Title: Amyloid Nephropathy of Ostertag with Special Reference to Renal Glomerular Giant Cells
Authors: Sharon Whelan Weiss, MD and David L. Page, MD (Both from the Department of Pathology, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD, USA)
Journal: American Journal of Pathology (1973, September)
Here's a link to the PDF of this article, if you'd like to follow along: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1904021/pdf/amjpathol00253-0109.pdf
This article is the oldest one I have related to fibrinogen amyloidosis, but you won't find the word "fibrinogen" anywhere in the article. So this article is part of what I would consider the history of fibrinogen amyloidosis, before the first fibrinogen mutation was identified in the early 1990s. Here is the abstract:
The pathology of an unusual form of nonneuropathic familial amyloidosis is presented. The disease, occurring in two sisters, is similar to a form of familial amyloidosis described by Ostertag in 1950 and is characterized by progressive renal failure and an autosomal dominant mode of inheritance. Widespread vascular amyloidosis and dense renal glomerular amyloid deposits characterize the disease pathologically. Renal interstitial foam cells and glomerular giant cells were found in the kidneys of one sister. The giant cells, probably of macrophage origin, contain amyloid fibrils within poorly formed non-membrane-bounded cytoplasmic vacuoles. Transitions to well-formed membrane-bounded cytoplasmic vacuoles with nonfibrillar material were also present. It is suggested that these cells function to degrade and resorb amyloid, and that as amyloid is changed to a nonfibrillar state, well-defined membranes can form around the degraded material (Am J Pathol 72:447-460, 1973).
Before jumping into the article, let's start by defining some of the terminology used in the title and in the abstract. (I'm not going to define all the medical terms here because there are many terms I still don't understand even after looking up the definition.)
Autosomal Dominant: A method of inheritance where an abnormal gene from only one parent is necessary to inherit the condition.
Glomerular: Having to do with the glomerulus, which is part of the cortex (outer part) of the kidney. Glomerular Filtration Rate (GFR) is an important indicator of kidney function.
Nephropathy: An abnormal state of the kidney.
Ostertag: Doctor in Germany who documented familial amyloidosis affecting the kidneys in 1950.
Renal: Having to do with the kidneys.
The article begins with this sentence: "The familial amyloidoses are unusual forms of systemic amyloidosis and may be divided into neuropathic and nonneuropathic forms." So we know at the time this article was written (1973) that familial forms of amyloidosis had been described and divided into two categories, neuropathic (dealing with the nervous system) and nonneuropathic. But based on the earliest publication dates of the articles listed on the Mutations in Hereditary Amyloidosis web site, it looks like the first genetic mutations for familial amyloidosis were identified in the early 1980s. So although some familial forms had been described, the underlying genetic causes had not been identified.
The first paragraph goes on to say two sisters presented with "an unusual form of nonneuropathic familial amyloidosis of a type reported only once before." There is a reference to an article from 1950 authored by a German doctor named Berthold Ostertag, whose name will come up again. So we're dealing with something that was quite rare in 1973, having only been reported in the medical literature once before in 1950.
The article then has a paragraph with a technical description of the laboratory methods used to analyze tissue samples. Yes, Congo red staining is mentioned. Each sister's case is then described.
The first sister was admitted to a US hospital in October of 1968 at the age of 47 for high blood pressure and persistent edema. At this hospital admission she also had proteinuria as well as very elevated creatinine and BUN levels. She was released from the hospital after two weeks, but was readmitted two months later for high blood pressure and pulmonary edema (fluid on the lungs). Her BUN level was higher and she still had proteinuria. The pulmonary edema responded to therapy, but she stopped producing urine and started peritoneal dialysis in the hospital. Despite the dialysis she continued to decline and died after just under two months in the hospital.
Here is some interesting family history on this patient. Her father and her daughter both died of renal disease, and the ages of 42 and 13, respectively. (I know from reading another article that there is a rare fibrinogen mutation that can produce symptoms at a very young age.)
The autopsy showed both kidneys were reduced in size, with extensive amyloid deposits (detailed in the article). Amyloid deposits were found to a lesser extent in other organs.
The other sister was 52 years old in 1971. Two of her three children have normal renal function, and one child has started to exhibit proteinuria and hematuria (blood in the urine). She (sister #2) started having minimal proteinuria in 1949, proceeding to heavy proteinuria in 1952 (age ~33). 16 years later, in 1968, her creatinine and BUN levels were both elevated, and things gradually got worse over the next two years, including high blood pressure. In July of 1971 she received a kidney transplant and one of her native kidneys was removed at the same time. She died 16 days after the kidney transplant due to Klebsiella pneumonia.
The autopsy findings on sister #2 were similar to those of sister #1. The article also describes in detail the findings via electron microscopy of the native kidney that was removed during the kidney transplant. Several pictures of slides are included as well. You need to be familiar with the internal structure of the kidney to fully understand that section. (I am not.)
The discussion section of the article compares the case of these two sisters to the patients described by Ostertag in 1950. Ostertag reported on two brothers with similar symptoms who died in their thirties, and this article mentions that based on the involvement of members in three generations of that family it has been suggested that the mode of inheritance is autosomal dominant. The case of these two sisters is similar in terms of symptoms and probable mode of inheritance, and then the article goes into some detail on the differences between the two cases, which may or may not be significant.
The last section of the article has the heading "Glomerular Giant Cells" and goes into quite a bit of detail that's way over my head. As mentioned above, I do know the glomerulus is part of the cortex (outer part) of the kidney, and "Glomerular" is the "G" in GFR.
Before concluding this post I want to mention two other articles from the 1970s that I do not have, but based on their titles and abstracts they can help shed some light on where things stood with this disease at that time. They are:
Title: Amyloid Nephropathy of Ostertag: Report of a kindred
Journal: Birth Defects (1974)
Abstract: This report describes a kindred with an unusual form of nonneuropathic familial amyloidosis. The disorder is similar to that described by Ostertag in 1950. [Based on information in other articles that refer to this one, this report discusses four patients in three generations. The authors are the same as the 1973 article being reviewed in this post, so these patients are likely from the same kindred (family).]
[Update: The following article was reviewed again on 8-30-13.]
Title: Familial renal amyloidosis: Case reports, literature review and classification
Journal: The American Journal of Medicine (1975, July)
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 amyloidosis which are briefly reviewed. The hereditary amyloidoses are classified with particular emphasis on neural and renal involvement. [Based on information in other articles that refer to this one, these siblings lived in Canada. They developed high blood pressure and kidney issues at the ages of 42, 52 and 58, and died at the ages of 49, 55 and 60.]
So we now know the medical literature on hereditary amyloidosis affecting the kidneys goes back to at least 1950 with one article, and three more articles appeared in the mid 1970s. We can't say for certain whether or not any of these patients had fibrinogen amyloidosis since there are some other familial forms that primarily affect the kidneys, such as apolipoprotein A1 and A2, and lysozyme. There are similarities to fibrinogen amyloidosis, such as the glomerular involvement, but without genetic testing on these patients or their descendants there is no way to know for certain. Since genetic testing wasn't exactly right around the corner in the mid 1970s, we'll have to wait awhile for that. But for now the common symptoms and the progression of the disease are starting to be documented, and the mode of inheritance seems to be autosomal dominant.
In the next article review we'll see what happens in the 1980s.