Consult Rounds: Cryoglobulins and paraproteinemias

What is the connection of cyroglobulins(cyro) with paraproteinemias or myelomas?

Cryoglobulins are Igs that reversibly precipitate at temperatures <37°C. The precipitation results in symptoms that are seen in vasculitis: rash, ischemia, ulcers, joint pains, fatigue, and glomerulonephritis. The pathogenesis of cryoglobulin-induced injury involves two main mechanisms, hyperviscosity and immune complex deposition, that activate complement and induce vascular inflammation. Classically, in the renal community, we see this in Hep C association and other infections. In the “Harvoni” era of Hep C treatment, cyro associated MPGN from Hep C is likely on a downtrend.

What about with paraproteinemias?

In the largest case series of type 1 cryoglobulinemia associated with MM, six of seven patients were men 28–69 years of age, and all had stage 1 indolent myeloma. Three patients had an IgGκ monoclonal protein, three had an IgGλ monoclonal protein, and one had an IgMλ monoclonal protein. Skin changes and rheumatologic failure were the most common presenting symptoms. Renal manifestations were reported in two patients who presented with nephrotic syndrome and AKI.

Pathology usually shows an MPGN pattern of injury on LM and hyaline thrombi within glomerular capillaries. IF may reveal staining for various Igs within hyaline thrombi and the subendothelial space, and monoclonal light chain restriction may be observed in types 1 and 2 cryoglobulinemia. On EM, cryoglobulins may appear as paired, curved microtubules with a diameter of 20–30 nm), although it should be noted that this feature is observed in only a subset of patients.

In patients with cryoglobulinemia associated with a lymphoproliferative disorder, treatment should focus on the underlying hematologic malignancy that is producing the cryoglobulin. Fludarabine- and rituximab-based regimens have been used to treat type 1 cryoglobulinemia associated with MGUS, Waldenstrom macroglobulinemia(WM), and NHL. Antimyeloma therapies, including bortezomib, thalidomide, and lenalidomide, have shown efficacy in the treatment of type 1 cryoglobulinemia associated with MM.  With WM, besides AL amyloidosis, cyro MPGN is commonly seen as the GN manifestation.

High index of suspicion is required to connect the dots and many times the bone marrow and testing might be negative. As we have learnt, the clone might not be that large but it is noxious to the kidney.

Check out this recent CJASN review from few years ago on Paraprotein associated GNs