N Engl J Med, March 4, 2026. DOI: 10.1056/NEJMoa2512854

PMID: 41780000

Hiddo J.L. Heerspink, Ph.D., Andreas L. Birkenfeld, M.D., David Z.I. Cherney, M.D., Ph.D., Helen M. Colhoun, M.D., Per-Henrik Groop, M.D., Linong Ji, M.D, Niels Jongs, Ph.D., Chantal Mathieu, M.D., Richard E. Pratley, M.D., Sylvia E. Rosas, M.D., M.S.C.E., Peter Rossing, M.D., Jay S. Skyler, M.D., Katherine R. Tuttle, M.D., Robert Lawatscheck, M.D., Meike Brinker, M.D., Markus F. Scheerer, Ph.D., Julie Russell, M.Sc., Patrick Schloemer, Ph.D., and Janet B. McGill, M.D., for the FINE-ONE Investigators 

WHY WAS THE STUDY DONE?

Type 2 diabetes accounts for >85% of patients diagnosed with diabetes.The management of diabetic kidney disease has been built on a narrow foundation comprising glycemic control, blood pressure optimization, and renin–angiotensin system blockade, yet residual CKD risk has been stubbornly high. While patients with type 2 diabetes have enjoyed a renaissance of therapies to address these residual risk, with SGLT2Is, GLP-1 RAs, and nsMRAs (finerenone), patients with type 1 diabetes have largely been left behind and excluded from these groundbreaking studies of newer therapeutics. Flozins of course have been tried and sotagliflozin caused ketoacidosis (Garg et al NEJM 2017).

Activation of the mineralocorticoid receptor drives sodium retention and promotes renal inflammation, oxidative stress, and fibrosis, accelerating injury in diabetic kidney disease (DKD). Nonsteroidal MRAs (nsMRA) supposedly selectively block this pathway, suppressing pro-inflammatory and pro-fibrotic signaling and slow structural kidney damage beyond their modest hemodynamic effects.

Several large studies have shown the worth of nsMRAs in patients with Type 2 diabetes. FIDELIO-DKD demonstrated a significant reduction in kidney failure and CV outcomes (HR 0.82 for the primary kidney composite), complemented by FIGARO-DKD and consolidated in the FIDELITY pooled analysis, which showed a 23% reduction in major kidney outcomes and a consistent effect across CKD stages. Mechanistically, these benefits appear tightly linked to albuminuria reduction (Agarwal et al, Annals of IM 2023). Early declines in UACR accounted for up to 84% of kidney protection with finerenone. This reinforced albuminuria as both a therapeutic target and a surrogate endpoint. This is the rationale for FINE-ONE attempting to translate a well-established T2D paradigm into the long-neglected space of DKD in patients with type 1 diabetes. 

HOW WAS THE STUDY DONE?

FINE-ONE included adults (≥18 years) with type 1 diabetes and chronic kidney disease. The eGFR cut-off for inclusion was between 25 to <90 ml/min/1.73 m² along with albuminuria (UACR 200 to <5000 mg/g). The proteinuria had to be documented for at least 3 months prior to screening. All participants were required to be on a stable dose of an ACE inhibitor or ARB for at least 4 weeks before enrollment. Additional inclusion criteria included HbA1c <10% and serum potassium ≤4.8 mmol/L at screening. Key exclusions included CKD due to causes other than type 1 diabetes, prior kidney transplantation, symptomatic heart failure with reduced ejection fraction, and recent use of flozins or GLP-1 RAs.

Participants were randomized 1:1 to receive finerenone or placebo. If eGFR was ≥60 ml/min/1.73 m², the starting dose was 20 mg once daily, and it was 10 mg daily in those with eGFR 25 to <60 ml/min/1.73 m². Dose reduction or temporary discontinuation was allowed for safety, particularly in the setting of hyperkalemia. The trial was double-blind, and all participants continued RAS blockade.

The primary outcome was the relative change in UACR from baseline over 6 months. Secondary outcomes were: Changes in eGFR, serum potassium, Blood pressure and adverse events, including hyperkalemia. Exploratory outcomes included categorical reductions in UACR (≥30% and ≥50%).

WHAT DID THE STUDY FIND? 

A total of 573 participants were screened, and 242 were randomized: 120 to finerenone and 122 to placebo. Treatment discontinuation during the 6-month period occurred in 6.7% of the finerenone group and 8.2% of the placebo group. As expected, UACR fell by 34% in the finerenone group vs 12% in the placebo group, translating to a 25% greater fall with nsMRA treatment. More than half of patients on finerenone achieved at least a 30% (with ⅓ achieving a 50% decline in UACR) reduction in albuminuria vs only 29% in the placebo arm. 

There was a greater decline in eGFR in the finerenone group of about −5.6 ml/min/1.73 m² at 6 months compared with −2.7 in the placebo group, giving a between-group difference of −2.9. This separation appeared early and then stabilized, and during the washout period eGFR in the finerenone arm moved back toward baseline. A decline of 30% or more in eGFR was seen in 9.2% of patients on finerenone and 7.4% on placebo.

Blood pressure changes were minimal, and there was no meaningful change in glycemic control or body weight over the course of the study.

Adverse events were broadly similar between the two groups, both in overall frequency and in serious events. What stood out, as expected, was hyperkalemia. It occurred in about 10% of patients receiving finerenone compared with just over 3% in the placebo group, and around 2% had to stop the drug because of it. There were no deaths in the finerenone group during the trial. Hypoglycemia was actually less frequent with finerenone than with placebo, though the numbers were small.

ARE WE IMPRESSED ?

So, FINE-ONE answers a question we have been circling for years. If MR activation matters in type 1 DKD, will blocking it actually do anything? The trial shows that it does. Albuminuria comes down. It comes down clearly and consistently over 6 months. That part is straightforward.

But once you move beyond that, things get a bit less clear. This is a trial built around albuminuria, and not kidney failure, long term eGFR decline, or dialysis. Just albuminuria. It is considered a useful marker, no doubt, but it is still far from outcomes that these fairly young and long-standing diabetic patients actually feel. The expectation is that lowering this number will translate into something bigger later on.

The eGFR story adds to that uncertainty. There is a drop early on with finerenone, larger than placebo, and then some recovery after stopping the drug. It looks like a hemodynamic effect. We have seen this pattern before with other kidney drugs. It is not alarming, but doesn’t show what happens over long follow-ups. The trial is also short. Six months is enough to show that a drug changes a number. It is not enough to show that it changes the course of a disease. The authors do mention that the curves look stable and suggest longer follow up may not change things much. However, kidney outcomes take time, sometimes a lot of time. Given the smaller number of patients, an outcome based trial may not be feasible, leaving us with this as the best available data.

Then there is the population itself. Out of 573 screened patients, more than half did not make it into the trial. That is a large number. The paper does not really break down why in detail. We know the criteria were strict. Potassium had to be low. Glycemic control had to be reasonable. Blood pressure couldn’t be too high or too low. No recent cardiovascular issues. No newer drugs (i.e., SGLT2i, GLP-1RA which are being used in selective patients with type 1 diabetes). This limits generalizability and does not mirror most of the type 1 diabetes patients seen in nephrology practice. One thing they did do well is handle missing data. The appendix goes into detail about how they imputed values and tested different assumptions. The results stayed consistent, which is reassuring. Safety looks like what we expect. More hyperkalemia with finerenone, not dramatic, but there. Otherwise, things are fairly similar between groups. 

So what do we take away from all this?

Right now, this feels like an early step. A good one, but still an early one. All patients with diabetes differ, and diabetic DKD is not a monolith. Ongoing testing of newer DKD agents in patients with type 1 diabetes is essential to evidence based care (e.g., SUGARNSALT trial)

CONCLUSION: 

Finerenone significantly reduces albuminuria over 6 months in patients with type 1 diabetes and CKD compared to placebo, with a modest and reversible decline in eGFR and a higher incidence of hyperkalemia. FINE ONE provides reassuring data when considering nsMRAs in patients with type 1 diabetes. Is this enough to start using finerenone in DKD due to type 1 diabetes - taken together with the T2D data from FIDELITY? Given the lack of other options in this patient population, that is a very sweet suggestion.

Summary by

Dr. Akshaya Jayachandran

Reviewed by 

Brian Rifkin and Swapnil Hiremath

#NephJC Chat

Tuesday, May 5th 2026, 9 pm Eastern on X and Bluesky

Lancet. 2026 Feb 7;407(10528):587-598., doi: 10.1016/S0140-6736(25)02255-X. Epub 2026 Jan 27.

TRPC6 inhibition for the treatment of focal segmental glomerulosclerosis: a randomised, placebo-controlled, phase 2 trial of BI 764198

Howard Trachtman, Matthias Kretzler, Loreto Gesualdo, Nicholas Cross, Biruh Workeneh, Jessica Kaufeld, Björn Meijers, Zhiming Ye, Qinkai Chen, Vimal K Derebail, Monica Suet Ying Ng, Bo Ji, Maximilian T Lobmeyer, Silke Retlich, Fabia T Licarião Rocha, Srinivasa Prasad, Nima Soleymanlou

PMID: 41616795

DOI: 10.1016/S0140-6736(25)02255-X

Introduction

Focal segmental glomerulosclerosis (FSGS) is a common histological pattern of glomerular scarring that can be due to diverse underlying pathophysiology,  including unknown immune-related ‘podocyte-toxic’ factors (primary) or various secondary causes (see Fig 52).  As genetic screening becomes more widespread, it has been suggested that known genetic causes of the hereditary FSGS account for upwards of 20% of cases (Satin S, et al. Clin J Am Soc Nephrol, 2011). The clinical presentation of FSGS is typically the nephrotic syndrome,  with progressive renal failure, although the exact prognosis and presentation may vary by underlying etiology. It is generally recommended to treat the underlying cause of FSGS in secondary disease and consider use of immunosuppression, such as steroids and calcineurin inhibitors, in primary disease. To date, only the dual-acting endothelin type A and angiotensin II receptor blocker, sparsentan, has been FDA-approved for the treatment of FSGS in 2026.

The transient receptor potential cation channel 6 (TRPC6) story is more recent and dates back to 2005, when a genetic variant was discovered in a large kindred with FSGS (Winn MP et al, Science, 2005). The variant was present on chromosome 11 and altered calcium signaling in podocytes and increased the activity of “calcium transients” (rapid, temporary increases in intracellular ionized calcium that are crucial signaling mechanisms). Higher calcium transients were suggested to cause disruption of the cytoskeleton, detachment, apoptosis, or decreased proliferation of podocytes. Patients with TRPC6 mutations typically present in the 3rd to 4th decade with severe proteinuria, and 50% of them progress to ESRD within two decades (Caridi et al, Pediatr Nephrol 2010).  In TRPC6 variants, truncated mutations have no clinical significance compared with missense and gain-of-function mutations (Wooden B et al, CJASN; McAnnallen SM et al, NDT, 2025).

Similar to medications being developed for APOL1-mediated kidney disease (AMKD), TRPC6 inhibitors, as part of precision therapy, were developed specifically for the inhibition of TRPC6 gain-of- function mutations (Zimmerman B et al, Nature, 2025).

In a mouse model of FSGS, the drug BI 749327 was observed to decrease kidney fibrosis and related fibrotic gene expression. Additionally,  infiltration by inflammatory CD3⁺ T cells was reduced, suggesting that BI749327 may have utility in non-TRPC6 variant causes of FSGS-related decline in kidney function as well (Lin BL et al, Physiology PNAS, 2019). This current phase 2 study was designed to look at the efficacy and safety of this novel FSGS therapy.

The Study

Methods

Study design

The study was a multicenter (31 centers), multinational (10 countries), parallel-group randomized controlled study. The data was collected from an online platform, BRAVE, through mobile research nurses under the supervision of an onsite investigator. 

This placebo-controlled trial studied patients with primary FSGS or genetic FSGS resulting from a TRPC6 variant. The study started on Jan 27, 2022 and was completed on Jan 3, 2025. 

Inclusion and Exclusion Criteria 

Concomitant CNI use was not permitted; participants on ACEI/ARB/finerenone/SGLT2I treatment were required to be on a stable dose for > 4 weeks prior to screening. In the initial phase, researchers included only those participants who had completed a steroid course, but with unresolved proteinuria >1.5 g/g. This was amended in Oct 2022 to include all participants with a stable dose of steroids >4 weeks prior to screening.

Randomization and masking

It was a double-blinded RCT. Participants were randomly allocated in a 1:1:1:1 ratio to receive one of three oral doses of BI 764198 (20 mg, 40 mg, or 80 mg) given once daily or a matched placebo with automated block randomization and further stratified according to the usage of steroids with interactive response technology. The drugs were shipped directly to the patient once allocation was verified; treatment was given for 12 weeks with follow-up on days 7 and 30 after treatment.

Procedure 

In the initial 2 visits, 24-hr urine protein was collected and averaged for a baseline. In later visits, urine PCR was quantified on day 4 (Visit 2) and weeks 4, 8, 12, and 13, and serum creatinine (eGFR) was measured on day 4 (Visit 2) and weeks 2, 4, 6, 8, 10, 12, and 13. Throughout the dosing interval, all doses maintained sufficient drug concentrations, even at trough levels, and target exposure was also adequate. 

Outcomes

Primary endpoint: Proportion of participants with a ≥25% reduction in 24-hour UPCR from baseline to week 12, with sensitivity analysis done with the per-protocol analysis set (PPS).

Secondary endpoints:

Change in  24h total urine protein excretion (TPE) from baseline to week 12

Change in 24h UPCR from week 3 to week 12 

Steady-state trough concentration of BI 764198 at week 4 and 12

Change in eGFR from baseline to week 12

Statistical analysis 

All statistical analyses were performed using SAS software, version 9.4, including PROC GLM and PROC LOGISTIC for efficacy analyses. The final analysis sets were as follows:

1) The Per Protocol Analysis Set (PPS): Contains all patients who were randomized and completed treatment with measurements of the primary endpoint at both baseline and end of treatment. It is used in sensitivity analysis.

2) The Electrocardiogram Pharmacokinetic Concentration Analysis Set (ECGPCS):

This set includes all subjects from the treated set, providing at least one pair of valid drug plasma concentrations and a corresponding ECG endpoint to be used in the exposure response analysis (e.g., drug concentration and QT plots).

3) Initial UPCR change from baseline was compared through ANOVA in different groups (placebo, 20 mg, 40 mg, and 80 mg). After including the corticosteroid as a covariate, researchers used the ANCOVA variant to ensure a formal distribution of covariates among all groups, removing the confounding effect of steroids.

Sample size & assumptions: 60 participants (15 per group) were chosen without a formal power calculation. Expected responder rates were 20%, 30%, and 40% for BI 764198 doses (20 mg, 40 mg, 80 mg) vs. 9% for placebo, giving a 73.4% chance of detecting a ≥25% difference. Missing data were not imputed.

• Interim analysis: An exploratory, unmasked interim analysis was done on the first 24 participants by the sponsor’s internal team, but no protocol or analysis plan changes were made. Trial staff and participants remained blinded.

• Primary endpoint analysis:

• Binary endpoint: ≥25% reduction in UPCR at week 12. Missing data classified as non-responders (hypothetical estimand).

• Continuous endpoint: Change in log-transformed UPCR at week 12 (treatment policy estimand). 

• Statistical methods:

• Logistic regression for binary endpoint (fixed effects: treatment, baseline UPCR, corticosteroid use).

• ANCOVA for continuous endpoint (same covariates).

• No multiplicity adjustments (exploratory phase 2 study).

• Side effects estimated via targeted maximum likelihood; 95% CIs calculated accordingly.

• Secondary endpoints & safety: Reported descriptively. Safety was explored with Wilson score CIs.

Funding

Funding was provided by the pharmaceutical company Boehringer Ingelheim. BI was involved in the design and conduct of the study, data collection, data analysis, and data interpretation, and funded medical writing support for the article.

Results

From March 10, 2022, to Sept 3, 2024, 139 participants were screened, and 67 were randomly assigned to receive placebo or BI 764198 at doses of 20 mg, 40 mg, or 80 mg.

Sixty-two participants received treatment; among them, 90% completed the study and treatment period.

The study had a male predominance of 60%, a mean age of 40.7 years, and a predominant white race of 63%. At random allocation, the baseline drugs included 81% of patients on ACEI/ARBs, 42% on SGLT2 inhibitors, and 23% on corticosteroids. Ten participants with documented TRPC6 variants (genetic variants) were enrolled, and seven had complete proteinuria data. 

In the 60 patients in the full analysis set, the primary endpoint, a 25% or greater reduction in UPCR from baseline at week 12, was seen in one (7%) of 14 participants receiving placebo and in 16 (35%) of 46 participants across all BI 764198 dose groups (odds ratio [OR] 4.9 [95% CI 1.0–48.8]). 

In the ANCOVA analysis, the 20 mg group saw a -40% decline in UPCR (95% CI: -56% to -17%). At the end of 12 weeks, 9 (23%) of BI 764198 patients attained less than 1 g/g of proteinuria. In the subgroup analysis of the TRPC6 variant set, which included 7 patients receiving the drug, there was a 100% response rate, indicated by a reduction in proteinuria of more than 25% from baseline. Though there was a rise in serum creatinine due to reversible inhibition of transport channels MATE1, MATE2-K, and OCT2, with no change in serum cystatin C and eGFR with cystatin C at 12 weeks of treatment. 

Treatment-related adverse events were similar in both the drug and placebo groups. Serious adverse events that were seen in the 20 mg group included: 1) edema and 2) osteonecrosis, but neither of them was attributed to the drug. Among 3 patients, the drug was stopped, but all were non-serious events and occurred in patients receiving 40 mg. A mild increase in liver enzymes was seen in one person in the placebo group, and non-severe QT prolongation without any events was seen in one person receiving the 80 mg dose. Lenticular opacity was seen in one person receiving the 20 mg dose.

Discussion

Discussion 

This phase 2 study demonstrated that the TRPC6 inhibitor BI 764198, a once-daily oral treatment for primary and TRPC6 variant FSGS, achieved significant reductions in proteinuria compared to a placebo. The study drug was well-tolerated, with a similar adverse event profile as the placebo. Stability of blood pressure and eGFR was presented as circumstantial evidence for a ‘direct’ beneficial effect of the study drug on podocytes, rather than as an effect secondary to hemodynamic alterations. The authors do note that a 20 mg dose was sufficient to achieve 90% inhibition of TRPC6 in vitro, and higher doses did not appear to have additional benefits or risks. 

It was clear that the trial faced difficulties in recruitment, despite being rolled out in 11 countries and multiple sites. This is acknowledged, while key amendments in version 3.0 dated Oct 2022 were stated. To ease the burden on participants, the frequency of visits was reduced, and single readings of baseline UPCR were made acceptable. Likewise, to ease the burden on trialists, inclusion criteria were expanded to include patients on stable steroid doses (for 4 weeks minimum), in contrast to the prior criteria of being off steroids > 4 weeks. Even the proteinuria criteria were lowered to ≥ 1gm/gm compared to the previous of ≥ 1.5gm/gm, making this study less aligned with findings from PARASOL. 

For being a phase 2a trial with a small sample size, the trial is heavy on statistics. Sample size calculations was not based on a formal power calculation but rather on expected response rates (20-40% vs 9% placebo), with unclear provenance (phase 1 signal vs external data not explicitly stated). The reported ~73% probability falls short of conventional power thresholds (80-90%), implying a non-trivial risk of false negatives. With ~15 patients per arm and heterogeneous inclusion criteria, signal detection becomes fragile. Dropouts were not accounted for, and missing data were not imputed, which is unusual and may have contributed to bias in the results. Wide-ranging baseline UPCRs are known to cause large variances in confidence intervals. To reduce the skewness, log-transformed urine protein measures were not used, and instead, 24-hour UPCR and total proteinuria were used to report the findings. Homoscedasticity (homogeneity of variance) violation, fifteen-yard penalty? This alone could invalidate statistical significance, which assumes that modeling errors all have the same variance. Biased standard errors lead to biased inferences, so the results of the hypothesis test are possibly wrong. This is a common problem with ANOVA statistical methods.

The authors state, “no missing data was imputed” several times. However, in an attempt to account for the intercurrent events causing missing data (including those leading to discontinuation, after which patient data was not collected), a hypothetical estimand was used. In practice, this assumes outcomes as if patients had remained on treatment- functionally similar to imputation, but without actual observed data. Conversely, the treatment policy estimand requires outcomes data irrespective of intercurrent events, but such data were not collected, creating a mismatch between the estimand definition and available data. For a phase 2 trial, this flexibility may be intentional- aimed at identifying a directional signal rather than definitive effect estimation. ORs are too wide for the primary endpoint (reflecting heterogeneity and small sample size again), giving us merely a ‘sense of direction of effect’ rather than an ‘effect size’, which may be good enough a reckoning for a phase 2 trial. And yet, the study findings support the adequacy of a 20mg dose of BI 764198.

Safety data was reported as per participant and not as the number of events, raising a question about the suitability of this approach in a phase 2a trial. A definitive statement regarding any participants having >1 AEs/SAEs would have helped; however, this is not to be found in the paper. If indeed a proportion of participants had multiple AEs/SAEs, it is supremely important that safety information is plainly stated in the paper.

Certain pharmacodynamic endpoints mentioned in the initial protocol are not mentioned in the current study. These endpoints are urinary biomarkers reflecting podocyte health (podocin [mRNA]: creatinine ratio [UPodCR], nephrin [mRNA]: creatinine ratio [UnephCR], and podocin [mRNA]: nephrin [mRNA] ratio [UPNR]) and drug target modulation (TRPC6 mRNA, nuclear factor of activated T-cells [NFAT] mRNA, and downstream markers of the calcineurin-NFAT pathway). This data could further support the idea that the effects are related to the improvement of podocyte function and longevity. Similarly, although pre-treatment biopsies were required, no post-treatment biopsies were performed.

Finally, the primary endpoint was a reduction in proteinuria, a reasonable surrogate for progressive CKD in many instances. FSGS has had difficulty identifying directed therapies because it is not a single disease process but rather a microscopic description of multiple nephropathologies. Is it useful to include all primary FSGS in a trial, or is there too much “noise” to determine a drug's effectiveness? There were animal models that showed that this medication might have down-steam effects on a common fibrosis pathway (Wu YL et al, KI 2017; Zheng Z et al, Int J Mol Sci 2022) and hence be useful in all varieties of FSGS and even diabetic nephropathy (Ran Sun et al, Mol Med Rep 2024). Although the numbers were small, the effects were certainly more impressive for those with a known TRPC6 mutation. We await more evidence for this, particularly from the NEPTUNE cohort, where biomarker-matched therapy is offered to TRPC6 variant-harboring participants (currently underway). Finally, is it proper to project expectations of eGFR from a 12-week trial in a disease like FSGS with significant variation in progression? Although it might be mildly reassuring that there was no change in cystatin C eGFR, this will need to be followed for a much longer period to show changes in chronic slope versus placebo.

Summary by

Sai Vani Yellampalli

Sayali Thakare

Reviewed by

Brian Rifkin, Swapnil Hiremath, Cristina Popa, Akshaya Jayachandran

Header image designed by AI prompts from Dr Saivani Yellampalli

#NephJC 10 post discussion

Tuesday, April 10th 2026, 9 pm Eastern on X and Bluesky

JAMA Netw Open. 2026 Mar 16;9(3):e261943. doi: 10.1001/jamanetworkopen.2026.1943

Hydralazine Use and Risk of Vasculitis

D Fremont, S Dhaliwal, M Canney, A Akbari, G L Hundemer, V K Derebail, M M Sood, D Massicotte-Azarniouch

PMID: 41838000

DOI:  10.1001/jamanetworkopen.2026.1943

Introduction

Hydralazine, a direct-acting vasodilator introduced in the 1950s, occupies a curious paradox in contemporary medicine. Though the therapeutic armamentarium for hypertension, pregnancy-related hypertension, and heart failure has expanded dramatically, this modest (thrice daily), inexpensive drug remains as an alternative choice when first-line agents are ineffective, contraindicated, or poorly tolerated. Its continued widespread use is thought to reflect a combination of availability, low cost, and a niche role at the periphery of guideline-directed care (McEvoy et al, Eur Heart J, 2024 | Jones et al, Hypertension, 2025 | Heidenreich et al, Circulation, 2022). It is more likely to reflect misguided choice for its fast action, unfounded fear of RASi in advancing CKD, hydralazine’s perceived metabolic neutrality, and race-tinged RASi science. More about that in the discussion.

The story of hydralazine's modern relevance, as with many drug-safety narratives, begins with a single patient. Case reports in the 1980’s described an unexpected constellation of immune phenomena- drug-induced lupus, and more ominously, antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis- often accompanied by rapidly progressive glomerulonephritis (Peacock, Br Med J (Clin Res Ed), 1981| Mason, J Clin Lab Immunol, 1986). Over the ensuing decades, a growing tapestry of observational signals reinforced the concern that the hemodynamic benefits of hydralazine may be overshadowed by immune dysregulation and devastating vasculitis (Choi et al, Arthritis Rheum, 2000| Kumar et al, Semin Arthritis Rheum, 2018| Santoriello et al, Kidney Int, 2021). These reports are largely derived from small case series and mechanistic conjecture rather than definitive causal trials, a limitation that is intrinsic to the study of rare adverse drug events. 

Drug-induced vasculitis presents a methodological impasse: low incidence, heterogeneous clinical presentation, and a reliance on imperfect coding or reporting systems can obscure true associations. Consequently, clinicians must navigate uncertainty between a faint “signal” of harm and the surrounding “noise” of background disease, all while the potential outcomes- small-vessel vasculitis, crescentic glomerulonephritis, pulmonary-renal syndromes are severe (Kumar et al, Semin Arthritis Rheum, 2018| Santoriello et al, Kidney Int, 2021).

A coherent biological explanation has been proposed. Hydralazine is hypothesized to react with carbonyl derivatives on myeloperoxidase (MPO) or to bind directly to MPO, inducing conformational changes that generate neo-epitopes. These altered MPO molecules can stimulate autoantibody formation, particularly anti-MPO antibodies, setting off a cascade that culminates in small-vessel vasculitis and glomerular injury (Xi et al, J Clin Invest, 2025). Although not proven definitively, this mechanistic pathway, along with many case studies, justifies clinical vigilance.

Medicine, by its nature, operates in realms of uncertainty; even therapies that have stood the test of time may harbor latent risks that surface only through fragmented evidence (Quizon et al, Clin Kidney J, 2025| Bomback, CJASN, 2017). Our prologue serves as an entry point into a deeper examination of how clinicians should interpret emerging population-level data on hydralazine-associated vasculitis, balancing the drug’s value against the rare but serious possibility of immune-mediated harm. Will Freemont et al study offer a rigorous epidemiologic lens through which to view this enduring paradox?

The Study

Methods

The investigators conducted a population-based retrospective cohort study using linked administrative health databases from ICES (Institute for Clinical Evaluative Sciences), covering Ontario’s universal single-payer healthcare system. The study period spanned January 2008 to December 2021, with follow-up extended to December 2022.

Population
The authors enrolled adults ≥66 years receiving a new outpatient prescription for either hydralazine or an ACE inhibitor/ARB. They set a lower age bound at 66 rather than 65 (the age of drug benefit eligibility) specifically to allow for a 1-year lookback window confirming true incident drug use. 

Exclusions: The study excluded individuals with a prior vasculitis diagnosis, prior hydralazine use, prior kidney transplant, age >105, non-Ontario residency, and missing eGFR at the index date. 

Exposure and comparator

The author defined the index date as the date of first dispensing. They employed a new-user active comparator design- comparing hydralazine users to new ACEi/ARB users rather than non-users. This choice reduces healthy-user bias by ensuring both groups share the act of initiating a cardiovascular medication for overlapping indications. In sensitivity analyses, the authors also tested new alpha-blocker users as a secondary comparator, representing an alternative 4th/5th line antihypertensive, and censoring when the drug was discontinued.

Outcome

The primary outcome was defined as any new vasculitis diagnosis after drug initiation, capturing it via ICD-10 codes from hospital and emergency department encounters. The authors chose a broad vasculitis code definition over AAV-specific codes because the latter yielded fewer than 6 events in hydralazine users- insufficient for analysis. This approach broadens sensitivity at the cost of specificity and cannot capture vasculitis that clinicians diagnosed and managed entirely in the outpatient setting. 

Confounding control

To overcome baseline differences between groups, the authors applied overlap propensity score weighting across 21 covariates. This method weights patients in the zone of clinical equipoise, supposedly producing more stable estimates than conventional inverse probability weighting.

Statistical analysis

The authors generated the primary hazard ratio using overlap-weighted Cox proportional hazards regression and pre-specified six sensitivity analyses:

1. Competing risk adjustment via Fine-Gray subdistribution hazards is important in the elderly, comorbid population, where death often precludes vasculitis

2. Censoring at drug discontinuation: estimating on-treatment risk 

3. Positive ANCA serology as an alternative, more specific outcome

4. Dose-response analysis: comparing above vs. below median daily does (40 mg)

5. Alpha-blocker comparator- replacing ACE/ARB with a similarly positioned drug class

6. Latency period analyses at 90, 180, and 365 days- accounting for potential delayed disease onset.

Funding 

The study received institutional funding from the Ontario Ministry of Health via ICES and the Vasculitis Foundation Young Investigator Grant held by the lead author. Neither funder had any role in the conduct or reporting of the study.

Results

The final cohort included 583,136 older adults, of whom 40,748 initiated hydralazine and 542,388 initiated an ACE inhibitor or ARB. The mean age was 73 years, and over half were female. Mean follow-up was approximately 5.9 years.

At baseline, hydralazine users were generally older and had more comorbidities and prior rheumatology visits. However, after overlap propensity score weighting, baseline characteristics seem balanced between groups, supporting comparability of groups.

Primary Outcome

During follow-up, vasculitis diagnoses occurred in 328 of hydralazine patients (absolute risk 0.8%) versus 2712 of ACE or ARB patients (absolute risk 0.5%). In weighted analyses, hydralazine use was associated with an increased risk of vasculitis of 1.19 (95% CI 1.04 to 1.37) when compared to ACE or ARB users. This corresponded to an absolute risk difference of 0.3% and higher crude incidence rates in the hydralazine group (234.7 vs 81.6 per 100,000 person-years). This three-times aka ~300% higher risk translates into only a ~ 20% higher risk through the magic of propensity score weighted analysis.

Time-to-event analysis showed that vasculitis occurred earlier in hydralazine users (median 545 days versus 1200 days, p<0.001), with separation of cumulative incidence curves over time.

Additional Analyses

Diagnoses of AAV (using AAV codes) were very rare in hydralazine users to calculate reliable risk estimation. When the competing risk of death was considered, the association was not statistically significant (1.01; 95% CI, 0.88 to 1.16).  Analyses censoring at treatment discontinuation yielded a higher estimated risk (HR 1.36), while a dose–response signal was observed, with higher doses (>40 mg/day) associated with increased risk (HR 1.28). However, when comparing with α-blockers, no significant difference was detected (HR 1.16, 95% CI, 0.98 to 1.37), and latency analyses at 90, 180, and 365 days showed non-significant associations.

Discussion

Since no prior studies directly compared hydralazine with ACEi or ARBs, this cohort provides one of the first population-level estimates of vasculitis risk in a real-world setting. In this cohort, hydralazine was associated with a risk for vasculitis in the weighted Cox model of 1.19, although the absolute risk difference was small (0.3%), and the association was no longer significant when accounting for additional analyses like the competing risk of death. These findings suggest that hospital-coded vasculitis following hydralazine exposure is uncommon, but they are less definitive in excluding under-recognized or incompletely captured cases (Fremont D et al, JAMA Netw Open, 2026). 

This is particularly important when considered alongside prior clinicopathologic studies. In a biopsy-based series, hydralazine-associated ANCA glomerulonephritis accounted for 4.3% of all ANCA-GN cases and was characterized by a distinctive overlap phenotype: high MPO positivity, dual ANCA seropositivity, anti-histone antibodies, hypocomplementemia, and immune-complex deposition (Santoriello et al, Kidney Int, 2021). Similar findings have been reported in other cohorts, reinforcing that hydralazine-associated disease frequently diverges from classic pauci-immune AAV and instead reflects a broader clinical spectrum of immune dysregulation with multiple phenotypes. This heterogeneity raises the possibility that reliance on administrative coding may underestimate the true burden of disease  (Santoriello et al, Kidney Int, 2021| Kumar et al, Semin Arthritis Rheum, 2018 | Choi HK et al, Arthritis Rheum, 2000). More recent case-based evidence further supports the ongoing clinical relevance of this entity. Contemporary reports of biopsy-proven hydralazine-associated ANCA-GN continue to describe severe renal presentations requiring immunosuppressive therapy (stopping the offending medication is insufficient), with consistent serologic and histopathologic overlap between drug-induced lupus and ANCA-associated vasculitis. Together, these suggest that although rare at the population level, hydralazine-associated vasculitis remains a reproducible and clinically meaningful syndrome (Quizon MR et al, CKJ, 2025). 

Historical data suggest a stronger signal when broader autoimmune outcomes are considered. Earlier prospective studies demonstrated a dose-dependent relationship, with incidence rates of hydralazine-induced autoimmune syndromes increasing substantially at higher doses and with prolonged exposure, mean cumulative dose 146 grams & mean time of three months. This aligns with the current cohort, in which events occurred after prolonged exposure and dosing. Differences in clinical descriptors, ranging from lupus-like to biopsy-proven vasculitis, likely explain the apparent discrepancy across studies (Cameron HA & Ramsay LE, BMJ, 1984 |  Timlin H et al, Cureus, 2019 | Kumar et al, Semin Arthritis Rheum, 2018, Fremont D et al, JAMA Netw Open, 2026). 

The divergence between analytic approaches further highlights the complexity of interpretation. While the Cox model suggests association, the competing risk model attenuates this signal. However, this should not be interpreted as definitive reassurance. In an older population with significant comorbidity, death may not only compete with vasculitis as an outcome but may also preclude its recognition (Fremont D et al, JAMA Netw Open, 2026). It is unclear how the much higher crude ratio (~ 3 times) gets attenuated to only 20% after propensity score matching. The censored analysis (with HR 1.36) after drug discontinuation might even be the more important result.

Mechanistic data provide additional support for a causal relationship between hydralazine and autoimmune vasculitis. Hydralazine has been shown to alter immune tolerance through multiple pathways, including modulation of neutrophil antigens such as MPO and PR3, promotion of autoantibody formation, and induction of immune-complex–mediated injury. These mechanisms align closely with the clinical and histopathologic features described in biopsy-based studies, reinforcing the biological plausibility of hydralazine-induced vasculitis despite its low observed incidence in population studies. (Xi G et al , JCI, 2025 | Santambrogio L, JCI, 2025 |  Drouzas K et al, Life (Basel), 2025 | Santoriello et al, Kidney Int, 2021).

Taken together, these findings suggest that hydralazine-associated vasculitis is a rare but biologically and clinically meaningful entity.

The apparent discrepancy between epidemiologic and clinicopathologic data likely reflects differences in outcome definition, ascertainment, and patient selection rather than true absence of effect.

Why use Hydralazine at all?

From a clinical perspective, these results emphasize the importance of vigilance for autoimmune complications, particularly in patients receiving higher doses or prolonged therapy. The authors suggest the risk of vasculitis is so low that it is not clinically meaningful given its risk-benefit. However, what benefit does it have? It is often used incorrectly for inpatient hypertension or hypertensive emergency. Inpatient hypertension does not need treatment and hydralazine use if associated with poor outcomes (eg Ghazi et al, J Hypertens 2023), and true hypertensive emergency has much more effective drugs (nitrates, nicardipine, clevidine, labetolol etc). In pregnancy, its use should follow labetolol, nifedipine, and alpha-methyldopa. Lastly, the heart failure trials (A-HeFT Taylor et al NEJM 2004) were done in the era when it was thought that skin color dictated RASi effect, and hydralazine was tested against placebo (not RASi, forget about flozins, MRAs, and beta-blockers, see Laurie Tomlinson rounds). There are no good indications for using hydralazine. When following a patient on hydralazine, we are left with the simple question, why-dralazine?

Strengths

• Large, population-based cohort 

• First study including comparison groups 

• Overlap propensity score weighting could control confounding variables

• Long follow-up, capturing delayed autoimmune events

• Multiple sensitivity analyses (competing risk, dose-response, alternative comparators)

Limitations

• Propensity score matched administrative database study with inherent limitations

• Outcome based on ICD-10 codes, with risk of misclassification and under-ascertainment

• Very low number of AAV-specific events, limiting phenotype-specific conclusions

• Hydralazine-associated disease heterogeneity (AAV–lupus overlap) and may not be fully captured by coding

• Restricted to older adults, limiting generalizability

Conclusions

Hydralazine-associated vasculitis appears to be rare at the population level but remains a biologically plausible and clinically significant condition. While this study helps address a long-standing evidence gap, it does not fully resolve whether hydralazine confers a clinically meaningful increased risk of AAV. For now, we should balance the risk, use when needed, but stay vigilant particularly in patients with prolonged exposure or higher dosing.

Summary by

Cristina Popa, Milagros Flores

Reviewed by 

 Brian Rifkin and Swapnil Hiremath

Header designed by AI and  prompts from Brian Rifkin

Friday, April 10th 2026, 12 pm Eastern- Space on X

Contemp Clin Trials. 2025 Jun:153:107911. doi: 10.1016/j.cct.2025.107911. Epub 2025 Apr 6.

System Interventions to Achieve Early and Equitable Kidney Transplants (STEPS): Protocol for STEPS, a randomized comparative effectiveness clinical trial

L Ebony Boulware, Patti L Ephraim, Tariq Shafi, Jamie A Green, Teri Browne, Tara S Strigo, Sarah Peskoe, Jonathan Wilson, Yuliya Lokhnygina, Aviel Alkon, George L Jackson, Matthew J Ellis, Debra Sudan, Blake Cameron, Pradeep K Vaitla, Ashley Cabacungan,  Lauren Brubaker, Emily L Obermiller, Clarissa J Diamantidis

PMID: 40199386

#NephTrials is an ongoing initiative between #NephJC and the ISN-ACT group. The ISN-ACT (Advancing Clinical Trials) is an International Society of Nephrology (ISN) initiative to encourage existing infrastructures within ISN to improve the global nephrology community’s participation in clinical trial research.

Introduction

Kidney transplantation remains the optimal therapy for kidney failure, yet access is neither early nor equitable. Despite decades of progress, only a minority of patients reach the transplant pathway before dialysis, and even fewer complete the steps required to receive a transplant. This gap reflects a fragmented process: patients are often identified late, inadequately informed, inconsistently referred, and infrequently able to complete the complex evaluation processes. As highlighted in the STEPS protocol, transplantation is not a single event but a multistep pathway, and failure at any single step can prevent patients from ever reaching the waitlist (Boulware et al,.Contemp Clin Trials, 2025).

Non-medical barriers, including health literacy, provider communication, system capacity, and logistical constraints, play a central role in limiting access to early transplant evaluation (Harding et al, Transplant Rev, 2021). At the same time, structural inequities remain deeply embedded in the system. Community-level vulnerability independently reduces access to living donor kidney transplantation (LDKT) and only partially explains racial disparities, with disproportionately worse effects among Black recipients (Killian et al, JAMA Surg, 2021). Meanwhile, these observations reinforce the need to move beyond simply describing inequities toward actively addressing them, as emphasized by Patzer, who highlighted bridging the gap between improved outcomes and unequal access to transplantation (Patzer R, JASN, 2024). More recently, these disparities have been reframed through an intersectional lens, recognizing how overlapping systems—race, geography, socioeconomic status, and healthcare infrastructure—interact to shape access long before transplant listing is even considered (Nonterah CW, Transpl Int, 2024).

Interventions targeting single components of the pathway have produced modest and inconsistent gains. Even multicomponent strategies, such as the pragmatic EnAKT LKD cluster randomized trial, improved selected steps but did not increase overall progression towards transplantation, underscoring the cumulative nature of barriers (Garg et al, JAMA Internal Medicine, 2023| NephJC summary | FF episode).

The STEPS trial (System Interventions to Achieve Equitable and Early Transplants) emerges in response to this gap. The trial tests a coordinated system-level intervention that combines automated electronic health record surveillance with proactive outreach and longitudinal patient navigation. Rather than improving isolated components, STEPS evaluated whether redesigning the transplant pathway itself can increase completion of the transplant evaluation and reduce disparities in access to kidney transplantation. 

How do you test a system-level intervention? The STEPS Trial Design

STEPS is a pragmatic, randomized comparative effectiveness trial designed to evaluate whether a coordinated health system intervention can improve access to kidney transplantation. The study examines whether redesigning how patients are identified, referred, educated, and navigated can change progression through the transplant pathway. The unit of intervention is the system, but the unit of inference is the patient, achieved through individual randomization embedded in routine care.

The STEPS intervention combines active electronic health record (EHR)–based surveillance with patient-centered outreach delivered by transplant social workers and coordinators. The surveillance registry was updated nightly within the EPIC electronic health record, identifying adults aged 18-74 years with CKD using objective criteria (two eGFR values < 60 ml/min/1.73 m²), followed by risk-based triggers: alerts at eGFR <30 ml/min/1.73 m² or ≥ 10% two-year risk using the Kidney Failure Risk Equation, and transplant referral prompts at eGFR ≤ 20 ml/min/1.73 m². This approach standardizes candidate identifications and reduces reliance on clinician recognition- one of the major sources of variability in previous studies. This multilevel approach targets key barriers across the transplant pathway- particularly among Black and rural individuals with advanced chronic kidney disease who are not yet on dialysis.

Importantly, the trial was conducted across three large and diverse U.S. health systems: Duke University Health System (DUHS), Geisinger Health System (GHS), and the University of Mississippi Medical Center (UMMC)- selected to capture different structural barriers to transplant access. DUHS and UMMC care for a high proportion of Black patients and rural populations, groups historically underrepresented in transplant access. Black individuals accounted for over 50% of kidney transplant recipients at DUHS and more than 70% at UMMC. In contrast, GHS has a highly rural population, enabling the study to also evaluate geographic disparities independent of race. By embedding the intervention within health systems that reflect real-world inequities in race and geography, STEPS is positioned not only to evaluate effectiveness but also to generate insights into how system-level interventions perform across populations disproportionately affected by limited access to transplantation. 

Can redesigning the health system improve access to kidney transplantation?

Following identification through the surveillance registry and enrollment, participants enter a structured pathway that reflects both methodological rigor and real-world applicability. Randomization was performed using a centralized, stratified block design, accounting for clinical site, race, and kidney function (eGFR ≤20 vs >20 ml/min/1.73m²), ensuring balance across factors closely linked to disparities in transplant access.

The trial successfully completed enrollment of 1,168 participants between March 2022 and March 2024. The trial was registered at ClinicalTrials.gov (NCT05014256). The planned sample size of approximately 1150 participants is expected to provide >80% power to detect a treatment effect for the primary outcome overall and specifically among Black participants, with conservative assumptions based on usual-care estimates across participating sites.

Once randomized, participants followed one of two care pathways. Participants assigned to arm 1, augmented usual care, continued to receive standard clinical management supported by EHR-based surveillance and best practice alerts, prompting clinicians to initiate nephrology referral and transplant evaluation when guideline thresholds are met. Participants in arm 2, STEPS intervention arm, receive a coordinated, multilevel intervention that integrated EHR-based identification, structured education, proactive outreach, and longitudinal patient navigation, designed to address barriers that traditional care does not systematically overcome.

A central component of STEPS is the integration of patient-centered educational and behavioral support strategies delivered by transplant social workers and nurse coordinators. Participants receive the “Living with Kidney Disease: All the Facts” booklet, developed to provide accessible, literacy-sensitive information about CKD progression and treatment options (Boulware et al, The PREPARE NOW Study, 2023). This is complemented by the TALK Social Worker Program, a structured intervention grounded in behavioral theory, which facilitates discussions about kidney transplantation, particularly LDKTs, among patients, their families, and providers (Boulware et al, AJKD, 2013). Through individualized and group sessions, the program helps patients identify personal, social, and logistical barriers while promoting informed decision-making and engagement in the transplant process.

Beyond education, STEPS incorporates active patient navigation, a critical element often missing in traditional care models. Transplant social workers and nurse coordinators maintain longitudinal contact with participants, assisting with scheduling, coordinating appointments, addressing financial and transportation barriers, and guiding patients through each step of the transplant evaluation. This coordinated approach reduces reliance on patient self-navigation, a well-recognized contributor to dropout along the transplant pathway.

Data collection in STEPS reflects its hybrid nature as both a clinical and behavioral intervention. Outcomes are assessed using electronic health records, administrative data, and centralized patient-reported measures collected at baseline and at 6, 12, and 18 months. The recruitment was centralized, having a dedicated data coordinating center to standardize the outcome ascertainment and minimize loss of follow-up.

The primary outcome is completion of the kidney transplant evaluation, defined using objective health system documentation, including evaluation completion, time to completion, listing decisions, or receipt of transplantation. This endpoint targets a critical bottleneck in the transplant pathway while avoiding confounding from organ availability. Secondary outcomes expand this perspective by examining intermediate steps along the pathway, including patient discussions with providers and family members, initiation and progression of transplant evaluation, and identification of potential living donors. Additionally, measures of patient knowledge, empowerment, and behavioral activation are included to better understand how the intervention influences decision-making and engagement.

Together, this design allows STEPS to move beyond traditional endpoints and evaluate whether a coordinated system-level intervention can meaningfully change both the trajectory and the experience of patients navigating the transplant pathway.

Statistical analysis follows an intent-to-treat framework, preserving randomization and minimizing bias from differential engagement with outreach and navigation. The primary comparison evaluates completion of transplant evaluation between groups using regression models adjusted for stratification variables (site, race, and baseline kidney function). Time-to-event analyses will assess progression through the pathway, accounting for variable follow-up. Secondary outcomes will be analyzed using generalized linear models appropriate for outcome type, with prespecified subgroup analyses by race, rural residence, and kidney function to examine effects on disparities. Missing patient-reported outcomes will be handled using multiple imputation, and sensitivity analyses will evaluate robustness to differential follow-up.

The study was funded by the Patient-Centered Outcomes Research Institute (PCORI) and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), with total project costs of approximately 12.95 million $, split between NIH (66%) and PCORI (54%). Investigators reported limited competing interests: one author served as an editor for the publishing journal, and another disclosed a consulting relationship and financial interest in a health coaching company.

Why STEPS Matters in Context?

In the absence of outcome data from STEPS, prior interventions offer important insights into bridging LDKTs disparities. Across studies, a consistent pattern emerges: interventions that target a single barrier can improve individual steps in the transplant pathway but rarely turn into sustained, system-wide gains.

Educational strategies, particularly when structured and guided, have demonstrated improvements in knowledge, readiness, and evaluation completion. For example, standardized transplant education programs have been associated with reduced disparities in access, while tailored interventions have improved patient engagement and decision-making (Patzer et al, CJASN, 2012; Arriola et al, Prog Transplant, 2025). Similarly, the navigator-based and culturally tailored programs have demonstrated meaningful benefits in donor identification and evaluation completion, particularly in disparity reductions. However, these effects are highly context-dependent and often difficult to reproduce at scale (Sullivan et al, CJASN, 2018). This variability becomes more apparent in larger pragmatic studies. Multisite navigator trials and system-wide interventions, such as EnAKT (Garg et al, JAMA Internal Medicine, 2023|  NephJC summary) have demonstrated that even well-designed multicomponent strategies may not improve overall progression toward transplantation when implemented across heterogeneous settings. 

Importantly, several studies suggest that interventions may have a greater impact among populations experiencing baseline disparities, indicating that targeting structural barriers can both improve access and advance equity. However, these gains remain inconsistent, underscoring the need for approaches that are multilevel, integrated, and sustained across the entire care pathway (Sullivan et al, CJASN, 2018;  Garg et al, JAMA Internal Medicine, 2023; Bailey et al, Wellcome Open Research, 2024). 

STEPS represents a methodological shift. Rather than testing education, navigation, or referral improvement in isolation, the trial integrates automated identification, augmented usual care, structured outreach, and longitudinal navigation within a single coordinated framework. The design targets multiple failure points along the transplant pathway (candidate identification, referral, evaluation completion, and donor engagement), while embedding the intervention within routine care workflows across diverse health systems.

The transplant pathway is not defined by a single decision point, but by a sequence of interdependent steps shaped by clinical, social, and structural factors. STEPS represents a critical evolution in trial design. Rather than focusing on isolated components of care, it tests whether aligning early identification, education, referral, and navigation within a coordinated system can meaningfully change how patients move through the transplant pathway.

The question is no longer whether individual interventions can work, but whether the system itself can be redesigned to deliver them effectively, equitably, and at scale—ultimately addressing the persistent burden of CKD and the ongoing disparities in access to kidney transplantation.

Join us this week on the X-space to explore this trial design with Dr Boulware and the ISN-NephJC team, on April 10, 12 pm EST! 

Summary prepared by
Milagros Flores, Cristina Popa

Reviewed by 
Brian Rifkin, Swapnil Hiremath

Tuesday, April 7th 2026, 9pm Eastern

NEJM Evid. 2026 Mar;5(3):EVIDoa2500086. doi: 10.1056/EVIDoa2500086. Epub 2026 Feb 24.

A Randomized Trial of Targeted Hyponatremia Correction in Hospitalized Patients

Julie Refardt, Laura Potasso, Anissa Pelouto, Moritz Trappe, Claudia Gregorian, Markus Koster, Ivana Dora Vodanovic, Dario Norello, Svenja Ravioli, Sadrija Cukoski, Maria Boesing, Basil Ryser, Lana Sambula, Nikola Rapsch, Sophie Monnerat, Julia Beck, Sven Lustenberger, Deborah R Vogt, Laura Werlen, Joyce Santos de Jesus, Martina Bontognali, Philipp Schuetz, Adrienne A M Zandbergen, Alessandro Peri, Darko Kastelan, Gregor Lindner, Joerg Leuppi, Stefan Bilz, Beat Mueller, Volker Burst, Ewout J Hoorn, Mirjam Christ-Crain

PMID:  41733398

DOI: 10.1056/EVIDoa2500086

Introduction

Don’t get salty, but you don’t know as much about sodium as you think you do. 

In 2017, you knew that increased sodium intake leads to increased urine sodium output. Then, Dr. Roger Rodby opined about why everything we know about sodium might be wrong (Some Thoughts on Spooky Sodium| NephJC). Ninety-eight percent of total-body sodium is confined in the extracellular fluid (ECF) compartment in young, healthy humans. However, about 80% of exchangeable sodium is found in the interstitial and connective tissues, and only about 15% of exchangeable sodium is in plasma. When dietary salt intake increases, urinary sodium excretion increases, but it does not match intake immediately and thus generates a positive sodium balance until excretion again equals intake. Increasing NaCl intake also increases body water in most situations, although this does not result predominantly from more fluid consumption but rather from fluid retention. When dietary salt intake rises from low to moderate levels, body water increases. When salt intake rises further, sodium accumulation may occur without an increase in water (Rokova et al, J Clin Invest, 2017).

In 2021, you thought you knew that increased sodium intake led to increased thirst and elevated blood pressure. Doctors Ellison and Welling looked at controversies in salt handling and blood pressure. Increased salt doesn’t always lead to increased thirst but rather increased hunger and higher calorie burn. Over-restricting salt may lead to insulin resistance and higher blood pressure. The mechanistic basis for the link between ECF volume and vascular tone remains contentious. Drinking saline solutions to increase salt intake increases protein catabolism, glucocorticoid production, and urea generation, whereas salt loading through diet, with access to free water, does not. (Ellison et al, NEJM, 2021)

In 2022, you knew that lowering salt intake was better for heart failure and hypertensive patients. However, implemented dietary counseling (reducing sodium below 2 grams daily) did not show added benefit in the largest trial performed in this population (Ezekowitz et al, Lancet, 2022| SODIUM-HF NephJC). Don’t even get me started on fluid restriction in heart failure- hint: it isn’t helpful, stop torturing your patients (Hermann et al, Heart, 2026).

In 2023, sodium correction limits were emphasized to reduce the risk of osmotic demyelination syndrome. However, Seethapathy et al. showed that slower sodium correction rates were associated with higher mortality and longer hospital stays. Because the study evaluated observed correction rates rather than treatment intent, the association should not be interpreted as causal and may reflect greater illness severity in patients whose sodium corrected more slowly (Seethapathy et al, NEJM Evid, 2023| Standing Corrected? NephJC).

Nowadays, we know that hyponatremia is associated with osteoporosis, falls, fractures, gait disturbance, and subtle cognitive impairment (Verbalis et al, J Bone Miner Res, 2010| Brinkkoetter et al, Sci Rep, 2019). So, my homeostasis amigos, shouldn’t we fix it? Among patients with mild to moderate asymptomatic hyponatremia, it remains unclear if normalization of sodium levels is clinically beneficial. 

Confused? Yeah, even we nephrologists still have much to learn about the ion that sets the tone for extracellular water. Homeostasis ain’t no joke!

The Study

Methods

This is a pragmatic, randomized, controlled, parallel-group, international, multi-center superiority trial with blinded outcome assessment.

The trial was conducted at 9 centers in Europe from August 2018 through April 2024.

Both university and community-based hospitals were included.

Inclusion and exclusion criteria are as follows. Patients with severe symptomatic hyponatremia requiring urgent correction, hypertonic hyponatremia, or end-of-life care were excluded.

Screening, Inclusion, and Randomization

Plasma sodium levels were reviewed by local trial physicians. Patients were invited to be included once hypotonic hyponatremia was confirmed (Na < 130 mmol/L, plasma osmolality ≤ 300 mOsm/kg). Hyponatremia could have occurred prior to, or during hospitalization. Patients could be enrolled anytime during their hospitalization. Initial assessment included reason for hospitalization, comorbidities, and additional lab values. A cognitive assessment was done with the Trail Making Test (essentially a connect-the-dots in numerical order). 

The trial was open-label with respect to treatment assignment, but outcome adjudication and follow-up assessments were performed by investigators blinded to treatment allocation. Randomization was centralized and performed in a 1:1 ratio without stratification.

Targeted Correction of Hyponatremia

Patients were then randomly assigned 1:1 to either targeted plasma sodium correction (intervention) or standard treatment (control). Treating physicians in the control group were not restricted from correcting hyponatremia. Therefore, sodium correction also occurred in the standard-of-care arm, consistent with the pragmatic design.

The targeted treatment of hyponatremia was based upon the following protocol derived from specialty guidelines.

The predominant cause of hyponatremia was determined by history, clinical presentation, assessment of fluid status, and lab testing. Hyponatremia determined to be due to “mixed etiologies” was classified by the predominant cause. Each classification of hyponatremia had its own stepwise treatment approach, determined by severity and response to therapy.

Treatment response and adherence were monitored daily. Treatment was intensified if sodium correction was < 2 mmol/L/d, was maintained if the correction was 2-12 mmol/L/d, and stopped if the correction was > 12 mmol/L/d (or > 18 mmol/L in 48 hours, considered an overcorrection). Overcorrection could be treated with hypotonic fluids with or without desmopressin. Apart from assuring adherence to the hyponatremia protocol, the trial team did not influence treatment or discharge decisions. After discharge, the treatment of hyponatremia was left to the treating physician.

Targeted plasma sodium was treated to a level of 135-145 mmol/L and was maintained for the duration of the hospitalization until discharge. Targeted correction was also stopped if the patient was hospitalized for > 30 days after inclusion, and they failed to attain normalization of sodium.

In the control group, patients received usual care, meaning hyponatremia was managed as in routine practice. Although described as “based on the European guidelines” (Spasovski et al, Eur J Endocrinol, 2014), no structured algorithm or treatment targets were mandated. Clinicians followed general principles, but therapy could range from active treatment to observation, and escalation to achieve normonatremia was not required. This contrasts with the intervention group, where care followed a predefined, stepwise protocol aimed at sodium normalization. Treatment decisions and sodium values were recorded retrospectively from the medical record after discharge.

Outcomes

Primary Outcome

-A combined risk of death or rehospitalization within 30 days of trial inclusion. The authors used no hierarchical weighting (death and rehospitalization were treated as equivalent events).

Secondary Outcomes

• Mortality and rehospitalization within 30 days and 1 year of trial inclusion

• Absolute change and rate of change of sodium levels

• Maximum change in sodium levels from inclusion to discharge

• Rate and time to normalization of sodium

• Rate of recurrence of hyponatremia within 30 days

• Complications due to overcorrection

• Length of hospital stay

• Falls and fractures within 30 days

• Quality of life questionnaire

• Trail Making test at admission and discharge

• Corrected 30-day rehospitalization/mortality rates based upon etiology, age, sex, and treatment

Events during the trial period were recorded by the trial team. Additional assessments were done following the hospitalization by a team blinded to treatment assignment.

Statistical Analysis

The sample size was calculated assuming an event rate of 23% in the standard care and 18% in the treatment group. To achieve 80% power with an alpha error rate of 5%, 2050 patients were needed for evaluation. 

The primary analysis followed a modified intention-to-treat approach, including all randomized patients who remained in the study for at least 24 hours. Predefined subgroups included severe hyponatremia (Na < 120), etiology, age (< or > 70 years), and sex. Secondary outcomes were considered exploratory without plans for multiple comparisons or adjustment of confidence intervals.
Missing outcome data were handled using available-case analysis without imputations.

Funding

The study was supported by a grant from the Swiss National Science Foundation. The funders had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Results

The per-protocol analysis included 2049 patients. In the full analysis set, 1079 were assigned to the intervention and 1094 to the control group.

The median age was 73, and 48% of the included patients were male. At inclusion the median plasma sodium level was 127 mmol/L in both groups. Roughly 6% of the entire cohort had severe hyponatremia (< 120 mmol/L).

Hyponatremia treatment strategies

Etiology-directed treatment was used more frequently in the intervention group, including fluid restriction for SIADH, isotonic saline for hypovolemia, and diuretic adjustments for hypovolemia. Hypertonic saline and desmopressin were used infrequently in both groups. Patients in the intervention group experienced a maximum absolute change of 10 +/- 5.6 mmol/L, while the control group had an 8.7 +/- 5.6 mmol/L change.

A normal sodium level was obtained by 60% of the intervention patients versus 46% of the control group. At discharge, 56% of intervention and 37% of control patients had normal sodium levels. Hyponatremia recurrence or persistence at 30-days was approximately 41% in both groups. The mean rate of sodium correction during hospitalization was modestly higher in the intervention group, but the overall sodium trajectories overlapped between groups. The median time to sodium normalization was shorter in the intervention arm.

Primary Outcome

Death or rehospitalization within 30 days of study inclusion occurred in 218 intervention patients versus 234 control patients (estimated absolute difference -1.3%; 95 CI: -4.9 to 2.2, p = 0.45). The observed event rate and sample size were consistent with the prespecified power assumptions. The finding was consistent when correcting for potential site effects, as well as best and worst-case scenario analyses, in which missing 30-day outcomes were assigned extreme assumptions favoring either the intervention or control group.

Secondary outcomes

Death occurred in 8% of both groups. In the same time frame, 13% of intervention patients and 14% of control patients were rehospitalized within 30 days. The intervention was not associated with time to the primary outcome, time to death, or time to rehospitalization. The median length of stay (7 days) was similar in both groups. There were no differences in cognitive assessment, quality of life, or rates of falls or fractures at 30-day follow-up. One-year mortality and rehospitalization rates likewise did not differ, indicating no sustained benefit of target sodium correction.

Subgroup analyses

Prespecified subgroups of etiology, severity, and sex did not suggest an association with the primary outcome. Tests for interaction were not statistically significant across prespecified subgroups, including baseline sodium severity, etiology, age, and sex. It is noteworthy that in patients > 70 years old, the intervention was associated with a lower risk of the primary outcome (OR 0.76, 95% CI, 0.57-1.00). This apparent age interaction was borderline and not adjusted for multiple comparisons. There was no evidence of correlation for reaching normal sodium levels and the primary outcome. However, reaching a normal sodium level (in either group) was associated with decreased odds of death or rehospitalization within 30 days (OR 0.74, 95% CI, 0.60-0.91). The association between normonatremia and improved outcomes appeared observational and was not modified by treatment assignment. 

Safety analysis

Overcorrection occurred in 2.3% of intervention and 1.4% of control patients. Most overcorrection events occurred within the first 48 hours of treatment and were managed with desmopressin and hypotonic fluids. Adverse events (e.g., prolonged hospitalization) occurred in 1.2% of intervention and 0.8% of control patients. No cases of osmotic demyelination syndrome were observed. Symptomatic worsening of hyponatremia occurred in 0.5% of intervention and 0.1% of control patients. All patients responded to therapy intensification. Rates of ICU transfer, neurologic complications, and treatment-related adverse events were low and similar between groups.

Weaknesses

• unblinded (design, with potential bias from increased awareness and monitoring of hyponatremia in the intervention arm)

• predominantly mild to moderate hyponatremia, limiting applicability to severe disease

• Intervention limited largely to the hospitalization period, with no standardized post-discharge management

• Modest separation between groups, with only small differences in achieved sodium level and substantial overlap in treatments

Strengths

• prospective, pragmatic, randomized design

• large sample size

• diverse (academic/community) hospital settings

• blinded outcome adjudication despite open-label treatment

• prespecified power calculation met with the expected event rate

• algorithm-based intervention grounded in physiology

• hard clinical primary endpoint (death or rehospitalization) rather than biochemical outcome 

Discussion

“To treat or not to treat?” is a profound question in asymptomatic hospitalized patients.

Therapeutic apathy and inertia can drive inactivity. However, there is precedent that intensifying treatments in the controlled hospital setting can lead to worse clinical outcomes and complications (e.g., hypoglycemia and hypotension) and often includes medication confusion following discharge. In the case of mild to moderate hyponatremia, the question arises- is euboxia and normonatremia the ultimate goal? It is interesting to note that in this well-run, large trial of hyponatremia, achieving a normal serum sodium (in either group) was associated with improved outcomes of death and rehospitalization at 30 days. However, this association does not establish causation and likely reflects improvement in the underlying disease rather than sodium correction itself. Hyponatremia represents disturbed water homeostasis and often serves as a marker of illness severity. This interpretation is consistent with pharmacological trials, such as vasopressin antagonists, which failed to show improved clinical outcomes despite normonatremia (Schrier et al, NEJM, 2006). Association versus causation appears to be in full effect for the hyponatremia correction conundrum.

This study found no significant difference in its primary outcome. However, the difference between treatment strategies was small (only 1.3 mmol/L higher in the intervention group), and therapies were not necessarily continued after discharge from the hospital setting. Despite greater normalization of sodium in the intensive group, there was a significant portion of patients who had recurrence of hyponatremia at 30 days (approximately 42% in both groups). Also, the use of therapies further down the algorithm was limited: only 8% were prescribed urea, and 3% vaptans. One could argue that urea is cheap, safe, and effective and could be used more (beyond what the guidelines call for). On the other hand, the vaptans are costly and do have significant side-effects (including liver toxicity and increased risk of GI bleeding) that might have limited their use, even in severe cases. One is left wondering if perhaps the intensive arm wasn’t intensive enough to make a significant difference. Especially since 40% of patients were discharged with uncorrected sodium levels. If we want to test if fixing the sodium makes a difference, we should use an algorithm that does a better job of fixing the sodium. 

The elderly (> 70 years old) appear to benefit the most from intensive interventions. This may be because this group is at higher risk for complications (cognitive, falls, fractures). Other than age, no other factors, including etiology and severity of hyponatremia, seem to have a significant association with the primary outcome. Because hyponatremia is common and ubiquitous, further large studies of subgroups might identify patients with a greater opportunity to benefit from intensification of sodium correction.

Hyponatremia is not a single disease but a manifestation of disturbed water homeostasis arising from multiple underlying conditions, including SIAD, diuretic use, hypovolemia, heart failure, cirrhosis, and endocrine disorders. Because these etiologies differ in pathophysiology, prognosis, and response to therapy, clinical studies of hyponatremia inherently pool biologically distinct populations. In this context, Hoorn and Zietse note that “the patient with hyponatremia does not exist”; because outcomes are largely characterized by the underlying disease complicated by hyponatremia rather than the sodium concentration itself (Hoorn, Zietse, JASN, 2017). Despite this heterogeneity, the present trial did not demonstrate differences in outcomes according to etiology. This might reflect both limited power for subgroup analysis and imprecision in diagnostic classification. Differentiating hypovolemic from euvolemic hyponatremia based on clinical assessment is unreliable, with reported sensitivities of 50-80% and specificities. 30-50%, and mixed etiologies are common. Patients frequently have multiple contributing mechanisms, further blurring etiologic distinctions. These diagnostic limitations dilute treatment effects in pragmatic trials and reduce the impact algorithm-based correction strategies, particularly when treatment is guided by imperfect volume classification. 

The HIT trial fits within this framework and provides randomized evidence addressing a central assumption underlying current guidelines. Both US (Verbalis JG, et al, Am J Med 2013) and European (Spasovski et al, Eur J Endocrinol, 2014) recommendations emphasize etiology-based therapy and cautious correction but differ in how strongly they prioritize biochemical normalization. The present trial shows that guideline-based intensification improves sodium normalization without improving short-term clinical outcomes. These findings suggest that, particularly in heterogenous populations with mild hyponatremia, normalization of sodium alone is unlikely to modify outcomes driven primarily by the underlying disease

Appropriately, the authors conclude that the trial does not suggest “do nothing” for patients with mild to moderate hyponatremia, but rather that intensive treatment does not confer clear or significant benefits over standard therapy. Increasing the number of therapeutics and intensifying treatment of moderate hyponatremia does not appear to be beneficial, at least in the short term. Standard treatment, which included doing nothing in 35% of patients, did not have any significant downside or safety issues.

Conclusion

In hospitalized patients with mild to moderate chronic hyponatremia, a more intensive targeted correction strategy modestly improved sodium levels but did not reduce 30-day mortality or rehospitalization, suggesting that in this population, where hyponatremia was generally mild, biochemical correction alone may be insufficient to influence short-term clinical outcomes.

Summary by

Brian Rifkin MD, FASN, FASDIN
Hattiesburg Clinic

Reviewed by

Cristina Popa, Joel Topf

The most fundamental advice for stone formers is simple: drink more.

How much? More. No matter how much urine you make, if you can make more you will do better, but more than 2.5 liters is the goal. We don’t actually care how much you drink—we care how much you pee. The goal is >2.5 liters of urine, because dilution fixes the chemistry that drives stones.

But patients don’t care about urine chemistries—they care about avoiding stones. And that’s where things get hard.

Stone trials with stone events are brutal. Events are slow, unpredictable, and unforgiving. They have a habit of wrecking dogma.

NOSTONE is the perfect example—thiazides improved urine chemistry and CT findings, but didn’t reduce patient facing stone events.

Now patient-centered outcomes come for the granddaddy of all advice: drink more water.

The PUSH trial (Lancet 2026) randomized patients to an aggressive, behaviorally engineered hydration strategy versus usual care (which, in stone disease, of course, is “MORE WATER”).
Once again, the RCT shows up and steals our favorite toy.

Let’s take a look at this trial before it is memory holed by every stone specialist.

Before we dive further into PUSH we should understand a bit of the prior art:

The most important study is an Italian RCT by Borghi, Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study (J Urol 1996) These guys enrolled patients, after their first kidney stone and randomized them to either:

1. Being told to drink a lot of water or

2. Being told, “Since it is your first kidney stone, there is no need to make changes to your diet.”

That’s it. That’s the intervention.

But the trialists must have been devastatingly persuasive.

People told to drink a lot of water immediately doubled their urine output and over time further increased their urine output to 2.6x their baseline urine volume. Patients in the control group had a modest 20% increase in urine volume for the first year and then reverted back to their baseline urine volume for years 2-5.

I hope I sound skeptical because I am. This sounds like bullshit to me. When Fred Coe (Changes in urine volume accomplished by physicians treating nephrolithiasis J Urol 2003) looked at how much urine volume increased following patients engaging a kidney stone doctor, he found a delta of 300 ml, not the 1600 ml the Italians “found.” Intrerestingly Coe found that the bump in urine volume was inversely proportional to the initial urine volume (reversion to mean or something else?).

Now back to PUSH

METHODS

Participants

The investigators targeted patients with a recent stone event (in the last 3-years, or in the last 5-years if there was also a new stone by U/S or CT).

Only patients with less than 2 liters of urine were randomized, exactly the patients we tell to drink more water. This setup raises a concern: regression to the mean could inflate urine improvements in both groups.

Intervention

Every nephrologist has their little advice they give people to get them to drink more and instagram has an entire cottage industry dedicated to convincing people to increase their water intake. PUSH didn’t just say “drink more”—it engineered behavior:

• Loss framed payments for drinking water. People were promised $1.50 a day unless they drank less than 2.5 liters a day. Very Kahneman and Tversky. This stimulus was gradually reduced over time

• Coaching with structured problem solving to get participants to DRINK MORE

• Text reminders and social nudges

The control got the usual, “drink more water” pep talk!

Assessment

Intake was tracked with Bluetooth water bottles. Very 2020s

Stone events were  investigated by a blinded adjudication committee. I love that patients qwere not trusted to adjudicate their own patient reported outcomes.

Secondary outcomes were exhaustive including serial CT scans and 24-hour urines.

Power analysis

The needed 821 group to reach 80% power to detect a 30% reduction in stone events at 2 years. Yikes, that is a large effect size. They assumed a 15% event rate with 20% attrition.

RESULTS

They nailed enrollment and retention, an under-appreciated win (1658 enrolled compared to 1642 estimated; 1367 retained, above the 1326 estimated).

Demographics

They had more women than men. We don’t see that often in studies. Maybe this was due to the requirement for low water intake for enrollment?

Baseline Urine

Baseline use of anti stone therapy was modest, 7% thiazide and 11% KCitrate.

Baseline urine chemistries were surprisingly normal. The standout abnormality was volume: 1.3 L/day.

Primary Outcome

After 2 years 19% in the intervention group had a stone events compared to 20% in the control group. No signal.

The intervention increased urine volume, but the effect faded over time and never reached the 2.5 liter target.

In the control group we have nice Hawthorne effect versus reversion to the mean.

The serial CT scans showed no difference in stone growth or reduction in the development of new stones.

Adverse effects

The intervention group drank ~28 extra gallons over 6 months.

And what was the payoff?

More urgency, more frequency, and more nocturia.

More water. More symptoms. No benefit.

The authors considered if the trial would have shown a different result if it went longer. They concluded, “The follow-up period was only 2 years; however, the PUSH trial exceeded the estimated event rate, and the Kaplan–Meier curves were nearly parallel, suggesting that a longer follow-up period for PUSH is unlikely to change the results.”

Conclusion

So what did PUSH actually show?

Not that water doesn’t work.

It showed that even an intensive, multi-layered, evidence-based behavioral intervention cannot increase hydration enough to prevent stones.

This is less a failure of physiology and more a failure of our ability to change behavior.

Ooof.

Kidney stones clinics take another one on the chin.

In this edition

• The Assist trial (Efficacy and Safety of Atrasentan in Patients with IgA Nephropathy Receiving Sodium-Glucose Cotransporter 2 Inhibitors: Placebo-Controlled, Crossover Trial; Heerspink et al, JASN 2026)

• 24-month data from APPLAUSE-IGAN (Iptacopan in IgA Nephropathy — Final 24-Month Data; Barratt et al NEJM 2026)

• Sexual Dimorphism and Age Effects in CKD and Type 2 Diabetes in the CONFIDENCE Trial (Agarwal et al, NDT, 2026)

• Acute eGFR Changes and Their Mediation of Albuminuria Reduction with Empagliflozin and Finerenone (Agarwal et al, JASN, 2026)

The Assist Trial

J Am Soc Nephrol. 2026 Mar 29. doi: 10.1681/ASN.0000001076. Online ahead of print.

Efficacy and Safety of Atrasentan in Patients with IgA Nephropathy Receiving Sodium-Glucose Cotransporter 2 Inhibitors: Placebo-Controlled, Crossover Trial

Hiddo J L Heerspink, Irene L Noronha, Jose Luis Górriz, Soo Kun Lim, Sradha S Kotwal, Gianna M Kirsztajn, José Barros Neto, Jessica Ryan, Mei Sian Fu, Sung-Gyun Kim, Jonathan Barratt, Yasmin Brahmbhatt, Greggory J Housler, Rong Jiao, Marion Dahlke, Amit Lodha, Amy K Mottl; Atrasentan and Sodium Glucose Co-transporter-2 Inhibitor Efficacy and Safety Trial (Assist) Investigator Group

PMID: 41904616

Why was this trial needed?

The natural history of IgA nephropathy (IgAN) is unforgiving: even after optimal RAS blockade, a proteinuria >0.5g/day predicts a 30-35% risk of end-stage kidney disease within two decades (KDIGO IgA group, Kidney Int, 2025 | NephJC summary). Recent “renoprotective” breakthroughs have turned flozins into the new backbone of supportive care (or “palliative” if you agree with Dr Barratt’s terminology) care. In the DAPA-CKD and EMPA-KIDNEY trials, patients with IgAN experienced a 26% reduction in albuminuria and a 71% decrease in the composite renal endpoint (Wheeler et al, Kidney Int, 2021| EMPA-KIDNEY Collaborative Group, Lancet Diabetes Endocrinol, 2024). Their mechanisms (tubulo-glomerular feedback-mediated reduction of intraglomerular pressure, natriuresis, anti-inflammatory, and podocyte-protective effects) soften the hemodynamic injury that fuels disease progression (Kim et al, NDT, 2026). Yet flozins alone leave a sizable residual risk. In both trials (which were not IgAN focused), median proteinuria after treatment remained >0.8 g/day, and the eGFR slope, although flatter, did not halt decline (Wheeler et al, Lancet Diabetes Endocrinol, 2021). Therefore, the sponsors and investigators believe IgAN calls for an additional, mechanistically distinct agent that targets the endothelin 1 (ET-1) pathway, a key driver of glomerular vasoconstriction, inflammation, and fibrosis. One could argue that targeting B Cells (or even complement - see the #NephMadness match-up) is more disease modifying than using Flozins and ETAs. Atrasentan, a selective endothelin-A receptor antagonist, achieves precisely this. In the phase-3 ALIGN study, atrasentan lowered the UACR by 38% versus a 3% rise with placebo (difference -36%, p<0.001) after 36 weeks, with a safety profile that lacked clinically relevant fluid overload (Heerspink et al, NEJM, 2025). Earlier SONAR data in DKD confirmed the proteinuria benefit and highlighted a manageable fluid retention signal when patients were carefully selected for low-risk phenotypes (Heerspink et al, Lancet, 2019 | NephJC summary).
The next logical question is whether adding atrasentan to a flozin amplifies the antiproteinuric effectS without compounding adverse effects. Real-world evidence with the dual endothelin-angiotensin blocker sparsentan (which shares the ETA antagonism of atrasentan) showed a 62% reductions in UPCR at 14 weeks when patients were already on maximal RAS blockers plus flozins (Schanz et al, CKJ, 2024). However, sparsentan confounds the interpretation because it simultaneously blocks the AT1receptor; a pure ETA antagonist, like atrasentan, is needed to isolate the endothelin contribution.

How was the trial done and what did it report?

The ASSIST phase II trial was a double-blind, placebo-controlled crossover study in which each participant receives atrasentan (0.75 mg daily) for 12 weeks, a 12-week washout, then placebo (or reverse sequence) while remaining on stable flozin dosing (Heerspink et al, Kidney Int, 2021). The crossover format maximizes statistical power- each subject acts as its own control - while limiting the sample size needed to detect modest but clinically meaningful changes in proteinuria and eGFR. Moreover, the trial stratifies enrollment by SGLT2i status (stable vs run-in) to ensure that any safety signal, such as the fluid retention observed in SONAR, is captured in the exact context of contemporary IgAN care. The proteinuria required for enrolment was >0.5g/day for flozinated patients, and > 0.85 g/day for flozin-naive, who underwent a flozin run-in period to ensure their post flozinated albuminuria was still high enough. Notable exclusions were type 1 DM (flozin’s risk for causing DKA), prior history of heart failure or BNP > 200 pg/ml, or anemia (Hgb < 9 g/dL), as ETAs can cause heart failure and anemia. The primary outcome was proteinuria reduction at 12 weeks, see figure 1 for details. The trial was powered for a 25% reduction in UPCR, requiring 52 participants. 

Overall, 54 patients were randomized, with a median GFR of 63 and UPCR of 1 g/g, and were mostly (65%) White. Only 13% were non-flozinated at baseline, requiring a flozin run-in phase. Atrasentan reduced proteinuria by 30% (versus 7% in placebo), thus hitting the powered for target and coming in at −25.3% (95% CI, −36.8 to −11.7; p < 0.001). Treatment sequence did not matter, and for those in sequence two who went on to receive atrasentan, there wasn’t much more of a proteinuria decrease at 24 weeks (treatment difference of -26.4% versus placebo).

The GFR slope at 12 weeks was a meaningless: 1.2 versus 1.5 ml/min/1.73m2. Though overall safety events seem similar, one patient had AKI deemed to be related to atrasentan, fluid retention was twice as common with atrasentan, BNP increased in sequence 1 but not sequence 2, and the hemoglobin dropped a bit with atrasentan. 

What does this trial change?

The trial proved atrasentan reduces proteinuria at 12 weeks in flozinated participants with UPCR > 0.5 g/day by about 25%. Does this matter, and is it really as safe as the authors claim? We would posit the answer to both is, “No”. 

Firstly, IgAN therapeutics are a crowded space with many efficacious disease modifying drugs (steroids, targeted-release budesonide, BAFF/APRIL, and complement inhibitors). Are ETAs disease-modifying or supportive/palliative therapies like RASi and flozins? Theoretical effects of ETAs aside, it is difficult to see them being disease modifying. Their effects are likely hemodynamic (the mechanistic lack of a huge effect on BP in an underpowered RCT should not be overinterpreted). Time will tell how good they are in establishing a position for themselves in this space. 

Unfortunately, safety remains a concern which cannot be allayed in a 54 patient RCT of 12 to 24 weeks of exposure. Even in this carefully selected (preserved GFR, no heart failure, low BNP) population, there were some concerning BNP signals (albeit in one sequence) and an associated hemoglobin drop. 

This trial is useful in showing the pharmacologically and volumetrically rationale combination of a flozin and ETA (note the ongoing trial with zibotentan and empagliflozin in DKD summarized here) is a promising option that attenuates the sodium retention abilities of ETAs while synergizing the anti-proteinuric effects. Will this supplant B-cell therapies? Again, the answer is, “No”. Is it good to have more options for the ‘most common primary glomerulonephritis’? To this we give a halfhearted, “Yes”. 

The APPLAUSE-IgAN Trial 24 month Data

N Engl J Med, 2026 Mar 29. doi: 10.1056/NEJMoa2600743. Online ahead of print.

Iptacopan in IgA Nephropathy — Final 24-Month Data

Jonathan Barratt, Necmi Eren, 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, Annabel Magirr, Ronny Renfurm, Thomas Hach, Vlado Perkovi; APPLAUSE-IgAN Study Group

PMID: 41910396

Why was this trial needed?

Yet another IgAN trial? (in fact, ASSIST and APPLAUSE were part of a dedicated IGAN trial session, and sandwiched a fascinating phase 2/3 trial of targeted release budesonide - aka nefecon alternative - that we look forward to reading when published). But our cynical snark aside, the foundation for the APPLAUSE-IgAN study rests on an established unmet need, a strong mechanistic rationale, and the regulatory requirement for confirmatory evidence. 

• Unmet need: despite optimized supportive care with RAS inhibitors, a significant proportion of patients with proteinuria > 1 g/day progress to end-stage renal disease (Reich et al, JASN 2007| Liu et al, Exp Ther Med, 2016). The use of systemic corticosteroids is limited by substantial toxicity (Kim et al, CJASN, 2025). This created the need for targeted, disease-modifying therapies. Keep in mind this RCT began enrolling in 2020, when all we had in IgAN was the initial TESTING data (Lv et al JAMA 2017 | NephJC summary). 

• Mechanism: the alternative complement pathway has been reported to be a driver of glomerular inflammation and injury in IgAN (Medjeral-Thomas et al, Semin Immunopathol, 2021). As Jon Barratt points out in his NephMadness commentary, it has been universally noted that for every bit of IgA deposited within the glomerulus, there is accompanying C3. The deposition of galactose-deficient IgA1 (Gd-IgA1) immune complexes in the mesangium activates the alternative pathway, leading to the formation of C3 and C5 convertases and the terminal membrane attack complex (MAC), which mediate tissue damage (Teh et al, AJKD, 2026). Iptacopan is a first-in-class oral inhibitor of Factor B, an important component of the alternative pathway C3 convertase. By selectively blocking the alternative pathway, it targets a central step in the disease’s inflammatory cascade without affecting the classical or lectin pathways, theoretically offering a more precise therapeutic strategy (Schubart et al, Proc Natl Acad Sci USA, 2019| Risitano et al, Lancet Hematol, 2021). Since we all need reminders of (or have nightmares of trying to remember) the complement pathway, here it is, along with the various therapeutic targets developed or in development.

• Regulatory imperative: while the initial data (Perkovic et al, NEJM, 2025) showed that iptacopan reduced proteinuria at 9 months in a dose-dependent manner, full regulatory approval requires the 24 month GFR slope data from a large-scale phase 3 trial. Based on the 9 month data, iptacopan has already received accelerated approval from the FDA in August 2024.  

How was this trial done, and what did it report?

This was a large multicenter prospective placebo-controlled trial, sponsored by Novartis (the maker of iptacopan) and overseen by the academic team. It was the typical IgAN trial design that you have read already on NephJC: patients with IgAN with more than 1g/g UPCR and GFR > 30, receiving iptacopan or placebo, on a background of RASi with optional (not mandated) flozin use. Kidney biopsy was required within 2 years for those with GFR 30-45 and within 5 years for those with GFR > 45, and with less than 50% IFTA (though this was the reported and not a central pathology re-reading of biopsies). Pneumococcal and meningococcal vaccination was required, and Hib vaccination was recommended, given planned complement inhibition. The primary outcome was the annualized GFR loss over the 24-month follow-up period with several secondary outcomes including a composite kidney-failure endpoint (sustained decline in the eGFR of ≥30% from baseline, a sustained eGFR of <15, initiation of dialysis, kidney transplant, or death from kidney failure, whichever occurred first) and the change from baseline to 9 months in the score on the Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue, version 4 (on a scale from 0 to 52, with higher scores indicating less fatigue). 

478 patients were enrolled, and the discontinuation rates were higher with placebo (37%) than with iptacopan (19%). The mean age was about 40 years, just over half were men, just over half were Asian, with the rest mostly White, a UPCR of 1.7 g/g and a GFR just over 60 ml/min at baseline. Almost all were on RASi, about 20% flozinated, with just over a quarter having previously received steroids and 75% with hematuria at baseline. Iptacopan slowed GFR progression by half, from about 6 to 3 ml/min/year (between-group difference of 3.02 ml per minute per 1.73 m2 per year, 95% CI, 2.02 to 4.0; adjusted p<0.001). The composite kidney outcome was also positive (HR 0.57, 95% CI, 0.40 to 0.81; adjusted p = 0.003) but the FACIT score was not, and thus the p values for subsequent hierarchical outcomes were not reported. From the subgroups (enrollment stratified a priori for GFR 30-45 and > 45, Asian or not, UPCR >/< 2 g/g), the effects were quite consistent. Though adverse events were overall similar, ~ 60% of them were infections (consider enrolment started 2020) and serious infections were more common with iptacopan (6.7% versus 2.1% with placebo). 

What does this trial change?

Clearly, trial results deserved the APPLASE it received at the presentation. Iptacopan does slow kidney disease progression at 24 months in IgAN, and seems safe in this large phase 3 trial. Notable aspects of the trial results are the substantial 3 ml/min/year GFR decline that still occurred in the iptacopan group (compared with presented telitacicept data of almost no decline, while atacicept data is awaited), the rapid proteinuria reduction with iptacopan, and the higher infection rates despite prior vaccination and close care provided in the trial setting. 

It is useful to revisit the therapeutic arena in IgAN as covered by NephMadness (and the superb GN in 10 podcast episode) to frame this discussion. We have B-cell therapies (APRIL/BAFF inhibitors) to act at the proximal hits in the IgAN pathophysiology. Complement inhibitors are clearly distal to that mechanism - so would that make them redundant in someone already on B-cell therapies? Quite possibly - or at least lower down in therapeutic importance? In an ideal world with unlimited money (or seamless access) one could even consider using both these agents? Actual disease progression is not as clean as it is portrayed in these mechanistic figures, and combination therapy might well be the best approach. We are still in the early phase of drug development in this area, so we won’t have empirical data to make these decisions and are relying on mechanisms and pathophysiology to read the tea leaves. Hopefully we will eventually have this data to make better decisions - and a drug that costs less than half a million dollars annually. Until then, we can applaud the development of another therapeutic agent, which also helps us understand how the complement pathway is intricately involved in IgAN disease progression.  

CONFIDENCE: Age and Sex interactions

Nephrol Dial Transplant. 2026 Mar 27:gfag075. doi: 10.1093/ndt/gfag075. Online ahead of print.

Sexual Dimorphism and Age Effects in CKD and Type 2 Diabetes in the CONFIDENCE Trial

Rajiv Agarwal, Jennifer B Green, Hiddo J L Heerspink , Johannes F E Mann, Janet B McGill, Amy K Mottl, Masaomi Nangaku, Julio Rosenstock, Muthiah Vaduganathan, Charlie Scott, Li Li, Na Li, Carolina Aldworth, Meike Brinker, Peter Rossing

PMID: 41894225

Why was this analysis needed?

The data arrives clothed in certainty: a larger fall in albuminuria, a tolerable drip in filtration, a modest lowering of the pressure. Yet, at the bedside, this order dissolves- and biology refuses abstraction. The CONFIDENCE trial (Agarwal et al., NEJM, 2025 | NephJC summary) enrolled a broad DKD population and reported an average ≈ 30% extra UACR fall, a modest, reversible dip in eGFR, and a small systolic blood pressure (SBP) decline (Vaduganathan, NDT, 2025). Those aggregate numbers are compelling, yet they mask two biologically potent variables- sex and age- that shape the natural history of diabetic kidney disease. If the combination behaves differently in a 45-year-old man versus a 78-year-old woman, clinicians must know it before committing patients to a new regimen.

Sex is not a neutral descriptor. Men tend to experience earlier glomerular hyperfiltration and progression to end-stage renal disease, while women, despite higher CKD prevalence, progress more slowly, partly because estrogen confers vascular protection (Farahmand et al., BMC Endocr Disord, 2021). A pooled analysis of the FIDELITY data set (Bansal et al, BMJ Open, 2024) highlighted that finerenone’s reduction in heart-failure hospitalizations was more pronounced in men, whereas preliminary observations from CONFIDENCE hinted that women were more likely to achieve a >30% UACR drop (Mottl, et al, JASN, 2025). These divergent hints suggest that the finerenone-empagliflozin duet may deliver different magnitudes of benefit depending on the patient’s sex. Ignoring this possibility would be equivalent to prescribing a one-size-fits-all approach to patients with CKD. 

On the other hand, age governs both risk and tolerance. Elderly patients carry a higher baseline cardiovascular risk and a reduced renal reserve, making them especially vulnerable to the acute eGFR dip and hyperkalemia that follows mineralocorticoid-receptor antagonism. Younger patients, by contrast, have the potential to harvest a lifetime of protection if aggressive albuminuria lowering is instituted early. The primary CONFIDENCE manuscript assures us that safety was “consistent across KDIGO risk categories”, yet “consistent” can conceal clinically meaningful gradients- especially in the oldest quartile, where potassium handling and blood pressure autoregulation can differ markedly (Mottl, et al, JASN, 2025). An age-stratified analysis would therefore quantify whether an 80-year-old safely tolerates the same initial dose titration as a 55-year-old and whether the magnitude of UACR reduction, and its downstream impact on hard outcomes, remains comparable.

Mechanistic certainty already exists for SGLT2i and ns-MRAs to decrease albuminuria. A mediation analysis demonstrated that early UACR reduction accounts for roughly 84% of finerenone’s kidney-protective effect and about 37% of its cardiovascular benefit, establishing albuminuria as a validated surrogate endpoint (Agarwal et al, Ann Intern Med, 2023). However, it examined finerenone alone, not the synergistic combination now under scrutiny. The CONFIDENCE interplay analysis supplies the raw efficacy signal of the duet (larger UACR decline, modest eGFR and SBP changes) but does not translate those averages into probabilities of achieving a clinically meaningful albuminuria response for a specific demographic group. Only by overlaying the mediation framework with age- and sex-specific outcomes can we predict how a 30% UACR fall will affect an individual’s risk of end-stage renal disease or heart-failure hospitalization.

How was it done, and what did it report?
To move beyond the aggregate data, the investigators conducted a prespecified exploratory analysis of the 798 patients in the CONFIDENCE trial. They employed a linear mixed-effects model to dissect the longitudinal trajectories in UACR, allowing evaluation of how age and sex influence response over the 180-day treatment period. Age was modeled both as a continuous variable and categorically by quartiles, while sex was analyzed as a binary variable. The models tested for interaction between these demographic factors and the treatment arms to determine if the benefits were uniform. The analysis showed:

• A linear age-efficacy gradient: advancing age was a robust factor predicting a greater albuminuria-lowering response. The analysis quantified a significant 10.2% incremental reduction in UACR for every 10-year increase in age (95 CI: -15.5 to -4.6; p=0.001). This demonstrates that therapeutic efficacy does not wane, but scales positively with age.

• Pronounced sexual dimorphism: the data revealed a sex-based difference in treatment response. Women achieved an 18.6% greater reduction in UACR compared to men by day 180 (95% CI 6.3 to 28.2, p=0.008).

• Treatment-independent biological effect: the age and sex effects were independent of specific therapy. Whether a patient received finerenone, empagliflozin, or a combination, the magnitude of their response was similarly modulated by their age and sex. This points toward a fundamental biological mechanism rather than a drug-specific interaction. Importantly, the enhanced efficacy in older patients and women was not accompanied by a compromised safety profile; the incidence of adverse events, including hyperkalemia and acute kidney injury, remained consistent across all age and sex cohorts (see table 4).

What does this analysis change?
The analysis reframes the interpretation of the CONFIDENCE trial, shifting it from a straightforward report on additive efficacy to a more nuanced text on precision nephrology. However, this enthusiasm must be tempered by the analyst's inherent limitations.
First, it provides a compelling, if preliminary, counter-narrative to the “prescribing paradox” in geriatric medicine. The pervasive clinical inertia that leads to under-prescription in older patients is directly challenged by data suggesting that albuminuria reduction is enhanced with age. This provides an evidence-based rationale to treat the elderly more aggressively (or at least, just as aggressively). A crucial note of caution, however, is that this conclusion is based on a 180-day reduction in a surrogate marker. We are assuming that this ultimately translates into cardiorenal benefits. 

Second, it generates a powerful hypothesis regarding the “female paradox” in DKD. The superior response in women makes the authors say that the historical disparities in outcomes may stem from systemic undertreatment, rather than biological resistance. However, while statistically robust, these exploratory findings are from a trial not powered to definitively assess sex-specific outcomes. Though prespecified, these are from smaller subgroups looking at surrogate outcomes.  Never-the-less these signals may inform future studies.

Finally, while this analysis sharpens our clinical focus, it is important to interpret its findings with scientific precision. The lack of a significant treatment interaction means that age and sex are prognostic factors for the response to these classes of drugs, not that the synergy of the combination is uniquely amplified in these subgroups. An older woman responds better to empagliflozin, finerenone, and their combination. Furthermore, the reliance on albuminuria as a surrogate endpoint, though supported by mediation analyses, is not suitable for hard outcome data. History is replete with trials where promising changes in surrogate markers failed to translate into clinical benefit.

Conclusion: This analysis doesn’t provide a definitive new set of rules but rather a map. It changes the questions we must ask at the bedside: not “Does this patient need combination therapy?" but, "How might this patient’s age and sex profile predict the magnitude of their response?” It forces a reevaluation of clinical biases, while simultaneously highlighting the urgent need for long-term outcome data to validate these provocative, but as yet incomplete findings. Bottom line, treat older people and women just as aggressively as you treat younger men. No need for sexism or ageism while erecting your four pillars of DKD. 

CONFIDENCE: Mediation analysis

J Am Soc Nephrol. 2026 Mar 29. doi: 10.1681/ASN.0000001071. Online ahead of print.

Acute eGFR Changes and Their Mediation of Albuminuria Reduction with Empagliflozin and Finerenone

Rajiv Agarwal, Ricardo Correa-Rotter, Sankar D Navaneethan, Kei Fukami, Hiddo J L Heerspink, Johannes F E Mann, Janet B McGill, Amy K Mottl, Masaomi Nangaku, Julio Rosenstock, Peter Rossing, Muthiah Vaduganathan, Charlie Scott, Li Li, Carolina Aldworth, Jennifer B Green, Matthew R Weir 

PMID: 41905767

Why was this analysis needed?

The progression of CKD is propelled by a destructive interplay among declining eGFR, rising systolic blood pressure (SBP), and increasing UACR. The pathophysiological triad creates a vicious cycle where systemic and intraglomerular hypertension damage the glomerulus, leading to albuminuria; this protein leakage then incites tubular inflammation and fibrosis, accelerating nephron loss and a further decline in eGFR (Martinez Leon et al., Nat Rev Endocrinol, 2026). Therefore, effective therapy must address the entire disease axis.

While foundational RAS inhibition tempers this cycle, substantial residual risk remains. The past decade has armed us with two mechanistically distinct therapies: the non-steroidal finerenone, which targets aldosterone - and possibly also inflammation and fibrosis as shown in FIDELIO-DKD (NephJC Summary) and FIGARO-DKD trials, and the flozins, which correct glomerular hemodynamics, with profound benefits seen in trials such as CREDENCE (NephJC Summary), DAPA-CKD (NephJC Summary) and EMPA-KIDNEY (NephJC Summary). Post-hoc analyses hinted at a powerful synergy, setting the stage for the CONFIDENCE trial to prospectively test the simultaneous initiation of both agents (Rossing, et al, Diabetes Care, 2022).

This context makes a detailed interplay analysis of the CONFIDENCE trial essential (Agarwal, et al, NEJM, 2025 | NephJC). The trial’s primary findings - superior albuminuria reduction with combination therapy, without a safety signal with simultaneous start - is the first step to a more complete picture. A holistic analysis of all these markers is required to confirm the therapeutic synergy, clarifying whether the UACR reduction is achieved without an excessive initial eGFR dip or concerning blood pressure effect. By mapping the trajectory of eGFR, SBP, and UACR over time, we can determine if the combination produces a more favorable cardiac/renal state than either drug alone. 

Furthermore, dissecting this interplay may provide mechanistic and safety insight. It allows us to untangle the hemodynamic effect, driven by empagliflozin, from the anti-inflammatory benefits of finerenone. This moves beyond simple adverse-event reporting to reveal the dynamic physiological trade-offs of combination therapy, such as whether the natriuretic effect of empagliflozin mitigates the hyperkalemia risk posed by finerenone. 

How was it done, and what did it report?

This analysis is somewhat similar to the one published in Annals for FIDELITY (Agarwal et al, Annals of IM 2023), but now applied to CONFIDENCE. In this exploratory analysis of the CONFIDENCE trial, the purpose was to ascertain if the acute eGFR decline (defined as > 30% from baseline to day 14) mediated the treatment effect of the interventions on the primary outcome (UACR decrease at 180 days). A linear mixed model using fixed effects was used for acute eGFR decline estimations. For more on mediation analysis, check out this helpful tutorial (Lange et al Epid Health 2017).

Determinants of acute GFR decline

The acute decline in GFR (> 30 at 14 days) was, as expected, highest in the combination, followed by empa and then finerenone - but the nadir came earlier (at day 14) for the combo and empa, and much later (~ day 90) for finerenone. 

This acute GFR decline was associated in those with higher baseline GFR, and those on concomitant diuretics. Higher baseline UACR was associated with the chronic, not acute decline (noting that chronic is still only over 180 days). Notably there was not much of a GFR decline noted in those with lower levels of kidney function, GFR ~ 30.

Determinants of any GFR decline

Examining > 30% decline at any time point over 180 days, combo therapy (versus either agent alone), higher baseline UACR, eGFR, and diuretic use were associated with this (Table 2, below). 

Mediation analysis

In the mediation analysis (table 3, below), comparing the effect on UACR at 180 days that was mediated by the acute eGFR decline, this contribution was seen much more in combination versus finerenone (28%) than combination versus empagliflozin (5.2%), suggesting little of the additional benefit provided by finerenone is mediated by the acute eGFR decline.

Adverse effects by eGFR decline

These are shown in table 5, and it is notable that hyperkalemia was slightly more common in those who had an acute eGFR decline than in those who did not. 

What does this analysis change? 

This study provides rich granular data exploring the determinants of 30% GFR declines as well as mediation analysis of whether the acute GFR decline is important in albuminuria reduction. The decline only seen in higher GFR might reflect regression to mean or hemodynamic unloading of hyperfiltrating glomeruli. The authors posit that since only 5% of the UACR effect of finerenone mediated by eGFR decline reflects the antiinflammatory and antifibrotic (dare we say ‘pleiotropic’) effects rather than hemodynamics. This would support synergistic and independent effects of finerenone compared to flozins or RASi in DKD. 

These results should not make you more or less inclined to use these drugs together, but they do help in how we think about the creatinine bumps and changes happening upon initiation. The lack of GFR decline in those with low GFR is reassuring - one should perhaps be bold at initiating flozin + finerenone together even if GFR is 30 ml/min. The hyperkalemia seen with the combination group was somewhat disappointing in CONFIDENCE, especially for those of us who were hoping empa would attenuate the hyperkalemia seen with finerenone. As suspected, (listen to Joel on the pod) this was mostly mediated by the higher rates of acute GFR decline seen with the combination. What should one make of the mediation analysis? ¯\_(ツ)_/¯. Does it matter how a drug works, if we know it works? No, not when making decisions on whether to use it - but possibly on future research pathways more than anything else.

By Swap Hiremath & Cristina Popa

Reviewed by Brian Rifkin

Yesterday the NephJC Editorial Internship class graduated.

As part of that graduation we awarded the 2026 NephJC Kidneys, the best looking trophy in nephrology.

Here are the previous winners:

The first four awards are voted on by the entire #NephTwitter community

The manuscript of the year goes to PISCES by showing that we can make a difference in hemodialysis.

2026 NephJC Kidney for Manuscript of the Year: Fish-Oil Supplementation and Cardiovascular Events in Patients Receiving Hemodialysis.

NephJC coverage | PubMed

We love to promote new and ambitious social media projects in social media and we dedicate this award to the person who started this whole movement, Nathan Hellman.

2026 Nathan Hellman Social Media Award goes to Roger Rodby and RUSH Nephrology for Renal Biopsy Cases

Visual abstracts changed the way we share and discuss manuscripts in the short-attention-span era of social media. CJASN and NephJC are the pioneers for this media.

2026 Visual Abstract of the Year goes to Husam Alzayer

Social Justice and social media go together like CKD and SGLT2i/ARB/GLP1/nsMRAs. Since 2020 NephJC has had a Social Justice Award. In a world full of insane changes, we need a little more justice.

The 2026 Social Justice Award goes to World Kidney Day- Kidney Health for All

The second series of awards are voted on by the NephJC Working group.

NephJC is a volunteer organization and is dependant on people donating their time and energy to making this work. The MVP goes to the person who best exemplifies this ethos. NephJC only gets better and better because of this persons unyielding efforts to get the job done.

The 2026 NephJC MVP goes to co-editor in chief Brian Rifkin

NephJC depends on a constant supply of new people to help run the program. Many of these people do great work but we recognize one that is the greatest…

The 2026 Rookie of the Year goes to Akshaya Jayachandran

NephJC asks scientists to participate in the chats and podcasts and really depends on them to provide a lot of the content that makes NephJC work. The work group votes on the best of these participants. This year’s winner is sharp, funny, and friendly IgA expert with an accent…

The 2026 Engaged Scientist of the Year goes to Jonathan Barratt

And the last award is decided on just by the editorial care of NephJC, Swap, Joel, Cristina, and Brian. We already announced this one but wanted to re-recognize Paresh Jadav for his generosity for the ASN Kidney Week party.

That’s a wrap on the 2026 NephJC Kidneys! In the end, it’s not about the awards, it’s about the we do, the education we share, the friendships we build, and the inspiration driving nephrology forward. Let’s keep creating the #FOAMed to light the way for the next generation of nephrologists. Congratulations to all the winners!

The updated table of winners…

But a new development is that med-mastodon no longer is supported, and is likely to be shut down. It seems Nick Marks is unable to maintain it - for the last little while, Ryan Wild has been running this. See their blog post from January with more details. Ryan has tried to contact Nick Marks (and so have I) to transfer ‘ownership’ with no response, and Ryan will be shutting down Med-Mastodon soon. 

Many of you may just shrug. But for those of you who have a med-mastodon account and don’t want to walk away - there is an option. You can switch instances. The simple way is:

• Create an account on another instance (I went to mastodon.social , Ryan Wild runs Universeodon.com)

• Create an ‘alias’ there via preferences>Account settings, and enter your med-mastodon handle

• Go to your med-mastodon account and Preference>Account>export and follow those steps 

• Voila, your followers will come over. 

• There are ways to do a more sophisticated move e.g. here 

Not everything moves - see this excellent blog for more on what you lose and more advice

Swap (now at @hswapnil@mastodon.social)

Header image from the AMNH

#NephJC Chat

Tuesday, March 10th 2026, 9 pm Eastern on Bluesky

Clin J Am Soc Nephrol. 2026 Jan 2. doi: 10.2215/CJN.0000000969. Online ahead of print.

A Randomized Clinical Trial of Kidney Autologous Cell Therapy in Diabetic Kidney Disease

Čižman, Borut; Butler, Emily L; Stavas, Joseph; Prakash, Rachita; Saad, Theodore; Silva, Arnold; Wooldridge, Thomas; Aqeel, Ahmed; Yan, Hongxia; Barysauskas, Constance M.; Culleton, Bruce

PMID: 41481370   

‘Failure is the simple opportunity to begin again, this time more intelligently’
Henry Ford

Introduction

Around 850 million people around the world suffer from CKD; among them, 50% is due to diabetic kidney disease (DKD). For many decades, the only proven available therapy was renin-angiotensin system inhibitors (RASi). However, there has been a recent renaissance of therapies to slow DKD progression with newer molecules like sodium glucose transport inhibitors (SGLT2i), non-steroidal mineralocorticoid blockers (ns-MRAs), and glucagon-like peptide-1 receptor antagonists (GLP-1 RAs), creating the four pillars of DKD goal-directed medical treatment (GDMT) (Neuen et al, NDT, 2025).

These drugs can slow the progression of kidney disease but not fully reverse it, indicating that there is still an unmet need in DKD. Recently, cellular therapy (i.e., regenerative medicine) has opened up new possibilities in CKD treatment, and this sci-fi-esque technology is now within reach. Mesenchymal stem cells (MSCs), present in bone marrow and other tissues, can generate any tissue depending on their surrounding milieu. MSCs are attracted to injured organs (due to cytokine signaling) and, therefore, are potential therapeutics for many chronic diseases (Farini et al,  Stem Cells Int, 2014). Unfortunately, up until now, the ability of the kidney to repair glomerular injury was limited by the kidney’s low regenerative potential, and DKD led to an inevitable downward spiral to ESKD (Bussolati et al, Nat Rev Neph, 2016). 

Although initial studies with renal progenitor cells gave positive results in animal models of CKD, their short life span and lower potential to regenerate nephrons have limited their use in kidney disease. As we are aware, there are many types of kidney cells, and some do regenerate. Clinical medicine tells us that ATN and tubule regeneration is possible over a period of days to months. Surviving renal epithelial cells, even in the absence of renal progenitor cells, can regenerate the entire tubular system following acute tubular injury (Lin et al, J Clin Invest, 2005). In addition, animal models showed that selective renal cell injections can decrease the progression of kidney disease, halting the NfKB and TGF-ꞵ progressive damage (Stenvinkel et al, KI Rep, 2016); hence, renal autologous cell therapy (REACT therapy) has attracted interest for clinical use. REACT cells are collected through renal biopsy samples and grown in culture media before they are reinjected into the kidney directly (Stavas et al, Am J Neph, 2022).

If a kidney transplant (whole organ) is the best renal replacement therapy, then is REACT (partial liquid transplant) the best preventative strategy for progressive DKD?

The Study

Methods

The REGEN-007 trial was a phase 2, multicenter, randomized, open-label trial designed to evaluate the safety and efficacy of rilparencel in adults with type 1 or type 2 diabetes mellitus and advanced CKD. The trial enrolled individuals aged 30 to 80 with an eGFR of 20 to 50 ml/min/1.73 m², a UACR between 30 and 5000 mg/g, and an HbA1c below 10%.

Inclusion and exclusion criteria

Preparation of Autologous Cells (Rilparencel)
An ultrasound-guided or CT-guided renal biopsy specimen was taken and transported to the prokidney manufacturing unit. The harvested tissue undergoes enzymatic digestion and density gradient separation to isolate a heterogeneous population of renal epithelial lineage cells (SRCs). These cells are expanded ex vivo for approximately four to six weeks under “good manufacturing practice” conditions before formulation into the final product rilparencel. The cell suspension is embedded in a thermolabile hydrogel carrier to facilitate cortical retention following injection.

Unlike most investigational regenerative approaches in nephrology, which rely on systemically administered mesenchymal cells, rilparencel represents a locoregional autologous cell therapy. The therapeutic premise is that injection of renal lineage cells directly into the kidney cortex may exert regenerative or reparative effects through paracrine signaling, modulation of local inflammation, and antifibrotic pathways. Preclinical models have suggested that these SRC populations may contain epithelial progenitor-like cells derived from multiple nephron lineages, including tubular epithelial and glomerular epithelial cells, although the exact functional contribution of these cell populations in human kidneys remains uncertain.   

The required dose is calculated depending on the kidneys’ volume by MRI. For each gram of kidney,  3×106 cells are required for transfusion. The rilparencel concentration of 100×106  per 3 ml is sufficient for 100 g of kidney tissue. The final rilparencel product was injected percutaneously under CT guidance back into the patient’s kidney cortex. 

Randomization and endpoints
The study’s primary efficacy endpoint was the change in the total (acute and chronic) slope of eGFR, calculated with the CKD-EPI 2009 equation, comparing the pre-injection period to the post-last injection period. Secondary efficacy endpoints included time to ≥40% eGFR decline, dialysis, renal or cardiovascular death, and composite renal outcomes. Safety endpoints encompassed biopsy-related complications, injection-related AEs, and product-related AEs. Analyses employed linear mixed-effects models for slope comparison and Kaplan-Meier methods for time-to-event outcomes. 

Patients were randomized 1:1 into two treatment groups.

• Cohort 1 (scheduled dosing): received two REACT injections—the first into 1 kidney and the second into the contralateral kidney approximately 3 months later.  

• Cohort 2 (triggered dosing): received one initial injection for the biopsied kidney and then evaluations every 3 months. A second injection was only administered if the patient met a “redose trigger," defined as an eGFR decline of ≥ 20% or a sustained UACR increase of ≥ 30%. If there were no triggers over a 15-month observation period following the first injection, then those patients would only receive a single injection.

Outcome Measurements, Safety Assessments, and Statistical Analysis
Efficacy analyses were performed on the modified intent-to-treat population and safety analyses on the safety set. The primary efficacy endpoint—fall in eGFR slope—was made from a linear mixed model.

Various subgroups

Primary safety endpoint: The percentage of participants with procedure-related and investigational product-related treatment-emergent adverse events (AEs and TEAEs).  Secondary safety endpoint: The percentage of participants with procedure-related death.

Determinants of 5-year and 2-year risk of ESRD

Funding Source
Funding done by ProKidney (NASDAQ: PROK), a late-clinical-stage biotechnology company involved in autologous cell therapy which makes the product, and many of the authors (including first/last) are employees of the company. The company people did all the analysis and wrote the manuscript.

Results

Between July 2021 and March 2023, 77 participants were screened across five clinical sites in the United States. Of these, 53 participants underwent randomization, with 27 assigned to Cohort 1 and 26 to Cohort 2. Overall, 45 participants completed study treatment (23 in Cohort 1 and 22 in Cohort 2).

The study population reflected a typical cohort of patients with advanced diabetic kidney disease. The mean age was 60 years, and approximately 2/3rd of the trial participants were male. The majority had type 2 diabetes (78%), and the mean baseline eGFR was 33 ml/min/1.73 m², indicating moderate to advanced CKD. Median albuminuria across the cohort was 421 mg/g. Most patients were on a RASi, around 30-40% were flozinated, with smaller numbers on a GLP1RA or an MRA. 

In the first cohort, most patients (24) received the two doses of rilparencel, while in the second cohort, 15/25 (~ 67%) needed a second injection because of eGFR decline of ≥ 20% or a sustained UACR increase of ≥ 30%. 

Primary endpoint
In Cohort 1, the annual change in kidney function in the preinjection period, as measured by the slope of eGFR, was −5.84 ml/min per 1.73 m² (95% CI, −7.97 to −3.70). In the period after the last injection, the annual change was −1.27 ml/min per 1.73 m² (95% CI, −3.97 to 1.43). The difference in the slope of eGFR between treatment periods was 4.57 ml/min per 1.73 m² (95% CI, 1.95 to 7.18). This represents a 78% improvement in the rate of eGFR decline for this group. 

In Cohort 2, the annual change in kidney function in the preinjection period, as measured by the slope of eGFR, was −3.40 ml/min per 1.73 m2 (95% CI, −5.03 to −1.77). In the period after the last injection, the annual change was −1.71 ml/min per 1.73 m2 (95% CI, −3.78 to 0.36). The difference in the slope of eGFR between treatment periods was 1.70 ml/min per 1.73 m2 (95% CI, −0.24 to 3.63).

Subgroup analyses evaluated the primary endpoint across baseline characteristics (including CKD stage, body mass index, HbA1c level, albuminuria category, and background therapy with SGLT2i or GLP-1RA). No consistent interaction between baseline characteristics and treatment response was identified, although subgroup sample sizes were small.

Secondary outcomes
Clinical events were relatively infrequent during follow-up. For the 3-component composite outcome (≥40% decline in eGFR, eGFR <15 ml/min/1.73 m², or kidney/cardiovascular death), events occurred in 7 participants (29%) in cohort 1 versus 5 participants (20%) in cohort 2.

When a fourth component (increase in albuminuria ≥30%) was included, the four-component composite outcome occurred in 10 participants (42%) in Cohort 1 and 15 participants (60%) in Cohort 2. The median event-free time for this composite outcome in Cohort 2 was 17 months.  

Risk prediction using the Kidney Failure Risk Equation (KFRE, 8 variable equation) suggested that kidney failure risk stabilized or improved in a proportion of participants following treatment. This was a prespecified endpoint of the study.

At 12 months after the first injection: 29% (7 patients) Cohort 1 and 16% ( 4 patients) Cohort 2 had the same or a lower predicted risk of ESKD compared with baseline. At 18 months, this was unchanged for Cohort 1 and had increased further to 28% in Cohort 2 showing stabilization or reduction in their predicted risk of kidney failure.

Four patients in cohort 1 and two patients in cohort 2 experienced a > 40% sustained drop in eGFR at 30 days. Additionally, six patients in cohort 1 and twelve patients in cohort 2 had a > 30% increase in UACR sustained at 90 days. The actual change in UACR is not found in the paper or supplement.

Safety
A total of 87 rilparencel injections were performed during the trial. Safety outcomes included adverse events related to 3 distinct components of the intervention: the kidney biopsy, the injection procedure, and the rilparencel itself. Procedure-related treatment-emergent adverse events occurred in 16 participants (33%). The most frequently reported events included injection site pain, renal hematoma, chills, headache, nausea. Six participants (12%) experienced product-related treatment-emergent adverse events, most of which were mild systemic symptoms such as nausea, dizziness, fatigue, or headache. 

Biopsy-related serious adverse events were reported in three participants and included subcapsular renal hematoma, acute kidney injury, and hematuria with hydronephrosis. One participant experienced a procedure-related subcapsular hematoma following injection.

Importantly, no product-related serious adverse events and no procedure-related deaths were reported during the study.

Discussion

In this phase 2, clinical trial, the use of the rilparencel was associated with a slower decline of eGFR compared to the previous trend, in patients with advanced  DKD (GFR ~ 30s, UACR ~ 400 mg/g) and a pre-infusion eGFR loss of ~ 3.4 to 5.8 ml/min/1.73m2/year. This suggests that even in such advanced disease when we usually think fibrosis and a cycle of inexorably declining kidney function has set in, injecting renal autologous cells may promote recovery or suppress further damage. In this limited sample size and follow up, rilparencel also seems to be well tolerated and safe. 

Strengths
For a phase 2 RCT, this was quite well done to demonstrate that the investigational agent has some promise of efficacy and is relatively safe. 

Limitations
No placebo or sham procedure arm was included, a decision driven largely by the procedural nature of the intervention. Because all participants required an initial kidney biopsy to manufacture the cellular product, the investigators elected to compare outcomes against each participant’s historical disease trajectory rather than against a concurrently treated control group. Consequently, the trial’s primary efficacy analysis relied on within-subject slope comparison, contrasting the pre-intervention decline in kidney function- derived from historical eGFR measurements spanning up to 24 months- with the slope observed after treatment. While this design increases statistical efficacy in small exploratory studies, it introduces important interpretive challenges, including susceptibility to regression to the mean, the Hawthorne effect, variability in historical laboratory measurements, and changes in concomitant therapies over time. Though the authors report changes in KFRE, they do not report actual pre/post UACR to allow us to understand what drove this change. 

Rilparencel or GDMT?
The present study allowed all baseline GDMT for DKD. During the study 80% of participants were on ACE inhibitors or ARBs, however only 37% were receiving SGLT2 inhibitors and 39% were on GLP-1 receptor agonists at baseline. This is actually better than average for most patients with DKD in the US. So the change in slope of eGFR attributed to rilparencel injections is not the full story. Even in 2021-2023, our optimal use of DKD medications remains low, and less than 10% of patients who would qualify for such GDMT are actually receiving all four medications.

Hence, this was not a comparison that allows us to pit rilparencel against GDMT - since GDMT is already approved, one cannot do such a trial, and it is likely that in a phase 3 RCT many (or most) patients will be on GDMT as baseline standard of care. Nevertheless, as we have seen with reported data, it is almost possible to achieve remission - or bring eGFR down slope to a level expected for age-related decline - with full GDMT. GDMT also has other systemic benefits: reduction in blood sugars, blood pressure, obesity, and cardiovascular outcomes. It is unsure (and unlikely) that rilparencel would have such benefits. However, it represents a one or two shot intervention, with no ongoing pill burden. As uptake of  GDMT medications increases, the need and effects of invasive procedures like REACT may be reserved for specific high risk DKD patients. Ultimately, the placebo-controlled phase 3 trial will determine whether rilparencel represents a new treatment option for patients with advanced type 2 diabetes mellitus and CKD.

What do other studies in this area show?
Various studies done with different cell lines in patients with AKI and CKD have been attempted, including stem cells and progenitor cells (Salybekov et al, Front Cell Dev Biol, 2024). 
These studies are not without controversy, and unfortunately  incorporate many elements that may lead to bias in observations. Current research is hindered by several common limitations including: selection of patients at different CKD stages and different underlying etiologies of the CKD. Only a few trials, such as the REACT studies, specifically target diabetes-related cases. This is problematic because different etiologies can lead to distinct types of kidney damage, which may affect the efficacy of the treatment. In addition, there remains no consensus on the optimal cell dosage. The absence of a standardized dosing protocol may lead to inconsistent results across studies, difficulties in conducting meta-analyses and systematic reviews, and challenges in clinical implementation. Finally, the small sample sizes in many studies contribute to a lack of randomization, low statistical power, limited generalizability, a higher risk of false positives, and potential biases.

Studies on autologous renal cells
Of course there are many potential advantages of autologous cell therapy over RRT and even transplantation. Being able to regenerate one’s own tissue to prevent organ failure and/or exposure to lifelong immunosuppression would be preferable to many patients. Infusions are also less stressful than organ surgery on elderly patients who might not otherwise qualify for kidney transplantation. Various studies are in the pipeline; some are completed, some are recruiting, and the majority of the studies are in the US.

Conclusion

The REGEN-007  phase 2 trial suggests that autologous renal cell therapy may alter the trajectory of kidney function in patients with diabetic CKD. The magnitude of the reported change in eGFR slope is notable, although interpretation is limited by the open-label design, reliance on historical controls, and small sample size. Whether rilparencel ultimately becomes part of the DKD therapeutic armamentarium will depend on the results of the ongoing placebo-controlled phase 3 trial, which are needed to determine whether the observed signal translates into meaningful clinical outcomes such as delayed dialysis or improved survival.

Summary by
Dr Sai Vani Yellampalli,
Consultant nephrologist 
Kurnool Kidney Care

Dr Akshaya Jayachandran
Assistant Professor, Nephrology
Christian Medical College & Hospital
Vellore, Tamilnadu, India

NephJC Interns, Class of 2025

Reviewed by
Cristina Popa, Brian Rifkin, Swapnil Hiremath

Header Image created by AI, based on prompts by  Akshaya Jayachandran