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.
