This year, the #NephJC crew is bringing you certain highlights from Kidney Week with daily blogs. Our focus will be mostly on the late breaking science, and any other simultaneous publications that we come across. There is a lot more at Kidney Week of course - but this is high level clinical science that we thought our readers would be interested in.
Day 3 Studies:
VISIONARY trial: phase 3, interim analysis- sibeprenlimab in IgAN, Perkovic V et al, NEJM, 2025
MIRO-CKD: balcinrenone with/ without dapagliflozin in albuminuric CKD- phase 2B trial, Heerspink HJL et al, Lancet, 2025
SInce only 2 trials on day 3 had simultaneous publications, we are taking editorial license to include a couple of other studies:
Rituximab for FR/SD nephrotic syndrome (Isaka et al, JAMA 2025)
CKD Prevalence in US (Gong et al JAMA Card 2025; simul-published with #AHA25)
Sibeprenlimab cuts proteinuria in IgAN, but will the kidneys follow?
N Engl J Med. 2025 Nov 8. doi: 10.1056/NEJMoa2512133. Online ahead of print.
Sibeprenlimab in IgA Nephropathy - Interim Analysis of a Phase 3 Trial
Vlado Perkovic, Hernán Trimarchi, Vladimir Tesar, Richard Lafayette, Muh Geot Wong, Jonathan Barratt, Yusuke Suzuki, Adrian Liew, Hong Zhang, Kevin Carroll, Vivekanand Jha, Alejandra Quevedo, Seung Hyeok Han, Manuel Praga, Bobby Chacko, Manisha Sahay, Chee Kay Cheung, Laura Kooienga, Michael Walsh, Jing Xia, Cecile Fajardo, Lokesh Shah, Jeffrey Hafkin, and Dana V. Rizk, for the VISIONARY Trial Investigators Group*
Why was the study done?
Therapeutic enthusiasm around IgA nephropathy has recently shifted from non-specific proteinuria control toward precise immune modulation. Among the emerging targets, APRIL (A- proliferation-inducing ligand) sits at the center of the IgAN pathogenic cascade- driving the overproduction of galactose-deficient IgA1 and downstream immune complex injury. Several strategies now converge on this pathway are dual BAFF/APRIL blockade (e.g. atacicept, telitacicept, povetacicept), selective APRIL inhibition (sibeprenlimab), and B-cell maturation modifiers. The focus seems all B-cell centric. Each aims to interrupt the disease earlier in its biology. Sibenprenlimab, a humanized monoclonal antibody neutralizing APRIL, represents the most advanced (or at least the same- see ORIGIN 3 trial) of these approaches. The VISIONARY phase 3 trial tested whether suppressing APRIL could translate mechanistic promise into measurable clinical benefit in IgA nephropathy (Perkovic V, et al, NEJM, 2025). This follows up on the phase 2 dose finding trial (previously also published in NEJM; Mathur et al NEJM 2024).
How was it done?
The VISIONARY trial is a phase 3, double-blind, randomized, placebo-controlled trial conducted across 31 countries and 240 sites. Adults with biopsy-confirmed IgAN, eGFR ≥30 mL/min/1/73 m2, and proteinuria ≥ 1g/day despite stable RAS blockade were randomized 1:1 to sibeprenlimab 400 mg subcutaneously every 4 weeks or placebo for 100 weeks. The prespecified interim analysis was triggered after 62.5% (n=320) completed 9 months of follow-up.
Baseline demographics (Table 1) showed a mean GFR of ~63 mL/min/1/73m2, median proteinuria ~1.2g/day, and ~60% Asian representation. About 40% used SGLT2i, and nearly all were on RAS blockade. At 9 months, with sibeprenlimab caused a -50.2% reduction in 24-hour urinary protein-to-creatinine-ratio versus a + 2.1% increase with placebo, corresponding to a 51.2% relative reduction (96.5% CI, 42.9-58.2, P<0.001).
Figure 1. Change from baseline in urinary protein-to-creatinine ratio, from Perkovic V et al, NEJM, 2025
The findings were consistent across sex, region, and eGFR subgroups (Figure S4). By 12 months, proteinuria remained ~57% lower than baseline (Table S7). Remission of proteinuria (<0.5g/day) occurred in 34.3% on sibeprenlimab vs 12.7% of placebo. Hematuria resolved in 80% of treated patients versus 31% in controls. (Fig. S5).
Pharmacodynamic data confirmed APRIL suppression by 95.8% and galactose-deficient IgA1 reduction by 67.1% at week 48. Serum IgA and IgM dropped by 70%, IgG by ~35%, without major immunodeficiency signals. Adverse events were comparable (serious AEs: 3.5 vs 4.4%), though a mild increase in COVID-19 cases and influenza were noted (Tables S8, S9). No deaths occurred.
What does it mean?
The interim analysis achieved its primary endpoint, validating APRIL blockade as an effective antiproteinuric strategy in IgAN. The magnitude of effect (~50%) rivals or exceeds that of budesonide (Lafayette R, et al. Lancet. 2023 | NefIgArd NephJC Summary), sparsentan (Heerspink HJL, et al, Lancet, 2023), and iptacopan (Perkovic V, et al, NEJM, 2025). Yet, without eGFR data, the full therapeutic picture remains incomplete. Proteinuria is a surrogate, not a verdict; the key question is whether immune recalibration can translate into sustained filtration preservation once the slope data arrive. If one wonders why these proteinuria data are being published hastily without GFR slope numbers - these data allow accelerated FDA approval while the GFR slope numbers are awaited (for more see Levey et al AJKD 2020).
VISIONARY and ORIGIN-3 (Lafayette et al, NEJM, 2025) trace parallel but distinct paths in testing the APRIL axis. Both trials show impressive antiproteinuric effects (roughly 45-50% vs placebo), but differ in biological scope and developmental maturity. Sibeprenlimab isolates APRIL inhibition, achieving >95% target suppression and ~67% reduction in galactose-deficient IgA1, suggesting that APRIL alone may be sufficient to silence the upstream autoimmune cascade. Atacicept demonstrated a 35% proteinuria reduction and early eGFR stabilization: mean + 0.8 vs -4.9 mL/min/1.73m2 at 36 weeks in the phase 2b trial(Lafayette R, et al. Kidney Int. 2024). Its phase 3 ORIGIN 2 extends that approach in a higher-risk cohort (baseline proteinuria of ~2g/day), with a similar SGLT2i background (~40-50%).
In sum, VISIONARY confirms that silencing APRIL alone can produce meaningful, rapid reductions in proteinuria, consolidating APRIL as a visible therapeutic target in IgAN. The comparison with atacicept suggests that selective inhibition may achieve similar biologic and clinical effects to dual BAFF/APRIL blockade, though whether it yields equivalent durability remains untested. Until eGFR slope data mature, the key question persists: has sibeprenlimab merely quieted the immunologic signal, or has it truly altered the disease’s trajectory?
MIRO-CKD: reflections on dual nephroprotection
The Lancet, DOI: 10.1016/S0140-6736(25)02014-8, online first November 08, 2025
Balcinrenone in combination with dapagliflozin compared with dapagliflozin alone in patients with chronic kidney disease and albuminuria: a randomised, active-controlled double-blind, phase 2b clinical trial
Hiddo J L Heerspink, José F Cardona, Shivinder Jolly, Pablo E Pergola, Erika de Sousa-Amorim, Anna L Eriksson, Martin Fredholm, Samvel B Gasparyan, Nicolas J Guzman, Judith Hartleib-Geschwindner, Yunyun Jiang, Maria Leonsson-Zachrisson, Prof Patrick B Mark, on behalf of the MIRO-CKD study investigators
Why was the study done?
The last decade in CKD therapeutics has been defined by two breakthroughs: flozins and non-steroidal mineralocorticoids (nsMRAs). Both slow CKD progression and reduced albuminuria, yet many patients remain at risk, especially those with residual albuminuria despite guideline-directed therapy. The MIRO-CKD (Heerspink HJL, et al, Lancet, 2025) tested whether balcinrenone, a novel selective MRA with potentially less hyperkalemia liability, could safely enhance nephroprotection when combined with dapagliflozin, compared with dapagliflozin alone (editorial note: Balcinrenone was previously called a selective MR modulator in Bamberg et al PLoS ONe 2018, and now is being called as a selective MRA - we need more data to understand this change in terminology). A previous phase 2 trial in heart failure + CKD had been underwhelmingly unmiraculous (MIRACLE, Lam et al Eur J HF 2024).
How was it done, and what did it show?
In this global, phase 2b, double blind, active-controlled trial across 15 countries, 324 adults with proteinuric CKD (eGFR 25 to <60 mL/min/1.73 m2, UACR 100-5000 mg/g) were randomized to balcinrenone 15 mg+ dapagliflozin 10 mg, balcinrenone 40 mg+ dapagliflozin 10 mg, or dapagliflozin+ placebo for 12 weeks, followed by a 8 week washout. Baseline characteristics (Table 1) reflected a typical CKD population: mean age 65 years, 56% with diabetes, mean eGFR 42 mL/min/1.73m2, median UACR 365 mg/g, and ~30% with potassium ≥ 4.8mmol/L- a subgroup often excluded from MRA trials.
The primary endpoint, change in UACR at 12 weeks, was met for both doses. Relative reductions versus dapagliflozin alone were -22.8% (90%CI -33.3 to -10.7; P=0/0038) for 15 mg and -32.8% (-42 to -22.1; p<0.0001). Over 50% of participants in the high-dose arm achieved ≥30% UACR reduction.
Figure 2. (A) Mean percentage change from baseline in UACR, and (B) proportion of participants with a reduction in UACR from baseline to week 12 of at least 30% or 50%, from Heerspink HJL, et al, Lancet, 2025
eGFR dipped modestly (-1.75 mL/min/1.73m2 vs control), consistent with hemodynamic effects, and reversed on discontinuation.
Figure 4B. Mean change from baseline in eGFR, from Heerspink HJL, et al, Lancet, 2025
Serum potassium rose slightly (+0.10 mmol/L at high dose, p=0.046), with laboratory hyperkalemia (K >5.5mmol/L) in 13% vs 5% on placebo, but no severe or persistent events.
What does it mean?
MIRO-CKD demonstrates that dual SGLT2i-MRA therapy can further lower albuminuria beyond dapagliflozin alone, validating the additive benefit across CKD phenotypes (Figure 3). Importantly, this occurred even in participants already on SGLT2i (56%) and in those with elevated baseline potassium, supporting balcinrenone’s favorable electrolyte profile.
The trial’s short 12-week duration, lack of balcinrenone monotherapy arm, and small sample size limit long-term interpretation. Whether these albuminuria gains will translate into sustained eGFR preservation or cardiorenal protection is still untested. Yet, as with the CONFIDENCE trial (Agarwal R, et al, NEJM, 2025| NephJC summary), pairing empagliflozin with finerenone, MIRO-CKD reinforces the principle that combining complementary pathways, natriuretic and anti-fibrotic, may offer synergistic kidney protection. (Jha V, Lancet, 2025)
Both MIRO-CKD to CONFIDENCE suggest that combining SGLT2 inhibition with an nsMRA safely augments albuminuria reduction beyond either class alone. MIRO-CKD demonstrated this across mixed CKD etiologies, while CONFIDENCE provided the validation in diabetic CKD. Both studies outline the translational trajectory from feasibility (CONFIDENCE) to early efficacy (MIRO-CKD), with both awaiting long-term confirmation of renal benefit, although it’s pretty intuitive.
Where does this field go next? Indeed it is an exciting time for aldo-enthusiasts, though spiro-stans may despair at the exciting trials being done with these shiny new agents (NephJC comment). Apart from the ns-MRA agents we also have the aldosterone synthase inhibitors (ASIs) including baxdrostat, vicadrostat, and lorundrostat.
Among ongoing studies are:
FIND-CKD: Finerenone in non-diabetic, proteinuric CKD (N = 1584, Heerspink et al NDT 2025)
EASiKIDNEY: Vicadrostat and/or empagliflozin in 11,000 patients with proteinuric CKD
ARCTIC: Baxdrostat and/or dapagliflozin in ~ 2500 with proteinuric CKD
PACIFIC: Baxdrostat and/or dapagliflozin for cardiorenal outcomes in ~ 5000 with hypertension and CKD (also called BaxDuoPACIFIC)
It will take some time till the dust settles on all these trials to understand which strategy will be most successful. Just like BAFF/APRIL or APRIL in IgAN - it will be interesting to see ASI and ns-MRA trial data come out in the coming conferences.
Not presented at Kidney week, published Nov 5 in JAMA
Finally, a Vitamin R RCT for FR/SD Nephrotic Syndrome in Adults
JAMA . 2025 Nov 5:e2519316. doi: 10.1001/jama.2025.19316. Online ahead of print.
Rituximab for Relapsing Nephrotic Syndrome in Adults: A Randomized Clinical Trial
Yoshitaka Isaka 1, Yusuke Sakaguchi 1, Maki Shinzawa 1, Shoichi Maruyama 2, Mika Sakaguchi 3, Hiroki Hayashi 4, Yusuke Kaida 5, Shin Goto 6, Tatsuo Tsukamoto 7, Akito Maeshima 8, Yoichiro Ikeda 9, Norihiko Sakai 10, Naoki Sawa 11, Kengo Furuichi 12, Kunihiro Yamagata 13, Takehiko Wada 14, Yugo Shibagaki 15, Keiju Hiromura 16
PMID: 41191364
Why was this study done?
Most minimal change disease (if we still keep calling it that) does respond to steroids, but how should we treat those with frequently relapsing or steroid dependent (FR/SD NS) nephrotic syndrome? If we keep giving steroids, the steroid toxicity gets ratcheted up. Steroid sparing drugs can be given, such as cyclophosphamide, rituximab, calcineurin inhibitors, MMF (KDIGO 1C), but the evidence is thin. KDIGO (Guidelines | NephJC Summary) suggests starting with cyclophosphamide in adults.
Figure 47 from KDIGO GL. Treatment of FR/SD MCD in adults. The choice of medication should be based on physician and patient preference.
The additional paradox is that in this case, KDIGO is extrapolating evidence from trials done in children. Perhaps adults are just big children. (see Michelle Rheault’s point about renalism in children). Among the research recommendations in the KDIGO guidelines was a point about doing a rituximab RCT in this population. Ergo this study.
How was this study done and What did it show?
This was a multicenter, double-blind, randomized, placebo-controlled trial conducted at 13 medical centers in Japan. Eligible participants were enrolled between 2020, and 2022 with the last follow-up completed on March 15, 2024. Eligible patients were those adults > 18 years with previously diagnosed FRNS (defined as2 or more relapses in 6 months) or SDNS (defined as inability to stop steroids due to 2 or more relapses) who were in remission. Additional inclusion criteria were peripheral blood CD20-positive cell count of 5/μL or greater,with select exclusion being secondary NS, GFR < 45, active infection and other usual exclusions. Patients were randomized 1:1 to receive rituximab or placebo stratified by the presence or absence of concomitant immunosuppression at the time of the last relapse and by presence of FRNS or SDNS. Rituximab was given as 375 mg/m2 per dose, or placebo at weeks 1, 2, and 25. The primary outcome was the proportion of patients who were free of relapse of nephrotic syndrome at 49-week follow-up. Proteinuria was measured at weeks 1, 2, 9, 17, 25, 33, 41, and 49 as well as at discontinuation or suspected relapse. The relapse-free rates at 1 year after administration of rituximab and placebo were anticipated to be 80% and 45%, respectively - thus needing ~ 32 in each arm. Special consideration was given to safety, and there was a post trial period where all participants in a relapse were offered rituximab.
72 participants were randomized though 6 (4 in R, 2 in placebo) withdrew before receiving drugs. Just over half the participants were females, with a mean age in late 40s. Just over half were SD (remaining FR) and over 80% were MCD (with 3 membranous sneaking in). GFR was quite well preserved in 70s, and the mean dose of prednisone at baseline was 10 mg with ~ 70% on a CNI in both groups. Rituximab worked spectacularly at preventing relapses with a 49-week relapse-free rate of 87.4% (95% CI, 69.8%-95.1%) versus 38.0% in placebo (95% CI, 22.1%-53.8%).
Figure 2. Relapse-Free Rate in the Double-Blind Period
The proportions of patients who discontinued corticosteroids at 49 weeks were 71.9% and 36.4% and those who discontinued cyclosporine at 49 weeks were 26.1% and 12.5% in the rituximab and placebo groups, respectively. The mean peripheral blood CD19+ B-cell counts in the rituximab group did decreased from 89 to 5 in the rituximab group. Infections occurred in 9 versus 6 in rituximab and placebo. Infusion reactions were more common with rituximab,
Table 2. Adverse Events in the Double-Blind Period (Safety Analysis Set)
What does it all mean?
The results are not really surprising, but are useful to establish the efficacy of rituximab clearly and unequivocally in this setting. In many jurisdictions, cyclophosphamide (or possibly CNIs) remain first choice due to the (poor quality, extrapolated) evidence, and access or indications. This will provide an indication and an argument to use rituximab as the first line in FR/SD NS. This is not a perfect study of course, and the 6 month follow up does not help us understand longer term safety or efficacy. Would patients need annual rituximab injections to remain remission free (Gauckler et al JASN 2025)? And this study was done in Japan - do we need confirmation elsewhere in terms of generalizability?
Overall, it is good to see such RCTs performed to provide a firm footing to things we might believe in or for which we do have a strong scientific rationale.
Study presented at AHA25, not Kidney week
JAMA Cardiology November 8, 2025. doi:10.1001/jamacardio.2025.4581
Chronic Kidney Disease Prevalence and Awareness Among US Adults
Jingyi Gong, MD; Muthiah Vaduganathan, MD, MPH; Rishi K. Wadhera, MD, MPP, MPhil
Why was this study done?
We recognize that CKD, cardiometabolic risk factors, and cardiovascular diseases frequently coexist and hence the American Heart Association recently introduced the concept of the cardiovascular-kidney-metabolic (CKM) syndrome (Ndumele et al Circ 2023) to emphasize the interdependence as well as to promote integrated care management. This study aimed to establish the prevalence of CKD and CKD awareness among US adults, particularly those with cardiometabolic conditions.
How was it done and what does it show?
The authors used data from the 2011-2012 to 2017 through March 2020 cycles of the US National Health and Nutrition Examination Survey (NHANES). The latest 2021-2023 NHANES survey cycle was not included, as serum creatinine values have not yet been released (and with funding cuts NHANES may or may not remain alive). The presence of CKD was defined as eGFR < 60 mL/min/1.73 m2 or urineACR > 30 mg/g. CKD awareness was defined as a “yes” response to the question “Ever told you had weak/failing kidneys?” among those with laboratory evidence of CKD.
The study included 24 646 US adults of whom 20 224 adults had cardiometabolic conditions - 78% with hypertension, 26% diabetes, 55% obesity, and 77% high cholesterol. The overall prevalence of CKD among US adults was 14.6%, similar to the prevalence of CKD among adults with cardiometabolic conditions was 16.7%. There has been little change over time.
Figure 1 from Gong et al, JAMA Card 2025
Among these, only 12.3% reported awareness of “weak/failing kidneys.” with a small improvement from 11% to 14% over time.
Figure 2 from Gong et al, JAMA Card 2025
Awareness was the lowest among younger adults, women, and Hispanic adults, and in those with earlier-stage CKD - as shown below, ranging from ~ 65% in those with GFR < 30, and lowest with albuminuria alone.
eFigure 2. Trends in Awareness of Chronic Kidney Disease Among US Adults With Cardiometabolic Risk Factors or Established Cardiovascular Disease With Alternative Definitions of Chronic Kidney Disease
CKD was defined as eGFR <60 (ml/min/1.73m2) or urine albumin/creatinine ratio ≥ 30 mg/g (red), or eGFR <60 (ml/min/1.73m2) (blue), eGFR <30 (ml/min/1.73m2) (black).
What does this study mean?
Overall, the CKD prevalence in US is similar to the GBD study reported yesterday at ~ 14%, and is slightly higher in those with CKM. The low awareness - especially in those with albuminuria - in whom we now have effective therapies (such as flozination, MRAs and GLP1RAs if diabetes, possible other diagnosis such as IgAN for others) is somewhat concerning and a problem worth addressing. Limitations are important - as the language in survey question may not align with how patients understand their diagnosis, especially among those with early-stage CKD. The definition of CKD was based on single measurement rather than repeated measurements over 3 months as is needed for true CKD definition. However - it is salutary to see such studies being conducted by cardiologists and being presented at the AHA - suggesting the AHA/ASN effort at promoting cardio-renal partnership to be fruitful (funny as the videos are).
Summary by Cristina Popa, and Swapnil Hiremath