The treatment of lupus nephritis (LN) in recent decades has relied on combined treatment with corticosteroids and either mycophenolate mofetil (MMF) or intravenous boluses of cyclophosphamide. In ...recent years the therapeutic possibilities for LN have expanded remarkably, thanks to the completion of several landmark randomised controlled trials (RCT) that have demonstrated the efficacy of new drugs. Drugs that have shown efficacy in the initial treatment of LN include calcineurin inhibitors (CNI). Several small local trials with cyclosporine and tacrolimus showed that these CNI increase the achievement of remission and have a strong antiproteinuric effect. Recently, the AURORA-1 study confirmed that voclosporin, a new CNI, added to corticosteroids and MMF was superior to placebo in obtaining complete remission with a good safety profile.1 Longer-term follow-up of patients suggests that voclosporin does not share the nephrotoxic effect of other CNIs. Belimumab, a drug that blocks BLyS (a stimulator of B lymphocyte proliferation), had shown efficacy in improving different extrarenal manifestations of systemic lupus erythematosus (SLE) and decrease immunological activity. The BLYS-LN study demonstrated that belimumab, added to corticosteroids and MMF, induces a significantly higher number of LN remission than placebo, with a satisfactory safety profile.2 Obinutuzumab, a newer anti-CD20 drug, has also shown encouraging preliminary data as initial therapy for NL. It is important to highlight that all these recent RCT compare triple therapy (corticosteroids plus MMF and the new drug under evaluation) with double therapy (corticosteroids plus MMF and placebo), so the addition of a CNI or belimumab for refractory cases or the use of triple therapy regimens from the onset for patients with high-risk profiles are recommended in recent guidelines.3 Conversely, new renoprotective and cardioprotective drugs, such as SGLT2 inhibitors, are starting to show their importance in the non-immunosuppressive treatment of LN.4 Despite these important successes in improving the initial treatment of LN, more studies are needed to determine the optimal maintenance treatment and criteria to personalize treatment duration in patients who achieve remission. Rovin BH, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021 May 29;397(10289):2070–2080. doi: 10.1016/S0140-6736(21)00578-X. Epub 2021 May 7. Erratum in: Lancet. 2021 May 29;397(10289):2048. Furie R, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020 Sep 17;383(12):1117–1128. doi: 10.1056/NEJMoa2001180. Rojas-Rivera JE, et al. Consensus document of the Spanish group for the study of the glomerular diseases (GLOSEN) for the diagnosis and treatment of lupus nephritis. Nefrologia (Engl Ed). 2023 Jan-Feb;43(1):6–47. doi: 10.1016/j.nefroe.2023.05.006. Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020 Oct 8;383(15):1436–1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. Learning Objectives Describe studies about the use of calcineurin inhibitors in LN Describe the use of belimumab in LN Discuss the option of triple versus double therapy as initial treatment in LN Discuss different treatment options according to a patient´s disease profile Discuss newer non-immunosuppressive treatments for renal and cardioprotection in LN
Obesity-related glomerulopathy (ORG) is characterized by glomerulomegaly accompanied in many patients by lesions of focal and segmental glomerulosclerosis. Slowly increasing subnephrotic proteinuria ...is the commonest presentation of ORG. Occasionally, massive proteinuria (>5-10 g/day) is detected, but the typical findings of nephrotic syndrome are characteristically absent even in patients with massive proteinuria. Superimposed obesity can fuel the progression of other renal diseases, and a reduced number of functioning nephrons (of congenital or acquired causes) synergizes with obesity to induce end-stage renal disease. Weight loss, either induced by diet or bariatric surgery, and renin-angiotensin blockers are effective treatments to slow progression, but a significant proportion of cases will develop end-stage renal disease.
The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the ...condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.
Summary Background IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in ...20–40% of patients within 10–20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov , number NCT01738035. Findings Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59–0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53–0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58–1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 88% of 49 in the TRF-budesonide 16 mg/day group, 48 94% of 51 in the TRF-budesonide 8 mg/day, and 42 84% of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide—deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). Interpretation TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation. Funding Pharmalink AB.
Pregnancy-associated atypical hemolytic uremic syndrome (aHUS) refers to the thrombotic microangiopathy resulting from uncontrolled complement activation during pregnancy or the postpartum period. ...Pregnancy-associated aHUS is a devastating disease for which there is a limited clinical understanding and treatment experience. Here we report a retrospective study to analyze the clinical and prognostic data of 22 cases of pregnancy-associated aHUS from the Spanish aHUS Registry under different treatments. Sixteen patients presented during the first pregnancy and as many as nine patients required hemodialysis at diagnosis. Identification of inherited complement abnormalities explained nine of the 22 cases, with CFH mutations and CFH to CFHR1 gene conversion events being the most prevalent genetic alterations associated with this disorder (66%). In thirteen of the cases, pregnancy complications were sufficient to trigger a thrombotic microangiopathy in the absence of genetic or acquired complement alterations. The postpartum period was the time with highest risk to develop the disease and the group shows an association of cesarean section with pregnancy-associated aHUS. Seventeen patients underwent plasma treatments with a positive renal response in only three cases. In contrast, ten patients received eculizumab with an excellent renal response in all, independent of carrying or not inherited complement abnormalities. Although the cohort is relatively small, the data suggest that pregnancy-associated aHUS is not different from other types of aHUS and suggest the efficacy of eculizumab treatment over plasma therapies. This study may be useful to improve prognosis in this group of aHUS patients.
The role of complement in IgA nephropathy Tortajada, Agustin; Gutierrez, Eduardo; Pickering, Matthew C. ...
Molecular immunology,
October 2019, 2019-10-00, 20191001, Letnik:
114
Journal Article
Recenzirano
Odprti dostop
•The complement factor H related proteins 1 and 5 associate with IgAN are implicated in IgAN pathogenesis.•Lectin pathway activation is implicated in IgAN pathogenesis in a subset of patients with ...severe disease.•Complement deregulation and activity may be dominant drivers of renal injury in IgAN.•Markers of complement activation may identify IgAN patients likely to progress to significant renal impairment.•Complement inhibition may emerge as an effective method of preventing and reducing glomerular injury in IgAN.
IgA nephropathy (IgAN) is common and often progresses to end stage renal disease. IgAN encompasses a wide range of histology and clinical features. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. Recent identification of specific complement pathways and proteins in severe IgAN cases had advanced our understanding of complement in IgAN pathogenesis. In particular, a growing body of evidence implicates the complement factor H related proteins 1 and 5 and lectin pathway as pathogenic in a subset of patients with severe disease. These data suggest complement deregulation and activity may be dominant drivers of renal injury in IgAN. Thereby, markers of complement activation may identify IgAN patients likely to progress to significant renal impairment and complement inhibition may emerge as an effective method of preventing and reducing glomerular injury in IgAN.
Hematuria is a cardinal symptom in IgA nephropathy, but its influence on the risk of disease progression has been scarcely investigated. We followed a cohort of 112 patients with IgA nephropathy for ...a mean±SEM period of 14±10.2 years, during which clinical and analytic risk factors (including urine sediment examination) were regularly recorded. According to the magnitude of time-averaged hematuria, we classified patients as those with persistent hematuria and those with negative or minimal hematuria. We also classified patients according to the magnitude of time-averaged proteinuria (>0.75 or ≤0.75 g/d). The proportion of patients reaching ESRD or a 50% reduction of renal function was significantly greater among patients with persistent hematuria than patients with minimal or negative hematuria (30.4% and 37.0% versus 10.6% and 15.2%, respectively;
=0.01). Multivariable analysis revealed time-averaged hematuria, time-averaged proteinuria, renal function at baseline, and the presence of tubulointerstitial fibrosis on renal biopsy as independent predictors of ESRD. After hematuria disappearance, which occurred in 46% of the patients, the rate of renal function decline changed from -6.45±14.66 to -0.18±2.56 ml/min per 1.73 m
per year (
=0.001). Patients with time-averaged proteinuria >0.75 g/d had significantly poorer renal survival than those with time-averaged proteinuria ≤0.75 g/d. However, on further classification by time-averaged hematuria, only those patients with time-averaged proteinuria >0.75 g/d and persistent hematuria had significantly worse renal survival than those in the other three groups. In conclusion, remission of hematuria may have a significant favorable effect on IgA nephropathy outcomes.
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