Today's article review is the first of three papers I will be reviewing that were presented at the eleventh annual International Symposium on Amyloidosis, which was held in Woods Hole, Massachusetts in November of 2006. The papers presented at this symposium can be found in the book XIth International Symposium on Amyloidosis, edited by Drs. Skinner, Berk, Connors and Seldin, all of the Amyloidosis Center at Boston University. The book was published in July of 2007 and is currently available for only $219.95 at Amazon.com ($154.54 for Amazon Prime members.) If you would like to look at the book without spending that much money, Muriel Finkel will loan out her copy. (But try not to keep it for four months like I did.)
In our first paper from the 2006 Symposium, fibrinogen amyloidosis continues its global spread, this time into Austria.
Title: Familial Amyloid Nephropathy of Fibrinogen A Alpha (E526V) Origin. Report of the First Case from Austria (1)
Authors: S. Hargassner, G. Biesenbach, G. Syre, K. Altland, and R. P. Linke (General Hospital Linz, Austria; Institute of Human Genetics, Giessen, Germany; and Max-Planck-Institute of Biochemistry, Marinsried, Germany)
Book: XIth International Symposium on Amyloidosis (2007)
Abstract: None
The patient in this article is a 63-year-old woman who initially presented with elevated serum creatinine. She was suspected of having lupus nephritis (kidney inflammation due to lupus) and was treated for that. Three months later she was admitted to the hospital with hypertension, serum creatinine of 3.18 mg/dl, proteinuria (3.5 grams per 24 hours), GFR of 16, and microhematuria (very small amount of blood in the urine). Her leading symptom was dyspnea (difficulty breathing), so she was initially treated for that, and then underwent further investigation.
A kidney biopsy was done, and Congo red staining showed significant amyloid deposits in the glomeruli. The biopsy was further analyzed immunohistochemically (staining against specific proteins), which showed the presence of fibrinogen. Genetic testing showed the patient had the Glu526Val mutation. She also had another fibrinogen mutation that, if I understand correctly, is a benign mutation that is randomly found in a small percentage of the population. She began hemodialysis a year later and was listed for a kidney transplant, although she was told a combined liver and kidney transplant might be curative.
There was no known history of kidney failure in her family. Both of her sons tested positive for the Glu526Val mutation, and her sister tested negative. The article then states that a de novo point mutation seems to be a possibility. (More on that later.)
The conclusion of the paper states some of the facts about fibrinogen amyloidosis that were known at the time, specifically:
- Inheritance is autosomal dominant
- Fibrinogen is produced in the liver
- Family history is usually negative (for kidney issues)
- Penetrance is incomplete
- Most patients suffer renal failure alone
- Combined liver and kidney transplantation appears to be curative
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This paper describes another case where the patient presents with the classic symptoms of fibrinogen amyloidosis, which are hypertension, elevated serum creatinine and proteinuria. A kidney biopsy showed the characteristic sign of fibrinogen amyloidosis, which is amyloid deposits in the glomeruli. An additional symptom noted with this patient that I do not recall seeing before is microhematuria, which is a very small amount of blood in the urine (not enough to cause discoloration.) As Dr. Benson stated at the recent familial amyloidosis meeting in Chicago, over time you see a pattern of symptoms develop in patients and there is a typical progression of the disease, but occasionally there will be a patient who has not read the book and has something outside of the norm.
Regarding the possibility that this was a de novo mutation, I suppose that is always a theoretical possibility until genetic testing is done on both parents of a patient. But this case does fit the pattern of the propositus (first person diagnosed) being the first person in the family known to have any kidney issues, so I don't really know why the authors of this paper bothered to include the sentence about the possibility of this being a do novo mutation.
In the next article review from the 2006 symposium, we have our first paper that could be considered a study of a large number of fibrinogen amyloidosis patients (20), instead of patients from only one or two families.
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Citation:
(1) Skinner M, Berk JL, Connors LH, Seldin DC. XIth International Symposium on Amyloidosis: Taylor & Francis; 2010.
[Edited December 23, 2013. Minor change to first sentence.]
In our previous episode, Mom's nephrologist, Dr. N, had taken her off of one medication for heart palpitations and prescribed two additional blood pressure medications, bringing the number of blood pressure medications she is on up to five as of November 8. And in the ongoing quest to determine the cause of her high calcium, he scheduled her for a CT scan of her chest, abdomen and pelvic region on Tuesday, November 12.
Dr. N went over the results of the CT scan with Mom while she was at dialysis on Friday, November 15. He said there is an abnormality in her chest cavity, but it might be due to the talc pleurodesis surgery she had in July of last year. Dr. N called the surgeon, Dr. J, and Dr. J suggested that Mom have a biopsy done to determine if the abnormality is due to the surgery or something else. (I suppose it could be the talc material or the scar tissue.) Dr. N also wants to have x-rays taken of Mom's legs. Hooray, more tests and procedures . . .
Speaking of high calcium, the upper limit of the normal range is 10. So anything above that can be considered high. Here is a chart of her corrected calcium going back to February of this year:
(That chart may run off the edge of the page when viewed on the blog, but the next smaller size was too small to read easily.)
There is not really a clear trend in that chart, but her calcium was definitely above normal for four months starting in July of this year, and it was still at the upper end of the normal range with the most recent reading in November. Maybe the calcium level is just something that fluctuates with some dialysis patients, and Mom's calcium happens to be high or almost high anyway. If that is true, then there may not really be any underlying cause that needs to be addressed. We will see what happens over the next few months.
On November 15 Dr. N also increased the dosages on two of Mom's new blood pressure medications. That is probably a routine occurrence when starting a patient on a new blood pressure medication, to start at a low dosage and then increase it if necessary based on how the patient responds. Mom had a follow-up appointment with her internist, Dr. M, on Tuesday, November 19. Dr. M said Mom's blood pressure was headed in the right direction, and Mom is not yet taking the maximum recommended dosage of the blood pressure medication, so that's good. A few days before that appointment, however, Mom's pulse was around 150 bpm when she got up in the morning, and it stayed that way until late in the morning. Dr. N has taken her off the medication she had been taking quite awhile for heart palpitations, so hopefully that elevated pulse will not be a recurring issue. I know we will all rest a little easier once this blood pressure is under control.
Next up: Back to the article reviews.
Before I begin today's update on Mom I want to discuss something that was recently mentioned in the online amyloidosis support group. It is an article titled "The Future of Amyloid Detection." Here is the link: http://www.prweb.com/releases/2013/11/prweb11303461.htm. It is about an imaging technique that has been developed to make amyloid deposits show up on a PET scan. I previously discussed a different amyloid imaging technique, SAP scintigraphy, in an article review posted on April 30 of this year. That method has been used by the UK National Amyloidosis Centre for many years, but as I understand it the substance the patient is injected with before the scan cannot be licensed for use in the US because it is derived from human blood. This latest method, developed at the University of Tennessee in the US, instead uses a synthetic peptide (known as P5), so it can be licensed for use assuming it is determined to be "safe." The article shows some comparisons of images using SAP scintigraphy vs. P5 PET scan in mice, and states that the two methods are equivalent for imaging the liver and the spleen, but P5 is better for imaging the heart and the pancreas.
I do not know how soon we can expect to see this scan in widespread use in the US, but there is a clinical trial for this peptide on the clinical trials.gov web site that recently changed its status from "Recruiting" to "Closed." The title of the trial is "Radioimmunoimaging of AL Amyloidosis" and the responsible party is Dr. Alan Solomon of the University of Tennessee, another well-known doctor in the amyloidosis community. I assume the study is essentially complete and the results will be published in the near future. It is hard to predict what impact this new tool will have on the diagnosis and treatment of amyloidosis in the US, but I think any additional tools available to doctors can only be a good thing.
Ok, now to Mom. After a difficult trip home from Chicago on Sunday and a trip to the emergency room on Monday, she was feeling better for her appointment with her internist, Dr. M, on Tuesday, October 29. We decided my sister Amy would take Mom to this appointment so we would have two sets of ears there, and also so Amy could give Dr. M more details than Mom could about what happened the day before with the emergency room visit. The three main things discussed with Dr. M were:
- The events since returning from Chicago. Dr. M said what happened can definitely be explained by the high blood pressure, the need for dialysis, and Mom not sleeping with her CPAP machine for three nights. Mom must sleep with her CPAP machine going forward, and we may have to be more cautious about letting her go three days without dialysis, such as from a Thursday to a Monday.
- Blood pressure. We have been concerned about Mom's blood pressure creeping up and getting harder to control with medication. Dr. M said Mom's nephrologist should really be on top of that, since the kidneys play such a large part in regulating blood pressure. Mom already had a prescription for hydralazine which she was to take only as needed, when her systolic blood pressure (top number) was over 180. Since she is having to take that so frequently now anyway, Dr. M gave her a prescription to take it three times per day.
- High calcium. Mom's nephrologist (Dr. N) is still trying to determine the cause of Mom's high calcium, but her internist (Dr. M) said Mom's September 16 blood tests did not show her calcium levels to be high. Well, that is confusing. Hopefully Mom can talk to Dr. N at the dialysis clinic on Friday.
The major concern now is the blood pressure, since after this latest addition Mom is now on three medications for her blood pressure. Earlier this year she was only taking one daily medicine for her blood pressure, with another one (clonidine) to take when her systolic pressure was over 160. Hopefully her nephrologist will get more involved and help bring her blood pressure down. She did feel well enough to drive down to Austin the following weekend and spend three nights. Yes, she did use her CPAP machine.
Mom usually sees the nephrologist at the dialysis clinic on Friday, but he was not there the first Friday after Mom's appointment with her internist so she did not see him until Friday, November 8 to discuss her blood pressure. In the meantime she had been keeping a close watch on it with the new medication prescribed by her internist, and it was better but still high at times. Dr. N agreed that they have to get her blood pressure down, so he made another change to her prescriptions. He took her off one medicine she was taking for heart palpitations, and he added two more for blood pressure. So now she is on five different blood pressure medications. (Geez, it was only three in the last paragraph.)
Dr. N did lower her dry weight, so that is some good news. Regarding the high calcium, he said he still wants to determine the cause although it was not very high. He did not know what the latest blood test results from the clinic showed, and Mom didn't either because the new dietitian has not been as consistent in providing those reports to the patients. (I do know it was 11.0 at her latest emergency room visit, which was after three days without dialysis.) The next test he wanted to have done is a CT scan (with contrast) of her chest, abdomen and pelvic region. She had that on Tuesday, November 12, but we will have to wait until the next blog post for those results.
