Susan Huang

Importance: The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain. Objective: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline. Design, Setting, and Participants: An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021. Interventions: Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group). Main Outcomes And Measures: The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure. Results: Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]). Conclusions and Relevance: Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01560052.

SIGNIFICANCE STATEMENT: Pregnancies in women with CKD carry greater risk than pregnancies in the general population. The small number of women in prior studies has limited estimates of this risk, especially among those with advanced CKD. We report the results of a population-based cohort study in Ontario, Canada, that assessed more than 500,000 pregnancies, including 600 with a baseline eGFR < 60 ml/min per 1.73 m 2 . The investigation demonstrates increases in risk of different adverse maternal and fetal outcomes with lower eGFR and further risk elevation with baseline proteinuria. BACKGROUND: CKD is a risk factor for pregnancy complications, but estimates for adverse outcomes come largely from single-center studies with few women with moderate or advanced stage CKD. METHODS: To investigate the association between maternal baseline eGFR and risk of adverse pregnancy outcomes, we conducted a retrospective, population-based cohort study of women (not on dialysis or having had a kidney transplant) in Ontario, Canada, who delivered between 2007 and 2019. The study included 565,907 pregnancies among 462,053 women. Administrative health databases captured hospital births, outpatient laboratory testing, and pregnancy complications. We analyzed pregnancies with serum creatinine measured within 2 years of conception up to 30 days after conception and assessed the impact of urine protein where available. RESULTS: The risk of major maternal morbidity, preterm delivery, and low birthweight increased monotonically across declining eGFR categories, with risk increase most notable as eGFR dropped below 60 ml/min per 1.73 m 2 . A total of 56 (40%) of the 133 pregnancies with an eGFR <45 ml/min per 1.73 m 2 resulted in delivery under 37 weeks, compared with 10% of pregnancies when eGFR exceeded 90 ml/min per 1.73 m 2 . Greater proteinuria significantly increased risk within each eGFR category. Maternal and neonatal deaths were rare regardless of baseline eGFR (<0.3% of all pregnancies). Only 7% of women with an eGFR <45 ml/min per 1.73 m 2 received dialysis during or immediately after pregnancy. CONCLUSIONS: We observed higher rates of adverse pregnancy outcomes in women with low eGFR with concurrent proteinuria. These results can help inform health care policy, preconception counseling, and pregnancy follow-up in women with CKD.

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.

OBJECTIVE: To evaluate discordant clinical and pathological diagnoses leading to pediatric enucleations over time. METHODS: All pathology reports of pediatric enucleation specimens (subjects aged 0 to 18 years) from 1960 to 2008 were reviewed. Specimens with discordant clinical and pathologic diagnoses were further analyzed. Formalin-fixed, paraffin-embedded sections of enucleated eyes of any misdiagnosed cases were reevaluated. RESULTS: Of 729 pediatric patients (746 eyes) who had enucleation from 1960 to 2008, 29 patients (4.0%) and 30 eyes (4.0%) had discordant clinical and pathological diagnoses. The misdiagnosis enucleation rate decreased with each respective decade studied, with the highest rate of 6.5% (18 of 276 eyes) in the 1960s and no misdiagnoses from 1990 to 2008. Of the 369 eyes enucleated for the clinical indication of malignancy, 22 eyes (6.0%) were misdiagnosed in that no evidence of malignancy was found on histopathological examination. Of the 377 eyes enucleated for benign clinical indications, 7 cases (1.9%) were found to be malignant by histopathology. CONCLUSIONS: Misdiagnoses leading to pediatric enucleation have decreased during the past 5 decades, likely owing to improved diagnostic techniques. Benign and malignant intraocular conditions can simulate each other, especially retinoblastoma, Coats disease, nematode and bacterial endophthalmitis, panuveitis, and persistent hyperplastic primary vitreous.

There is a belief that there should be a minimum of 5 cm between two cannulating needles of an arteriovenous fistula. This study examined the effect of reduction of space between needles from 5 cm to 2.5 cm on access recirculation, the measurement of access blood flow rate (by indicator dilution technology), and dialysis efficiency (by effective ionic dialysance). Twelve patients were studied, with half having their dialysis needles placed 2.5 cm apart for five consecutive dialysis treatments followed by placing needles 5 cm apart for a further five consecutive treatments. The other half initiated with 5 cm followed by 2.5 cm distance for a similar number of treatments. All 120 dialyses had successful cannulations with access recirculation excluded. Access blood flow (Qa mL/min) measurement was attempted for each patient twice, with each of the two needle positions. The Qa with needles 2.5 cm apart was 1310.95 ± 525.7 mL/min (M ± SD, n = 21) and was 1001.0 ± 240.4 mL/min when 5 cm apart (n = 22) (p = 0.014). There was a correlation between these two sets of Qa values (r = 0.554; p = 0.011). The effective ionic dialysance values obtained with needles 2.5 cm or 5 cm apart were similar and correlated strongly (r = 0.71; p = 0.000). Hemodialysis treatments using arteriovenous fistulae and two needles as close as 2.5 cm apart are possible without access recirculation and impairment of clearance. Indicator dilution access blood flow measurements are not recommended under these circumstances.