The #NephJC crew landed on #KidneyWk, and the team is back to bring you the science behind the headlines! From Thursday through Saturday, we’ll be sharing selected highlights, focusing on late-breaking clinical trials with simultaneous publications.
For each study, we’ll unpack the findings, limitations, and consider what they could mean for kidney care. Whether you’re joining the meeting or following along online, pull up a chair and join the discussion.
We did this last year (link) with excellent feedback, so we are bringing it back. Swap and Cristina talked about the rationale (mostly FOMO!) and how this was done here.
Day 3 Studies (flozins dominate)
Povetacicept in IgA (RAINIER AIS D08) Barratt et al NEJM 2026
Empagliflozin therapy in patients with ADPKD, Selinger et al, JASN, 2026
Flozins increase Hgb: Metanalysis, Yang et al JAMA 2026
A post hoc analysis from CONFIDENCE on apparent treatment resistant hypertension, (Agarwal et al, JACC Advances 2026)
NEJM | Original article
Interim Analysis of a Phase 3 Trial of Povetacicept in IgA Nephropathy
Jonathan Barratt, Hong Zhang, Seung Hyeok Han, Yuzuke Suzuki, James Tumlin, Bobby Chacko, Irene L. Noronha, Arvind Madan, Raphael Duivenvoorden, Jamil R. Azzi, Carla Nester, Cassie Dong, Neil Ahluwalia, Jiahua Li, Carmen Bozic, Ogo Egbuna, Muh Geot Wong, and Richard Lafayette, for the RAINIER AIS-D08 Trial Group
Published October 23, 2026 DOI: 10.1056/NEJMoa2608682
Why was the study done?
Still with us? IgA nephropathy is not leaving the stage just yet. After targeting a complement with ravulizumab on day 2, we move back upstream to the antibody supply. Enter BAFF and APRIL—two signals that help sustain the B cells and plasma cells involved in producing pathogenic IgA. If those names sound familiar, atacicept, sibeprenlimab and telitacicept coverage might explain why! NephJC summary, TELIGAN
Povetacicept is an engineered TACI–Fc fusion protein that inhibits both BAFF and APRIL. The idea is to reduce galactose-deficient IgA1 and the immune complexes that set kidney inflammation in motion. Its enhanced binding properties are an interesting design feature; whether they deliver better clinical outcomes than dual inhibition or APRIL alone is a separate question.
While earlier trials provided an encouraging opening act, demonstrating UPCR reduction (RUBY-3, Madan et al, KI Reports 2026). The phase 3 RAINIER trial evaluates monthly dual BAFF/APRIL blockade to deliver proteinuria reduction with placebo, on top of supportive care? A different target, but can say the same immediate focus as ravulizumab.
What did they do?
This is a randomized, double-blind, placebo-controlled trial conducted at 224 sites in 29 countries. Adults had biopsy-confirmed IgA nephropathy, eGFR ≥30 mL/min/1.73 m², and persistent proteinuria ≥1 g/day or UPCR ≥0.75 g/g, despite stable background therapy. Participants were randomized 2:1 to subcutaneous povetacicept 80 mg or placebo every four weeks.
Figure S1, RAINER trial design, from Barratt, NEJM 2026
The main cohort included 557 participants, but only the first 199 randomized participants contributed to this interim efficacy analysis. The efficacy population was defined by sufficient opportunity for follow-up, not simply by selecting treatment completers; participants who discontinued early could still qualify.
The primary endpoint was changed in 24-hour UPCR at week 36. The secondary endpoints were Gd-IgA1 change and hematuria resolution among participants with hematuria at baseline.
Figure S1, RAINER enrollment diagram, from Barratt, NEJM 2026
What do the results say?
At week 36, UPCR decreased by 52.0% with povetacicept versus 4.3% with placebo, corresponding to an approximately 49.8% lower adjusted UPCR relative to placebo (95% CI, 39.2–58.6; P<.001).
Gd-IgA1 decreased by 77.4% with povetacicept, compared with a 9.1% increase with placebo. Among participants with baseline hematuria, 85% versus 23% met the resolution definition, an adjusted absolute difference of 62 percentage points. Both secondary endpoints were statistically significant.
In the safety population, overall adverse events occurred in 75% versus 78%, and serious adverse events in 3% versus 4%. However, infections were numerically more frequent (46% vs 41%), as were injection-site reactions (15% vs 2%). No deaths occurred.
Figure 1, Percentage change in 24-hour UPCR and in spot UPCR, from Barratt, NEJM 2026
How should we interpret it?
Another IgAN trial, another substantial proteinuria reduction, but RAINIER adds a biologic coherence to the story. Proteinuria, galactose-deficient IgA1, and hematuria all improved, supporting activity against the disease’s underlying immune pathway. The design, the relevant add-on setting, the prespecified analysis and controlled testing strengthen these findings.
However, lowering proteinuria is not a surrogate of long term kidney protection. This interim efficacy analysis included 199 participants, and the effects on eGFR slope, disease progression, and longer-term safety await the 104-week analysis. Hematuria “resolution” also allowed small amounts of blood on dipstick, so it should not be read as complete disappearance in every patient.
Monthly subcutaneous administration could be convenient, not sure if comparative superiority or cost-effectiveness. RAINIER cannot tell us whether povetacicept is better than atacicept, telitacicept, or APRIL-only inhibition, or which combinations offer the best balance of benefit and risk. Immunoglobulin reductions and numerically more infections warrant continued surveillance, despite similar short-term serious adverse event rates. Extensive sponsor involvement also deserves consideration. For now, povetacicept offers convincing evidence of reduced disease activity; whether it delivers durable kidney protection remains the next test. Perhaps at #KidneyWk 2027?
Journal of the American Society of Nephrology Publish Ahead of Print, October 24, 2026.
Empagliflozin Therapy in Patients with Autosomal Dominant Polycystic Kidney Disease: A Feasibility Randomized Controlled Trial
Stephen L. Seliger, Berenice Gitomer, Zhiying You, Wei Wang, Anna Ostrow, Emily Andrews, Charalett Diggs, Diana George, Miranda West, Kristen L. Nowak, Terry Watnick, and Michel Chonchol
Flozins appear now in almost every CKD algorithm except one. Patients with ADPKD, the most common inherited kidney disease, were excluded from DAPA-CKD (Heerspink et al, NEJM, 2017| NephJC summary) and EMPA-KIDNEY (EMPA-KIDNEY collab group, NEJM, 2022| NephJC summary). The US labels for dapagliflozin and empagliflozin still advise against using them for kidney protection in PKD. Tolvaptan remains the only disease-modifying drug (Torres et al, NEJM, 2017 | NephJC summary), and its aquaresis and liver signal keep many eligible patients off it.
The physiology argues both ways. On the optimistic side, young adults with ADPKD already show a raised filtration fraction and reduced renal plasma flow while GFR is still preserved (Meijer et al, CJASN, 2010), which is precisely the lesion that restoring tubuloglomerular feedback should ease. Flozins also induce mild ketosis, and higher beta-hydroxybutyrate levels track with slower eGFR decline in ADPKD (Knol et al, NDT, 2024), and in a human organoid-on-chip, glucose uptake drove cystogenesis while SGLT inhibition limited it (Li et al, Nat Commun, 2022).
The pessimist has an equally good story. The body answers an osmotic diuresis by conserving water, and copeptin rises on SGLT2i (Lytvyn et al, Diabetes Metab, 2020; Marton et al, JACC, 2024). In ADPKD that is the wrong hormone to provoke, since the vasopressin-V2R-cAMP axis is the very cyst engine that tolvaptan blocks. The animal data are a muddle (Naeem et al, Ren Replace Ther, 2026): the only clear win came from phlorizin, a nonselective SGLT1/2 inhibitor, in a non-orthologous rat model with proximal cysts (Wang et al, Kidney Int, 2013), while selective dapagliflozin raised cyst volume by 23% in PCK rats (Kapoor et al, PLoS One 2015), and canagliflozin did nothing useful in an adult-onset Pkd1 mouse (Leonhard et al, EbioMedicine, 2019). Empagliflozin also enlarges rodent kidneys simply by increasing cell size in the S3 segment and collecting duct (Sinha et al, Front Pharmacol, 2023), so on this drug class TKV is not automatically a cyst measure.
Table 1. Pre-clinical evidence of SGLT2i in PKD animal models, from Naeem et al, Ren Replace Ther, 2026
Human data are thin and contradictory. In an open-label cross-over of 27 tolvaptan-treated patients, dapagliflozin slowed kidney enlargement and chronic eGFR decline over 6 months (Uchiyama et al, Kidney Int Rep, 2025), whereas a retrospective series described TKV increases (Morioka et al, J Clin Med, 2023). Before committing to a 400-patient trial, the investigators asked a narrower question (Selinger et al, Am J Nephrol, 2026): can non-diabetic adults with rapidly progressive ADPKD take empagliflozin 25 mg for a year without trouble, and does anything worrying happen to kidney volume, eGFR, or copeptin along the way?
How was the study done, and what did it show?
This is a double-blind, placebo-controlled, parallel group feasibility trial at two US centers (Maryland and Colorado), with 1:1 randomization blocked by site at 12 months of treatment. This is the final analysis, and funding was academic (NIDDK, PKD Foundation, philanthropy). Patients started on empagliflozin 10 mg and moved to 25 mg at 1 month if they tolerated and eGFR had not fallen by more than 30% or below 20. The 25 mg dose was chosen in 2021, before EMPA-KIDNEY settled on 10mg.
Eligible adults had ADPKD by modified Pei-Ravine criteria, a CKD-EPI 20221 eGFR of 30-90, Mayo class 1C-1E, and stable function over 3 months. Diabetes, HFrEF, loop diuretics, current urogenital infection, and tolvaptan were all exclusions. The co-primary outcomes were safety (all AEs and SAEs, plus AKI, UTI, and genital infection) and tolerability, defined as taking 25 mg at 12 months and answering yes to the TEMPO-era question: can the patients tolerate the drug for the rest of their life? At least 70% tolerability on empagliflozin was the prespecified signal to proceed to phase 3. Secondary outcomes at 3 and 12 months included hTKV by blinded 3T MRI, piecewise eGFR slopes, aPWV, copeptin, urinary KIM-1, and ADPKD Impact scale.
50 of 104 screened patients were randomized, with no losses to follow-up. Mean age was 42, 96% were White, mean eGFR was 70 +/- 17; and 88% took an ACEI or ARB. Randomization left imbalances that matter for a volume endpoint: the empagliflozin arm had more men (60% vs 48%), higher eGFR (73 vs 67), larger kidneys (median htTKV 1,114 cs 1,030 mL/m) and more Mayo 1E patients (32 vs 20%).
Figure 1. CONSORT diagram: flow of the trial, from Selinger et al, JASN, 2026
Tolerability was 24 of 25 in both arms (96%; exact 95% CI 79.7-99.9), well clear of the 70% bar (P=0.002). One patient per arm stopped after a hospital admission (myocardial infarction on empagliflozin, cholecystitis on placebo). Any AE occurred in 12 vs18 patients (P=0.15) with one SAE per arm; empagliflozin brought two UTIs and one genital infection, and the only AKI was on placebo.
Table 2. Safety and tolerability, by treatment assignment, from Selinger et al, JASN, 2026
The secondary outcomes held the surprise. htTKV grew 10.5% per year on empagliflozin (95% CI 8.2-12.7) against 5.1% per year on placebo (95%CI 3-7.3), a difference of 5% per year (95%CI 2.0-8.1, P=0.001 for time x treatment). Post hoc adjustment for Mayo class and sex did not change this.
Figure 2. Median (IQR) values of htTKV per group over time, from Selinger et al, JASN, 2026
eGFR showed the expected acute dip at 1 month (-6.2 vs +1; between-group -5.5, 95% CI -9.6 to -1.3) followed by a chronic slope of -0.77 vs-2.87 ml/min/1.73m2 per year (difference 1.4; 95%CI -3.3 to 6.2; P= .04). A PWV, copeptin, urinary KIM-1 and ADPKD-IS did not differ.
Table 3. Secondary efficacy outcomes, from Selinger et al, JASN, 2026
What does it all mean?
The feasibility question was answered convincingly: 96% tolerated empagliflozin 25mg for 12 months, with no excess of adverse events. The secondary finding is less reassuring: htTKV increased at about twice the placebo rate (10.5% vs 5.1% per year).
How much weight signal deserves is debatable. It is one of five unadjusted secondary outcomes in 50 patients; the empagliflozin arm started with bigger kidneys, and the analytic models differ from those in the published protocol. Yet the difference interval sits well clear of zero, adjustment did not erase it, and it matches the PCK rat. Placebo kidneys grew about as Mayo 1C_1E predicts, whereas 10.5% per year is well beyond the >6% that defines class 1E (Irazabal et al, JASN, 2015). Whether the extra volume is cyst is another matter. On our rough arithmetic from cross-sectional medians, most of the divergence happens in the first 3 months (=3.1% vs +0.6%) with near-parallel growth from month 3 to 12 (=5% vs 4.5). An early step like that looks more like tubular hypertrophy or another non-cystic shift than accelerated cystogenesis. Copepetin did not rise, but three fasting samples cannot exclude a meaningful increase, and there was no cyst-versus-parenchyma segmentation, no off-drug MRI, and albuminuria. The chronic eGFR slope leans toward empagliflozin, but its interval spans -3.3 to +6.2, and without a washout, hemodynamics and structure cannot be untangled.
The patients were mostly White, nondiabetic, tolvaptan-naive registry volunteers, given a dose no efficacy trial uses. If any harm runs through V2 receptors, flozins on top of tolvaptan might behave quite differently, which is what Uchiyama’s crossover hints at (Uchiyama et al, Kidney Int Rep, 2025).
The results also complicate the larger trials now underway: EMPA-PKD (Bahlmann-Kroll et al, BMJ Open, 2024), DAPA-PKD and STOP-PKD (Muller et al, NDT, 2025). If flozins enlarge kidneys without growing cysts, a TKV-primary trial could penalise a drug that preserves kidney function, while an eGFR-slope trial has to handle the dip. Until those trial reports, this pilot gives no reason to start SGLT2i in ADPKD outside established indications such as heart failure or DKD.
Table 2. Overview of clinical trials investigating SGLT2i in ADPKD, from Naeem et al, Ren Replace Ther, 2026
Sodium-Glucose Cotransporter 2 Inhibitor Use and Levels of Hemoglobin, Markers of Iron Metabolism, and Erythropoiesis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials
Yaqin Yang, MD; Changyuan Yang, MD; Yanmei Wang, MD, Pien Rawee, MSc; Aleix Cases, MD, PhD; David E. Leaf, MD, MMSc Lucia del Vecchio, MD; Taulant Muka, MD, PhD; Hiddo J. L. Heerspink, PharmD, PhD; Ron T. Gansevoort, MD, PhD; Michele F. Eisenga, MD, PhD
JAMA Published Online: October 24, 2026 doi: 10.1001/jama.2026.19921
Why was the study done?
Flozins reduce rates of kidney failure, hospitalization with heart failure and cardiovascular as well as all-cause mortality in patients with diabetes, kidney disease or heart failure. Whilst flozinating these patients, one may notice the hemoglobin creeping up cometimes. The initial thought was that this might just be hemoconcentration from the osmotic natriuresis, however the natriuresis and volume contraction is rather mild - and the effect seems to be sustained. Since then, the mechanism is thought to be mediated by hypoxia induced erythropoietin stimulation, but even increased iron utilization is noted as seen by lower ferritin levels - and also lower hepcidin levels. This mechanistic study suggests that this might be mediated by the erythroferrone–transferrin-receptor-protein-1 driven reduction in hepcidin (Ferreira et al JACC 2025). See image below for this mechanism. However, a proper quantitation of this hemoglobin rise - as well as iron indices, and in different populations has not been done from the RCT data.
Figure: Possible mechanisms of Flozin (made with Nano banana)
How was it done and What did it show?
The systematic review included RCTs of flozins in diabetes, CKD, or heart failure populations, with a double-masked design, and reporting some hemoglobin index or iron metabolism numbers. The primary outcomes were change in hemoglobin and hematocrit with iron parameters and RBCs being secondary outcomes. The metanalytic component was fairly standard, with the usual assessment of publication bias, risk of bias, sensitivity and subgroup analysis which we will discuss in more detail with the actual results.
Overall, of the 6000 odd studies screened, 85 RCTs with ~ 70,500 individuals made it to the final analysis. Empa (30 RCTs) followed by dapa (25) lead the pack, with cana (8) ertu (7) and then the other less well known ipra (6), luseo (4), sota (3) and bexagliflozin (1) contributing the rest. Most trials were just for DM, though notably 9 each were CKD and CV trials, but with an additional 14 HF trials. More details in the table below.
Table 1 from Yang et al, JAMA 2026
Overall, there was a small, but significant and consistent increase in hemoglobin with flozination (~ 0.6 g/dL) with tight 95% CI given the large N. Only one small trial reported no change in hemoglobin.
Figure 2 from Yang et al, JAMA 2026
Flozination was also associated with a small increase in erythropoietin levels (N = 8 trials) with significant heterogeneity, a small increase in RBC number (pooled effect 0.2 x 1012/L). For iron indices, flozination was associated with a small decrease in ferritin, transferrin saturation, and hepcidin (figure 3 below).
Figure 3 from Yang et al, JAMA 2026
The subgroups were pretty consistent when it came to use in different patient populations, age, geographic region. For different durations there was no significant interaction for hemoglobin, but there was one for hematocrit - with a greater increase noted over time. Notably this was seen for both hemoglobin and hematocrit in the multivariable metaregression (eTables 9, 10, not shown here). .
Figure 4 from Yang et al, JAMA 2026
What does it all mean?
Flozins work for hard outcomes, what should we care about their effect on hemoglobin? For some reasons this is an important result - known to many of us, but good to see a properly conducted quantitative result. Could this be a partial explanation for the clinical outcomes? After all in DKD one can explain away flozin effects on the basis of TGF, but in non-diabetic CKD, in HF etc - just natriuresis seems insufficient - and is usually explained away as ‘pleiotropic’ mambo-jumbo. Flozins have several salutary metabolic effects - unlike RASi they reduce K a bit, unlike thiazides they lower blood sugars, uric acid and don’t cause hyponatemia. They may indeed help a bit in ameliorating hyponatremia or hypomagnesemia. Admittedly none of this metabolic effects are impressive by themselves but they do add up - and the hemoglobin and increased iron metabolism may be a similar contributor - especially in the heart failure population. In CKD - using flozination may help delay the need to use ESAs - or may help in using lower doses of ESAs?
Another aspect to note is that sometimes this effect may be too much - case reports exist of the risk of polycythemia - and though the absolute risk is small, the relative risk was estimated to be about 6 times higher (Marques et al, Eur J Int Med 2026). This risk is slightly higher with COPD, smoking etc (perhaps in ADPKD?). As they note, it may be useful in patients with polycythemia to deflozinate before investigating for more esoteric causes.
Finerenone-Empagliflozin Combination Therapy in Apparent Resistant Hypertension: A CONFIDENCE Trial Post Hoc Analysis
Rajiv Agarwal MD, MS, Sankar D. Navaneethan MD, MS, MPH, Ricardo Correa-Rotter MD, Michelle M. Estrella MD, MHS, Hiddo J.L. Heerspink PhD, Janet B. McGill MD, Amy K. Mottl MD, Masaomi Nangaku MD, PhD, Julio Rosenstock MD, Peter Rossing MD, Muthiah Vaduganathan, Javier Morales, Yehuda Handelsman MD, Jennifer B. Green MD, Johannes F.E. Mann MD, Charlie Scott MSc, Li Li MD, MBA, Meike Brinker MD, Matthew R. Weir MD
JACC Advancesdoi: 10.1016/j.jacadv.2026.103388
Why was this study done?
In treatment resistant hypertension, based on the PATHWAY trial (Williams et al Lancet 2015), the first option should be spironolactone. In this patient population, it results in a blood pressure lowering of about 10 mmHg. This could be followed by beta blockade, alpha blockade or other agents. In this space, flozins have become very attractive, since they do lower blood pressure to an extent (Tran et al Am J HT 2020). In diabetes, the lowering of blood pressure may be anywhere from 5 to 10 mm, though in non-diabetic settings, it’s probably around 3 to 4 mm. On the other hand, finerenone itself has a very small effect on BP lowering about 2 to 3 mm. Hence spiro has remained a fan favorite when BP lowering is important.
There is a significant overlap between patients who have resistant hypertension, and those who have diabetic kidney disease, and 40-50% of people living with CKD may have resistant hypertension, the proportion increasing as GFR decreases, and albuminuria increases. In someone with blood pressure that is uncontrolled despite three BP, lowering medications, and who have diabetic kidney disease, should you reach for spironolactone, or for a flozin or for finerenone? Maybe both? The individual flozin or finerenone trials cannot answer this question - but the CONFIDENCE trial could.
How was it done and what did it show?
We have already discussed the trial methodology, so we will not belabor that. Briefly, patients with diabetic kidney disease received either empagliflozin, finerenone, or both for six months. The main outcome in the trial was proteinuria reduction, and safety outcomes, including GFR reduction, and potassium levels. In this analysis, the focus was on BP lowering. The population was optimized on the basis of baseline blood pressure. The subgroup of interest is those who BP was not controlled (SBP > 130) despite three or more BP lowering agents of any class, or any BP when or 4 or more BP lowering drugs. Since we need a 24 hour ABPM to truly classify patients as resistant hypertension which was not done in this trial, this patient population is labelled as ‘ apparent’ treatment resistant hypertension (aTRH). The outcomes of the present analysis were the change in SBP following randomization (days 14, 30, 90, 180, and 210) and the percentage of participants with a ≥10 mm Hg drop in systolic BP at day 180.
From table 1 (not shown here) - the interesting part is the drugs they were on. Though RASi was mandated, only 47% (no aTRH subgroup) to 86% (TRH) were on a CCB. The diuretic was even more stark, with little use in the ‘no aTRH’ group (18%) to 66% in the TRH group. Hence beta-blockers and other worse agents helped clinch the ‘apparent’ part of the TRH definition. For BP response (defined as > 10 mm Hg SBP drop) - the combination of empa + finerenone seemed to have a greater effect - and in the regression (figure 2) it is clear that this effect was more pronounced in the aTRH group (as well as with lower GFR).
Figure 1 from Agarwal et al JACC Advances 2026
Figure 2 from Agarwal et al JACC Advances 2026
If you then examine the actual BP drop in the aTRH subgroup, it was about 11 mmHg by day 30 and 9 mm Hg at day 180. Empa and finerenone alone were about 7 to 5 mmHg at the same points, in the aTRH subgroup. The effect of empa was greater than the effect of finerenone alone in the no aTRH subgroup (data in Table S1, not shown here). Data broken down by various subgroups (figure 3) suggests, again, that the combination of empa-finerenone is more potent with decreasing GFR and in the aTRH group.
Figure 3 from Agarwal et al JACC Advances 2026
For safety (table 3, not shown here) all adverse effects were more common in the TRH subgroup - which is a sicker population - but notably there was no more hyperkalemia than the no aTRH subgroup.
What does it mean?
The authors wish to suggest that this should correct the prevailing sentiment that spiro is better for hypertension, and that the empa-finerenone combination provides similar BP lowering in proteinuric DKD. However the spiro effect seen in PATHWAY was in all comers with resistant hypertension, and not proteinuric DKD. Would spiro effect be more or less in such a population? Naysayers would point out that PATHWAY was enriched with primary aldosteronism (not formally tested, but in additional analyses the spiro effect did correlate with lower renin values) which may have contributed to its seemingly outsize benefit. Nevertheless, we use empagliflozin (or any flozin) and finerenone not for BP lowering - but for their effect on clinical outcomes. This analyses serves to reassure us that the BP lowering effects that come along are not trivial.
Summaries by Cristina Popa, Akshaya Jayachandran ,
Brian Rifkin, Milagros Flores, Swapnil Hiremath