As I said, today's article under review is from 1975. I mentioned this article toward the end of the February 24, 2013 blog post, but now I can do a slightly more thorough review and even more importantly, reveal something important about these patients that was discovered long after this article was published.
Title: Familial renal amyloidosis: Case reports, literature review, and classification (1)
Authors: Fred Alexander and E. Laurence Atkins (University of Calgary Medical School)
Journal: The American Journal of Medicine (1975)
Abstract:
Three siblings (two brothers and a sister) of Polish origin, presented in late middle age with the features of the nephrotic syndrome and hypertension. Glomerular deposition of amyloid was found in all on renal biopsy. No amyloid was seen on rectal or gingival biopsy. Their mother and a maternal aunt died in middle age with a clinically similar disease. These cases are compared with other forms of hereditary amyioidosis which are briefly reviewed. The hereditary amyloidoses are classified with particular emphasis on neural and renal involvement.
This article, published in 1975, is one of the early articles describing familial renal amyloidosis. Although this family was not the first reported case of renal involvement in familial amyloidosis, the authors suspected there was something different about their case. Here is a very telling sentence from the first section of the article: "The syndrome in this family may represent a new variety of hereditary amyloidosis: this is the first report of familial renal amyloidosis in a non-Jewish family of Polish extraction." It turns out the authors were correct in their suspicion, because this family was later determined to have the fibrinogen Glu526Val mutation. So this article is actually the first published clinical description of fibrinogen amyloidosis. The symptoms described in the five case reports from this family should sound familiar.
Case 1: This patient was a 58 year old man who presented in November of 1968 with hypertension and renal insufficiency. He had proteinuria and his serum creatinine was 4.8 mg/100 ml. He had seven siblings, and at the time one sister also had kidney disease and high blood pressure. His mother (Case 5 in this article) had died of kidney disease at the age of 46. He had 10 children.
A bone marrow biopsy was normal, and a kidney biopsy showed amyloid. In January of 1970 his serum creatinine had risen to 6.2 and his hemoglobin was down to 8.8 g/100 ml. Just before he died in April of 1971 at the age of 60 his serum creatinine was 18.0 and his hemoglobin was 6.0.
The kidney biopsy showed almost complete replacement of the glomeruli by amyloid. No amyloid was found elsewhere in the kidney. Post-mortem examination showed amyloid deposits in the kidneys, andrenal and spleen, but nowhere else.
Case 2: This patient was the brother of Case 1. He presented in May of 1969 at the age of 54 with proteinuria and hypertension. The proteinuria had been noted three years earlier, at the age of 51. A kidney biopsy showed the glomeruli were largely replaced by amyloid. He died of renal failure in February of 1970 at the age of 55.
Case 3: This patient was a sister of the previous two cases. Proteinuria was detected in 1960 during a pregnancy. She first became ill in 1967 with a sudden onset of edema in her legs. She was admitted to a hospital for proteinuria, hypertension and renal insufficiency in January of 1969, and died of renal failure at the age of 69. The glomeruli in the kidney biopsy specimen were almost completely replaced by material staining positively for amyloid.
Case 4: This patient was a maternal aunt of the three siblings described in the previous three cases. She first became ill in 1953 at the age of 42, and died in 1964 at the age of 53. The final diagnosis was chronic nephritis with hypertension, edema and proteinuria. There was no kidney biopsy or diagnosis of amyloidosis.
Case 5: This patient was the mother of the three siblings described in the first three cases of this article. She died in 1938 at the age of 46. The available hospital records indicate she had renal insufficiency. She was born in Poland and moved to Canada at an early age. Her parents lived to be elderly and there was no previous history of kidney disease in the family. (I think we are all familiar with that.)
The similarities of the first three cases (siblings) are then summarized:
- A nephrotic presentation (proteinuria, edema, and hypoproteinemia (low protein in the blood))
- Hypertension
- Kidney biopsy showing amyloid almost exclusively within the glomeruli
- Renal failure as the primary cause of death
The article then does a very thorough comparison of these cases of renal amyloidosis to other types of renal amyloidosis that have been previously described. I will not cover all of that here, but the main thing that differentiates these cases from most others is that the symptoms are all related to the kidney being the affected organ, and there is very little involvement of other organs. Although amyloids may affect the kidneys with other types of familial amyloidosis, kidney failure is usually not the main symptom that patients present with.
Here are a few sentences from the closing paragraph of the article, which in hindsight we know are exactly correct:
"The distinctive features of the family reported here are the pure renal symptoms -- an insidious onset of nephrotic syndrome and hypertension. . . . We, therefore, believe that they justify inclusion as having a further variety of familial renal amyloidosis. Study of the following generation as they reach middle age will help to define this entity more clearly."
So there we have the first published description of the fibrinogen Glu526Val mutation. Since these three siblings had 15 offspring between them, and we don't know how many of the other five siblings also had the mutation or how many offspring they had, we would expect there to be several individuals in the next generation who also inherited the mutation. We can be certain there was at least one who tested positive for the mutation, since that is how they know this family has the Glu526Val mutation.
So there we have the first published description of the fibrinogen Glu526Val mutation. Since these three siblings had 15 offspring between them, and we don't know how many of the other five siblings also had the mutation or how many offspring they had, we would expect there to be several individuals in the next generation who also inherited the mutation. We can be certain there was at least one who tested positive for the mutation, since that is how they know this family has the Glu526Val mutation.
Next up are some newly found articles from the 1980s, where the cause or causes of familial renal amyloidosis are investigated.
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Citations:
(1) Alexander, F., and E. L. Atkins. 1975. Familial renal amyloidosis, case reports, literature review and classification. Am. J. Med. 59:121-128.
