Saturday, March 29, 2014

Article Review (2011) - The Role of Liver Transplantation in Hereditary Non-Neuropathic Systemic Amyloidosis

Today's article review will be a short one because it covers a rather short abstract. This abstract was presented at the 2011 Digestive Disease Week medical conference, which, according to their web site, is an annual event described as "the world’s largest gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery." Another reason for the short review is although this abstract continues our recent theme of organ transplantation, it does not really give us much new information, other than some comparison to other types of familial amyloidosis. But in the interest of completeness, it gets its own blog entry.

Title: The Role of Liver Transplantation in Hereditary Non-Neuropathic Systemic Amyloidosis

Authors: Prayman Sattianayagam, Simon D. Gibbs, Jennifer H. Pinney, Ashutosh D. Wechalekar, Helen J. Lachmann, Hawkins N. Philip, Dorota M. Rowczenio, Janet A. Gilbertson, Julian D. Gillmore

Journal: Gastroenterology (2011)

Here is a link to a one-page PDF file if you would like to follow along:

The title of the abstract is an indication that it is not limited to fibrinogen amyloidosis. Data is presented on two other types of familial amyloidosis, specifically apolipoprotein A1 and lysozyme. Apolipoprotein A1 amyloidosis is similar to fibrinogen amyloidosis because they both primarily affect the kidneys and combined liver and kidney transplantation (LKT) is often an appropriate method of treatment. Lysozyme amyloidosis, on the other hand, primarily affects the liver, often causing it to rupture.

After a short explanation of these types of familial amyloidosis and the role of organ transplants in their treatment, the abstract then gives the outcomes for all transplant patients with these types of amyloidosis who were followed up at the National Amyloidosis Centre in the UK between 1996 and 2010.

  • Fibrinogen (AFib) - Combined liver and kidney transplant (LKT) was done in nine patients, ranging in age from 49 to 61. Six of those patients were still alive through 2010, with the time since transplant ranging from 3.1 to 13.6 years. The six surviving patients underwent transplants either before or shortly after reaching end stage renal failure, whereas the three patients who were no longer living had been on dialysis for a prolonged period of time before undergoing their transplants.

  • Apolipoprotein A1 (AApoA1) - LKT was done in three patients at the ages of 27, 52 and 56. All three of these patients were alive through 2010, with the time since transplant at 11.9 years. One patient required a second liver transplant due to complications.

  • Lysozyme (ALys) - Three patients had liver transplants (due to ruptured livers) at the ages of 15, 24 and 34. Although all three lysozyme patients did have some indication that amyloid was recurring in the transplanted livers, all were alive through 2010, with the time since transplant at 5.8, 9.0 and 11 years.

The abstract concludes by stating combined liver and kidney transplantation is a viable option in some patients with AFib or AApoA1. In the case of AFib patients, better outcomes can be obtained if LKT is done before a prolonged period on dialysis.


This abstract gives us a bit of information about two other rare types of familial amyloidosis, apolipoprotein A1 and lysozyme. Based on this abstract alone it seems like apolipoprotein A1 is most similar to fibrinogen, as it primarily affects the kidneys and the liver is the main source of the variant protein (but probably not the sole source like it is for fibrinogen). I do not know much about the rare familial types other than fibrinogen, so I will not be discussing those in any detail.

The AFib patients discussed in this abstract were evaluated at the NAC in London, so they were almost certainly included in one of the previously published articles I have already reviewed. But this abstract does make a point of stating that in the case of combined liver and kidney transplant for fibrinogen amyloidosis patients, better outcomes are associated with transplants that occur before the patient has spent a long time on dialysis. That is another reason patients need to move quickly when symptoms develop, to get on a transplant waiting list as soon as possible. (A patient can be removed from the waiting list at any time if they decide against having a transplant.) What helps people move quickly when symptoms initially develop? Learning about the disease before symptoms develop. Why would someone learn about the disease before developing symptoms? Genetic testing.

The next article up for review is a long term follow-up of a large group of fibrinogen amyloidosis patients concentrated in a relatively small geographic area.

Saturday, March 22, 2014

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:

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.


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.



(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.

Friday, March 14, 2014

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. 



(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 4314-43

(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.

Friday, March 7, 2014


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:

United Arab Emirates