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Light microscopy of the 3 cases of immune complex–mediated glomerulonephritis. The cases show varying degrees of glomerular activity from (a) global endocapillary hypercellularity with endothelial cell swelling, intracapillary mononuclear cells, neutrophils, and apoptotic debris (case 1) and (b) segmental endocapillary hypercellularity and moderate mesangial hypercellularity (case 2) to (c) global endocapillary and mesangial hypercellularity with double contours (case 3). A full house immunofluorescence pattern was present in all cases (case 3 had only minimal C1q). (d) Granular glomerular basement membrane (GBM) and segmental mesangial staining for C3 (case 1). (e) Granular mesangial and segmental GBM staining for IgG (case 2). (f) Global granular mesangial and GBM staining for IgG (case 3). Electron microscopy showing (g) subendothelial and mesangial electron-dense deposits and activated endothelium in a glomerular capillary loop (case 1) and (h,i) mesangial and paramesangial deposits (cases 2 and 3, respectively).
Source publication
Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been report...
Contexts in source publication
Context 1
... eticular inclusions were seen. These features were consistent with an acute immune complex glomerulo- nephritis with a lupus-like pattern of immune complex deposition (Table 4 and Figure 2a, d, and g). ...
Context 2
... findings, along with the clinical features, supported an active immune complex-mediated glomerulonephritis with a lupus-like pattern of immune complex deposition. There was also a background of moderate glomerular and tubulointerstitial scarring, possibly from chronic injury from hepatorenal syndrome (Table 4 and Figure 2b, e, and h). ...
Context 3
... mofetil was dis- continued. Azathioprine was substituted as a steroid- sparing agent; however, her joint pain continued, so she was switched back to mycophenolate mofetil (Figure 2b). By 12 weeks after treatment, her arthritis improved and there was no evidence of relapse of glomerulonephritis. ...
Context 4
... large and confluent subendothelial, mesangial, paramesangial and intramembranous electron dense deposits were present and did not show substructures. These findings were consistent with a severe active and chronic immune complex-mediated glomerulonephritis resembling a diffuse proliferative lupus nephritis (Table 4 and Figure 2c, f, and i). ...
Citations
... To our knowledge, there have been no reports of new-onset RA after DAA therapy except for our previously reported case (5). However, cases of new-onset or worsened MPGN have been reported after achieving SVR following DAA therapy (27)(28)(29), which supports our data. The incidence of RA varies among studies, and some incidences change with time (30). ...
Background and study aims:
The long-term comprehensive prognosis of chronic hepatitis C after direct-acting antiviral (DAA) therapy is unclear. This study aimed to investigate the prognosis and incidence of immunological and oncological complications after DAA therapy.
Patients and methods:
The study included a total of 1461 patients who received DAA therapy in our university hospital and affiliated hospitals between September 3, 2014 and September 30, 2018.
Results:
The incidence rates of total malignancies in overall or female patients after DAA therapy were significantly greater than expected in the corresponding general population. The same was true for lung malignancies. Predictive risk factors associated with the occurrence and recurrence of hepatic malignancies after DAA therapy in patients with sustained virological response were cirrhosis and insulin use, protein induced by vitamin K absence or antagonist-II level, and albumin-bilirubin score, respectively. Eight (0.5%) patients were diagnosed with autoimmune diseases after starting DAA therapy. Importantly, the attending physician considered a possible causal relationship between DAA therapy and these autoimmune diseases in five cases (four rheumatoid arthritis and one membranoproliferative glomerulonephritis). The 5-year overall survival rate was 91.6%. The most frequent primary cause of death was malignancy in 41 (60.2%) patients, including 25 with hepatic malignancies. Lung and colorectal cancers were the next most common.
Conclusions:
Given that the incidence of total and lung cancers might increase and DAA-related autoimmune diseases might emerge after DAA therapy, we should be alert for the development of these diseases as well as hepatic malignancies.
... Pathological changes in MN (Murakami et al., 2018), FSGS (Hogan et al., 2017), and lupus-like nephritis (Sise et al., 2016) occurred in patients with chronic hepatitis C infection after receiving direct-acting antivirals (including ribavirin, simeprevir, sofosbuvir, and ledipasvir). Kidney damage from such drugs may include direct podocyte toxicity and immune complex deposition. ...
Podocytes form a key component of the glomerular filtration barrier. Damage to podocytes is referred to as “podocyte disease.” There are many causes of podocyte injury, including primary injury, secondary injury, and gene mutations. Primary podocytosis mostly manifests as nephrotic syndrome. At present, first-line treatment is based on glucocorticoid administration combined with immunosuppressive therapy, but some patients still progress to end-stage renal disease. In Asia, especially in China, traditional Chinese medicine (TCM) still plays an important role in the treatment of kidney diseases. This study summarizes the potential mechanism of TCM and its active components in protecting podocytes, such as repairing podocyte injury, inhibiting podocyte proliferation, reducing podocyte apoptosis and excretion, maintaining podocyte skeleton structure, and upregulating podocyte-related protein expression. At the same time, the clinical efficacy of TCM in the treatment of primary podocytosis (including idiopathic membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis) is summarized to support the development of new treatment strategies for primary podocytosis.
... The most frequent causes of CKD and CKD 5 in liver and multivisceral solid organ transplants are attributed to calcineurin inhibitor toxicity, thrombotic microangiopathy, nephrocalcinosis, iron overload, acute tubular injury with infections, hypertension, glomerulopathy, or polyomavirus nephropathy [1][2][3][4]. De novo glomerular disease has also been associated with progressive CKD and CKD 5 in patients with liver transplant (LT), particularly IgA nephropathy and hepatitis B-and C-associated glomerulonephritis [1,5,6]. ...
Background:
We propose a novel clinically significant finding, de novo lupus-like glomerulonephritis (DNLLGN), in patients with autoantibodies and kidney abnormalities in pediatric liver transplant (LT) and intestinal inclusive transplants (ITx).
Methods:
We describe the clinical, serologic, and histopathologic presentation and kidney outcomes in eight patients from our center found to have DNLLGN on kidney biopsy.
Results:
Pediatric recipients of non-kidney solid organ transplants developed an unusual de novo immune complex glomerulonephritis with morphologic similarity to lupus nephritis. Six had isolated LT (0.9% of all pediatric LT at our center) and two had ITx (2.1% of all ITx). Five (63%) presented with nephrotic syndrome. Five patients had autoantibodies. Patients underwent kidney biopsy at a mean of 11.5 years in LT and 2.8 years in ITx after the index transplant. Biopsies demonstrated changes similar to focal or diffuse active lupus. Follow-up eGFR at a mean of 6 years after biopsy showed a mean decrease of 30 ml/min/1.73 m2 in all patients (p = 0.11).
Conclusions:
DNLLGN has not been previously recognized in this clinical setting, yet 8 kidney biopsies from pediatric recipients of LT and ITx at our center in 25 years demonstrated this finding. DNLLGN appears to be an under-reported phenomenon of clinical significance. A higher resolution version of the Graphical abstract is available as Supplementary information.
... DAAs are largely considered non-nephrotoxic; with large series showing extremely low rates of acute kidney injury attributed to DAA therapy (13). However, small case series have linked DAA use with lupus-like glomerulonephritis and podocytopathies, and there have also been case reports of acute interstitial nephritis (14)(15)(16)(17). However, these rare reports should not deter the use of DAAs in patients with CKD. ...
Through the discovery of direct-acting antiviral therapies over the last decade, Hepatitis C virus (HCV) has been transformed from a highly morbid and potentially fatal chronic viral infection to a curable illness. HCV is common in patients with kidney disease and is a risk factor for progression of chronic kidney disease, is associated with higher morbidity and mortality in dialysis patients and leads to worse allograft and patient outcomes in kidney transplant recipients. Clinical trial and real-world data of direct acting antivirals in patients with kidney disease demonstrate extremely high cure rates and favorable adverse event profiles. This review covers the transformative effects of curative HCV therapies on patients with kidney disease including patients with chronic kidney disease, end-stage kidney disease, and kidney transplant recipients.
... In addition, plasma exchanges to remove cryoglobulins may be indicated in severe cases [115]. The development of a dangerous immune complex-mediated glomerulonephritis represents worsening evolution of the immunologic disorder initially triggered by HCV infection [119] that could impair renal function. In this setting, the evaluation of a minimal residual disease in rituximab-treated patients with MC through the assessment of FLCs, heavy/light chains pairs or vascular endothelial growth factor (VEGF) may be crucial to improve the prognosis [42]. ...
Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.
... 115,116 Furthermore, de novo glomerulopathies, including lupus nephritis and focal segmental glomerulosclerosis, have been described in HCV-infected patients. [117][118][119][120] In the context of strong clinical trial evidence from the interferon-ribavirin era that rituximab provides superior outcomes for cryoglobulinemic MPGN, the 2018 guideline recommends rituximab as a first-line option for patients who do not respond to antiviral therapy alone or as part of first-line therapy for patients with severe manifestations of cryoglobulinemic vasculitis who require upfront immunosuppression. 121,122 Implementation and Challenges ...
The first KDIGO (Kidney Disease: Improving Global Outcomes) guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection was published in 2008. The ensuing decade bore witness to remarkable advances in the treatment of HCV infection following the approval of direct-acting antiviral (DAA) agents that deliver cure rates routinely >95%. In this context, the KDIGO organization correctly recognized the need for an updated HCV guideline that would be relevant to the treatment of HCV-infected patients with kidney disease in the DAA era. The current NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) commentary provides an in-depth review and perspective on the 2018 KDIGO guideline. Of note, the KDIGO work group made significant updates to guideline chapters 2 and 4 as a direct result of the availability of DAAs. The intent of this commentary is to provide useful interpretation for nephrologists and other practitioners caring for HCV-infected patients with chronic kidney disease, including dialysis patients and kidney transplant recipients. The availability of DAA agents that are safe and highly effective has created new opportunities, such as the transplantation of kidneys from HCV-infected kidney donors. The ability to treat HCV infection in patients with kidney disease will have a significant impact on the care of our patients and should favorably influence long-term outcomes as well.
... It has been suggested that rapid elimination of HCV might favor a dysregulation of immune surveillance through a variety of mechanisms. Sise et al. [28] have described three cases of lupus-like immune complex glomerulonephritis with 'full house' immunofluorescence in patients with cirrhosis who were treated with IFN-free all-oral DAA regimens. It is possible that this autoimmune phenomenon represents an immune reconstitution syndrome. ...
Objectives To evaluate the effect of direct-acting antiviral agents (DAAs) on hepatitis C virus (HCV)-associated thrombocytopenia. Background The prevalence of thrombocytopenia in HCV infection ranged from 0.16 to 45.4%. The pathophysiology of HCV-associated thrombocytopenia is poorly understood and multifactorial. Cellular immunity has an important role. Antiplatelet antibodies are common. Production of thrombopoietin may be reduced. Infection of megakaryocytes with HCV may impair platelet production. Clearance of HCV with DAA is expected to restore innate functions of the hepatocytes and immune system reconstitution. Patients and methods This was a prospective study on 104 patients with HCV-associated thrombocytopenia receiving DAA (sofosbuvir and daclatasvir); the selected patients were followed up every 4 weeks during antiviral therapy, and at 24 weeks, clinically, and by complete blood count. Results The results show that the platelet counts initially decreased on starting the antiviral treatment, then increased gradually and steady during and after the treatment. Thirty-four patients obtained a normal platelet count of more than 150 000 × 103/mm3 at 24 weeks of starting the treatment, and 72 patients obtained a platelet count of more than 100 000 × 103/mm3 at 24 weeks of starting the treatment. There was a significant correlation with the Child–Pugh class, and FibroScan score, and no significant correlation with splenomegaly. Conclusion DAA therapy is an effective and safe treatment, and is recommended as a first-line treatment for HCV-associated thrombocytopenia. The main postulated mechanism of HCV-associated thrombocytopenia is the immune-mediated effects of HCV, and DAA therapy has the ability of immune system reconstitution.
... Finally, we suggest that serum creatinine and urinary abnormalities should be monitored with accuracy in all patients after antiviral treatment with DAAs. New-onset or relapsing glomerular disease has been noted by some authors in patients who achieved SVR with regimens based on DAAs [18][19][20]. Figure 2 shows purpuric manifestations in the lower limbs in a patient with HCV-related cryogobulinemic patient who received DAAs. After DAAs, the patient obtained SVR but cryoglobulins remain detectable in serum. ...
Glomerular disease is an extra-hepatic manifestation of hepatitis C virus infection (HCV) and membranoproliferative glomerulonephritis is the most frequent glomerular disease associated with HCV. It occurs commonly in patients with HCV-related mixed cryoglobulinemia syndrome. Patients with HCV-related glomerular disease have been historically a difficult-to-treat group. The therapeutic armamentarium for HCV-related glomerular disease now includes antiviral regimens, selective or non-specific immunosuppressive drugs, immunomodulators, and symptomatic agents. The treatment of HCV-associated glomerular disease is dependent on the clinical presentation of the patient. The recent introduction of all-oral, interferon (IFN)-free/ribavirin (RBV)-free regimens is dramatically changing the course of HCV in the general population, and some regimens have been approved for HCV even in patients with advanced chronic kidney disease. According to a systematic review of the medical literature, the evidence concerning the efficacy/safety of direct-acting antiviral agents (DAAs) of HCV-induced glomerular disease is limited. The frequency of sustained virological response was 92.5% (62/67). Full or partial clinical remission was demonstrated in many patients (n = 46, 68.5%) after DAAs. There were no reports of deterioration of kidney function in patients on DAAs. Many patients (n = 29, 43%) underwent immunosuppression while on DAAs. A few cases of new onset or relapsing glomerular disease in patients with HCV successfully treated with DAAs have been observed. In summary, DAA-based combinations are making easier the management of HCV. However, patients with HCV-induced glomerular disease are still a difficult-to-treat group even at the time of DAAs.
... In our small series, the increase in protein / creatinine index was not associated with the treatment with ledipasvir / sofosbuvir, the HCV genotype or the type of renal disease, in a signifi cant way. Other studies have also described the appearance of proteinuria in patients treated with DAAs, which include 5 patients with focal and segmental glomerulonephritis development and another case with development of glomerulonephritis mediated by lupuslike immune complexes [19][20][21][22][23]. ...
... 8 Case reports of HCV-CryoVas relapse have been described either as the reappearance or increase of cryoglobulin levels despite SVR following DAAs. 9,10 This suggests that some patients may continue to have B-lymphocyte clonal stimulation by HCV particles after SVR. The aim of the present study was to search for the presence of HCV RNA in serum and cryoprecipitate of HCV-CryoVas patients who had a sustained virological response after DAAs and who remain cryoglobulin positive. ...
Objective
To search for the presence of HCV RNA in serum and cryoprecipitate of patients presenting with HCV‐cryoglobulinemia vasculitis (HCV‐CryoVas) after direct acting agents (DAAs).
Methods
Samples of 15 HCV‐infected and 4 HCV‐non infected symptomatic CryoVas patients were analyzed. All HCV‐infected patients received interferon‐free DAAs. HCV RNA viral loads were performed on sera and cryoprecipitates.
Results
HCV‐infected CryoVas patients were aged 59±10 yrs, including 44% cirrhotic. Three groups of HCV patients were defined based on the presence of clinical manifestations of CryoVas and cryoglobulin in the serum. Group 1 included 5 patients with symptomatic CryoVas before DAAs. They were all found positive for HCV viral load and cryoprecipitate. All other patients with either both positive cryoglobulin and symptomatic Cryovas (group 2, n=4) or positive cryoglobulin without symptom (group 3, n=6) proved negative for the presence of HCV RNA in serum and cryoprecipitate after sustained virological response to DAAs. In addition, 4 HCV‐seronegative patients who had symptomatic CryoVas were all tested negative for the presence of HCV RNA in their serum and cryoprecipitate.
Conclusions
HCV‐CryoVas patients who remain cryoglobulin‐positive after DAAs do not have HCV RNA in their cryoprecipitate anymore, suggesting that cryoglobulin production became autonomous.
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