Cryoglobulinemic Glomerulonephritis Research Articles

#2672 Cryoglobulin-Induced membranoproliferative glomerulonephritis in a HEV-infected kidney transplant recipient: outcomes post ribavirin failure

Abstract Background and Aims Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. It is the most prevalent hepatitis virus worldwide. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced in immunocompromised patients such as transplant recipients. CHE can induce extra-hepatic manifestations, such as immune-mediated thrombocytopenia, neurological symptoms, and kidney injuries. Few cases of glomerulonephritis (GN) and cryoglobulinemia in transplant patients have been related with CHE, with a good progression thanks to viral control with ribavirin introduction. There have been no reported cases in the literature of good progress in renal function in renal transplant patients despite failure of treatment with Ribavirin. Method We report here what is to our knowledge, the first documented case of HEV-induced de novo cryoglobulinemic membranoproliferative glomerulonephritis in a renal transplant patient with a ten-year history of CHE infection unsuccessfully treated with ribavirin. Results A 69-year-old man underwent a kidney transplant for diabetes type 1. 7 years after transplantation, he was diagnosed with a chronic genotype 3.1H-HEV infection. He was treated by Ribavirin, but it did not allow to eradicate HEV but a biochemical response. At 18 years post transplant, he presented with asthenia, abdominal pains and increased liver enzyme levels: liver tests were disrupted with cytolysis and cholestasis. He presented also a nephritic syndrome with high blood pressure, oedemas, increased serum creatinine level, proteinuria with hypoalbuminemia and de novo microscopic hematuria. Biological analysis revealed presence of type 2 cryoglobulinemia with monoclonal IgM Kappa (2285 mg/L), and polyclonal immunoglobulins association. Rheumatoid factor was increased (573 UI/ml) and C4 level was reduced (0.04 g/L). The concentration of HEV RNA in the serum was 750 000 UI/mL. Viral serologies were performed for HBV, HCV, HAV, HIV, EBV, CMV. Hematologic diseases were ruled out by analyzing a bone marrow biopsy specimen. Histologic analysis of a kidney biopsy specimen revealed diffuse endocapillary proliferation, diffuse mesangial proliferation and focal glomerular basal membrane duplication. One arteriolar section showed a focal lesion of vasculitis (Fig. 1). There was no argument for allograft rejection. Immunofluorescence microscopy revealed mesangial and capillary wall deposits of IgM, IgG, C3 and C1q, polytypic for k and l light chains. We suspected cryoglobulinemic membranoproliferative glomerulonephritis induced by VHE. The initial treatment plan involved 10 sessions of plasmapheresis and steroid pulses (500 mg/d for 3 days), alongside a course of rituximab (1 g/week for 4 weeks). However, the patient experienced intolerance to rituximab, prompting a switch to Obinutuzumab. Subsequently, the anti-HEV therapy was modified, and the patient was placed on a course of Sofosbuvir. Consequently, three months after treatment kidney function kidney improved with return to baseline and cryoglobulinemia became undetectable. However, proteinuria remained impaired and VHE RNA was still present. Conclusion Cryoglobulinemia is rarely associated with glomerular disease in HEV infection, and cases currently reported in the literature showed a favorable outcome with ribavirin. This case is the first to display a chronic HEV infection with cryoglobulin-induced glomerulonephritis with global improvement despite unsuccessful treatment with ribavirin. Although the difficulty of managing immunity in the treatment of cryoglobulinemia by immunodepleting treatment, with the risk of increased viral replication in the absence of an effective antiviral, it seems interesting to offer a first-line treatment of cryoglobulinemia that appears to improve renal function despite continued viral replication. These results need to be confirmed in further studies.

#1297 Approaches to renal response assessment in rare monoclonal immunoglobulin related glomerulopathies

Abstract Background and Aims AL-amyloidosis (AL) and monoclonal immunoglobulin (MIg) deposition disease are common types of MIg-related glomerulopathies (MIgG) and are well-studied including approaches to treatment and hematological and renal responses (RR) assessment. Other rare MIgG comprise very diverse patterns of glomerular injury e.g. proliferative glomerulonephritis with MIg deposition (PGNMID), C3-glomerulopathy, fibrillary glomerulonephritis etc. Although RR defined as decrease in 24 h proteinuria by 30% without kidney function decline was validated only for renal AL it is widely used for MIg deposition disease and rare MIgG without validation. Nevertheless, the best approach to RR assessment in rare MIgG is still unclear. To shed some light on this problem we performed this study. Method We retrospectively analyzed 31 patients with rare MIgG who were treated with clone-specific treatment and had available follow-up (FUP) ≥6 months (mo). The following morphological patterns were diagnosed: PGNMID (n = 9), C3-glomerulopathy (n = 9), thrombotic microangiopathy (n = 5), cryoglobulinemic glomerulonephritis (n = 3), fibrillary glomerulonephritis (n = 3), immunotactoid glomerulonephritis (n = 1) and membranous nephropathy (n = 1). Patients’ baseline parameters are shown on Fig. 1 as well as treatment modalities. Hematological response defined according to currently accepted criteria is demonstrated on Fig. 1. We evaluated two approaches to the RR assessment: 1) at least partial renal response (PR) defined as 24 h proteinuria decreased by 50% from the baseline and <3.5 g, and 2) according to Palladini's criteria for AL (AL-RR) i.e. 24 h proteinuria decreased by 30% from the baseline or <0.5 g. Both RR were considered as achieved only in the absence of estimated glomerular filtration rate (eGFR) decline >25%. Time points for RR assessment were 6, 12 and 24 mo from the clone-specific treatment initiation. Renal outcome was estimated as initiation of renal replacement therapy or eGFR <15 ml/min/1.73 m2 at the end of follow-up. Death-censored renal survival was analyzed by the Kaplan-Meier method. Cox regression analysis was applied to determine which RR was independently associated with long-term kidney outcome. P-value was assumed at <0.05. Median FUP was 19 (7; 50) mo. FUP ≥12 and ≥24 mo were available in 26 and 17 patients, respectively. Results Total number of patients who achieved AL-RR at any RR assessment time point was 22 (71%). At 6, 12 and 24 mo the achievement of AL-RR was registered in 17, 16 and 10 patients, respectively. PR cumulatively was achieved in 19 (61%) patients: at time points of 6, 12, and 24 mo it was registered in 14, 14 and 9 cases, respectively. The 5-year cumulative renal survival in those who had AL-RR was better than in not responders (Fig. 2A). Patients who ever achieved PR had better cumulative renal survival compared with patients with no renal remission (Fig. 2B). In univariate Cox regression analysis the achievement of AL-RR (Exp(β) 0.158 (95% CI 0.03; 0.819)) was associated with renal outcome as well as the achievement of PR (Exp(β) 0.074 (95% CI 0.09; 0.626)). In multivariate Cox regression model adjusted for eGFR at the time of kidney biopsy AL-RR vs no response was estimated as an independent predictor of renal long-term prognosis (Exp(β) 0.082 (95% CI 0.009; 0.725)) as well as eGFR (Exp(β) 0.89 (95% CI 0.821; 0.985)). The only independent predictor of renal outcome in the model including eGFR at the time of kidney biopsy (Exp(β) 0.85 (95% CI 0.72; 0.99), p = 0.05) was PR (Exp(β) 0.011 (95% CI 0; 0.547), p = 0.021). Conclusion The classical concept of complete and partial renal remission seems to be more appropriate for rare MIgG and requires further validation studies.

#2284 Clinical characteristics and renal survival of patients with monoclonal gammopathy of renal significance (MGRS)

Abstract Background and Aims Monoclonal gammopathy of renal significance (MGRS) comprises a diverse group of renal disorders related to a nephrotoxic monoclonal immunoglobulin. Due to the rarity of the disease and the recent definition of MGRS-associated kidney lesions, data about long-term clinical outcomes remain limited. Method A single-center, retrospective cohort study was conducted including data of all patients with biopsy-proven MGRS who were followed at our center between 2005 and 2023. We examined the clinicopathologic characteristics and renal survival of the patients. Disease progression was defined as an eGFR decline >30% or end-stage kidney disease (ESKD). Univariate Cox regression analysis was used to assess the relationship between clinical features and disease progression. Results A total of 23 adults (males 43.5%) with a median age of 65 years (IQR 55-70) were included in our study. At presentation, median eGFR was 51 ml/min/1.73 m2 (IQR 40-80) and proteinuria 3.94 g/24 h (IQR 2.00-6.26). Serum or urine monoclonal protein was not detected in 4 patients (18.2%). MGRS-associated renal lesions included Ig-related amyloidosis (n = 8), monoclonal immunoglobulin deposition disease (n = 7), cryoglobulinemic glomerulonephritis (n = 2), C3 glomerulopathy (n = 2), proliferative glomerulonephritis with monoclonal IgG deposits (n = 1), immunotactoid glomerulopathy (n = 1) and miscellaneous (n = 2). Most patients were treated with a plasma cell-directed regimen (77.3%) and the rest with B-cell-directed (13.6%) or conservative therapy (9.1%). Median follow-up for the cohort was 45 months (IQR 27-67). Thirteen patients responded to treatment (52.1%), achieving a reduction in proteinuria (0.44 vs 3.94 g/24 h, p:001) and maintenance of eGFR (60 vs 56 ml/min, p:0.363) at the last follow-up visit. All responders had received clone-directed therapy. Disease progression occurred in 8 patients (34.8%), three of whom reached ESKD (13.0%). Renal survival, defined as survival without ESKD, was 84.6% at 48 months (CI 73.3-101.7). Factors that were associated with disease progression were Ig-related amyloidosis (HR: 6.94, CI: 1.30-36.84, p:0.023) and eGFR < 45 ml/min at diagnosis (HR: 14.73, CI: 1.62-132.95, p:0.017). Conclusion MGRS is a heterogeneous clinical entity manifesting with varying degrees of proteinuria and kidney injury. Impaired kidney function at diagnosis and Ig-related amyloidosis correlated with worse renal prognosis in our cohort. Early identification and clone-directed treatment of MGRS may improve long-term renal survival.

Acquired Fanconi syndrome in mixed cryoglobulinemia patients: a single-center case series.

Cryoglobulinemia is a pathological condition characterized by the presence of cryoglobulins in the blood, with cryoglobulinemic glomerulonephritis being the most frequent form of renal involvement. Fanconi syndrome presents as a generalized dysfunction of the proximal tubule, characterized by the presence of polyuria, phosphaturia, glycosuria, proteinuria, proximal renal tubular acidosis, and osteomalacia. We aimed to present five cases co-occurring with Fanconi syndrome and cryoglobulinemia. We retrospectively summarized the cases of five patients with Fanconi syndrome and cryoglobulinemia at Peking Union Medical College Hospital from January 2012 to June 2022. The clinical features, diagnosis, treatment, and prognosis were systematically analyzed. All five patients exhibited typical features of Fanconi syndrome, and cryoglobulinemia was concurrently detected in all cases. These patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, and IgM constitutes the predominant monoclonal component in cryoglobulins. In addition to supplemental treatment, timely immunosuppressive therapy may potentially benefit the long-term renal prognosis of patients with this condition. Our findings highlight the rare co-occurrence of Fanconi syndrome and cryoglobulinemia in clinical practice. Despite the lack of causal evidence, the coexistence of Fanconi syndrome and tubulointerstitial injury is also noteworthy in patients with cryoglobulinemia, underscoring the importance of thorough evaluation and tailored management in patients presenting with overlapping renal manifestations. Key Points • Patients with mixed cryoglobulinemia can clinically present with tubulointerstitial injury, specifically manifesting as Fanconi syndrome. • In addition to typical symptoms of Fanconi syndrome, these patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, while IgM constitutes the monoclonal component in cryoglobulins. • Timely immunosuppressive therapy may improve long-term renal prognosis in these patients.

Monoclonal Gammopathy of Renal Significance Presenting as Cryoglobulinemic Glomerulonephritis

Monoclonal Gammopathy of Renal Significance Presenting as Cryoglobulinemic Glomerulonephritis

Hepatitis B virus-infection related cryoglobulinemic vasculitis. Clinical manifestations and the effect of antiviral therapy: A review of the literature.

Hepatitis B virus (HBV) infection causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Furthermore, about 20% of the patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV), polyarteritis nodosa, non-rheumatoid arthritis, glomerulonephritis and non-Hodgkin lymphoma. This review analyzed literature data on clinical manifestations of HBV-related CV and the impact of antiviral therapy with analoques nucleotide. A PubMed search was performed to select eligible studies in the literature, up to July 2022. Some studies have analyzed clinical manifestations in HBV-related CV and have investigated the role of antiviral therapy with nucleotides analogues (NAs). Clinical manifestations of CV vary from mild to moderate (purpura, asthenia and arthralgias) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, and non-Hodking lymphoma). NAs therapy leads to suppression of HBV-DNA; therefore, it is capable of producing clinical response in the majority of patients with mild to moderate symptoms. Antiviral therapy with NAs is the first choice for HBV suppression and control of mild to moderate disease. In severe vasculitis (glomerulonephritis, progressive peripheral neuropathy and leg ulcers), rituximab alone or with plasma-exchange is always indicated in combination with antiviral therapy.

Acute kidney injury due to cryoglobulinemic glomerulonephritis as the initial presentation of Chronic Lymphocytic Leukemia

Cryoglobulinemic vasculitis presents with systemic vasculitis including vasculitic rash, fever, peripheral neuropathy and rarely renal involvement. This could be secondary to infections like hepatitis C, malignancies like myeloma, Non Hodgkin’s lymphoma and chronic lymphocytic leukemia. We encountered a patient who presented with fever, anemia, purpuric skin rash and acute kidney injury due to acute glomerulonephritis with nephritic picture and fluid overload that required hemodialysis.Investigations revealed hemolytic anemia, cryoglobulinemia, proliferative glomerulonephritis with Ig M intra-capillary deposits and hyaline thrombi. Bone marrow biopsy clinched the diagnosis of Chronic lymphocytic B cell lymphoma with CD 20 positivity. Treatment was instituted with Rituximab and Bendamustine. Plasmapheresis was done for hyperviscosity syndrome. With treatment, hemodialysis could be discontinued after 10 weeks and renal functions recovered partially with serum creatinine settling at 1.5 mg/dl. We present this case to highlight the presentation of chronic lymphocytic leukemia with cryoglobulinemic vasculitis that presented with purpura and rapidly progressive renal failure that required dialysis.

Successful treatment of infectious endocarditis-associated glomerulonephritis during active hepatitis C infection: a case report

BackgroundHepatitis C virus (HCV) may play a pathogenic role in several forms of immune complex glomerulonephritis (GN). We present a patient whose initial clinical presentation instilled suspicion of HCV-related renal involvement. Yet, histopathologic data oriented towards a different diagnosis.Case presentationA 68-year old man presented with kidney dysfunction, cryoglobulins, low C4 level, high HCV—RNA and cutaneous vasculitis. The first hypothesis was a hepatitis C-related cryoglobulinemic glomerulonephritis. Renal biopsy revealed endocapillary and mesangial cells hypercellularity with complement C3 and IgM deposits. The echocardiography showed an infectious endocarditis (IE) on aortic valve. Appropriate antibiotic therapy and a prosthetic valve replacement were performed, obtaining recovery of renal function.ConclusionHCV infection may be linked to multiple renal manifestations, often immune-complex GN such as cryoglobulinemic membrano-proliferative GN. Renal disease due to IE is usually associated to focal, segmental or diffuse proliferative GN, with prominent endocapillary proliferation. The most common infectious agents are Staphylococcus aureus and Streptococcus species.This case report may be relevant because the renal dysfunction was highly suggestive of a cryoglobulinemic GN on a clinical ground, but the histologic pattern after performing the renal biopsy oriented towards a different cause of the underlying disease, that required a specific antibiotic treatment. The renal biopsy is always required to confirm a clinical suspicious in patients affected by multiple comorbidities.

Extrahepatic Manifestations of Chronic HBV Infection and the Role of Antiviral Therapy.

The hepatitis B virus (HBV) infection leads to chronic hepatitis, cirrhosis, and hepatocarcinoma. However, about 20% of patients experience extrahepatic manifestations such as polyarteritis nodosa, non-rheumatoid arthritis, non-Hodgkin lymphoma, cryoglobulinemic vasculitis, and glomerulonephritis. These influence the patient's morbidity, quality of life and mortality. The treatment of an HBV infection is based on nucleotide analogues (NAs) which are safe and effective for the suppression of HBV-DNA in almost 100% of cases. A few studies have shown that NAs induce a viral response and an improvement of extrahepatic diseases. There is a lack of a thorough analysis of the available treatments for extrahepatic HBV manifestations. In 90% to 100% of cases, the NAs stop the HBV replication, and they produce a clinical response in the majority of patients with mild to moderate extrahepatic signs/symptoms. Arthritis can definitely disappear after the HBV elimination and, in some cases, the HBV eradication following NAs therapy appears to improve the renal function in HBV-related nephropathies. Plasma exchange can be used in subjects who are suffering from the most aggressive forms of cryoglobulinemic vasculitis and glomerulonephritis, progressive peripheral neuropathy, and life-threatening cases, and this can be combined with glucocorticosteroids and antiviral agents. In selected refractory patients, the use of rituximab in conjunction with NAs therapy can be considered. The review provides an update on extrahepatic conditions that are linked to HBV and the impact of treating HBV with NAs.

Clinicopathologic characteristics and prognostic analysis of monoclonal gammopathy of renal significance (MGRS) in patients with IgM monoclonal gammopathy: a case series

Monoclonal gammopathy has emerged as an important cause of renal injury. Since the clinicopathologic features related to monotypic monoclonal gammopathy of renal significance with IgM monoclonal gammopathy (IgM-MGRS) are poorly described and it is uncertain if intervention improves renal survival and mortality, we report a series of such patients, characterizing their clinicopathologic spectrum and outcomes. We retrospectively analyzed 38 patients referred to one medical center between 2009 and 2019 with detectable serum monoclonal IgM by immunofixation, performance of a bone marrow biopsy and kidney biopsy-proven MGRS. Of the 38 patients identified, about half patients were amyloidosis, followed by cryoglobulinemic glomerulonephritis. Patients were divided into two groups on the basis of their kidney pathology: amyloid and non-amyloid. Patients with non-amyloidosis were more likely to have renal dysfunction, hematuria, anemia and hypocomplementemia and κ light chain was predominant in this sub-group. Amyloid patients were more often treated with chemotherapy than the non-amyloid patients (P = 0.002). There were no significant differences between amyloid and non-amyloid patients in mortality (48% vs 29%, P = 0.467) and incidence of ESRD (19% vs 59%, P = 0.103). The incidence of ESRD was lower in patients treated with chemotherapy and/or ASCT, compared to those without chemotherapy (25% vs 57%, P = 0.049), and it was also lower in the hematologic responders than non-responders (10% vs 40%, P = 0.047). Our study confirmed a diverse variety of clinicopathological features and outcomes in patients with IgM-MGRS. Chemotherapy and/or ASCT and deep hematologic responses might improve renal prognosis.

Recognizing the true face of noninfectious cryoglobulinemic glomerulonephritis

Cryoglobulinemia encompasses a group of diseases with circulating aberrant Igs, which can cause systemic cryoglobulinemic vasculitis, including cryoglobulinemic glomerulonephritis. The complexities of different types and changing etiologies of cryoglobulinemias determine its heterogeneous clinical manifestations and diagnostic difficulties. In this issue of Kidney International, Javaugue etal. have emphasized the diagnostic points of cryoglobulinemic glomerulonephritis and hematological disorders as the major culprits of noninfectious cryoglobulinemic glomerulonephritis in a large cohort.

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

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.

Cryoglobulinemic Glomerulonephritis Presenting as Acute Kidney Injury on Chronic Kidney Disease in Rheumatoid Arthritis

Cryoglobulinemic vasculitis (CV) is one of the manifestations of rheumatoid arthritis (RA). Here, we present a case of a 69-year-old woman with uncontrolled long-standing RA who presented with heart failure exacerbation and had an incidental finding of persistent acute kidney injury, which led to the diagnosis of CV. The rarity of its co-occurrence with RA and the serious consequences from progressive kidney damage makes this case a key learning encounter.

244 Cryoglobulinemic Glomerulonephritis Type 1 Clinically Presenting as Type 2 Vasculitis due to Marginal Zone B Cell Lymphoma

244 Cryoglobulinemic Glomerulonephritis Type 1 Clinically Presenting as Type 2 Vasculitis due to Marginal Zone B Cell Lymphoma

Our cases of monoclonal gammopathy renal significance (MGRS): Single center experience

Objective: To analyze the clinical, pathological spectrum and prognosis of patients with Monoclonal Gammopathy of Renal Significance (MGRS). Methods: Patients with kidney biopsy-proven MGRS at Dr Lütfi Kırdar City Hospital between 2015 and 2019 were included, clinical data, kidney pathology type, treatment and prognosis were collected. Results: Thirteen patients, constituting 0.77% of kidney biopsies, were recorded. Eight MGRS patients had amyloidosis. 2 patients had monoclonal immunoglobulin deposition disease. 1 patient with proliferative glomerulonephritis with monoclonal immunoglobulin (G) deposits, 1 patient with cryoglobulinemic glomerulonephritis and one patient with C3 glomerulonephritis. All of our patients were treated with chemotherapy and/or stem cell transplantation. The mean follow-up period was 26 ± 34 months. Multiple myeloma developed in one patient at 19 months during follow-up. At the end of the follow-up, 2 patients (%) died, 3 patients (%) developed End-Stage Renal Disease (ESRD). Conclusion: MGRS is a rare form of hematological disorder that causes kidney damage presenting with a wide range of pathological lesions. Amyloidosis is the most common form. Early diagnosis and close follow-up are important because renal survival of MGRS patients can be improved with early treatment. Keywords: monoclonal gamopaties; renal injury; proteinüria.

Clinicopathological Spectrum of Cryoglobulinemic Glomerulonephritis without Evidence of Autoimmunity Disorders: A Retrospective Study from a Single Institute of China

Background: Cryoglobulinemic glomerulonephritis (Cryo-GN), caused by circulating cryoglobulins, has varied etiology and clinical-pathologic manifestations. This study aimed to investigate the clinicopathological spectrum and outcome of patients with various Cryo-GN in China. Methods: A retrospective review of 74 Chinese patients with biopsy-proven cryoglobulin-related renal lesions in Peking University First Hospital from 2010 to 2020 was performed. Results: The mean age at diagnosis was 52.9 ± 15.0 years, and the female-to-male ratio was about 2/5. For the etiology screening, serum/urine monoclonal immunoglobulin could be detected on immunofixation electrophoresis in 34% of patients, including 6 patients who had hematological malignancies. Fifty-seven percent of patients had HBV infection, far more than HCV infection (5%). Ten percent of patients had other infections, and 27% of patients were classified as essential or idiopathic. Eleven out of the 15 patients with type II cryoglobulinemia had a consistent monotype of serum monoclonal immunoglobulins and monoclonal cryoprecipitate. The clinical manifestations were similar between various types of cryoglobulinemia. Hematuria, proteinuria, hypertension, anemia, and chronic renal insufficiency were the most common features. Fifty-three percent of patients presented with nephrotic syndrome, and 32% experienced acute kidney injury. Hypocomplementemia, serum-positive rheumatoid factor activity, and skin lesions were reported in 45%, 29%, and 28% of patients, respectively. After a median of 24 months follow-up, 18 patients reached end-stage kidney disease. The clone-targeted treatment could retard the renal deterioration compared with immunosuppressive therapy. Conclusions: This was the largest single-center, clinicopathological retrospective study of Cryo-GN in China. Our data strongly support the association between monoclonal gammopathy and type II Cryo-GN. The renal responsive rate of immunosuppressant therapy is still suboptimal. The clone-targeted treatment shows promising effects in patients with type I or II Cryo-GN.

Multiple Myeloma as a rare cause of membranoproliferative glomerular nephritis

Multiple myeloma (MM) is a relatively uncommon cancer characterized by the neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin(Ig). Renal failure in multiple myeloma is around 48% and it may be the presenting manifestation of MM.[1] Renal involvement is multifactorial including light chain cast nephropathy amyloidosis, monoclonal Ig deposition disease and less frequently cryoglobulinaemic glomerulonephritis and proliferative glomerulonephritis.[2-5] Hence membrano proliferative glomerulonephritis (MPGN) is a rare form in MM. Here we report a case of multiple myeloma with MPGN in a 60-year-old male who succumbed to death while on chemotherapy.

A Rare Case of Mild COVID-19 Disease Associated with Type 1 Cryoglobulinemia and Thrombotic Thrombocytopenic Purpura

Introduction:Type I cryoglobulinemia (Type I CG) usually develops in the setting of protein-secreting monoclonal gammopathies [1,2]. The estimated frequency of renal involvement is 30% in Type 1 CG. Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening disease in which there is a deficiency in ADAMTS13, a protease which normally functions to cleave von Willebrand factor (vWF). A deficiency leads to persistence of large vWF multimers and the formation of platelet-rich thrombi in the microvasculature. We present a case of 52 years old female with Type 1 CG and acquired autoimmune TTP secondary to mild Covid-19 disease.Case Report:A 52-year-old woman with medical history significant for CKD stage 2, with baseline creatinine (Cr) of 2.5, Diffuse Large B-Cell Gastric Lymphoma (DLBCL), in complete remission, and recent diagnosis with COVID-19 presented to the ED for evaluation of three days of a petechial rash on her bilateral extremities. Significant labs on arrival included hemoglobin (Hgb) 8.9, platelet count 65, Cr of 3.65, and K+ 6.6, meeting criteria for acute kidney injury (AKI). Peripheral blood smear showedthrombocytopenia and normochromic normocytic anemia with no schistocytes or microangiopathic changes. ADAMTS13 was 43% and there was no clinical suspicion for TTP. The patient's Cr continued to worsen up to 8.1 during admission, prompting renal biopsy. Renal biopsy showed Type 1 cryoglobulinemic glomerulonephritis with vasculitis and 30 to 40% fibrosis of glomeruli. The patient was started on systemic steroids, plasma exchange every 2-3 day (completed 6 sessions) and hemodialysis. Her platelet counts steadily increased to 212 but had a significant drop to 32 when rechecked seven days later, prompting further investigation. ADAMTS13 was rechecked and found to be 5% with presence of inhibitor, Hgb was 7.7, haptoglobin was <20, and a diagnosis of TTP was made. The patient was started on daily plasmapheresis, rituximab, Caplacizumab and high dose systemic steroid therapy. Our patient had prior history of DLBCL and was treated with radiation therapy. Restaging PET/CT and EGD with biopsy showed no evidence of recurrence. Bone marrow biopsy was negative for evidence of lymphoma. Several serologic tests were used to rule out other etiologies of Type I CG and came back negative including: SLE, HIV, hepatitis C, multiple myeloma, and Waldenstrom's macroglobulinemia. The patient had elevations in multiple immune markers including IgG, IgM, free kappa light chains, and free lambda light chains. She also had hypocomplementemia of both C3 and C4.Discussion:The relationship of Type I CG and COVID-19 is unclear, though viral infections can trigger autoimmune diseases [3]. Previously, all patients with Type I CG had either ahematologic malignancy, solid-organ malignancy, infection, or autoimmune syndromes. Interestingly, in our patient, several serologic tests were performed and negative, which ruled out these etiologies of Type I CG. Our patient's manifestation of Type I CG was petechial rash on extremities and acute on chronic renal disease. Specific treatment of CG can include plasma exchange, corticosteroids, rituximab, and hemodialysis, depending on underlying cause. Our patient was started on systemic steroids, plasma exchange every 2-3 days, and hemodialysis due to worsening renal functions. Despite cases of covid-19 and TTP being reported, the relationship between the disease processes remains unclear. COVID-19 infection can cause disproportionate activation of the complement system and lead to excessive coagulation and thrombotic events. Systemic infection can decrease ADAMTS-13 activity, and this has also been noted in COVID studies. ADAMTS-13 deficiency has no pathophysiologic relevance specific to Type 1 CG. Our patient developed anemia and thrombocytopenia, and ADAMTS13 activity testing was found to be 5% with presence of an inhibitor. Considered as high-risk disease, our patient was started on steroids, rituximab, Caplacizumab and daily plasmapheresis. Repeated weekly ADAMTS13 level was 26% and platelets were stabilized at 69k/microL.Conclusion:Suggests that Covid-19 virus has the capability to induce cryoglobulinemia through an unknown mechanism• There are two other case reports of an association between Covid-19 and TTP.• May be the first case indicating a possible association of Covid-19 with cryoglobulinemia. DisclosuresNo relevant conflicts of interest to declare.

Pathology spectrum of kidney damage in Hodgkin’s lymphoma, non-Hodgkin lymphoma/leukemia, and lymphoplasmacytic lymphoma in the real practice

Background: Kidney damage in lymphomas/leukemia’s presents with either acute kidney injury (AKI), chronic kidney disease (CKD), or both; and whilst AKI leads to evaluation often based on the clinical data, in some AKI and in almost all CKD cases kidney biopsy gives a clue to the diagnosis. Methods: A single center non-interventional retrospective study identified 36 patients with biopsy-proven kidney damage: 6 with Hodgkin’s lymphoma (HL), 18 with non-Hodgkin’s lymphoma/leukemia (NHL/CLL), and 12 with lymphoplasmacytic lymphoma (LPL). Results: Fifty-eight percent males and 42% females mean age 56.2 ± 17.4 years, presented with nephrotic syndrome in 47.2%, and with AKI in 11.1% of cases; 75% of patients diagnosed with CKD; in 13.9% AKI was superimposed on CKD. Patients with NHL/CLL presented with AKI significantly more often compared to HL and LPL—44% versus 16.6% versus 0 respectively. Monoclonal immunoglobulin (MIg) related glomerulopathies (GP) were found in 83.3% versus 16.6% cases in the LPL and NHL/CLL sub-groups, respectively ( p = 0.013). Patterns of damage included intracapillary monoclonal deposition disease, light and heavy chain amyloidosis, monotypic membranous nephropathy (MN), cryoglobulinemic glomerulonephritis (GN) and C3-GN in the LPL; and monotypic MN and proliferative GN with MIg deposits in the NHL/CLL sub-groups respectively. Paraneoplastic GPs were found in 83.3%, 38.8%, and 16.6% of patients with HL, NHL/CLL, LPL, respectively (HL vs LPL, p &lt; 0.001), and included minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and IgA-nephropathy in the HL; membranoproliferative GN, MN, and MCD in NHL/CLL; and FSGS in the LPL sub-groups. Tubulointerstitial damage revealed in NHL/CLL sub-group only, and found in every other case with 80% of lymphoid infiltration. Conclusions: Pattern glomerular damage depends on lymphoma type: paraneoplastic GPs are typical for HL, MIg-related GPs dominate in LPL, NHL/CLL presents mainly as paraneoplastic with single MIg-related patterns. Tubulointerstitial damage due to specific kidney infiltration attributable to NHL/CLL.

Clinicopathological characteristics of patients with paraproteinemia and renal damage

BackgroundThis study aimed to analyze the clinicopathological characteristics of patients with paraproteinemia and renal damage.MethodsNinety-six patients from 2014 to 2018 with paraproteinemia and renal damage were enrolled and the clinical data, renal pathology, treatment and prognosis data were collected.ResultsA total of 96 patients (54 male and 42 female), accounting for 2.7% of all renal biopsies, were enrolled in this study. Among them, 42 were monoclonal gammopathy of renal significance (MGRS), 21 were renal monotypic immunoglobulin alone (renal monoIg), and 19 were monoclonal gammopathy of undetermined significance (MGUS). Individuals with multiple myeloma (MM) accounted for the fewest number of patients (n = 14). In the MGRS group, the main diseases were amyloidosis (n = 25) and cryoglobulinemic glomerulonephritis (n = 7), while in the MM group, the main diseases were cast nephropathy (n = 9) and light chain deposit disease (n = 3). In the MGUS group, it was mainly IgA nephropathy (IgAN, n = 10) and idiopathic membranous nephropathy (n = 5); while in the renal monoIg group, most of the cases were IgAN (n = 19). Chemotherapy was mainly administered to patients in the MM group, while immunosuppression therapy was mostly administered to patients in the renal monoIg group. Most patients with renal monoIg exhibited a major response, followed by the patients with MGUS and MGRS, while most of the patients with MM had a partial response but none had a major response. Approximately more than half (57.1%) of the patients with MM progressed to end-stage renal disease (ESRD), followed by MGRS (33.3%); however, the mortality rate was low in both the MGRS and MM groups. The survival analysis reviewed that serum creatinine, hemoglobin levels, and the serum κ/λ ratio were independent risk factors for ESRD in patients with MGRS.ConclusionsThe clinicopathological changes in patients with MGRS were between those in patients with MM and MGUS. The treatment for MGRS and MM was more intensive, and the overall mortality rate was low. Both MGUS and renal monoIg alone exhibited slighter clinicopathological features than MGRS and MM, and the treatment was focused mostly on primary renal diseases.