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In contrast, mucosally residing plasma cells synthesize IgA1 that is predominantly polymeric, poorly O -galactosylated, and secreted onto mucosal surfaces, with little, if any normally entering the circulation. While there is some evidence for defective homing receptor expression by lymphocytes in IgAN, much more work is required to define precisely the pattern of B cell trafficking in IgAN [ 47 , 48 , 49 , 50 ]. A number of studies have examined immune responses to mucosal antigen challenge in IgAN and the majority have reported exaggerated systemic IgA responses to mucosal antigen challenge [ 51 , 52 , 53 , 54 , 55 , 56 ].

There has been increasing interest examining links between alterations in gut permeability, the gut microbiome, and interaction with the mucosal immune system in IgAN, and these studies have recently been reviewed [ 57 , 58 ]. One mucosal antigen that has attracted particular attention is gliadin, a component of gluten. Mice subjected to a gluten-free diet from birth, and then exposed to a gluten-rich diet, developed increased IgA deposition, with anti-gliadin IgA found in the serum and glomerular deposit eluates [ 59 ].

Furthermore, in a recently developed transgenic mouse model that expresses both human IgA1 and human CD89, and develops IgAN spontaneously, in those fed a gluten-free diet for three generations, there was a reduction in mesangial IgA deposition and glomerular inflammatory cell infiltration [ 60 ]. Exposure of these mice to gluten led to increased mesangial IgA deposition and formation of anti-gliadin IgA. Further studies regarding potential links between dietary antigens and IgA immune complex formation are needed.

The molecular basis of regulation of the mucosal immune response, and in particular mucosal B cell programming, in health, and IgAN are complex. TLRs can be found on a diverse range of cells including macrophages and dendritic cells, and the stimulation of TLRs initiates signaling cascades that result in a variety of cellular responses including the production of interferons IFNs , and pro-inflammatory and effector cytokines that direct the adaptive immune response. Besides driving mucosal IgA production, TLR activation can also modify glycosyltransferase activity through methylation of the Cosmc gene resulting in reduced activity of C1GalT1, favoring production of poorly O -galactosylated IgA1 [ 66 , 69 ].

BAFF is necessary for B-cell maturation and survival, and levels of BAFF are elevated in many autoimmune diseases and correlate with autoantibody concentration [ 70 , 71 , 72 , 73 , 74 ]. Importantly, this IgA deposition is dependent on activation of the mucosal immune system. Zhai et al. In a recent study, Muto et al.

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A proposed pathogenic model for IgAN with a focus on potential therapeutic targets. As a result of mis-homing of a proportion of these mucosal B cells to systemic sites mucosal IgA is secreted directly into the circulation resulting in elevated serum levels of polymeric, poorly galactosylated IgA1. In susceptible individuals, O -glycan-specific antibodies are formed with the consequent generation of circulating IgA immune complexes, which have a propensity for mesangial deposition. Glomerular accumulation of these IgA immune complexes results in mesangial cell activation, and release of pro-inflammatory and pro-fibrotic mediators, and complement activation.

In contrast to targeted mucosal immunomodulation, systemic B cell depletion with rituximab is not effective in IgAN, reinforcing the importance of the mucosal immune system in the pathogenesis of IgAN. In a small open-label randomized controlled trial use of rituximab compared to conventional therapy without immunosuppression , resulted in more adverse events, did not significantly improve renal function or proteinuria over 1 year and did not reduce serum levels of poorly O-galactosylated IgA1 or anti-IgA1 IgG autoantibodies, despite effective circulating B cell depletion [ 81 ].

Blisibimod is a selective peptibody antagonist of BAFF. Hydroxychloroquine is a potent inhibitor of TLR-9, and to a lesser extent TLR-7 and TLR-8, and inhibits antigen processing and presentation via alkalinization of proteasomes [ 82 , 83 ]. Further validation in larger randomized studies with longer-term follow-up will be required. Formation of circulating IgA-immune complexes in IgA nephropathy. Polymeric poorly galactosylated IgA1 molecules form the substrate for immune complex formation.

O -glycan-specific antibodies: either IgG and IgA1 autoantibodies, or cross-reacting anti-microbial antibodies, bind to the exposed neo-epitopes within the poorly galactosylated IgA1 hinge region. An alternative hypothesis for the formation of circulating IgA immune complexes is that soluble CD89 sCD89 is shed from myeloid cells in response to polymeric IgA1, and form large circulating IgA1-sCD89 immune complexes. It has been hypothesized that changes in O -galactosylation of the IgA1-hinge region could result in conformational change of the molecule and exposure of novel epitopes within the hinge region.

One intriguing possibility is that during mucosal infections it is the increased production of antimicrobial mucosal antibodies that heightens the serum O -glycan-specific immunoreactivity and drives immune complex formation in IgAN, resulting in a temporary flooding of the glomeruli with IgA immune complexes and short-lived severe glomerular inflammation with development of synpharyngitic hematuria. It is also possible that antimicrobial mucosal antibodies generated at the time of a mucosal infection include poorly galactosylated IgA1, contributing further to both the pool of the target protein and O -glycan-specific antibodies in IgAN Fig.

In support of a pathogenic role for O -glycan-specific autoantibody production in IgAN, the strongest signal in genome-wide association studies in IgAN localizes to susceptibility loci on chromosome 6p within the human leucocyte antigen region. These loci are important in determining antigen-processing and presentation, and this association suggests that a dysregulated adaptive immune response may play a role in preferentially presenting poorly O -galactosylated IgA1 as a self-antigen and in the permissive production of O -glycan-specific antibodies in IgAN [ 44 , 92 ].

Two isoforms of sCD89 have been described in vivo with the smaller isoform present in healthy subjects and IgAN, while the larger isoform is only present in the serum of patients with IgAN. It has been proposed that in IgAN, circulating polymeric IgA1-containing immune complexes induce cleavage and shedding of the extracellular domain of membrane-bound CD89, forming high molecular weight IgA1-CD89 complexes that are prone to mesangial deposition.

Murine studies suggest that activation of mesangial cells by IgA1-containing immune complexes requires sCD89, a process that is also dependent on tissue transglutaminase 2 [ 94 , 95 , 96 ]. Recent data suggests that recurrent IgAN following transplantation is also associated with higher levels of IgA-sCD89 complexes [ 97 ].

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There have, however, been conflicting studies reporting that sCDpIgA1 immune complexes are not specific or relevant to the development of IgAN [ 98 , 99 , ]. IgA1 immune complexes deposit in the mesangium and trigger mesangial cell activation, resulting in release of pro-inflammatory, chemotactic, and pro-fibrotic mediators. Released soluble mediators result in mesangial cell proliferation, extracellular matrix ECM synthesis, recruitment of inflammatory cells, and in severe cases, glomerular crescent formation.

Filtered mesangial cell-derived mediators cause podocyte damage glomerulopodocytic crosstalk and with damage to the permselective glomerular basement membrane filtered IgA immune complexes compound podocyte injury. Filtered mesangial cell-derived mediators and IgA immune complexes are also capable of injuring proximal tubule epithelial cells PTECs , promoting tubulointerstitial inflammation and scarring glomerulotubular crosstalk.

Recognition of mesangial IgA deposits by resident glomerular cells is incompletely understood. The best-characterized receptor for mesangial IgA is the transferrin receptor CD71 , which is expressed by mesangial cells. CD71 is a multi-ligand receptor that has been shown to bind polymeric IgA1 [ ].

CD71 is overexpressed on the surface of proliferating human mesangial cells in IgAN, and co-localization of CD71 with IgA1 immune deposits has been demonstrated in kidney biopsies [ ]. Furthermore, the binding of poorly O -galactosylated IgA1 to CD71 appears to further enhance the expression of CD71 on proliferating mesangial cells, creating an autoamplification loop for self-perpetuating glomerular injury [ ]. Importantly, there is strong evidence that CD71 is not the only mesangial cell IgA receptor, however, none of the other well-characterized IgA receptors, including CD89, polymeric immunoglobulin receptor, and the hepatic asialoglycoprotein receptor, are expressed by human mesangial cells in health or in IgAN and the nature of this receptor s is not known [ ].

Most studies examining renal injury in IgAN have focused on the effects of IgA on mesangial cell biology, however, with damage to the glomerular basement membrane, there is emerging evidence that IgA immune complexes can enter the urine and directly interact with other cells within the nephron [ ]. Data supports a direct interaction between filtered IgA immune complexes and podocytes and proximal tubule epithelial cells [ , ], resulting in podocyte injury and loss, and epithelial—mesenchymal transformation with consequent tubulointerstitial scarring, respectively.

These effects appear to be specific to IgA immune complexes generated in IgAN and may be related, at least in part, to the poorly O -galactosylated hinge region of the IgA1 molecule. Understanding how filtered IgA immune complexes interact with podocytes and proximal tubule epithelial cells may help us understand why some patients with IgAN have mesangial deposition only, while others display marked podocyte injury and tubulointerstitial scarring, and why the degree of mesangial deposition does not correlate with the severity of ensuing renal inflammation and injury.

With the advent of a plethora of tyrosine kinase inhibitors, there is increasing interest in defining the intracellular biochemical pathways activated by IgA immune complexes in the kidney in IgAN. Spleen tyrosine kinase Syk signaling is of particular interest in IgAN as it is not only active in mesangial and proximal tubule epithelial cells but is also involved in immunoreceptor signaling in B cells and immunoglobulin production. Glomerular Syk phosphorylation is increased in rodent models of proliferative glomerulonephritis and correlates with serum creatinine and histological features of disease activity [ ].

Inhibiting Syk signaling reduces pro-inflammatory cytokine production, tissue inflammation and damage in both in vivo and in vitro models of kidney injury [ , ]. Kim et al. A diagnosis can be established from a kidney biopsy that shows focal and segmental glomerulosclerosis. The first-line treatment for idiopathic FSGS with nephrotic syndrome is a prolonged course of corticosteroids.

However, steroid resistance or steroid dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to end-stage renal failure. In addition, in some cases, FSGS can recur on a graft after kidney transplantation: an unidentified circulating factor may be implicated.

Understanding of its physiopathology is unclear, and it remains an important challenge for the scientific community to identify a specific diagnostic biomarker and to develop specific therapeutics. Abstract: The etiology of nephrotic syndrome is complex and ranges from primary glomerulonephritis to secondary forms. Patients with nephrotic syndrome often need immunosuppressive treatment with its side effects and may progress to end stage renal disease. This review focuses on recent advances in the treatment of primary causes of nephrotic syndrome idiopathic membranous nephropathy iMN , minimal change disease MCD , and focal segmental glomerulosclerosis FSGS since the publication of the KDIGO guidelines in Current treatment recommendations are mostly based on randomized controlled trials RCTs in children, small RCTs, or case series in adults.

Recently, only a few new RCTs have been published, such as the Gemritux trial evaluating rituximab treatment versus supportive antiproteinuric and antihypertensive therapy in iMN. In addition to reviewing recent clinical studies, we provide insight into potential new targets for the treatment of nephrotic syndrome from recent basic science publications. Abstract: Autoimmune thyroiditis AIT is generally associated with hypothyroidism. The evidence of thyroid function- and thyroid autoantibody-unrelated microproteinuria in almost half of patients with AIT and sometimes heavy proteinuria as in the nephrotic syndrome point to a link of AIT with renal disease.

The most common renal diseases observed in AIT are membranous nephropathy, membranoproliferative glomerulonephritis, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, antineutrophil cytoplasmic autoantibody ANCA vasculitis, and amyloidosis. Different hypotheses have been put forward regarding the relationship between AIT and glomerulopathies, and several potential mechanisms for this association have been considered. This is because these patients have both a greater risk of complications of the disease, including thromboembolic and cardiovascular events, and the highest likelihood of progressive disease.

In addition, although there is some evidence of equal treatment efficacy even after waiting for clear deterioration of renal function [ 17 ], this approach risks irreversible nephron loss given that the measured estimated glomerular filtration rate eGFR may underestimate the underlying structural damage [ 18 , 19 ]. It is highly likely that this relationship will modify our approach to MN management by providing new identifiers of those most likely to spontaneously remit, those most likely to respond to treatment and those most likely to progress.

Recently, the recognition of the high-affinity binding of the PLA2R antibodies to the specific GAg provides a possible explanation of the very low or absence of circulating antibody even when there is positive tissue staining [ 20 ]. A recent paper indicated, for instance, a higher relapse rate, despite equal depletion of circulating anti-PLA2R, in patients with persistent GAg staining [ 20 ]. The anti-PLA2R titer has been linked to therapeutic responsiveness and low levels correlated with good prognosis [ 21 ]. Retrospective studies have associated high antibody levels and a poor prognosis.

This may, however, only reflect time to response, given that remission rates by study end were virtually identical in the high versus low categories of antibody at presentation [ 12 ]. A recent case, however, suggests this may not be specific and reported both positive circulating antibody and kidney tissue staining of THSD7A in an MN patient with cancer [ 23 ]. Many questions remain including why IMN patients initiate antibody formation to a self-protein and what are the environmental triggers that stimulate this immune response in genetically susceptible individuals [ 24 ].

This prolonged survival time, combined with the only current regulatory approved outcomes of doubling of serum creatinine or ESKD, has motivated investigators to look for surrogate measures. Complete remission CR in IMN is associated with prolonged renal survival [ 13 ] and recently was deemed acceptable as a surrogate endpoint for clinical trials for drug licensing in IMN. The evidence supporting partial remission PR as a surrogate endpoint was judged to be weaker because of the persistence of proteinuria and the greater likelihood of relapse after PR compared with CR. This is an additional important niche for anti-PLA2R antibody measurement.

If a percentage reduction or attaining undetectable levels indicates immunologic remission and always happens in advance of clinical remission, this should lead to altering IS therapy earlier than currently done. This approach has not yet been confirmed in prospective studies, but there is enticing retrospective data [ 27 ]. New acceptable surrogate markers in IMN would result in significant reduction in trial length thereby accelerating interest in new approaches to disease management [ 28 , 29 ].

Integrating genetic and antigen—antibody profiling could significantly modify our classification and approach to individual patient management. Conservative therapy needs to be instituted early even in those at the lowest risk of disease progression given our current inability to predict spontaneous remitters from those who will worsen over time. A marker indicating immunological inactivity e.

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In contrast, a persistent high-titer anti-PLA2R might suggest a different management approach given the higher likelihood of post-transplant recurrence under these conditions [ 28—30 ],. The Ponticelli regimen in IMN has the highest recommendation in the guidelines, 1 B [ 6 , 31 , 32 ], given the evidence supporting its association with long-term improved renal survival [ 31 ].

Specifics of the routine are outlined in Table 1. Table 1 Specific treatment regimens. Although none of the cases had symptoms and the stimulation method is not the current standard for testing for adrenal insufficiency, it raises an important possible additional risk, especially given the increasing age of the current IMN patient. The latter has been combined with a delayed start of IS until renal insufficiency is established [ 17 ]. RCTs proving these variations having equal efficacy are still lacking [ 6 ]. The cancer rate was found to be three times that of a matched nonexposed population [ 34 ].

This delayed introduction of potent IS treatment reduces the likelihood of over-treatment, a definite advantage, but is tempered by the potential permanent loss of nephron mass [ 18 , 36 ]. They were recommended in the guidelines when a regimen of cyclophosphamide and corticosteroids is contraindicated, failed or refused by the patient. The routines used in published RCTs are set out in Table 1. This approach should remain at the heart of assessing CNI therapy.

Contributions to Nephrology(v.181), New Insights into Glomerulonephritis

Although not statistically significant, they are well-recognized AEs of CNI therapy and include glucose intolerance, hypertension and transient, dose-dependent but usually reversible changes in renal function. A recent RCT from China compared 9 months of tacrolimus with a day course of cyclophosphamide in 73 patients, with both groups receiving equal amounts of prednisone. Study limitations include the nonstandard cyclophosphamide duration compared with Ponticelli regimen and short follow-up that was likely to underestimate relapse rates.

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There was also inconsistent use of angiotensin-converting enzyme ACE inhibitors and angiotensin receptor blocker ARBs [ 40 ]. There have been two meta-analyses comparing tacrolimus with cyclophosphamide in Chinese patients with IMN with the most recent one showing similar results as above [ 42 ], although the first analysis did show tacrolimus superiority in terms of CR rate.

Anti-PLA2R autoantibodies change correlated with proteinuria and serum albumin in both arms. Relapse rates and hard endpoints were not described in this short study [ 43 ]. Multiple observational studies have subsequently been published with larger numbers and more prolonged follow-up and all indicate a similar or higher short-term success rate and reduced AE rate compared with the alkylating and calcineurin regimens.

Although the literature is still somewhat unclear, unless there is a contraindication, this prophylactic approach when using long-term IS in general in GN should be considered. Short-term AEs with rituximab causes infusion reactions, usually mild and manageable. Multifocal leukoencephalopathy has been reported with its use, but not when given as monotherapy [ 47 ]. The single-dose regimen is of particular interest given the high cost of the drug, but the results are inconsistent with recent results suggesting that too low a dose decreases efficacy [ 51 , 52 ].

This is an important point and strongly suggests that no additional IS should be given for at least 6 months following this treatment. There has been one completed RCT using rituximab and two others are ongoing. The other two RCTs remain ongoing. There is also a pilot study ongoing using the combination of rituximab plus cyclosporine, with the latter tapered after 6 months and a repeated rituximab infusion at that point ClinicalTrials.

The advantages of rituximab are its low rate of AEs, the almost guaranteed adherence and patient acceptance, but relapse rates, resistant cases and high costs remain important questions in comparison with other regimens. Anti-PLA2R antibody monitoring is included in all these protocols and is likely to give us answers to important questions like whether we can change IS therapy based on the change in antibody titer.

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The natural form of ACTH was first used for therapy in patients with nephrotic syndrome over half a century ago [ 57 ]. Cushingoid-like AEs were minimal with only two patients having to temporarily hold their medications. A small number of patients showing an unusual bronzing of the skin suggested an action through the melanocyte or melanocyte receptor, of particular interest given the latter has recently been found on the surface of the podocyte [ 59 ]. Both of these findings were significantly different from the original RCT and the authors suggested this agent should not be used in IMN treatment [ 60 ].

In contrast, using the original natural ACTH gel preparation, a significant reduction in proteinuria proportionate to drug exposure and a more acceptable AE profile was seen in IMN patients [ 61 ]. Although available for more than 20 years, the role of mycophenolate mofetil MMF in IMN treatment remains in question.

Mycophenolic acid is the active metabolite of MMF and selectively suppresses T- and B-lymphocyte proliferation, antibody formation and adhesion molecule glycosylation via its inhibition of de novo purine nucleotide synthesis in lymphocytes and monocytes, suggesting it should have a beneficial role in IMN management.

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The current evidence indicates, however, as monotherapy or as an induction agent, it is either ineffective or only transiently beneficial [ 64 , 65 ]. Similar to lupus nephritis, an adjunctive role in IMN is suggested by a small open-label randomized study from China comparing MMF plus prednisone with an alkylating agent plus prednisone in 20 nephrotic MN patients. The study was not blinded, sample size was small and follow-up limited, and the differences could be related to the Asian ethnicity of the patients [ 66 ].

This approach to utilization of MMF needs further study. Table 2 summarizes the advantages and disadvantages of the current therapeutic treatment options. Certain concepts, well established in oncology, of targeting disease control versus cure should prompt a similar approach in IMN, i. Drugs similar to rituximab but that deplete plasma cells and other professional antibody-producing cells may be another possibility, but larger studies and careful assessment of the risk to benefit need to be done [ 68 ].

These investigators are also testing the potential capacity of this herbal agent to modulate T cell function ClinicalTrials. An RCT in IMN of the anti-C5 inhibitor, eculizumab, versus placebo targeting complement inhibition has been done [ 70 ] and no differences in proteinuria were noted over 16 weeks. However, in a 1-year open-label extension study, a reduction in proteinuria was seen; overall the evidence is weak and compounded by the lack of formal publication of the study.

This is in contrast to strong evidence that complement activation occurs in experimental MN and seems likely to play a significant role in human disease [ 71 ]. The recent recognition of a dominant early epitope in PLA2R offers the possibility of a new strategy that involves the development of specific and rapid anti-PLA2R removal from the serum through the use of immunoabsorption columns.

There is currently indirect evidence of potential benefit when accelerated removal of the antibody was seen in a small series of resistant IMN cases. The addition of plasma exchange and Intravenous immunoglobulin IVIG combined with rituximab resulted in rapid depletion of anti-PLA2R antibody titer in association with proteinuria reduction [ 72 ].