Iptacopan in IgA Nephropathy - Final 24-Month Data

Jonathan Barratt, Necmi Ere, Naoki Kashihara, Bart Maes, Dana V Rizk, Brad Rovin, Hernán Trimarchi, Hong Zhang, Weiming Wang, Ismail Kocyigit, Chuanming Hao, Vladimir Tesař, Kenan Turgutalp, Li Yang, Guangqun Xing , Valter Duro Garcia, Seung Hyeok Han, Wanhong Lu, Antonio Pisani, Julia Weinmann-Menke, Frank Eitner, Nicolas Guerard, Dmytro Butylin, Luca Monaco, Emil Scosyrev, Annabel Magirr, Ronny Renfurm, Thomas Hach, Vlado Perkovic; APPLAUSE-IgAN Study Group

Collaborators, Affiliations Expand

PMID: 41910396

DOI: 10.1056/NEJMoa2600743

Why was the study done?

And the hits keep on coming! Ever since the elucidation of the 4-hit model in IgA nephropathy (IgAN) there has been the introduction of a plethora (a plethora? Yes, a plethora!) of new therapeutics based upon the various pathways of destruction. NephJC reviewed the KDIGO IgAN guidelines in 2025, which didn’t even incorporate iptacopan use, as the preliminary APPLAUSE results had been contemporaneously released (Perkovic et al. New Engl J Med, 2025). The excellent work by the PARASOL project, and the use of proteinuria as a reliable clinical trial endpoint for rare kidney disease, has moved medications from the lab to human studies to market at a breakneck speed. However, we are often left with questions about how effective these new treatments will be in the real world. We all hold our collective breath and await the GFR data to hopefully prove what we “already know”. Iptacopan, a complement factor B binder (alternative pathway) that inhibits C3 convertase, has shown efficacy in Paroxysmal Nocturnal Hemoglobinuria (PNH), C3 nephropathy (C3GN), and IgAN. The 9-month APPLAUSE interim analysis of this phase 3 trial of iptacopan showed a significant reduction (38%) in the 24-hour urinary protein-to-creatinine ratio as compared with placebo. We now have the 24-month data of eGFR in IgAN…and hopefully no surprises.

How was the study done?

This was a phase 3, international, double blind, randomized, placebo-controlled trial. The trial included a screening period, a run-in period of up to 90 days, and a 24-month treatment period. At the start of the treatment period, eligible patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan at a dose of 200 mg twice daily or matching placebo, along with supportive care. After the treatment period, eligible patients could receive open label iptacopan in a rollover extension study.

Eligible patients were 18 years of age or older and had biopsy-confirmed IgA nephropathy, an eGFR of at least 30 ml per minute per 1.73 m², and a 24-hour urinary protein-to-creatinine ratio of 1 or higher, despite RASi use for at least 90 days before the receipt of iptacopan or placebo.

The primary end point for the final analysis was the annualized total eGFR slope estimated over a period of 24 months. Secondary end points a composite kidney-failure (defined as a sustained decline in the eGFR of ≥30% from baseline for ≥4 weeks, a sustained eGFR of <15 ml per minute per 1.73 m2 for ≥4 weeks, initiation of maintenance dialysis, receipt of a kidney transplant, or death from kidney failure), which was assessed in a time-to-event analysis. Safety end points, including adverse events, laboratory variables, and vital signs, were also assessed. 

What do the results say?

The trial population was representative of the wider population of patients with IgA nephropathy. Overall, 19% of the patients were taking an SGLT2 inhibitor at baseline. During the 24-month treatment period, alternative or rescue medication was taken because of disease progression by 4.6% of the patients in the iptacopan group and by 13.4% of those in the placebo group. Discontinuation was asymmetric (18.9% iptacopan vs 36.8%), mainly driven by the prespecified ≥ 30% eGFR decline stopping rule.

Iptacopan resulted in a significantly slower eGFR decline than placebo (whew, no surprises). The between-group difference in the eGFR slope was 3.02 mL per minute per 1.73 m² per year (95% CI, 2.02 to 4.01) in favor of iptacopan. Iptacopan resulted in a smaller decrease from baseline to month 24 in the eGFR than placebo. The effect of iptacopan on the eGFR decline appeared to be consistent across prespecified subgroups defined according to age, sex, geographic region, 24-hour urinary protein-to-creatinine ratio category, eGFR category, the presence or absence of hematuria at baseline, SGLT2 inhibitor use at baseline, and the MEST-C score at biopsy. The SGLT2i at baseline subgroup showed a numerically larger benefit (diff 2.97 vs 2.71 without), hypothesis-generating for combination synergy but not powered for interaction testing.

The iptacopan group had a significantly higher number of patients with a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 (difference of 26.4 percentage points [95% CI, 18.7 to 34.0]). The risk of a composite kidney-failure end-point event was also significantly lower in the iptacopan group than in the placebo group (hazard ratio, 0.57; 95% CI, 0.40 to 0.81). FACIT-Fatigue change was not significantly different between arms- likely because baseline scores in both groups already approximated general population norms, leaving little room to detect improvement. 

Overall adverse event incidence was similar between groups (87% with iptacopan vs 89.1% with placebo). As was the serious AE incidence (12.2% vs 11.7%), with no deaths in either arm. However, serious infections were more common with iptacopan (6.7 vs 2.1%), predominantly pneumonia; 2 iptacopan-treated patients had confirmed S. pneumoniae infections despite prior vaccination (both resolved with antibiotics; both discontinued per protocol). No meningococcal or H. influenzae infections occurred. Serious adverse events pertaining to kidney and urinary disorders occurred in 5 patients (2.1%) receiving iptacopan and in 4 patients (1.7%) receiving placebo, and neoplasms were reported in 4 (1.7%) and 3 (1.3%), respectively. 

Critical Review

So, we expected that the preliminary 9-month results of iptacopan in IgAN would show decreased proteinuria and a favorable safety profile. Now we have the eGFR data at 24-months that we also anticipated, with an improvement in eGFR slope of 3 mL per minute per 1.73 m² per year versus placebo. We can be at least a little cynical that the comparison group was placebo and additionally note that SGLT2 inhibitor use was still fairly uncommon during the study period (approximately 20%). Also, the standards for IgAN treatment are increasing, and the goal is slowing eGFR loss to background aging (0.5-1 ml per minute per 1.73 m² per year). So, we have another useful tool for IgAN, though one that still leaves a residual chronic eGFR loss of 3 mL/min/year and carries a real (if manageable) infection cost. 

The bigger issue for most nephrologists was not going to be if iptacopan decreases proteinuria and slows eGFR decline, but rather where does iptacopan fit in the grand scheme of IgAN treatments. It will definitely not be a “stand-alone” medication, but will it be enough when used with maximal non-immunosuppressive medications (i.e. RASi, DERA, SGLT2i)? Now that we have definitive eGFR data (and soon to be released sibeprenlimab eGFR data that was previewed at GlomCon 2026), there will be a push for studies with data with combined therapeutics (early versus late versus simultaneous initiation), just like GDMT in diabetic nephropathy. It is a new age, and I for one am happy to see KDIGO IgAN guidelines already out of date and badly in need of revising, less than 12 months after their release. It is a wonderful time to be a nephrologist with interest in rare glomerular diseases, because innovation and hard data have been a long time coming. A round of APPLAUSE for iptacopan the study group, and its proven benefits to a wide assortment of patients with varying severity of IgAN.

Summary by

Brian Rifkin

Reviewed by

Cristina Popa

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N Engl J Med. 2026 Jun 12. doi: 10.1056/NEJMoa2600526. Online ahead of print.

Sodium Bicarbonate for Critically Ill Adults with Metabolic Acidosis and Shock

SODa-BIC Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group; Ary Serpa Neto, Mairead McNamara, Kyle White, D Jamie Cooper, Tomoko Fujii, Alisa M Higgins, Carol L Hodgson, Leanlove Navarra, Alistair Nichol, Sandra Peake, Alvaro Réa-Neto, Paul Secombe, Fiona Osborne, Hugh Burrill, Emily See, Meredith Young, Fernando G Zampieri, Mark Plummer, Connor Christie, Leo Nunnink, Josephine Mackay, Shay McGuinness, Joradee Marmol, Ravindranath Tiruvoipati, Michael Bailey, Paul J Young, Rinaldo Bellomo, Andrew Udy

PMID: 42283370

DOI: 10.1056/NEJMoa2600526

Introduction

Metabolic acidosis, a common manifestation in critically ill patients with shock, is independently associated with increased mortality, poor myocardial contractility, and impaired catecholamine response. Although identifying and correcting the underlying cause is the primary goal, there is still debate about whether correcting metabolic acidosis leads to improved clinical outcomes.

Intravenous sodium bicarbonate has been widely used for the correction of acidosis. Early trials (Cooper et al, Ann Int Med 1990; Mathieu et al, Crit Care Med 1991) corrected the acidosis without moving cardiac output to survival. Consequently, international guidelines recommend against sodium bicarbonate for hypoperfusion-induced lactic acidemia with pH ≥ 7.15, while conceding the evidence is weak (Surviving Sepsis Guidelines, Rhodes et al, Crit Care Med, 2016).
BICAR-ICU trial (Jaber et al, Lancet, 2018| NephJC summary)- a multicentric open-label randomized controlled trial- reopened the question: no day-28 mortality benefit overall, but lower mortality and RRT need in the AKI subgroup. To note the open-label design: renal replacement therapy (RRT) initiation is a clinician's judgment call, and an unblinded clinician who knows the patient is on bicarbonate has every incentive to defer dialysis a little longer. A subgroup RRT signal generated this way can be considered at least as consistent with detection bias as with a true renal effect- the trial cannot completely distinguish the two. A subsequent meta-analysis nonetheless reinforced a mortality benefit in AKI and shock (Ghauri et al, Cureus 2019), prompting the 2021 Surviving Sepsis Guidelines to endorse bicarbonate in septic shock with AKI (Evans et al, Crit Care Med, 2021)- guidance built on the same unblinded foundation- and setting up BICAR-ICU2. BICAR-ICU2 (Jung et al, JAMA 2025| NephJC Short) restricted enrollment to severe acidosis plus severe AKI, remained open-label, and still found no 90-day mortality benefit; its RRT reduction is open to the same criticism. A target-trial emulation in 1764 patients reported an association between bicarbonate and reduced mortality- observational, and therefore unable to settle what 2 unblinded RCTs already could not (Blank et al. Intensive Care Med, 2025). An individual-patient-data meta-analysis of BICAR-ICU trials concluded bicarbonate functions, at best, as an RRT-sparing strategy, with a mortality signal confined to pH ≤7.10—a conclusion built entirely on open-label data and inheriting all of its confounding (Fosset et al, Crit Care, 2026).
Taken together, this evidence points to a narrow niche- severe acidosis with concurrent AKI, RRT-sparing rather than survival-improving—and leaves patient selection, timing, target pH, and etiology dependence (lactic, septic, renal) unresolved. A more recent meta-analysis found no overall mortality benefit, but a 31% reduction in dialysis need in patients with acidosis and AKI (Chen et al, Crit Care Med, 2026).
Against this backdrop, SODa-BIC’s rationale rests on three unaddressed gaps. First, every positive trial to date was open-label, and any renal signal from an open-label trials is inseparable from performance bias in the RRT-initiation decision. Second, prior trials intervened only after severe acidemia was already established, leaving early correction untested. Third, only BICAR-ICU2 used a kidney-specific endpoint; the rest measured mortality or global organ dysfunction, diluting any renal-specific signal early correction might produce. 
After assessing feasibility in a smaller cohort (Serpa Neto et al, Crit Care Med, 2023), the SODA-BIC trial was designed as a double-blind, placebo-controlled trial to evaluate the effect of sodium bicarbonate treatment on MAKE30 (Major Adverse Kidney Events within 30 days), a composite kidney-specific outcome in critically ill patients with shock and moderate metabolic acidosis (pH <7.30) in. The central question SODA-BIC intended to answer was whether early correction of metabolic acidosis improves kidney-specific patient outcomes.

The Study

Methods

Population

All patients (>18 years) admitted to the ICU with metabolic acidosis and receiving vasopressors were screened for eligibility. Metabolic acidosis was defined as a pH < 7.30, a base excess ≤ -4 mEq/L, and a PaCO₂ ≤ 45 mmHg (non-intubated) or ≤ 50 mmHg (intubated) within the 2 hours prior to randomization. These 3 criteria together ensure the acidosis is truly metabolic, excluding primary respiratory acidosis, and is clinically significant (pH). The higher PaCO₂ threshold for intubated patients accounts for permissive hypercapnia from lung-protective ventilation. All 3 criteria (pH, PaCO₂, and base excess) needed to be met within the 2 hours preceding randomization. Patients with shock and metabolic acidosis for >48 hours, suspected secondary cause for metabolic acidosis (GI, urinary losses or DKA), eGFR <30, dyselectrolytemia (dysnatremia, serum K <2.5 mEq/L, iCa <0.8 mmol/L), or currently receiving RRT/ planned to start within 3 hours were excluded. Patients deemed at inevitable high risk of cerebral edema and clinicians’ decision for enrollment (pragmatic approach) were also excluded.

Study design

This pragmatic, adaptive, placebo-controlled, double-blind, phase III randomized clinical trial (NCT05697770) was conducted in 55 centers across seven countries between April 2023 to December 2025. Randomization was performed by variable block method and stratified for centres, pH (<7.25 or ≥7.25), and creatinine level (<150 or ≥150 𝞵mol/L). At each site, the investigator who randomized the patient and prepared the study drug was distinct from the (blinded) investigator collecting outcome data, to preserve the blinding.

The adaptive design had 2 components: 
1. A blinded sample-size re-estimation after the first 100 patients had outcome data, performed by an independent statistician unaware of treatment allocation, using the observed pooled event rate with the originally assumed relative effect held constant- bounded such that the sample size would be capped at 700 if recalculation exceeded this, and would not fall below the original 500 even if the observed event rate were higher than assumed 
2. A single formal Data and Safety Monitoring Board (DSMB) interim safety review at 125 patients (25% of target, with 90-day follow-up complete), conducted June 2025, after which the DSMB recommended continuation without protocol changes. Informed consent (or waiver, where locally permitted) was obtained per jurisdiction; if a patient died before consent, data were included where local regulation and ethics approval allowed.

Intervention

Trial participants were randomized to sodium bicarbonate or placebo groups and received infusion as per the algorithm given in Fig 1. The intervention group received either sodium bicarbonate infusion (300 ml sodium bicarbonate (8.4%) added to 500 ml 5% dextrose after removing 300 ml dextrose; final concentration 600 mEq/L) or placebo infusion (5% dextrose). The two solutions were macroscopically indistinguishable, as validated in a prior pilot trial (Serpa Neto et al, Crit Care Med, 2023). The study drug was permanently withheld if a contraindication developed (hypernatremia, hypocalcemia, refractory severe hypokalemia, clinically significant fluid overload, or per treating clinician judgment). Open-label bicarbonate after the infusion window was discouraged but permitted at clinician discretion, guided by non-mandatory suggested triggers (pH < 7.10 with PaCO₂ < 40; HCO₃⁻ < 8 mmol/L, BE < -15; or K > 7 with a pH <7.10)

Outcomes

Baseline serum creatinine was determined hierarchically using the following order: the most recent outpatient value obtained 7 days to 3 months before ICU admission; an in-hospital value measured within 7 days before admission; or, if no measured value was available, an estimated creatinine calculated using the formula: 0.74 − 0.20 (if female) + 0.08 (if Black) + 0.003 × age.
The primary outcome was evaluated across eight prespecified subgroups: baseline pH (<7.25 vs ≥7.25), AKI stage (KDIGO stage 2–3 vs none/stage 1), PaCO₂ (≤45 vs 46–50 mmHg), acidosis type (high anion gap >12 vs non-anion gap ≤12 mmol/L), illness severity (APACHE II score above vs at or below the median), pre-randomization bicarbonate use, presence of septic shock, and admission type (medical vs surgical).

Sample size estimation

Based on the data from the BICAR-ICU trial (Fujii T et al, Crit Care 2021 and Mochizuki et al, Crit Care and Resusc 2023), assuming 40% incidence of MAKE30 in the control group with 90% power, 5% alpha-error and attrition considered, 500 patients were required to detect an absolute difference of 14%. Sample size was re-estimated using the event rate observed after completing the study of 100 patients and capped between 500-700 patients. 

Statistical analysis

A modified intention-to-treat analysis was performed with a two-sided superiority hypothesis (α=0.05). A mixed-effects generalised linear regression with a binomial distribution and an identity link was used to estimate the absolute risk difference, with clustering and stratification variables as random effects. Kaplan-Meier curves were used to display survival at days 30 and 90, with adjusted hazard ratios and 95% CIs estimated using shared-frailty Cox proportional hazards models (site as the frailty term). Heterogeneity of treatment effects across the 8 prespecified subgroups was tested via a treatment-by-subgroup interaction term. Sensitivity analysis was also performed, accounting for age, sex, pre-randomization open-label bicarbonate use, APACHE II and SOFA score. No correction for multiplicity was applied to secondary or exploratory outcomes; these are reported as point estimates with 95% CIs that should not be used to infer definitive between-group differences.

Funding 

The trial was funded by the National Health and Medical Research Council of Australia and coordinated by the Australian and New Zealand Intensive Care Research Centre at Monash University. The funding body had no role in design, trial conduct, analysis, or reporting of the data.

Results

Baseline demographics

In 33 months (April 2023-Dec 2025), 500 of 3060 patients were enrolled, and 498 were included in the analysis (Fig 1). Patients were recruited from 7 countries, predominantly from Australia and New Zealand. Enrolled patients were elderly, with a median age of 66 years. The majority were admitted to the ICU from the operating theatre and the emergency department, accounting for  76% of enrolled patients (Table S3). The median APACHE II and SOFA scores were 21 and 7, respectively, suggesting an association with higher mortality risk.

Approximately 50% patients were admitted with a medical diagnosis, and septic shock was the most common cause for metabolic acidosis (48%). Prevalence of severe AKI was slightly higher in the sodium bicarbonate group (46.9% vs 40%) than in the placebo group (Table S3). The median pH at enrollment was 7.26 with a median base excess of -9 mmol/L; approximately 40% had pH <7.25.

Notably, trial participants were substantially sicker than the general ICU population at the same centres over the same period (APACHE III 77.2 vs 55.4, hospital mortality 23.1% vs 10.4%, Table S2).

Intervention and outcomes

498 patients received the intervention, of whom 244 received sodium bicarbonate infusion (median dose 300 mmol or mEq). Infusion-rate adjustment per protocol was required in half of the patients in the bicarbonate group (49.8%) versus only 23.2% of the placebo group—expected since the algorithm responds to biochemical correction, which happened more often and faster with the active drug. Open-label sodium bicarbonate was given more often in the placebo arm (15.2% vs 7% in Fig S8), consistent with a lower need for rescue therapy once the study drug had already corrected the pH.  Protocol deviations (Table S5) were also more frequent in the bicarbonate arm, driven predominantly by infusion rate non-adjustment (13.5 vs 2.8% in the placebo group)- expected, since the titration algorithm fires more often with faster correction, not a conduct failure. Randomization of ineligible patients was balanced between arms (5.4% overall), and shouldn’t be counted as part of this pattern.  

Protocol deviations (Table S5) were more common in the bicarbonate group, driven largely by “infusion rate not adjusted per protocol” (13.5% vs 2.8%); randomization of ineligible patients, by contrast, was similar between arms (4.9% vs 5.9%; combined 5.4% overall) and was not a bicarbonate-arm-specific problem.

Primary endpoint 

At 30 days there was no significant difference in the incidence of MAKE30 between the two groups (40.2% vs 39.4%; P=0.78). 

There was no significant difference in persistence of kidney dysfunction in the prespecified subgroup analysis (Fig S7).

Sensitivity analyses were concordant: further adjustment for age, sex, pre-randomization bicarbonate use, APACHE II and SOFA gave an adjusted difference of 0.7 pp (-7.3 to 8.6), and an alternative eGFR-based definition of persistent renal dysfunction gave 1.3 pp (-7.2 to 9.8) (Table S9). A confidence distribution analysis of the primary result (Fig S4) estimated only 38.9% confidence that bicarbonate reduces MAKE 30 to any degree- i.e., the point estimate leans, non-significantly, toward no benefit or harm rather than benefit.

Secondary and additional endpoints

One fourth of the enrolled patients died within 30 days in both groups (25.4% bicarbonate vs 24% placebo; HR 1.09, 0.76-1.56- Fig 2A), same as death by day 90 (fig S9). RRT use within 30 days was numerically lower with bicarbonate, but not significantly so (16.8% vs 20.9%- Fig 2B), as was persistent renal dysfunction (14% vs 18.3%- subgroup analysis Fig S7). RRT dependence and ICU death by day 30 were also similar (Table 3).

AKI incidence at 7 days was similar between groups (about 64%), but recurrence of metabolic acidosis was lower with bicarbonate (32 vs 55.7%). Though reaching the pH target was earlier in the bicarbonate group, patients in both groups had similar pH after day 7 of randomization (Fig S2).

The number of vasopressor-free days, renal-replacement therapy–free days, and ICU-free days on day 30, and the number of hospital-free days on day 90, were also similar between the two trial groups (Table 3, distributions in fig S10).
Adverse effects were uncommon: 1.6% with bicarbonate vs none with placebo; driven by hypokalemia needing correction, with one patient also developing hypernatremia. No serious adverse effects occurred in either group.

Discussion

The SODa-BIC trial was a pragmatic trial that randomized 500 patients from 55 ICUs to receive sodium bicarbonate or dextrose infusions. They included critically ill patients dependent on vasopressors with a pH < 7.30, BE ≤ -4 mEq/L, and PaCO2 ≤ 45 mmHg (≤ 50 mmHg if intubated), representing a very common phenotype seen in the ICU. In this trial, sodium bicarbonate (an infusion of 8.4% sodium bicarbonate solution, 1000 mEq/L) did not reduce major adverse kidney events within 30 days (MAKE30) of randomization compared with an infusion of 5% dextrose.
MAKE30 is a well-validated, patient-centered composite: it captures both injury severity and survival. Here, the composite was driven almost entirely by death of any cause (25.4% vs 24%), while every renal component moved in a numerically favorable direction without reaching significance:  renal replacement therapy (16.8% versus 20.9% in placebo), persistent renal dysfunction (14% versus 18.3%), and dialysis dependence at day 30 (5.7% versus 9.1%). Three consistent point estimates favouring bicarbonate and none of them being significant is evidence of an underpowered trial, a genuinely absent effect, or both, and this trial cannot distinguish between these issues.
A  comparator is the PRESERVE trial - IV bicarbonate versus saline for the prevention of contrast-associated AKI, using a composite of death, dialysis, or persistent kidney impairment, and was stopped early for futility (Weisbord et al, NEJM, 2018). Two bicarbonate trials, two patient-centered composites, and two null results. That’s not a coincidence worth explaining away with endpoint choice. Perhaps the question is not whether MAKE30 was the right endpoint—it almost certainly was. Rather, isn’t it naive to think that correcting metabolic acidosis would somehow reverse such a complex multisystemic pathophysiology? 
Interestingly, despite protocolized treatment, clinicians retained the ability to administer open-label sodium bicarbonate whenever deemed clinically necessary. Although crossover was relatively limited, 14.3% of patients in the bicarbonate arm and 9.1% in the placebo arm had already received bicarbonate before randomization, while additional rescue bicarbonate administration occurred after randomization in both groups. This pragmatic design reflects real-world practice, but may also have attenuated any treatment separation. For what it is worth, the prespecified subgroup analyses were similarly unremarkable, with no evidence of heterogeneity across the evaluated subgroups. Neither the presence of septic shock, illness severity, baseline bicarbonate administration, nor admission type appeared to modify the treatment effect. 
BICAR-ICU2’s finding- lower RRT with bicarbonate- deserves more scrutiny than it usually gets (Jung et al, JAMA 2025| NephJC short). The primary endpoint, 90-day mortality, was neutral; RRT initiation, unlike death, is not a hard endpoint; it is a clinician’s judgment call, made in real time, by an unblinded physician. Faced with worsening acidosis in a patient already on bicarbonate, the path of least resistance is more bicarbonate—cheaper, non-invasive, and reassuringly proactive-feeling—rather than escalating to dialysis. This is evidence that open-label trials let treatment knowledge steer secondary endpoints. SODa-BIC, being double-blind, removes exactly this confounder, and the RRT signal shrank accordingly: 16.8% vs 20.9%, overall not significant. In the pH <7.25 subgroup, an 11-point difference persisted (17.2% vs 28.3%, 95% CI -22.3 to 0.4)—but with blinding intact, this is the honest version of the question BICAR-ICU2 never answered.

Old treatment, new trial

SODa-BIC differs from its predecessors in phenotype: vasopressor-dependent metabolic acidosis rather than severe acidemia and AKI. While BICAR-ICU suggested benefit in the subgroup with severe AKI and BICARICU-2 confirmed a reduction in kidney replacement therapy without improving death (dissociation more plausibly explained by unblinded clinicians than by a kidney-specific drug effect), SODa-BIC, blinded, found neither. Perhaps most consistent was the finding of no change in mortality.

Strengths

SODA-BIC used MAKE30, a patient-centered composite outcome, while accounting for competing risks and variation in baseline kidney function. Second, the trial incorporated a prespecified blinded sample-size re-estimation, improving confidence that the final sample size was adequate for the planned effect. Most importantly, the trial was also pragmatic and multicenter, increasing its relevance to real-world ICU practice across different health-care systems

Limitations

Several limitations are also important. Open-label bicarbonate was permitted when clinically indicated, and other sodium- or buffer-containing therapies were not fully controlled, potentially reducing treatment separation. Although the intervention corrected acidemia rapidly, it was brief, raising uncertainty about whether it was sustained long enough to influence a 30-day outcome. In addition, although blinding was carefully maintained, changes in pH and bicarbonate may have allowed clinicians to infer treatment allocation in some cases. The study did not collect physiological data at the time of initiation of renal replacement therapy, limiting interpretation of whether dialysis decisions differed between groups. Finally, the trial was powered to detect a moderate-to-large treatment effect. Therefore, while it convincingly excludes a major benefit, smaller but potentially clinically relevant effects, and here we are talking about kidney-specific outcomes, cannot be ruled out.

So, where does the SODA-BIC trial leave us? Sodium bicarbonate corrects the numbers, yes, but it still fails to correct patient-oriented outcomes and prevent death. Routine administration to prevent MAKE30 is difficult to justify. However, let’s imagine a real-world scenario. In a deteriorating patient with metabolic acidosis, vasopressor dependency and no clear contraindication, many clinicians may still use sodium bicarbonate as a “wait-it-out” measure - not because it improves survival, but because transient correction of acidemia may provide physiological support while the underlying cause is addressed (and it makes us clinicians feel better, like we’ve done something). Considering these aspects, maybe the takeaway message isn't that “bicarbonate isn’t useful”, but rather “don’t expect bicarbonate to change the prognosis”.  

Conclusion

In the SODa-BIC trial, sodium bicarbonate infusion in critically ill patients in the ICU with metabolic acidosis did not improve mortality or MAKE30 outcome.

Summary by

Srinivasavaradan Govindarajan
Assistant Professor (Ped Neph)
VMMC and Safdarjung Hospital, India

Anca Elena Stefan
Nephrology specialist
Romania

Reviewed by

Brian Rifkin, Cristina Popa, Sai Vani, Akshaya Jayachandran

Header image created by AI and prompts from Brian Rifkin

The prior NephJC discussion of finerenone versus spironolactone concluded that the comparative evidence base was asymmetric: explanatory trial design, not necessarily pharmacology, explained finerenone’s superior track record. Two papers published concurrently in June 2026 extended the evidence base beyond diabetic CKD and permitted a more direct test of that claim- a prespecified exploratory subgroup analysis of FIND-CKD restricted to glomerular disease (Neuen BL et al, JAMA, 2026) and INFINITY, a prespecified individual-participant-data pooled analysis of three phase 3 trials- FIDELIO-DKD, FIGARO-DKD, FIND-CKD (Neuen BL et al, Lancet, 2026). 

FIND-CKD (Heerspink HJL et al, NEJM, 2026 | NephJC Summary) randomized 1584 adults with non-diabetic CKD (eGFR 25- <60 ml/min/1.73 m² with UACR 200-500 mg/g, or eGFR 25-90 with UACR 500-3500 mg/g) to finerenone 10/20 mg or placebo on maximized RAS blockade. The primary outcome, total eGFR slope to month 32, favored finerenone by 0.7 ml/min/1.73 m²/year (95% CI, 0.3-1.1; P<0.001)- magnitude comparable to the effect sizes reported for RAS inhibitors and SGLT2i in similar populations. 

Resources: Brenner BM et al, NEJM, 2001, Holtkamp FA et al, Kidney Int,  2011| Heerspink HJL et al, Lancet Diabetes Endocrinol, 2021| EMPA-KIDNEY Collaborative Group, Lancet Diabetes Endocrinol, 2024| Heerspink HJL et al, NEJM, 2026

The prespecified hierarchical secondary composite (kidney failure, sustained ≥57% eGFR decline, heart failure hospitalization, or cardiovascular death) reached significance at HR 0.77 (95% CI, 0.60-0.99). 

JAMA. 2026 Jun 5:e269923. doi: 10.1001/jama.2026.9923. Online ahead of print.

Finerenone in Patients With Chronic Kidney Disease Due to Glomerular Diseases: A Randomized Clinical Trial

Brendon L Neuen, Vlado Perkovic, Rajiv Agarwal, David Z I Cherney, Carolyn S P Lam, Christoph Wanner, Katherine R Tuttle, Pantelis Sarafidis, Jonathan Barratt, Anna Burgner, Xiangmei Chen, Alfredo Chew-Wong, Vladimir A Dobronravov, Jürgen Floege, Kieran McCafferty, Masaomi Nangaku, David Packham, Evangelos Papachristou, Pablo E Pergola, Marijn M Speeckaert, Arunkumar Subbiah, Sydney C W Tang, Shuifu Tang, See Cheng Yeo, Niels Jongs, J David Smeijer, Mario Berger, Meike Brinker, Rania Dayoub, Jay Elliott, Na Li, Katharina Mueller, Nicole Rethemeier, Marina Yael Finkelsztein, Hiddo J L Heerspink; FIND-CKD Investigators

PMID: 42246414

DOI: 10.1001/jama.2026.9923

Why was the study done? 

Glomerular diseases account for a substantial proportion of global CKD-attributable kidney failure and disproportionately affects younger patients. For most glomerular disease subtypes, disease-specific therapeutic options remain limited, creating an unmet need for interventions that target shared mechanisms of progression independent of underlying etiology. While the selective, nonsteroidal mineralocorticoid  receptor agonist (nsMRA) finerenone is well-established in diabetic nephropathy (FIDELIO-DKD, NephJC summary| FIDELITY), clinical evidence evaluating its efficacy and safety within primary glomerular disease cohorts has historically been scarce.

The mechanistic basis for extending selective mineralocorticoid receptor (MR) blockade to podocytopathies- notably focal segmental glomerulosclerosis (FSGS)- is rooted in cell-specific receptor localization (Lazareth H et al, Kidney Int, 2025). The MR is functionally expressed on podocytes, which is the primary cellular injury site in FSGS. Pathological MR overactivation drives podocyte cytoskeletal disruption, slit diaphragm effacement, and the upregulation of pro-inflammatory and profibrotic pathways. Preclinical models demonstrate that selective MR antagonism halts this cascade, mitigating podocyte injury and slowing the progression of glomerulosclerosis (Shibata B et al, Nat Med, 2008, Tagaki N et al, Nephron Extra, 2012).

Methods 
This was a prespecified exploratory subgroup analysis of FIND-CKD (Heerspink HJL et al, NEJM, 2026| NephJC summary). Of 1584 randomized participants, 57% had investigator-reported glomerular disease, 712 (78.8%) biopsy-confirmed: IgA nephropathy 46.1%, FSGS 23.8%, membranous nephropathy 10%, MPGN 2.9%, and other 17.3%.

 Table1. Demographics of participants with glomerular diseases at baseline, from Neuen BL et al, JAMA, 2026

Mean baseline eGFR was 48 mL/min/1.73 m², and the median UACR was 839 mg/g. Randomization was stratified by screening UACR category and baseline SGLT2i use, but not by CKD etiology. Therefore, comparisons across glomerular disease subtypes don’t retain the protection afforded by randomization and may be affected by measured or unmeasured baseline imbalances. This limitation doesn’t compromise the internal validity of the trial but constrains causal interpretation of subtype-specific comparisons.

What do the results say?

The total GFR slope was -3.5 mL/min/1.73 m²/year with finerenone versus -4.23 with placebo; the between-group difference was 0.73 (95% CI, 0.22-1.24).

Figure 2. Change in eGFR over time allocation in participants with glomerular diseases, from Neuen BL et al, JAMA, 2026

Treatment effect was consistent across disease subtypes, with no evidence of heterogeneity (P for interaction = 0.52). The estimate was 1.34 (95% CI -0.29 to 2.38) in FSGS and 0.61 (95% CI, -0.14 to 1.36) in IgAN. Among biopsy-confirmed cases, the estimate was 0.89 (95% CI, 0.31-1.47). UACR decreased by 42% (95% CI 35-48%) at 12 months, similarly across subtypes.

Figure 3. Subgroup analysis according to glomerular disease etiology, from Neuen BL et al, JAMA, 2026

Kidney failure or ≥40% eGFR decline occurred less frequently with treatment (7.42 vs 9.60 events per 100 patient-years, HR 0.74, 95% CI 0.57-0.97). 

Figure 4A. Time to event analysis of key secondary and exploratory efficacy outcomes in participants with glomerular disease, from Neuen BL et al, JAMA, 2026

Results were consistent across subtypes and in biopsy-confirmed disease (HR 0.74, 95% CI, 0.55-0.99) (Figure 5). However, this composite was selected post hoc because it generated the most events and should be interpreted as exploratory. Serious adverse events were similar between groups, including serious hyperkalemia (0.9% in both).

Critical view

Three issues limit the strength of inference. First, surrogate endpoint validation: the CKD-EPI Clinical Trials Consortium meta-analysis (Inker A et al, Nat Med, 2023) established that a total eGFR slope effect of 0.75 mL/min/1.73 m²/year in a trial of comparable size (900 participants) confers a 99% probability of benefit on clinical kidney outcomes, with a median predicted HR of 0.74- a threshold the observed 0.73 mL/min/1.73 m²/year effect sits just under—and a predicted HR that matches the observed composite-outcome HR of 0.74 exactly. This concordance is reassuring but should be read as internal consistency between a surrogate and a clinical outcome measured in the same trial, not as an external replication. 

Second, the FSGS estimate was nominally significant but imprecise (N=215, 1.34 ml/min/1.73 m²/year; 95% CI 0.29-2.38). The subgroups are not powered for a definitive subtype-specific conclusion. Moreover, DUPLEX - the largest completed phase 3 FSGS trial- found no clear benefit of sparsentan over irbesartan on eGFR decline, increasing the evidentiary threshold for claiming efficacy in FSGS (Rheault MN et al, NEJM, 2023| NephJC summary). 

Third, generalizability was limited by the cohort’s demographics: mean age 51 years, 57-62% male, approximately 60-65% Asian, and few Black participants. About 20% lacked biopsy confirmation, while many available biopsies were historical rather than obtained at enrollment. Interaction tests were not adjusted for multiple comparisons, increasing the risk of chance-positive findings; their limited power also means that significant interactions do not establish uniform treatment effects across subtypes.

Lancet. 2026 Jun 13;407(10546):2375-2386.doi: 10.1016/S0140-6736(26)01009-3. Epub 2026 Jun 5.

Efficacy and safety of finerenone in patients with chronic kidney disease: an individual participant data pooled analysis (INFINITY)

Brendon L Neuen, Hiddo J L Heerspink, Vlado Perkovic, David Z I Cherney, Carolyn S P Lam, Katherine R Tuttle, Christoph Wanner, Pantelis Sarafidis, Stefan D Anker, Gerasimos Filippatos, Bertram Pitt, Peter Rossing, Luis M Ruilope, Niels Jongs, J David Smeijer, Meike Brinker, Christiane Ahlers, Andrea Lage, Andrea Horvat-Bröcker, Patrick Schloemer, Thomas Eissing, Rania Dayoub, Robert Lawatscheck, Rajiv Agarwal; FIND-CKD, FIDELIO-DKD and FIGARO-DKD Investigators

PMID: 42248158

DOI: 10.1016/S0140-6736(26)01009-3

Why was the study needed?

No individual finerenone trial was powered for kidney failure alone or all-cause mortality definitively. Pooling individual-participant data increased power for these hard time-to-event outcomes and enabled assessment of effect modification by diabetes status, which FIND-CKD could not address because it excluded patients with diabetes. 

How was the study done?

14,574 participants pooled across FIDELIO-CKD, FIGARO-DKD, and FIND-CKD.

Table 1. Baseline characteristics, from Neuen BL et al, Lancet, 2026

The protocol was prospectively registered to PROSPERO prior to FIND-CKD completion. Systematic search (PubMed, Embase, to March 31, 2026) identified no additional eligible trials; 301 records were screened to 3 included studies (figure S1), each assessed as low risk of bias across RoB2 domains (figure S2). 

The main kidney outcome was kidney failure or sustained ≥57% eGFR decline (matching the earlier FIDELITY definition). The main cardiovascular outcome was heart failure hospitalization or cardiovascular death; undetermined deaths were excluded. Important methodological differences exist across the trials: cardiovascular and mortality events were independently adjudicated in FIDELIO-DKD and FIGARO-DKD, but in FIND-CKD these events were investigator-reported via structured case-report forms without independent adjudication. The polled hazard ratios for cardiovascular and mortality outcomes therefore combine data collected under two different ascertainment standards.

What do the results say?

The composite kidney outcome occurred at 22.3 versus 28.8 events per 1000 patient-years (HR 0.76, 95% CI 0.68-0.86). Kidney failure alone was reduced more modestly (HR 0.85, 95% CI 0.74-0.99), with the upper confidence limit close to null. The HR for dialysis or transplantation alone was 0.77 (95% CI, 0.64-0.94), while sustained ≥57% eGFR decline alone had an HR of 0.71 (95% CI, 0.61-0.81- Table S5).

Figure 1. Cumulative incidence functions for key efficacy outcomes, from Neuen BL et al, Lancet, 2026

The cardiovascular composite occurred at 19.1 vs 23.9 events per 1000 patient-year (HR 0.80, 95% CI, 0.70-0.91). The HR was 0.78 for heart failure hospitalization (p= 0.0024) and 0.82 for cardiovascular death (95% CI 0.67-0.999). All-cause mortality was also lower (HR 0.88, 95% CI 0.79-0.99).

Figure 2. Kidney, cardiovascular, and mortality outcomes in the overall INFINITY population, from Neuen BL et al, Lancet, 2026

There was no evidence of effect modification by glycated hemoglobin (P for interaction = 0.51, figure 3), CKD etiology, eGFR, UACR, or SGLT2i use (figure 4), or trial origin (all P for interaction ≥0.40; figure S6).

Figure 4. Effect of finerenone on the composite kidney outcome across prespecified subgroups, from Neuen BL et al, Lancet, 2026

Hyperkalemia occurred in 14.3% of participants receiving finerenone and 7.6% receiving placebo (Table 2). Hospitalizations for hyperkalemia were uncommon (0.9% vs 0.2%), with no fatal events. The risk of serious hyperkalemia requiring hospitalization differed by diabetes status: HHR 6.21 (95% CI, 3.18-12.12) with diabetes versus 1.48 (95% CI, 0.47-4.67) without diabetes (P for interaction = 0.034). This might reflect the greater prevalence of type 4 renal tubular acidosis in diabetic kidney disease. 

The number needed to treat for the kidney-cardiovascular composite was 29.2, compared with a reported number needed to harm of -114.5 for hyperkalemia during hospitalizations (table S7), indicating an approximately fourfold benefit-to-harm ratio at the population level. Per 1000 patients treated for 3 years, finerenone was estimated to prevent 34 kidney-cardiovascular composite events, 21 kidney events, 14 heart failure hospitalizations or CV death events, and 10 deaths. Larger absolute cardiovascular and mortality benefit in participants with diabetes reflected their higher baseline risk rather than a greater relative treatment effect. NNT remains a dubious metric.

Figure 5. Estimated absolute effects of finerenone per 1000 patients treated over 3 years by diabetes status, from Neuen BL et al, Lancet, 2026

Critical view

FIND-CKD cardiovascular and mortality events were not independently adjudicated. Combining these with adjudicated events from FIDELIO-DKD and FIGARO-DKD introduces potential ascertainment bias (making some members of the study group more or less likely to be included in the study than others). No sensitivity analysis specifically excluding FIND-CKD from cardiovascular and mortality analyses was reported. 

No source trial enrolled participants with screening eGFR <25 mL/min/1.73 m² or non-albuminuric CKD. The findings do not support extrapolation to advanced or non-albuminuric CKD, as in “across the entire spectrum of CKD."

Subgroup interaction tests were not adjusted for multiple comparisons. A nonsignificant interaction test may also reflect limited power and should not be interpreted as proof of uniform benefit across all subgroups.

All three trials and the pooled analysis were funded by Bayer. Several authors were Bayer employees with disclosed equity interests, and Bayer funded medical writing support. Although the data were independently reanalyzed at University Medical Center Groningen, the evidence base remains entirely manufacturer-funded. 

External evidence provides partial support. FINEARTS-HF showed a heart failure benefit in HFpEF irrespective of diabetes status (Solomon SD et al, NEJM, 2024). Pooled FIDELIO/FIGARO analyses found heart failure benefits emerging within the first 6 months (Ostrominski JW et al, JACC, 2026). CONFIDENCE showed greater albuminuria reduction with combined finerenone and empagliflozin than with either drug alone, without increased acute kidney injury (Agarwal R et al, NEJM, 2025| NephJC summary). These findings support the biological and clinical rationale but don’t affect INFINITY’s outcome adjudication or eGFR-floor limitation.

Conclusion

FIND-CKD established that finerenone slows eGFR decline in non-diabetic CKD at an effect size consistent with established kidney-protective therapies; this finding is self-contained and doesn’t depend on the two subsequent analyses for validity. The JAMA subgroup analysis tests whether that effect generalizes across etiology and does not reject the null hypothesis of homogeneity- a result that is informative but constrained by the absence of etiology-based randomization, limited events in the rarer subtypes, and uncorrected multiplicity. INFINITY tests generalization across diabetes status and supplies, for the first time, adequately powered estimates for kidney failure and all-cause mortality- at the cost of pooling across trials with differing outcome ascertainment standards and a shared eGFR floor and albuminuria requirement that bound the population to which these estimates apply. 

Together, these analyses suggest that finerenone’s effect reflects mineralocorticoid receptor activity rather than a specific CKD etiology or glycemic state. This interpretation is supported by consistent findings across etiologic and glycemic subgroups and by external evidence from FINEARTS-HF and CONFIDENCE. However, efficacy remains untested in non-albuminuric CKD and at eGFR <25 mL/min/1.73 m², while cardiovascular outcomes were not uniformly adjudicated. These limitations define the population and outcomes to which the findings can be applied and the priorities for future trials.

Written by

Cristina Popa

Reviewed by

Brian Rifkin

2026 Jun 4. doi: 10.1056/NEJMoa2604625.

Finerenone in Persons with Chronic Kidney Disease without Diabetes

Hiddo J L Heerspink, Brendon L Neuen, Rajiv Agarwal, David Z I Cherney, Carolyn S P Lam,  Katherine R Tuttle, Christoph Wanner, Pantelis Sarafidis, Niels Jongs, J David Smeijer, Meike Brinker, Nicole Rethemeier, Patrick Schloemer, Paula Vesterinen, David Goldsbury, Sara Dizayee, Jon W Mares, Vlado Perkovic; FIND-CKD Investigators

PMID: 42246672

DOI: 10.1056/NEJMoa2604625

Introduction

Few drugs have moved up the ranks as quickly as finerenone in treatment of diabetic kidney disease. Following the landmark FIDELIO-DKD (Bakris DL et al, NEJM 2020 |NephJC Summary), FIGARO-DKD (Pitt B et al, New Engl J Med 2021) and the FIDELITY pooled analysis (Agarwal R et al, European Heart Journal 2022), it has become one of the pillars of management of diabetic kidney disease (DKD) in type 2 DM along with RASi and SGLT2 inhibitors aka flozins. FineONE is doing the same for it in type 1 DM (Heerspink H et al, NEJM 2026 |NephJC Short) with significant antiproteinuric effects, and FINEARTS in HFpEF (NephJC summary). Can the cardiorenal benefits seen in DKD be extended to the much larger population of patients with CKD without diabetes? 

Mineralocorticoid receptor overactivation not only causes fluid and sodium retention but it is also a well-recognized driver of inflammation and fibrosis, which are fundamental pathways underlying CKD progression, irrespective of the underlying cause. In a post hoc analysis of the FIDELIO-DKD, finerenone reduced albuminuria and improved kidney outcomes irrespective of baseline glycemic control or insulin use, suggesting that its kidney protective effects extend beyond glucose lowering.(Rossing P et al, Diabetes Care 2022) But a convincing biological hypothesis does not guarantee clinical benefit. Spironolactone, a steroidal MRA, improves albuminuria and hypertension, but its widespread use in CKD has been limited mostly by lack of robust evidence demonstrating improvement in clinical kidney outcomes. The hypothesis that finerenone, a highly specific, nonsteroidal antagonist of mineralocorticoid receptors (nsMRA) can improve renal outcomes in patients with CKD who do not have diabetes required prospective testing. So, let’s FIND out!

Methods

Study Design
The FIND-CKD study design (Heerspink et al, NDT 2025) was published in 2025. In this multicenter, randomized, double-blind, parallel-group, phase 3 trial, across 24 countries, investigators studied the clinical efficacy and safety of finerenone at doses of 10 mg and 20 mg daily versus placebo in slowing the progression of chronic kidney disease among participants without diabetes.

Study population
The study enrolled male and female patients older than 18 years of age with a clinical diagnosis of CKD without evidence of diabetes. The investigators chose patients with high risk of progression of CKD by eGFR and albuminuria. Accordingly, two categories of inclusion were made: 

• those with eGFR of ≥25 to 60 ml/min/1.73m² with low level albuminuria (UACR ≥ 200 to < 500 mg/g); total number of patients in this group was capped at 10% of total enrollment planned AND

• those between eGFR ≥25 to 90 ml/min/1.73m², if the UACR was ≥ 500 to < 3500 mg/g at the time of screening

The proteinuria / albuminuria of anytime in the prior 3 months could be used, and if not done in the prior 3 months, then the pre-screening investigation could be used to identify patients. The key inclusion and exclusion criteria are shown in figure below: 

Thus those with a clear indication (eg HF or DKD) were excluded, and so were those with lupus, ANCA vasculitis or those on active immunosuppression. Patients with prior organ transplantation, recent dialysis-requiring acute kidney injury, uncontrolled blood pressure or nephrotic-range albuminuria (UACR >3500 mg/g) were also excluded. 

Intervention
The protocol of Finerenone dosing and follow up is shown in the figure below. Notably, there was no run-in period unlike with the FIDELIO/FIGARO trials.

Participants were randomly assigned in a 1:1 ratio to receive oral finerenone or matching placebo in addition to standard-of-care therapy. Participants were randomized using an interactive response technology system, with stratification according to baseline flozin use (yes vs no) and screening UACR (≤1000 vs >1000 mg/g). 

Finerenone (or matching placebo) was initiated at 10 or 20 mg once daily according to baseline kidney function, with protocol-directed dose adjustments throughout follow-up. Participants receiving 10 mg were eligible for uptitration to the target dose of 20 mg after one month if serum potassium remained ≤4.8 mmol/L and eGFR had not declined by ≥30%. Hyperkalemia was managed using a predefined algorithm: treatment was temporarily withheld for serum potassium >5.5 mmol/L and restarted once potassium decreased to ≤5.0 mmol/L. The protocol allowed temporary interruption and rechallenge rather than routine permanent discontinuation. If hyperkalemia recurred despite resumption at the lower dose and no alternative cause was identified, permanent discontinuation of study treatment was recommended. Notably, the protocol did not mandate the use of potassium-binding agents as part of hyperkalemia management. 

An important methodological consideration was the handling of flozins, which had rapidly emerged as foundational therapy even for non-diabetic CKD during the conduct of the trial. The investigators permitted but did not require the co-administration of flozins. For those with a clear clinical indication, the protocol preferred that these agents be started and stabilized at a fixed dose for a minimum of four weeks prior to the screening process. Flozination following randomization was also allowed if deemed necessary by the clinician, though only after the participant had maintained a steady study drug regimen for at least one month. 

Outcomes
The primary efficacy outcome was the total eGFR slope, defined as the mean annual rate of change in the eGFR from baseline to month 32. To account for the expected early hemodynamic decline with finerenone, eGFR was modelled using a two-slope mixed-effects model that separated the acute (baseline to Month 3) and chronic (Month 3 onward) phases of treatment. Secondary outcomes were tested using a prespecified hierarchical strategy and included:

(i) Composite kidney or cardiovascular outcome: 

• Sustained ≥57% decline in eGFR (confirmed for ≥4 weeks; equivalent to doubling of serum creatinine), 

• Kidney failure (eGFR <15 mL/min/1.73 m² confirmed after ≥4 weeks, long-term dialysis for ≥30 days, or kidney transplantation), 

• Hospitalization for heart failure, or 

• Cardiovascular death.

(ii) Kidney-specific composite outcome:

• Sustained ≥57% decline in eGFR, or

• Kidney failure.

(iii) Cardiovascular composite outcome:

• Hospitalization for heart failure, or

• Cardiovascular death.

There were several exploratory outcomes as well as predefined safety (mostly related to hyperkalemia).

Sample size assumptions
The sample size was calculated to provide >90% power to detect a between-group difference of 0.7 mL/min/1.73 m²/year in the total eGFR slope over a 32-month period, requiring the enrollment of approximately 1,500 participants. The primary efficacy analysis followed the intention-to-treat principle and used a two-slope linear mixed-effects model to estimate the acute (baseline to Month 3) and chronic (thereafter) phases of eGFR decline. Secondary time-to-event outcomes were analyzed using stratified Cox proportional hazards models, with statistical significance assessed according to a prespecified hierarchical testing strategy to control for multiple comparisons.

Funding
FIND-CKD was funded and sponsored by Bayer. Seven co-authors were Bayer employees (clinical development, statistics, regulatory affairs, medical affairs, and related functions). Bayer co-designed the trial with the Steering Committee, performed the primary statistical analyses, and participated in manuscript submission. Analyses were independently verified by investigators at the University Medical Center Groningen, and safety oversight was provided by an independent Data Monitoring Committee. 

Results

A total of 1584 participants were randomized and included in the full analysis set, indicating that nearly half of those enrolled (perhaps meaning those screened?) met the eligibility criteria.

The median treatment duration was 36.6 months. Overall, 1566 participants completed the full study, including the month 32 visit. 

The mean age was 55 years; 35% were women, and the median UACR was 819 mg/g. The mean eGFR was 47 ± 16 mL/min/1.73 m², with approximately 80% of participants having an eGFR <60 mL/min/1.73 m². Hypertension was highly prevalent and RASi use was nearly universal (99.7% - as mandated by trial protocol) with most participants receiving an ARB, and 17% of participants were flozinated. Just over half (~ 57%) had chronic GN identified as their underlying cause of CKD.

Primary outcome 
Following the early hemodynamic dip, kidney function declined more slowly with finerenone than with placebo. This treatment effect became evident after the initial 3 months and was sustained throughout follow-up. The primary outcome of total eGFR change was -3.3 vs -4 ml/min/1.73m²/year in finerenone and placebo groups respectively (CI = 0.3-1.1, p<0.001).

Separating the acute and chronic eGFR slopes highlighted the biphasic response to finerenone. During the first 3 months, the acute eGFR slope with finerenone was 1.2 mL/min/1.73 m²/year greater than with placebo. Notably, after treatment discontinuation (in the washout phase), eGFR increased in the finerenone group (+1.2 mL/min/1.73 m²) but continued to decline in the placebo group (−0.5 mL/min/1.73 m²), supporting the reversible nature of the initial hemodynamic dip. 

Secondary outcomes
The secondary composite kidney–cardiovascular outcome (sustained ≥57% decline in eGFR, kidney failure, hospitalization for heart failure, or cardiovascular death) occurred less frequently with finerenone than with placebo (13.9% vs. 16.9%; HR 0.77, 95% CI 0.60–0.99; p=0.04). The next outcome missed the threshold for significance (see figure below for more).

The treatment effect was primarily driven by kidney outcomes, whereas cardiovascular events were infrequent, with no significant reduction in hospitalization for heart failure or cardiovascular death (HR 0.60, 95% CI 0.27–1.33).

With regard to the exploratory outcomes, finerenone was associated with a sustained reduction in albuminuria, with a 35.4% greater reduction in UACR than placebo at month 6, an effect that persisted throughout follow-up. More than half of the patients achieved a ≥30% reduction in UACR (56.0% vs. 24.4%; OR 3.99). Also, 4 weeks after treatment discontinuation, the decline in eGFR remained smaller with finerenone than with placebo (between-group difference, 2.4 mL/min/1.73 m²), supporting the reversible nature of the initial hemodynamic effect. 

Subgroup analysis of annual rate of change in eGFR from baseline to month 32 showed a consistent benefit of finerenone in all subgroups.

Safety outcome 
Overall adverse events and serious adverse events were similar between groups. As expected, hyperkalemia was more frequent with finerenone (17.0% vs. 13.3%); however, serious hyperkalemia events were uncommon (1.0% vs. 0.6%), no fatal hyperkalemia events occurred, and permanent treatment discontinuation due to hyperkalemia was infrequent (1.5% vs. 0.1%). 

Discussion

The FIND-CKD trial reports that the addition of finerenone in mostly proteinuric, but non-diabetic CKD, on background of RASi results in a meaningful reduction in albuminuria, and a significantly slower decline in GFR slope.

Strengths

This was properly designed, powered, blinded RCT. It included patients in whom we have little data beyond (low quality) RASi and (high quality) flozins to slow down GFR decline, and there remains a high residual risk of kidney failure. the RCT was appropriately enriched with patients who have proteinuria, and used validated outcomes (total GFR slope) while also demonstrating significant effect on UACR which is presumably in the mechanistic pathway. The risk of hyperkalemia was there, but low. Finerenone seems quite safe to use in this setting.

Limitations

• The study population was not fully representative of the overall non-diabetic CKD population. Most participants were men, had significant albuminuria thus limiting the generalizability of the findings. Thus, patients with polycystic kidney disease, or others with non-proteinuric CKD were excluded. It would be harder to show an effect in these as GFR decline is slower - as also the pathophysiology may not be MR related.

• Also excluded were those with lupus nephritis, ANCA-associated vasculitis, and other GNs on active immunosuppression. This is somewhat appropriate as the specific immune pathways need to be targeted rather than these non-specific supportive or palliative therapies. In GN, finerenone (possibly like flozins) might be quite useful in chronic or burnt out disease, not in the active state.

• Other excluded populations include those with GFR < 25 (as is common - but also perhaps too late, or at high risk of hyperkalemia) - but there were also very few Black patients (~ 5%). APOL1 and FSGS is quite common and it would be useful to have strong data in that population.

• Only 17% of participants were receiving an SGLT2 inhibitor, although flozins were allowed during the trial period.  Trial enrollment took place during a transitional period (2021–2023), before flozins became widely established in patients with non-diabetic CKD. Though table S2 includes changes in BB, CCB, statins etc they exclude flozins. We would not expect differential use of flozins, needless to say, and the effect size was consistent in those on flozins and those who were not.

• The relatively low number of cardiovascular events limited the statistical power to detect differences in cardiovascular outcomes. This was a patient population at much higher risk of kidney than CV outcomes.

• Finally, efficacy is only part of the equation. As CKD management increasingly shifts toward a multi-drug approach combining RAS inhibitors, SGLT2 inhibitors, and finerenone, an important unanswered question is whether these therapies will be equally accessible in routine practice. FIND-CKD was not designed to address cost-effectiveness or affordability, but these factors will inevitably influence how widely FIND-CKD findings can be translated into clinical care. 

How do we interpret these results?

Rather than relying on a traditional time-to-event kidney composite, FIND-CKD used total eGFR slope, an endpoint that has gained increasing acceptance as a surrogate marker of CKD progression and is accepted by FDA in DKD and non-DKD populations. This approach is supported by a meta-analysis of 66 randomized trials showing a strong association between treatment effects on eGFR slope and hard kidney outcomes, including sustained ≥57% eGFR decline and kidney failure (Inker LA et al, Nature medicine 2023). 

The GFR slope is very familiar to previous trials. Despite slight differences in the definition of the acute phase (4 months in FIDELIO versus 3 months in FIND-CKD), both studies showed the same biphasic pattern: an early hemodynamic eGFR dip followed by a slower chronic decline in kidney function. In FIND-CKD, finerenone improved the total eGFR slope by 0.7 mL/min/1.73 m²/year, similar to FIDELIO. Together, these findings suggest that this characteristic eGFR trajectory is an intrinsic effect of finerenone rather than a diabetes-specific phenomenon. The overall kidney effect was still far from 'remission in CKD' however.

One of the most consistent findings across studies of finerenone is the early and sustained reduction in albuminuria. In FIDELIO-DKD (Barkis GL et al, N Engl J Med 2020) and FIGARO-DKD (Pitt B et al, N Engl J Med 2021), finerenone reduced UACR by approximately 31% and 32% versus placebo, respectively. Similarly, FIND-CKD demonstrated a 35.4% placebo-corrected reduction in UACR at 6 months, indicating a similar antiproteinuric effect regardless of diabetes status. The clinical trials of finerenone across the spectrum of CKD are shown in the table below:  

Safety data was similar to what we have seen with other trials with finerenone. Hyperkalemia remained the main adverse event associated with finerenone (17.0% vs. 13.3%), but serious events were rare (1.0% vs. 0.6%), no fatal hyperkalemia occurred, and treatment discontinuation due to hyperkalemia remained uncommon (1.5%). 

FIND-CKD attempted to answer one important question—but immediately raised the next one.  If finerenone works in non-diabetic CKD (probably by targeting shared mechanisms of CKD progression), should we still think in terms of adding therapies one by one? Or is the future an upfront combination strategy with a flozins, similar to what is proposed in DKD? (CONFIDENCE trial, Agarwal R et al, New Engl J Med 2025 | NephJC Summary). Additionally, are we now heading into ‘GDMT’ like 4 pillars in non-DKD as well? Apart from RASi, flozins, now finerenone, we also have preliminary data from GLP1RAs on albuminuria (Apperloo et al Nat Med 2025) and GFR (Colhoun et al Nat Med 2024). To reiterate - this mostly applies to proteinuric CKD - in patients who are beyond the initial immunosuppression window. Also read the accompanying NephJC Short for discussion of the GN subgroup and INFINITY analysis.

Lastly - where does this leave spiro-stans? The authors disparagingly quote BARACK-D (Hobbs et al, Nat Med 2024 | NephJC commentary). There has also been the recent SPIRRIT-HF trial (Design: Lund et al EJHF 2025) which did not report a benefit. Though we await final publication, just like BARACK-D, most patients in this trial did not stay on spironolactone. This has been a frustrating few years in futile spironolactone trials, and it is possibly time to move on. Only the onset of ASIs may threaten to dethrone the expansion of finerenone indications across the CKM space.

Conclusion

Finerenone clearly slows progression of GFR decline in (mostly proteinuric) non-diabetic CKD, similar to effects in DKD, and is safe to use. Access and implementation will remain important barriers.

Summary by

Andreea Manolea, Nephrology resident, Clinical Hospital "Dr. C. I. Parhon" Romania

Smita Divyaveer,
Associate Professor,
Department of Nephrology,
PGIMER, Chandigarh, India

Reviewed by 

Akshaya Jayachandran, Brian Rifkin, Swapnil Hiremath,
Cristina Popa, Pallavi Prasad, Milagros Flores

Header created by AI from prompts by Brian Rifkin

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]]>Beyond Diabetic Kidney Disease: FIND-ing Finerenone's Next RoleVisual AbstractMilagros FloresFri, 17 Jul 2026 21:24:40 +0000http://www.nephjc.com/news/2026/7/17/find-ckd-the-visual-abstract535bcb2fe4b05fe61b320c51:535bd92ae4b0a78001c0e260:6a5a635204458c5f833eec7cIs finerenone ready to move beyond diabetes?

The FIND-CKD phase 3 arrived from the #ERA26 and is the first one to show kidney protection with finerenone in non-diabetic CKD.

The next challenge is no longer whether finerenone belongs in non-diabetic CKD, but how to best combine with the rest of the pillars to maximize protection.

Check out the newest VA created by our intern Raquel Barba

Low-Dose Rivaroxaban and Cardiovascular Events in Advanced Kidney Disease:

The TRACK Randomized Clinical Trial

Sunil V. Badve, PhD; Vlado Perkovic, PhD; Vivekanand Jha, MD; Raja Ramachandran, DM; Lily Mushahar, MMed; Jan Menne, MD; An S. De Vriese, PhD;Patrick Rossignol, PhD; Adrien Flahault, MD; Maha Al Ammari, MPH; Habib Skhiri, PhD; Michael Walsh, PhD; David Collister, PhD; Adrian Liew, MD;Laurent Billot, MRes; Severine Bompoint, BSc; Anthony Devaux, PhD; Min Jun, PhD; Enmoore Lin, PhD; Aline Ramos da Cruz, BBA; Jeffrey T. Ha, PhD;John W. Eikelboom, MBBS; Ahmed Shaman, PhD; Meg J. Jardine, PhD; Shilpanjali Jesudason, PhD; Muh Geot Wong, PhD; Craig S. Anderson, PhD;Amit X. Garg, PhD; Hiddo J. L. Heerspink, PhD; Helen Monaghan, BSc; Anushka Patel, PhD; Patrick B. Mark, PhD; David C. Wheeler, MD; Jicheng Lv, PhD;Li Zuo, PhD; Helen Pilmore, MD; Martin Gallagher, PhD; for the TRACK Trial Investigators

PMID: 42240165

DOI: 10.1001/jama.2026.9379

Introduction

The concept of cardiovascular nihilism in advanced kidney disease stems from a paradox: heart disease is the leading killer in end-stage kidney disease, yet standard cardiological interventions consistently fail. While statin therapy reduces events in the general population, the AURORA (Fellstrom BC et al, NEJM, 2007) and 4D (Wanner C et al, NEJM, 2005) trials proved that aggressively slashing cholesterol was associated with zero reduction in cardiovascular death or strokes on dialysis. Similarly, the ISCHEMIA-CKD trial shattered the belief that mechanical intervention could fix the pathophysiology, revealing that immediate invasive revascularization failed to lower death rates and instead triggered a four fold increase in strokes (Bangalore S et al, NEJM, 2019| NephJC summary). In the uremic milieu, traditional lipid-driven and macrovascular models of heart disease stop applying. 

Driven by these failures, the scientific narrative shifted toward targeting hypercoagulability. Landmark trials in broader populations offered hope: COMPASS (Eikelboom JW et al, NEJM, 2017) demonstrated that adding low-dose rivaroxaban to aspirin significantly reduced major adverse cardiovascular events (MACE), with subanalyses hinting at greater benefits in mild-to moderate CKD (Fox KAA et al, JACC, 2019). This was reinforced by the VOYAGER PAD trial (Bonaca MP et al, NEJM, 2020), which proved that dual pathway inhibition decreased ischemic limb and cardiovascular events after peripheral revascularization, and the ATLAS TIMI ACS 51 trial, which showed a reduction in composite of cardiovascular death, myocardial infarction and stroke along with a significant reduction in risk of secondary outcome of stent thrombosis post-acute coronary syndrome (Mega JL et al, NEJM, 2012). 

However, these practice-changing trials systematically excluded patients with stage 4 or 5 CKD and those on dialysis. Clinicians were caught in a dangerous blind spot: the KDIGO heat map definitively illustrates that as eGFR drops and albuminuria rises, CV risk skyrockets into the deepest red zone (KDIGO CKD guidelines 2024I NephJC Summary). 

Yet, advanced kidney disease simultaneously induces severe platelet dysfunction and elevates the bleeding risk(Genovesi S et al, NDT, 2024). Doctors were forced to extrapolate data from healthier cohorts, flying blind without knowing if the ischemic protection seen in COMPASS, VOYAGER, and ATLAS would be wiped out by devastating hemorrhagic complications. 

The evidence gap justifies the need for the TRACK trial, which puts low-dose rivaroxaban to the test in patients with stage  4 or 5 CKD, including those on dialysis. 

The Study 

Study design

Investigator-initiated, randomized, quadruple-blind, placebo-controlled trial

Methods

The study was conducted at 90 centers in 12 countries (Australia, Belgium, Canada, France, Germany, India, Malaysia, Nepal, Saudi Arabia, Singapore, Taiwan, and Tunisia). The enrollment of patients was from January 18, 2021, to July 31, 2025. The trial was stopped early on August 7, 2025, based on the recommendation of the data and safety monitoring board, and final follow-up occurred on October 30, 2025.

Funding

The major funding was provided by the National Health and Medical Research Council (NHMRC) Australia project grant, and additional funding was supplied by other participating centers. All funding was approved by the International Coordinating Centre for the George Institute of Global Health. Rivaroxaban and placebo tablets were provided by Bayer AG free of cost through the Investigator-Initiated Research Support Scheme. The funders had no role in the design and conduct of the study, the data collection, management, analysis, or interpretation of the data, the preparation or review of the manuscript, or the decision to submit for publication. 

Study population

Eligible participants were adults aged 18 or older with advanced CKD, defined as CKD stage 4 or 5, including those with dialysis-dependent kidney failure. All participants were required to have at least one additional cardiovascular risk factor, which could include established coronary artery disease, non-hemorrhagic non-lacunar stroke, peripheral artery disease, diabetes, or age 65 or older. Atrial fibrillation (AF) was not an inclusion criterion, but an exclusion criterion (see below). 

Key exclusion criteria included mechanical/prosthetic heart valve, anticoagulation indication/contraindication, high bleeding risk or active bleeding, P2Y12 or phosphodiesterase inhibitor use, prior hemorrhagic/lacunar stroke, severe heart failure (EF < 30% or NYHA III/IV), hemoglobin < 90 g/L, thrombocytopenia, uncontrolled hypertension or a functioning kidney transplant. Patients with AF were excluded unless anticoagulation was not indicated.

Run-In Phase and Randomisation 

Eligible patients were given a placebo for 21 days; the patients who were deemed to have < 80% adherence were excluded from the study (NephTrials on run-in periods for more). Randomization was performed through a web-based password-protected system, using a covariate-balancing adaptive allocation algorithm. The algorithm was designed to minimize between-group imbalances across four pre-specified stratification variables: diabetes, CKD stage, dialysis-dependency and aspirin use. Participants were allocated in a 1:1 ratio to receive either rivaroxaban 2.5 mg twice a day or matching placebo. All participants, investigators, study coordinators, site pharmacists, treating physicians, and outcome assessors were blinded to treatment allocation throughout the trial. 

Outcomes

The primary efficacy outcome was a MACE composite of cardiovascular death, nonfatal MI, nonfatal stroke, or nonfatal peripheral artery disease event. The outcome was assessed by two investigators who were blinded; one was an on-site investigator and another member of the independent clinical outcome review committee (CORC).

Secondary outcomes included all-cause mortality; individual components of the primary composite outcome; a composite of CV death, MI, or stroke; a composite of infarction, stroke, or peripheral artery disease event; and venous thromboembolism. All deaths were adjudicated similar to the primary outcome.

The net clinical benefit outcome, initially classified as a secondary outcome, (later converted to a non secondary outcome before data review) was defined as a composite of CV death,nonfatal MI,non fatal stroke, a nonfatal peripheral artery disease event, fatal bleeding, or symptomatic bleeding into a critical area or organ. 

Tertiary outcomes were thrombosis of dialysis vascular access among participants with AVF or AV graft and health-related quality of life (QOL) using EuroQ-5D-5L and cost-effectiveness. Cost effectiveness and EQ5D-5L were reported after getting complete data.

Safety outcomes were major bleeding (modified iSTH criteria: fatal bleeding, critical organ bleeding, bleeding requiring reoperation, or bleeding leading to hospitalization) and gastrointestinal bleeding. All bleeding was adjudicated by the CORC.

Additional data: Race and ethnicity were collected from the participants, as Asians are more prone to bleeding (Liang Y et al, JACC Asia 2024) and other comorbidity data were collected from medical records.

Statistical considerations

This trial planned to enroll 1900 participants over 3 years, with a follow-up period of 5 years. Assuming a control group primary event rate of 10 per 100 person-years, this sample size would provide a 90% power to detect a 25% relative risk reduction (hazard ratio 0.75) with a two-sided type I error rate of 5%. It was planned to conduct two equally spaced interim analyses with Haybittle-Peto efficacy boundaries, corresponding to a Z value of 3 standard deviations at each interim analysis. This yielded two-sided significance levels of 0.27% for each interim analysis and a final significance level of 4.82%. A total of 515 primary outcome events were required to achieve 90% power, and this number of events provided 80% power with a 22% relative risk reduction (HR 0.78).

All analyses were conducted according to the intention-to-treat principle. The primary outcome was analyzed as the time from randomization to the first event using a shared frailty Cox proportional hazard model with a random site effect, adjusted for the three stratification variables: 1) baseline aspirin use, 2) dialysis dependency and 3) diabetes. The final significance level was set at a 2-sided alpha of 4.86%, accounting for 1 interim analysis performed after 181 events. 

The secondary outcome was also analyzed using the same Cox model. To control the family-wise error rate at 5% across the five key secondary outcomes—all-cause death and the four individual components of the primary composite—a Holm-Šídák step-down approach was applied. For the remaining secondary outcomes, no formal hypothesis testing was performed; only point estimates and 95% confidence intervals were reported. The proportion of adverse events, such as bleeding and severe adverse events, was analyzed using the Fisher exact test.

Results

Of 5,979 prescreened patients, 1,777 met initial eligibility criteria. After the run-in phase, 1,463 patients were randomized. Median follow-up was 1.7 years, with 93% completing the follow-up assessment. Loss to follow-up was minimal and similar in both groups (4% lost contact, 2.3% withdrew consent).

The enrolled cohort was predominantly male (70%), had a mean age of 63 years, and nearly half (49%) had dialysis-dependent kidney failure. Most patients had diabetes (78%) and almost half (47%) were aged >65 years. Only 18% had established coronary artery disease and 6.6% had peripheral artery disease. Roughly two-thirds of the cohort met inclusion criteria based solely on diabetes or age, rather than prior CV disease. Aspirin use was identical between the arms (approximately 46%). Geographic representation was heavily concentrated in India and Malaysia (41.5% and 21%, respectively) (eTable 3 from Badve S et al, JAMA 2026)

The trial was stopped early (Aug 2025), after 254 primary outcome events had occurred (49.3% of the 515 anticipated events). The Data and Safety Board recommended termination due to concerns about net harm. 

Primary outcome

The primary composite outcome occurred in 164 patients (23%) receiving rivaroxaban vs 151 (21%) receiving placebo. This translated to 13 vs 11.8 events per 100 person-years, with a hazard ratio of 1.09 (95% CI 0.87-1.36). Rivaroxaban showed no benefit.

Subgroup analyses confirmed uniformity of the null effect. Across age, sex, country, aspirin use, diabetes, CKD stage, and smoking history, no subgroups showed benefit. Aspirin use at baseline did not modify the treatment effect (HR 1.06 among aspirin users vs 1.11 among non-users).

Mortality 

All-cause mortality showed no difference. In the rivaroxaban group, 25.6% died compared with 23% in placebo- 13.9 versus 12.4 events per 100 person-years (HR 1.14, 95% CI, 0.92-1.40). There were 18 more deaths in the rivaroxaban group overall. 

The competing risk analysis examined whether the high non-cardiovascular death burden distorted the primary outcome estimate. Accounting for the non-cardiovascular death as a competing event yielded a subdistribution HR of 1.08 (95% CI 9.86-1.34) for the primary outcome. As regards the cumulative mortality (eFigure 1) at 48 months, the rivaroxaban curve remained above placebo (51% vs 47%)

The breakdown of mortality causes (eTable 4 below) showed that 60% were cardiovascular deaths in the rivaroxaban arm. Sudden cardiac death, occurring outside the 30-day window after acute MI, dominated both groups (40% in the rivaroxaban arm vs 45% in the placebo arm). Infections were the leading non-CV cause, followed by renal failure and other organ-system failures. 

Secondary outcomes

Individual components of the primary outcome were comparable between the two arms. Additionally, when the events were recombined into secondary composite endpoints, rivaroxaban showed no advantage across any configuration (Table 2 below).

Venous thromboembolism

Fewer VTE events occurred on rivaroxaban than on placebo (0.6% vs 1.9%), with aHR 0.29, 95%CI 0.09-0.87.

Among patients on hemodialysis, access thrombosis occurred more frequently on rivaroxaban (7.6% vs 5.4%), but the result was not significant (HR 1.44, 95% CI, 0.75-2.74).

Safety outcomes: major bleedings

Major bleeding events occurred more in the rivaroxaban group (8.8% vs 6%), with a HR of 1.51 (95% CI 1.02-2.22).

The sites and characteristics of major bleeding are detailed in eTable5 (below). The gastrointestinal tract was the most common site. These events included overt bleeding confirmed by endoscopy, overt bleeding of unknown origin, and presumed occult bleeding with hemoglobin decrease.

Intracranial and intraocular bleeding were numerically higher in the rivaroxaban group. Fatal bleeding occurred in 1 patient on rivaroxaban and 2 patients in the placebo group.

Bleeding by age

Major bleeding risk showed significant age interaction (eFigure 5 below). In patients ≥65 years, major bleeding occurred in 10% on rivaroxaban vs 5.6% on placebo. In those <65 years, the rates were lower (rivaroxaban 7.3% vs 6.4% in placebo) and comparable.

Net clinical benefit 

The net clinical benefit outcome (composite of cardiovascular events and fatal/critical bleeding events) was comparable between the two arms  (24.2% rivaroxaban vs 21.3% placebo, HR 1.14, 95% CI 0.92-1.41- details in Table 3 above)

Serious adverse events 

They were similar between the groups. Infections were the most common (17.6% rivaroxaban vs 18.1% placebo). Overall, 50.5% of rivaroxaban patients and 45.8% of placebo patients experienced ≥ 1 serious adverse event.

Discussion

TRACK randomized more than 1400 patients with CKD stage 4, 5 or dialysis-dependent kidney failure, enriched for CAD, prior stroke, PAD, diabetes, or age 65 and older, to rivaroxaban 2.5 mg daily or placebo. The question was whether the “vascular dose” anticoagulation in COMPASS (Eikelboom JW et al, NEJM, 2017) and VOYAGER PAD (Bonaca MP et al, NEJM, 2020) would be of benefit to a population with advanced CKDs, and… it wasn’t. The primary MACE composite (CV death, MI, stroke, and PAD event) was not significantly different in rivaroxaban vs placebo (22.6% vs 20.7%). What’s even worse, major bleeding was higher on rivaroxaban, so this was not a benign intervention. The DSMB stopped the trial early after a post hoc conditional-power calculation put the chance of eventual benefit at 16% with a HR of 0.78 even if the trial continued till the pre-specified 515 primary events. Net clinical benefit, the composite meant to weigh efficacy against safety, was also negative. The study excluded patients with a clear indication for anticoagulation; rather, it tested whether across the board anticoagulation was worthwhile in high-risk CKD patients whose vasculature has already been modified by uremia. 

Context

The vascular-dose approach isn’t new. ATLAS TIMI 51 (Mega JL et al, NEJM, 2012) identified 2.5 mg twice daily as the dose that balanced antithrombotic benefit against bleeding, and a pooled analysis of seven trials across over 45,000 patients with CAD or PAD found low-dose rivaroxaban added to antiplatelet therapy reduced CV events (HR 0.86, 95% CI 0.78-0.94) and ischemic stroke (Bucci T et al, J Clin Med, 2024). Trials like COMPASS (Eikelboom JW et al, NEJM, 2017) and VOYAGER PAD (Bonaca MP et al, NEJM, 2020) enrolled patients with established atherosclerotic disease. TRACK’s population looked different: only ~19% had coronary disease, ~ 6% had prior stroke, ~6% had PAD, and 57% qualified on the strength of a single risk factor, usually age or diabetes alone (eTable 3). Either way, this looks closer to a primary-prevention population that the trials TRACK was built to extend, and it points to a precedent worth naming directly: aspirin’s own run of primary-prevention trials a decade earlier. Three trials tested low-dose aspirin for primary cardiovascular prevention in similarly enriched, disease-free populations. ASCEND, in adults with diabetes and no prior cardiovascular disease, found a 12% relative reduction in vascular events “largely counterbalanced” by a 29% increase in major bleeding, in the authors’ own phrasing (The ASCEND Study Collaborative Group, NEJM, 2018). ASPREE, in adults 70 and older without prior cardiovascular disease, found daily aspirin gave no cardiovascular benefit and significantly increased major hemorrhage (McNeil JJ et al, NEJM, 2018). ARRIVE, in moderate-risk adults without diabetes, found that aspirin had neither benefit nor safety (Gaziano JM et al, Lancet, 2018). None of these 3 trials used rivaroxaban or any other DOAC. But TRACK’s age and diabetes-heavy cohort sit roughly in the territory they mapped, and a different antithrombotic drug, tested there again, produced the same shape of result: no measurable protection and hemorrhagic side effects.

Guidelines

KDIGO’s 2024 CKD guideline draws a sharp line between two questions it treats differently. (KDIGO CKD Work group, Kidney Int, 2024| NephJC summary). For secondary prevention- aspirin in people with established CVD- it gives a strong graded recommendation (1C), built on Antithrombotic Trialists’ Collaboration meta-analysis: a roughly 19% relative reduction in serious vascular events (RR 0.82, 95% CI 0.75-0.87) (ATT collaboration, Lancet, 2009). For primary prevention, aspirin in people at high risk without established disease (the category TRACK mostly falls into), KDIGO issues no graded recommendation at all, only a call for more research. Its reasoning was that ASCEND, ASPREE, and ARRIVE all showed bleeding harm counterbalancing aspirin’s CV benefit. A CKD-specific Cochrane meta-analysis of more than 40,000 participants in antiplatelet versus placebo trials found similar results: MI reduced (RR 0.88, 95% CI 0.79-0.99), major bleeding increased (RR 1.35, 95% CI 1.10-1.65)- though that analysis didn’t separate primary from secondary prevention (Natale P et al, Cochrane Database Sys Rev, 2022).

The answer is “No”

Advanced CKD is often described as a state where clotting and bleeding risk rise together. The mechanism implies uremic toxins impair platelet adhesion and drive endothelial nitric oxide and prostacyclin production that further suppresses clotting, leaving CKD patients roughly 1.5 times more likely to bleed than people with normal kidney function, independent of antithrombotic use (Ocak G et al, J Thromb Haemost, 2018). Hemodialysis adds a further 1.5-fold risk over peritoneal dialysis (van Eck van der Sluijs A et al, NDT, 2021), and roughly one in seven older patients on dialysis has a major bleed within 3 years of initiation (Sood MM et al, Kidney Int, 2013). TRACK asked a fair question and got a clear answer. Rivaroxaban didn’t protect against clots, and it increased bleeding~ extra 1.7 events per 100 patients-years(Table 3). The only positive, VTE (HR 0.29), is more a pharmacological note- with what clinical significance? The bleeding risk fell hardest on patients 65 and older (interaction P = .03), the group most likely to get this drug in clinical practice.

On a less nihilistic view, a negative, well-done trial like TRACK is an answer. The mechanism was plausible, the drug worked in other settings, and the patients carried a real risk- reason enough to run the trial. The result, rigorously tested and honestly reported, is worth as much as a positive one: it tells clinicians where not to engage in speculative benefit when there is significant risk of harm. Aspirin’s primary prevention trials reached a similar answer a decade ago, in a different population, with a different drug. TRACK adds a boundary, drawn a second time in roughly the same place - here is where “thin the blood, protect the vessel" stops working.

Strengths

TRACK trial was a dedicated, investigator-initiated, randomized, double-blind, placebo-controlled trial across 90 centers in 12 countries, enrolling adults with CKD stage 4 or 5, including dialysis. Randomization was stratified and blinded at all relevant levels, with a covariate-adaptive algorithm balancing key prognostic factors. Prespecified outcomes were adjudicated by an independent clinical outcomes committee (essential when effects are modest and noise is abundant).

Limitations

The trial was powered for 1900 participants and 515 primary events, but it stopped early at 1463 randomized patients based on DSMB recommendation for futility (conditional power ~ 16% for HR 0.78), not a prespecified efficacy boundary. Follow-up was a median of 1.7 years, shorter than planned, and formal tablet counts were disrupted by COVID-19, though self-reported adherence was collected. Permanent discontinuation was 28%, which likely attenuated any true effect. The confidence interval for the primary outcome (0.87-1.36) rules out a large benefit but leaves modest effects uncertain. 

About generalizability: there were no US patients and almost no Black patients. Regional variation was observed (Australia/Europe/Canada- for primary outcomes: HR 1.82, 95% CI 1.02-3.22), but interaction tests were not significant, and this was an unadjusted subgroup comparison, hypothesis-generating only.  Nearly 40% of all-cause deaths in both arms were sudden cardiac death, a category that no anticoagulant was likely to prevent, which sets a biological ceiling on what this class could achieve. Minor bleeding was not collected, and quality-of-life data are deferred to a separate report. While 46% of patients were on aspirin at baseline, the trial did not mandate aspirin nor test the fixed combination- unlike COMPASS and VOYAGE PAD. 

Conclusion

TRACK doesn’t solve advanced CKD’s oldest problem- a body where treating one risk worsens another, with no drug built for that narrow ground. It settles the case against rivaroxaban. Unfortunately, push clotting down, and bleeding rises to meet it: the scales of hypercoagulability and excessive bleeding are never completely balanced. The boulder keeps returning to the bottom by a different route, and no antithrombotic strategy tried so far has gone over the hill instead of around it. That may be the shape of the answer for this population: something closer to a limit than a solution, since one antithrombotic therapy alone was always going to run up against the complex CKD pathophysiology. 

Summary by, 

Cristina Popa

and Sai Vani Yellampalli

Reviewed by Brian Rifkin, Pallavi Prasad, Swapnil Hiremath

Telitacicept for IgA Nephropathy - Interim Analysis of a Phase 3 Trial

Jicheng Lv, M.D., Lijun Liu, M.D., Wenxiang Wang, Ph.D., Xinyue Wang, Ph.D.,Qing Zuraw, M.D., Vlado Perkovic, M.D., Ph.D., Jianmin Fang, Ph.D.,and Hong Zhang, M.D., Ph.D., for the TELIGAN Investigators

PMID:  42127391

DOI:10.1056/nejmoa2514415

Why was this study needed?

We’re at quite an interesting juncture in IgAN therapeutics. Five years ago, we were still debating what dose of steroids should remain in the conversation after TESTING | (NephJC Summary). Today, the challenge is almost the opposite: there are so many promising therapies that reduce proteinuria, and the question is which drug to select and which pathway to target for which patient.

We’ve seen targeted-release budesonide (NefIgArd) | (NephJC Summary) focus on the gut mucosal immune system. Complement inhibition entered the scene with Iptacopan (APPLAUSE - IgAN) | (NephJC). More recently, APRIL-directed therapies such as sibeprenlimab (VISIONARY) | (NephJC Summary) and atacicept (which is dual BAFF-APRIL, ORIGIN) | (NephJC Summary | Podcast) have delivered striking reductions in proteinuria. Telitacicept now joins this increasingly crowded field,  sharing the distinct biological proposition of atacicept: simultaneous blockade of both BAFF and APRIL rather than targeting either pathway alone.  

With a slew of drugs already approved for IGAN, why does this trial matter?

BAFF and APRIL signaling sit in the space of B-cell survival, plasma-cell maturation, and immunoglobulin production. Elevated levels of both cytokines have been linked to IgAN activity. Telitacicept is essentially a soluble TACI-Fc fusion protein that acts as a decoy receptor, binding both BAFF and APRIL simultaneously. Theoretically, this should reduce production of pathogenic galactose-deficient IgA1 and downstream immune complex formation. The TELIGAN trial asks a direct question - exactly the same as with ORIGIN (atacicept): can dual BAFF/APRIL inhibition meaningfully alter disease activity (in the form of proteinuria and GFR stabilization) in high-risk IgAN? This question has been asked and answered for various groups of drugs in IgAN. After atacicept, do we need another -tacicept? Why not - the more the merrier! So, hit me baby one more time.

How was the study done and what did it find?

TELIGAN is a phase 3, multicentre, double-blind, placebo-controlled study conducted across 72 centres in China. They included adults with biopsy-proven IgAN, UPCR ≥0.5 g/g, eGFR ≥30 mL/min/1.73 m², and persistent proteinuria despite ≥12 weeks of maximally tolerated RAS blockade. This paper represents a prespecified interim analysis (stage A) focused on proteinuria at 39 weeks, while the ongoing stage B will evaluate longer-term kidney function outcomes through 104 weeks. The trial is being funded by Remegen (the company manufacturing telitacicept).  If you have read any of the IgAN trials linked above, feel free to skip the methods, they are almost a CTRL-C/CTRL-V of each other. 

A total of 318 adults with biopsy-proven IgAN were randomized 1:1 to weekly subcutaneous telitacicept 240 mg or placebo on a background of standard of care. Patients had persistent proteinuria despite optimized Renin Angiotensin System(RAS) blockade, eGFR ≥30 ml/min/1.73m², and were not receiving glucocorticoids or other immunosuppressive therapies. About one-third were already flozinated, reflecting contemporary practice. Unlike RAS blockade, flozination was allowed, but not required as part of standard of care. 

The primary endpoint for this analysis was reduction in 24-hour urinary protein-creatinine ratio at week 39.

What were the results?

The mean age was 38 years, with women comprising just over 50% of the study population. Mean eGFR was around 75 mL/min/1.73 m², and the median baseline 24-hour urinary protein-to-creatinine ratio was 1.26 g/g. Approximately 1/3rd of participants had eGFR < 60 mL/min/1.73 m². Histologic characteristics showed  M1 lesions present in ~79% and crescents (C1/C2) in ~45% of patients with available biopsy data. Around 70% had hematuria. All patients were receiving background RAS blockade at randomization. 

At 39 weeks, proteinuria fell by 58.9% with telitacicept compared with only 8.8% with placebo, with a relative treatment effect of −55% (95% CI −61.3 to −47.6; P<0.001). Separation from placebo appeared as early as week 4 and continued to widen over time. Equally striking was the proportion achieving a UPCR below 0.8 g/g: 61% with telitacicept versus only 19.5% with placebo.  

Mean eGFR was essentially preserved in the telitacicept group (−1.0%) while declining in the placebo arm (−7.7%) over 39 weeks. Likewise, fewer patients experienced a ≥30% eGFR decline (6.3% vs 27%).  Interestingly - in China they are allowed to present GFR data at this stage (you may note that the ORIGIN atacicept phase 3 trial suppressed that - the FDA only allows that to be analysed at 2 years).

The clinical response was also accompanied by pharmacodynamic effects. Circulating CD19-positive B cells fell by nearly 50%, while immunoglobulin levels declined substantially. Serum IgA levels decreased by approximately 60%, supporting the notion that the drug is engaging the intended disease pathway.

The overall adverse event rate was higher with telitacicept (89% vs 79%), largely driven by injection-site reactions and expected immunoglobulin reductions. Serious adverse events were actually less frequent with Telitacicept (2.5% vs 8.2%). Infection rates were broadly similar between groups. No deaths occurred. With regard to the HBV data, among 68 patients with latent hepatitis B infection, no reactivation occurred in those receiving Telitacicept during the 39-week study period. For clinicians practicing in Asia, where latent HBV is common, this is clinically relevant, although the sample size and follow up remains modest at this time.

WHAT ARE THE IMPLICATIONS?

TELIGAN shows that telitacicept produces one of the greatest reductions in proteinuria seen in contemporary IgAN therapeutics - similar to what was seen with sibeprenlimab and atacicept. The effect is consistent across subgroups, appears within four weeks, and is accompanied by reductions in circulating B cells, immunoglobulins and serum IgA, engaging a central pathogenic pathway in IgA nephropathy. This is also supported by the fall in hematuria (post-hoc analysis) from ~71% to ~21% with telitacicept and essentially unchanged with placebo. This matters because proteinuria can improve through hemodynamic mechanisms, but hematuria is often considered a marker of active glomerular inflammation, and since telitacicept improves both, it could be a disease-modifying effect. Given all these strengths, the enthusiasm generated by TELIGAN is understandable 

This remains a short term proteinuria reduction data report however (like all recent IgAN trials). The kidney function data are encouraging but shouldn’t be overinterpreted. The apparent eGFR preservation and lower frequency of a 30% eGFR fall favour telitacicept, but these were secondary analyses, the study was not powered for kidney outcomes and is just an interesting sidenote - we have to await 2 year GFR data (same as with other IgAN new therapeutics).

When we compare it with other phase 3 IgAN trials, we get an interesting context. Unlike ORIGIN, VISIONARY and APPLAUSE-IgAN, which enrolled multinational cohorts, TELIGAN was conducted exclusively in a Chinese population. Patients in TELIGAN were randomized a median of more than four years after biopsy, compared with around 2.5 years in ORIGIN and 1.5 years in VISIONARY and APPLAUSE-IgAN. 

Baseline proteinuria was among the lowest across these studies (median UPCR ~1.3 g/g in TELIGAN and VISIONARY,  ~1.9 g/g in APPLAUSE-IgAN, and ~2.2 g/g in ORIGIN). Also, this was also a well-treated cohort - with baseline standard of care similar to other IgAN trials (with supportive/palliative therapies). All patients received optimized RAS blockade and 35% were already receiving SGLT2 inhibitors, compared with 50% in ORIGIN, 40% in VISIONARY and 12% in APPLAUSE-IgAN. This suggests that the study population consisted of patients with established, persistent IgAN.

Again, with established disease and already on baseline RASi/ some SGLT2i,  the placebo arm still achieved an 8.8% fall in proteinuria. The numerically greater decrease in proteinuria with telitacicept than all other trials cannot be signal - comparing across studies with heterogeneous populations is fraught with uncertainty.

At present, it is difficult to know whether dual BAFF/APRIL blockade represents a genuine therapeutic advance over selective APRIL inhibition or simply another effective approach targeting the same biological pathway. As direct comparative trials are unlikely until several years from now, this question will probably be answered gradually through accumulating clinical experience and longer-term outcome data. While telitacicept may (or may not) make it to European or North American populations - would Chinese pharmaceutical companies be interested in making these drugs available in other parts of the world - especially across Asia where IgAN is so prevalent and where only steroids are available so far? Will they make it cheaper than sibeprenlimab, atacicept et al? One can hope. 

BOTTOMLINE?

TELIGAN is a well designed phase 3 study that delivers a remarkably consistent and biologically plausible treatment signal. The magnitude of proteinuria reduction is among the largest reported in IgAN, seems to have a convincing target engagement, and the short term safety profile appears acceptable

By

Akshaya Jayachandran

Reviewed by 

Brian Rifkin, Cristina Popa and Swapnil Hiremath

A secondary analysis of the TESTING trial predicted individual patient response to corticosteroid treatment in IgA nephropathy

Mark Canney 1, Sana Shan 2, Lee Er 3, Laurent Billot 2, Jialin Han 4, Muh Geot Wong 5, Helen Monaghan 2, Michelle Hladunewich 6, Lai Seong Hooi 7, Vivek Jha 8, Jicheng Lv 9, Vlado Perkovic 2, Hong Zhang 9, Daniel C Cattran 10, Sean J Barbour 11; TESTING trial steering committee

PMID: 41571096

Why was this study done? 

The TESTING trial (Lv et al, JAMA 2022| NephJC summary) is the largest RCT of corticosteroids in IgA nephropathy (IgA) with 503 adults with proteinuria ≥1 g/d on optimized RAS blockade. Oral methylprednisolone halved the risk of the composite kidney endpoint (HR 0.53, 95% CI 0.39–0.72), with an absolute risk reduction of 16.1% at 4 years. These results were quite impressive. However, the study also showed significant toxicity with corticosteroids, which led to a mid-trial protocol revision from full dose (0.6–0.8 mg/kg/d) to a reduced-dose regimen (0.4 mg/kg/d). The clinical conundrum is the effectiveness of a treatment in an IgAN population with heterogeneous risk and variable drug tolerability. The finding of 47% relative risk reduction is an average across many individuals who likely differ substantially in their clinical risk and disease progression patterns. 

The principal question this post hoc analysis of TESTING is: Can we predict, for a given patient, what their individual absolute risk reduction from methylprednisone would actually be?

Now you may ask, why does this matter when we have so many other options for treatment of IgAN, when even more treatment options are appearing rapidly? Not surprisingly, because in many parts of the world steroids are all you have (apart from RASi, flozins, and possibly MRAs). Even if new therapies become available, they will be very expensive and less accessible, at least in the near future. Second, these methods are cool - exploring the heterogeneity of effects to draw some tentative conclusions for shared decision making. They apply to other intervention in different settings, so worthwhile trying to understand this methodology. 

How was the study done, and what did it show? 

This was a secondary analysis of 483 of the 503 TESTING participants (20 excluded for missing MEST-C or covariate data). The analytic approach followed the PATH statement in four steps:

• Cox proportional hazards model with backward elimination (P < 0.2) to select main-effect treatment effect modifiers

• Selected variables entered with treatment exposure and all treatment × variable interaction terms (no selection on interactions)

• Ridge regression applied throughout

• For each patient, predicted 4-year absolute risk generated under both treatment scenarios; the difference = individual ARR

The primary outcome was the same as TESTING: ≥40% eGFR decline, kidney failure, or death from kidney disease.

Study population

After backward elimination, the following variables were selected as main effects and forced into the model with interaction terms: eGFR, age, proteinuria, RAAS blockade dose, ethnicity, time from biopsy, systolic blood pressure, sex, BMI, T-score, and C-score (MEST-C).

Results 

This figure shows the point estimates for each interaction term (treatment multiplied by each variable) on the hazard ratio scale. Variables to the right of the dashed line are associated with a better response to methylprednisolone; variables to the left with a worse response.

Better response to methylprednisolone:

• Higher eGFR

• Male sex

• MEST-C score: T1/T2 (vs T0)

• MEST-C score: C1/C2 (vs C0)

Worse response to methylprednisolone:

• Higher proteinuria

• Higher RASi dose

• Chinese ethnicity

Minimal impact: Age, SBP, BMI, time from biopsy to enrollment. 

Of note, time from biopsy to enrollment had minimal impact on modifying treatment response, likely in part because most patients enrolled relatively soon after biopsy (median 5 months), limiting variability in this predictor.

This is the distribution of individual-level predicted 4-year absolute risk reduction across the entire cohort. The colors represent tertiles - lightest blue is the lowest tertile, darkest blue is the highest. So, what are tertiles? The model generates a predicted absolute risk reduction (ARR) for every patient. Then all 483 patients are ranked from lowest to highest predicted benefit and divided into three equal groups (tertiles) of 161. The lowest tertile contains patients predicted to benefit least, some are predicted to have no benefit or even harm. The highest tertile contains patients predicted to benefit most.

The key finding here is the broad spread of the predicted ARR ranging from about −10% to +40%, compared to the average of 16.1% (in the trial). This illustrates exactly why the average treatment effect is insufficient for individual decision-making. Patients at the left tail may experience no benefit or even harm from treatment, while those at the right tail have substantial benefit. Wouldn’t that be nice to know before you prescribe a given treatment?

This is the key clinical finding. The model was used to split patients into two groups: those with predicted ARR of 10% or less, and those with predicted ARR greater than 10%. Among patients predicted to have ARR greater than 10%, the observed ARR was 24% (95% CI 13% to 36%). That's a large, statistically significant benefit. Among patients predicted to have an ARR of 10% or less, the observed ARR was −5% (95% CI −25% to 15%). That's no benefit and the point estimate actually suggests possible harm.

Overall, the model successfully identifies a subgroup with no observed benefit and a subgroup with substantial benefit. The 10% threshold was chosen as a clinically meaningful treatment threshold, but this can be adjusted based on individual patient values and risk tolerance. For example, a risk-averse patient might want a higher threshold, while a risk-accepting patient might accept a lower one.

Two key metric performances were used: 

• Restricted mean survival time (RMST): If only patients with predicted ARR >10% were treated (targeted treatment policy), the RMST was 1,194 event-free days, compared with 1,028 days under random allocation. This gives 166 additional event-free days with targeted treatment.

• C-statistic for benefit: the C-statistic for benefit was 0.63 (95% CI 0.56 to 0.70). As discussed earlier, this should not be compared to the 0.7–0.8 threshold for prognostic models. The C-for-benefit predicts an inherently unobservable quantity (the individual treatment effect) which introduces fundamental noise. Values of 0.55–0.65 are considered meaningful. For context, the SYNTAX Score II, one of the best-validated benefit prediction models in all of cardiology, achieved a C-for-benefit of about 0.59. So, 0.63 is actually quite good for this type of metric. 

Lastly, calibration showed good agreement between predicted and observed ARR, with mild overestimation at the low end and underestimation at the high end. Sensitivity analyses across reduced and full-dose subgroups were consistent. eGFR slope analyses selected similar predictors. Notably, adverse events did not increase across predicted benefit tertiles, and patients predicted to benefit most did not experience more toxicity.

The PRED-IgAN tool

A web-based calculator is publicly available at www.gnpredict.com. Inputs include eGFR, age, proteinuria, RAAS blockade dose, ethnicity, time from biopsy, systolic BP, sex, BMI, T-score, and C-score. Output is a predicted 4-year ARR from methylprednisolone, which can be used with any clinician-chosen threshold in shared decision-making.

Here are two examples on PRED-IgAN in which the first patient is unlikely to benefit (low ARR) and the second patient is likely to benefit (high ARR).

What are the implications? 

This is the first individual treatment effect prediction tool for immunosuppression in IgAN, and it addresses a real clinical need. PRED-IgAN could help frame the risk-benefit discussion for patients, particularly relevant given that most patients likely fall in a zone of genuine equipoise for corticosteroids.

That said, important caveats deserve emphasis. The absence of external validation is the most significant limitation and, as the authors acknowledge, a second large corticosteroid RCT in IgAN is unlikely. The cohort is 74% Chinese, limiting generalizability to other populations. Overfitting risk persists despite ridge regression, given 483 patients and 174 events with many interaction terms. MEST-C scoring relied on local pathology reports without central review. Finally, the model predicts benefit, not individual-level harm so adverse event analysis remains at the group level.

Contextually, KDIGO 2025 now positions targeted-release budesonide (Nefecon) as first-line immunosuppression in IgAN, with systemic corticosteroids reserved for settings where budesonide is unavailable (grade 2B).

Yet corticosteroids remain the only accessible immunosuppressive option across much of the world.

For those contexts, PRED-IgAN offers a practical tool to optimize who receives treatment and who might reasonably be spared. One should remember that claims of Nefecon’s superiority or safety over prednisone have been made without any direct comparisons. Nefecon withdrawal can result in adrenal insufficiency (thus there is clear, significant systemic effects) as described by Laxamana et al Clin Kid J 2026. Even ordinary budesonide might be just as good as ‘targeted release’ budesonide for IgAN patients ( Jhaveri and Reich, KI Reports 2026). Even in places where it is available, the cost of Nefecon is prohibitively high, and it is always good to have cheaper and effective options.  

The question of whether a C-statistic for benefit of 0.63 is sufficient to change practice is fair, however perhaps the right framing is whether it improves on ‘doing nothing’. In a disease where the average ARR is 16% but individual responses are heterogeneous and toxicity is real, even modest discrimination has value. The model is best used not as an absolute gatekeeper, but as a conversation starter for shared-decision making. The treatment threshold, which is the minimum predicted benefit that justifies accepting the risks of corticosteroids, really depends on individual patient values. This is what personalized evidence-based medicine looks like in practice. The tool doesn't replace clinical judgment; it informs it with individualized data. 

Summary

ARR = absolute risk reduction; IgAN = IgA nephropathy; PATH = Predictive Approaches to Treatment effect Heterogeneity; RAAS = renin–angiotensin–aldosterone system; RMST = restricted mean survival time; RCT = randomized controlled trial.

Summary by Sumaiya Ahmed
Nephrology Fellow, University of Ottawa

Reviewed by Swapnil Hiremath, Brian Rifkin