The characteristics of seronegative and seropositive non-hepatitis-associated cryoglobulinemic glomerulonephritis

Vincent Javaugue, Anthony M. Valeri, Insara Jaffer Sathick, Samar M. Said, Sibel Erdogan Damgard, David L. Murray, Tyler Klobucher, Nicole K. Andeen, Sanjeev Sethi, Fernando C. Fervenza, Nelson Leung, Samih H. Nasr

Research output: Contribution to journalArticlepeer-review


The clinicopathologic characteristics and long-term outcome of non-hepatitis-associated cryoglobulinemic glomerulonephritis (CryoGN) are not well-defined and cases with undetectable serum cryoglobulin (seronegative CryoGN) have not been investigated. To resolve this, we retrospectively identified 81 patients with biopsy-proven non-hepatitis CryoGN, including 22 with seronegative CryoGN. The median age was 61 years and 76% presented with nephritic syndrome. A hematologic condition was found in 89% of patients, including monoclonal gammopathy of renal significance (65%) and symptomatic lymphoproliferative disorder (35%). In the seropositive group, 56% had type II, 29% type I, and 8% type III cryoglobulin. Extrarenal manifestations, mostly of skin, were present in 64% and were significantly less common in seronegative CryoGN. Glomerular deposits by immunofluorescence were IgM dominant (84%) and polytypic (70%) in the seropositive group, whereas 52% of seronegative cases had monotypic deposits (i.e., type I cryoglobulin). Ultrastructurally, the deposits were organized in 77% of cases. Substructure appearance significantly differed according to the type of CryoGN, forming most commonly short cylindrical structures in type II and other organized substructures in type I CryoGN. Most patients were treated with clone-directed therapy. On follow up (median 33 months), 77% had partial or complete remission, 10% reached kidney failure and 14% died. Predictors of kidney failure on univariate analysis were AKIN stage 3, positive rheumatoid factor and biclonal gammopathy at diagnosis. We conclude that most CryoGN cases (types I and II) are due to a hematologic condition and are associated with favorable outcome after clone-directed therapy. Seronegative CryoGN accounts for about a quarter of cases and is mostly a kidney-limited disease. Thus, further investigations are needed to unravel the pathophysiology of seronegative CryoGN.

Original languageEnglish (US)
Pages (from-to)382-394
Number of pages13
JournalKidney international
Issue number2
StatePublished - Aug 2022


  • MGRS
  • MPGN
  • cryoglobulinemic glomerulonephritis
  • kidney biopsy
  • serum cryoglobulin

ASJC Scopus subject areas

  • Nephrology


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