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How does an abnormal serum free light chain (sFLC) help in the diagnosis of renal disease?
Renal biopsies from patients may suggest a monoclonal process, and serum free light chain assays at that time aids with the process of diagnosis. I always suggest the test to the clinicians, and especially the nephrologists, to support the diagnosis of the renal biopsies. For example, a diagnosis of a light chain cast nephropathy is difficult, and the staining is seldom monoclonal. In most cases both light chains are present because the cast had been produced slowly over time, except in some cases of acute cast nephropathy where the more pertinent light chain gets trapped in the cast. Many patients present with acute renal failure, without a previous history of myeloma. Therefore, testing for abnormal free light chains in the serum is a simple way to confirm renal biopsy results.
If injury to the kidney is one of the cardinal features of plasma cell disorders, do you see early kidney damage in monoclonal gammopathies (MGUS) patients?
I see a significant number of renal biopsies from patients who have been followed for MGUS. Early manifestations of renal damage associated with monoclonal light chains present in the serum are commonly observed in the renal biopsies, whereas the bone marrow may not have clear cut evidence of plasma cell disorder or myeloma. Once you see the lesion in the renal biopsy, it's no longer an MGUS. Now it becomes a disease that should be treated. So the kidney biopsy is becoming a very important tool in deciding which patients require treatment as opposed to continued monitoring.
There are different clinical presentations of the renal disease, including renal failure, hematuria, and proteinuria/nephrotic syndrome. Do you think that sFLC should be measured in all the patients who present with the evidence of renal disease?
Yes, at least in some categories of patients. There was a time 25 years ago when I was at the University of Alabama Birmingham, it was routine for every patient who came into the hospital to get a serum protein
electrophoresis, as well as urine protein electrophoresis for Bence Jones proteins. These days, any patient over 50 with unexplained acute renal failure should probably get tested for free light chains in the serum in order to rule out a plasma cell disorder. There is no question that a significant percentage of the patients I see with acute renal failure have myeloma related disease. In addition, nine out of ten patients I diagnose with amyloidosis present initially with renal manifestations.
Dr. Herrera, do you think serum free light chain assays could help decrease the number of kidney biopsies performed?
It would definitely complement the biopsy diagnosis tremendously. To know whether the kidney damage is due to circulating light chains, one would need to do a diagnostic biopsy, with the sFLC test providing additional supportive evidence for the biopsy findings. There are significant problems with diagnosing light chain related renal disease in the clinical laboratory, primarily because of the low sensitivity of serum protein electrophoresis in demonstrating the presence of monoclonal serum free light chains, and so one needs to resort to testing the urine for light chains. This creates problems as often samples need to be concentrated because the amount of light chains may be small. To me, the serum free light chain overcomes these problems.
Can the sFLC assay be used to monitor these patients?
To monitor patients, yes. Most times the renal biopsy is done to make a diagnosis, and we often don't see sequential biopsies. Instead, patients are followed with other clinical parameters.
Is light chain cast nephropathy reversible in some instances?
It is reversible, but the long term prognosis is not good because it tends to recur. You can reverse an acute episode of cast nephropathy, and regain renal function. But renal failure remains the eventual outcome in many patients.
What percentages of patients with renal disease have immunoglobulin light chain mediated kidney damage?
Well, it depends. In my practice, I would say it could be as high as ten percent of the population. It is a combination of cast nephropathy, [Light Chain Deposition Disease], AL amyloidosis and interstitial inflammation
associated with acute tubular damage. Now that we routinely run the sFLC assay for kappa and lambda light chains to rule out a plasma cell dyscrasia, we are probably detecting more than previously.
If a serum free light chain assay is available, do you still think we need to collect a 24-hour urine sample?
Probably not. What is that going to tell me? That it went through the kidney? You already know light chains are present in the serum, you already know it can result in a kidney lesion, and to me that's plenty.
Are you going to miss anything by not doing the 24-hour urine test?
I don't think so. Previously, measuring Bence Jones proteins was the only way to find free light chains in the urine. We didn't have serum free light chain tests, and many did not show up on regular serum protein
electrophoresis. Now there are two ways to substantiate our diagnosis - by detecting monoclonal free light chains in the serum, or by confirming the presence of Bence Jones protein in the urine. To me, serum is a better option because as they go through the kidney, the light chains undergo changes that may make it difficult to detect them. In addition, some of these light chains adhere to structures in the kidneys, especially in light chain deposition disease, and if it's an AL amyloid it may never make it to the urine. You may have false negative urine, whereas you are less likely to have a false negative serum. I haven't seen a case where we have proven that there is a clonal plasma cell associated lesion in the kidney, that hasn't had the corresponding free monoclonal light chain in the serum. As you can see, it is a lot easier and better to test for it in the serum rather than in the urine.
Dr Batuman and you have suggested that light chain nephrotoxicity in multiple myeloma often presents with proximal tubular functional abnormalities. Is the process reversible if sFLC were to detect the monoclonal process earlier?
Most pathologists don't understand or recognize the lesion, and though it is a common lesion, it is difficult to diagnose as many of these light chains don't form casts. They just destroy the nephron. The good thing
about this lesion is that it's fully reversible. Normally the light chains get metabolized in the proximal tubule by lysosomes, but the abnormal light chains are not degraded by lysosomes, which leads to proximal tubular abnormalities. The proximal tubule is capable of regaining its function if the injurious agent is removed. If you tell me you have the lesion plus abnormal free light chains, you can add one plus one and have a diagnosis that should convince the hematologist that the patient needs therapeutic intervention, because many of these patients have been called MGUS.
You have been engaged for two decades in the study of glomerular damage in monoclonal light chain related renal disease. Would you like to reflect on it?
That's an even more interesting subject for free light chains, because the damage that occurs in light chain deposition disease and in AL amyloidosis is centered in the glomerulus, and it only happens because the light chain gets trapped there. After getting trapped in the glomerulus, the light chains interact with receptors and then produce tissue injury. If the light chain gets trapped there, then they are not going to be found in the urine because most of them remain in the kidney, where they inflict damage. This is a situation in which a false negative urine test for Bence Jones protein is very common. You should find the monoclonal free light chain in the serum, because that's where they're coming from. So that's another example of why I think measuring free light chains is very helpful.
Is the damage to nephron reversible?
It's a bit more complex. Of course if you detect the light chains early, you have a better chance of saving the nephron. I think once the nephron is dead, there's nothing you can do about it. But the process leading to light chain nephrotoxicity can be quite long, and in that setting looking for the free light chains at an early stage can help to make therapeutic decisions.
Lastly, Dr. Herrera, what type of screening and diagnostic algorithm would you recommend for monoclonal gammopathies or plasma cell dyscrasias?
Well, from the renal pathologist's perspective, I think that if the diagnosis starts with a kidney biopsy, and it is not known if the patient has plasma cell dyscrasia, then I would definitely measure serum free light chains. It's the easiest way to confirm the presence of a monoclonal serum protein and monoclonal gammopathy. The alternative, and more tedious option, would be to do a serum protein electrophoresis, followed by immunofixation electrophoresis (IFE), serum free light chains and urine electrophoresis. Recently, I saw a renal biopsy with amyloid deposits in a transplant patient, and for diagnosis purposes suggested a serum free light chain test before the bone marrow biopsy.
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