B-Cell Dysregulation in Idiopathic Nephrotic Syndrome: What We Know and What We Need to Discover.

The therapeutic efficacy of B-cell depletion by anti-CD20 treatment in pediatric and, more recently, in adult idiopathic nephrotic syndrome patients suggests a key role of B cells in the pathogenesis of the disease. However, their exact role is still unclear. B cells are able to secrete a large variety of antibodies that can protect against infections. However, B-cell dysregulation is well-established in a variety of autoimmune diseases. In parallel with their ability to produce antibodies, pathogenic B cells display altered effector functions by expressing activating surface molecules, which can strongly modify the immune homeostasis, or by producing specific cytokines, which can directly affect either podocyte structure and functions or modulate T-cell homeostasis. Herein, we report the most relevant clinical and experimental evidences of a pathogenic role of B cells in idiopathic nephrotic syndrome. We further highlight similarities and differences between children and adults affected by non-genetic forms of the disease and discuss what needs to be investigated in order to define the exact mechanisms underlying the pathogenic role of B cells and to identify more tailored therapeutic approaches.

Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS. Glomerular IgM deposits are also prominent in some patients, raising the possibility that IgM is a trigger of classical pathway activation. In the present study, we examined the pattern of complement activation in the glomeruli and plasma of patients with nephrotic syndrome. We also tested whether patients with FSGS and MCD have elevated levels of natural IgM reactive with epitopes on glomerular endothelial cells and cardiolipin. We found evidence of classical pathway activation in patients with idiopathic nephrotic syndrome compared with healthy control subjects. We also detected higher levels of self-reactive IgM to both targets. Based on these results, IgM and classical pathway activation may contribute to disease pathogenesis in some patients with FSGS and MCD.NEW & NOTEWORTHY IgM is detected in biopsies from some patients with nephrotic syndrome, although this has been attributed to passive trapping of the protein. We found, however, that IgM colocalizes with complement activation fragments in some glomeruli. We also found that affected patients had higher levels of IgM reactive to glomerular endothelial cell epitopes. Thus, IgM activates the complement system in the glomeruli of some patients with nephrotic syndrome and may contribute to injury.

Renal Morphology in Coronavirus Disease: A Literature Review.

Renal biopsy is useful to better understand the histological pattern of a lesion (glomerular, tubulointerstitial, and vascular) and the pathogenesis that leads to kidney failure. The potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the kidneys is still undetermined, and a variety of lesions are seen in the kidney tissue of coronavirus disease patients. This review is based on the morphological findings of patients described in case reports and a series of published cases. A search was conducted on MEDLINE and PubMed of case reports and case series of lesions in the presence of non-critical infection by SARS-CoV-2 published until 15/09/2020. We highlight the potential of the virus directly influencing the damage or the innate and adaptive immune response activating cytokine and procoagulant cascades, in addition to the genetic component triggering glomerular diseases, mainly collapsing focal segmental glomerulosclerosis, tubulointerstitial, and even vascular diseases. Kidney lesions caused by SARS-CoV-2 are frequent and have an impact on morbidity and mortality; thus, studies are needed to assess the morphological kidney changes and their mechanisms and may help define their spectrum and immediate or long-term impact.

Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy.

Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. We recruited a cohort of 18 subjects with glucocorticoid-dependent or glucocorticoid-resistant childhood-onset minimal change NS who received rituximab either due to CNI nephrotoxicity, or due to persistent glucocorticoid toxicity with inadequate response to cyclophosphamide or CNIs. Immunological subsets, T-cell activation assays and plasma cytokines were measured at baseline and 6-months post-rituximab. Time to relapse was bifurcated: 56% relapsed within one year ("early relapse"), while the other 44% entered remission mainly lasting ≥3 years ("sustained remission"). At baseline, early relapse compared to sustained remission group had lower regulatory T-cells (Tregs) [2.94 (2.25, 3.33)% vs 6.48 (5.08, 7.24)%, P<0.001], PMA-stimulated IL-2 [0.03 (0, 1.85)% vs 4.78 (0.90, 9.18)%, P=0.014] and IFNγ [2.22 (0.18, 6.89)% vs 9.47 (2.72, 17.0)%, P=0.035] levels. Lower baseline Treg strongly predicted early relapse (ROC-AUC 0.99, 95% CI 0.97-1.00, P<0.001). There were no differences in baseline plasma cytokine levels. Following rituximab, there was significant downregulation of Th2 cytokines in sustained remission group (P=0.038). In particular, IL-13 showed a significant decrease in sustained remission group [-0.56 (-0.64, -0.35)pg/ml, P=0.007)], but not in the early relapse group. In conclusion, early relapse following rituximab is associated with baseline reductions in Treg and T-cell hyporesponsiveness, which suggest chronic T-cell activation and may be useful predictive biomarkers. Sustained remission, on the other hand, is associated with downregulation of Th2 cytokines following rituximab.

Tertiary lymphoid organs are associated with the progression of kidney damage and regulated by interleukin-17A.

Background: Tertiary lymphoid organs (TLOs) occur after multiple chronic kidney injuries. interleukin-17A (IL-17A) has been reported to associate with the development of TLOs in inflammatory diseases. However, regulation of the renal TLOs and its clinical significance to the pathogenesis of chronic kidney injury are unknown. Methods: To evaluate the clinical significance and regulation of renal TLOs, we analyzed the progression of patients with kidney damage based on the existence and absence of TLOs in a larger multicenter cohort. We also blocked the recruitment of lymphocyte cells into the kidney by FTY720 (fingolimod) in vivo. Besides, we used aged IL-17A genetic knocked out mice and IL-17A-neutralizing antibody to explore the role of IL-17A in renal TLOs formation. Results: We demonstrated that renal TLOs of IgA nephropathy patients were associated with disease severity and were independent risk factors for renal progression after adjustment for age, sex, mean arterial pressure, proteinuria and, baseline eGFR and MEST-C score, especially in the early stage. Plasma levels of TLO-related chemokines CXCL13, CCL19, and CCL21 were higher in patients with renal TLOs. Inhibiting the formation of renal TLOs by FTY720 could reduce the intrarenal inflammation and fibrosis, and early intervention was found to be more effective. IL-17A was increased in renal TLOs models, and genetic depletion of IL-17A or treatment with anti-IL-17A antibody resulted in a marked reduction of the TLOs formation as well as alleviation of renal inflammation and fibrosis. Conclusion: These results indicate that TLOs are associated with the progression of kidney damage and regulated by IL-17A and may be effective targets for the treatment of kidney damage.

Minimal change disease in a patient receiving checkpoint inhibition: Another possible manifestation of kidney autoimmunity?

BACKGROUND: Nivolumab has been associated with immune-related adverse events, including nephritis, with acute interstitial nephritis being the most commonly reported renal manifestation. CASE: We describe the first case to our knowledge of minimal change disease with nephrotic syndrome associated with the PD-1 checkpoint inhibitor, Nivolumab. Minimal change disease has been reported with other immune checkpoint inhibitors; however, this is the first reported case with Nivolumab. We report development of nephrotic syndrome with acute kidney injury in a 57-year-old man, 1 month after commencement of Nivolumab for metastatic squamous cell carcinoma of the tongue. Minimal change disease was confirmed by renal biopsy. Management with corticosteroids and cessation of Nivolumab failed to improve kidney function or nephrosis. CONCLUSION: This case adds to current literature identifying minimal change as an additional complication of immune checkpoint inhibitor-associated acute kidney injury. Given the increasing use of immune checkpoint inhibitors for a range of malignancies, nephrologists, oncologist and generalists should be aware of the spectrum of kidney pathologies associated with their use.

Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology.

BACKGROUND: Although many pediatric nephrologists consider focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) as separate clinical entities, whether the initial histology could affect clinical courses in children with steroid-resistant nephrotic syndrome (SRNS) suspected of having an immune-based etiology remains unknown, especially for long-term outcomes. METHODS: We retrospectively reviewed long-term outcomes (> 3 years; median follow-up, 9.1 years) of 21 children with initial SRNS (FSGS, N = 9; MCD, N = 12) who achieved complete remission with immunosuppressive agents, including cyclosporine. RESULTS: At NS onset, incidence of acute kidney injury (67% vs. 8%, P < 0.05) and proportion of patients with non-selective proteinuria (56% vs. 0%, P < 0.01) were significantly higher in the FSGS group than the MCD group. Furthermore, median days until complete remission after treatment was significantly longer in the FSGS group than the MCD group (116 days vs. 45 days, P < 0.001). Although subsequent biopsy histology of the 12 patients in the MCD group was still identical in all MCD, three of nine patients in the FSGS group were reclassified from FSGS to MCD at second biopsy. At last visit, all patients maintained complete remission, and none developed chronic kidney disease. CONCLUSIONS: Initial presentation in the FSGS group was characterized by more severe clinical manifestations than the MCD group. If complete remission is achieved, FSGS and MCD in children with immune-mediated SRNS may constitute a single disease spectrum because the long-term outcomes are favorable, irrespective of initial histology.

Efficacy of repeat-dose rituximab maintenance therapy for minimal change disease in adults.

BACKGROUND: Rituximab (RTX) has been reported to effectively treat minimal change disease (MCD) in adults. However, the efficacy of RTX as maintenance therapy, especially in older patients, remains unclear. This study aimed to evaluate the efficacy of repeat-dose RTX maintenance therapy regardless of age. METHODS: We retrospectively reviewed the clinical courses of 13 biopsy-proven adult MCD patients receiving RTX and evaluated the relapse rate, concomitant steroid and immunosuppressant use, relationship between B-cell depletion time and relapse, and adverse events. RESULTS: Mean patient age at start of RTX therapy was 51.5 ± 20.1 years. Each RTX induction consisted of a single 375 mg/m2 dose. One patient received two RTX doses with a 1-year interval. The remaining 12 patients received RTX at 6-month intervals up to four times after RTX introduction. The median observation period was 28 (16-60) months after RTX induction, median relapse frequency was significantly decreased from 0.83 (0.18-1.92) to 0 (0-0.71) times/year (P < 0.001), and median prednisolone dose was reduced from 25 (5-40) mg to 2.5 (0-10) mg (P < 0.001). CD19-positive B cells remained depleted during RTX administration in 6-month intervals. No serious adverse events were observed after RTX administration. CONCLUSIONS: Repeat-dose RTX as maintenance therapy efficiently prevented recurrence and was well tolerated in adult MCD patients including older. This regimen has the potential to maintain prolonged remission. Future studies in larger cohorts are needed to identify the optimal dose and frequency and evaluate the long-term effectiveness and safety of this regimen.

Parvovirus B19 infection and kidney injury: report of 4 cases and analysis of immunization and viremia in an adult cohort of 100 patients undergoing a kidney biopsy.

BACKGROUND: The seroprevalence of human Parvovirus B19 (PVB19) is 70-85% in adults worldwide. PVB19 is the etiologic agent of the fifth disease, is a cause of aplastic anemia, and can be associated with kidney injury. We aimed to describe the cases of 4 patients with kidney injury related to PVB19 primary infection, and to evaluate the seroprevalence of PVB19 and the incidence of PVB19 primary infection in patients undergoing a native kidney biopsy. METHODS: Cases of PVB19 infection with kidney injury were reviewed from the archives of the department of Nephrology. A systematic screening of anti-PVB19 IgG and IgM antibodies and viral DNA was performed in sera from 100 consecutive patients with a kidney biopsy in 2017-2018. RESULTS: The 4 patients with PVB19 infection-associated kidney disease displayed: one lupus-like glomerulonephritis (GN) without lupus auto-antibodies, one minimal change disease with tubular necrosis, one secondary hemolytic and uremic syndrome and one membrano-proliferative GN. In the 100 patients biopsied, 67 had elevated anti-PVB19 IgG, among whom 8 had elevated IgM, without circulating viral DNA, without any particular renal pathological pattern. One additional patient showed a seroconversion at the time of kidney biopsy, which revealed a class V lupus nephritis. CONCLUSION: PVB19 primary infection can be associated with different kidney diseases. The seroprevalence of PVB19 among patients with a kidney biopsy is similar to the overall population, and primary infection is rarely documented (1%) after systematic screening. Whether PV19 is nephrotoxic, or triggers renal endothelial injury and immune activation, remains to be elucidated.

Rituximab Induces Complete Remission of Proteinuria in a Patient With Minimal Change Disease and No Detectable B Cells.

Minimal change disease (MCD) is a common cause of nephrotic syndrome. Treatment with steroids is usually effective, but frequent relapses are therapeutic challenges. The anti-CD20 antibody rituximab has shown promising results for treatment of steroid-sensitive nephrotic syndrome. Since predictive biomarkers for treatment efficacy and the accurate rituximab dosage for effective induction of remission are unknown, measurement of CD19+ B cells in blood is often used as marker of successful B cell depletion and treatment efficacy. A male patient with relapsing MCD was successfully treated with rituximab, but developed relapse of proteinuria 1 year later, although no B cells were detectable in his blood. B and T cell populations in the patient's blood were analyzed before and after treatment with rituximab using FACS analysis. Rituximab binding to B and T cells were measured using Alexa Fluor 647 conjugated rituximab. We identified a population of CD20+ CD19- cells in the patient's blood, which consisted mostly of CD20+ CD3+ T cells. Despite the absence of B cells in the blood, the patient was again treated with rituximab. He developed complete remission of proteinuria and depletion of CD20+ T cells. In a control patient with relapsing MCD initial treatment with rituximab led to depletion of both CD20+ B and T cells. Rituximab induces remission of proteinuria in patients with MCD even if circulating B cells are absent. CD20+ T cells may play a role in the pathogenesis of MCD and might be a promising treatment target in patients with MCD.

Low-dose corticosteroid and mycophenolate for primary treatment of minimal change disease.

BACKGROUND: Mycophenolate has been shown to be effective in glomerular disease. However, the role of mycophenolate in the first-line treatment of adult-onset idiopathic minimal change disease (MCD) has not been systematically studied in a randomized fashion. AIM: To evaluate the therapeutic efficacy of enteric-coated mycophenolate sodium combined with low-dose corticosteroid as first-line treatment for MCNS. DESIGN: A prospective, open-label, randomized clinical trial. METHODS: Twenty adult patients with biopsy proven MCD were recruited and randomly assigned to receive either enteric-coated Mycophenolate Sodium (EC-MPS) plus low-dose prednisolone (Group 1: Prednisolone 0.25 mg/kg/day, n = 10) or standard-dose prednisolone (Group 2: Prednisolone 1 mg/kg/day, n = 10). RESULTS: After 24 weeks of therapy, eight patients in Group 1 vs. seven of patients in Group 2 achieved complete remission (P = 0.606). Both groups showed a significant reduction of urine protein excretion (P < 0.05) and increased serum albumin (P < 0.001) vs. baseline levels. However, no significant between-group differences were demonstrated. The relapse rate was also similar in both groups. Both treatment regimens were well tolerated but there were more patient reported adverse effects in the standard-dose prednisolone group. CONCLUSION: EC-MPS plus low-dose prednisolone is non-inferior to standard-dose prednisolone therapy in inducing clinical remission and preventing relapse in adult-onset idiopathic MCD and is associated with better tolerability and less adverse effects. This trial is registered with the ClinicalTrials.gov number NCT01185197.

Acute Cellular Rejection With Severe Interstitial Lymphoplasmacytic Infiltrate and Edema Associated With Minimal Change Disease.

We describe a case of a 24-year-old female renal transplant recipient who, 10 years after receiving a deceased-donor kidney, presented with acute and massive increases in serum creatinine and proteinuria levels of 13 g over 24 hours. At a previous outpatient clinic visit, her baseline serum creatinine was noted to be 87 µmol/L; on admission, serum creatinine was 1377 µmol/L. Renal biopsy results were consistent with acute cellular rejection with severe interstitial lymphoplasmacytic infiltrates and edema with no evidence of glomerular pathology, including transplant glomerulopathy. The immunofluorescence test results were negative, and the ultrastructural features were consistent with podocytopathy with no immune deposits present. We believe thatthis is the first case of acute cellular rejection typified by severe interstitial lymphoplasmacytic infiltrates and edema with severe proteinuria secondary to minimal change disease (or podocytopathy).

Antiphospholipid Antibodies in Patients with Membranous Nephropathy.

BACKGROUND/AIM: The aim of this study was to investigate the prevalence and significance of antiphospholipid antibodies in patients with membranous nephropathy (MN). METHODS: Patients hospitalized with MN during June 2015 to June 2017 were selected and patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) in the same period were selected as controls. RESULTS: Overall, 267 patients with MN and 131 patients with MCD/FSGS (n = 101 MCD and n = 30 FSGS) were analyzed. There was a significant difference in the detection rate of anti-ß2-glycoprotein I (anti-ß2-GPI) antibodies (11.9% in MN vs. 4.5% in MCD/FSGS, p = 0.018) and IgG-anti-ß2-GPI antibodies (3.7% in MN vs. 0% in MCD/FSGS, p = 0.034) between the 2 groups. Anti-ß2-GPI antibody-positive MN patients (n = 32) had a lower serum C4 level than anti-ß2-GPI antibody-negative MN patients (n = 235; 21.6 ± 7.6 vs. 24.6 ± 7.1 mg/dL, p = 0.030). Anti-ß2-GPI antibody-positive MN patients had significant improvement of serum creatinine compared to anti-ß2-GPI antibody-negative patients after 24 weeks of treatment (p = 0.006). CONCLUSIONS: Anti-ß2-GPI antibody may play a role in the progression of MN, and this process might involve classic complement activation.

Therapeutic efficacy of rituximab for the management of adult-onset steroid-dependent nephrotic syndrome: a retrospective study.

BACKGROUND: Recent reports have described the efficacy of rituximab in treating steroid-dependent nephrotic syndrome (SDNS) in pediatric patients. However, few reports describe data regarding adult-onset SDNS. We investigated the efficacy of rituximab for the management of adult-onset SDNS. METHODS: We performed a retrospective cohort study investigating eight patients with adult-onset SDNS who were treated with rituximab. Clinical data were obtained at the initiation of rituximab therapy. The primary outcomes evaluated were successful suppression of relapses and CD19+ cells after rituximab treatment. The corticosteroid- and immunosuppressant-sparing effect and adverse events were additionally evaluated. RESULTS: All eight patients were diagnosed with minimal change nephrotic syndrome and received immunosuppressants in addition to corticosteroid. Total number of relapses was 10.5 times as a median value. Rituximab administration was repeated in two patients, whereas six received single-dose rituximab. Three of eight (37.5%) patients showed relapse after rituximab therapy. A rituximab-induced depletion in CD19+ cells noted initially was followed by their reappearance in all patients. There were cases with no relapse after the reappearance of CD19+ cells. The median relapse time pre- and post-rituximab therapy showed a decrease from 1 time/year (interquartile range [IQR] 1-3 times/year) to 0 time/year (IQR 0-1 time/year). Rituximab treatment induced a significant reduction in the required doses of corticosteroid and cyclosporine (P < 0.01). No serious adverse events were observed. CONCLUSION: Rituximab treatment was effective not only in childhood-onset but also in adult-onset SDNS. Further studies are needed to establish optimal treatment regimens.

Immunoglobulin E and G Levels in Predicting Minimal Change Disease before Renal Biopsy.

PURPOSE: The diagnosis of minimal change disease in adults relies mainly on renal biopsy, but this procedure is not without complications. Despite the advancements in technique of percutaneous renal biopsy, biopsy-related complications still occur. Bleeding is one of the major complications, which may lead to hemodynamic instability and, sometimes, even death. Thus, we developed a model to predict MCD for high-risk patients unsuitable for renal biopsy. METHODS: We enrolled 142 patients with nephrotic syndrome who received renal biopsy between October 2007 and April 2011 at one tertiary medical center in this study. Demographic, clinical, and prebiopsy laboratory variables were retrospectively recorded and analyzed. RESULTS: The overall prevalence of MCD was 26.8%. Age, hemoglobin levels, 24-hour urine protein, immunoglobulin (Ig) G, and IgE differed significantly between the MCD and non-MCD groups. Logistic regression analysis showed a significant increase in the risk of developing MCD as the number of Ig risk factors, namely, IgG < 450 mg/dl and IgE > 110 mg/dl, increased. Having both risk factors significantly increased the chances of receiving a diagnosis of MCD (by 31.84-fold, P =.007) compared with having neither. Combining the aforementioned clinical model and the 2 Ig risk factors was the best in predicting the diagnosis of MCD, with the area under a receiver-operating characteristic curve of 0.91. CONCLUSIONS: Combining clinical model and this 2 Ig risk factors provides physicians simple and valuable clinical markers to diagnose MCD.

An open-label randomized controlled trial of low-dose corticosteroid plus enteric-coated mycophenolate sodium versus standard corticosteroid treatment for minimal change nephrotic syndrome in adults (MSN Study).

First-line therapy of minimal change nephrotic syndrome (MCNS) in adults is extrapolated largely from pediatric studies and consists of high-dose oral corticosteroids. We assessed whether a low corticosteroid dose combined with mycophenolate sodium was superior to a standard oral corticosteroid regimen. We enrolled 116 adults with MCNS in an open-label randomized controlled trial involving 32 French centers. Participants randomly assigned to the test group (n=58) received low-dose prednisone (0.5 mg/kg/day, maximum 40 mg/day) plus enteric-coated mycophenolate sodium 720 mg twice daily for 24 weeks; those who did not achieve complete remission after week 8 were eligible for a second-line regimen (increase in the prednisone dose to 1 mg/kg/day with or without Cyclosporine). Participants randomly assigned to the control group (n=58) received conventional high-dose prednisone (1 mg/kg/day, maximum 80 mg/day) for 24 weeks. The primary endpoint of complete remission after four weeks of treatment was ascertained in 109 participants, with no significant difference between the test and control groups. Secondary outcomes, including remission after 8 and 24 weeks of treatment, did not differ between the two groups. During 52 weeks of follow-up, MCNS relapsed in 15 participants (23.1%) who had achieved the primary outcome. Median time to relapse was similar in the test and control groups (7.1 and 5.1 months, respectively), as was the incidence of serious adverse events. Five participants died from hemorrhage (n=2) or septic shock (n=3), including 2 participants in the test group and 3 in the control group. Thus, in adult patients, treatment with low-dose prednisone plus enteric-coated mycophenolate sodium was not superior to a standard high-dose prednisone regimen to induce complete remission of MCNS.

Minimal change disease associated with anti-PD1 immunotherapy: a case report.

BACKGROUND: Oncologic immunotherapy is a form of therapy intended to reactivate the immune response to tumor cells using agents that modulate immune checkpoints, such as programmed cell death protein 1 and its ligand (PD-1/PD-L), and cytotoxic T-lymphocyte-associated antigen 4. Along with activation of the immune system to tumors, immune-mediated kidney side effects have been reported, most of which are cases of interstitial nephritis. Glomerular disease, however, appears rare. CASE PRESENTATION: Herein, we describe a patient with nephrotic syndrome related to treatment with an anti-PD1 antibody for Hodgkin lymphoma. Following the third dose of anti-PD1 antibody, the patient developed massive proteinuria and nephrotic syndrome. Kidney biopsy showed diffuse podocyte foot process effacement upon electron microscopy, which was consistent with minimal change disease. Corticosteroid treatment yielded full and rapid remission of nephrotic syndrome in 1 month. CONCLUSION: The present case suggests an association between anti-PD1 therapeutic immune activation and the development of nephrotic syndrome. Given the increasing prevalence of oncologic immunotherapy, patients should be routinely monitored for kidney side effects associated with these agents.