We report a series of four patients with noninfectious mixed CGN in whom MGUS was diagnosed using the conventional methods for paraprotein detection (16, 27). One in every five patients assessed in our hospital cohort of noninfectious mixed CGN was found to have MGUS, although the true incidence of this association remains uncertain owing to a paucity of data in the major published series (11, 28, 29). This is partly because of limited biochemical analysis in these studies, which tended to focus only on typing of the cryoglobulin by means of immunofixation of the cryoprecipitate. Whilst this remains a highly sensitive technique for detecting mIg (>0.05g/L) in patients with type 1 or 2 cryoglobulinaemia, for example in comparison to SPEP (>0.5g/L) (30), its role in diagnosis of MGUS is not established. Thus all 20 patients in one series of noninfectious mixed CGN were shown to have type 2 CGN, with monoclonal gammopathy reported in 18 patients, yet without reference to cryoglobulin quantitation, SPEP, SIFE, SFLC, UPEP or UIFE (29). This data was also not available in a recent series of 80 patients with noninfectious mixed CGN comprising 75 patients with type 2 CGN (11).
Conditions other than MGUS were present in our cohort potentially accounting for the development of mixed CGN. Thus pSS, which represents the commonest cause of mixed cryoglobulinaemia/CGN after HCV infection (8, 9, 11, 28, 29), was present at time of diagnostic renal biopsy in three patients (conforming to current EULAR/ACR criteria (31)). pSS involves a disease process of continuous polyclonal B cell activation, with malignant transformation of B cell clones in some cases, based on the increased incidence of lymphoma in patients with pSS (32, 33) (especially those with mixed cryoglobulinaemia (34, 35)). Of note, MGUS may also be more common in patients with pSS, and may confer an increased risk of developing lymphoma (36, 37) or myeloma (38). Yet co-presence of pSS and MGUS has not been previously reported in non-infectious mixed CGN. These observations raise questions regarding the underlying pathophysiological processes responsible for type 2 CGN in our three patients with pSS. The patient in our cohort who did not have pSS was one of three cases in which only a very small monoclonal band (<1g/L) was identified, emphasizing the need for further studies in which robust biochemical analysis is undertaken, if the association of mixed CGN with MGUS is to become established.
It remains unclear from our study whether the identification of MGUS in a patient with noninfectious mixed CGN provides any guide to treatment and prognosis. A designation of MGRS would imply the need for clonally targeted therapies to be considered in preference to conventional immunosuppression, with the primary aim of improving renal outcomes (24). Evidence for this approach in patients with noninfectious mixed CGN consists largely of retrospective studies of rituximab, mostly involving patients with type 2 CGN and a monoclonal IgM-k cryoglobulin (11, 28, 29, 39). As in previous series (11, 28), our cohort
received multiple therapies including rituximab but also conventional immunosuppressive agents (11, 28). Outcomes were generally favourable, and of the two patients with chronic kidney disease stage 3B at last follow-up, both had shown significant (25-40%) interstitial fibrosis on pre-treatment biopsies (potentially due to pSS-associated interstitial nephritis in one of these cases). Given previous, larger cohorts of noninfectious mixed CGN showing ESKD rates of 9-10% at 4 years (11, 29), our study possibly indicates that MGUS does not always confer a treatment-resistant course. No patient in our series received bortezomib, for which a single instance of use in refractory noninfectious mixed CGN is reported, in a patient with type 2 CGN and a monoclonal IgM-k component, but no detectable monoclonal band on SPEP (40).