Skip to main content

Noninfectious mixed cryoglobulinaemic glomerulonephritis and monoclonal gammopathy of undetermined significance: a coincidental association?



Cryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection.

Case presentation

We present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years’ follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren’s syndrome in three cases.


Our study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.

Peer Review reports


Cryoglobulinaemia is defined by the presence of circulating immunoglobulin (Ig) that aggregates in vitro at temperatures < 37 °C, and redissolves on rewarming [1]. For cryoglobulinaemia to be detected, blood sampling, clotting and serum separation by centrifugation must ideally be performed at 37 °C, before serum storage at 4 °C for up to 7 days [2]. Any significant cryoprecipitate (usually > 0.05 g/L or cryocrit > 1%) may then be quantified and analyzed by electrophoresis and immunofixation after washing and redissolving at 37 °C. The classification system for cryoglobulinaemia devised by Brouet and colleagues distinguishes three main types [3]. Type 1 cryoglobulins consist of monoclonal Ig (mIg) or biclonal Ig, and occur in patients with clonal B cell or plasma cell disorders [4]. So-called ‘mixed’ cryoglobulins are considered as immune complexes typically comprising either monoclonal (type 2) or polyclonal (type 3) Ig (mostly IgM) with rheumatoid factor activity against the Fc portion of polyclonal IgG. Infections are the commonest cause of mixed cryoglobulinaemia, notably hepatitis C virus (HCV) [5] and hepatitis B virus (HBV) [6], together with human immunodeficiency virus (HIV) and numerous other viral, bacterial, parasitic and fungal infections [1, 7]. Noninfectious causes of mixed cryoglobulinaemia include autoimmune diseases, especially primary Sjögren’s syndrome (pSS) [8], and the malignant clonal disorders [9].

There is some uncertainty as to whether cryoglobulins are truly pathogenic in vivo, given that disease manifestations including systemic vasculitis occur in only a minority of patients with detectable cryoglobulinaemia [10]. The systemic vasculitis of cryoglobulinaemia is exemplified by cryoglobulinaemic glomerulonephritis (CGN), which can be classified as type 1 or mixed according to which type of cryoglobulin is found in association. Classic renal histological features of CGN, including membranoproliferative glomerulonephritis (MPGN), intracapillary ‘pseudothrombi’, crescents and small vessel vasculitis are fairly nonspecific [11]. On the other hand, the impression that renal causation is directly attributable to glomerular deposition of cryoglobulins may be strengthened by electron microscopy (EM) showing curvilinear microtubules, suggestive of aggregated cryoglobulins [12, 13], or immunohistochemistry showing light chain restriction of pseudothrombi in the case of type 1 CGN [14, 15].

Monoclonal gammopathy is diagnosed when mIg secreted into the circulation by a proliferating clone of plasma cells or B cells is detected by means of serum protein electrophoresis (SPEP), immunofixation (SIFE) or free light chain assays (SFLC), or urine protein electrophoresis (UPEP) or immunofixation (UIFE) [16]. Further evaluation is often required for one or other of the malignant clonal disorders, which include multiple myeloma, Waldenström’s macroglobulinaemia, B cell lymphoma and chronic lymphocytic leukemia. However, in most patients, monoclonal gammopathy of undetermined significance (MGUS) or another pre-malignant condition is diagnosed. Previous studies have established a clear association of type 1 CGN not only with malignant clonal disorders, but also with MGUS [14, 17,18,19,20]. This has led to the inclusion of type 1 CGN within the disease classification of monoclonal gammopathy of renal significance (MGRS) [21,22,23]. This term recognizes that certain renal lesions may be the result of nephrotoxic mIg produced by small (i.e. pre-malignant) plasma cell or B cell clones, with confirmation in many cases based on light chain restricted renal staining [24].

We undertook this study in our patient cohort to assess whether mixed (type 2 or 3) CGN is also sometimes diagnosed in patients with MGUS, as noted above for type 1 CGN. Our investigation was prompted by the surprising inclusion of type 2 CGN within the MGRS disease classification [21,22,23], despite having only a very weak association with MGUS in the published medical literature, and the inability to confirm light chain restriction of renal tissue owing to the polyclonal Ig component of type 2 cryoglobulins [11]. We included cases for the period 2002–2019 in which renal histology was compatible with CGN, with cryoglobulinaemia (> 0.05 g/L) and the detection of a serum monoclonal band based on SPEP/SIFE. Patients were excluded where type 1 cryoglobulinaemia was confirmed on immunofixation of the cryoprecipitate and/or light chain restricted staining (as assessed by immunofluorescent staining of paraffin-embedded tissue after protease digestion (paraffin-IF) [25]). Patients with a malignant clonal disorder were also excluded (with a minimum requirement in our study for bone marrow aspirate and trephine (BMAT) with flow cytometry of the aspirate and/or peripheral blood, and computed tomography with positron emission tomography (CT-PET)). Finally, patients with a potential infectious aetiology for mixed cryoglobulinaemia were excluded (with a minimum requirement for blood cultures, HBV surface antigen, and HBV core, HCV, and HIV antibodies), as were those in whom vasculitis was potentially due to recognised causes other than cryoglobulinaemia (based on serologies comprising at a minimum anti-neutrophil cytoplasmic, anti-glomerular basement membrane, anti-double stranded DNA, anti-U1-ribonucleoprotein and anti-cardiolipin antibodies, and lupus anticoagulant).

Case presentation

Of twenty patients at our hospital with noninfectious mixed CGN in whom SPEP/SIFE was performed, we present four cases with confirmed MGUS, including three females and one male (Table 1). Median age at presentation was 54 years (range 47–66 years). All patients had microscopic haematuria and proteinuria, with a median urinary protein creatinine ratio (uPCR) of 106 mg/mmol (range 70-134 mg/mmol). Renal function was significantly impaired in three of the four patients, with a median serum creatinine overall of 221 μmol/L (range 80-292 μmol/L) and eGFR of 27 mL/min per 1.73m2 (range 15-70 mL/min per 1.73m2, MDRD). All patients had mildly reduced serum albumin levels, and serum complement C4 ± C3 levels were low in three patients. All three female patients had previously been diagnosed with pSS and showed seropositivity for antinuclear, SSA/Ro and SSB/La antibodies. In the weeks following diagnosis of CGN, Patient 2 underwent laparotomy for an incidental finding of cholangiocarcinoma.

Table 1 Demographic and renal clinical features at time of renal biopsy

Renal biopsy revealed histological features of CGN in all four patients (Fig. 1 and Table 2). These included MPGN in three patients, cellular crescents with arteriolar necrosis and thrombosis in one patient, and intracapillary pseudothrombi in three patients. Interstitial fibrosis ≥25% with mild glomerulosclerosis was also present in three cases. Immunohistochemistry showed variable IgG, IgM and C3 staining in capillary loops and the mesangium, with IgM and/or IgG staining of pseudothrombi in two cases. No case showed light chain restriction on paraffin-IF. EM was performed in three cases, revealing intracapillary curvilinear deposits in one case and unstructured glomerular deposits in the other two cases.

Fig. 1

Histology. Light microscopy in patient 1 with a periodic acid-Schiff (PAS) stain and b silver stain showing MPGN with double contours and striking intraluminal, PAS-positive pseudothrombi. Equal (+++) intensity of paraffin-IF staining of pseudothrombi for c κ and d λ light chain. In patient 2, e silver stain showing a small cellular crescent with necrosis, and f haematoxylin and eosin stain of a small artery with concentric intimal arteritis. Magnification ×40

Table 2 Renal histology

Serum biochemistry at presentation (Table 3) included a median cryoglobulin concentration of 0.43 g/L (range 0.1–0.62 g/L) in three cases, with a cryocrit of 9% in the fourth case. Immunofixation of the cryoprecipitate confirmed type 2 cryoglobulinaemia with a monoclonal IgM-κ component in two patients and type 3 cryoglobulinaemia in one patient, and was not performed in the remaining patient. SPEP revealed generally small monoclonal bands of median concentration < 1 g/L (range < 1 - 2 g/L). In all four cases, the paraprotein was IgM-κ, with an IgG-κ paraprotein also present in one case (Patient 2). No patient showed bone marrow evidence of a malignant plasma cell or B cell disorder (Table 4).

Table 3 Biochemistry at time of renal biopsy
Table 4 Bone marrow aspirate and trephine

Treatment consisted of corticosteroids in all patients, cyclophosphamide in three patients, plasma exchange in three patients, and rituximab in two patients, one of whom (Patient 4) later received maintenance therapy for a diagnosis of seronegative lupus nephritis with mycophenolate mofetil (Table 5). At a median follow-up of 3.5 years (range 1.5–11 years), no patient had developed a malignant clonal disorder or end-stage renal failure, or was deceased. Renal parameters were improved in all cases but one (Patient 4), with a median uPCR at last follow-up of 103 mg/mmol (range 24 – 302 mg/mmol), serum creatinine of 133 μmol/L (range 62 - 168 μmol/L), and eGFR of 45 mL/min per 1.73m2 (range 30-90 mL/min per 1.73m2). Serum C4 remained undetectable in two patients. Cryoglobulinaemia was undetectable at last follow up in all four patients, and SPEP/UPEP was negative. However, SIFE revealed an IgM-κ paraprotein (< 1 g/L) in one patient, and the SFLC ratio was elevated at 2.09 in one other patient, with no evidence for persisting monoclonal gammopathy in the remaining two patients.

Table 5 Treatment and last follow-up

Discussion and conclusions

We report four patients with noninfectious mixed CGN in whom MGUS was diagnosed using conventional methods for paraprotein detection [16, 26]. One in every five patients assessed in our cohort of noninfectious mixed CGN was found to have MGUS, although the true incidence of any such association remains uncertain owing to a paucity of data in the major published series [11, 27, 28]. This is partly because of limited biochemical analysis in previous studies, which have focussed exclusively on immunofixation of the cryoprecipitate. Whilst this remains a highly sensitive technique for detecting circulating mIg (> 0.05 g/L) in patients with type 1 or 2 cryoglobulinaemia, for example in comparison to SPEP (> 0.5 g/L) [29], 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 [28]. These data were 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 could potentially account for the development of mixed CGN in our cohort. pSS, which represents the commonest cause of mixed cryoglobulinaemia/CGN after HCV infection [8, 9, 11, 27, 28], was present in three of our four patients (conforming to current EULAR/ACR criteria [30]), including both cases of confirmed type 2 CGN. 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 [31, 32] (especially those with mixed cryoglobulinaemia [33, 34]). Of note, MGUS may also be more common in patients with pSS, and may confer an increased risk of developing lymphoma [35, 36] or myeloma [37]. It is therefore surprising that, prior to our study, coexistence of pSS and MGUS has not been reported in noninfectious mixed CGN. The additional finding in one of these patients of cholangiocarcinoma is also novel, although other solid organ malignancies have previously been reported in patients with noninfectious mixed CGN [38]. The one patient in our cohort who was confirmed as having type 3 CGN and who did not have pSS (Patient 3), was one of three cases in which only a very small monoclonal band (< 1 g/L) was identified. These observations raise important questions regarding the underlying pathophysiological processes responsible for noninfectious mixed CGN in the setting of multiple possible aetiologies, and the need for robust biochemical analysis as part of future studies, before causation should be attributed principally to MGUS.

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 implies the need for clonally targeted therapies to be considered, with the primary aim of improving renal outcomes [24]. Evidence for anticlonal therapy in patients with noninfectious mixed CGN consists largely of retrospective studies of rituximab, mostly in patients with type 2 CGN involving a monoclonal IgM-κ component [11, 27, 28, 39]. As in previous series of noninfectious mixed CGN [11, 27], our patients received multiple therapies including rituximab but also conventional immunosuppressive agents [11, 27]. 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 previously reported, larger cohorts of noninfectious mixed CGN showing ESKD rates of 9–10% at 4 years [11, 28], 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-κ component, but no detectable monoclonal band on SPEP [40].

In conclusion, our study shows conclusively that MGUS may be present in a subset of patients with noninfectious mixed CGN. Even where this is the case, however, a designation of MGRS for cases of type 2 CGN may be open to question, given the observation of potential aetiologies for noninfectious mixed CGN other than MGUS.

Availability of data and materials

All data generated or analysed during this study are included in this published article.



Cryoglobulinaemic glomerulonephritis


Monoclonal gammopathy of renal significance


Monoclonal immunoglobulin


Serum protein electrophoresis


Monoclonal gammopathy of undetermined significance


Hepatitis C virus


Hepatitis B virus


Human immunodeficiency virus


Primary Sjögren’s syndrome


Serum Immunofixation


Serum free light chains


Urine protein electrophoresis


Urine immunofixation


  1. 1.

    Roccatello D, Saadoun D, Ramos-Casals M, Tzioufas AG, Fervenza FC, Cacoub P, Zignego AL, Ferri C. Cryoglobulinaemia. Nat Rev Dis Primers. 2018;4(1):11.

    PubMed  Article  Google Scholar 

  2. 2.

    Sargur R, White P, Egner W. Cryoglobulin evaluation: best practice? Ann Clin Biochem. 2010;47(Pt 1):8–16.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974;57(5):775–88.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Terrier B, Karras A, Kahn JE, Le Guenno G, Marie I, Benarous L, Lacraz A, Diot E, Hermine O, de Saint-Martin L, Cathebras P, Leblond V, Modiano P, Leger JM, Mariette X, Senet P, Plaisier E, Saadoun D, Cacoub P. The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine (Baltimore). 2013;92(2):61–8.

    CAS  Article  Google Scholar 

  5. 5.

    Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992;327(21):1490–5.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Annear NM, Cook HT, Atkins M, Pusey CD, Salama AD. Non-hepatitis virus associated mixed essential cryoglobulinemia. Kidney Int. 2010;77(2):161–4.

    PubMed  Article  Google Scholar 

  7. 7.

    Terrier B, Marie I, Lacraz A, Belenotti P, Bonnet F, Chiche L, Graffin B, Hot A, Kahn JE, Michel C, Quemeneur T, de Saint-Martin L, Hermine O, Leger JM, Mariette X, Senet P, Plaisier E, Cacoub P. Non HCV-related infectious cryoglobulinemia vasculitis: results from the French nationwide CryoVas survey and systematic review of the literature. J Autoimmun. 2015;65:74–81.

    PubMed  Article  Google Scholar 

  8. 8.

    Galli M, Oreni L, Saccardo F, Castelnovo L, Filippini D, Marson P, Mascia MT, Mazzaro C, Origgi L, Ossi E, Pietrogrande M, Pioltelli P, Quartuccio L, Scarpato S, Sollima S, Riva A, Fraticelli P, Zani R, Giuggioli D, Sebastiani M, Sarzi Puttini P, Gabrielli A, Zignego AL, Scaini P, Ferri C, De Vita S, Monti G. HCV-unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian Group for the Study of Cryoglobulinaemias (GISC). Clin Exp Rheumatol. 2017;35 Suppl 103(1):67–76.

    PubMed  Google Scholar 

  9. 9.

    Terrier B, Krastinova E, Marie I, Launay D, Lacraz A, Belenotti P, de Saint-Martin L, Quemeneur T, Huart A, Bonnet F, Le Guenno G, Kahn JE, Hinschberger O, Rullier P, Diot E, Lazaro E, Bridoux F, Zenone T, Carrat F, Hermine O, Leger JM, Mariette X, Senet P, Plaisier E, Cacoub P. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;119(25):5996–6004.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012;379(9813):348–60.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Zaidan M, Terrier B, Pozdzik A, Frouget T, Rioux-Leclercq N, Combe C, Lepreux S, Hummel A, Noel LH, Marie I, Legallicier B, Francois A, Huart A, Launay D, Kaplanski G, Bridoux F, Vanhille P, Makdassi R, Augusto JF, Rouvier P, Karras A, Jouanneau C, Verpont MC, Callard P, Carrat F, Hermine O, Leger JM, Mariette X, Senet P, Saadoun D, Ronco P, Brocheriou I, Cacoub P, Plaisier E. CryoVas study G. spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN. J Am Soc Nephrol. 2016;27(4):1213–24.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Ojemakinde K, Turbat-Herrera EA, Zeng X, Gu X, Herrera GA. The many faces of cryoglobulinemic nephropathy: a clinico-pathologic study of 47 cases with emphasis on the value of electron microscopy. Ultrastruct Pathol. 2014;38(6):367–76.

    PubMed  Article  Google Scholar 

  13. 13.

    Paueksakon P, Revelo MP, Horn RG, Shappell S, Fogo AB. Monoclonal gammopathy: significance and possible causality in renal disease. Am J Kidney Dis. 2003;42(1):87–95.

    PubMed  Article  Google Scholar 

  14. 14.

    Harel S, Mohr M, Jahn I, Aucouturier F, Galicier L, Asli B, Malphettes M, Szalat R, Brouet JC, Lipsker D, Fermand JP. Clinico-biological characteristics and treatment of type I monoclonal cryoglobulinaemia: a study of 64 cases. Br J Haematol. 2015;168(5):671–8.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Sidana S, Rajkumar SV, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Hayman SR, Dingli D, Kapoor P, Gonsalves WI, Go RS, Hwa YL, Leung N, Fonder AL, Hobbs MA, Zeldenrust SR, Russell SJ, Lust JA, Kyle RA, Kumar SK. Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia. Am J Hematol. 2017;92(7):668–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Bird J, Behrens J, Westin J, Turesson I, Drayson M, Beetham R, D'Sa S, Soutar R, Waage A, Gulbrandsen N, Gregersen H, Low E. Haemato-oncology task force of the British Committee for Standards in haematology UKMF, Nordic myeloma study G. UK myeloma forum (UKMF) and Nordic myeloma study group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol. 2009;147(1):22–42.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Neel A, Perrin F, Decaux O, Dejoie T, Tessoulin B, Halliez M, Mahe B, Lamy T, Fakhouri F, Jego P, Agard C, Vigneau C, Guenet L, Grosbois B, Moreau P, Hamidou M. Long-term outcome of monoclonal (type 1) cryoglobulinemia. Am J Hematol. 2014;89(2):156–61.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Karras A, Noel LH, Droz D, Delansorne D, Saint-Andre JP, Aucouturier P, Alyanakian MA, Grunfeld JP, Lesavre P. Renal involvement in monoclonal (type I) cryoglobulinemia: two cases associated with IgG3 kappa cryoglobulin. Am J Kidney Dis. 2002;40(5):1091–6.

    PubMed  Article  Google Scholar 

  19. 19.

    Nasr SH, Markowitz GS, Reddy BS, Maesaka J, Swidler MA, D'Agati VD. Dysproteinemia, proteinuria, and glomerulonephritis. Kidney Int. 2006;69(4):772–5.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Sethi S, Zand L, Leung N, Smith RJ, Jevremonic D, Herrmann SS, Fervenza FC. Membranoproliferative glomerulonephritis secondary to monoclonal gammopathy. Clin J Am Soc Nephrol. 2010;5(5):770–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Leung N, Bridoux F, Hutchison CA, Nasr SH, Cockwell P, Fermand JP, Dispenzieri A, Song KW, Kyle RA, International K. Monoclonal Gammopathy research G. monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012;120(22):4292–5.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Fermand JP, Bridoux F, Kyle RA, Kastritis E, Weiss BM, Cook MA, Drayson MT, Dispenzieri A, Leung N, International K. Monoclonal Gammopathy research G. how I treat monoclonal gammopathy of renal significance (MGRS). Blood. 2013;122(22):3583–90.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Leung N, Bridoux F, Batuman V, Chaidos A, Cockwell P, D’Agati VD, Dispenzieri A, Fervenza FC, Fermand JP, Gibbs S, Gillmore JD, Herrera GA, Jaccard A, Jevremovic D, Kastritis E, Kukreti V, Kyle RA, Lachmann HJ, Larsen CP, Ludwig H, Markowitz GS, Merlini G, Mollee P, Picken MM, Rajkumar VS, Royal V, Sanders PW, Sethi S, Venner CP, Voorhees PM, Wechalekar AD, Weiss BM, Nasr SH. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2018;15:45–59.

    PubMed Central  Article  Google Scholar 

  24. 24.

    Sethi S, Rajkumar SV, D’Agati VD. The complexity and heterogeneity of monoclonal immunoglobulin–associated renal diseases. J Am Soc Nephrol. 2018;29(7):1810–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Larsen CP, Messias NC, Walker PD, Fidler ME, Cornell LD, Hernandez LH, Alexander MP, Sethi S, Nasr SH. Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits. Kidney Int. 2015;88(4):867–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M, Dimopoulos MA, Drake MT, Fonseca R, Harousseau JL, Joshua D, Lonial S, Niesvizky R, Palumbo A, Roodman GD, San-Miguel JF, Singhal S, Weber DM, Zangari M, Wirtschafter E, Yellin O, Kyle RA. Monoclonal gammopathy of undetermined significance: a consensus statement. Br J Haematol. 2010;150(1):28–38.

    PubMed  Google Scholar 

  27. 27.

    Foessel L, Besancenot JF, Blaison G, Magy-Bertrand N, Jaussaud R, Etienne Y, Maurier F, Audia S, Martin T. Clinical spectrum, treatment, and outcome of patients with type II mixed cryoglobulinemia without evidence of hepatitis C infection. J Rheumatol. 2011;38(4):716–22.

    PubMed  Article  Google Scholar 

  28. 28.

    Matignon M, Cacoub P, Colombat M, Saadoun D, Brocheriou I, Mougenot B, Roudot-Thoraval F, Vanhille P, Moranne O, Hachulla E, Hatron PY, Fermand JP, Fakhouri F, Ronco P, Plaisier E, Grimbert P. Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection. Medicine (Baltimore). 2009;88(6):341–8.

    Article  Google Scholar 

  29. 29.

    Batko K, Malyszko J, Jurczyszyn A, Vesole DH, Gertz MA, Leleu X, Suska A, Krzanowski M, Sulowicz W, Malyszko JS, Krzanowska K. The clinical implication of monoclonal gammopathies: monoclonal gammopathy of undetermined significance and monoclonal gammopathy of renal significance. Nephrol Dial Transplant. 2018;34(9):1440–52.

  30. 30.

    Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, Mariette X. International Sjogren's syndrome criteria working G. 2016 American College of Rheumatology/European league against rheumatism classification criteria for primary Sjogren's syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017;76(1):9–16.

    PubMed  Article  Google Scholar 

  31. 31.

    Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165(20):2337–44.

    PubMed  Article  Google Scholar 

  32. 32.

    Nocturne G, Mariette X. Sjogren syndrome-associated lymphomas: an update on pathogenesis and management. Br J Haematol. 2015;168(3):317–27.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Tzioufas AG, Boumba DS, Skopouli FN, Moutsopoulos HM. Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjogren's syndrome. Arthritis Rheum. 1996;39(5):767–72.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Nishishinya MB, Pereda CA, Munoz-Fernandez S, Pego-Reigosa JM, Rua-Figueroa I, Andreu JL, Fernandez-Castro M, Rosas J, Loza SE. Identification of lymphoma predictors in patients with primary Sjogren's syndrome: a systematic literature review and meta-analysis. Rheumatol Int. 2015;35(1):17–26.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Brito-Zeron P, Retamozo S, Gandia M, Akasbi M, Perez-De-Lis M, Diaz-Lagares C, Bosch X, Bove A, Perez-Alvarez R, Soto-Cardenas MJ, Siso A, Ramos-Casals M. Monoclonal gammopathy related to Sjogren syndrome: a key marker of disease prognosis and outcomes. J Autoimmun. 2012;39(1–2):43–8.

    PubMed  Article  Google Scholar 

  36. 36.

    Yang Y, Chen L, Jia Y, Liu Y, Wen L, Liang Y, An Y, Chen S, Su Y, Li Z. Monoclonal gammopathy in rheumatic diseases. Clin Rheumatol. 2018;37(7):1751–62.

    PubMed  Article  Google Scholar 

  37. 37.

    Tomi AL, Belkhir R, Nocturne G, Desmoulins F, Berge E, Pavy S, Miceli-Richard C, Mariette X, Seror R. Brief report: monoclonal Gammopathy and risk of lymphoma and multiple myeloma in patients with primary Sjogren's syndrome. Arthritis Rheumatol. 2016;68(5):1245–50.

    PubMed  Google Scholar 

  38. 38.

    Spatola L, Generali E, Angelini C, Badalamenti S, Selmi C. HCV-negative mixed cryoglobulinemia and kidney involvement: in-depth review on physiopathological and histological bases. Clin Exp Med. 2018;18(4):465–71.

    PubMed  Article  Google Scholar 

  39. 39.

    Terrier B, Launay D, Kaplanski G, Hot A, Larroche C, Cathebras P, Combe B, de Jaureguiberry JP, Meyer O, Schaeverbeke T, Somogyi A, Tricot L, Zenone T, Ravaud P, Gottenberg JE, Mariette X, Cacoub P. Safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis: data from the French autoimmunity and rituximab registry. Arthritis Care Res (Hoboken). 2010;62(12):1787–95.

    CAS  Article  Google Scholar 

  40. 40.

    Bazari H, Mahindra AK, Farkash EA. Case records of the Massachusetts General Hospital. Case 3-2014. A 61-year-old woman with gastrointestinal symptoms, anemia, and acute kidney injury. N Engl J Med. 2014;370(4):362–73.

    CAS  PubMed  Article  Google Scholar 

Download references


Not applicable.


TDB is supported through a Jacquot research foundation award.

Author information




ALF performed the case studies and literature review, wrote the draft manuscript, and edited and reviewed subsequent revisions. ROF and MJF performed specimen analysis and reviewed the manuscript. ERS and SGH edited and reviewed the manuscript. TDB designed the study and wrote the manuscript. All authors contributed significantly and have read and approved the final manuscript.

Corresponding author

Correspondence to Adam L. Flavell.

Ethics declarations

Ethics approval and consent to participate

The study was conducted under Melbourne Health research ethics approval (HREC2016.176), and written consent to participate was obtained from all patients.

Consent for publication

Written informed consent was obtained from the patients for publication. A copy of the written consent is available for review.

Competing interests

None declared.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Flavell, A.L., Fullinfaw, R.O., Smith, E.R. et al. Noninfectious mixed cryoglobulinaemic glomerulonephritis and monoclonal gammopathy of undetermined significance: a coincidental association?. BMC Nephrol 21, 293 (2020).

Download citation


  • Cryoglobulinaemia
  • Monoclonal gammopathy of renal significance
  • Glomerulonephritis