Friday, February 28, 2014

Article Review (2010) - Fibrinogen amyloidosis: the clot thickens!

Today's post will actually be a continuation of the previous article review plus a review of another article from the same journal issue that discusses the findings and recommendations of the first article. To help you keep things straight, let's refer to the article reviewed in the previous post (February 21, 2014) as Article A. And we will refer to today's article as Article B. First I want to discuss some of the findings in Article A, then I will discuss Article B. (There will be some overlap.)

Article A, the study of 22 patients, gave us some new information in two important areas. First, the initial symptoms these patients presented with (proteinuria and hypertension) was typical of what has been reported in previous cases of fibrinogen amyloidosis. Nothing new there. But the prevalence of other health issues reported in these patients is something we have not seen before. Fifteen of these patients (68%) had some sort of cardiovascular issue. Twenty patients (91%) had some type of autonomic neuropathy affecting the heart only (5), GI tract only (8) or both (7). (I did not mention it in the previous post, but no peripheral neuropathy was found in these patients.) We have only seen occasional reports of cardiovascular or autonomic issues prior to this article, including the study of 71 AFib patients reviewed in the January 12, 2014 blog post. I do find it odd that there were no similar reports in the study of 71 patients, since many of the patients in the study of 22 were also included in the study of 71.

Regarding the cardiovascular issues, it is interesting that significantly more patients had a family history of cardiovascular issues than kidney issues (17 vs. 5). People tend to think of fibrinogen amyloidosis as a kidney issue so they look for a family history of kidney problems. Based on this small sample size, however, it may be just as important, if not more important, to look for a family history of cardiovascular issues.

When talking about cardiovascular issues due to amyloidosis it helps me to separate them into two groups. (Keep in mind that I am not a medical professional so there may be some inaccuracies here. There are certainly some oversimplifications.) The first group of issues is when the heart itself is impacted by amyloids. This is when the walls thicken and get stiff due to amyloid deposits between the cells of the heart. That is the classic cardiac amyloidosis like what was described in a French patient in the article I reviewed on January 6, 2014. The second group of cardiovascular issues, which this article focuses on a bit more, is the buildup of plaque in the blood vessels surrounding the heart. That is a problem that can have many causes, such as high cholesterol, but this article reports that some of these plaque buildups were analyzed and found to be at least partly composed of variant fibrinogen. We know cardiac amyloidosis is underdiagnosed because the symptoms are so similar to "normal" congestive heart failure. So these issues involving a buildup of plaque are even more likely to be underdiagnosed since there is no reason to suspect amyloidosis based solely on plaque buildup in blood vessels.

The second area of significant new information in Article A is the results of combined liver and kidney transplantation (LKT) in nine patients. Based on the follow-up of the LKT patients, all indications are that the amyloid buildup and its effects were either halted or reversed after LKT. The follow-up of patients who had received isolated kidney transplants, on the other hand, clearly indicates that amyloid buildup continues due to the continued presence of variant fibrinogen.

Previous articles have suggested that liver transplant is curative for fibrinogen amyloidosis, but this is the first one that actually recommends just a liver transplant early in the course of the disease and provides some guidelines for when that may be appropriate (GFR above 50). When we inquired about a liver transplant for Mom we were told there was a hard cutoff of 40 for GFR at this particular transplant center (Baylor in Dallas). The medication given after a liver transplant is very hard on the kidneys, so they do not want to give someone a liver transplant and have them end up on dialysis as a result of the medications. One of the 22 patients in this study was initially listed for a liver transplant but then had to be listed for a liver and kidney transplant, so at the time of publication of this article (April of 2010), there had been no isolated liver transplants for fibrinogen amyloidosis. I wonder how long we will have to wait for the first one . . .

Now it's time to move on to Article B, the subject of today's review.

Title: Fibrinogen amyloidosis: the clot thickens! (1)

Author: Maria Picken (Loyola University Medical Center)

Journal: Blood (2010)

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

This short article appears in the same issue of Blood as the previous article that reported on 22 patients. It was written by Dr. Maria Picken, who, as I mentioned in the January 24, 2014 blog post, is a leading pathologist in the field of amyloidosis. She states that the article by Stangou et al expands the current medical literature in two significant ways. These are more or less what I already discussed above, but with some additional analysis.

The first way is the description of the high prevalence of other health issues seemingly related to fibrinogen amyloidosis in these patients, specifically the cardiovascular and neurologic involvement. Dr. Picken notes that the authors of the Stangou article concluded that fibrinogen amyloidosis was a cause of the cardiovascular issues seen in these patients, whereas the authors of the article reporting on a study of 71 patients reached a different conclusion, which was that the incidence of cardiovascular involvement was "comparable to that seen in patients with chronic kidney disease in general, and thus secondary to the process." So the big question is this: Are cardiovascular issues in AFib patients caused by the mutant fibrinogen (among other factors), or are the cardiovascular issues what we would expect to see in patients with any type of chronic kidney disease?

The second significant way the medical literature is expanded is the results of combined liver and kidney transplants. I will not repeat what I already wrote above, but I will quote two sentences from the article that deal with isolated liver transplants for treating AFib. "Because hepatorenal transplantation appears to prevent disease progression and allow reversal of some organ dysfunction, the authors advocate early or even preemptive transplantation of liver alone, that is, before renal failure and significant cardiovascular amyloidosis develop, especially because the latter may preclude transplantation. This is certain to be a contentious isssue, but Stangou et al provide important data to consider in designing the best approach for individual patients."

In the next post we will see just how contentious the issue of isolated liver transplantation is, as well as some questioning of the conclusions reached in the Stangou article.



(1) Picken MM. Fibrinogen amyloidosis: the clot thickens! Blood. 2010;115(15):2985-2986.

(2) 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.

(3) 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.

Friday, February 21, 2014

Article Review (2010) - Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation

As promised, today's article review covers one of the more important journal articles dealing with treatment for fibrinogen amyloidosis. It reaches some conclusions and makes some recommendations we have not seen before, which exposes some disagreement among the medical community which continues to this day. I will cover this article and the points of disagreement over the next few posts, so don't worry about having to absorb everything at once.

Title: Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation (1)

Authors: Arie J. Stangou, Nicholas R. Banner, Bruce M. Hendry, Mohamed Rela, Bernard Portmann, Julia Wendon, Mark Monaghan, Philip MacCarthy, Muriel Buxton-Thomas, Christopher J. Mathias, Juris J. Liepnieks, John O'Grady, Nigel D. Heaton, and
Merrill D. Benson (King's College Hospital, London, UK; Royal Brompton and Harefield NHS Trust, London; Imperial College London; King's College London; National Hospital for Neurology and Neurosurgery, London; Indiana University School of Medicine, Indianapolis, IN, USA)

Journal: Blood (2010)

Variants of fibrinogen A α-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m–labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.
Here is a link to the PDF of this article if you would like to follow along:

If you look at the hospital affiliations of the authors of this article you might notice two things. First, out of 14 authors, all but two (Dr. Benson and Dr. Liepnieks) are affiliated with hospitals in London. Second, none of those 12 authors from London are associated with the National Amyloidosis Centre in London. Keep that in mind for later.

As it says in the abstract, this article reports on 22 patients with fibrinogen amyloidosis (AFib) who were assessed for combined liver and kidney transplantation. (I am occasionally going to use the acronym "LKT" for "liver and kidney transplant" in this review to save myself some typing.) The topic of this article may seem familiar to you because there was a previous article review that also covered LKT assessments in a large number of patients (20). That article, reviewed in the November 30, 2013 blog post, was a paper presented at the XIth International Symposium on Amyloidosis in 2006. The older article covered 20 patients evaluated between 1996 and 2006, whereas today's article covers 22 patients evaluated between 1996 and 2007. Although there are only two additional patients in the current article, and six people were listed as authors on both articles, we can expect the current one to be somewhat more thorough with the details since its length is not limited like papers presented at symposia usually are. Plus, it has the benefit of about three more years of clinical experience following these patients.


The introduction of this article lists the types of hereditary renal amyloidosis (fibrinogen, lysozyme, apolipoprotein A1 and apolipoprotein A2), and states that there are a total of 25 different mutations among those types. Fibrinogen amyloidosis (AFib) appears to be the most common type of hereditary renal amyloidosis in Europe and in the US.

Isolated kidney transplantation has been done as a treatment for the renal failure associated with AFib, but the article states it is of limited value because the transplanted kidney (often referred to as an "allograft" or simply "graft") is usually lost within 1 to 7 years due to recurrence of amyloid. Of the 18 reported kidney transplants to date, only one graft (5.5%) has survived at least 10 years. That compares poorly with the 10-year graft survival rate of 64% among all kidney transplants. This poor outcome with isolated kidney transplants led the team at King's College Hospital in London to evaluate combined liver and kidney transplantation for AFib. That would not only restore renal function but also potentially prevent recurrence of amyloid by eliminating the source of the mutant fibrinogen, the liver.


For this study, 22 AFib patients were assessed for combined liver and kidney transplantation between 1996 and 2007. One of these patients had the Arg554Leu mutation and the rest had the Glu526Val mutation. The median age at presentation was 55 years, and the median age of assessment for LKT was 57 years. Three of these patients had previously been misdiagnosed as having AL amyloidosis, with one of those receiving chemotherapy. There is a table in the article that gives some demographics and medical information on all 22 patients (age, sex, presenting features, grams per day of proteinuria, etc.) One interesting piece of information is just one patient was known to have the mutation before presenting with symptoms, but only four others had a family history of kidney problems.

The article then goes into great detail on the methods used to evaluate the patients at baseline and during follow-up. Most of that is way beyond my understanding so I am not going to try to discuss it. We are interested in the results anyway.


Other than the obvious evaluation of kidney function, these patients were also evaluated for cardiac function and autonomic neuropathy. The results of those evaluations for each patient are given in a table and discussed in the results section of the article. I will just provide the highlights in bullet form here.

  • 12 patients initially presented with proteinuria.
  • 9 patients initially presented with hypertension or a related condition.
  • 1 patient was diagnosed due to genetic testing after a family member was diagnosed.
  • The median time from initial presentation to diagnosis was 23 months.
  • 2 patients had liver amyloidosis.

  • 15 patients had coronary atherosclerotic disease. Six of those patients had 40% to 80% narrowing of a coronary artery, without any symptoms.
  • 12 patients had severe systemic vascular disease.
  • 11 patients (out of 21) had abnormal echocardiograms, with findings consistent with amyloid.

  • 12 patients had autonomic neuropathy affecting the heart.
  • 15 patients had autonomic neuropathy affecting the GI tract.

  • All kidney biopsies showed extensive amyloid deposits in the glomeruli, with minimal amyloid deposits elsewhere.
  • 4 patients experienced ruptured spleens (three during transplant surgery). The removed spleens had widespread amyloid deposits.
  • 3 out of the 4 heart biopsies showed substantial amyloid deposits which did stain positive for fibrinogen. 

14 of these 22 patients were initially accepted for combined liver and kidney transplant, and nine of those 14 patients had received transplants as of the time this article was written. Four of the remaining patients were removed from the list due to deteriorating health, and one patient was still on the waiting list.

The nine liver and kidney transplants (LKT) occurred between January 1996 and September 2009. At a median follow-up of 67 months, six of those nine patients are alive and well. Five of the six have good kidney function. The sixth patient developed chronic allograft nephropathy, which is the leading cause of kidney transplant failure. (Therefore it was not due to recurrence of amyloid in the transplanted kidney.) Transplant outcomes were better for patients who either had not started dialysis or had been on dialysis less than six months.

Periodic echocardiograms in 8 patients after LKT show no progression of cardiac amyloidosis, up to 12 years post transplant. The autonomic GI issues improved in all patients who received LKT. Two of these patients previously had kidney transplants, and their GI issues had continued after those transplants.

Another indicator of the success of LKT is the results of periodic SAP scintigraphy (an amyloid imaging technique I discussed in the April 30, 2013 blog post). Patients who received liver and kidney transplants showed a reduction in amyloid deposits as soon as one year post-transplant, and the patient with the longest follow-up still did not show any new amyloid deposits with SAP scintigraphy 13 years after transplant. In contrast, two of these patients had previously received kidney only transplants, and SAP scintigraphy showed their amyloid deposits progressing.

Four of the nine patients who received LKT were part of a domino liver transplant, which means their livers were transplanted into patients on the liver transplant waiting list. One of those domino recipients had SAP scans and echocardiograms for five years, with no evidence of amyloid deposits. One had normal liver and kidney function after 2.5 years, and the other two were not followed-up on after they returned to their country of origin.


The discussion section is where things get very interesting. It begins with some background information on fibrinogen and fibrinogen amyloidosis, and then it states that the data in this article suggest that fibrinogen amyloidosis is neither solely nephrotic (affecting the kidneys) nor solely nonneuropathic (not affecting the nervous system). So while it is true that fibrinogen amyloidosis primarily affects the kidneys, the authors of this article are saying that it should be viewed more as a systemic disease, with particular emphasis on potential cardiovascular involvement.

Remember when I mentioned that only five patients out of this series of 22 had a family history of kidney problems? Another bit of data on each patient that can be found in the same table is whether or not there was a family history of cardiovascular problems, and the table indicates that 17 of these patients did have such a family history. Of course the question that needs to be asked is whether or not the family members with cardiovascular problems also had the mutation for fibrinogen amyloidosis, and the article states that DNA testing of family members either confirmed they did have the mutation or they were obligatory carriers due to their relationship to other family members who were confirmed to have the mutation. So for this small group of 22 AFib patients, only 5 (23%) had a family history of kidney problems but 17 (77%) had a family history of cardiovascular problems.

The type of cardiovascular disease prominent among these AFib patients and their family members is described as cardiovascular atheromatous disease, which is essentially a buildup of plaque on the inner walls of the blood vessels. A reasonable question to ask is whether this buildup is due to the variant fibrinogen that is present in the bloodstream, the effects of kidney failure, or one of the other known causes of plaque buildup. Well, in the few cases where they could analyze this material that was removed from patients, biochemical analysis showed that it was indeed composed of variant fibrinogen. The article proposes that it is a combination of factors such as hypertension, hyperlipidemia (high cholesterol), and declining kidney function that may accelerate the formation of plaque deposits composed of variant fibrinogen on the inner walls of the blood vessels. Since the glomeruli in the kidneys are essentially blood vessels, that is exactly what appears to be happening the kidneys.

The article then presents three facts that point to liver transplant being curative for fibrinogen amyloidosis. They are:
  • The amyloid deposits in AFib patients have been shown to be made exclusively of variant fibrinogen, unlike in ATTR amyloidosis, where the amyloid deposits consist of both mutant and wild-type (normal) transthyretin.
  • Variant fibrinogen is eliminated after a liver transplant. (We learned that in the article reviewed in the December 18, 2013 blog post.)
  • AFib patients who are long-term recipients of liver and kidney transplants have shown no amyloid progression at up to 12 years of follow-up.
Another related piece of data supporting the suggestion that liver transplant is curative is in the post-transplant analysis of kidney function in two transplant recipients. These patients received LKT before starting dialysis, so they had some remaining kidney function at the time of transplant. Since the native kidneys are typically left in place with a kidney transplant, the function of these native kidneys could be evaluated after transplant. They found that the native kidney function had stabilized, such that they were still providing 15% to 20% of total renal function up to five years post-transplant.
The discussion section closes with a few recommendations regarding organ transplants to treat fibrinogen amyloidosis. The third one is something we have not seen before.
  • Patients with low cardiovascular risk should be considered for combined liver and kidney transplant.
  • Patients with higher cardiovascular risk for liver transplant, or who have been on dialysis for a long time, should be considered for a kidney transplant.
  • Patients who are in the early stages of kidney involvement due to AFib should be considered for isolated liver transplantation, to prevent progression to end stage renal failure and the progression of other systemic issues as described in this article.

Regarding the isolated liver transplantation, the article recommends that a patient listed for a liver transplant be monitored monthly to ensure the GFR remains above 50 ml/min. (Units for GFR are actually ml/min/1.73 m^2, which is not only clunky to write but is difficult to grasp intuitively. Just think of it as percentage of kidney function.) If it falls below 50 the patient should be listed for combined liver and kidney transplant. I did not realize it until I read the article again for this review, but one of the patients in this study was initially listed for an isolated liver transplant but had to be listed instead for LKT when his GFR dropped too low. He is the patient still waiting for a liver and kidney transplant at the time this article was written.


Ok, there is a lot to talk about in that article. But since this post is long enough already I am going to save the discussion for the next article review, which is actually a short article about this article, from the same issue of the same journal.



(1) 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. 

[Edit 2-24-14: Minor typo.]

Friday, February 14, 2014

Article Review (2010) - New-Onset Proteinuria With Massive Amorphous Glomerular Deposits

At the end of the last post I mentioned that the next article review would be about one of the more important articles regarding treatment for fibrinogen amyloidosis. I am going to review a different article first, which was published the same month as the one I thought I was going to review.

Title: New-Onset Proteinuria With Massive Amorphous Glomerular Deposits (1)

Authors: Dylan V. Miller, Ahmet Dogan, Sanjeev Sethi (Mayo Clinic, Rochester, MN, USA)

Journal: American Journal of Kidney Diseases (2010)

Abstract: None

This article is presented as a kidney biopsy teaching case, which appears to be a feature in each issue of the American Journal of Kidney Diseases. This article presents two cases where kidney biopsies were done in an attempt to diagnose the cause of decreased kidney function. It is important to note that the authors of this article work in the Division of Anatomic Pathology at Mayo Clinic. As we learned in the December 6, 2013 post, Mayo Clinic has analyzed a lot of tissue biopsies of amyloidosis patients.

Case 1 was a 57-year-old man who presented with nephrotic syndrome and decrease kidney function. He had a serum creatinine level of 2.0 mg/dL, estimated GFR of 57, and proteinuria of 10.2 grams per day. He was on medication for mild hypertension. His brother, mother and grandmother all had a history of either kidney disease or proteinuria.

Case 2 was a 59-year-old man who presented with shortness of breath. He was found to have decreased kidney function with serum creatinine level of 8.2 mg/dL and estimated GFR less than 10. (With those lab results I doubt he was having an annual physical exam.) He also had a history of mild hypertension, but he had no family history of kidney disease.

After describing the two cases and the initial attempts at diagnosis, the results of the kidney biopsies are described. As is typical with fibrinogen amyloidosis, extensive amyloid deposits were found in the glomeruli by Congo red staining. There was only weak staining for various amyloid types, including fibrinogen in one patient. The amyloid could not be typed through immunohistochemistry, so they next performed laser capture microdissection and mass spectrometry (often referred to as mass spectrometry or simply mass spec), which is a technique that first uses a laser to cut out the areas of the biopsy with the heaviest concentration of amyloid deposits, and then subjects those samples to a process that can determine the various proteins in each sample. That seems to be the most accurate method currently available for typing amyloid deposits. As you might expect, the diagnosis for both of these patients was fibrinogen amyloidosis.

The article then gives some follow-up on these two patients. Three months after the kidney biopsy, Patient 1 had a slightly increased serum creatinine level. (But the article says it was 1.9 mg/dL, which is actually lower than the original presentation.) Interestingly his proteinuria had decreased slightly, with the only therapy being an ACE inhibitor for hypertension, and fish oil supplementation. Patient 2 was on dialysis and being considered for a combined liver and kidney transplant at nine months after the biopsy.

The next section of the article begins with a discussion of the differential diagnosis (considering the possible causes) based on the initial kidney biopsy finding, described as "nodular glomerulosclerosis." The language is definitely geared toward nephrologists (membranoproliferative glomerulonephritis, anyone?), but in the end, the positive Congo Red staining and the fibrils seen with electron microscopy confirmed the diagnosis of amyloidosis.

After discussing the basic methods of determining whether a biopsy is AL or AA amyloid, typing the more rare types of amyloid is discussed. The limitations of methods like immunohistochemistry are that relatively large amounts of sample are required, each stain focuses on a single protein, and they often have an unfavorable signal-to-noise ratio. (I believe that means when trying to interpret the results of a specific staining, it can be difficult to pick out the stained amyloid material for evaluation because there is so much other material that may also be stained.) Methods such as mass spectrometry, on the other hand, do not have those issues because only the section dissected by a laser is analyzed, and the equipment is very sensitive.

The article then describes the typical characteristics of fibrinogen amyloidosis on kidney biopsies, which include:
  • Massive amyloid deposits are essentially isolated to the glomeruli.
  • Amyloid deposits do not stain positive for immunoglobulin light chains (AL amyloidosis).
  • There is very little if any amyloid deposition in the vascular or tubulointerstitial compartments (blood vessels and other areas outside the glomeruli).
  • There will often be changes in blood vessels due to hypertension.
  • Interstitial fibrosis (damage to the tubules and the capillaries) will often be present. (That specific term was used in Mom's biopsy report.)
The article closes with some statements about amyloidosis being part of the differential diagnosis in kidney failure, and the importance of correctly typing the amyloidosis to guide treatment.


This article gives us two more cases where things went right and the patients were correctly diagnosed. It is the only article I can recall that goes into such depth on the other possible diagnoses that were considered, which I think is an important point. There are many causes of reduced kidney function whose symptoms are similar to those of fibrinogen amyloidosis, and many of those will appear similar in a kidney biopsy. The Congo Red staining seems to be the best way (perhaps the only way) to rule out those other causes and direct someone to a diagnosis of amyloidosis.

The next article up for review, as promised, will be a very important article on treatment for fibrinogen amyloidosis.



(1) D. V. Miller, A. Dogan, and S. Sethi, "New-Onset Proteinuria With Massive Amorphous Glomerular Deposits," American journal of kidney diseases : the official journal of the National Kidney Foundation, vol. 55, pp. 749-754, 2010.

Friday, February 7, 2014

Article Review (2010) - Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis

Before getting to today's article review I have an interesting update on Mom. You may recall that she received a letter from the transplant committee in November of 2013 stating that she had been removed from the kidney transplant list because she was unable to find a living donor. Mom had been on the approved list for over a year, so we knew that letter was coming and it was not much of a surprise. What was a surprise, however, was the phone call she and I both received from the transplant coordinator on January 31. It seems they have eliminated the category of transplant candidates being approved only with a living donor, and as a result they are reevaluating some people who were recently removed from the transplant list. They have scheduled Mom for some appointments later this month to see if she qualifies to be put back on the transplant list.

As I mentioned at the end of the previous post, the article being reviewed today is about a drug treatment that is applicable to patients with fibrinogen amyloidosis. This drug is the infamous CPHPC that has been discussed in the amyloidosis community for many years. It must be a popular search term because two of the three most often viewed posts on this blog have "CPHPC" in the title, and five of the top ten search terms that direct people here include "CPHPC."

Title: Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis (1)

Authors: Julian D. Gillmore, Glenys A. Tennent, Winston L. Hutchinson, Janet Ruth Gallimore, Helen J. Lachmann, Hugh J. B. Goodman, Mark Offer, David J. Millar, Aviva Petrie, Philip N. Hawkins, Mark B. Pepys (National Amyloidosis Centre, London, UK; University College London Medial School, London, UK)

Journal: British Journal of Haematology (2010)

Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group. These promising clinical observations merit further study.

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

I have mentioned CPHPC and this particular article in a few previous posts, but I will write this post as if it is the first mention of either one so you do not have to read any of the older posts. But if you want to see what was written before, just search for "CPHPC" using the search box on the right side of the blog.

First I want to set the stage for the subject in this article. When a disease is caused by the buildup of some substance in the body, it can be addressed in a few different ways. One way is to prevent the buildup from occurring, which can be done by halting the production of the substance itself or some other substance that allows it to build up. Another way is to introduce another substance, usually a medication, that causes the unwanted buildup to dissolve so the body can get rid of it.

In the case of fibrinogen amyloidosis, a liver transplant halts the production of the substance that is building up (variant fibrinogen). In the case of AL amyloidosis, a stem cell transplant is an attempt to halt the overproduction of certain blood components so they are once again in the correct ratio. (In AL amyloidosis, think of the bone marrow as a factory that produces all the parts for building automobiles. Normally the various parts are produced in the correct ratio such that they all get used to build complete cars, with very few parts left over. When a person has AL amyloidosis, the factory produces way too many of one part, such as steering wheels. These extra steering wheels never get used to build cars, so they accumulate in the blood, eventually building up to form amyloid deposits throughout the body.)

So halting the production of the substance that builds up will be different for the different types of amyloidosis. Today's article is about an attempt to develop a drug that could be applicable to all types of amyloidosis, by either dissolving existing amyloid deposits, preventing further buildup, or both. The article begins with a one-paragraph overview of amyloidosis, and then it tells us what "serum amyloid P component" is. Serum amyloid P component (SAP) is a protein that normally circulates in the blood, but its function is unknown. That's right, in spite of all the advanced medical knowledge available today, the function of SAP, which is a component of your blood, is unknown. What is known, however, is that it is found in all types of amyloid deposits and it seems to help stabilize them.

Long before he was knighted by the Queen of England for services to biomedicine, Dr. Mark Pepys and some of his colleagues at the National Amyloidosis Centre in London developed a drug that was intended to prevent SAP from binding to amyloid deposits, with the hopes that the amyloid deposits could then be cleared by the body in a normal fashion. This drug, with the chemical name (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2 carboxylic acid, is referred to as CPHPC.

When CPHPC was first used in human patients, however, there were some unexpected results. They were hoping the CPHPC would prevent SAP from binding to amyloid deposits, as well as loosen the SAP that was already bound to those deposits. What they discovered was the SAP circulating in the blood would bind to the CPHPC, and that compound was easily cleared by the liver, reducing the level of SAP circulating in the blood to almost zero. If the level of SAP drops to essentially zero, that means there is very little SAP available to bind to amyloid deposits. Since there were no known side effects of not having SAP, nobody knows what it does anyway, and mice without SAP seem to do just fine, they decided to do the small study presented in this article.

From 2001 to 2006 they studied 31 amyloidosis patients who agreed to be given CPHPC for a year. They began with patients with advanced AL amyloidosis who were ineligible for additional chemotherapy treatment and had a poor prognosis. Once they were comfortable there were no adverse effects in administering CPHPC to humans, they treated patients with other types of amyloidosis, including six patients with fibrinogen amyloidosis. The results for each type of amyloidosis are thoroughly discussed within the article, and there is also a table of results with one row for each of the 31 patients. Given the title of this blog, I will focus on the results of the fibrinogen amyloidosis patients.

Of these six AFib patients, one was on dialysis when started on CPHPC and the other five were not. Of the five who were not on dialysis, their proteinuria ranged from 2.5 to 10.9 grams per day at the beginning of treatment. These five patients were compared to a group of six AFib patients who were not given CPHPC and had similar baseline measurements. The results were generally positive. In four patients given CPHPC, proteinuria decreased over that time period, whereas it increased in all of the Afib patients who were not given CPHPC. On the other hand, the rate of decline of GFR (glomerular filtration rate) among the CPHPC patients was only slightly lower than the GFR decline among the non-CPHPC patients. But the rate of decline of GFR varies over such a wide range anyway that the difference was not considered statistically significant.

Another measurement used for comparison, which I do not recall seeing before, is the ratio of urine protein to creatinine. If I understand it correctly, this measurement is important because as renal failure progresses and GFR declines, there is less protein loss in the urine because less filtration is occurring. The ratio of protein to creatinine in the urine tends to correct for that loss of GFR. An increase in that ratio indicates that a higher percentage of protein is being lost in the urine. The starting point for that ratio among the Afib patients who received CPHPC was 543, and among those not receiving CPHPC it was 539. (The units are mg/mmol.) Among the patients not receiving CPHPC, the median increase in the urine protein to creatinine ratio was 292, with a range of 169 to 428. Among the patients who did receive CPHPC, the median change was a decrease of 92, which ranged from a decrease of 245 to an increase of 108. So that measurement definitely indicated positive results for the CPHPC users.

A slightly subjective measurement done on all patients in the study was SAP scintigraphy, which is like a CT scan that shows amyloid deposits throughout the body. When these scans are compared over a period of time in an amyloidosis patient not undergoing any treatment, the amount of amyloid in the body (referred to as the whole body amyloid load) can clearly be seen to increase. Yet again we have positive results from the patients who received CPHPC. Quoting from the article: "None of the CPHPC-treated AFib patients showed the progressive amyloid deposition which is usual in this condition."

Although we have a few measurements showing positive results among the AFib patients who received CPHPC, what did it really do for the patients in the end? Well, at least three AFib patients felt they were benefitting enough to keep taking CPHPC for an additional year when it was offered. Although the results of this study were not good enough to call it a cure, the CPHPC definitely slowed down the progression of this disease in these patients. That slowing down is evident when comparing the onset of dialysis of the group that received CPHPC to the group that did not. Patients who did not receive CPHPC were on dialysis a median of 17 months after their initial measurements were taken, with a range of 9 to 24 months. Of the five patients who did receive CPHPC before they became dependent on dialysis, one had a kidney and liver transplant 41 weeks into the study, one was still not on dialysis nearly seven years after beginning the study (wow), and the other three started dialysis after 31, 39 and 71 months. Quoting from the article again, "renal survival was significantly longer in the CPHPC group."


This initial study of CPHPC in humans showed some good results, but it is a long way from being a miracle cure for all types of amyloidosis. The results in the fibrinogen amyloidosis patients were the most notable and featured prominently in the article. Although the use of CPHPC did not appear to stop or reverse the progression of the disease, it clearly slowed the progression. That is good news as it preserves kidney function, which delays the onset of the need for dialysis. Slowing the progression also gives a patient more time to consider transplant options and possibly qualify for a liver only transplant instead of a combined liver and kidney transplant. Hopefully the ongoing clinical trials with CPHPC at the NAC will bring us a little closer to a non-surgical cure for fibrinogen amyloidosis.

The next article up for review is another very important article regarding treatment for fibrinogen amyloidosis. As an added bonus, it initiates some discussion between two groups of doctors who disagree on some conclusions and recommendations in the article, and we get to see some of that debate unfold in the following month's issue of the same journal.

 =====Monthly Blog Status Update=====

As of January 31, 2014:

Total posts: 124 (6 in January)

Total pageviews: 11,000 (~600 in January)

Email subscribers: 7

Total number of countries that have viewed the blog: 79

No new countries viewed the blog in January.  :-(



(1) Gillmore JD, Tennent GA, Hutchinson WL, et al. Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis. Br J Haematol. 2010;148(5):760-767. 

[Edit 3-1-14: Corrected year in monthly blog stats.]