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)
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.