Saturday, February 28, 2015

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)


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.


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.



(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.


Edit 4-17-15: Added citation.

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