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Kidney Int. 2026 Apr 23:S0085-2538(26)00305-4. doi: 10.1016/j.kint.2026.03.015

Clinical and histologic predictors of non-diabetic kidney disease in patients with diabetes mellitus

TN Caza, V Charu, DF Dai, VG Davis, F Boyd, L Spenst, PD Walker 

PMID: 42034202 

Audio Abstract: https://audioscholar.cc/pdf/q2brtw2u7b?t=0

Introduction

Diabetic nephropathy (DN) has long been recognized as the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide, correlating with the escalating global prevalence of diabetes mellitus (Zouh et al, Lancet, 2024). Historically, the clinical paradigm assumed an inevitable progression of renal decline in diabetic patients, characterized by a predictable transition from hyperfiltration to overt proteinuria and eventually ESKD. However, the advent of modern nephroprotective therapies has altered this natural history (Afkarian et al, JAMA, 2016), making atypical clinical courses more common and questioning the assumption that all kidney dysfunction in these patients is solely attributable to diabetes. It is increasingly recognized that patients with diabetes frequently develop non-diabetic kidney disease (NDKD), either as an isolated pathology or superimposed on underlying DN (Fiorentino et al, Nephrol Dial Transplant, 2017).

Recent global literature highlights that the prevalence of NDKD among diabetic patients undergoing kidney biopsy is remarkably high, frequently ranging from 18% to over 62%, depending on the specific cohort and biopsy thresholds utilized (Zeng et al, BMC Endocr Discord, 2022). The accurate identification of NDKD is critical because it dramatically alters a patient's prognosis and therapeutic trajectory. Many secondary diagnoses, such as acute interstitial nephritis, IgA nephropathy, or crescentic glomerulonephritis, are potentially reversible with targeted interventions like immunosuppression. Consequently, identifying and treating these conditions can significantly delay or entirely prevent the onset of ESKD.

Despite the high prevalence of NDKD, routine kidney biopsy is not universally performed in this population, and clinicians often face a diagnostic dilemma when evaluating kidney function impairment in diabetics. While emerging non-invasive diagnostic models and clinical predictors such as a short duration of diabetes (e.g., less than five years), the absence of diabetic retinopathy, active urinary sediment (hematuria), and acute, rapidly progressive renal failure provide valuable guidance, they cannot replace the definitive diagnostic utility of a tissue biopsy.

Currently, there are no established, universal guidelines dictating precisely when to perform a renal biopsy in a patient with diabetes for the identification of underlying non diabetic kidney disease. To address this critical knowledge gap Caza et al (Kidney Int, 2026) present the largest retrospective cohort study till date of patients with diabetes who have undergone native kidney biopsies, comprising 49,075 cases. By leveraging this unprecedented dataset, this study aims to robustly quantify the true frequency of NDKD, map the distribution of specific histopathological diagnoses, and identify the clinical indications and demographic parameters that significantly increase the odds of discovering NDKD.

The Study

Methods

Study Design

This study represents the largest retrospective analysis till date of native renal biopsies from patients with diabetes. The research was conducted following institutional review board (IRB) approval and utilized a vast database of biopsies received at Arkana Laboratories (Little Rock, Arkansas, USA) between 2001 and 2024.

Cohort Development and Characterization

The study population was derived from a primary database of 229,026 native kidney biopsies. From this pool, 78,886 biopsies (34.4%) were identified as originating from patients with a clinical history of diabetes mellitus.

To ensure diagnostic accuracy and specimen adequacy, cases with fewer than 10 glomeruli by light microscopy were excluded. This resulted in the finalization of two primary cohorts:

• Cohort 1 (n = 49,075): This large-scale cohort was utilized to determine the overall frequency of non-diabetic kidney disease (NDKD), the distribution of specific renal diagnoses, and the clinical morbidities present at the time of biopsy. 

• Cohort 2 (n = 13,995): A subset of Cohort 1, this group consisted of patients with biopsy-proven diabetic nephropathy (DN) where the specific clinical indication for the biopsy was available. This indication was determined through a meticulous manual review of clinical data, including age, gender, ethnicity, and the specific diagnosis the clinician intended to rule out.All kidney biopsies in diabetic patients were included from 2001-2013. From 2013 to 2024, the first 1000 biopsies in patients with DM were included every year. 

• Clinical Subset (n = 400): A subset of consecutively diagnosed patients was further analyzed for granular clinical parameters, including serum creatinine, quantitative proteinuria at presentation, and inpatient versus outpatient status.

Histopathological Evaluation

All renal tissue samples underwent comprehensive processing for light microscopy, immunofluorescence, and electron microscopy using standard diagnostic techniques. The pathologic evaluation included:

• RPS Classification: Diabetic nephropathy was graded according to the Renal Pathology Society (RPS) classification system by a single pathologist

• Chronicity Indices: Quantitative assessment of global glomerulosclerosis, segmental glomerulosclerosis, interstitial fibrosis and tubular atrophy (IFTA), arteriosclerosis, and arteriolar hyalinosis

• NDKD Identification: All non-diabetic renal lesions were recorded, whether they occurred in isolation or concurrently with diabetic nephropathy

Clinical Indications for Biopsy

Clinical indications were self-reported by the treating clinicians and categorized for Cohort 2. These indications included:

1. Acute Kidney Injury (AKI)

2. Acute Nephritic Syndrome

3. Rapidly Progressive Renal Failure

4. Isolated Hematuria

5. Suspected NDKD

6. Proteinuria significantly greater than expected for the degree of DN

7. Chronic Kidney Disease (CKD) of unclear etiology

Analysis of Outcomes and ESKD Progression

To evaluate the long-term prognostic impact of NDKD, biopsy results were integrated with the United States Renal Data Service (USRDS) database (data available through 2022). Renal survival and progression to end-stage kidney disease (ESKD) were compared across three groups:

• DN alone

• DN with concurrent NDKD

• NDKD alone

Kaplan-Meier survival analysis was performed for cases collected between 2001 and 2019, ensuring a minimum of 3 years of follow-up for outcome evaluation.

Statistical Analysis

Descriptive statistics (means, SDs, counts, and percentages) were used to summarize the data. The association between clinical exposures and outcomes was evaluated using:

• Odds Ratios (ORs): With 95% confidence intervals (CIs) to assess the likelihood of NDKD based on clinical indications.

• Breslow-Day Test: To evaluate heterogeneity among ORs.

• Cochran-Armitage Trend Test: To assess linear associations between ordinal measures (e.g., RPS class) and binary outcomes.

• Survival Analysis: Kaplan-Meier curves and Cox regression models were used to determine hazard ratios (HR) for ESKD progression based on NDKD status.

• Multiple Testing Correction: X² tests utilized the Benjamini-Hochberg correction for categorical variables, while continuous variables were analyzed via t-tests or Kruskal-Wallis tests as appropriate.

Results

The cohort included 49,075 kidney biopsies from patients with diabetes analyzed between 2001 and 2024. Among biopsied patients, DN alone was present in 41.2%, 22.9% had DN and concurrent NDKD, and 35.9% had isolated NDKD(not 18.3% as erroneously mentioned at one place in the article describing cohort characteristics), resulting in an overall NDKD prevalence of 58.8% of all biopsies. Patients with NDKD were more frequently biopsied in the inpatient setting and more commonly had positive autoimmune serologies or concurrent infections. A second cohort of 13,995 patients with biopsy-proven DN and documented biopsy indications was subsequently analyzed to assess predictive variables of concurrent NDKD. Mean age was 58.5 years, with male predominance in all three diagnostic categories. Among patients with known diabetes type, 83.2% had T2DM. Hypertension and obesity were significantly more common in patients with DN alone. 

Overall the most prevalent NDKD diagnoses included acute tubular injury (ATI), acute interstitial nephritis (AIN), proliferative glomerulonephritis, IgA nephropathy (IgAN), and crescentic glomerulonephritis. ATI was the most common  diagnosis in both the cohort with DKD + NDKD and those with NDKD, the most frequent concurrent diagnoses were ATI, IgAN, and AIN, while in isolated NDKD, the most common findings included ATI, arterionephrosclerosis, membranoproliferative glomerulonephritis (MPGN), crescentic glomerulonephritis, focal segmental glomerulosclerosis (FSGS), and IgA nephropathy.   The biopsy incidence of DN has steadily increased over time, from 7% of native renal biopsies between 2001–2007 to 17% between 2015–2022.

The highest odds of concurrent NDKD diagnosis was associated with acute nephritic syndrome in a 59% (OR 4.01, 95% CI 2.99 to 5.38), followed by rapidly progressive renal failure (OR 2.38, 95% CI 1.66 to 3.4), acute kidney injury (OR 3.01, 95% CI 2.79 to 3.26), and hematuria (OR 1.60, 95% CI 1.03 to 2.48). Meanwhile, proteinuria (17%) as well as CKD (9%) were associated with the lowest diagnostic yield, making DN alone the most probable diagnosis in these clinical settings. 

Common second diagnoses in patients with DN as per clinical indication were as follows: 

• AKI: ATI (46%), Infection associated GN, Acute interstitial nephritis

• RPRF- crescentic GN (49%), ATI 

• Acute nephritis- infection associated GN(51%), ATI, crescentic GN

• Unexpected increase in proteinuria- ATI(19%), MN , IgAN

• Hematuria- IgAN (44%), Infection associated GN

• CKD- ATI (32%), IgAN, AIN

• Suspicion of NDKD- ATI (18%), Infection associated GN

Kidney biopsies were performed to rule out a specific diagnosis for 19.8% of cases, most commonly for monoclonal gammopathy of renal significance confirmed in only 7% of these patients. Among rule-out biopsies, minimal change disease had the highest diagnostic accuracy (45%), followed by ATI (33%) and membranous nephropathy (30%).

Patients younger than 30 years and older than 60 years had the highest prevalence of NDKD, increasing steadily over 80 years, particularly when diagnosing AKI or acute nephritic syndrome. Black and Hispanic patients were less likely to have an NDKD diagnosis (OR 0.75 and 0.76, respectively), but more frequently demonstrated severe DN on biopsy.

Earlier diabetic nephropathy lesions (RPS class I–II) were associated with higher rates of NDKD compared with advanced diabetic lesions (RPS class III–IV), with a prevalence of 51% versus 23%, respectively. This was a nearly 2-fold difference across almost all clinical indications. 

Among the 13,061 patients who progressed to end-stage kidney disease (ESKD), patients with an NDKD had significantly better kidney outcomes compared with those with DN alone. The presence of DN alone  was associated with a markedly higher risk of progression to ESKD compared to those without DN (HR 2.56; 95% CI 2.45 to 2.68), and this association held across sex, diabetes type, and age groups.

Discussion

This large retrospective cohort of 49,075 kidney biopsies represents the most comprehensive analysis to date examining the prevalence and predictors of NDKD in diabetic patients. The authors report that 58.8% of biopsied patients harbored NDKD either alone or concurrent with diabetic nephropathy (DN), broadly consistent with the prior study, in which 36% of patients had isolated NDKD and an additional 27% had concurrent DN and NDKD (Sharma et al,,CJASN, 2013). 

How should we interpret this finding? Do these data suggest that most diabetic patients with kidney disease require biopsy, or do they instead demonstrate that biopsy selection strongly determines diagnostic yield? The striking heterogeneity in NDKD prevalence across studies, ranging from 3% to 82.9% —is likely explained by differences in patient selection and biopsy thresholds (Fiorentino M et al, NDT 2017). For instance, those who prospectively biopsied consecutive patients with moderate CKD and/or significant proteinuria regardless of clinical suspicion, reported only 33.6% NDKD (18.2% NDKD alone +15.4% NDKD+DKD) (Basu et al, BMJ Open Diabetes Res Care, 2022); while those who biopsied based on multiple atypical indications, reported a higher NDKD prevalence of 74.9% (64% NDKD +10.1% DKD+NDKD)(Sakaci T et al, Clin Nephrol, 2024).

One of the most clinically relevant findings of this study is the multiple clinical parameters examined as potential predictors of NDKD. Patients presenting with AKI, rapidly progressive kidney dysfunction, or hematuria had markedly higher odds of harboring NDKD. These findings reinforce the evidence from prior studies and meta-analyses suggesting that acute or inflammatory presentations should prompt consideration of kidney biopsy in diabetic patients, particularly when the clinical trajectory appears inconsistent with classic diabetic nephropathy (Sreedharan S et al, Cureus, 2026 | Sakaci T et al, Clin Nephrol, 2024 | Bermejo et al, Nefrologia, 2024| Vignesh S et al, Indian Journal of Kidney Diseases, 2024 | Chemouny et al, AJN, 2021| Bermejo et al, Nefrologia, 2016). 

The histologic findings further emphasize the heterogeneity of kidney disease in diabetes. Notably, ATI and AIN emerged among the highest scores of NDKD, findings that were less prominently reported in earlier biopsy cohorts (Sharma et al, CJASN, 2013). Interestingly, this distribution differs from prior studies in which glomerular diseases such as FSGS predominated among NDKD diagnoses (Sreedharan S et al, Cureu, 2026 | Sakaci T et al, Clin Nephrol, 2024 | Vignesh S et al, Indian Journal of Kidney Diseases, 2024| Bermejo et al, Nefrologia, 2016). This discrepancy may reflect differences in biopsy practices, including the broader inclusion of inpatient biopsies and patients presenting with acute kidney injury or inflammatory syndromes in the current study. Taken together, these findings suggest that contemporary diabetic biopsy populations may increasingly capture acute and potentially treatable tubulointerstitial or infection-related pathologies rather than exclusively chronic glomerular diseases.

It is important to note that despite its size and clinical relevance, there are several limitations.

Since this study is a retrospective pathology-based cohort, it is inherently subject to referral and selection bias, such that only patients appropriate for biopsy were included.

Baseline kidney function, longitudinal clinical follow-up, and standardized biopsy criteria were unavailable for many patients. Moreover, the evolution of diabetes therapies and changes in biopsy practice over the two-decade study period may also have impacted both biopsy indications and histologic findings.

Although the KDIGO 2020 Diabetes in CKD guideline recognizes uncertainty of atypical presentations, it does not provide specific recommendations regarding when kidney biopsy should be pursued in diabetic patients. This study highlights the need for systematic and integrated biopsy frameworks that combine clinical features, rather than isolated predictors alone (Gesualdo et al, CKJ 2023). 

This study does offer compelling evidence that kidney disease in diabetics is more heterogeneous than commonly appreciated. These findings challenge the traditional assumption that progressive renal dysfunction in diabetes reflects DN alone, and calls for a more individualized approach to kidney biopsy consideration. In particular, the observation that patients with NDKD demonstrated significantly lower risk of progression to ESKD reinforces the clinical value of obtaining a tissue diagnosis when atypical features are present.

Conclusion

In a time of precision nephrology, this study suggests that kidney biopsy is still considered one of the most useful diagnostic techniques applicable to diagnose the existence and the presence of unexplained or non-classic kidney disease in diabetics.

Summary by

Priya John, Milagros Flores

Reviewed by 

Brian Rifkin, Pallavi Prasad

Header designed by AI and prompts from Brian Rifkin

The NephJC internship is built around a simple but powerful idea: that the best way to learn medicine is to engage with its evidence directly, critically, and in community. Our interns don’t just read papers; they work through the full editorial process, learning to appraise methodology, interrogate study design, challenge conclusions, and translate complex research into a clinical context. Under close mentorship, they develop the kind of rigurous, evidence-based thinking that separates good clinicians from great ones, and that stays with them for most of their career.
Good critical appraisal, it turns out, also has a way of teaching us something about ourselves. It was never really about finding fault- it is about asking honest questions of the evidence we depend on to care for patients. Our interns quickly discover that a well-designed study and a poorly-designed one can look remarkably similar on first read, and that spotting the difference is a skill that takes practice, patience, and more than a little humility. The kind of thinking that makes you a better reader of the literature has a funny way of making you a better clinician, too.

But the internship is only as rich as the community surrounding it. Or interns will be showing up on social media feeds, contributing to journal club discussions, and putting their critical appraisal skills to work, alongside you. That kind of learning takes courage and thrives when met with generosity. So, give our interns a follow on Bluesky/X, and bring your questions and experience to the table. The best critical appraisal happens in dialogue, and that dialogue has always been what makes NephJC worth coming back to.

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N Engl J Med. 2026 Apr 9;394(14):1376-1387. doi: 10.1056/NEJMoa2504068.

Multifaceted Strategies for Hypertension Control in Low-Income Patients

Katherine T Mills, Marie Krousel-Wood, Erin M Peacock, Jing Chen, Farah Allouch, Amy K Carreras, Siyi Geng, Alecia Cyprian, Gerrelda Davis, Sonja R Fuqua, Darie Gilliam, Angelique Greer, Tammy Mitchell, Wylea Gray-Winfrey, Shondra Williams, Gary M Wiltz, Keith L Winfrey, Hua He, Paul K Whelton, Jiang He

PMID: 41950472 
DOI: 10.1056/NEJMoa2504068

Introduction

Hypertension affects over 1.3 billion adults globally, with prevalence rising fastest in low- and middle-income countries (NCD Risk Factor Collaboration, Lancet 2021| Mills KT et al, Nature Review Nephrology, 2020). Elevated systolic blood pressure (SBP) contributed to nearly 11 million deaths in 2021 (Martin SS et al, Circulation, 2025). For every 10 mmHg reduction in SBP, there is a reduction in major cardiovascular events by 20%, stroke by 27%, and all-cause mortality by 13%- evidence that makes the persistence of uncontrolled hypertension not merely a clinical frustration, but a preventable human tragedy (Ettehad D et al, Lancet, 2016).

Yet hypertension doesn’t hurt; its silence is its cruel feature. Nonadherence to therapy is not a character flaw but rather a consequence of poverty, an architecture of chaos where daily survival consumes cognitive bandwidth. Across the globe, social determinants consistently predict worse outcomes: income-related inequalities persist even within wealthy nations like Japan, where hypertension prevalence is nearly double in low-income vs high-income groups (Aida J et al, Hypertens Res, 2024). Neighborhood deprivation drives undiagnosed hypertension in the US (River CA et al, Hypertension, 2024), and social determinants mediate one-third of the Black-White difference in uncontrolled BP (Akinyelure OP et al, Hypertension, 2023). “Clinical inertia”- failure to intensify therapy despite uncontrolled BP- compounds the problem, accounting for 40% of treatment failures in some real-world datasets (Satoh M et al, Hypertens Res, 2024).

Single-level strategies, when employed, have failed. A meta-analysis of 121 trials found that provider training alone yielded no significant BP reductions, while team-based care with nonphysician medication titration, health coaching, and home monitoring reduced SBP by 7.1, 3.9, and 2.7 mmHg respectively (Mills KT, Ann Intern Med, 2018). Task sharing with community health workers proved effective, even in resource-poor settings: a trial among uninsured patients in Argentina achieved a 6.6 mmHg reduction over 18 months (He J et al, JAMA, 2017). Yet Argentina’s national system bears little resemblance to the landscape of US federally qualified health centers, where insurance instability and mistrust add up to impair care. The IMPACTS-BP trial (Mills KT et al, NEJM  2026) was designed to find out whether these strategies could be employed into that uniquely challenging context- and whether intensive BP targets could be achieved safely in a low-income population.

The Study

Methods

IMPACTS-BP was a cluster-randomized, effectiveness-implementation hybrid type 2 trial (Landes SJ et al, Psychiatry Res, 2019) conducted in 36 federally qualified health center (FQHC) clinics across Louisiana and Mississippi. The investigators aimed to answer 2 questions simultaneously: whether intensive hypertension treatment improves blood pressure control in underserved populations and whether resource-limited primary care clinics can realistically adopt and sustain a complex implementation strategy. 

Randomization was done at the clinic level because the intervention targeted the entire care system, including providers, nurses, workflows, audit systems, and patient coaching. Clinics were randomized 1:1 to either the intervention or enhanced usual care arm, with stratification by FQHC organization to minimize imbalance between health systems. 

The investigators used the Consolidated Framework for Implementation Research (CFIR) to guide both intervention development and implementation evaluation. 

Study population

Eligible participants were adults aged ≥40 years with uncontrolled hypertension and high cardiovascular risk. Participants had to have SBP ≥140 mmHg if untreated or ≥130 mmHg while receiving antihypertensive therapy. High cardiovascular risk included prior cardiovascular disease, chronic kidney disease, diabetes, estimated 10-year ACVD risk ≥10%, or age ≥65 years. Pregnant women and patients with end-stage kidney disease were excluded. Eligibility BP was confirmed using the average of six standardized measurements obtained during two screening visits.

Intervention strategy

The intervention consisted of a multifaceted, team-based implementation strategy targeting barriers to hypertension control at the system, provider, and patient levels. 

The core clinical component was protocol-based intensive blood pressure management adapted from the SPRINT trial (SPRINT Research group, NEJM, 2015). The target BP was SBP <120mmHg and DBP <80 mmHg. A stepped-care algorithm guided medication intensification: if BP remained above target, providers were expected to uptitrate therapy or add another antihypertensive agent unless contraindicated. 

Follow-up was intentionally intensive to reduce therapeutic inertia. Patients attended monthly visits during the first 3 months and then every 3 months thereafter; additional monthly visits continued until BP targets were achieved.

The implementation strategy incorporated team-based care involving physicians, nurses, medical assistants, and health coaches. Staff were trained in standardized BP measurement, lifestyle counseling, and medication adherence support. All intervention patients received home BP monitors and were instructed to measure BP three days per week. Providers incorporated both clinic and home BP readings into treatment decisions. Health coaching addressed medication adherence, lifestyle modification, reminder systems, low-cost medication planning, and social barriers to care. Quarterly BP audit and feedback sessions reviewed patients with uncontrolled hypertension. Providers also underwent initial and annual retraining on intensive BP management and the SPRINT-based treatment protocol.
Control group

Enhanced usual care clinics continued routine hypertension management. Providers attended a webinar reviewing the ACC/AHA hypertension guidelines and SPRINT findings and received training in standardized BP measurement, but no additional implementation strategies were introduced.

Outcome assessment

The primary effectiveness outcome was the change in SBP from baseline to 18 months. Secondary clinical outcomes included achievement of SBP <120 mmHg, SBP <130 mmHg, reduction in SBP >30 mmHg, change in diastolic BP, quality-of-life measures, and adverse events such as hypotension, falls, and kidney function decline. 

The primary implementation outcome was an adherence summary score ranging from 0 to 4. This composite incorporated four domains: high medication adherence, treatment intensification, home BP monitoring, and receipt of health education. Higher scores reflected better implementation fidelity and patient engagement. 

Additional implementation outcomes included acceptability, feasibility, adoption, fidelity, sustainability, provider experience, and organizational readiness. These were assessed through surveys, electronic health records, provider assessments, and coaching completion data.

Blood pressure measurement

Blood pressure measurement was rigorously standardized. Measurements were obtained using an automated Omron HEM-907XL device with appropriate cuff sizing. Patients rested in the seated position for 5 minutes before measurements and were instructed to avoid caffeine, smoking, alcohol, and exercise for at least 30 minutes beforehand. Three BP measurements were obtained at each visit. 

Statistical methods

The trial was powered to detect a 5 mmHg between-group difference in SBP, assuming an intraclass correlation coefficient of 0.063 and 20% attrition.

Missing data were addressed using multiple imputation by chained equations, generating 40 imputed datasets. The imputation model incorporated demographic variables, baseline BP, BMI, hypertension history, and cardiovascular comorbidities.

Sensitivity analyses included tipping-point analyses in which progressively worse systolic BP values were imputed into the intervention arm to determine the threshold at which statistical significance would be lost.

Funding and oversight

The study was primarily funded by the National Heart, Lung, and Blood Institute, with additional support from other NIH institutes. Oversight was provided by an independent Data and Safety Monitoring Board, and the protocol was approved by the Tulane University Institutional Review Board. 

Results

A total of 1,272 participants from 36 Federally Qualified Health Center clinics across Louisiana and Mississippi underwent randomization. 642 were assigned to the multifaceted intervention strategy and 630 to enhanced usual care. 

The study population reflected the communities these clinics were designed to serve - the mean age was 58.8 years, nearly two-thirds of participants were African American, over three-quarters were unemployed, and almost three-quarters reported an annual family income below $25,000. More than 90% were already receiving antihypertensive medications at baseline, and many had lived with hypertension for over a decade.

Primary efficacy outcome 

Over 18 months, systolic blood pressure fell substantially in both groups, although the decline was greater in the intervention arm. Mean systolic blood pressure decreased by 15.5 mmHg in the intervention group compared with 9.1 mmHg in the enhanced usual care group, yielding a net between-group difference of 6.4 mmHg. Most of this separation emerged within the first six months and was then largely sustained through follow-up. Diastolic blood pressure showed a similar pattern, with a net reduction of 3.4 mmHg favoring the intervention.

Secondary effectiveness outcomes

Secondary effectiveness outcomes also favored the intervention strategy. At 18 months, around 22% of patients in the intervention group and 15% in the enhanced usual care group achieved a systolic BP <120 mm Hg. Systolic BP <130 mm Hg was achieved in 48% and 36% of intervention and control patients, respectively. 18.7% of the intervention group versus 10.9% of the control group had a systolic BP reduction of >30 mm Hg from baseline. The mean reduction in diastolic blood pressure was −8.7 mm Hg in the intervention arm compared with −5.3 mm Hg in the control arm, with a between-group difference of −3.4 mm Hg. Changes in physical and mental SF-12 quality-of-life scores were similar between groups. 

The results were robust across sensitivity analyses. The complete case analysis, which included only patients with complete data, showed an even larger effect: -16.1 mmHg in the intervention group vs -9 mmHg in controls, yielding a between-group difference of -7.1 mmHg (95% CI, -9.7 to -4.4). The tipping point analysis (table S8) demonstrated that missing data would need to be inflated by +6.5 mmHg in the intervention group before the result lost statistical significance, confirming the robustness of the primary finding.

In the subgroup analysis, the intervention appeared to work similarly across age groups, in both men and women, among Black and non-Black participants, and across different levels of income, education, and insurance status. It also showed similar benefits in participants with and without cardiovascular disease, diabetes, or chronic kidney disease. The magnitude of reduction varied slightly between groups, however there was no clear evidence that the intervention worked substantially better or worse in any particular subgroup. Sensitivity analyses, including complete-case and tipping-point analyses, did not materially alter the primary findings.

Implementation outcomes

Implementation outcomes favored the intervention group throughout the trial. The trial showed that the fidelity scores (which reflect adherence to major intervention components like medication intensification, home BP monitoring, and health coaching) were consistently higher in the intervention clinics. Treatment intensification occurred in more than 90% of intervention participants compared with 71.5% in the control arm, and home blood pressure monitoring was nearly universal in the intervention group. Interestingly, self-reported medication adherence did not significantly differ between groups despite the greater blood pressure reduction observed in the intervention arm.

Another noteworthy point is that, over the course of follow-up, the rates of both provider and health coaching visit completion decreased. Health coaching visit completion reduced from 94.1% at baseline to 53.4% at 3 months and then fluctuated between 43% and 66% during later follow-up visits. A similar pattern was observed for provider visits, with completion rates falling from 87.1% at baseline to 52.2% at 3 months and remaining between 40% and 56% thereafter. 

Serious adverse events were seen in both groups with similar frequencies of around 20%. There wasn’t a significantly increased frequency of hypotension, syncope, falls, or kidney-related adverse events in the intervention arm.

Discussion

At first glance, this trial appears to be about blood pressure reduction, but the more one sits with the paper, the clearer it becomes that the intervention was not simply the intensification of drugs. It was about the restructuring of care. The discussion of any trial usually focuses on the trial methodology, the results, and if the “significant” values were actually significant. However, this trial gives us an entirely different direction of discussion. In a single word: implementation.

The investigators did not try out a novel drug or some breakthrough biologic pathway. They simply tried to redesign/reframe the rules surrounding hypertension management. BP was just measured more carefully, reviewed more frequently, discussed more consistently, and acted upon more aggressively. They coached, followed, and reminded the patients, and the patients were drawn into the process through home monitoring and repeated engagement. The study asked a question which seems deceptively simple: what happens when vulnerable patients receive the kind of organized hypertension care that guidelines assume already exists?

The answer? A 6.4 mmHg greater reduction in systolic blood pressure. This is not a trivial finding, more so because the population was already heavily treated at baseline. It’s also notable that the benefit was achieved in an underserved population frequently excluded from tightly controlled efficacy trials: predominantly low-income patients who receive care in resource-limited settings. These are places where factors such as therapeutic inertia, fragmented follow-up, and multiple other barriers dominate everyday practice more than drugs and doctors do.

Notably, IMPACT-BP’s impact isn't an isolated one. Previous community-based hypertension studies have shown that even relatively simple, culturally grounded interventions can produce meaningful improvements in BP control when it is accessible and persistent. The landmark “barbershop trial” among Black men (Victor RG et al, NEJM 2018) is perhaps the best example of this, where blood pressure reduction was achieved by combining trusted community spaces with pharmacist-led medication management. 

So we are led to believe that a multipronged strategy = BP lowering in low-resource settings. Case closed. And yet, the study becomes more interesting as we think further and deeper.

The control group also had nearly 9 mmHg reduction in systolic BP, and this points us towards a simple fact. Medical attention, by itself, is therapeutic. Standardized BP measurement, education of the healthcare providers, repeated follow-up, and participation in a trial most likely improved care even in those who didn't get the full intervention package. What does this mean? This makes the between-group difference more credible, but it also highlights how poorly measured BP, in conjunction with irregular follow-up, may contribute to apparent “treatment-resistant” hypertension in routine practice.
A key observation is that the intervention arm had meaningful BP reduction even though the medication adherence wasn’t significantly better. This disconnect raises huge questions. Was the scale used (Morisky Adherence Scale) simply too blunt to capture the real behavioral change? Did the medication intensification protocol overcome the not-so-good adherence? Or is self-reported adherence fundamentally unreliable? These are the socially vulnerable populations where medication-taking behaviour is fluid. Does this factor make adherence hard to measure? The trial does not fully answer this, but it shows that there are many factors apart from patient-reported drug adherence that lead to BP control.

This trial also exposes the persistent discord between evidence and implementation. Although the intervention was modeled after SPRINT-style intensive BP control, fewer than 1/4th of participants ultimately achieved a systolic BP below 120 mmHg. The authors suggest that providers may have hesitated to pursue such aggressive targets because there are quality benchmarks in Federally Qualified Health Centers that still emphasize less stringent thresholds. This, in itself, shows that there is a wide gap between what guidelines recommend, what doctors practice, and what is best for any individual patient. While trials increasingly support lower BP targets, individualized BP goals will always eclipse population-based goals.

Although the results seem overwhelmingly favorable towards the intensive strategy, we have to be cautious about certain points. This was a bundled intervention, making it impossible to determine which component carried the greatest weight. Was it home BP monitoring or the health coaching? Audit and feedback? Medication intensification? Or simply more human contact? The intervention succeeded as a package, but the ability to scale it may depend on knowing which pieces are essential and which are merely supportive. At the end of the day a more selective approach may be more cost-effective and generalizable.

From a nephrologist’s perspective, there was a small proportion of participants with CKD in the trial. This limits direct extrapolation to higher-risk CKD populations.  Also, hypertension management in CKD is often complicated by volume overload, polypharmacy, fluctuating kidney function, and competing cardiovascular risks. Although the subgroup analyses were consistent, the study was not specifically designed to answer whether these implementation strategies perform similarly in patients with advanced kidney disease.

Whatever is said and done, the crux of hypertension management is the drugs we use to control BP. Interestingly, there are no data regarding the choice and sequence of drugs used and how many percent of the trial population that received each drug, and at what dose. That would have added more scientific rigor and guidance from this implementation study.

Another issue is with the sustainability of this package. This intervention was done within the structured plan of a fully funded clinical trial, and yet the provider and health coach visit completion rates significantly declined over time. The average implementation cost approached $760 per participant, which may appear reasonable from a public health perspective, but  is pretty challenging for under-resourced primary care systems already operating under financial strain. Finally, this study was only 18 months, what kind of intensity and expense would be expected over potentially decades (a lifetime) of treatment? The trial proves that intensive hypertension management can work in low-income populations. Whether health systems are willing to invest in maintaining that intensity is a separate question entirely.

Conclusion

IMPACT-BP  showed that meaningful blood pressure reduction is possible in underserved populations when provided with structured, consistent, and team-based care. At the same time, it reminds us that sustaining this level of intensity of care outside a clinical trial remains challenging. 

Summary by
Akshaya Jayachandran
Cristina Popa

Reviewed by
Brian Rifkin, Swapnil Hiremath

Header Image created by AI, based on prompts by Cristina Popa

Polymyxin B haemoadsorption in endotoxic septic shock (Tigris): a multicentre, open-label, Bayesian, randomised, controlled, phase 3 trial

Javier A Neyra, Matthieu Legrand, Mark A Tidswell, Ali Al-Khafaji, Claude Galphin, Ronald Rains, Danielle Davison, Ashita Tolwani, Jen-Ting Chen, William S Bender, Laurence W Busse, Nikhil K Meena, Jeffrey DellaVolpe, George W Williams, Kianoush B Kashani, Kyle J Gunnerson, Blaithin A McMahon, Jonathan Eaton, Sobia Khan, Roopa Kohli-Seth, Sugeet Jagpal, David Klein, Esha Kamaluddin, Debra M Foster, Paul M Walker, George Tomlinson, John A Kellum

PMID: 41887242

What is polymyxin B hemoperfusion?

Polymyxin B (PMX) is an antibiotic that binds strongly to endotoxin (lipopolysaccharide or LPS)- a component of the outer membrane of gram-negative bacteria that triggers overwhelming inflammation in septic shock. The catch, of course, is that systemic polymixin B is not a therapy we can casually give to crashing ICU patients, because nephrotoxicity and neurotoxicity make intravenous use untenable. 

The workaround was elegant on paper and deeply attractive to device logic: immobilize polymixin B on polystyrene fibers inside a cartridge, run blood through it for 90 to 120 minutes, and claim endotoxin is captured as the blood is “cleansed” and returned. The cartridge has been around for decades, used in Japan since 1994, in Europe since 1998, and by more than 100,000 patients worldwide (Shoji H, Ther Apher Dial, 2003). Thus, it is established enough to persist and controversial enough to still need justification.

Why was this study needed?

The evidence before Tigris was deeply inconsistent. EUPHAS reported a mortality reduction from 53% to 32% but enrolled only 65 patients and stopped early, most likely overestimating treatment effects (Cruz DN, et al, JAMA, 2009). ABDOMIX found no benefit; 28-day mortality was 27.7% with PMX versus 19.5% without, and one third of the patients never received the second treatment session (Payen DM et al, Intensive Care Med, 2015). EUPHRATES, the largest and most rigorous trial (N=450, double blind, sham-controlled), showed no mortality difference (37.7% vs 34.5%) (Dellinger RP et al, JAMA, 2018).

Then came a post-hoc analysis of EUPHRATES. The Endotoxin Activity Assay (EAA) measures circulating endotoxin on a 0 to 1 scale. Values above 0.9 cannot be accurately quantified and may represent endotoxin burdens exceeding the cartridge’s adsorption capacity. When patients with EAA ≥ 0.9 (thus possibly the most severe sepsis and arguably the ones who might benefit the most) were removed, the analysis suggested a 10.7% absolute mortality reduction in those with EAA 0.60-0.89 (Klein DJ et al, Intensive Care Med, 2018). This was hypothesis-generating, non-confirmatory- yet it became the foundation for Tigris (Neyra JA et al, Lancet Respir Med, 2026). The study was needed because the US Food and Drug Administration required a prospective trial targeting this specific subgroup before considering approval.

How was the study done?

Tigris (Neyra JA et al, Lancet Respir Med, 2026) was a prospective, multicenter, open-label, randomized controlled phase 3 trial at 19 US hospitals between September 2019 and APRIL 2025. Eligible adults had septic shock requiring vasopressors for ≥2 hours, multiple organ dysfunction (MODS>9, SOFA>11), and EAA between 0.60 and 0.89 units. The EAA is a rapid (30-minute) whole blood immunoassay that quantifies endotoxin by measuring neutrophil chemiluminescent response- essentially, how strongly a patient’s white blood cells react to the endotoxin in their own blood. Key exclusion criteria included inability to maintain MAP ≥65 mmHg despite vasopressors and end-stage renal disease. 

Randomization was 2:1 (106 PMX, 51 control), stratified by site. The intervention consisted of two PMX hemoperfusion sessions (Toraymyxin PMX-20R cartridge) of 90-120 minutes each, approximately 24 hours apart, at a blood flow rate of 80-120 mL/min. Controls received standard medical care alone. The primary outcome was 28-day mortality; the key secondary outcome was 90-day mortality.

The statistical analysis was Bayesian, which is sensible when the sample is tiny, but it also means the result is shaped by prior beliefs, not just by the new trial.

In Tigris, that mattered because only 157 patients were enrolled out of 14,890 screened, so the authors leaned on the EUPHRATES treatable cohort and then discounted it by 25%, formalized as a 75% weighted prior on the log-odds ratio for treatment effect. This means the analysis started with 94.2% posterior probability that PMX was beneficial before seeing any Tigris data (see table 2 below). Success was defined as a posterior probability p(OR<1) ≥ 95%. 

The problem? The choice of 75% weighting is not derived from any objective criterion, and current data equally suggest a reasonable heuristic, but it is still heuristic. The sensitivity (eTable 5a) shows the consequences: at 50% weight, the posterior probability of benefit falls to 89.9% (below the 95% threshold); at 72%, it crosses 95%. The primary analysis, therefore, succeeds only in a negative trial with a post-hoc subgroup finding, which should be discounted more heavily, and would reasonably reject the 28-day conclusion.

Funding came from Spectral Medical, the manufacturer of the EAA assay and the trial sponsor. Sponsor employees participated in the study design, data interpretation, and manuscript writing. The senior author is a full-time Spectral employee holding company stock.

Results

Among 157 patients (106 PMX, 51 control), 100 patients in the PMX group and 51 in the control group received treatment and comprised the safety cohort. 

Baseline characteristics were balanced. Mean APACHE II scores were 32.8 (PMX) and 31.7 (control); mean SOFA ~14, and 92% on norepinephrine >0.1 mcg/kg/min (Table 1). Endotoxin activity was balanced. The Tigris control group had a higher proportion of documented gram-negative infections (29%) than the EUPHRATES prior cohort (11%) and higher norepinephrine requirements (92% vs 84%). 

Primary outcome (28-day mortality). Observed mortality was 38.7% in the PMX group versus 45.1% in controls- an absolute risk reduction of 6.4%. The adjusted odds ratio was 0.67 (95% credible interval 0.39-1.08). The posterior probability of benefit was 95.3%, meeting the prespecified threshold. A two-sided 95% credible interval excluded 1.0 only when the posterior probability of benefit exceeds 97.5%. At 95.3%, the analysis cannot rule out no effect or even harm. 

Key secondary outcome (90-day mortality). Observed mortality was 43.4% versus 60.8% - an absolute reduction of 17.4%. The adjusted OR was 0.54 (95% credible interval 0.32-0.87), with a posterior probability of benefit >99%. The result seems robust. Even with an uninformative prior (eTable 5c), the posterior probability at 90 days is 98.4%.

The divergence between 28 and 90-day mortality raises a question: why would a two-session intervention given in the first 24 hours have a larger effect three months later? The author suggests that early shock resolution prevents persistent organ dysfunction that drives late deaths. This might sound plausible to the gullible readers, but the open-label design means clinicians know who received PMX, which could influence withdrawal of life-sustaining therapy and post-discharge care, potentially affecting survival trajectories beyond the acute phase.

Sensitivity analyses reveal fragility at the 28-day finding. As shown in eTable 5a, the posterior probability of benefit at 28 days exceeds 95% only when the prior weight is ≥ 72%. At 50% weight, the probability drops 89.9%- below the success thresholds. The 28-day results depend heavily on borrowing information from EUPHRATES. At 90 days, by contrast, the findings hold across all weights.

The frequentist analysis of Tigris alone (Figure 3) doesn’t support the conclusion of benefit at conventional levels of statistical significance. The hazard ratio is 0.68 (95% CI 0.43-1.07), with a confidence interval that crosses 1.0. The Bayesian analysis (Table 2) reaches significance only by incorporating prior data from EUPHRATES, the trial that had its primary analysis negative and whose positive subgroup was post-hoc. Does the prior deserve 75% weight? If prior discounts were more heavily discounted, the 90-day result might also vanish. 

Survival and safety. A Bayesian Cox model for survival to 90 days (eTable 6) gave a hazard ratio of 0.68 (95% credible interval 0.47-0.95) with a posterior probability of benefit of 98.8%. 

Serious adverse events occurred in 30% of PMX patients and 22% of controls. Two treatment-related serious adverse events: one hypotension probably related to PMX, and one bleeding event definitely related to the dialysis catheter (eTable 7b). The safety profile may be considered acceptable for an extracorporeal therapy in critically ill patients, but it is difficult to be confident given small numbers.

Does it change anything?

The 28-day result is fragile, at best. The credible interval includes 1.0. The observed 6.4% absolute risk reduction would not be statistically significant by conventional standards. The analysis crosses its Bayesian threshold only through a 75% weighted prior, possibly justifiable but clearly an arbitrary choice. A reader who believes EUPHRATES should be discounted more heavily (say 50%) would not consider the 28-day results convincing. 

The 90-day result is stronger but raises a different concern. Control mortality was 60.8%, higher than the 43.9% in the EUPHRATES’ MODS >9 subgroup (Dellinger RP et al, JAMA, 2018) and higher than most contemporary septic shock trials. Why? The authors do not fully explain. In the controlled group mortality, which is atypically high, the 17.4% absolute risk reduction may be thus inflated. If this is the true natural history of endotoxic shock, then prior trials underestimated the baseline risk. Either way, generalizability is not guaranteed. 

The open-label design also introduces potential bias. Mortality is objective, but knowledge of allocation can influence decisions about withdrawal of life support and discharge planning. In a disease where treatment limitations are common, unblinded status matters. The authors note that research teams were distinct from clinical teams, but complete separation is impossible. 

What changes for clinical practice? 

In the US, Tigris will likely nudge the FDA toward approval. Spectral Medical probably already has its hand on the submit button. In Europe and Japan, where PMX has been available for decades, proponents will feel vindicated; skeptics will shrug. The full catalog- EUPHAS (positive but flawed), ABDOMIX (negative), EUPHRATES (negative), and Tigris (positive only if you accept the Bayesian terms)- remains underwhelming, unimpressive and deeply debatable. The next version of the KDIGO AKI guidelines might endorse its use, but, like its endorsement of NAC for CIN, these recs would be mostly ignored by sensible peeps. Inserting a dialysis catheter when there may not be AKI, measuring something which most centers do not have access to make dialysis decisions, for uncertain benefit dependent on Bayesian voodoo and prejudiced priors? Really?

What changes for sepsis research?

Fifteen thousand screens. One hundred fifty-seven patients. That is a one percent capture rate. Tigris did not validate the elegant δ-phenotype of liver failure, shock, and coagulopathy (Seymour CW et al, JAMA, 2019); it validated an EAA test that most ICUs do not run. Bayesian methods are clever, but regulatory usefulness is not clinical truth. The real lesson is darker: after 30 years and tens of thousands of screens, we have a signal in 157 patients that still depends on how much faith you place in prior.  

Conclusion

The 28-day result only reaches certainty because the authors chose a prior weight that guaranteed it. Adjust that assumption even slightly, and the benefit evaporates. The 90-day finding is complicated by a control group whose mortality was higher than the contemporary benchmark, leaving the true treatment effect uncertain. Strip away the borrowed confidence from a prior trial that never proved a positive outcome, and what remains? A signal too fragile to trust. This is not practice-changing evidence. It is a post-hoc hypothesis clothed in Bayesian formality. 

By Cristina Popa

Reviewed by 

Brian Rifkin and Swapnil Hiremath

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