A case of renal damage induced by cryoglobulinemia associated with Monoclonal Gammopathy of Renal Significance.

Background

Cryoglobulinemia is a rare condition with an estimated prevalence of approximately 1 in 100,000. It predominantly affects women, with a female-to-male ratio of 3:1, and the typical age of onset ranges from 42 to 52 years [ 1 , 2 ]. Cryoglobulins are abnormal immunoglobulins present in circulation, capable of precipitating at lower temperatures and redissolving upon rewarming to body temperature (37 °C) [ 2 , 3 ]. The vasculitis induced by cryoglobulins through complement activation is known as cryoglobulinemic vasculitis, and renal involvement due to this process is termed cryoglobulinemic nephritis. Notably, some individuals with cryoglobulinemia remain asymptomatic and do not exhibit organ tissue damage.

According to Brouet’s immunochemical classification of cryoglobulinemia [ 4 ], the disease is categorized into three subtypes. Type I cryoglobulinemia involves monoclonal immunoglobulins (typically IgM, or less commonly IgG or IgA [ 5 ]), often observed in disorders such as multiple myeloma, Waldenström’s macroglobulinemia, B-cell lymphoma, and chronic lymphocytic leukemia. Type II is characterized by a monoclonal IgM (usually IgMk [ 6 ]) combined with polyclonal IgG, while Type III involves both polyclonal IgM and polyclonal IgG. Types II and III are collectively referred to as mixed cryoglobulinemia, where immune complexes are formed by IgM with rheumatoid factor activity and IgG [ 7 ]. Type III is considered a transitional form, representing a stage in the progression to type II cryoglobulinemia [ 8 ]. Types II and III are more commonly associated with chronic infections (e.g., HCV, HBV, EBV, CMV, parvovirus, bacteria) and autoimmune diseases (e.g.,systemic lupus erythematosus, sjogren syndrome, rheumatoid arthritis) [ 9 ].

Here, we present a case of cryoglobulinemic nephritis due to Monoclonal Gammopathy of Renal Significance. The patient was treated with a combination of prednisone, rituximab and cyclophosphamide. Follow-up showed significant improvement in proteinuria and immunological indicators, and renal function stabilized.

Case presentation

A 60-year-old male was admitted to our hospital on June 1, 2024, primarily due to “bilateral lower limb edema for one month.” One month prior to hospitalization, the patient had been treated locally for a “transient ischemic attack,” during which he developed bilateral lower limb edema, increased urinary foam, persistent fatigue, and elevated blood pressure, with a peak reading of 180/100 mmHg. Subsequent investigations suggested a diagnosis of “nephrotic syndrome,” and the patient received antihypertensive treatment, lipid-lowering therapy, and symptomatic support. His condition improved, and he was discharged.

Upon presentation to our hospital for further treatment, the patient has remained conscious and mentally stable since the illness began, despite a poor appetite and some difficulty sleeping. Over the course of the past month, he had experienced a weight loss of approximately 5 kg.

Clinical examination and diagnostic findings

The patient has no significant personal, familial, or past medical history. Upon admission, his blood pressure was 153/84 mmHg. Physical examination revealed no abnormalities in the heart, lungs, or abdomen, but notable findings included edema of the face and lower limbs, along with purpura on the skin of the lower extremities.

Laboratory investigations

Urinalysis and urine sediment analysis : Protein: 3+, occult blood: 2+. Stool analysis and occult blood : No abnormalities detected. Urine culture and colony count : Negative. Anti-phospholipase A2 receptor (PLA2R) antibody : Negative. Immunofixation electrophoresis (Blood) : IgM κ monoclonal band detected. Cryoglobulin test : The qualitative test for cryoglobulin was positive.

Additional autoimmune and infectious testing

Negative for anti-nuclear antibody spectrum, Immunoglobulin IgG4,anti-neutrophil cytoplasmic antibody (ANCA), anti-glomerular basement membrane (GBM) IgG, and thyroid function, Hepatitis B, Hepatitis C, HIV, TP, EBV-DNA, procalcitonin and other infectious tests, Urine immunofixation electrophoresis, Coombs test, and Ben-Zhou protein test were also negative.The other initial laboratory investigation results at presentation are displayed in Table 1 . And the results of the routine imaging studies are presented in Table 2 .

Table 1 Initial laboratory investigation at presentation Laboratory investigation Patient’s result Reference range Hemoglobin, g/L 111 120–175 Uric acid,µmol/L 625 208–428 Blood urea nitrogen, mmol/L 12.0 3.1-8.0 Plasma creatinine,µmol/L 138 51–97 Plasma albumin, g/L 35.1 40–55 RBC in urinalysis, p/µL 46.20 0–5 Urine microalbumin, mg/L 3966.89 0–30 Urine microalbumin/ Urine creatinine, mg/g 2199.83 0–30 Urine transferrin, mg/L 192.08 0–2 Urine IgA, mg/L 30.22 0-6.79 Urine IgG, mg/L 121.44 0-17.5 Urine IgM, mg/L 28.39 0-3.94 Urine α-microglobulin, mg/L 30.68 0–12 Urine retinol binding protein, mg/L 1.18 0-0.7 24-hour urine protein quantification, g/24 h 5.88 0-0.2 Glycosylated hemoglobin,% 5.4 < 6.5 Complement C4,g/L < 0.02 0.1–0.4 Rheumatoid factor, IU/mL 2310.0 0–20 Serum IgG, g/L 4.77 8.6–17.4 Serum IgM, g/L 10.20 0.3–2.2 Blood kappa chain, mg/dL 1250.00 629–1350 Blood lambda chain, mg/dL 235.00 313–723 Urine kappa chain, mg/dL 18.00 0-1.85 Urine lambda chain, mg/dL 7.48 0–5 Plasma protein electrophoresis II(α1-globulin),% 4.80 1.4–4.6 RBC: red blood cell, IgA: Immunoglobulin A, IgG: Immunoglobulin G, IgM: Immunoglobulin M

Table 2 Initial imaging studies at presentation Imaging studies Result Electrocardiogram Normal. Abdomen ultrasound Both kidneys exhibited homogeneous parenchymal echogenicity, with right kidney dimensions of 11.3 cm × 5.1 cm and left kidney dimensions of 11.1 cm × 5.9 cm. Liver cysts and splenomegaly were noted, along with bilateral renal cysts. Heart ultrasound Enlargement of the left atrium, with micro-regurgitation of the mitral, tricuspid, and aortic valves. Lower extremity Vasculature ultrasound Multiple plaques in the arteries of both lower limbs. Renal arteries ultrasound Increased resistance index in both renal arteries. Urinary system ultrasound Left kidney cyst, prostatic hyperplasia. Chest (Lung) CT Evidence of aortic and coronary artery atherosclerosis, along with splenomegaly. Brain MRI No acute infarct or hemorrhage identified; cerebral artery atherosclerosis and multiple vascular stenosis observed.

Renal Biopsy (June 4, 2024): Light microscopy revealed 46 glomeruli, including 1 exhibiting glomerular sclerosis and 1 with ischemic sclerosis. The remaining glomeruli demonstrated moderate to severe diffuse proliferation of mesangial cells and matrix, with some displaying nodular hyperplasia. Segmental capillary endothelial cell proliferation was present, accompanied by mild neutrophil infiltration. Other findings included mild thickening of the basement membrane, segmental double-track formations, and subendothelial, mesangial, and subepithelial deposits. Additionally, segmental tram-tracking structures and PAS-positive microthrombus-like deposits were noted. Renal tubular changes included vacuolar and granular degeneration of tubular epithelial cells, focal shedding of the brush border, and small focal atrophy (approximately 5%), with a few protein casts observed in the tubular lumen. The renal interstitium exhibited focal lymphocytic and mononuclear cell infiltration with fibrosis (approximately 5%). Arteriolar vessel walls showed hyalinization, intimal fibrosis, and sclerosis. Congo red staining was negative. The overall renal histopathology was consistent with membranoproliferative glomerulonephritis, with a high likelihood of renal damage secondary to cryoglobulinemia, as illustrated in Fig. 1 .

Fig. 1 Pathological examination results of the patient’s renal tissue (light microscope x400). A : PASM staining reveals segmental double-track sign formation, indicating membranoproliferative glomerulonephritis; B : PAS staining shows the formation of microthrombus-like structures

Immunofluorescence IgG: ±, IgA: -, IgM: 2+, C3: 2+, C1q: 1+, fibrinogen: -, κ chain: 2+–3+, λ chain: ±–1+, IgG1: -, IgG2: -, IgG3: -, IgG4: -. Granular deposition was observed in the mesangial areas and capillary loops, as illustrated in Fig. 2 .

Fig. 2 Pathological examination results of the patient’s renal tissue (Immunofluorescence x400). A : IgM (2+) exhibits granular deposition in the mesangial area and capillary loops. B : κ chain (2 + to 3+) exhibits granular deposition in the mesangial area and capillary loops

Electron microscopy

Moderate to severe proliferation of mesangial cells and matrix in the glomeruli, with an increased number of cells in segmental capillaries. Electron-dense deposits were identified in the subendothelial and mesangial regions, with some deposits occluding the capillary lumina. A segmental double-track sign was noted in the basement membrane, accompanied by extensive fusion of epithelial foot processes. Renal tubular epithelial cells exhibited vacuolar degeneration, with increased lysosomal and partial loss of microvilli, as well as some atrophic changes. Focal lymphomonocytic infiltration and collagen fiber deposition were seen in the renal interstitium. The electron microscopy findings, in conjunction with light microscopy, were consistent with membranoproliferative glomerulonephritis, cryoglobulinemia-related renal damage should still be considered, as shown in Fig. 3 . It is recommended to perform immunoelectron microscopy to further assess the possibility of monoclonal immunoglobulin-related renal damage. However, the patient declined this additional examination.

Fig. 3 Pathological examination results of the patient’s renal tissue (Electron Microscopy). Electron-dense deposits were identified in the subendothelial and mesangial regions, with some deposits occluding the capillary lumina. A segmental double-track sign was noted in the basement membrane, accompanied by extensive fusion of epithelial foot processes. Focal lymphomonocytic infiltration and collagen fiber proliferation were seen in the renal interstitium

Hematologic investigations

Bone marrow puncture : Plasma cells accounted for 2% of nucleated cells, with bone marrow and peripheral blood lymphocytes predominantly consisting of mature cells. Bone marrow biopsy : No trabecular space invasion was observed, which ruled out Waldenström’s macroglobulinemia.

PET/CT scan :No evidence of lymphoma.

Hematological disease immunophenotyping (Flow Cytometry)

Abnormal monoclonal B lymphocytes (CD5 + CD10-) comprised 4.03% of nuclear cells, exhibiting small-to-medium cell size. The CLi score was 3, and the phenotype did not resemble chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Monoclonal plasma cells accounted for 0.10% of nuclear cells, with no significant phenotypic abnormalities. Both B lymphocytes and plasma cells expressed the kappa light chain.

MYD88 L265P mutation gene test

Negative.

The patient was diagnosed with monoclonal gammopathy. Considering the renal pathology findings, a treatment regimen consisting of medium dose of prednisone, rituximab (cumulative dose: 2 g), valsartan, and symptomatic supportive care was initiated. Follow-up for 3 months, monitoring revealed a reduction in 24-hour urine protein levels and an increase in plasma albumin concentrations compared to baseline. However, there was no significant improvement in plasma creatinine levels, and there were no notable changes in complement, or rheumatoid factor. Subsequently, a combined oral cyclophosphamide(50 mg, administered every other day)treatment regimen was initiated, leading to a substantial decrease in the rheumatoid factor relative to prior levels, with renal function remaining largely stable.The specific treatment process of this patient and the changes in laboratory investigations before and after treatment are shown in Figs. 4 and 5 . The patient continues to be under regular follow-up care.

Fig. 4 Serial changes in plasma creatinine (µmol/L), plasma albumin (g/L), complement C4 (g/L) and urine total protein (UTP) (g/24 h) observed in the patient

Fig. 5 The patient was treated with 4 doses of 500 mg rituximab that were administered intravenously on days 1, 14, 30,and 45,respectively. Total dose was 2,000 mg.Concurrently, a medium dose of prednisone was administered. Following a poor response to treatment after four months of follow-up, combination therapy with oral cyclophosphamide (50 mg, administered every other day) was initiated. At the six-month point of monitoring, CD19 levels showed a significant increase, prompting the administration of an additional 2 doses of 500 mg rituximab (administered at 2-week intervals) to the patient for intensified treatment

Discussion and conclusions

This case involves a middle-aged male presenting with bilateral lower limb edema, skin purpura, massive proteinuria, microscopic hematuria, anemia, mild renal impairment, and a decreased complement C4 level. Laboratory findings showed a significantly elevated immunoglobulin IgM, positive rheumatoid factor, and negative autoantibody screening. The blood light chain ratio was unbalanced, and the plasma albumin level was inconsistent with the 24-hour urine protein quantification. Immunofixation electrophoresis revealed an IgMκ monoclonal immunoglobulin.Renal biopsy pathology was consistent with membranoproliferative glomerulonephritis, with microthrombus-like structures observed. Immunofluorescence staining showed prominent IgM (2+) and κ chain (2 + to 3+) deposits.Two positive qualitative cryoglobulin test results further supported the diagnosis of cryoglobulinemia renal damage.

In this case, the patient was positive for rheumatoid factor, blood immunofixation electrophoresis was positive for IgMk, and immunofluorescence primarily showed IgM and κ chain deposition, which is compatible with type II cryoglobulinemia. A literature review by Surasak Faisatjatham et al. [ 10 ] on non-infectious mixed (type II) cryoglobulinemic glomerulonephritis found that all reported cases with monoclonal gammopathy were linked to serum IgM κ monoclonal gammopathy. It has been suggested that IgM monoclonal gammopathy may possess a high level of autoantibody activity, facilitating the formation of immune complexes, as seen in Waldenström’s macroglobulinemia. Additionally, type II cryoglobulins are reported to be more common than type I in patients with IgM monoclonal gammopathy associated with glomerular disease [ 11 ].

Mixed cryoglobulinemia typically manifests with systemic vasculitis and multiple organ involvement, presenting with symptoms such as fatigue, skin purpura (which may closely resemble IgA-vasculits, an important tip point), joint pain, and peripheral neuropathy. Fever is reported in a subset of patients. Among the various organs affected, the kidneys are particularly susceptible [ 12 – 14 ]. Cryoglobulinemic glomerulonephritis (Cryo-GN) is the principal manifestation of renal involvement, usually manifesting as varying degrees of microhematuria, proteinuria (UTP), hypertension, and/or renal failure [ 14 , 15 ]. The typical pathological finding of mixed cryoglobulinemia is, which involves medium and, more often, small blood vessels [ 16 , 17 ], and is diagnosed by a skin biopsy of recent vasculitic lesions.It typically presents as leukocytoclastic vasculitis and hyaline thrombosi [ 18 ]. As it is less invasive than renal biopsy, skin biopsy could provide useful supportive evidence for cryoglobulinemic vasculitis.The patient presented with purpura on the lower limbs, which became more pronounced upon exposure to cold. The skin lesions were not severe and could even resolve spontaneously, so a skin biopsy was not performed, which is also a limitation of this study.Laboratory tests often reveal elevated serum rheumatoid factor (RF) levels, along with reduced complement C3 and C4 levels, with C4 often showing a more marked decrease. In this case, the patient exhibited skin purpura(especially noticeable when exposed to cold conditions), renal involvement, significantly elevated RF levels, and decreased complement C4, which aligns with the characteristics of mixed cryoglobulinemia. This reinforces the need for heightened clinical suspicion for this condition in middle-aged and elderly patients presenting with skin purpura. Cryoglobulinemia can involve the nervous system through a vasculitic process [ 19 ], with an uncertain frequency of involvement and an incidence rate of approximately 50–60% [ 20 ]. Among these cases, peripheral nervous system involvement is more common, while central nervous system (CNS) involvement is relatively rare, accounting for about 0–3% [ 19 , 21 , 22 ]. Clinical manifestations range from stroke/transient ischemic attack or progressive reversible ischemic neurological deficits to encephalopathic syndromes such as seizures, coma, or syncope [ 19 , 21 ]. Brain magnetic resonance imaging may reveal ischemic or hemorrhagic brain lesions.Currently, there is no standardized method for diagnosing or treating the neurological complications of cryoglobulinemia [ 20 ]. The patient had experienced a “transient ischemic attack” one month prior to hospitalization, and a potential correlation between the two cannot be ruled out.

Histopathologically, cryoglobulinemia typically presents as membranoproliferative glomerulonephritis, with the formation microthrombus-like structures in the capillary lumina. These findings were consistent with those observed in the present case.The patient’s immunofluorescence test showed significant deposits of IgM and kappa chains, with IgG deposits being ±.The lack of IgG staining in immunofluorescence testing for type II cryoglobulinemia appears paradoxical but has an underlying mechanism.The possible reason for the occurrence of this phenomenon may be that monomeric IgM (rheumatoid factor) tightly binds to the Fc region of polyclonal IgG, physically masking the key epitopes recognized by anti-IgG antibodies. This masking effect is difficult to remove under the unique stability of cold globulin complexes and the standard conditions of immunofluorescence procedures. However, IgM and light chains usually show positive staining and display monoclonal characteristics, due to the presence of numerous accessible epitopes or incomplete masking of their binding sites. Only some of the deposits in cryoglobulinaemic glomerulonephritis are organized, and electron microscopy reveals electron-dense deposits in the subendothelial and intraluminal regions of the glomerular capillary wall, along with highly ordered microtubules or ring-like substructures.Of note, organized deposits are not always observed in cryoglobulinaemic glomerulonephritis [ 23 ]. However, not all electron microscopes can detect the aforementioned microtubular substructures that are of great diagnostic value [ 14 ]. The diagnosis of cryoglobulinemic glomerulonephritis should not be denied solely based on the absence of these substructures [ 13 , 14 , 24 , 25 ]. The patient in this case did not exhibit these typical features, which may be attributed to the heterogeneity of electron microscopy findings in cryoglobulinemia and the lack of specificity inherent to this method. Despite the absence of these classic structures on electron microscopy, the positive cryoglobulin test supports the diagnosis of cryoglobulinemic nephritis.The laboratory criteria for cryoglobulinemia require that the patient must have at least two positive serum cryoglobulin tests, conducted at intervals of 12 weeks [ 26 ]. We conducted two cryoglobulin tests before rituximab administration, both of which were positive, and did not perform this test again thereafter. During future follow-ups, we will encourage patients to undergo repeat cryoglobulin testing to provide further evidence for clarifying the diagnosis.

Monoclonal Gammopathy of Renal Significance (MGRS) refers to a condition in which M-proteins produced by non-malignant B cells or plasma cells deposit in the kidneys or indirectly cause renal damage, without meeting the diagnostic criteria for a hematologic malignancy [ 27 – 29 ]. The new consensus from the International Kidney and Monoclonal Gammopathy Research Group (IKMG)definition of MGRS includes all B cell or plasma cell proliferative disorders that produce a nephrotoxic monoclonal immunoglobulin [ 23 , 30 – 33 ]. Low-grade CLL and low-grade B cell non-Hodgkin lymphomas are also considered to be MGRS when they are associated with renal lesions [ 23 , 34 – 37 ].These low-grade proliferative disorders would be classified as MGUS, and affected patients would be monitored for progression but not offered treatment if not for the renal injury [ 23 , 38 ]. In patients who develop renal lesions as a result of the monoclonal immunoglobulin, therapeutic intervention is required to prevent further damage resulting in end-stage renal disease [ 23 ].In this patient, no evidence of chronic infection was found, and there were no clinical signs of autoimmune disease other than the positive RF and negative results on other autoantibody screens. The absence of symptoms such as joint swelling or pain further excludes autoimmune etiologies. Based on the results of serum immunofixation electrophoresis and immunofluorescence, there is a clear indication of the presence of monoclonal gammopathy.Despite the presence of monoclonal gammopathy, comprehensive hematologic testing, including bone marrow puncture and biopsy, PET/CT, flow cytometry, and genetic testing, did not suggest a hematologic malignancy. Thus, the diagnosis of cryoglobulinemic nephritis due to monoclonal gammopathy of renal significance (MGRS) is considered more likely. The flow cytometry shows that abnormal monoclonal B lymphocytes (CD5+CD10-) comprised 4.03% of nuclear cells.This discovery may represent a borderline lymphoproliferative disorder.This type of clone is commonly seen in pre-MZL (marginal zone lymphoma) states or in clones associated with IgM-type monoclonal gammopathy of undetermined significance (MGUS).Approximately 10–15% of patients develop overt lymphoma, primarily splenic marginal zone lymphoma or lymphoplasmacytic lymphoma, within 5 years. If combined with cryoglobulinemia, the risk of progression escalates to 20–30% because of chronic antigen stimulation that promotes clonal evolution.For such minimal B-cell proliferations, although the clone is small, it is highly toxic, and the clone size does not correspond with the degree of organ damage. Once a diagnosis of MGRS is established, irrespective of the clone size, if it results in end-organ damage, active clone-targeted therapy is necessary.Cryoglobulinemia is relatively common in MGRS, although many patients with MGRS do not present with the classic symptoms of cryoglobulinemia and may lack significant tissue deposits. A retrospective study involving MGRS patients reported that 12 of 17 had monoclonal gammopathy-associated glomerulonephritis (PGNMID), and cryoglobulin testing was positive in 5 of 7 cases [ 39 ]. This supports the hypothesis that MGRS-related cryoglobulinemia can present in a manner that is less typical and may often go unrecognized without the inclusion of cryoglobulin testing.

Rituximab (RTX) combined with glucocorticoids (GCs) is considered the first-line treatment for non-infectious mixed cryoglobulinemia, particularly in severe cases. Approximately two-thirds of patients achieve a complete clinical response with this combination therapy [ 40 ]. A retrospective study involving 242 patients with non-infectious mixed cryoglobulinemia found that the combination of GCs and RTX resulted in a higher clinical response rate compared to other treatment regimens, particularly GCs alone or GCs combined with alkylating agents. However, 5–11% of patients demonstrate resistance to this combination therapy [ 41 ]. Furthermore, one-third of patients who initially respond to treatment experience early relapse within the first year after induction therapy [ 41 , 42 ]. In the current case, the patient initially was treated with a cumulative dose of 2 g of rituximab combined with a medium dose of prednisone, and followed up for 3 months. During the follow-up period, plasma albumin levels returned to normal, and urine protein excretion significantly decreased. However, plasma creatinine levels did not show a notable reduction, and immunological markers such as complement levels and rheumatoid factor remained largely unchanged. Following a poor response to treatment after four months of follow-up, combination therapy with oral cyclophosphamide (50 mg, administered every other day) was initiated. At the six-month point of monitoring, CD19 levels showed a significant increase, prompting the administration of an additional 2 doses of 500 mg rituximab (administered at 2-week intervals) to the patient for intensified treatment.Subsequently, the levels of rheumatoid factor showed a significant decrease compared to before.The patient’s suboptimal response to rituximab may be due to complement activation or rituximab resistance. In a study by Andrej Škoberne et al., 41% of patients with monoclonal gammopathy of renal significance (MGRS) exhibited serum markers of complement involvement, with serum C5b-9 and anti-factor H autoantibodies being the most common [ 39 ]. These patients demonstrated poor responses to rituximab treatment, with all patients who had anti-factor H autoantibodies and 75% of those with elevated C5b-9 levels failing to respond. For patients who are resistant to RTX, alternative treatment strategies, such as combining anti-CD20 monoclonal antibodies with belimumab, alkylating agents, or using alkylating agents alone, have shown higher clinical response rates compared to other therapies [ 40 ]. Mouse model studies have highlighted the significance of BAFF (B-cell activating factor) in modulating the threshold for anti-CD20-mediated B-cell depletion, particularly in marginal zone and germinal center B cells. These B cells are resistant to complete depletion with anti-CD20 antibodies alone; however, combining anti-CD20 with anti-BAFF antibodies can lead to more extensive B-cell depletion in these regions [ 43 ]. While this combination therapy may be effective, it increases the risk of serious infections, necessitating careful monitoring and caution in clinical application.

Cryoglobulinemia, although not rare, is often under-recognized in clinical practice, leading to a high rate of missed diagnoses. In middle-aged and elderly patients, symptoms such as skin purpura, decreased complement C3 and/or C4 levels, and positive RF (with the exception of type I) are important points of cryoglobulinemic vasculitis. Renal pathology typically reveals membranoproliferative glomerulonephritis (MPGN) with thrombus-like deposits, a hallmark of cryoglobulinemic nephritis. For confirmation, cryoglobulin testing and electron microscopy are essential. It is crucial to adhere to strict protocols for cryoglobulin qualitative testing, particularly in type II cryoglobulinemia, where monoclonal gammopathy is rare but can present as an initial manifestation of MGRS-related kidney involvement. Bone marrow biopsy, immunofixation electrophoresis, and other tests should be conducted to clarify the underlying cause of monoclonal gammopathy.Once MGRS is diagnosed, clone-targeted therapy should be initiated as soon as possible.This case presents certain limitations: First, no typical structures were observed on electron microscopy. Immunoelectron microscopy, which could identify the electron-dense deposits as IgMk type, was not performed due to patient refusal. Second, the testing frequency for cryoglobulin is less than twice within a 12-week interval, and the patient did not undergo quantitative cryoglobulin detection, nor was immunofixation electrophoresis performed on the precipitate (cryoglobulins) to further classify the type.Third, this patient did not undergo a skin biopsy.During the follow-up period, we will again encourage patients to undergo skin biopsy.The patient’s lack of response to rituximab may suggest rituximab resistance. The patient has since been treated with cyclophosphamide. Upon administering a cumulative dose of 2 g of cyclophosphamide, the rheumatoid factor demonstrated a notable decrease compared to its prior levels. However, the treatment response is average, and further follow-up is required to assess efficacy and outcomes. If necessary, the addition of belimumab could be considered as a treatment strategy. Furthermore, measuring serum C5b-9 levels, anti-factor H autoantibodies, and C3 nephritic factor will be important to evaluate complement involvement. Ongoing follow-up will be crucial to monitor the patient’s progress and response to therapy.

Publisher’s note

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

Acknowledgements

Our thanks to Peking University First Hospital for the electron microscope diagnosis of the case.

Author contributions

Y.Z. and K. Z. carried out the studies, participated in collecting data, and drafted the manuscript. J.W. performed the data analysis and participated in its design. Q. H. performed and diagnosed the histological examinations of the kidney biopsy sample. X.M., Y.X., J.S., S.W. participated in acquisition, analysis, or interpretation of data. All authors read and approved the final manuscript.

Funding

None.

Data availability

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

Declarations

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of Ethics Committee of Weifang People’s Hospital. All participants were informed about the study protocol and provided written informed consent to participate in the study. I confirm that all methods were performed in accordance with the relevant guidelines. All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent for publication

All authors confirm our participants gave written informed consent for their personal or clinical details along with any identifying images to be published in this study.

Competing interests

The authors declare no competing interests.

Abbreviations

Albumin-to-Creatinine Ratio

Chronic lymphocytic leukemia

Small lymphocytic lymphoma

Monoclonal Gammopathy of Renal Significance

Monoclonal gammopathy-associated glomerulonephritis

Rituximab

Glucocorticoids

Membranoproliferative glomerulonephritis

Phospholipase A2 receptor

Anti-neutrophil cytoplasmic antibody

Glomerular basement membrane

Cryoglobulinemic glomerulonephritis

Rheumatoid factor

Central nervous system

International Kidney and Monoclonal Gammopathy Research Group

Marginal zone lymphoma

Monoclonal Gammopathy of Undetermined Significance

References

1. Takada S, Shimizu T, Hadano Y et al. Cryoglobulinemia (review). Mol Med Rep. 2012;6:3–8. 10.3892/mmr.2012.861 22484457

2. Mariscal-Rodríguez A Villar Guimerans LM López-Trascasa M Hernández González M Moga Naranjo E Laboratory guidelines for the diagnosis of patients with cryoglobulinaemic syndrome Rev Clin Esp 2019 219 505 13 30577994 10.1016/j.rce.2018.10.006 Mariscal-Rodríguez A, Villar Guimerans LM, López-Trascasa M, Hernández González M, Moga Naranjo E. Laboratory guidelines for the diagnosis of patients with cryoglobulinaemic syndrome. Rev Clin Esp. 2019;219:505–13. 30577994 10.1016/j.rce.2018.10.006

3. Ramos-Casals M Stone JH Cid MC Bosch X The cryoglobulinaemias Lancet (London England) 2012 379 348 60 21868085 10.1016/S0140-6736(11)60242-0 Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet (London England). 2012;379:348–60. 21868085 10.1016/S0140-6736(11)60242-0

4. 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 57 775 88 4216269 10.1016/0002-9343(74)90852-3 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;57:775–88. 4216269 10.1016/0002-9343(74)90852-3

5. Ghembaza A Boleto G Bommelaer M Prognosis and long-term outcomes in type I cryoglobulinemia: A multicenter study of 168 patients Am J Hematol 2023 98 1080 6 37139676 10.1002/ajh.26944 Ghembaza A, Boleto G, Bommelaer M, et al. Prognosis and long-term outcomes in type I cryoglobulinemia: A multicenter study of 168 patients. Am J Hematol. 2023;98:1080–6. 37139676 10.1002/ajh.26944

6. Sorunke A, Pinto C, Saleem MD, Tahir F. Mixed cryoglobulinemia syndrome associated with Non-HCV B-Cell lymphoproliferative disorder presenting with gangrene and peripheral neuropathy. R I Med J (2013). 2024;107:15–9. 39186395

7. Treppo E Quartuccio L De Vita S Recent updates in the diagnosis and management of cryoglobulinemic vasculitis Expert Rev Clin Immunol 2023 19 1457 67 37698547 10.1080/1744666X.2023.2249609 Treppo E, Quartuccio L, De Vita S. Recent updates in the diagnosis and management of cryoglobulinemic vasculitis. Expert Rev Clin Immunol. 2023;19:1457–67. 37698547 10.1080/1744666X.2023.2249609

8. Tissot JD Invernizzi F Schifferli JA Spertini F Schneider P Two-dimensional electrophoretic analysis of cryoproteins: a report of 335 samples Electrophoresis 1999 20 606 13 10217176 10.1002/(SICI)1522-2683(19990301)20:3<606::AID-ELPS606>3.0.CO;2-N Tissot JD, Invernizzi F, Schifferli JA, Spertini F, Schneider P. Two-dimensional electrophoretic analysis of cryoproteins: a report of 335 samples. Electrophoresis. 1999;20:606–13. 10217176 10.1002/(SICI)1522-2683(19990301)20:3<606::AID-ELPS606>3.0.CO;2-N

9. Codes-Méndez H, Jeria S, Park HS et al. Clinical and serological profiles in cryoglobulinemia: analysis of isotypes and etiologies. J Clin Med. 2024;13. 10.3390/jcm13206069 PMC11508573 39458019

10. Faisatjatham S Uaprasert N Iampenkhae K Udomkarnjananun S Detectable serum IgM monoclonal gammopathy in non-hepatitis-associated mixed cryoglobulinemic glomerulonephritis: A case report and literature review SAGE Open Med Case Rep 2022 10 2050313x221140648 36507058 10.1177/2050313X221140648 PMC9726840 Faisatjatham S, Uaprasert N, Iampenkhae K, Udomkarnjananun S. Detectable serum IgM monoclonal gammopathy in non-hepatitis-associated mixed cryoglobulinemic glomerulonephritis: A case report and literature review. SAGE Open Med Case Rep. 2022;10:2050313x221140648. 36507058 10.1177/2050313X221140648 PMC9726840

11. Higgins L Nasr SH Said SM Kidney involvement of patients with Waldenström macroglobulinemia and other IgM-Producing B cell lymphoproliferative disorders Clin J Am Soc Nephrology: CJASN 2018 13 1037 46 10.2215/CJN.13041117 PMC6032586 29848505 Higgins L, Nasr SH, Said SM, et al. Kidney involvement of patients with Waldenström macroglobulinemia and other IgM-Producing B cell lymphoproliferative disorders. Clin J Am Soc Nephrology: CJASN. 2018;13:1037–46. 10.2215/CJN.13041117 PMC6032586 29848505

12. Terrier B Carrat F Krastinova E Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey Ann Rheum Dis 2013 72 374 80 22586172 10.1136/annrheumdis-2012-201405 Terrier B, Carrat F, Krastinova E, et al. Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Ann Rheum Dis. 2013;72:374–80. 22586172 10.1136/annrheumdis-2012-201405

13. Zaidan M Terrier B Pozdzik A Spectrum and prognosis of noninfectious renal mixed cryoglobulinemic GN J Am Soc Nephrology: JASN 2016 27 1213 24 10.1681/ASN.2015020114 PMC4814186 26260165 Zaidan M, Terrier B, Pozdzik A, et al. Spectrum and prognosis of noninfectious renal mixed cryoglobulinemic GN. J Am Soc Nephrology: JASN. 2016;27:1213–24. 10.1681/ASN.2015020114 PMC4814186 26260165

14. Zhang X Yu XJ An CW Clinicopathological spectrum of cryoglobulinemic glomerulonephritis without evidence of autoimmunity disorders: A retrospective study from a single Institute of China Kidney Dis (Basel) 2022 8 253 63 35702704 10.1159/000522537 PMC9149548 Zhang X, Yu XJ, An CW, et al. Clinicopathological spectrum of cryoglobulinemic glomerulonephritis without evidence of autoimmunity disorders: A retrospective study from a single Institute of China. Kidney Dis (Basel). 2022;8:253–63. 35702704 10.1159/000522537 PMC9149548

15. Chen YP Cheng H Rui HL Dong HR Cryoglobulinemic vasculitis and glomerulonephritis: concerns in clinical practice Chin Med J 2019 132 1723 32 31283654 10.1097/CM9.0000000000000325 PMC6759094 Chen YP, Cheng H, Rui HL, Dong HR. Cryoglobulinemic vasculitis and glomerulonephritis: concerns in clinical practice. Chin Med J. 2019;132:1723–32. 31283654 10.1097/CM9.0000000000000325 PMC6759094

16. Lamprecht P Gause A Gross WL Cryoglobulinemic vasculitis Arthritis Rheum 1999 42 2507 16 10615995 10.1002/1529-0131(199912)42:12<2507::AID-ANR2>3.0.CO;2-# Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arthritis Rheum. 1999;42:2507–16. 10615995 10.1002/1529-0131(199912)42:12<2507::AID-ANR2>3.0.CO;2-#

17. Ferri C Mascia MT Cryoglobulinemic vasculitis Curr Opin Rheumatol 2006 18 54 63 16344620 10.1097/01.bor.0000198002.42826.c2 Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol. 2006;18:54–63. 16344620 10.1097/01.bor.0000198002.42826.c2

18. Cacoub P Vieira M Saadoun D Cryoglobulinemia - One name for two diseases N Engl J Med 2024 391 1426 39 39413378 10.1056/NEJMra2400092 Cacoub P, Vieira M, Saadoun D. Cryoglobulinemia - One name for two diseases. N Engl J Med. 2024;391:1426–39. 39413378 10.1056/NEJMra2400092

19. Casato M Saadoun D Marchetti A Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests J Rhuematol 2005 32 484 8 15742440 Casato M, Saadoun D, Marchetti A, et al. Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests. J Rhuematol. 2005;32:484–8. 15742440

20. Feldman L Dhamne M Li Y Neurologic manifestations associated with cryoglobulinemia: A single center experience J Neurol Sci 2019 398 121 7 30708209 10.1016/j.jns.2019.01.041 Feldman L, Dhamne M, Li Y. Neurologic manifestations associated with cryoglobulinemia: A single center experience. J Neurol Sci. 2019;398:121–7. 30708209 10.1016/j.jns.2019.01.041

21. Petty GW, Duffy J, Houston J. 3rd. Cerebral ischemia in patients with hepatitis C virus infection and mixed cryoglobulinemia. Mayo Clinic proceedings. 1996;71:671-8. 10.4065/71.7.671 8656709

22. Jung Y Lee EE Yeo J A case of overlap syndrome of systemic sclerosis and cryoglobulinemic vasculitis with central nervous system involvement J Rheumatic Dis 2021 28 242 6 10.4078/jrd.2021.28.4.242 PMC10324908 37476365 Jung Y, Lee EE, Yeo J, et al. A case of overlap syndrome of systemic sclerosis and cryoglobulinemic vasculitis with central nervous system involvement. J Rheumatic Dis. 2021;28:242–6. 10.4078/jrd.2021.28.4.242 PMC10324908 37476365

23. Leung N Bridoux F Batuman V The evaluation of monoclonal gammopathy of renal significance: a consensus report of the international kidney and monoclonal gammopathy research group Nat Rev Nephrol 2019 15 45 59 30510265 10.1038/s41581-018-0077-4 PMC7136169 Leung N, Bridoux F, Batuman V, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the international kidney and monoclonal gammopathy research group. Nat Rev Nephrol. 2019;15:45–59. 30510265 10.1038/s41581-018-0077-4 PMC7136169

24. Matignon M Cacoub P Colombat M Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection Medicine 2009 88 341 8 19910748 10.1097/MD.0b013e3181c1750f Matignon M, Cacoub P, Colombat M, et al. Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection. Medicine. 2009;88:341–8. 19910748 10.1097/MD.0b013e3181c1750f

25. 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 Experimental Med 2018 18 465 71 10.1007/s10238-018-0514-5 29956004 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 Experimental Med. 2018;18:465–71. 10.1007/s10238-018-0514-5 29956004

26. De Vita S Soldano F Isola M Preliminary classification criteria for the cryoglobulinaemic vasculitis Ann Rheum Dis 2011 70 1183 90 21571735 10.1136/ard.2011.150755 PMC3103668 De Vita S, Soldano F, Isola M, et al. Preliminary classification criteria for the cryoglobulinaemic vasculitis. Ann Rheum Dis. 2011;70:1183–90. 21571735 10.1136/ard.2011.150755 PMC3103668

27. Amaador K Peeters H Minnema MC Monoclonal gammopathy of renal significance (MGRS) histopathologic classification, diagnostic workup, and therapeutic options Neth J Med 2019 77 243 54 31582582 Amaador K, Peeters H, Minnema MC, et al. Monoclonal gammopathy of renal significance (MGRS) histopathologic classification, diagnostic workup, and therapeutic options. Neth J Med. 2019;77:243–54. 31582582

28. Leung N Bridoux F Hutchison CA Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant Blood 2012 120 4292 5 23047823 10.1182/blood-2012-07-445304 Leung N, Bridoux F, Hutchison CA, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012;120:4292–5. 23047823 10.1182/blood-2012-07-445304

29. Miao J Herrmann SM Obaidi Z Caza T Bonilla M Paraprotein-Mediated glomerular diseases Adv Kidney Disease Health 2024 31 358 73 10.1053/j.akdh.2024.02.005 39084761 Miao J, Herrmann SM, Obaidi Z, Caza T, Bonilla M. Paraprotein-Mediated glomerular diseases. Adv Kidney Disease Health. 2024;31:358–73. 10.1053/j.akdh.2024.02.005 39084761

30. Kyle RA Monoclonal gammopathy of undetermined significance. Natural history in 241 cases Am J Med 1978 64 814 26 645746 10.1016/0002-9343(78)90522-3 Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med. 1978;64:814–26. 645746 10.1016/0002-9343(78)90522-3

31. Strati P Shanafelt TD Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification Blood 2015 126 454 62 26065657 10.1182/blood-2015-02-585059 PMC4624440 Strati P, Shanafelt TD. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood. 2015;126:454–62. 26065657 10.1182/blood-2015-02-585059 PMC4624440

32. Kyle RA Benson JT Larson DR Progression in smoldering Waldenstrom macroglobulinemia: long-term results Blood 2012 119 4462 6 22451426 10.1182/blood-2011-10-384768 PMC3362362 Kyle RA, Benson JT, Larson DR, et al. Progression in smoldering Waldenstrom macroglobulinemia: long-term results. Blood. 2012;119:4462–6. 22451426 10.1182/blood-2011-10-384768 PMC3362362

33. Kyle RA Greipp PR Smoldering multiplemyeloma N Engl J 1980 302 1347 9 10.1056/NEJM198006123022405 7374679 Kyle RA, Greipp PR. Smoldering multiplemyeloma. N Engl J. 1980;302:1347–9. 10.1056/NEJM198006123022405 7374679

34. Li SJ Chen HP Chen YH Renal involvement in non-Hodgkin lymphoma: proven by renal biopsy PLoS ONE 2014 9 e95190 24733356 10.1371/journal.pone.0095190 PMC3986362 Li SJ, Chen HP, Chen YH, et al. Renal involvement in non-Hodgkin lymphoma: proven by renal biopsy. PLoS ONE. 2014;9:e95190. 24733356 10.1371/journal.pone.0095190 PMC3986362

35. Poitou-Verkinder AL Francois A Drieux F The spectrum of kidney pathology in B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma: a 25-year multicenter experience PLoS ONE 2015 10 e0119156 25811382 10.1371/journal.pone.0119156 PMC4374947 Poitou-Verkinder AL, Francois A, Drieux F, et al. The spectrum of kidney pathology in B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma: a 25-year multicenter experience. PLoS ONE. 2015;10:e0119156. 25811382 10.1371/journal.pone.0119156 PMC4374947

36. Da’as N Polliack A Cohen Y Kidney involvement and renal manifestations in non-Hodgkin’s lymphoma and lymphocytic leukemia: a retrospective study in 700 patients Eur J Haematol 2001 67 158 64 11737248 10.1034/j.1600-0609.2001.5790493.x Da’as N, Polliack A, Cohen Y, et al. Kidney involvement and renal manifestations in non-Hodgkin’s lymphoma and lymphocytic leukemia: a retrospective study in 700 patients. Eur J Haematol. 2001;67:158–64. 11737248 10.1034/j.1600-0609.2001.5790493.x

37. Luciano RL Brewster UC Kidney involvement in leukemia and lymphoma Adv Chronic Kidney Dis 2014 21 27 35 24359984 10.1053/j.ackd.2013.07.004 Luciano RL, Brewster UC. Kidney involvement in leukemia and lymphoma. Adv Chronic Kidney Dis. 2014;21:27–35. 24359984 10.1053/j.ackd.2013.07.004

38. Merlini G Stone MJ Dangerous small B-cell clones Blood 2006 108 2520 30 16794250 10.1182/blood-2006-03-001164 Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006;108:2520–30. 16794250 10.1182/blood-2006-03-001164

39. Škoberne A Škerget M Kojc N Complement activation and cryoglobulinemia are common in monoclonal gammopathy of renal significance: data from a case series Clin Nephrol 2021 96 16 23 34643486 10.5414/CNP96S03 Škoberne A, Škerget M, Kojc N, et al. Complement activation and cryoglobulinemia are common in monoclonal gammopathy of renal significance: data from a case series. Clin Nephrol. 2021;96:16–23. 34643486 10.5414/CNP96S03

40. Pouchelon C Visentini M Emmi G Management of nonviral mixed cryoglobulinemia vasculitis refractory to rituximab: data from a European collaborative study and review of the literature Autoimmun Rev 2022 21 103034 34995764 10.1016/j.autrev.2022.103034 Pouchelon C, Visentini M, Emmi G, et al. Management of nonviral mixed cryoglobulinemia vasculitis refractory to rituximab: data from a European collaborative study and review of the literature. Autoimmun Rev. 2022;21:103034. 34995764 10.1016/j.autrev.2022.103034

41. Terrier B Krastinova E Marie I Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey Blood 2012 119 5996 6004 22474249 10.1182/blood-2011-12-396028 Terrier B, Krastinova E, Marie I, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;119:5996–6004. 22474249 10.1182/blood-2011-12-396028

42. Terrier B Marie I Launay D Predictors of early relapse in patients with non-infectious mixed cryoglobulinemia vasculitis: results from the French nationwide CryoVas survey Autoimmun Rev 2014 13 630 4 24418300 10.1016/j.autrev.2013.11.006 Terrier B, Marie I, Launay D, et al. Predictors of early relapse in patients with non-infectious mixed cryoglobulinemia vasculitis: results from the French nationwide CryoVas survey. Autoimmun Rev. 2014;13:630–4. 24418300 10.1016/j.autrev.2013.11.006

43. Gong Q, Ou Q, Ye S et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol (Baltimore, Md: 1950). 2005;174:817–26. 10.4049/jimmunol.174.2.817 15634903