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Signature ✍️
Paraprotein (serum/urine) + 1 of 3 flavors:
- [AKI-predominant]
- [Type 2 RTA, Tubular Proteinuria, CKD]
- [Proteinuria-predominant]
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Tweetorial 🐣
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DDx by Syndrome (@ASanchez_PS) 🏳️🌈
Quantitative Paraprotein Disorder
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- Myeloma: Light chain cast nephropathy (glomerulopathic features may be a superimposed feature as light chains can cause qualitative defects below)
- Waldenstrom’s: Hyperviscosity syndrome (monoclonal IgM deposition within glomerular capillaries, shown below)
⚪ The 2 diseases above are not technically MGRS as they are Myeloma-defining & Waldenstrom’s-defining findings (i.e. they represent true “cancer”)
Qualitative Paraprotein Disorder (i.e. MGRS)
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- Light chain proximal tubulopathy (aka Light chain Fanconi Syndrome)
- Crystal-storing histiocytosis (crystal-engorged histiocyte infiltration of marrow, cornea, …)
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- Organized deposits (”FIAT” mnemonic)
- Fibrillary GN (n/a)
- Immunotactoid GN (n/a)
- AL amyloidosis (HFpEF, autonomic dysfunction)
- Type I cryo. GN (vascular occlusion +/- hyperviscosity)
- Non-organized deposits (”PD” mnemonic)
- Proliferative GN w/ monoclonal Ig deposits (n/a)
- Deposition disease (asx.)
- ⊖ Ig deposits (”CT” mnemonic)
- C3 Glomerulopathy (n/a)
- TMA w/ monoclonal gammopathy (POEMS)
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DDx Algorithm (@MatthewHoMD) 🏳️🌈
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Principles ❗
🩸Monoclonal Gammopathy of Clinical Significance (MGCS)
- Quantitative paraprotein issues: “The first group of renal disorders requires the secretion of large amounts of all or part of the monoclonal Ig and is only observed in the setting of a high tumor mass B-cell proliferation. This is typically illustrated by the massive precipitation of light chain (LC) in the lumen of distal tubules, which characterizes light-chain cast nephropathy, the most common cause of AKI in myeloma. Light-chain cast nephropathy is considered a myeloma-defining event because it always forms as the result of high monoclonal LC production, indicating a high tumor burden. Although rare, another example is glomerular intracapillary deposition of monoclonal IgM to form thrombi in high tumor mass Waldenström’s macroglobulinemia.”
- Qualitative paraprotein issues: “The other group is renal diseases associated with low-grade lymphoproliferative disorders. Although they may occur during symptomatic B-cell proliferations, these other monoclonal Ig-related renal lesions are mainly encountered in patients with a small B-cell clone and low malignant potential. In this setting, structural peculiarities of the monoclonal Ig, particularly the variable domain, and not the rate of production, are the main determinants of renal lesions.”
- Tubular proteinuria: refers to low molecular weight proteins that are normally filtered but then captured in urine testing. Since proximal tubule cells normally re-absorb these proteins, the presence of these low molecular weight proteins in the urine signals proximal tubule dysfunction. In pure proximal tubule dysfunction, 24-hour protein excretion is usually < 2 grams.
- Paraprotein testing: “In many cases, the monoclonal Ig can be identified in the serum or urine by a conventional EP. However, in some cases, the monoclonal Ig levels are very small and may not be detected by EP, likely reflecting the small size of the underlying B-cell clone and/or the affinity of the monoclonal Ig for tissues and organs. In fact, in several MGRS renal lesions, the monoclonal Ig may seemingly be demonstrated only in a kidney biopsy by IF or immunohistochemistry.
Serum and urine immunofixation should be performed in all cases to identify the monoclonal Ig isotype, even if the serum protein EP is not informative, because it is more sensitive for detecting monoclonal Ig than serum protein EP. Furthermore, it is more sensitive than the FLC assay among patients with small clones that produce mostly intact immunoglobulins. Finally, MGRS is frequently associated with a small clone, which may be difficult to identify, and it may not be driven by free LC.”
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