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

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

PMID:  42127391

DOI:10.1056/nejmoa2514415

Why was this study needed?

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

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

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

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

How was the study done and what did it find?

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

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

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

What were the results?

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

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

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

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

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

WHAT ARE THE IMPLICATIONS?

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

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

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

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

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

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

BOTTOMLINE?

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

By

Akshaya Jayachandran

Reviewed by 

Brian Rifkin, Cristina Popa and Swapnil Hiremath

Tuesday, June 23rd 2026, 9 pm Eastern on X and Bluesky

N Engl J Med. 2026 Jun 5., doi: 10.1056/NEJMoa2602678. Online ahead of print.

Obinutuzumab or Tacrolimus in Primary Membranous Nephropathy

Fernando C Fervenza, Fan Fan Hou, Chuan-Ming Hao, Gianna M Kirsztajn, Loreto Gesualdo, Tomasz Hryszko, Antonio Pisani, Dario Roccatello, Andrew S Bomback, Julie Rae, Farima Barmaki, Eriola Berisha, Thomas Schindler, Theodore A Omachi, Jay P Garg, Ana Malvar; MAJESTY Trial Investigators

PMID: : 42246654

DOI: 10.1056/NEJMoa2602678

Introduction

If you’re a fan of trying to shoot fish in barrels, then maybe a career in designing obinutuzumab trials is for you. Simply ask ‘Does rituximab work for this condition?’, and then show that obinutuzumab can get the job too - hence the ongoing trials in ANCA vasculitis, frequently relapsing nephrotic syndrome, and this feature - the MAJESTY trial in primary membranous nephropathy (pMN).

We are well aware that rituximab (RTX) has efficacy in pMN; remember the NephJC summary of the MENTOR trial, in which investigators compared RTX to 12 months of the calcineurin inhibitor (CNI) ciclosporin, and looked at a primary outcome of complete remission (CR) at 24 months. Partly as large numbers of patients relapsed once discontinuing the short-acting CNI, and didn’t relapse when treated with the long-acting RTX, the trial was a significant success for RTX. Even though the sponsor didn’t apply for a label for the indication, ever since RTX has been used off-label by nephrologists with access.

Now the same first author is back for MAJESTY, though the B-cell depletor is swapped to obinutuzumab (OBI) and the CNI is swapped to tacrolimus (TAC). OBI is a type II anti-CD20 monoclonal antibody (whereas RTX is type I), with a glycoengineered Fc region that confers greater antibody-dependent cellular cytotoxicity and direct B-cell apoptosis.  RTX, by contrast, relies more on complement-dependent cytotoxicity and is more prone to CD20 internalization, a potential resistance mechanism. These differences translate into more profound and sustained B-cells depletion with OBI, including superior clearance from peripheral sites like lymph nodes and spleen (Mossner E et al, Blood, 2010| Reddy V et al, Rheumatology, 2017).  OBI’s first trip to NephJC got it off to a very good start, as though LUNAR was negative (with caveats) for adding rituximab to standard of care in lupus nephritis, OBI in the REGENCY trial was actually able to show nice additional benefit. It has been around for over a decade for the treatment of chronic lymphocytic leukeamia (CLL), but then excitingly also recently gained a license for lupus nephritis, and case reports about OBI efficacy in treatment-resistant cases of almost all of our immune-mediated kidney diseases continue to grow.  

CNIs reduce proteinuria partly via hemodynamic effects (afferent arteriolar vasoconstriction) without necessarily inducing immunologic remission, contributing to high relapse rates after withdrawal - unlike B-cell depleters, that target the autoantibody source (Faul C et al, Nat Med, 2008). 

In pMN we have already had case series such as this one of 20 ‘RTX-resistant’ patients with pMN who were given OBI, with encouraging results (Su X et al, KI reports, 2024). There is also an ongoing need in first line therapies in pMN, as currently a substantial proportion of patients fail to achieve complete response, remission occurs slowly (especially in those with very high starting PLA2R titres), and relapses occur - this has set the stage to see what would happen when more potent B-cell depletion strategies are used up front rather than just in a resistant cohort.

The Study

Methods

MAJESTY was a multinational, randomised, open-label, phase 3 trial of obinutuzumab against tacrolimus, conducted at 49 sites across 11 countries.

Inclusion criteria

Adults aged 18–75 years with all of:

• Biopsy-proven, primary membranous nephropathy

• Persistent nephrotic-range proteinuria despite optimized supportive therapy

• uPCR ≥5 g/g (>565mg/mmol) for at least 3 months, or

• uPCR ≥4 g/g (>450mg/mmol) for at least 6 months

• eGFR ≥40 mL/min/1.73 m²

Patients previously treated with immunosuppression could be included, provided at least 6 months has passed since they’d had CNI or cyclophosphamide, or 9 months for RTX, and they’d not demonstrated resistance to RTX or CNI in the past. Other exclusion criteria included evidence of spontaneous remission, diabetes, or suspected secondary MN.

Randomisation

Patients were randomised 1:1 to receive open label:

Obinutuzumab

• 1000 mg IV at day 1, week 2, week 24, and week 26

or

Tacrolimus

• Starting dose 0.05 mg/kg/day, in 2 divided doses

• Trough target 5–7 ng/mL

• Maintained through week 52 (unless complete proteinuria response, in which case tapering could start from week 36)

• Tapered over 8 weeks

Randomisation was stratified by region, and anti-PLA2R antibody level (≥175 U/mL vs lower). 

If patients met pre-defined failure criteria in either arm there were 4 time points at which their treatment would change, as below, which they called ‘escape criteria’:

Primary endpoint

Complete remission (CR) at week 104, defined as::

• uPCR ≤0.3 g/g (<34mg/mmol) on 24 hour urine collection, AND

• Stable kidney function (eGFR ≥85% of baseline), AND

• No intercurrent events (escape therapy, treatment failure, early study withdrawal)

Key secondary endpoints (tested in hierarchical order)

Partial remission (PR) was defined as a 50% reduction in uPCR from baseline but still in the 0.3 - 3.5g/g range (35 - 396mg/mmol) AND with stable eGFR.

Specifically based on MENTOR, they estimated that a sample size of 140 patients would provide the trial at least 90% power to detect a difference between trial groups in the percentage of patients who had complete remission (25% with OBI vs. 5% with TAC) at a two-sided alpha level of 0.05. The efficacy analyses were performed in the intention-to-treat population, which included all the patients who had undergone randomisation, with patients grouped according to the treatment assigned rather than the treatment received. 

As seen in Figure S1 above, there is a study of longer term safety planned for a further 2 years, the results of which are not yet available.

Funding

The sponsor (Roche) designed the trial, participated in the collection, analysis, and interpretation of the data, and contributed to manuscript preparation - with their employees amongst the authors.

Results

The consort diagram is found in figure S2:

The baseline characteristics are shown in Table 1:

Of note, the population had a mean age of 50 years with male and white pre-dominance, and around 78% PLA2R positivity, all of which is representative of pMN. Mean eGFR was >80, and mean 24 hour urinary protein level was around 10g/day despite great uptake of RAASi, with mean serum albumin of 29. Around 30% had received prior immunosuppressive therapy.  Rates of supportive care with baseline SGLT2i were not reported (and their addition was not permitted during the trial).

Slightly confusingly, the eGFR range seems to go down to 24 mL/min/1.73 m² in Table 1, and the uPCR range down to 1.7g/day, making it unclear how these patients were recruited, as these values fall outside the inclusion criteria (our assumption being their lab values changed between screening and first visit).

Primary Endpoint

The trial met its primary endpoint convincingly - at week 104, 37% of patients in the OBI group had reached complete remission (CR), versus only 6% in the TAC arm, which (as you’d guess) was highly statistically significant.

Analysis showed consistent results across all sub-groups.

The peak remission rate with obinutuzumab occurred by week 76, and was sustained thereafter. For key secondary endpoints: overall remission at week 104 was 51% vs 13% (P<0.001), and complete remission at week 76 was also significant (44% vs 14%).  Patients on TAC who had achieved CR/PR relapsed very frequently after drug weaning at 52 weeks, as shown in Figure 2.

Sequentially next, the sustained eGFR reduction endpoint showed no difference (6% in both arms; HR 1.10, 95% CI 0.18-6.61), at which point hierarchical testing stopped. Consequently, the duration of CR and PROMIS fatigue score changes were not formally tested and their CIs are descriptive only (though the fatigue scores don’t appear to have a meaningful clinical difference).

Escape Therapy

A vast majority (61%) of the TAC arm met escape criteria and therefore received OBI, with what appears to be a reasonably even split between meeting escape criteria during the first or second year of the study (with 10 patients at week 24, 3 at week 52, 17 due to relapse after week 52, and 9 due to increased serum creatinine while on TAC).  In the OBI arm 28% met escape criteria (meaning that 44% of the entire trial population met escape criteria at some stage). Data on total OBI doses given across the original arms and then in the escape groups was not reported. Only 2/70 patients in the OBI arm had to start an additional non-glucocorticoid immunosuppressant due to treatment failure.

Immunologic remission and B-cell depletion

Immunological remission (defined as a change in anti-PLA2R autoantibody status from positive to negative) can of course only be explored in PLA2R positive patients. As can be seen in Figure S6(A), OBI gave faster, more effective, and more sustained PLA2R suppression when compared to TAC, with consistent results seen even when looking at patients with high starting PLA2R titres (defined here as ≥175 U per milliliter).

Fig S6 A/B. Immunologic remission of anti-PLA2R. Fervenza FC, et al. N Engl J Med, 2026.

OBI certainly does what it says on the label - depletion of CD19+ B cells seen in Figure S8(A).

The pattern of complete B cell depletion (levels <10 cells per microliter) is interesting, tailing off a little before the second course of OBI was administered at 6 months, getting to 94% of the patients with complete depletion at week 52, which gradually dropped to only 14% by week 104. Notably, the protocol defined depletion as ≤5 cells/ microliter, and no justification for this threshold change compared to protocol was offered.

Safety

The analysis of any safety signals gets a bit hard to interpret and needs some background knowledge to read - Table 3 reports the randomised safety data for the 104 week trial, but not if they left, as directed for escape therapy. Therefore, what you are seeing in Table 3 is NOT safety data for all the patients who received OBI (remembering that 61% of the original TAC group met escape criteria and then received OBI). In fact, no systematic escape period safety data are reported anywhere. At a glance, you might think no deaths occurred, but actually, as is explained in the legend, two deaths did occur during escape therapy with OBI (one from each original treatment arm), attributed to covid-19 pneumonia and cardiac arrest.  The main article text states that investigators did not think the pneumonia death was related to the OBI received (though how exactly one adjudicates a death due to infection as unrelated to the potent long-acting B-cell depleter you have given them is not justified further, especially given deaths due to covid-19 were much less common by the time recruitment opened in summer 2021).

Table 3. Adverse events. Fervenza FC, et al. N Engl J Med, 2026.

Infections occurred at a rate of 61 events per 100 patient years in the OBI arm and 57 per 100 patient years with TAC. Serious adverse event rates per 100 patient-years were 11 (OBI) vs 14 (TAC). Table 3 reports a 4% neutropenia rate with OBI, though the relevance of this is less clear when overall the infection comparison data is reassuring.

There was a 38% infusion reaction rate with OBI, but they specifically note that these were manageable with infusion-rate adjustments and symptomatic treatment. I think we’d interpret Table 3 and it’s legend as saying two subclinical HepB re-activation events occurred, one in the OBI arm and maybe one after OBI was given for escape criteria (as if re-activation occurred on TAC it would be recorded in Table 3, which it is not) - it is unclear, and it’s also not stated whether the re-activation occurred despite antiviral prophylaxis or not.

The number of patients in both arms who had a sustained eGFR decrease of >30% at week 76 was low, at 6% in both arms.

Serum IgG levels actually increased over the course of the trial in both arms, likely due to decreased IgG losses in the urine as nephrosis improved, and not indicating less IgG recovery with OBI over TAC. 

Discussion

MAJESTY results analysis

No one is surprised to see the pattern of MENTOR’s results reproduced here 7 years later - patients who stop their CNI then frequently relapse over the next year, whereas the patients who instead received long-acting B cell depletors are much more likely to achieve and stay in remission.  

It is nice to see not only that OBI works in a large cohort, but in particular the immunological remission data looked impressive. There was no difference in renal function between groups, as would be expected over a 2-year follow-up of a group with relatively preserved kidney function at baseline.

The catchphrase of seemingly all Phase 3 trials presented at ERA was ‘there were no new or unexpected safety signals’. Equal infection rates between arms looked reassuring, as did the IgG data, but given there is a black box warning regarding hepatitis B reactivation on OBI’s FDA prescribing label, I don’t think it is too much to ask for them to be more explicit on whether the 2 patients who had subclinical HepB reactivation during the trial had both had OBI, as the text leaves you guessing. Rates of neutropenia of 4% with OBI were lower than the 14% seen in REGENCY (Furie RA et al, NEJM, 2025), probably because these patients with SLE were also on MMF, and in keeping with this, the placebo control arm in REGENCY also had high neutropenia rates at 6%. They do make it clear in MAJESTY that both patients who died during the trial had received OBI, even mentioning this in their abstract. As in REGENCY, a death due to COVID-19 after OBI in this trial could be seen as a marker of increased viral morbidity, though somehow here the investigators judged the COVID-19 death and having received OBI as unrelated to each other, which, at face value, is baffling. The supplement in REGENCY gave further details about deaths, but no further details were given here. It also appears the local investigators have flagged up more ‘adverse events related to the study drug’ in the TAC arm than with OBI, with 34 events in the OBI arm - though with 27 infusion reactions and 36 patients having infections in the OBI arm, it isn’t clear how that maths stacks up, and it’s just hard to see how an investigator could confidently judge an infusion reaction or infection to be unrelated to their open label B-cell depletor immunosuppression. Very disappointingly, there is also a major safety reporting gap of adverse events during escape therapy, with no mention of infusion reaction or infection rates for the large crossover population, which you’d have thought would have been common sense to include.

Comparison with MENTOR and rituximab

OBI isn’t trying to inherit the throne from CNI therapy in countries that will be able to afford OBI access - it’s trying to succeed rituximab. While MAJESTY was obviously not designed to test whether OBI is superior to rituximab, and comparing different trials must be done with caution, nephrologists will still be tempted to compare results here with those from MENTOR (Fervenza FC et al, NEJM, 2019).

Inclusion criteria were similar enough, and baseline characteristics of the population were also broadly similar. MENTOR and MAJESTY differed in their exact outcome definitions, in that MAJESTY more stringently also required eGFR preservation ≥85% of baseline in both their CR and PR definitions on top of proteinuria remission, whereas MENTOR had proteinuria criteria only. In that context, looking at CR at week 104, it was 37% in MAJESTY with OBI versus 35% in MENTOR with RTX.  In MAJESTY at week 104 CR and PR combined was only at 51% with OBI, whereas it was up at 60% with RTX. However, if the eGFR criteria were removed from the MAJESTY definition and instead just the proteinuria definitions were applied to both, then at 52 weeks, OBI CR rates were 26% versus 14% in MENTOR, and by week 104 OBI got 49% to complete proteinuric response versus the 35% in with RTX.

‘Reading the tea leaves’ of the above, you could say that OBI’s results look better than the RTX results, if not dramatically so.  It’s not clear why the eGFR criteria for PR/CR were added between studies.  

What about the patients with high starting PLA2R titres? To remind you of table S13 from MENTOR, when they split their patients into tertiles of PLA2R level, the immunological response rate did tail off a lot in their highest PLA2R cohort, unlike OBI’s results here (accepting the number of patients in each group by that stage of subdivision is relatively small).

In terms of safety, MENTOR did not include neutropenia or IgG data, and did report that RTX had numerically fewer infection events than ciclosporin. They did not have any deaths during the trial, which is the norm across pMN trials, and contrasts with MAJESTY. Infusion reactions to RTX were at 25% (which certainly seems higher than I’d have expected), versus the 38% rate with OBI.

MAJESTY limitations

The open-label design certainly risks influencing more subjective outcomes like ‘AEs related to study drug’ and fatigue score, if less so the hard ‘number based’ outcomes of the trial, and blinding would have been difficult (given the high rates of transfusion reaction and need to adjust TAC doses based on levels) and time-consuming. Treatment durability and safety beyond 2 years is currently unknown, and the further 2 years of observation is underway.

However, the big talking point of MAJESTY will be the decision to have the comparator as 52 weeks of TAC, rather than against RTX. In recent years, we’ve been inundated with trial designs that aren’t exactly what patients or their doctors would have chosen - voclosporin not being compared to TAC for lupus, or finerenone against other MRAs, to name a few - and here finding that B cell depletion therapy beats 52 weeks of CNI at a 104 week endpoint was certainly not providing the world with new scientific information.  

Supporting the choice of TAC in MAJESTY is that 7 years ago a study of US prescribing patterns still put TAC use at 40% (O'Shaughnessy MM et al, Kidney Int Rep. 2019), though you’d expect this to have shifted significantly since MENTOR, and the fact that TAC is on the KDIGO GN guidelines (at least for patients at moderate risk, though you’d guess actually many MAJESTY patients actually fell into the high risk group, in whom KDIGO would not have recommended CNI - I’m looking at that 3043 U/ml PLA2R titre in Table 1…). But most importantly, the increase in sample size that would have been required for a superiority trial of OBI versus RTX would have been entirely prohibitive, put at n=2500 patients if assuming 45% versus 35% remission rates, which can’t be done in rare disease. The ‘need’ to have a feasible trial done has been said to be that it is hard to access RTX in the US given the lack of license for the pMN indication, whereas now hopefully OBI will soon be licensed - though anecdotally plenty of US physicians do seem to access RTX without any problems as things stand.

The escape criteria were enacted to standardise the implementation of an effective rescue therapy - interestingly, the initial protocol had TAC as the switch option for patients failing on OBI, but this was replaced in later iterations by a second course of OBI, which seems reasonable. The large breadth of the escape criteria was important, as investigators knew patients randomised to the TAC arm were going to relapse like wildfire when they discontinued the TAC at 52 weeks in the same way that occurred many years prior in MENTOR, but the huge 61% of patients on TAC meeting escape criteria did make this trial feel almost closer to a cohort study of OBI rather than an RCT of two effective therapies. The primary estimand’s composite strategy (counting escape as non-response) correctly penalizes the TAC arm, preserving intent-to-treat validity.  However, the treatment policy sensitivity analysis (counting escape responses) showed a similar effect (44% vs 14%), confirming robustness (table S5).

MAJESTY’s TAC monotherapy arm contrasts with STARMEN’s (Fernandez-Juarez G et al, Kidney Int, 2021) sequential TAC-RTX regimen (58% CR/PR at 24 months). The 20% CR/PR rate in MAJESTY’s TAC arm at 24 months is far lower, confirming that adding RTX at TAC withdrawal (as in STARMEN) prevents relapse, but still likely underperforms OBI monotherapy (accepting that in clinical practise most would add the RTX earlier than in the STARMEN protocol in the hope of improved outcomes).

The question is, would you let your family member be recruited into a trial in which, by their own numbers, they (accurately) predicted a primary outcome achievement rate in one arm of 5%, when a much more effective therapy exists? To be fair, relapse is not a disaster in pMN when the patient is closely watched, but would you risk randomisation to TAC if their eGFR was 40 and proteinuria >10g/day? I’m really not so sure. However, if you were hoping this is the last pMN trial of ‘new agent versus CNI’ then you haven’t heard of the Phase 3 PROMINENT trial of felzartamab versus TAC with completion expected in 2029, or the Phase 2/3 ALMOND trial of zanubrutinib versus TAC also on the horizon - so it looks like we’re getting everything compared to TAC (except, of course, for voclosporin) for a while yet. How we’ll sort out which agent is best in 5 years when they have never been directly compared to one another is anyone's guess for now, but the industry interest in pMN will hopefully be a great thing for patients going forward.

Will clinicians now use OBI first line?

It is accepted that OBI has superior speed and depth of B-cell depletion compared to RTX, particularly in lymph nodes and spleen; for the simple-minded like me, it can be thought of as ‘super-rituximab’, much like sparsentan for IgAN sits in my brain as ‘super-ACEi’, with increased efficacy but also concern regarding an uptick in side-effects that goes along with that. While waiting to see if OBI gets approval for pMN in their healthcare system, nephrologists will meanwhile gain experience with OBI from the lupus nephritis indication, and we’ll be eager to see more and more trials in disease areas where RTX is good but there’s room for improvement, for example, in this phase 2 in AAV, which, fantastically, they have finally called OBI-WAN.

Now, on top of the reports that OBI can overcome the pMN disease that is resistant to RTX, we have this MAJESTY data, which indicates an impressive immunological response even in patients with high starting PLA2R titres (which may be lacking with RTX), and likely favourable proteinuria outcomes at 2 years with OBI compared to what RTX achieved in MENTOR.  If access to both were equal, you can imagine many reaching for OBI first line now if their patient is in agreement, though the safety data outlined above may put some off. If having a license for the pMN indication makes a huge difference to access in an insurance-based system, then first-line OBI will become the norm in those areas, whereas in systems which (forgive me) sensibly recognise the rituximab efficacy data and prioritise value over formal application for indication, then it seems possible that OBI will be rationed in some healthcare systems only for resistant patients, especially with generic RTX now available. Of course, some clinicians will want to reach for OBI in patients with high PLA2R titers, but others might make do with RTX in combination with a few early months of CNI for their higher-risk patients, or give more doses of RTX than usual in the hope of deeper B-cell depletion. Overall, it will be good for patients to have increasing options, and the toxicity of cyclical cyclophosphamide/steroid protocols will be seen less as treatment resistance is increasingly consigned to the past.

Conclusion

MAJESTY had no surprises by showing obinutuzumab beats 52 weeks of tacrolimus in primary membranous, with markedly fewer relapses and escape-therapy requirements.

No doubt a label application will come and be successful, and then we’ll constantly hear how obinutuzumab is “the only licensed treatment for membranous nephropathy”.  For the future it’s great that patients will have increasing options with additional efficacy, but if where you work still has you reaching for rituximab rather than obinutuzumab for now, on balancing the available efficacy and safety data it seems unlikely your patients are missing out too much.

Written by Jamie Willows

Renal and GIM Consultant

South Tyneside and Sunderland Foundation Trust

UK

Reviewed by 

Joel Topf, Cristina Popa, Brian Rifkin, Pallavi Prasad

Audiosummary prompted by Nikhil Shah

Header designed by AI and prompts from Brian Rifkin

Measured and Estimated Glomerular Filtration Rates and Risk of Adverse Health Outcomes

Edouard L Fu, Antoine Créon, Morgan E Grams, Josef Coresh, Arvid Sjölander, Anne-Laure Faucon, Michelle M Estrella, Friedo W Dekker, Michael G Shlipak, Lesley A Inker, Andrew S Levey, Juan-Jesus Carrero

PMID:  42240159

DOI: 10.1001/jama.2026.9639

Why was this study needed?

Let us begin with an uncomfortable truth. The entire edifice of CKD classification, the thresholds of 60, 45, 30, and 15 mL/min/1.73 m2, rests on associations between estimated GFR and adverse outcomes (Levey AS et al, Kidney Int, 2011). This is a circular argument. We use eGFR to define disease, then validate that definition by showing that eGFR predicts outcomes. The implicit assumption has always been that eGFR is a faithful proxy for true GFR, differing only by random, non-systematic error. But we have known for decades that this assumption is false.

Creatinine, the workhorse biomarker, is a byproduct of muscle metabolism influenced by a patient’s frailty, high-protein intake and/or tubular secretion. (Stevens LA et al, NEJM, 2006). Cystatin C, while more independent of muscle mass, is an acute-phase reactant potentially influenced by inflammation, obesity, smoking, and glucocorticoids (Stevens LA et al, AJKD, 2008| Russel WA et al, JASN, 2025 | also see NephJC discussions here and here). The non-GFR determinants of these markers are systematic biases that correlate with the very outcomes we are trying to predict. A patient with sarcopenia has both a falsely elevated eGFRcr and an increased risk of death, but from different causes. A patient with chronic inflammation has both a falsely depressed eGFRcys and an increased cardiovascular risk. The central question, then, is not whether eGFRcr predicts outcomes - we know it does, redundantly - but whether the risk signal we are measuring actually originates from GFR itself.

The study by Fu et al, simultaneously published during ERA26, breaks this circularity by anchoring risk to measured GFR (mGFR) (Fu EL et al, JAMA, 2026). Using iohexol plasma clearance - a marker that is freely filtered, neither secreted nor reabsorbed, with very low extra-renal clearance (Delanaye P et al, Clin Biochem Rev, 2016) - the authors provide the first large-scale, direct quantification of how true mGFR associates with adverse outcomes. They then ask a second, equally important question: which of our common eGFR equations most faithfully captures these mGFR-based risk associations?

How was the study done?

The investigators used the Stockholm CREAtinine Measurement (SCREAM, an homage to Edvard Munch?) project to identify 6174 adults who underwent clinical mGFR using single-sample plasma iohexol clearance. The protocol was rigorous: a 5 mL iohexol injection, timed blood sampling tailored to expected GFR (approximately 4 hours if GFR >40, 6-8 hours if GFR 15-40, and 24 hours if GFR <15), quantification via ultra-high-performance liquid chromatography with UV detection, and the Jacobsson equation for clearance calculation (eMethods- supplement 1). Importantly, 78% of patients had mGFR, creatinine, and cystatin C measured on the same day, eliminating temporal confounding between the gold standard and estimators. The analytical coefficient of variation for the iohexol method was 2.31% for a control sample at 32 mg/L and 2.04% at 65 mg/L- acceptable but not negligible. 

We must be clear about what mGFR is and is not. While iohexol clearance is the best available reference method, it is not error-free. The within-person biological coefficient of variation for mGFR has been estimated at approximately 5-10% across studies (Rowe C et al, Kidney Int, 2019| Delanaye P et al, Clin Biochem Rev, 2016). The single-sample method, while practical, is less accurate than multi-sample protocols, particularly at extremes of GFR and in patients with altered extracellular fluid volumes. The supplementary materials note that patients with extensive edema or ascites were not excluded; in such patients, plasma clearance protocols can be inaccurate, and urinary clearance would be preferred. This is a limitation the authors acknowledge but cannot fully address. 

The key design feature was the simultaneous measurement of serum creatinine and cystatin C, allowing direct comparison of mGFR with 3 eGFR equations: eGFRcr (CKD-EPI 2021), eGFRcys (CKD-EPI 2012), and eGFR-cys (CKD-EPI 2021). The study population (eTable2) shows that 28% had missing BMI and 21% had missing UACR, requiring multiple imputation. To note, patients with complete data had substantially lower eGFR (median 68 vs 91 mL/min/1.73 m2) and higher cystatin C (1.36 vs 1.05 mg/L) than those with missing data. They also had higher prevalence of hypertension (53% vs 25%), diabetes (27% vs 12%), and heart failure (14% vs 6%). “Missingness” was clearly not random, and patients with complete data were sicker with more advanced CKD. The imputation model, which included event indicators and the Nelson-Aalen estimator, is a best practice, but it assumes data are missing at random, a strong assumption that may not hold.

eTable 2. Baseline characteristics of persons undergoing mGFR testing using plasma clearance of iohexol in Stockholm with simultaneous creatinine and cystatin C testing during 2011-2021, with versus without missing data of UACR and body mass index, from Fu EL et al, JAMA, 2026

The authors employed Cox proportional hazard regression with restricted cubic splines to model GFR as a continuous, non-linear variable, adjusting for the covariates detailed in eTable 1. To avoid index event bias - a form of selection bias that occurs when individuals with a prior history of the outcome are included in the analysis of incident events - they correctly excluded such individuals from each outcome-specific model (eFigure1)- only applied to secondary outcomes. Additionally, to quantify the statistical uncertainty around the hazard ratios comparing eGFR, the authors used bootstrap resampling with 500 iterations, a robust and methodologically appropriate technique for constructing confidence intervals in this context.

Results

First finding: the current GFR threshold of 60 mL/min/1.73m2 was associated with significantly higher risks of both all-cause mortality (HR 1.21, 95% CI 1.14-1.28) and kidney failure requiering replacement therapy (HR 2.85, 95% CI 2.06-2.94). As measured GFR declined further, these risks increased steeply: at an mGFR of 30 mL/min/1.73m2, the hazard ratio was 38.5; at an mGFR of 15, it was 200.3. The graded, monotonic relationship between lower true GFR and higher risk is unambiguous. The heatmaps from the CKD Prognosis Consortium are not mere artifacts of estimation (Grams ME et al, JAMA, 2023). The threshold of 60 mL/min/1.73m2 holds.

Below 90 mL/min/1.73m2, eGFRcr systematically underestimates mortality risk (ratio of HR at 60, 0.87, 95% CI 0.79-0.95), while eGFRcys systematically overestimates it (ratio of HR at 60, 95%CI 1.08-1.27). In contrast, eGFRcr-cys showed no significant deviation from mGFR-based risk across the entire GFR range (eFigure 4, panel A).

The supplementary materials add critical nuance. For kidney failure with replacement therapy, the confidence intervals for the HRs were extremely wide- for eGFRcr at 60 mL/min/1.73m2, the 95% CI ranged from 0.00 to 1.17 (eFigure 4, panel B). The authors cite limited power, but an alternative explanation is that kidney failure is a kidney-specific outcome, while mortality is influenced by systemic factors. The non-GFR determinants of creatinine and cystatin C may be less correlated with progression to kidney failure than with death. 

In addition, an interesting finding can be seen in eTable 6. In the general population of 1.58 million Stockholm residents, the HR for mortality at an eGFRcr of 120 (vs 90) was 4.43 (95% CI, 4.34-4.52), more than double that observed in the mGFR cohort (2.10, 95% CI 1.76-2.50). The well-described U-shaped association between high eGFRcr and mortality was markedly attenuated in the selected mGFR cohort. Patients referred for mGFR testing- typically for drug dosing, liver cirrhosis, transplant evaluation, or eGFRcr-eGFRcys discordance- have a different risk profile than the general population. These results may not generalize to patients who would not ordinarily undergo mGFR testing. 

eTable 11 and eFigure 10 show that including individuals with a history of heart failure substantially attenuated the HRs for eGFRcys and eGFRcr-cys. At an mGFR of 15, the HR for eGFRcys dropped from 4.25 (excluding prevalent cases, eTable 7) to 2.96 (including them, eTable 11). This attenuation suggests that the overestimation of risk by eGFRcys is most pronounced in patients without pre-existing heart failure, where cystatin C is less confounded by non-GFR determinants.

eTables 7 and 8 show consistent results using the older CKD-EPI 2009/2012 equations and the European Kidney Function Consortium (EKFC) equations. The combined equation outperformed single-marker equations across all GFR ranges, strengthening the conclusion that the principle of combining markers- not the specific coefficients of any one equation- is what matters.

How would the study change the practice?

First, eGFRcr alone is insufficient for risk stratification in patients with muscle wasting, chronic inflammation, or corticosteroid use. The bias is quantifiable: at an mGFR of 60, the mortality HR based on eGFRcr is 13% lower than the true HR. The 2024 KDIGO guidelines recommend cystatin C when greater accuracy is required (KDIGO CKD Work Group, KI, 2024). The study provides empirical justification: eGFRcr-cys is the only estimator whose risk associations are statistically indistinguishable from those of mGFR. 

Second, the study reframes the race-free equation controversy. The 2021 CKD-EPI equation removed the Black race coefficient because race is a social, not biological, construct (Inker LA et al, NEJM, 2021). That decision was ethically correct. But the more fundamental problem is the use of a single, non-specific biomarker. eGFRcr-cys, which requires no race coefficient, provides the most accurate risk estimation regardless of race.

Third, the study raises a subtle question about the nature of risk. If eGFRcys overestimates risk because it captures inflammation, and inflammation is itself a true risk factor, is the overestimation truly a “bias”? For the question, “what is the patient’s prognosis?”, the discrepancy between eGFRcr and eGFRcys-low eGFRcr with normal eGFRcys suggesting muscle-wasting, or low eGFRcys with normal eGFRcr suggesting inflammation, may be prognostic in its own right. 

Fourth, the study has implications for trial design. If eGFRcr underestimates risk in frail patients and eGFRcys overestimates it in inflamed patients, using either single marker as an inclusion criterion or endpoint could introduce bias. Trials using eGFRcr-cys for enrollment may achieve more homogeneous risk populations and greater statistical power.

Limitations

 Several limitations temper our enthusiasm. Missing data were substantial: patients with complete data had a standardized mean difference of 0.63 for eGFRcr and 0.56 for mGFR compared to those with missing data (eTable 2). The imputation model may have been inadequate if “missingness” was related to unmeasured factors such as frailty. 

The generalizability concern from eTable 6 is not trivial. The mGFR cohort was selected by clinicians. The attenuated U-shaped mortality curve at high eGFRcr suggests that healthy individuals with high eGFRcr were systematically excluded. These results may apply primarily to patients with established CKD or complex comorbidities.

eTable 10 shows that excluding kidney transplant recipients (approx. 2.7% of the cohort) did not materially change the results, which is reassuring for generalizability to non-transplant CKD populations. 

Finally, the study had insufficient power to assess mGFR-related risks across albuminuria categories. Given that albuminuria is an independent and synergistic risk factor- central to the KDIGO heatmaps- this is an important gap.

Conclusion

Fu and colleagues have confirmed that our current GFR threshold of 60- derived from eGFR- holds up when tested against measured GFR. They have also shown that eGFR underestimates risk, eGFRcys overestimates it, and eGFRcr-cys corrects most of this bias. The supplement adds important caveats: the biases differ by outcome, weaken in some sensitivity analyses, and may not apply to unselected populations. 

None of this means abandoning creatinine. It remains an excellent screening tool. But when the stakes are high, when a patient’s eGFR falls on the border of a major clinical decision, we owe it to them to be honest about the limits of our estimates. eGFRcr-cys is a better map, though not a perfect one. When even that is not enough for dosing highly toxic chemotherapy, evaluating living donors with discordant markers, or confirming CKD in frail patients with borderline creatinine, measured GFR remains the territory we must be willing to visit.  

By Cristina Popa

Reviewed by 

Brian Rifkin and Swapnil Hiremath

Tuesday, June 2nd 2026, 9 pm Eastern on X and Bluesky

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.

The NephJC 2026 Interns:

#NephJC Chat

Tuesday, May 19th, 2026, 9 pm Eastern on Bluesky and Twitter

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