Diagnosis and treatment of lupus nephritis: a summary of the Consensus Document of the Spanish Group for the Study of Glomerular Diseases (GLOSEN).

Lupus nephritis (LN) is the most frequent serious manifestation of patients with systemic lupus erythematosus (SLE). Up to 60% of SLE patients develop LN, which has a significant impact on their quality of life and prognosis. Recent advances have improved the diagnostic approach to LN, and new drugs that block specific pathways and kidney damage progression have been developed. Several randomized and well-powered clinical trials have confirmed the efficacy of these agents in terms of proteinuria remission and preservation of kidney function in the medium and long term, with an acceptable safety profile and good tolerance. The combination of different therapies allows for reduction of the dose and duration of corticosteroids and other potentially toxic therapies and leads to an increase in the number of patients achieving complete remission of the disease. This consensus document carried out by the Spanish Group for the Study of Glomerular Diseases (GLOSEN) provides practical and updated recommendations, based on the best available evidence and clinical expertise of participating nephrologists.

Chronic kidney disease: the missing concept in the 2019 EULAR/ERA-EDTA recommendations for lupus nephritis.

Chronic kidney disease (CKD) is diagnosed when glomerular filtration rate (GFR) falls below 60 ml/min/1.73 m2 or urinary albumin:creatinine ratio (UACR) reaches ≥30 mg/g, as these two thresholds indicate a higher risk of adverse health outcomes, including cardiovascular mortality. CKD is classified as mild, moderate or severe, based on GFR and UACR values, and the latter two classifications convey a high or very high cardiovascular risk, respectively. Additionally, CKD can be diagnosed based on abnormalities detected by histology or imaging. Lupus nephritis (LN) is a cause of CKD. Despite the high cardiovascular mortality of patients with LN, neither albuminuria nor CKD are discussed in the 2019 European League Against Rheumatism (EULAR)/European Renal Association-European Dialysis and Transplant Association recommendations for the management of LN or the more recent 2022 EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases. Indeed, the proteinuria target values discussed in the recommendations may be present in patients with severe CKD and a very high cardiovascular risk who may benefit from guidance detailed in the 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice. We propose that the recommendations should move from a conceptual framework of LN as an entity separate from CKD to a framework in which LN is considered a cause of CKD and evidence generated from large CKD trials applies unless demonstrated otherwise.

Consensus document of the Spanish Group for the Study of the Glomerular Diseases (GLOSEN) for the diagnosis and treatment of lupus nephritis.

A significant number of patients with systemic lupus erythematosus (between 20% and 60% according to different reported series) develop lupus nephritis in the course of its evolution, which directly influences their quality of life and vital prognosis. In recent years, the greater knowledge about the pathogenesis of systemic lupus and lupus nephritis has allowed relevant advances in the diagnostic approach and treatment of these patients, achieving the development of drugs specifically aimed at blocking key pathogenic pathways of the disease. Encouragingly, these immunomodulatory agents have shown in well-powered, randomized clinical trials good clinical efficacy in the medium-term, defined as proteinuria remission and preservation of kidney function, with an acceptable safety profile and good patient tolerability. All this has made it possible to reduce the use of corticosteroids and other potentially more toxic therapies, as well as to increase the use of combined therapies. The present consensus document carried out by the Glomerular Diseases Working Group of the Spanish Society of Nephrology (GLOSEN), collects in a practical and summarized, but rigorous way, the best currently available evidence about the diagnosis, treatment, and follow-up of lupus nephritis patients, including cases of special situations, with the main objective of providing updated information and well-founded clinical recommendations to treating physicians, to improve the diagnostic and therapeutic approach to our patients.

Novel Treatments Paradigms: Membranous Nephropathy.

Primary membranous nephropathy (MN) is a kidney-specific autoimmune glomerular disease and the leading cause of nephrotic syndrome (NS) in White adults, usually caused by antiphospholipase A2 receptor (PLA2R) antibodies, although several new target antigens have been recently identified. It is characterized by the diffuse thickening of the glomerular basement membrane secondary to immune complex deposition. In patients with persistent NS without response to maximizing conservative therapy including the use of renin-angiotensin system (RAS) blockers, the use of immunosuppressive agents is warranted. However, the optimal immunosuppressive treatment has not yet been established. Classical immunosuppressants, such as cyclophosphamide plus steroids, are effective but may cause clinically relevant adverse effects, limiting their use. Rituximab offers efficacy with a better safety profile whereas calcineurin inhibitors (CNIs) are marred by high relapse rates and nephrotoxicity. Nevertheless, up to 30% of patients fail to respond to standard therapy. Novel and specific therapies targeting B cells and plasma cells have shown encouraging preliminary results, in terms of clinical efficacy and safety profile, especially in patients with poor tolerance or refractory to conventional treatments. In this brief review, we discuss the benefits and limitations of the current therapeutic approach to MN and describe emerging novel therapies that target its pathogenesis.

Gain-of-function TLR7 and loss-of-function A20 gene variants identify a novel pathway for Mendelian lupus and lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic and inflammatory autoimmune disease of unknown origin that may cause kidney disease, i.e. lupus nephritis (LN). Within a wider trend towards an expanding field of genetic causes of kidney disease, two recent reports have emphasized the role of Mendelian autoimmune disorders in causing LN both in children and in young adults. Loss-of-function (LOF) variants of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and gain of function (GOF) variants of Toll-like receptor 7 (TLR7) cause SLE and LN, respectively. Interestingly, both genes regulate the same signaling route, as A20, the protein encoded by TNFAIP3, inhibits nuclear factor ĸB (NF-ĸB) activation while TLR7 promoted NF-ĸB activation. Moreover, TNFAIP3 and TLR7 variants are relatively frequent, potentially contributing to polygenic risk for LN. Finally, they both may be expressed by kidney cells, potentially contributing to the severity of kidney injury in persons who have already developed autoimmunity. The fact that both genes regulate the same pathway may lead to novel therapeutic approaches targeting the shared molecular pathway.

Recent Clinical Trials Insights into the Treatment of Primary Membranous Nephropathy.

Immunosuppressive therapy is mandatory for primary membranous nephropathy with persistent nephrotic proteinuria or anti-phospholipase A2 receptor antibodies, reduced kidney function, or another risk factor for progression. Rituximab has demonstrated efficacy for proteinuria remission compared with renin-angiotensin system blockade or cyclosporine in two well-powered randomized controlled trials. More recently, STARMEN showed that alternating glucocorticoid-cyclophosphamide is superior to sequential tacrolimus-rituximab for proteinuria remission, although it was associated with a higher risk of non-serious adverse events. However, sequential tacrolimus-rituximab involved delayed lower dose rituximab and was the worst-performing rituximab regimen among those tested in randomized clinical trials. The RI-CYCLO pilot study did not demonstrate superiority of glucocorticoid-cyclophosphamide over rituximab and found no difference in adverse events. Overall, STARMEN and RI-CYCLO confirmed the efficacy of glucocorticoid-cyclophosphamide in patients with high-risk membranous nephropathy and the role of rituximab as a valid alternative. However, none of the trials tested an optimized rituximab protocol involving a second rituximab cycle before declaring treatment failure. Calcineurin inhibitors should be considered third-line drugs and sequential use of calcineurin inhibitor rituximab did not add over rituximab-only regimens. We critically review recent randomized controlled trials, propose a research agenda, and call for multinational pragmatic trials that enroll patients at referral centers to address unmet research needs.

Primary membranous nephropathy in the era of autoantibodies and biological therapies. / Nefropatía membranosa primaria en la era de los autoanticuerpos y de las terapias biológicas.

Primary membranous nephropathy is an autoimmune kidney disease and the most common cause of nephrotic syndrome in adults. About 70%-80% of cases are caused by anti-PLA2R antibodies. Its association with anti-THSD7A antibodies and other autoantibodies has also been described. Recent pilot studies and clinical trials have shown that several biological agents targeting autoantibody-producing cells are effective in controlling the disease with an acceptable safety profile. In this narrative review, we update key concepts about the pathogenesis, autoantibody-based diagnosis, and kidney biopsy findings in primary membranous nephropathy. In addition, we propose a diagnostic and therapeutic algorithm, including guidance on monitoring the response to therapy. We compare the efficacy and safety of currently available treatments, including rituximab and new biological agents, and identify unmet clinical needs.

Slo-Mo anti-neutrophil cytoplasmic antibody-associated renal vasculitis.

Nephrologists are familiar with severe cases of anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) presenting as rapidly progressive glomerulonephritis. However, less is known about AAV with slowly progressive renal involvement. While its existence is acknowledged in textbooks, much remains unknown regarding its relative frequency versus more aggressive cases as well as about the optimal therapeutic approach and response to therapy. Moreover, this uncommon presentation may be underdiagnosed, given the scarce familiarity of physicians. In this issue of Clinical Kidney Journal, Trivioli et al. report the largest series to date and first systematic assessment of patients with AAV and slowly progressive renal involvement, defined as a reduction in estimated glomerular filtration rate (eGFR) of 25-50% in the 6 months prior to diagnosis after excluding secondary causes. Key findings are that slowly progressive AAV may be less common than previously thought, although it still represents the second most common presentation of renal AAV, it usually has a microscopic polyangiitis, anti-myeloperoxidase, mainly renal phenotype in elderly individuals, diagnosis may be late (over one-third of patients had end-stage kidney disease at diagnosis), clearly identifying an unmet need for physician awareness about this presentation, but those not needing renal replacement therapy at diagnosis still responded to immunosuppression.

The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy.

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.

Treatment of idiopathic membranous nephropathy in adults: KDIGO 2012, cyclophosphamide and cyclosporine A are out, rituximab is the new normal.

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for glomerulonephritis shed light on the complex world of glomerulonephritis therapy. However, they may no longer apply to idiopathic membranous nephropathy, as recently concluded by the KDIGO 2019 Working Group. This is due to the discovery of autoantibodies such as anti-phospholipase A2 receptor (anti-PLA2R) that allow disease monitoring as well as to results from recent clinical trials, comparative cohort studies and meta-analyses. Perhaps the most disruptive of them is the Membranous Nephropathy Trial of Rituximab (MENTOR) trial comparing rituximab with cyclosporine A, which supports the superiority of rituximab in efficacy and safety. Furthermore, rituximab results compared favourably with the short-term results of classical clinical trials that supported the KDIGO 2012 recommendation of immunosuppressive cyclophosphamide-based regimens as first choice for active treatment of idiopathic membranous nephropathy. Thus, the KDIGO recommendations for cyclophosphamide-based regimens or calcineurin inhibitors as the first line of active treatment regimens for idiopathic membranous nephropathy with nephrotic syndrome may no longer apply. By contrast, rituximab-based regimens or other B-cell-targeted therapies appear to represent the present and future of membranous nephropathy therapy.

Atrasentan for the treatment of diabetic nephropathy.

INTRODUCTION: Endothelin-1 (ET-1) is the most potent vasoconstrictor, and is involved in the renal regulation of salt and water homeostasis. When produced in excess in the kidney, ET-1 promotes proteinuria and tubulointerstitial injury. There is great interest in the clinical use of endothelin receptor antagonists (ERAs) in chronic kidney disease (CKD), mainly in diabetic nephropathy (DN). Areas covered: Physiopathological actions of ET-1 on the kidney. Both dual ETAR/ETBR (bosentan) or ETAR specific endothelin antagonists (avosentan and atrasentan, among others), which have progressed to early clinical development, with particular emphasis on atrasentan. Expert opinion: Different phase I and II clinical trials with ERAs in DN, mostly with atrasentan, have shown that these drugs have a marked anti-proteinuric effect on residual proteinuria when administered as add-on therapy in addition to ACEi or ARAII treatment. In the past few years, a series of randomized controlled trials investigating new approaches to DN have provided negative or inconclusive data, or even were terminated due to safety concerns or lack of efficacy. Therefore, we eagerly but cautiously await the results of the ongoing SONAR trial with atrasentan in more than 4,000 patients including assessment of renal and cardiovascular hard-end points (estimated primary completion date, July 2018).

Eculizumab in secondary atypical haemolytic uraemic syndrome.

Background: Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods: We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 10 9 /L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results: Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion: Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.

Beneficial long-term effect of aldosterone antagonist added to a traditional blockade of the renin-angiotensin-aldosterone system among patients with obesity and proteinuria.

INTRODUCTION: Over the past decade, obesity has become a risk factor for developing chronic kidney disease. Proteinuria is known to be an independent determinant of the progression of chronic kidney disease, and adipose tissue is a recognized source of components of the renin-angiotensin-aldosterone system (RAAS). Recent studies have shown that plasma aldosterone levels are disproportionately higher in patients with obesity. Drugs that block the RAAS are unable to inhibit aldosterone in the long term. The aim of our study was to analyze the renoprotective effect of an aldosterone antagonist in combination with RAAS blockers in patients with obesity and proteinuric nephropathy. MATERIAL AND METHODS: This study is a substudy of previously published study on the renoprotective effect of mineralocorticoid receptor blockers in patients with proteinuric nephropathies. Patients with proteinuria levels >1g/24h who were taking spironolactone and were being treated with other RAAS blockers were divided according to body mass index (BMI) into an obesity group (BMI ≥30kg/m2) and a control group. RESULTS: Seventy-one patients were included in the study, with a mean age of 56.7±15.1 years. More than 50% of the patients in both groups had diabetes. Thirty-two patients were included in the obesity group and 39 were included in the control group. There were no significant differences in renal function, proteinuria, blood pressure, serum potassium levels and the percentage of RAAS blockers in both groups. After a follow-up of 28.9 (14-84) months, there was a 59.4% reduction in proteinuria in the obesity group (2.8±2.1 vs. 1.3±1.6g/24h, p<.05). The reduction in proteinuria was greater than 50% in 22 (68.8%) cases, and the mean blood pressure showed a significant decrease (from 100.6±9 to 92.1±7.4mm Hg, p<.05). The control group showed a 69.6% reduction in proteinuria (1.9±1.4 to 0.8±0.5, p<0.05). The reduction of proteinuria was higher than 50% in 22 (68.8%) cases in obese patients and in 33 (84.6%) cases in non-obese group. Renal function remained stable in both groups during the follow-up. Nine patients (28.1%) in the obesity group experienced gynecomastia. The incidence of hyperkalemia was similar for the 2 groups (6.3%). CONCLUSION: Aldosterone antagonist treatment in obese patients with proteinuric nephropathies induces a drastic and sustained reduction in proteinuria but not more than the non-obese group. There was a trend toward slowing progression of renal failure with few adverse events.

Rapidly progressive IgA nephropathy: a form of vasculitis or a complement-mediated disease?

A rapidly progressive and crescentic IgA nephropathy (IgAN) is uncommon, but it has a high risk of progression to end-stage renal disease and variable response to immunosuppression. The importance of a positive anti-neutrophil cytoplasmic antibody (ANCA) serology in this group of patients is not fully understood but may have prognostic significance. On the other hand, there is growing evidence of the role of complement in the pathogenesis of IgAN, especially in cases of crescentic IgAN. Therapies directed against the complement system are a potential and rational therapeutic approach. In this issue, two clinical studies of crescentic IgAN are presented. The first work, is a retrospective case-control study describing clinical presentation, histological findings and response to treatment of crescentic IgAN/positive ANCA patients, comparing them with IgAN/negative ANCA patients and ANCA vasculitis patients. The second is a case report showing the effect of eculizumab, a humanized monoclonal antibody that is a terminal cascade complement inhibitor, as salvage therapy for crescentic IgAN resistant to conventional immunosuppression. Both studies broaden our approach to patients with aggressive forms of IgAN.

A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study.

BACKGROUND: Patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome have a high risk of progression to end-stage renal disease. The Ponticelli protocol (steroids with alkylating agents) is the most effective immunosuppressive therapy for this condition, but it has severe adverse effects. Tacrolimus and rituximab have demonstrated efficacy for remission of nephrotic syndrome in MN with a safer profile. However, the published evidence is largely based on small or short-term observational studies, historical cohorts, comparisons with conservative therapy or clinical trials without appropriate control groups, and there is no head-to-head comparison with the Ponticelli protocol. METHODS: The STARMEN randomized clinical trial will compare the efficacy of sequential tacrolimus-rituximab therapy with a modified Ponticelli protocol (steroids plus cyclophosphamide). The trial will also evaluate the role of antibodies against the M-type phospholipase A2 receptor (anti-PLA2R) and other antibodies as markers of response to treatment and long-term prognosis. RESULTS: The trial has already started with 23 patients having been enrolled as of 1 April 2015, an estimated 21.7% of the estimated sample.

Use of sevelamer in chronic kidney disease: beyond phosphorus control.

Sevelamer is a non-calcium phosphate binder used in advanced chronic kidney disease (CKD) and in dialysis for hyperphosphataemia control. Several experimental, observational studies and clinical trials have shown that sevelamer has pleiotropic effects, beyond hyperphosphataemia control, including actions on inflammation, oxidative stress, lipid profile and atherogenesis, vascular calcification, endothelial dysfunction and the reduction of several uremic toxins. This is the biological basis for its global effect on cardiovascular morbidity and mortality in patients with chronic kidney disease. This review focuses on these pleiotropic actions of sevelamer and their impact on cardiovascular health, with the experience published after more than ten years of clinical expertise.