Amantia Imeraj

Background C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway.We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade.Methods APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study of iptacopan versus placebo (both in addition to supportive care [renin-angiotensin-aldosterone system (RAAS) inhibitors] and immunosuppression).Adult participants (aged 18-60 years) with biopsy-confirmed C3 glomerulopathy were enrolled from 35 hospitals or medical centres in 18 countries.Inclusion criteria included reduced serum C3 concentration (ie, <77 mg/dL [defined as <085 lower limit of the central laboratory normal range]) at screening, urine proteincreatinine ratio (UPCR) of 10 g/g or higher at day -75 and day -15 before randomisation, estimated glomerular filtration rate (eGFR) of 30 mL/min per 173 m or higher at screening and day -15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae.All eligible participants were randomised 1:1 via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both (yes or no).During the 6-month double-blind period, participants orally received either iptacopan 200 mg twice daily or placebo; this was followed by a 6-month open-label period in which all participants received iptacopan 200 mg twice daily.The primary endpoint was relative reduction in proteinuria (measured by logtransformed ratio to baseline in UPCR sampled from a 24-h urine collection) at 6 months.The primary analyses were done in the full analysis set (ie, all participants to whom study treatment was assigned by randomisation); all participants who received at least one dose of study treatment were included in the safety analysis.This trial was registered with ClinicalTrials.gov(NCT04817618) and the adult cohort has been completed.Findings Between July 28, 2021, and Feb 15, 2023, 132 participants were screened, of whom 58 did not complete the screening period and 74 (64% male; 69% White) were randomised 1:1 to receive either iptacopan (n=38) or placebo (n=36).One participant in the placebo group discontinued treatment during the open-label period.The 24-h UPCR percentage change relative to baseline at 6 months was -302% (95% CI -428 to -148) in the iptacopan group and 76% (-119 to 313) in the placebo group.In the iptacopan group, the geometric mean of 24-h UPCR was 333 g/g (95% CI 279 to 397) at baseline and 217 g/g (162 to 291) at 6 months; in the placebo group, this was 258 g/g (218 to 305) at baseline and 280 g/g (237 to 330) at 6 months.The primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 351% (138 to 511; p=00014).30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events, compared with 24 (67%) of 36 participants in the placebo group; most of these were of mild or moderate severity.There were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections.Serious adverse events were reported in three (8%) participants in the iptacopan group and one (3%) participant in the placebo group.Interpretation Iptacopan showed a statistically significant, clinically meaningful proteinuria reduction in addition to RAAS inhibitors and immunosuppression at 6 months.Iptacopan was well tolerated with an acceptable safety profile in patients with C3 glomerulopathy.

Hemolytic uremic syndrome (HUS) is a rare life-threatening disease of unrestrained complement system dysregulation, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure in genetically predisposed individuals. In this report, we describe two cases of SARS-CoV-2-associated HUS treated with eculizumab, a C5-blocking monoclonal antibody reported to be remarkably effective in the treatment of HUS. Detailed biochemical and genetic complement system analysis is reported, and the prompt clinical response after C5 pharmacological blockade is documented. Our report provides the rationale and supports the use of terminal complement pathway inhibition for the treatment of SARS-CoV-2-associated HUS.

Abstract Background and Aims C3 glomerulopathy (C3G) and immune complex-membranoproliferative glomerulonephritis (ic-MPGN) are two complement-mediated rare kidney disorders affecting both adults and children for which innovative therapies are under development. Due to the low prevalence and difficult diagnosis of the diseases, demographic and kidney outcome data are scarce. To obtain such information, we interrogated the European Rare Kidney Disease Registry (ERKReg), a Pan-European database of patients with rare kidney diseases treated at specialized adult and pediatric nephrology centers. Method Data on all patients diagnosed with C3G or ic-MPGN were extracted from the ERKReg database, to which more than 22, 000 incident and prevalent patients with rare kidney diseases were enrolled between October 2018 and December 2023. After exclusion of 32 patients with reported disease onset prior to 1998 to ensure compliance with contemporaneous diagnostic and treatment standards, 225 C3G and 173 ic-MPGN patients from 32 pediatric and 12 adult nephrology units in 16 European countries were available for analysis. Among these, 20.4% of C3G and 10.4% of ic-MPGN were incident patients who were enrolled either within 3 months of diagnosis or had diagnostic confirmation of suspected disease during prospective follow-up in ERKReg. Kaplan Meier actuarial survival analysis was performed to calculate time to kidney failure. Survival rates are given as median estimates and 95% confidence intervals. The impact of disease type and age at disease onset on kidney survival was assessed by Cox regression analysis. Results Overall, 80.9% of C3G and 33.5% of ic-MPGN patients had disease onset in childhood; the median (IQR) age at diagnosis was 12.4 (8.4-16.2) years for C3G and 38.9 (12.1-57.6) years for ic-MPGN. Genetic variants in CFH, CFHR1/3/5 and CFB were identified in 13 C3G (10.7% of tested) and 4 (14.8% of tested) ic-MPGN patients, and CFH autoantibodies in another 7 (17% of tested) C3G patients. Among the incident patients, 71.7% presented in CKD1 and 6.5% in CKD4/5 for C3G, as compared to 27.8% CKD1 and 27.7% CKD4/5 for ic-MPGN. Nephrotic-range proteinuria was present in 34% of incident C3G and 44% of ic-MPGN patients respectively. At last observation, 7.8% of childhood-onset and 17.1% of adult-onset C3G patients were on kidney replacement therapy (KRT) (thereof 71% and 86% with functioning transplant, respectively). For ic-MPGN at last observation, 14.6% of childhood-onset and 38.9% of adult-onset received KRT (thereof 62.5% and 69.0% with functioning graft, respectively). Kidney survival rates are given in the table below: The risk of progression to kidney failure within the observation period was approximately 60% higher in ic-MPGN vs. C3G (HR: 1.6; CI 95%: 0.9-2.8; p = 0.06) and was twice as high in patients with adult vs. pediatric disease onset (HR: 2.0; CI 95%: 1.2-3.3; P = .01). Conclusion C3G tends to manifest at earlier age than ic-MPGN. Altered complement regulation can be identified in subsets of patients with both disorders. Functional kidney impairment at first disease manifestation is more common and progression to kidney failure occurs more rapidly with ic-MPGN vs. C3G. Disease onset at adult age is associated with a more rapid disease progression compared to childhood-onset disease.

Chronic kidney disease and cardiovascular disease are strictly connected each other with a bidirectional interaction. Thus, the prevention of cardio-renal damage, as its appropriate treatment, are essential steps for a correct management of long-term patients' prognosis. Several preventive and therapeutic strategies, pharmacological and not, are now available for cardio-renal damage prevention and treatment, and for the management of its complications. The second part of this consensus document focuses on the management and treatment of cardio-renal damage, directing the attention on the correct use of drugs that may slow renal disease progression, on the application of preventive strategies in case of invasive cardiac procedures with the use of contrast agents, and on the accurate use of cardiological drugs in patients with chronic kidney disease.

L’insufficienza renale cronica (IRC) e la malattia cardiovascolare (CV) sono due condizioni ad elevata prevalenza nella popolazione generale e strettamente correlate tra di loro; possono, infatti, contribuire in maniera biunivoca allo sviluppo o alla progressione l’una dell’altra. Nei pazienti con IRC la principale causa di morbilità e mortalità è la malattia CV, che può essere esacerbata dalla malattia renale, in quanto l’IRC accelera il processo aterosclerotico tramite l’incremento dell’infiammazione, la perturbazione del metabolismo lipidico e modifiche nel metabolismo dei minerali a livello osseo. D’altro canto, una stretta relazione esiste tra IRC ed i classici fattori di rischio CV, quali diabete mellito, ipertensione arteriosa e dislipidemia, altamente prevalenti nella popolazione di pazienti nefropatici, con necessità, da un lato, di inquadrare correttamente il rischio CV di questa popolazione al fine di identificare i target terapeutici da raggiungere e, dall’altro, di ottimizzare il trattamento farmacologico, complicato dalla coesistenza delle due condizioni. La prima parte di questo documento di consenso esplora i meccanismi di danno cardio-renale e l’impatto, nonché la gestione, dei principali fattori di rischio CV nell’ambito dell’IRC.