Renal Amyloidosis – What We Need to Consider, Practical Tips

The AJKD Atlas of Renal Pathology II has recently provided a succinct summary of the diagnosis of AL (light chain) amyloidosis, the most common type of renal amyloidosis, and compared it with hereditary and other non-AL amyloidosis.  Related disorders such as light chain deposition disease (LCDD) were also recently covered.  While amyloidosis is perceived to be relatively rare, clinically relevant kidney involvement is seen in essentially all major types of systemic amyloidosis.  Moreover, patients may present relatively early in the disease process with proteinuria/nephrotic syndrome, and/or with progressing renal failure, prompting a kidney biopsy.  Furthermore, unlike most other solid organ biopsies, kidney biopsies are examined using an extended work-up, including immunofluorescence and electron microscopy, which further facilitate the detection of amyloid.  Thus, enhanced suspicion of amyloidosis among renal pathologists and nephrologists is warranted since renal pathologists and nephrologists alike are more likely than other specialties to encounter patients with systemic amyloidoses.

Below is a summary of the practical points:

  1. Congo Red stain should be examined to rule out early amyloidosis and not just to confirm its presence based on suspicion derived from the H&E morphology. We need to think about amyloid even when glomeruli are seemingly “normal”.
  2. It is NOT TRUE that thicker sections are necessary for Congo Red stain. It is only true that, in thicker sections, small deposits of amyloid are more likely to be present within the section.  To compensate for this, more than just one section should be examined, preferably from different levels in the paraffin block.
  3. Congo Red stain examined under polarized light continues to be the gold standard in the diagnosis of amyloid deposits. It is well known that polarization can be difficult to interpret and, therefore, proper optics are mandatory.  Additionally, to increase the sensitivity of Congo Red stain, slides may be pre-screened under fluorescent light (Image. 1).  Thioflavin (T or S) stain can also be used.  Other histochemical stains (e.g., crystal violet, etc) are not only less sensitive, but also less specific.
  4. Amyloid typing in renal pathology is unlike other areas of surgical pathology, largely owing to the availability of frozen sections. These sections produce less background staining caused by serum protein entrapment during fixation in paraffin sections. However, stringent criteria should be applied to the interpretation of stains.

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Image 1.  Three photographs (A-C) demonstrate Congo Red stained paraffin section with kidney glomerulus.   Image 1A shows slide viewed in normal light (bright light), Image 1B shows the same field viewed under polarized light and Image 1C shows the same field viewed under fluorescence light using TRITC filter.  While only deposits detected under polarized light are truly diagnostic of amyloid, examination of Congo Red stained slides under fluorescence dramatically increases its sensitivity and thereby helps the viewer to spot small deposits. All images courtesy of Dr. Maria M. Picken.

The main differential diagnosis in amyloidosis typing is the distinction between AL versus other types.  Careful examination of a panel of immunofluorescence stains, including immunoglobulin light chains, is helpful not only in detecting immune complex diseases but also in recognizing many pathologies associated with monoclonal gammopathies, such as AL and LCDD.  However, some cases of AL may be clearly negative or not clear cut.  It is imperative that such cases are reported as “undetermined” and then studied further by other methods in specialized laboratories.  It should be stressed that ancillary clinical studies are helpful in supporting the diagnosis of the amyloid type, but not in making it.  The amyloid type must be determined by evaluation of the deposits in tissue sections.

In the US and other developed countries, AL continues to be the most prevalent type of systemic amyloidosis affecting the kidney parenchyma, while AA is largely a “third world” problem.  Over the last few decades, we have witnessed a decline in the number of AA diagnoses in North America, while ALECT2 (amyloidosis derived from leukocyte chemotactic factor 2) has been diagnosed with increasing frequency.  In the Southwest US, this has become a leading cause of amyloidosis among Mexican Americans, accounting for more than half of amyloidosis cases.  While systematic studies of ALECT2 outside of North America are only just emerging, it appears that ALECT2 in Egypt may be the second most common type (after AA) of renal amyloid cases, with AL being in third position (C. Larsen, personal communication).  It is also worth pointing out that most of the non-AL amyloidoses were first discovered in kidney specimens.  Hence, although individually rare, collectively the non-AL cases constitute a significant proportion, estimated at 15%.   It is likely that additional types will be identified in the future.  To this end, prior in vitro experiments have shown that apolipoprotein C2 can form amyloid fibrils in the lipid-free state and that certain mutations in the protein can promote amyloid fibrillogenesis.  Most recently, reports of this type of amyloidosis, occurring in humans, have emerged (S. Nasr, personal communication).

For now, however, the most important task is identifying patients early in the disease process and distinguishing who may benefit from amyloid type-specific therapy without harming those who have an amyloid type for which no specific therapy is currently available.  Thus, “primum non nocere” – first do no harm – should be an important consideration.

Maria M. Picken, MD, PhD
Loyola University Medical Center, Chicago
AJKD Kidney Biopsy Teaching Case Advisory Board member

Please visit the Atlas of Renal Pathology II (freely available) at for related installments on this and other topics.

3 Comments on Renal Amyloidosis – What We Need to Consider, Practical Tips


  2. Thank you very much indeed. I wonder what is the evidence of practical point 1 where you mentioned that we need to think of Amyloidosis even when glomeruli on HE slides appear normal?! I beleive that renal pathologist is the only one who can judge when to request for or examine Congo red stain taking into account clinical data.
    Thanks again for the informative article.

  3. Thank you for Sharing helpful Practical Information About Renal Amyloidosis

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