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.
Is dual BAFF-APRIL blockade the next IgA nephropathy turning point?
N Engl J Med. 2025 Nov 6. doi: 10.1056/NEJMoa2510198. Online ahead of print.
A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy
Richard Lafayette, Sean J. Barbour, Robert M. Brenner, Kirk N. Campbell, Tom Doan, Necmi Eren, Jürgen Floege, Vivekanand Jha, Beom Seok Kim, Adrian Liew,9 Bart Maes, Atanu Pal, Roberto Pecoits‐Filho, Richard K.S. Phoon, Dana V. Rizk, Hitoshi Suzuki, Vladimir Tesař, Hernán Trimarchi, Xuelian Wei, Hong Zhang, and Jonathan Barratt, for the ORIGIN Phase 3 Trial Investigators
PMID: 41196369
The rationale for atacicept in IgA nephropathy stems from the ability to neutralize BAFF and APRIL, key cytokines for the production of galactose-deficient IgA1 (Gd-IgA1), the autoantigen central to the disease cascade.
Fig 1. Schematic representation of relevant cytokines and cytokine receptors affected by atacicept, from Kaegi C, et al, Front Immunol. 2020
This mechanistic appeal was first explored in the small, randomized JANUS phase II study (N=16), which demonstrated dose-dependent reductions in IGA, IgG, IgM, and Gd-IgA1 by week 24, sustained to week 72, along with proteinuria improvement and preserved eGFR (Barratt J, et al. Kidney Int Rep. 2022). Building on this, the ORIGIN phase 2b trial enrolled 116 patients with biopsy-proven IgAN and persistent proteinuria despite optimal RAS blockade. Atacicept 150 mg weekly achieved a 35% greater UPCR reduction versus placebo at 36 weeks and a mean eGFR difference of +5.8mL/min/1.73m2 (Lafayette R, et al. Kidney Int. 2024). The GFR slope with atacicept (blue line below) is almost flat.
The last 96-week report (Barratt J, et al. J Am Soc Nephrol, 2025) showed a durable effect: proteinuria decreased 52%, Gd-IgA1 fell 66%, hematuria declined 75%, and the annualized eGFR slope flattened to -0.6mL/min/1.73 m2, close to physiological aging rates. Adverse events were mainly mild injection-site reactions and transient infections; no opportunistic infections or immunodeficiency syndromes occurred.
The phase 3 ORIGIN-3 trial (Lafayette et al, NEJM, 2025) enrolled 203 adults with biopsy-proven IgA nephropathy and persistent proteinuria despite optimized care. The mean age was 39, 65% were men, about half Asian, and 49% white. Median proteinuria was 1.5 g/g, mean eGFR approx. 59 ml/min/1.73m2 (range 30-90). All received maximal RAS blockade, and about 50 % used flozins. Most had moderate chronic histologic activity (MEST-C lesions common, one third with segmental sclerosis or crescents). Immunosuppression within 6 months was excluded, creating a treatment-naive, moderate-risk cohort representative of contemporary IgA practice.
The phase 3 trial randomized 1:1 placebo vs 150 mg atacicept sc weekly. It confirmed atacicept’s antiproteinuric effect, achieving a 45.7% mean proteinuria reduction versus 6.8% with placebo, over 36 weeks. Immunoglobulin reductions paralleled target engagement without major safety imbalances: adverse events occurred in 59% vs 50%, mostly mild, with no excess severe infections or hypogammaglobulinemia.
The trial’s interim nature and proteinuria-based endpoint temper our enthusiasm. Effects on eGFR slope, histologic progression, and durability are still unknown. A longer follow-up will determine whether atacicep’s antiproteinuric signal translates into durable kidney protection. Powering for renal outcomes and ensuring consistent background therapy- including flozins and endothelin antagonists- will be interesting as the field shifts toward combination regimens. At present, atacicept appears to achieve what previous B-cell targeted agents failed to: meaningful proteinuria reduction with acceptable safety. Whether this dual BAFF-APRIL blockade can redefine the IgAN nephropathy therapeutic hierarchy depends on the forthcoming 2-year renal outcomes.
Reinaissance on point
Kidney International, Article in press, Nov 06, 2025
From Progression to Remission: A New Paradigm for Success in Chronic Kidney Disease
Navdeep Tangri, Brendon L. Neuen, David Z. Cherney, Katherine R. Tuttle, Vlado Perkovic
Tangri et al.’s Kidney International paper reframes chronic kidney disease (CKD) not as a one-way descent toward failure but as a dynamic, reversible process. Their argument rests on the convergence of pharmacologic and mechanistic advances that now permit remission, which is defined by near-stable eGFR (<1mL/min/1.73m2 per year decline) and resolution of albuminuria, in both diabetic and glomerular disease.
The argument isn’t rhetorical. Flozins, nonsteroidal MRAs, GLP-1RA, and B-cell targeted biologics have collectively shifted eGFR decline rates from -4 to -1 mL/min/1.73m2. In diabetic kidney disease, combined flozin-GLP1RA or flozin-nsMRA therapy achieves >50% reduction in albuminuria and durable stabilization of renal function. In IgAN, dual immune and hemodynamic blockade delivers a similar slope, similar to healthy aging. The editorial states it clearly: remission is not the cure; it is controlled homeostasis under therapy. The task ahead is operational: early detection, population screening, and elimination of clinical inertia to deploy combination therapy before irreversible injury sets in.
This article signals a pivot in nephrology self-conceptions. CKD is no longer defined by inexorable decline, but by the capacity for functional recovery when upstream molecular, metabolic, and immune drivers are simultaneously addressed (pun intended). Remission has become measurable, and potentially the standard!
Albuminuria as a surrogate in kidney disease: reliable signal or overused shortcut?
Published: 06 November 2025, Nat Med
A meta-analysis of albuminuria as a surrogate endpoint for kidney failure
Hiddo J. L. Heerspink, Willem H. Collier, Juhi Chaudhari, Shiyuan Miao, Hocine Tighiouart, Gerald B. Appel, Fernando Caravaca-Fontán, Jürgen Floege, Thierry Hannedouche, Enyu Imai, Tazeen H. Jafar, Julia B. Lewis, Philip K. T. Li, Francesco Locatelli, Bart D. Maes, Brendon L. Neuen, Vlado Perkovic, Ronald D. Perrone, Giuseppe Remuzzi, Francesco P. Schena, Christoph Wanner, Tom Greene & Lesley A. Inker
The Nature Medicine meta-analysis by Heerspink et al, 2025, pooled 41 randomized trials (over 190,000 participants) to test whether short-term changes reliably predict kidney failure across diverse CKD etiologies. Their findings strengthen the correlation but expose the fragility of the surrogate relationship when applied broadly.
Across studies, each 30% reduction in albuminuria corresponded to a 22% relative risk reduction in kidney failure (95%CI, 18-26). However, predictive accuracy varied substantially by disease type and therapy mechanism: R2 was 0.68 for RAS blockade but dropped to 0.37 for non-hemodynamic interventions such as endothelin antagonists or immune modulators. When limited to diabetic kidney disease, the relationship remained robust; in glomerular and non-proteinuric CKD, the link weakened or disappeared.
Table 3. Proportion of treatment effect on the clinical endpoint explained by UACR for different intervention classes, from Heerspink et al, Nat Med, 2025
The investigators further showed that only 46% of the total treatment effect on kidney outcomes could be statistically explained by albuminuria change, implying that more than half of the therapeutic benefit arises from albuminuria-independent pathways. This gap is most evident for SGLT2 inhibitors and GLP-1 RA, where kidney protection persists despite modest or transient albuminuria declines.
What does it mean?
Albuminuria reduction remains a meaningful but incomplete surrogate, mostly reliable in proteinuric, hemodynamically driven disease, least informative where structural or immune mechanisms dominate. Its short-term responsiveness enables efficient trial design, yet its biological non-specificity risks overinterpreting transient filtration effects as durable renal protection. The meta-analysis underscores the need to pair albuminuria with eGFR slope, tubular injury biomarkers, and imaging markers of fibrosis to capture multidimensional disease modification. Heerspink et al’s data-driven caution is clear: albuminuria is still the best early signal we have, but no longer sufficient as the only one.
Post-hoc CONFIDENCE analysis: Who gains most from dual pillar therapy?
J Am Soc Nephrol. 2025 Nov 6. doi: 10.1681/ASN.0000000928. Online ahead of print.
Baseline Kidney Function, Albuminuria, and Urine Albumin-Creatinine Ratio Reduction with Finerenone, Empagliflozin, or Both: Post Hoc Analyses of CONFIDENCE Trial
Amy Mottl, Charlie Scott, Jennifer B Green, Hiddo J L Heerspink, Johannes F E Mann, Janet B McGill, Masaomi Nangaku, Julio Rosenstock, Peter Rossing, Li Li, Na Li, Muthiah Vaduganathan, Rajiv Agarwal; CONFIDENCE Trial Investigators
PMID: 41196655
The CONFIDENCE trial (Agarwal R, et al, NEJM, 2025| NephJC summary) established that combining dinerenone and empagliflozin produces a ~30% greater reduction in albuminuria than either agent alone over 180 days, with acceptable safety trade-offs. The design was intentionally translational; its true purpose was to test whether simultaneous initiation of both drugs was feasible and safe in real-world diabetic CKD, not to chase long-term endpoints.
The post hoc analysis (Mottl A, et al, JASN, 2025) of 796 treated participants extends this pragmatic intent. Using mixed-effects models across eGFR and UACR strata, investigators examined who benefits the most from early dual therapy. The combination consistently outperformed either monotherapy, doubling the odds of achieving ≥ 30-50% UACR reduction (OR ~2.1 vs each single agent), without heterogeneity across kidney function or baseline albuminuria. Patients with higher baseline eGFR and higher UACR showed slightly greater proportional benefit. Predictors with higher baseline eGFR and higher UACR showed slightly greater proportional benefit. Predictors of strong UACR response included older age, female sex, and ASCVD subgroups historically underrepresented in CKD trials.
Safety outcomes paralleled the parent study: transient eGFR dips > 3% occurred in 6% with dual therapy (vs 4% finerenone, 1% empagliflozin), hyperkalemia in ~9% vs ~11% and 4%, and symptomatic hypotension in ≤1%. No excess of serious events emerged, confirming that concurrent start is clinically tenable.
A few highlights:
The analysis reinforces implementation feasibility, not long-term efficacy (limited by 6 months duration, surrogate endpoints, and exploratory nature)
Albuminuria remains the imperfect surrogate; UACR response explained only part of the expected renal benefit, demanding correlation with future eGFR slope data
Despite its short follow-up, the study strengthens confidence that dual-pillar therapy can safely begin together across CKD severities.
Summary by Cristina Popa,
Reviewed by Swapnil Hiremath