibrinogen A alpha-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver transplantation.

Here is a link to the article (not free) if you would like to follow along:  http://informahealthcare.com/doi/abs/10.3109/13506129.2012.668503



As stated in the abstract, this article discusses the use of organ transplantation (primarily liver) in the treatment of fibrinogen and apolipoprotein amyloidosis. This review will focus on fibrinogen amyloidosis.

The article begins by stating that the use of organ transplantation in the treatment of transthyretin-related amyloidosis (ATTR) has been widely studied, in contrast to the use of organ transplantation in the treatment of non-TTR amyloidosis types, such as fibrinogen, apolipoprotein, lysozyme and gelsolin. That fact becomes obvious when comparing the number of transplants reported to the FAP World Transplant Registry (http://www.fapwtr.org/) for ATTR vs. the non-TTR mutations.

If you think there is a mistake in the first sentence of the abstract, you are correct. The word "renal" is missing. It should state that ". . . amyloidosis due to variants in the AFib and ApoA1 genes are the most common types of hereditary renal amyloidosis in Europe and the United States." The beginning of the section on fibrinogen amyloidosis does state that fibrinogen amyloidosis is the most common form of hereditary renal amyloidosis in the UK, Ireland and the US.

Some of the basic characteristics of fibrinogen amyloidosis (AFib) are presented, specifically:

• Six different mutations, with the most common being Glu526Val
• Amyloid deposits consist solely of variant fibrinogen (no wild-type)
• Patients typically progress to end stage renal failure within 1 to 5 years of presenting with proteinuria and hypertension.
• In the past, AFib has been regarded as solely nephropathic (affecting the kidneys)

The article then makes the case that fibrinogen amyloidosis is a systemic disease, with reported fibrinogen amyloid deposition in the heart, spleen, vessel walls, abdominal fat, and gastrointestinal tract, in addition to reports of cardiovascular disease and autonomic neuropathy. A series of nine pictures of biopsy slides showing AFib deposits in various organs are shown on this page of the article.

Transplant outcomes are then discussed. Outcomes of isolated kidney transplantation are poor due to rapid recurrence of amyloid in the transplanted kidney. On the other hand, combined liver and kidney transplantation (LKT) is curative but poses significant transplant risks, especially in patients who have been on dialysis for a long time. It is preferred to perform LKT in patients before they begin dialysis. At the time this article was published, twelve cases of combined liver and kidney transplantation for fibrinogen amyloidosis patients had been reported to the FAP World Transplant Registry, with ten of those performed in the UK and two in the US.

The article then mentions that when patients have received a combined liver and kidney transplant before going on dialysis, their residual native kidney function (the remaining function of the patient's original kidneys that are not removed during kidney transplantation) has been salvaged. (That situation was described in greater detail in the 2010 article by Stangou, et al, reviewed in the February 21, 2014 blog post.) This data encourages evaluation of isolated liver transplantation early in the course of the disease to prevent progression to end stage renal failure. Then we have this sentence, informing us that it has, in fact, been done: "The first preemptive isolated liver transplant for AFib was carried out successfully in an AFib patient with moderate renal impairment at the San Francisco Liver Transplant Unit in 2011 (personal communication)."

For those of you who don't know, that patient was our very own Cathy T., who received a liver transplant exactly four years ago today, on July 12, 2010. (Not 2011 as stated in the article.) She was blogging about her experience at the time, so if you want to read about her journey you can start with the first post or jump right to the date of her transplant. She has not blogged in a few years, probably because she is too busy enjoying her bounty of grandchildren which I believe was approaching 20 when Mom and I saw Cathy and her husband at the Familial Support Group meeting in Chicago in October of 2013.

We have seen a few articles suggest an isolated liver transplant may be appropriate for AFib patients who still have a moderate amount of kidney function (GFR above 50 is often given as a recommendation). As you can see from some of Cathy's data near the bottom of the Patient Timelines page, her GFR was considerably lower than that, somewhere between 20 and 30 at the time of her liver transplant. In spite of that, she did receive a liver transplant just before the need for dialysis. (She was also part of a domino transplant, which means her liver was transplanted into another patient.) If she had waited for a liver and kidney transplant, she very likely would have needed dialysis before receiving that transplant.

Cathy's kidney function did improve to some extent after her liver transplant, such that she was no longer eligible for a kidney transplant. My understanding is that even after the source of the amyloid is removed, improvement in kidney function is slow and limited due to the scar tissue that develops. So she is living with the issues that go along with having reduced kidney function, and although her kidney function will likely never get back to "normal," here we are four years post-transplant and she still has not needed dialysis or a kidney transplant. The results of this one case certainly support the suggestion that an isolated liver transplant will halt the progression of fibrinogen amyloidosis. I would expect a patient with more kidney function remaining (higher GFR) at the time of transplant to fare even better.

As far as I know, Cathy is still the only fibrinogen amyloidosis patient to receive just a liver transplant. And I believe this article is the only mention of her transplant in the medical literature to date. Hopefully her case will be published at some point, but until then, if anybody out there is in a similar situation such that an isolated liver transplant is being considered, know that it has been done and it did appear to halt progression of the disease.

This article does give us another way to look at how rare fibrinogen amyloidosis is and how late the diagnosis is, since there had been only 12 combined liver and kidney transplants (and one isolated liver transplant) performed on AFib patients at the time this article was written. That is less than one per year since the first description of a fibrinogen amyloidosis mutation was published in 1993. Going forward, earlier diagnosis in relatives of AFib patients should lead to more cases in which a liver or combined liver and kidney transplant is a viable option. On the other hand, if one or more of the drug treatments under development reduce or eliminate the need for organ transplants in AFib patients, there may be very few additional liver or liver-kidney transplants. Indeed, the times they are a-changin'.


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Citation:

1. Stangou AJ, Lobato L, Zeldenrust S, et al. Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses. Amyloid. 2012;19 Suppl 1:81-84.


=====Monthly Blog Status Update===== 

As of June 30, 2014:

Total posts: 139 (1 in June)

Total pageviews: 17,200 (~1200 in June)

Email subscribers: 10 (no change)

Total number of countries that have viewed the blog: 97

3 new countries viewed the blog in June:

Jamaica
Libya
Luxembourg

=====

Article Reviews (2005 and 2008) - AFib in Portugal

Today's blog post will actually cover two more abstracts, both of which describe fibrinogen amyloidosis patients in Portugal

Title: Fibrinogen A-alpha Chain Amyloidosis: Homozygosity for the Glu526Val Mutation

Authors: Carlos M. Matos, Isabel Tavares, Paul Moreira, Elísio Carvalho, Maria J. Saraiva, Luisa Lobato. (Nephrology, Hospital Geral de Santo António, Porto, Portugal; Nephrology, Hospital de São João, Porto, Portugal; Molecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal.)

Here is a link to this abstract if you would like to follow along:  http://www.abstracts2view.com/era_archive/view.php?nu=ERA5L_1540

This paper is an abstract presented at the XLII ERA-EDTA Congress in June of 2005. ERA-EDTA is the European Renal Association - European Dialysis and Transplant Association.

The previously reviewed article (in the April 5, 2014 blog post) described the first case of fibrinogen amyloidosis in Portugal. The current abstract, from 2005, presents another case from Portugal with an interesting twist we have not seen before. The patient in this case was a Portuguese woman who presented with hypertension and renal failure (among other things) at the age of 44. A kidney biopsy showed extensive amyloid deposits in the glomeruli. She started hemodialysis at the age of 45 and received a kidney transplant six years later. Nothing unusual about this case so far . . .

Her original kidney biopsy was re-evaluated by immunohistochemistry and found to be positive for fibrinogen. DNA analysis showed she had the Glu526Val mutation, but instead of being heterozygous (one gene is normal, one is mutated) she was homozygous for the mutation. That means she inherited the mutation from her mother and from her father. Both of her parents died in their 80s without any known kidney issues. The only family history of kidney disease she was aware of was an aunt on her father's side who developed end-stage renal disease late in life.

At the time this abstract was written, it was 8 years after her kidney transplant and she had stable kidney function with no proteinuria and a serum creatinine level of 1 mg/dL.

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We cannot reach any firm conclusions about the effects of being homozygous vs. heterozygous for the Glu526Val mutation from this one case. It does mean 100% of her fibrinogen was variant instead of 50% for heterozygous patients. On the one hand, she required dialysis at the age of 45, which is toward the low end of the range (36 to 82) presented in the 2009 article by Gillmore, et al. On the other hand, her kidney transplant was showing no clinical sign of amyloid after 8 years. They did find that her fibrinogen levels were low but her blood clotting times were normal.

The fact that this patient inherited the Glu526Val mutation from both parents means the mutation was present in two different family trees that happened to join together when her parents married and had offspring. So the chances are good that some more cases from Portugal will be reported. Sure enough, three years later, at this same conference, another abstract is presented that reports on fibrinogen amyloidosis patients in Portugal.


Title: Fibrinogen Amyloidosis: Report of the Portuguese Cluster

Authors: Isabel Tavares, Luciana Moreira, Joaquim Pinheiro, M. João Rocha, Elíseo Carvalho, Paulo P. Costa, Luísa Lobato. (Unit of Inv. and Research in Nephrology (FCT-725), Portugal, Fac. of Medicine, Porto, Portugal; Centro Estudos Paramiloidose, INSA, Porto, Portugal; Depart. Nephrology, Hospital Militar, D. Pedro, Porto, Portugal; Depart. Nephrology, Hospital Geral Santo António, Porto, Portugal)


Here is a link to this abstract if you would like to follow along: http://www.abstracts2view.com/era_archive/view.php?nu=ERA08L_454

This paper is an abstract presented at the XLV ERA-EDTA Congress in May of 2008. It states that Portuguese patients with amyloidosis, proteinuria or renal failure since 1985 were evaluated for this study. Biopsies were tested by immunohistochemistry, and if AL, AA, or ATTR amyloidosis could not be identified, then DNA analysis was done to identify mutations in apolipoprotein A1 and A2, fibrinogen and lysozyme. They did not identify any patients with apolipoprotein A1 or A2, or lysozyme, but they did identify 12 patients with the fibrinogen Glu526Val mutation, including the homozygous patient described in the 2005 abstract. (That does explain why her kidney biopsy was re-evaluated, as mentioned in the previous abstract.)

Since all of these patients were from Portugal, a country with a population of about 10 million, that alone seems like a high concentration of fibrinogen amyloidosis patients. But now consider the fact that all of these patients are from the Braga district in northern Portugal, which has a population between 800 and 900 thousand, and it is clear that the word "cluster" to describe this group of AFib patients is appropriate. These kindreds had no known relation to each other, but it is quite likely they have a common ancestor, given the geographical distribution of the families.

The abstract gives some more clinical data on these patients, and it does state that organ involvement in addition to kidneys was frequent with them. I am not going to discuss those details at this point because it is repeated in the next article up for review, which was published three years later in 2011. But I will let you know that the homozygous patient described in the 2005 abstract still had no sign of recurring amyloidosis when this 2008 abstract was written, 11 years after her kidney transplant.

The next article to be reviewed will have more information on these Portuguese patients, plus it will have the benefit of three more years of follow-up. We will take a closer look at the symptoms among this group, and we will also find out about the homozygous patient and her kidney transplant. Stay tuned . . .

Article Review (2010) - Recurrence of Amyloidosis in a Kidney Transplant

Today's article being reviewed is another kidney biopsy teaching case from the American Journal of Kidney Diseases. (I reviewed an earlier teaching case in the February 14, 2014 blog post.) In keeping with our recent discussion of organ transplants, this article describes a case in which a transplanted kidney was affected by amyloidosis. It closes with an overview of the published data regarding transplant outcomes for fibrinogen amyloidosis, and includes a suggestion that I find a little strange.


Title: Recurrrence of Amyloidosis in a Kidney Transplant (1)

Authors: Sanjeev Sethi, Fernando Fervenza, Dylan Miller, Suzanne Norby, Nelson Leung (Mayo Clinic, Rochester, MN, USA)

Journal: American Journal of Kidney Diseases (2010)

Here is a link to the article (not free) if you would like to follow along:  http://www.ajkd.org/article/S0272-6386(09)01594-7/fulltext


This article starts by mentioning there are many reasons kidney transplants fail over time, with rejection, hypertension and infection being some of the more common causes. It then states that the cause of transplant dysfunction in this case was identified on a biopsy.

This case is somewhat interesting because it includes a misdiagnosis of AL amyloidosis. Around 1990, a 50-year-old man developed hypertension and type 2 diabetes. At the age of 58 he was found to have proteinuria, and a kidney biopsy showed amyloidosis. Stem cells were collected in anticipation of a stem cell transplant, but the stem cell transplant did not proceed because his kidney failure progressed to the point where he required dialysis.

In May of 2000, at the age of 60, this patient was evaluated at the Mayo Clinic for a second opinion regarding his advanced kidney disease and treatment for amyloidosis. A bone marrow biopsy and fat pad biopsy were negative for amyloidosis, and a cardiac echocardiogram showed no evidence of amyloid. Since there was no evidence of a plasma cell dyscrasia (abnormality) to indicate AL amyloidosis, familial amyloidosis was suspected. Genetic testing showed he had a mutation for fibrinogen amyloidosis.

The patient received a kidney transplant from a living donor in August of 2003. There were some minor complications discussed in the article, but it was successful. After things stabilized his serum creatinine was 1.7 mg/dL, and his measured GFR was 61. (Side note: Normally we see estimated GFR, sometimes written as "eGFR." But there are methods to actually measure the GFR based on how quickly something is filtered out of the blood or into the urine.) The article then gives the results of his annual evaluations for the next several years (skipping 2006). Kidney biopsies were done most years as a matter of protocol.

2004: Biopsy showed no sign of rejection.

2005: Creatinine=1.7; GFR=53; Proteinuria = 59 mg/day. Biopsy showed "a mild increase in interstitial fibrosis."

2007: Creatinine=1.8; GFR=43. Congo Red staining of the kidney biopsy was negative, but some amyloid fibrils were visible under electron microscopy. This was the first indication that amyloidosis was recurring. Mass spectrometry showed the amyloid deposits were composed primarily of variant fibrinogen.

2008: Creatinine=2.0; GFR=40; Proteinuria=86 mg/day. Biopsy showed amyloidosis on light, immunofluorescence, and electron microscopy.

2009: As of July of 2009, nearly six years post-transplant, measurements of kidney function were essentially the same as they were in 2008.

The articles then goes into some more detail on the findings of the all of the kidney biopsies, both pre- and post-transplant. The Discussion section of the article gives a basic overview of how amyloidosis is diagnosed and typed, then it gives a summary of this particular case. There was a significant decrease in kidney function four years after transplant although Congo Red staining was negative at four years and positive at five years post-transplant.

After a quick overview of fibrinogen amyloidosis, the kidney transplant results from the 2009 article by Gillmore, et al (reviewed January 12, 2014) are discussed. That article reported on 12 kidney transplants, with three failing due to technical difficulties (not amyloidosis related) and amyloidosis recurring in four of the remaining nine. One of those kidney transplants in which amyloidosis has recurred was still functional after 12 years.

The use of combined liver-kidney transplants (LKT) is then discussed, with the article mentioning that LKT has been successful in preventing recurrence of amyloidosis because removing the liver removes the source of the variant fibrinogen. Near the end of the article is a sentence that includes a suggestion regarding organ transplantation that I do not recall seeing before: "Because recurrent fibrinogen A alpha-chain amyloidosis is slow to develop, it has been suggested that liver transplant be performed only after recurrence results in transplant failure." That would certainly not be my suggestion, but I can see how someone could make a case for that. In my opinion, if you think you might need a liver transplant after a kidney transplant fails, and you think you will be healthy enough for it, then you might as well get a combined liver and kidney transplant now.

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Although we have seen several articles mention recurrence of amyloidosis in kidney transplants, this article is the first one to provide the details of the clinical history of such a recurrence. Keep in mind that the time from transplant to amyloid recurrence to transplant failure varies over a wide range, and this case is just one sample from that group. A few important items to note from this article are:

• The progression of kidney failure when amyloid recurs is slow, much like it is was when the native kidneys were first affected by amyloid.
• As a result of this slow progression, recurrence of amyloid in a kidney transplant does not indicate an imminent failure of the transplanted kidney. (I think it would be fair to say a recurrence of amyloid does indicate an eventual failure of the transplanted kidney.)

The topic of transplant options was also discussed in this article, including a suggestion that seems a little strange at first glance. (Do not get a liver transplant until after your first kidney transplant fails.) There are typically no easy answers regarding organ transplants to treat fibrinogen amyloidosis, and we have seen that there is not a consensus of opinion in the medical community. Since we seem to be discussing transplants a lot lately, and our knowledge base is expanding quite rapidly as we include more and more published data, I am in the early stages of developing another standalone page to present the pros and cons of the various transplant options. So that page may magically appear in the next month or two.

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Citation:

(1) Sethi S, Fervenza FC, Miller D, Norby S, Leung N. Recurrence of Amyloidosis in a Kidney Transplant. Am J Kidney Dis 2010; 56: 394-398.

Article Review (2010) - Response to the Stangou article

Today's article review will actually cover a letter to the editor that was written in response to the article I reviewed in the February 21, 2014 and February 28, 2014 blog posts, plus a response to that letter from the authors of the original article.

Title: Hereditary fibrinogen A alpha-chain amyloidosis: clinical phenotype and role of liver transplantation. (1)

Authors: JD Gillmore, HJ Lachmann, A Wechalekar, PN Hawkins (National Amyloidosis Centre, London, UK)

Journal: Blood (2010)


You may recall that none of the authors of the original article (the study of 22 patients) were from the National Amyloidosis Centre (NAC) in London. Well, all four authors of this letter to the editor are from the National Amyloidosis Centre, and they clearly state their differences of opinion. At the beginning they refer to the 2009 article they were all coauthors of that followed 71 fibrinogen amyloidosis patients (reviewed in the January 12, 2014 blog post), and state that 20 of the patients in the 2010 article by Stangou et al were also part of this group of 71. The two main points of contention are whether or not fibrinogen amyloidosis fits the definition of a systemic disease, and the use of organ transplantation in the treatment of fibrinogen amyloidosis.

To make the rest of this review a little easier to read, instead of writing something like "the letter to the editor states that . . ." I will write "Gillmore states that . . ." Similarly, when referring to the authors' response to the letter to the editor, I will write something like "Stangou says . . ." To help you keep things straight, here is a list of the articles and letters that are involved here, and the lead author of each one:

 - Study of 71 AFib patients published in 2009; Gillmore (2)
 - Study of 22 AFib patients published in 2010; Stangou (3)
 - Letter to the editor responding to study of 22 AFib patients; Gillmore
 - Response to letter to the editor; Stangou



Is Fibrinogen Amyloidosis a Systemic or a Renal Disease?

The 2010 Stangou article clearly tries to establish that fibrinogen amyloidosis is a systemic disease, referring to cardiovascular issues as well as autonomic neuropathy. Gillmore, in the letter to the editor, states that in their experience at the NAC, AFib is primarily a renal disease that is not associated with cardiac amyloidosis or autonomic neuropathy in a clinically significant way. He states that few if any AFib patients have the necessary combination of features to fit the international consensus definition of cardiac amyloidosis. Gillmore also states that simply finding amyloid deposits in tissue does not confirm a diagnosis of amyloidosis, since amyloidosis is a clinical disease that results from amyloid deposition. For instance, amyloid deposits are often found in elderly persons who do not have amyloidosis.

Stangou responds by first pointing out that Gillmore’s study of 71 patients showed, via SAP scintigraphy, adrenal amyloid deposits in 21% of patients and splenic deposits in 89%. She also points out that SAP scintigraphy cannot visualize amyloid deposits in the heart or the nerves, and 10 of the 20 patients who were part of both studies had echocardiographic features consistent with cardiac amyloidosis. Stangou then states that the international consensus criteria for distinguishing between localized and systemic amyloidosis supports characterizing AFib as systemic amyloidosis.

Organ Transplantation to Treat Fibrinogen Amyloidosis

Gillmore states that the use of combined liver and kidney transplantation (LKT) to treat fibrinogen amyloidosis is highly contentious due to high early mortality and insufficient follow-up to date that shows a renal or overall survival benefit. He then offers statistics comparing the survival of patients who received just a kidney transplant versus the survival of those receiving a liver and a kidney. Stangou counters with her own statistics which seem to show a benefit of LKT. Stangou also mentions that the side effects of long-term hemodialysis and the advancement of AFib disease in other organs also impacted the early mortality in three of six LKT patients, which highlights the importance of patient selection and timing for transplantation. I am not going to dig into the statistics from either side to try to determine who is right, but just be aware that there are multiple ways of analyzing any set of data. There is often one statistic that seems to show one thing and another statistic that seems to show something contradictory.

So how does Dr. Gillmore feel about Dr. Stangou’s suggestion to consider preemptive isolated liver transplantation in AFib patients? Quoting from the letter to the editor, he considers it “completely unfounded.” First I want to make sure we understand what Stangou means by “preemptive.” Toward the end of the 2010 article, Stangou suggests that isolated liver transplantation be considered “early in the course of amyloid nephropathy,” before end stage renal failure develops, to avoid the need for kidney transplantation. So in that context, “preemptive” is after symptoms develop, but before dialysis or a kidney transplant is needed. It is not before any symptoms develop at all. Gillmore makes it clear that liver transplantation before symptoms develop, which could in theory be considered for someone who has tested positive for an AFib mutation but is asymptomatic, is not advisable because “most carriers never develop any disease.”

Once symptoms do appear, though, Gillmore still is not in favor of isolated liver transplantation because of the substantial kidney damage that is usually present at the time of clinical presentation. He states that significant kidney damage occurs in approximately 35% of liver transplant recipients anyway, so the stress of a liver transplant followed by long-term anti-rejection medication would place kidneys already damaged by AFib at even greater risk. Stangou had already addressed those concerns in the original article (suggesting GFR > 50 as a requirement for isolated liver transplantation), and in her response to Gillmore she mentioned the fact that in both of the patients who received liver and kidney transplants before reaching end stage renal failure, they determined that the patients’ original kidneys maintained their function post‑transplant. Then she simply states again that isolated liver transplantation is a feasible and rational approach that should be considered for patients in the early stages of the disease, with the results evaluated regularly.


My Two Cents

Regarding the question of whether fibrinogen amyloidosis is a systemic or a renal disease, it certainly appears to be a renal disease when patients first present. But we have seen many documented cases of other organs involved such as the spleen, liver, and heart, not only in these recent articles but in many of the previously published articles. The involvement of other organs definitely does not occur as frequently as kidney involvement, but much like the penetration of AFib in general, which is less than 100% (less than 100% of patients with the mutation will develop symptoms), the penetration into other organs appears to be lower still. If we can call AFib a renal disease with less than 100% penetration into the kidneys, we should be able to call it a systemic disease with less than 100% penetration into other organs. I suspect as more AFib patients are followed and live longer, more cases of other organ involvement will be documented.

Regardless of any official classification, treatment options are still what really matters to the patients. Setting aside potential drug treatments for now, the options for organ transplants to treat AFib are kidney only, liver plus kidney, and liver only. With isolated kidney transplantation, the patient’s kidney function is restored but the transplanted kidney tends to become affected by amyloid deposits at some point. The time required for that to take place varies over a wide range, so it is difficult if not impossible to predict how long a transplanted kidney will last. Combined liver and kidney transplantation (LKT) satisfies the need to restore kidney function and also eliminates the source of the variant fibrinogen. The best reported outcomes have been after combined liver and kidney transplants, since the data clearly shows amyloid deposits regress after LKT, and no additional amyloid deposits develop.

Based on outcomes alone, it would seem like a combined liver and kidney transplant is a better option than kidney transplant alone. But there is a lot to consider in addition to the potential outcome. One has to also weigh the risks of any medical procedure, which are significant in the case of organ transplants and very dependent on the patient’s current health status. My understanding is that a liver transplant is much more complicated (riskier) than a kidney transplant, and that was the point Gillmore was making in response to the Stangou article. So when deciding between a kidney only vs. a liver and kidney transplant, the patient’s current health and life expectancy are important factors to consider.

Regarding liver only transplants for AFib, there is no published data to refer to since the first one was done in July of 2010, a few months after these articles were published. That patient, our very own Cathy T., underwent a liver transplant with a GFR well under 30, which is considerably lower than the minimum of 50 that was recommended in the Stangou article. As of three years post-transplant she was doing very well, and she did recover enough kidney function such that she is no longer eligible for a kidney transplant. I am not aware of any other liver-only transplants for AFib patients, so we only have this one example from which to draw any conclusions. Based on that one data point, though, it seems reasonable to consider an isolated liver transplant early in the course of the disease.

In conclusion, when treating fibrinogen amyloidosis, the decision on which type of organ transplant to pursue, if any, must take a lot of factors into consideration. There are no easy answers and there are differences of opinion even among the experts within the medical community. If you add in the possibility of drug treatments that are currently in clinical trials, there is even more to consider. That is one reason it is so important to consult with doctors at a center of experience if at all possible, since they will have access to the latest information regarding treatment options.

The question of which type of organ transplant is definitely a situation where the patient needs to be informed enough to participate in the decision-making process. There is a lot to consider and it takes time to process it all, which is another reason possibly affected family members should consider genetic testing sooner rather than later. A person who waits until symptoms develop before learning about treatment options is at a big disadvantage compared to a person who starts learning about treatment options before symptoms develop. 

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Citations:

(1) Gillmore JD, Lachmann HJ, Wechalekar A, Hawkins PN. Hereditary fibrinogen A alpha-chain amyloidosis: clinical phenotype and role of liver transplantation. Blood. 2010;115(21):4313; author reply 4314-4315.

(2) Gillmore JD, Lachmann HJ, Rowczenio D, et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol 2009; 20: 444-451.

(3) Stangou AJ, Banner NR, Hendry BM, et al. Hereditary fibrinogen A alpha-chain amyloidosis: Phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 2010; 115: 2998-3007.

Reevaluation

In today's post we will take a break from the article reviews and instead give an update on Mom, followed by the always exciting monthly blog stats at the end. (After a three-month hiatus, the blog's quest for worldwide coverage resumed at a furious pace in February.)

Generally speaking, things are going ok at dialysis. Some days there are no issues, but on other days Mom's arm starts hurting so much that she has to have them stop dialysis before the full four hours have completed. Her hemoglobin was dipping below 9 earlier this year for some reason, and she was feeling a little more anemic as a result of that. But it was back up to 11.2 at the end of February, so hopefully that problem is behind us.

Her new nephrologist changed her medication a little near the end of February. He increased the dosage of Carvedilol from 25 mg daily to 37.5 mg daily, and he also replaced the Amlodopine with Nifedipine.

As I mentioned in the February 7, 2014 post, we were notified in January that Mom might have a chance of being placed on the kidney transplant list again, as a result of the elimination of the "living donor only" category. I went with her to some appointments with the pre-transplant group on Thursday, February 27, to begin her reevaluation.

The first appointment was with a transplant surgeon. As soon as Mom arrived they took her vital signs then sent her back to the waiting area. She told me her blood pressure was 114 over 46, and her pulse was 43. Yikes. Today was the first day she took the Nifedipine instead of Amlodopine, so the Nifedipine is definitely having an effect. She said she felt a little dizzy, so I was a little concerned. We met with the transplant surgeon, Dr. K. He asked some basic health questions and went over what they actually do in a kidney transplant (the basic plumbing connections) and what some of the potential complications are with the surgery itself. He said the typical wait time for a kidney is four years, which was a little depressing because that would mean four more years of dialysis for Mom, while her health would likely deteriorate. We did ask him if he thought Mom would be a candidate for a liver and kidney transplant, and he was rather quick to say no, given her age.

The next appointments were at a different location and we had plenty of time to get there. Mom asked if we could stop somewhere along the way so she cold get something to eat, hoping that would make her feel better. We did that, and she felt a little better but was still not feeling 100% well. I knew one of the next appointments would be with a nephrologist, so we could discuss it at that time.

When they took Mom's vital signs at the next location, they took them with Mom sitting and then standing. Her blood pressure was 115/70 sitting, 115/64 standing. Her pulse was 50 sitting, 48 standing. So things are getting a little better. The nephrologist we met with was Dr. R. That appointment went very well, and she definitely gave us the impression that Mom was a good candidate for a kidney transplant. She was very impressed with how much weight Mom had lost since they last saw her in July of 2012. She said assuming the medical records from Mom's cardiologist and dermatologist do not indicate any problems, she would recommend Mom for a transplant. She also went over some of the possible side effects of the medications people are on after a kidney transplant. Dr. R said most kidney transplant patients say they do not really feel like themselves until about three months after transplant. I got the impression that the most likely long term side effect might be some shakiness, especially in the hands, similar to the early signs of Parkinson's disease. In spite of all the potential side effects, Dr. R said the only patients who have told her they regret getting a kidney transplant have been some who were doing peritoneal or hemodialysis at home before the transplant.

Regarding the four year waiting time that Dr. K had mentioned, Dr. R said that Mom's waiting time started when she was first listed for a transplant, and she is still accruing time although she is not listed as eligible right now. That is obviously good news because it means her wait time has been accruing since August of 2012. So if the typical waiting time for a kidney is four years, she really did not lose anything by being first listed as eligible only for a living donor, and then listed as ineligible since November of last year.

We told Dr. R about Mom starting the Nifedipine today and what effect that was having. She did not seem overly concerned or alarmed and agreed that it was most likely Mom's body adjusting to the medication change. We then met with Mom's transplant coordinator, whom we had both spoken to over the phone before on multiple occasions, so it was good to put a face to a name. She said she would present Mom to the transplant committee after gathering the records from her other doctors, and we should know something within three weeks.

In summary, we came away from these appointments feeling pretty good about Mom's chances of getting a kidney transplant. Since that day, Mom has had a kidney ultrasound and also met with the social worker at the pre-transplant group. We don't have any results from the ultrasound yet, but Mom thinks the appointment with the social worker went well. Then at dialysis on Wednesday of this week Mom was talking to her nephrologist about it, and he looked in her records and saw that Dr. R had submitted her report and recommended Mom for a transplant. Mom's blood pressure has also been fine since that first day she took the Nifedipine, so maybe her current combination of blood pressure medications will keep that under control for awhile.

So right now Mom's doing well, all things considered, and things appear to be moving toward getting Mom on the waiting list for a kidney transplant, this time without the living donor requirement.

Next up: A little disagreement in the medical community.

=====Monthly Blog Status Update=====

As of February 28, 2014:

Total posts: 128 (4 in February)

Total pageviews: 12,200 (~1300 in February)

Email subscribers: 8 (gained 1 in February)

Total number of countries that have viewed the blog: 85

6 new countries viewed the blog in February:

Algeria
Azerbaijan
Bolivia
Croatia
Macau
United Arab Emirates

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Article Review (2009) - Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen A alpha-Chain Amyloidosis

Today's article under review is one of the more important articles on fibrinogen amyloidosis. It follows 71 patients who were diagnosed at the National Amyloidosis Centre (NAC) in the UK. Prior to this article, the largest number of patients covered in one article was 20, from the paper presented at the XIth International Symposium on Amyloidosis in 2006. Those patients were also evaluated in the UK, and I reviewed that paper in the November 30, 2013 blog post. It should be very clear by now that fibrinogen amyloidosis is much more prevalent in the UK than in any other country.

Title: Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen A alpha-Chain Amyloidosis (1)

Authors: Julian D. Gillmore, Helen J. Lachmann, Dorota Rowczenio, Janet A. Gilbertson, Cai-Hong Zeng, Zhi-Hong Liu, Lei-She Li, Ashutosh Wechelekar, Philip N. Hawkins (National Amyloidosis Centre, London, UK; Nanjing University School of Medicine, Nanjing, Peoples Republic of China)

Journal: Journal of the American Society of Nephrology (2009)

Abstract: 

Mutations in the fibrinogen A -chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A -chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0 –12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.

Here is a link to the PDF of the article if you would like to follow along: http://jasn.asnjournals.org/content/20/2/444.full.pdf

Note: In this review I will occasionally write "Afib" instead of "fibrinogen amyloidosis."

There is a lot of information packed into that abstract, and even more in the article. Having so much data can seem a little overwhelming, but hopefully by presenting much of the data in a more visually appealing way (bullet points) you can understand what most or all of this data means and decide what matters to you.

Before starting the review I want to define a non-medical term that appears several times in the abstract and will likely appear several times in my review. That term is "median." You may recall studying mean, median and mode in one of your math classes in school. The "mean" of a group of numbers is simply the average. For instance, to find a student's average test score you just add up all of his or her test scores and divide by the number of tests. That number is the average, or mean.

The "median" refers to the value in the middle when the test scores are sorted in order. For example, if a student's scores on five tests were:

85, 95, 68, 100, 90

We first arrange them in order:  68, 85, 90, 95, 100

And we can see that the middle value, the median, is 90. On the other hand, the mean, or average, of those five grades is 87.6. (If the number of test scores were an even number, the median would be the average of the two values in the middle.) If we know the median of a set of numbers, we know half the values are higher than the median and half the values are lower. So the median is the midpoint of a set of numbers when they are sorted in order. Unlike the average (the mean), the median is not impacted by values at one extreme or the other. But if you want to say "average" to yourself when you see the word "median," you will still get the same general idea that is being presented.

That concludes today's math lessons boys and girls. Please put away your calculators and get out your copy of today's article.

The article starts with brief histories of hereditary renal amyloidosis and fibrinogen amyloidosis. It then states that this article reports on 71 fibrinogen amyloidosis patients who were diagnosed and studied at the UK National Amyloidosis Centre between 1992 and 2007. (Later in the article it gives an ending date of February 2008.) The article has one large section in the middle where the majority of the data is presented, so there are no useful section headings to help us navigate. But it looks to me like the data can be grouped into seven categories: symptoms, diagnosis, biopsy results, genetic testing results, progression of the disease, treatment (transplants), and comparison to other diseases. I will use those categories as section headings for this review.


Symptoms

• 100% of patients had proteinuria.
• 72% had hypertension
• 54% had some impairment of renal function. (The article does not say how that was measured, but the typical measurements would include serum creatinine and GFR.)
• The median age at presentation (first visit with a doctor regarding symptoms) was 58 years old, and it ranged from 38 to 83.
• The median time from presentation to diagnosis was 8 months, with a range from zero to 164 months. (The zero would be patients who were known to have the mutation before symptoms developed.)
• Despite the odd number of patients, the male-female distribution was equal according to the article. (35 and 36 is close enough.)

Diagnosis

• 64 patients were diagnosed with amyloidosis based on kidney biopsies. The other 7 patients were known to have Afib in their family and were diagnosed based on genetic testing, renal dysfunction, and SAP scintigraphy.
• SAP scintigraphy was done on 63 of the 71 patients. It showed amyloid deposits in the kidneys of every patient who had not already reached end stage renal disease.
• 89% of patients had amyloid deposits in the spleen. (no symptoms)
• 21% of patients had amyloid deposits in the adrenal glands. (no symptoms)
• At their initial evaluations, no patients had echocardiograms that indicated cardiac involvement.
• One patient with a novel Afib mutation (discussed later) had peripheral neuropathy that a biopsy showed was due to amyloid.
• 12 patients had been incorrectly diagnosed with AL amyloidosis. Five of those patients received chemotherapy and one received a stem cell transplant before receiving the correct diagnosis of fibrinogen amyloidosis. (For more on misdiagnosis of hereditary amyloidosis as AL amyloidosis, see the article reviewed in the blog on May 12, 2013.)
• 46% of patients had no family history of renal disease or amyloidosis.

Biopsy Results

• Every kidney biopsy showed amyloid deposits concentrated almost exclusively in the glomeruli.
• Immunohistochemical staining for fibrinogen was positive in 93% of the patients with kidney biopsies. (That is surprisingly high based on what I have read in other articles.)
• In the other 7% of cases, the patients were known to have a fibrinogen amyloidosis mutation and the overall clinical picture was typical for Afib.

Genetic Testing Results

• 64 patients were heterozygous for the Glu526Val mutation of the fibrinogen A alpha chain. Six of those patients were from a single German family, and the rest were of British Caucasian ancestry.
• Two British patients were heterozygous for the Arg554Leu mutation. (That was the first Afib mutation discovered, published in 1993.)
• Four new Afib mutations were discovered at the NAC during this time period:
• Two German sisters had the Glu540Val mutation. (I previously discussed their case toward the end of the December 30, 2013 blog post.)
• One Chinese patient had a frameshift mutation caused by a deletion at codon 525.
• One Chinese patient had a substitution of lysine for threonine at position 538. (Thr538Lys)
• One Afro-Caribbean patient had a substitution of histidine for proline at position 552. (Pro552His)
• Other than peripheral neuropathy in the patient with the Thr538Lys mutation, the clinical history and kidney biopsies of patients with these newly discovered mutations was similar to that of patients with the Glu526Val mutation.

Progression of the Disease

• The patients were followed for a median of 4 years after diagnosis.
• 17 of the patients died during this study. Median age at death was 67 years, with a range of 57 to 85.
• Causes of death were:
• Infection (6)
• Metastatic malignancy (cancer) (3)
• Dialysis withdrawal (2)
• Transplant-related mortality (2)
• Gastrointestinal blood loss (1)
• Unknown (3)
• The estimated median survival from presentation was 15.2 years.
• The estimated median survival from diagnosis was 10.9 years.
• 44 patients reached end stage renal disease (ESRD). The median age when dialysis began was 60, with a range of 36 to 82.
• Median time from presentation with proteinuria to ESRD was 4.6 years (range 0 to 10.2).
• Median time from diagnosis of amyloidosis to ESRD was 2 years (range 0 to 10.2).
• Among the 23 patients with an initial estimated GFR of over 20 ml/min, the mean rate of GFR loss was 11.5 ml/min per year.
• Thirteen of the 44 patients who reached end stage renal disease died during follow-up.
• The estimated median survival from the start of dialysis was 8.2 years (range 0.2 to 24.8).
• No patients developed the classic signs of cardiac amyloidosis, although various cardiac and cerebral events were reported.
• Amyloid deposits in the liver were detected in only two patients, both of whom had presented more than 8 years previously.
• No patients developed clinically significant autonomic neuropathy.

Transplants

• Ten patients received kidney transplants, including two patients who received a second transplanted kidney after the first one failed. (12 transplanted kidneys total.)
• The median follow-up after kidney transplantation was 5.8 years.
• Five transplanted kidneys were still functioning and seven had failed. (Three failed immediately up transplantation, so that was obviously not recurrence of amyloid.)
• The estimated median survival of the transplanted kidneys that did not fail immediately was 6.7 years (range 0.9 to 12.2).
• Three transplanted kidneys, including two in the same patient, failed due to recurrence of amyloid after 5.8, 6.0 and 7.4 years. The fourth failed transplanted kidney did not have evidence of amyloid.
• The longest surviving kidney transplant was 12.2 years. Surprisingly, this patient had proteinuria 7.6 years after transplant, and SAP scintigraphy shows amyloid in the transplanted kidney.
• Seven patients received combined liver and kidney transplants. The longest survivor in this group was healthy and completely free of amyloid 11.5 years after the transplant. One patient died perioperatively (during pre-op, surgery, or recovery) due to acute necrotizing pancreatitis, and the other five patients were doing well with no evidence of recurring amyloid. Median follow-up from combined liver-kidney transplant was 24 months.

Comparison To Other Diseases

• For these Afib patients, the median time to progress from proteinuria to end stage renal disease was 4.6 years. This is longer than untreated AL amyloidosis (7.5 to 14 months) but shorter than apolipoprotein A1 amyloidosis (8 years).
• For these Afib patients, the estimated median survival after presentation was 15.2 years, which is significantly less than for AL amyloidosis, both untreated (less than 2 years) and treated (5 years).
• For these Afib patients, the median survival from the start of dialysis was 8.2 years, which is longer than the median survival among all nondiabetic patients in the UK, aged 55 to 64, who commenced dialysis between 1997 and 2001.

Another interesting finding was regarding family members who were known to have the mutation but were asymptomatic. There were 23 people (not part of the 71) who were in that category, with a median age of 50 years (range 31 to 84). Out of those 23, six of them were older than the oldest family member who did have symptoms and was part of this study. They also did SAP scintigraphy on 12 of these asymptomatic patients, and their SAP scans were normal. I would have expected, especially in the older asymptomatic patients, some evidence of amyloid deposits in the SAP scans. Perhaps some day we will know why some people with the mutation develop amyloid deposits and some do not.

The results section of the article concludes by stating that combined liver and kidney transplantation typically provides a better outcome than kidney transplant alone, but it comes with additional risks associated with the surgery and recovery. Since it takes several years to realize the benefits of liver-kidney transplantation over an isolated kidney transplant, the authors state that their practice is to recommend liver-kidney transplants only in their younger, healthier patients.

The last section of the article just goes into some of the details on some of the analyses that were done as part of this study.

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With this article we have by far the largest number of fibrinogen amyloidosis patients described in one article. In terms of study size, 71 is still a small number compared to typical study sizes in most medical studies. But with a rare disease like this one you just are not going to find studies that include hundreds or thousands of patients.

Other than the four new Afib mutations that were discovered, there was not much unusual, or out of the norm, about these patients. One patient had peripheral neuropathy due to amyloid, and 21% of the patients had adrenal amyloid deposits (but no symptoms).

Let's look at the symptoms first. Every patient had proteinuria, with hypertension being the second most common symptom and renal impairment being third. Those are the three symptoms that have typically been mentioned in the previously published articles, so no real surprise there. But it is good to know that the first sign of amyloids affecting the kidneys may not be renal impairment. The median age at presentation was 58, which is comparable to the presentation ages previously reported.

In the diagnosis section we learn that 89% of these patients had amyloid deposits in the spleen, but no symptoms associated with that. Although previous articles had reported some spleen involvement (such as splenic rupture), this finding tells us that fibrinogen amyloid deposits are almost as likely to build up in the spleen as they are in the kidneys. Based on previous articles it seems like significant symptoms with the spleen only occur many years after kidney issues develop, although anemia among Afib patients seems to be rather common. There was no mention of anemia in this article.

The biopsy results of these patients all exhibited the classic Afib pattern of amyloid deposits almost exclusively in the glomeruli. As previously noted, there was a very high success rate (93%) of typing the amyloid in these biopsies using immunohistochemical staining.

There was no surprise with the genetic testing results, as 64 out of 71 patients (90%) had the Glu526Val mutation, which had already been presumed to be the most common Afib mutation. The four new mutations brings the total number of published Afib mutations up to nine according to the article.

The section on Progression of the Disease is what I suspect most people are really interested in. If you know you have the mutation, you want to know the answer to this question: "Once I develop symptoms, how long will it be before X happens?" There is no need to repeat the data here in paragraph form, but before you draw any firm conclusions from the data in this article, keep in mind the following points:

• This study included only 71 patients, and the median length of the follow-up period was only four years. That means only about 35 of these patients had been followed for over four years.
• If you look at the range given for each piece of data, you can see that the progression of this disease varies tremendously from patient. The median time from presentation to end stage renal disease was 4.6 years, but that varied from a low of 0 years to a high of 10.2. That means that from the time a patient presents with proteinuria, there is a 50% chance that patient will reach end stage renal disease within about four and a half years. But it could happen in less than a year, or it could take 10 years to happen.
• The decline of GFR is an important piece of information we have not seen in previous articles. GFR (estimated glomerular filtration rate) can be thought of as a rough approximation of the amount of remaining kidney function. For example, a GFR of 35 means the kidneys are functioning at approximately 35%. Previous articles have stated that fibrinogen amyloidosis is inexorably progressive, meaning it just steadily marches on and on if left untreated. It does not go into remission like some types of cancer do. This annual decline of GFR is a measure of that progression of the disease.

In the section on transplants we learn that ten of these patients received kidney transplants and seven received combined liver-kidney transplants. Previous articles have reported the failure of kidney transplants due to recurring amyloid, and this article mentions three that failed for that reason between 5 and 8 years after the kidney transplant. This article clearly shows the benefit of liver-kidney transplant over kidney transplant, while acknowledging the increased risk of the combined transplant. As with most significant medical decisions, each patient's case will be slightly different, and what is best for one patient may not be the best for another patient. This whole subject of organ transplants is one reason I think it is so important for family members to be tested for the mutation. I would much prefer having plenty of time to learn about treatment options and the pros and cons of each, rather than being faced with a transplant decision relatively soon after being diagnosed.

In the section on comparison to other disease, the article provides some data that show fibrinogen amyloidosis compares favorably to AL amyloidosis in terms of both progression to end stage kidney disease and length of survival after presentation.

In summary, there is a lot of data presented in this article that gives us an idea of what typically happens with a patient with fibrinogen amyloidosis. But the main thing to realize is that there is a very wide range of possibilities for any category of data presented here, with no way to predict what will happen with any individual patient. We already know that some people with the mutation will never develop symptoms, and among the patients in this article, all of whom did develop symptoms, the age at which symptoms were noted ranged from 38 to 83. Once symptoms do develop we know they will progress to end stage renal disease if left untreated, but we do not know how quickly that will occur. The fact that you have a fibrinogen mutation in the first place means you are not "average," so the progression of your disease may not turn out to be "average" either.

Next up: Another report on a "large" group of patients, from another European country.

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Citation:

(1) Gillmore JD, Lachmann HJ, Rowczenio D, et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol 2009; 20: 444-451.